User login
California bans “Pay for Delay,” promotes black maternal health, PrEP access
AB 824, the Pay for Delay bill, bans pharmaceutical companies from keeping cheaper generic drugs off the market. The bill prohibits agreements between brand name and generic drug manufacturers to delay the release of generic drugs, defining them as presumptively anticompetitive. A Federal Trade Commission study found that “these anticompetitive deals cost consumers and taxpayers $3.5 billion in higher drug costs every year,” according to a statement from the governor’s office.
The second bill, SB 464, is intended to improve black maternal health care. The bill is designed to reduce preventable maternal mortality among black women by requiring all perinatal health care providers to undergo implicit bias training to curb the effects of bias on maternal health and by improving data collection at the California Department of Public Health to better understand pregnancy-related deaths. “We know that black women have been dying at alarming rates during and after giving birth. The disproportionate effect of the maternal mortality rate on this community is a public health crisis and a major health equity issue. We must do everything in our power to take implicit bias out of the medical system – it is literally a matter of life and death,” said Gov. Newsom.
The third bill, SB 159, aims to facilitate the use of pre-exposure prophylaxis and postexposure prophylaxis against HIV infection. The bill allows pharmacists in the state to dispense PrEP and PEP without a physician’s prescription and prohibits insurance companies from requiring prior authorization for patients to obtain PrEP coverage. “All Californians deserve access to PrEP and PEP, two treatments that have transformed our fight against HIV and AIDS,” Gov. Newsom said in a statement.
AB 824, the Pay for Delay bill, bans pharmaceutical companies from keeping cheaper generic drugs off the market. The bill prohibits agreements between brand name and generic drug manufacturers to delay the release of generic drugs, defining them as presumptively anticompetitive. A Federal Trade Commission study found that “these anticompetitive deals cost consumers and taxpayers $3.5 billion in higher drug costs every year,” according to a statement from the governor’s office.
The second bill, SB 464, is intended to improve black maternal health care. The bill is designed to reduce preventable maternal mortality among black women by requiring all perinatal health care providers to undergo implicit bias training to curb the effects of bias on maternal health and by improving data collection at the California Department of Public Health to better understand pregnancy-related deaths. “We know that black women have been dying at alarming rates during and after giving birth. The disproportionate effect of the maternal mortality rate on this community is a public health crisis and a major health equity issue. We must do everything in our power to take implicit bias out of the medical system – it is literally a matter of life and death,” said Gov. Newsom.
The third bill, SB 159, aims to facilitate the use of pre-exposure prophylaxis and postexposure prophylaxis against HIV infection. The bill allows pharmacists in the state to dispense PrEP and PEP without a physician’s prescription and prohibits insurance companies from requiring prior authorization for patients to obtain PrEP coverage. “All Californians deserve access to PrEP and PEP, two treatments that have transformed our fight against HIV and AIDS,” Gov. Newsom said in a statement.
AB 824, the Pay for Delay bill, bans pharmaceutical companies from keeping cheaper generic drugs off the market. The bill prohibits agreements between brand name and generic drug manufacturers to delay the release of generic drugs, defining them as presumptively anticompetitive. A Federal Trade Commission study found that “these anticompetitive deals cost consumers and taxpayers $3.5 billion in higher drug costs every year,” according to a statement from the governor’s office.
The second bill, SB 464, is intended to improve black maternal health care. The bill is designed to reduce preventable maternal mortality among black women by requiring all perinatal health care providers to undergo implicit bias training to curb the effects of bias on maternal health and by improving data collection at the California Department of Public Health to better understand pregnancy-related deaths. “We know that black women have been dying at alarming rates during and after giving birth. The disproportionate effect of the maternal mortality rate on this community is a public health crisis and a major health equity issue. We must do everything in our power to take implicit bias out of the medical system – it is literally a matter of life and death,” said Gov. Newsom.
The third bill, SB 159, aims to facilitate the use of pre-exposure prophylaxis and postexposure prophylaxis against HIV infection. The bill allows pharmacists in the state to dispense PrEP and PEP without a physician’s prescription and prohibits insurance companies from requiring prior authorization for patients to obtain PrEP coverage. “All Californians deserve access to PrEP and PEP, two treatments that have transformed our fight against HIV and AIDS,” Gov. Newsom said in a statement.
FDA approves Descovy as HIV PrEP for men and transgender women who have sex with men
The decision, backing the earlier recommendation of the FDA’s Antimicrobial Drugs Advisory Committee, was based upon results from DISCOVER, a pivotal, multiyear, global phase 3 clinical trial that evaluated the safety and efficacy of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25-mg tablets for PrEP, compared with Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300-mg tablets).
DISCOVER included more than 5,300 adult cisgender men who have sex with men or transgender women who have sex with men.
In the trial, Descovy achieved noninferiority to Truvada.
Descovy has a Boxed Warning in its U.S. product label regarding the risk of posttreatment acute exacerbation of hepatitis B, according to the company.
The Descovy label also includes a Boxed Warning regarding the risk of drug resistance with PrEP use in undiagnosed early HIV-1 infection. The effectiveness of Descovy for PrEP in individuals at risk of HIV-1 from receptive vaginal sex was not tested, and thus cisgender women at risk for infection from vaginal sex were not included in the population for which the drug was approved.
The Descovy label and safety information is available here.
The FDA version of the announcement is available here.
The decision, backing the earlier recommendation of the FDA’s Antimicrobial Drugs Advisory Committee, was based upon results from DISCOVER, a pivotal, multiyear, global phase 3 clinical trial that evaluated the safety and efficacy of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25-mg tablets for PrEP, compared with Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300-mg tablets).
DISCOVER included more than 5,300 adult cisgender men who have sex with men or transgender women who have sex with men.
In the trial, Descovy achieved noninferiority to Truvada.
Descovy has a Boxed Warning in its U.S. product label regarding the risk of posttreatment acute exacerbation of hepatitis B, according to the company.
The Descovy label also includes a Boxed Warning regarding the risk of drug resistance with PrEP use in undiagnosed early HIV-1 infection. The effectiveness of Descovy for PrEP in individuals at risk of HIV-1 from receptive vaginal sex was not tested, and thus cisgender women at risk for infection from vaginal sex were not included in the population for which the drug was approved.
The Descovy label and safety information is available here.
The FDA version of the announcement is available here.
The decision, backing the earlier recommendation of the FDA’s Antimicrobial Drugs Advisory Committee, was based upon results from DISCOVER, a pivotal, multiyear, global phase 3 clinical trial that evaluated the safety and efficacy of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25-mg tablets for PrEP, compared with Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300-mg tablets).
DISCOVER included more than 5,300 adult cisgender men who have sex with men or transgender women who have sex with men.
In the trial, Descovy achieved noninferiority to Truvada.
Descovy has a Boxed Warning in its U.S. product label regarding the risk of posttreatment acute exacerbation of hepatitis B, according to the company.
The Descovy label also includes a Boxed Warning regarding the risk of drug resistance with PrEP use in undiagnosed early HIV-1 infection. The effectiveness of Descovy for PrEP in individuals at risk of HIV-1 from receptive vaginal sex was not tested, and thus cisgender women at risk for infection from vaginal sex were not included in the population for which the drug was approved.
The Descovy label and safety information is available here.
The FDA version of the announcement is available here.
Clinical Pharmacists Improve Patient Outcomes and Expand Access to Care
The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.1 Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.2
The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.
It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.3 A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.
Background
The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.
Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.
Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.
Methods
The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.
These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.
Results
The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.4 Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.
DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.
In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.
HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.
Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. 5 Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.
Discussion
These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.
Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.
Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.
Conclusion
The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.2 The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.
Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.
1. Buttorff C, Ruder T, Bauman M. Multiple Chronic Conditions in the United States. Santa Monica, CA: Rand Corp; 2017.
2. Dall T, West T, Chakrabarti R, Reynolds R, Iacobucci W. The complexities of physician supply and demand: projections from 2016 to 2030, 2018 update. Association of American Medical Colleges. March 2018.
3. Giberson S, Yoder S, Lee MP. Improving patient and health system outcomes through advanced pharmacy practice. A report to the U.S. Surgeon General 2011. https://www .accp.com/docs/positions/misc/improving_patient_and _health_system_outcomes.pdf. Updated December 2011. Accessed September 11, 2019.
4. Lip G, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation. CHEST guideline and Expert Panel Report. Chest. 2018;154(5):1121-1201.
5. Babb S, Marlarcher A, Schauer G, Asman K, Jamal A. Quitting smoking among adults—United States, 2000-2015. MMWR Morb Mortal Wkly Rep. 2017;65(52):1457-1464.
The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.1 Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.2
The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.
It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.3 A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.
Background
The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.
Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.
Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.
Methods
The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.
These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.
Results
The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.4 Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.
DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.
In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.
HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.
Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. 5 Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.
Discussion
These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.
Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.
Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.
Conclusion
The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.2 The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.
Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.
The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.1 Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.2
The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.
It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.3 A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.
Background
The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.
Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.
Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.
Methods
The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.
These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.
Results
The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.4 Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.
DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.
In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.
HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.
Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. 5 Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.
Discussion
These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.
Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.
Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.
Conclusion
The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.2 The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.
Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.
1. Buttorff C, Ruder T, Bauman M. Multiple Chronic Conditions in the United States. Santa Monica, CA: Rand Corp; 2017.
2. Dall T, West T, Chakrabarti R, Reynolds R, Iacobucci W. The complexities of physician supply and demand: projections from 2016 to 2030, 2018 update. Association of American Medical Colleges. March 2018.
3. Giberson S, Yoder S, Lee MP. Improving patient and health system outcomes through advanced pharmacy practice. A report to the U.S. Surgeon General 2011. https://www .accp.com/docs/positions/misc/improving_patient_and _health_system_outcomes.pdf. Updated December 2011. Accessed September 11, 2019.
4. Lip G, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation. CHEST guideline and Expert Panel Report. Chest. 2018;154(5):1121-1201.
5. Babb S, Marlarcher A, Schauer G, Asman K, Jamal A. Quitting smoking among adults—United States, 2000-2015. MMWR Morb Mortal Wkly Rep. 2017;65(52):1457-1464.
1. Buttorff C, Ruder T, Bauman M. Multiple Chronic Conditions in the United States. Santa Monica, CA: Rand Corp; 2017.
2. Dall T, West T, Chakrabarti R, Reynolds R, Iacobucci W. The complexities of physician supply and demand: projections from 2016 to 2030, 2018 update. Association of American Medical Colleges. March 2018.
3. Giberson S, Yoder S, Lee MP. Improving patient and health system outcomes through advanced pharmacy practice. A report to the U.S. Surgeon General 2011. https://www .accp.com/docs/positions/misc/improving_patient_and _health_system_outcomes.pdf. Updated December 2011. Accessed September 11, 2019.
4. Lip G, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation. CHEST guideline and Expert Panel Report. Chest. 2018;154(5):1121-1201.
5. Babb S, Marlarcher A, Schauer G, Asman K, Jamal A. Quitting smoking among adults—United States, 2000-2015. MMWR Morb Mortal Wkly Rep. 2017;65(52):1457-1464.
CAR T-cell therapy found safe, effective for HIV-associated lymphoma
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
FROM CANCER
New engineered HIV-1 vaccine candidate shows improved immunogenicity in early trial
ALVAC-HIV vaccine showed immunogenicity across several HIV clades in an early trial involving 100 healthy patients at low risk of HIV infection, according to a study by Glenda E. Gray, MBBCH, FCPaed, of the University of the Witwatersrand, Johannesburg, South Africa, and colleagues that was published online in the Sep. 18 issue of Science Translational Medicine.
ALVAC-HIV (vCP1521) is a live attenuated recombinant canarypox-derived virus that expresses gene products from the HIV-1 gp120 (92TH023/clade E), Gag (clade B), and Pro (clade B) that is cultured in chicken embryo fibroblast cells.
Four injections of ALVAC-HIV were given at months 0, 1, 3, and 6. At months 3 and 6, two booster injections were given of AIDSVAX/BE, a bivalent HIV glycoprotein 120 (gp120) that was previously studied in the RV144 trial. The HVTN 097 trial examined primary immunogenicity endpoints including the frequency and magnitude of IgG and IgG3 antibody binding, measured in serum specimens obtained at baseline, at a peak time point (2 weeks after second ALVAC/AIDSVAX vaccination), a durability time point (6 months after second ALVAC/AIDSVAX vaccination), and the response rates and magnitudes of CD4+ and CD8+ T-cell responses at the baseline, peak, and durability time points. One hundred healthy adults at low risk for HIV infection were randomized in 3:1:1 ratio to group T1 (HIV vaccines, tetanus vaccine, and hepatitis B vaccine), group T2 (HIV vaccine only), and the placebo group T3 (tetanus vaccine and hepatitis B vaccine). There were no meaningful differences in HIV immune responses between the HIV vaccine recipients with or without the tetanus and hepatitis B vaccines, so the researchers pooled the data from groups T1 and T2 in their analysis.
At the peak immunogenicity time point, the vaccine schedule predominantly induced CD4+ T cells directed to HIV-1 Env; this was measured by expression of interleukin-2 and/or interferon-gamma. The Env-specific CD4+ T-cell response rate was significantly higher in HVTN 097 vaccine recipients than it was in those in the RV144 trial (51.9% vs. 36.4%; P = .043). The HVTN 097 trial also showed significantly higher response rates for CD40L(59.3% for HVTN 097 vs. 33.7% for RV144; P less than .001) and for interferon-gamma (42.6% in HVTN 097 vs. 19.5% in RV144; P = .001).
However, durability at 6 months after the second vaccine injection remained an issue, with the frequency of circulating Env-specific CD4+ T-cell responses among vaccine recipients declining significantly; the response rate dropped from 70.8% to 36.1%.
“These data may indicate that cross-clade immune responses, especially to non-neutralizing epitopes correlated with decreased HIV-1 risk, can be achieved for a globally effective vaccine by using unique HIV Env strains,” Dr. Gray and associates concluded.
The authors declared that they had no competing interests.
SOURCE: Gray GE et al. Sci. Transl. Med. 2019 Sep 18. doi: 10.1126/scitranslmed.aax1880..
ALVAC-HIV vaccine showed immunogenicity across several HIV clades in an early trial involving 100 healthy patients at low risk of HIV infection, according to a study by Glenda E. Gray, MBBCH, FCPaed, of the University of the Witwatersrand, Johannesburg, South Africa, and colleagues that was published online in the Sep. 18 issue of Science Translational Medicine.
ALVAC-HIV (vCP1521) is a live attenuated recombinant canarypox-derived virus that expresses gene products from the HIV-1 gp120 (92TH023/clade E), Gag (clade B), and Pro (clade B) that is cultured in chicken embryo fibroblast cells.
Four injections of ALVAC-HIV were given at months 0, 1, 3, and 6. At months 3 and 6, two booster injections were given of AIDSVAX/BE, a bivalent HIV glycoprotein 120 (gp120) that was previously studied in the RV144 trial. The HVTN 097 trial examined primary immunogenicity endpoints including the frequency and magnitude of IgG and IgG3 antibody binding, measured in serum specimens obtained at baseline, at a peak time point (2 weeks after second ALVAC/AIDSVAX vaccination), a durability time point (6 months after second ALVAC/AIDSVAX vaccination), and the response rates and magnitudes of CD4+ and CD8+ T-cell responses at the baseline, peak, and durability time points. One hundred healthy adults at low risk for HIV infection were randomized in 3:1:1 ratio to group T1 (HIV vaccines, tetanus vaccine, and hepatitis B vaccine), group T2 (HIV vaccine only), and the placebo group T3 (tetanus vaccine and hepatitis B vaccine). There were no meaningful differences in HIV immune responses between the HIV vaccine recipients with or without the tetanus and hepatitis B vaccines, so the researchers pooled the data from groups T1 and T2 in their analysis.
At the peak immunogenicity time point, the vaccine schedule predominantly induced CD4+ T cells directed to HIV-1 Env; this was measured by expression of interleukin-2 and/or interferon-gamma. The Env-specific CD4+ T-cell response rate was significantly higher in HVTN 097 vaccine recipients than it was in those in the RV144 trial (51.9% vs. 36.4%; P = .043). The HVTN 097 trial also showed significantly higher response rates for CD40L(59.3% for HVTN 097 vs. 33.7% for RV144; P less than .001) and for interferon-gamma (42.6% in HVTN 097 vs. 19.5% in RV144; P = .001).
However, durability at 6 months after the second vaccine injection remained an issue, with the frequency of circulating Env-specific CD4+ T-cell responses among vaccine recipients declining significantly; the response rate dropped from 70.8% to 36.1%.
“These data may indicate that cross-clade immune responses, especially to non-neutralizing epitopes correlated with decreased HIV-1 risk, can be achieved for a globally effective vaccine by using unique HIV Env strains,” Dr. Gray and associates concluded.
The authors declared that they had no competing interests.
SOURCE: Gray GE et al. Sci. Transl. Med. 2019 Sep 18. doi: 10.1126/scitranslmed.aax1880..
ALVAC-HIV vaccine showed immunogenicity across several HIV clades in an early trial involving 100 healthy patients at low risk of HIV infection, according to a study by Glenda E. Gray, MBBCH, FCPaed, of the University of the Witwatersrand, Johannesburg, South Africa, and colleagues that was published online in the Sep. 18 issue of Science Translational Medicine.
ALVAC-HIV (vCP1521) is a live attenuated recombinant canarypox-derived virus that expresses gene products from the HIV-1 gp120 (92TH023/clade E), Gag (clade B), and Pro (clade B) that is cultured in chicken embryo fibroblast cells.
Four injections of ALVAC-HIV were given at months 0, 1, 3, and 6. At months 3 and 6, two booster injections were given of AIDSVAX/BE, a bivalent HIV glycoprotein 120 (gp120) that was previously studied in the RV144 trial. The HVTN 097 trial examined primary immunogenicity endpoints including the frequency and magnitude of IgG and IgG3 antibody binding, measured in serum specimens obtained at baseline, at a peak time point (2 weeks after second ALVAC/AIDSVAX vaccination), a durability time point (6 months after second ALVAC/AIDSVAX vaccination), and the response rates and magnitudes of CD4+ and CD8+ T-cell responses at the baseline, peak, and durability time points. One hundred healthy adults at low risk for HIV infection were randomized in 3:1:1 ratio to group T1 (HIV vaccines, tetanus vaccine, and hepatitis B vaccine), group T2 (HIV vaccine only), and the placebo group T3 (tetanus vaccine and hepatitis B vaccine). There were no meaningful differences in HIV immune responses between the HIV vaccine recipients with or without the tetanus and hepatitis B vaccines, so the researchers pooled the data from groups T1 and T2 in their analysis.
At the peak immunogenicity time point, the vaccine schedule predominantly induced CD4+ T cells directed to HIV-1 Env; this was measured by expression of interleukin-2 and/or interferon-gamma. The Env-specific CD4+ T-cell response rate was significantly higher in HVTN 097 vaccine recipients than it was in those in the RV144 trial (51.9% vs. 36.4%; P = .043). The HVTN 097 trial also showed significantly higher response rates for CD40L(59.3% for HVTN 097 vs. 33.7% for RV144; P less than .001) and for interferon-gamma (42.6% in HVTN 097 vs. 19.5% in RV144; P = .001).
However, durability at 6 months after the second vaccine injection remained an issue, with the frequency of circulating Env-specific CD4+ T-cell responses among vaccine recipients declining significantly; the response rate dropped from 70.8% to 36.1%.
“These data may indicate that cross-clade immune responses, especially to non-neutralizing epitopes correlated with decreased HIV-1 risk, can be achieved for a globally effective vaccine by using unique HIV Env strains,” Dr. Gray and associates concluded.
The authors declared that they had no competing interests.
SOURCE: Gray GE et al. Sci. Transl. Med. 2019 Sep 18. doi: 10.1126/scitranslmed.aax1880..
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: “These data may indicate that cross-clade immune responses ... can be achieved for a globally effective vaccine by using unique HIV Env strains.”
Major finding: At the peak immunogenicity time point, the vaccine schedule predominantly induced CD4+ T cells directed to HIV-1 Env .
Study details: A phase 1b randomized, double-blind, placebo-controlled trial to assess the safety and immunogenicity of the ALVAC-HIV vaccine in 100 healthy patients at low risk of HIV infection.
Disclosures: The study was supported by the National Institute of Allergy and Infectious Diseases and other global health agencies. The authors declared that they had no competing interests.
Source: Gray GE et al. Sci Transl Med. 2019 Sep 18. doi: 10.1126/scitranslmed.aax1880.
Stem cells gene edited to be HIV resistant treat ALL, but not HIV
Gene editing of donor stem cells prior to transplantation into a patient with both HIV infection and acute lymphoblastic leukemia (ALL) was safe and effectively treated the patient’s leukemia, but failed to resolve his HIV, investigators reported.
The 27-year-old man received an HLA-matched transplant of hematopoietic stem and progenitor cells (HSPCs) that had been genetically engineered to lack CCR5, a key gateway for HIV entry into cells.
Although the transplant resulted in complete remission of leukemia with full donor chimerism, only about 9% of the posttransplant lymphocytes showed disruption of CCR5, and during a brief trial of antiretroviral therapy interruption his HIV viral load rebounded, reported Hongkui Deng, PhD, and colleagues from Peking University in China.
Although the experiment did not meet its goal of a drug-free HIV remission, it serves as a proof of concept for the use of CRISPR-Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9) gene editing to treat HIV infection, the authors contend.
“These results show the proof of principle that transplantation and long-term engraftment of CRISPR-edited allogeneic HSPCs can be achieved; however, the efficiency of the response was not adequate to achieve the target of cure of HIV-1 infection,” they wrote in a brief report published in the New England Journal of Medicine.
As previously reported, other research groups have investigated genetic editing to mimic a naturally occurring mutation that effectively disables the CCR5 HIV coreceptor, preventing the retrovirus from entering healthy cells. The mutation was first identified in a man named Timothy Brown who came to be known as “the Berlin patient” after he was apparently cured of HIV infection after a bone marrow transplant from a donor who had the mutation.
Dr. Deng and colleagues took advantage of HSPC transplantation, a standard therapy for ALL to see whether it could also have beneficial effects on concomitant HIV infection.
They treated donor HSPCs with CRISPR-Cas9 to ablate CCR5 and then delivered them to the patient along with additional CD34-depleted donor cells from mobilized peripheral blood.
The transplant was a success, with neutrophil engraftment on day 13 and platelet engraftment on day 27, and the leukemia was in morphologic complete remission at week 4 following transplantation. The patient remained in complete remission from leukemia throughout the 19-month follow-up period, with full donor chimerism .
However, when a planned interruption of antiretroviral therapy was carried out at 7 months post transplant, the serum viral load increased to 3 × 107 copies/ml at week 4 following interruption, and the patient was restarted on the drug. His viral levels gradually decreased to undetectable level during the subsequent months.
The investigators noted that 2 weeks after the drug interruption trial was started there was a small increase in the percentage of CCR5 insertion/deletions.
“The low efficiency of gene editing in the patient may be due to the competitive engraftment of the coinfused HSPCs in CD34-depleted cells and the persistence of donor T cells. To further clarify the anti-HIV effect of CCR5-ablated HSPCs, it will be essential to increase the gene-editing efficiency of our CRISPR-Cas9 system and improve the transplantation protocol,” they wrote.
The study was funded by the Beijing Municipal Science and Technology Commission and others (unspecified). All authors reported having nothing to disclose.
SOURCE: Xu L et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1817426.
Gene editing of donor stem cells prior to transplantation into a patient with both HIV infection and acute lymphoblastic leukemia (ALL) was safe and effectively treated the patient’s leukemia, but failed to resolve his HIV, investigators reported.
The 27-year-old man received an HLA-matched transplant of hematopoietic stem and progenitor cells (HSPCs) that had been genetically engineered to lack CCR5, a key gateway for HIV entry into cells.
Although the transplant resulted in complete remission of leukemia with full donor chimerism, only about 9% of the posttransplant lymphocytes showed disruption of CCR5, and during a brief trial of antiretroviral therapy interruption his HIV viral load rebounded, reported Hongkui Deng, PhD, and colleagues from Peking University in China.
Although the experiment did not meet its goal of a drug-free HIV remission, it serves as a proof of concept for the use of CRISPR-Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9) gene editing to treat HIV infection, the authors contend.
“These results show the proof of principle that transplantation and long-term engraftment of CRISPR-edited allogeneic HSPCs can be achieved; however, the efficiency of the response was not adequate to achieve the target of cure of HIV-1 infection,” they wrote in a brief report published in the New England Journal of Medicine.
As previously reported, other research groups have investigated genetic editing to mimic a naturally occurring mutation that effectively disables the CCR5 HIV coreceptor, preventing the retrovirus from entering healthy cells. The mutation was first identified in a man named Timothy Brown who came to be known as “the Berlin patient” after he was apparently cured of HIV infection after a bone marrow transplant from a donor who had the mutation.
Dr. Deng and colleagues took advantage of HSPC transplantation, a standard therapy for ALL to see whether it could also have beneficial effects on concomitant HIV infection.
They treated donor HSPCs with CRISPR-Cas9 to ablate CCR5 and then delivered them to the patient along with additional CD34-depleted donor cells from mobilized peripheral blood.
The transplant was a success, with neutrophil engraftment on day 13 and platelet engraftment on day 27, and the leukemia was in morphologic complete remission at week 4 following transplantation. The patient remained in complete remission from leukemia throughout the 19-month follow-up period, with full donor chimerism .
However, when a planned interruption of antiretroviral therapy was carried out at 7 months post transplant, the serum viral load increased to 3 × 107 copies/ml at week 4 following interruption, and the patient was restarted on the drug. His viral levels gradually decreased to undetectable level during the subsequent months.
The investigators noted that 2 weeks after the drug interruption trial was started there was a small increase in the percentage of CCR5 insertion/deletions.
“The low efficiency of gene editing in the patient may be due to the competitive engraftment of the coinfused HSPCs in CD34-depleted cells and the persistence of donor T cells. To further clarify the anti-HIV effect of CCR5-ablated HSPCs, it will be essential to increase the gene-editing efficiency of our CRISPR-Cas9 system and improve the transplantation protocol,” they wrote.
The study was funded by the Beijing Municipal Science and Technology Commission and others (unspecified). All authors reported having nothing to disclose.
SOURCE: Xu L et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1817426.
Gene editing of donor stem cells prior to transplantation into a patient with both HIV infection and acute lymphoblastic leukemia (ALL) was safe and effectively treated the patient’s leukemia, but failed to resolve his HIV, investigators reported.
The 27-year-old man received an HLA-matched transplant of hematopoietic stem and progenitor cells (HSPCs) that had been genetically engineered to lack CCR5, a key gateway for HIV entry into cells.
Although the transplant resulted in complete remission of leukemia with full donor chimerism, only about 9% of the posttransplant lymphocytes showed disruption of CCR5, and during a brief trial of antiretroviral therapy interruption his HIV viral load rebounded, reported Hongkui Deng, PhD, and colleagues from Peking University in China.
Although the experiment did not meet its goal of a drug-free HIV remission, it serves as a proof of concept for the use of CRISPR-Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9) gene editing to treat HIV infection, the authors contend.
“These results show the proof of principle that transplantation and long-term engraftment of CRISPR-edited allogeneic HSPCs can be achieved; however, the efficiency of the response was not adequate to achieve the target of cure of HIV-1 infection,” they wrote in a brief report published in the New England Journal of Medicine.
As previously reported, other research groups have investigated genetic editing to mimic a naturally occurring mutation that effectively disables the CCR5 HIV coreceptor, preventing the retrovirus from entering healthy cells. The mutation was first identified in a man named Timothy Brown who came to be known as “the Berlin patient” after he was apparently cured of HIV infection after a bone marrow transplant from a donor who had the mutation.
Dr. Deng and colleagues took advantage of HSPC transplantation, a standard therapy for ALL to see whether it could also have beneficial effects on concomitant HIV infection.
They treated donor HSPCs with CRISPR-Cas9 to ablate CCR5 and then delivered them to the patient along with additional CD34-depleted donor cells from mobilized peripheral blood.
The transplant was a success, with neutrophil engraftment on day 13 and platelet engraftment on day 27, and the leukemia was in morphologic complete remission at week 4 following transplantation. The patient remained in complete remission from leukemia throughout the 19-month follow-up period, with full donor chimerism .
However, when a planned interruption of antiretroviral therapy was carried out at 7 months post transplant, the serum viral load increased to 3 × 107 copies/ml at week 4 following interruption, and the patient was restarted on the drug. His viral levels gradually decreased to undetectable level during the subsequent months.
The investigators noted that 2 weeks after the drug interruption trial was started there was a small increase in the percentage of CCR5 insertion/deletions.
“The low efficiency of gene editing in the patient may be due to the competitive engraftment of the coinfused HSPCs in CD34-depleted cells and the persistence of donor T cells. To further clarify the anti-HIV effect of CCR5-ablated HSPCs, it will be essential to increase the gene-editing efficiency of our CRISPR-Cas9 system and improve the transplantation protocol,” they wrote.
The study was funded by the Beijing Municipal Science and Technology Commission and others (unspecified). All authors reported having nothing to disclose.
SOURCE: Xu L et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1817426.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Donor cells depleted of the HIV coreceptor CCR5 effectively treated ALL, but not HIV.
Major finding: The patient had a sustained complete remission of ALL, but HIV persisted after transplantation.
Study details: Case report of a 27-year-old man with ALL and HIV.
Disclosures: The study was funded by the Beijing Municipal Science and Technology Commission and others (unspecified). All authors reported having nothing to disclose.
Source: Xu L et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1817426.
Summary: Preexposure prophylaxis for the prevention of HIV infection USPSTF recommendation statement
It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.
Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.
With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
Screening
In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.
When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:
- Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
- Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
- Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).
The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.
Treatment
The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.
Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.
Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.
While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
Bottom Line
It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health
Reference
Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.
It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.
Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.
With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
Screening
In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.
When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:
- Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
- Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
- Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).
The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.
Treatment
The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.
Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.
Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.
While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
Bottom Line
It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health
Reference
Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.
It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.
Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.
With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
Screening
In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.
When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:
- Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
- Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
- Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).
The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.
Treatment
The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.
Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.
Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.
While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
Bottom Line
It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health
Reference
Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.
A Veteran Presenting With Leg Swelling, Dyspnea, and Proteinuria
*This article has been corrected to include a missing author.
Case Presentation. A 63-year-old male with well-controlled HIV (CD4 count 757, undetectable viral load), epilepsy, and hypertension presented to the VA Boston Healthcare System (VABHS) emergency department with 1 week of bilateral leg swelling and exertional shortness of breath. He reported having no fever, cough, chest pain, pain with inspiration and orthopnea. There was no personal or family history of pulmonary embolism. He reported weight gain but was unable to quantify how much. He also reported flare up of chronic knee pain, without swelling for which he had taken up to 4 tablets of naproxen daily for several weeks. His physical examination was notable for a heart rate of 105 beats per minute and bilateral pitting edema to his knees. Laboratory testing revealed a creatinine level of 2.5 mg/dL, which was increased from a baseline of 1.0 mg/dL (Table 1), and a urine protein-to-creatinine ratio of 7.8 mg/mg (Table 2). A renal ultrasound showed normal-sized kidneys without hydronephrosis or obstructing renal calculi. The patient was admitted for further workup of his dyspnea and acute kidney injury.
► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. William, based on the degree of proteinuria and edema, a diagnosis of nephrotic syndrome was made. How is nephrotic syndrome defined, and how is it distinguished from glomerulonephritis?
► Jeffrey William, MD, Nephrologist, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The pathophysiology of nephrotic disease and glomerulonephritis are quite distinct, resulting in symptoms and systemic manifestations that only slightly overlap. Glomerulonephritis is characterized by inflammation of the endothelial cells of the trilayered glomerular capillary, with a resulting active urine sediment with red blood cells, white blood cells, and casts. Nephrotic syndrome mostly affects the visceral epithelial cells of the glomerular capillary, commonly referred to as podocytes, and hence, the urine sediment in nephrotic disease is often inactive. Patients with nephrotic syndrome have nephrotic-range proteinuria (excretion of > 3.5 g per 24 h or a spot urine protein-creatinine ratio > 3.5 g in the steady state) and both hypoalbuminemia (< 3 g/dL) and peripheral edema. Lipiduria and hyperlipidemia are common findings in nephrotic syndrome but are not required for a clinical diagnosis.1 In contrast, glomerulonephritis is defined by a constellation of findings that include renal insufficiency (often indicated by an elevation in blood urea nitrogen and creatinine), hypertension, hematuria, and subnephrotic range proteinuria. In practice, patients may fulfill criteria of both nephrotic and nephritic syndromes, but the preponderance of clinical evidence often points one way or the other. In this case, nephrotic syndrome was diagnosed based on the urine protein-to-creatinine ratio of 7.8 mg/mg, hypoalbuminemia, and edema.
► Dr. Li. What would be your first-line workup for evaluation of the etiology of this patient’s nephrotic syndrome?
► Dr. William. Rather than memorizing a list of etiologies of nephrotic syndrome, it is essential to consider the pathophysiology of heavy proteinuria. Though the glomerular filtration barrier is extremely complex and defects in any component can cause proteinuria, disruption of the podocyte is often involved. Common disease processes that chiefly target the podocyte include minimal change disease, primary focal and segmental glomerulosclerosis (FSGS), and membranous nephropathy, all by differing mechanisms. Minimal change disease and idiopathic/primary FSGS are increasingly thought to be at differing points on a spectrum of the same disease.2 Secondary FSGS, on the other hand, is a progressive disease, commonly resulting from longstanding hypertension, diabetes mellitus, and obesity in adults. Membranous nephropathy can also be either primary or secondary. Primary membranous nephropathy is chiefly caused by a circulating IgG4 antibody to the podocyte membrane antigen PLA2R (M-type phospholipase A2 receptor), whereas secondary membranous nephropathy can be caused by a variety of systemic etiologies, including autoimmune disease (eg, systemic lupus erythematosus), certain malignancies, chronic infections (eg, hepatitis B and C), and many medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).3-5 Paraprotein deposition diseases can also cause glomerular damage leading to nephrotic-range proteinuria.
Given these potential diagnoses, a careful history should be taken to assess exposures and recent medication use. Urine sediment evaluation is essential in the evaluation of nephrotic syndrome to determine if there is an underlying nephritic process. Select serologies may be sent to look for autoimmune disease, such as systemic lupus erythematosus and common viral exposures like hepatitis B or C. Serum and urine protein electrophoreses would be appropriate initial tests of suspected paraprotein-related diseases. Other serologies, such as antineutrophil cytoplasmic antibodies or antiglomerular basement membrane antibodies, would not necessarily be indicated here given the lack of hematuria and presence of nephrotic-range proteinuria.
► Dr. Li. The initial evaluation was notable for an erythrocyte sedimentation rate > 120 (mm/h) and a weakly positive antinuclear antibody (ANA) titer of 1:40. The remainder of his initial workup did not reveal an etiology for his nephrotic syndrome (Table 3).
Dr. William, is there a role for starting urgent empiric steroids in nephrotic syndrome while workup is ongoing? If so, do the severity of proteinuria and/or symptoms play a role or is this determination based on something else?
► Dr. William. Edema is a primary symptom of nephrotic syndrome and can often be managed with diuretics alone. If a clear medication-mediated cause is suspected, discontinuation of this agent may result in spontaneous improvement without steroid treatment. However,in cases where an etiology is unclear and there are serious thrombotic complications requiring anticoagulation, and a renal biopsy is deemed to be too risky, then empiric steroid therapy may be necessary. Children with new-onset nephrotic syndrome are presumed to have minimal change disease, given its prevalence in this patient population, and are often given empiric steroids without obtaining a renal biopsy. However, in the adult population, a renal biopsy can typically be performed quickly and safely, with pathology results interpreted within days. In this patient, since a diagnosis was unclear and there was no contraindication to renal biopsy, a biopsy should be obtained before consideration of steroids.
► Dr. Li. Steroids were deferred in anticipation of renal biopsy, which showed stage I membranous nephropathy, suggestive of membranous lupus nephritis Class V. The deposits were strongly reactive for immunoglobuline G (IgG), IgA, and complement 1q (C1q), showed co-dominant staining for IgG1, IgG2, and IgG3, and were weakly positive for the PLA2 receptor. Focal intimal arteritis in a small interlobular vessel was seen.
Dr. William, the pathology returned suggestive of lupus nephritis. Does the overall clinical picture fit with lupus nephritis?
► Dr. William. Given the history and a rather low ANA, the diagnosis of lupus nephritis seems unlikely. The lack of IgG4 and PLA2R staining in the biopsy suggests that this membranous pattern on the biopsy is likely to be secondary to a systemic etiology, but further investigation should be pursued.
► Dr. Li. The patient was discharged after the biopsy with a planned outpatient nephrology follow-up to discuss results and treatment. He was prescribed an oral diuretic, and his symptoms improved. Several days after discharge, he developed blurry vision and was evaluated in the Ophthalmology clinic. On fundoscopy, he was found to have acute papillitis, a form of optic neuritis. As part of initial evaluation of infectious etiologies of papillitis, ophthalmology recommended testing for syphilis.
Dr. Strymish, when we are considering secondary syphilis, what is the recommended approach to diagnostic testing?
► Judith Strymish, MD, Infectious Diseases, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The diagnosis of syphilis is usually made through serologic testing of blood specimens. Methods that detect the spirochete directly like dark-field smears are not readily available. Serologic tests include treponemal tests (eg, Treponema pallidum particle agglutination assay [TPPA]) and nontreponemal tests (eg, rapid plasma reagin [RPR]). One needs a confirmatory test because either test is associated with false positives. Either test can be done first. Most laboratories, including those at VABHS are now performing treponemal tests first as these have become more cost-effective.6 The TPPA treponemal test was found to have a lower false negative rate in primary syphilis compared with that of nontreponemal tests.7 Nontreponemal tests can be followed for response to therapy. If a patient has a history of treated syphilis, a nontreponemal test should be sent, since the treponemal test will remain positive for life.
If there is clinical concern for neurosyphilis, cerebrospinal fluid fluorescent (CSF) treponemal antibody needs to be sampled and sent for the nontreponemal venereal disease research laboratory (VDRL) test. The VDRL is highly specific for neurosyphilis but not as sensitive. Cerebrospinal fluid fluorescent treponemal antibody (CSF FTA) may also be sent; it is very sensitive but not very specific for neurosyphilis.
► Dr. Li. An RPR returned positive at 1:512 (was negative 14 months prior on a routine screening test), with positive reflex TPPA (Table 4). A diagnosis of secondary syphilis was made. Dr. Strymish, at this point, what additional testing and treatment is necessary?
► Dr. Strymish. With papillitis and a very high RPR, we need to assume that he has ophthalmic syphilis. This can occur in any stage of syphilis, but his eye findings and high RPR are consistent with secondary syphilis. Ophthalmic syphilis has been on the upswing, even more than is expected with recent increases in syphilis cases.8 Ophthalmic syphilis is considered a form of neurosyphilis. A lumbar puncture and treatment for neurosyphilis is recommended.9,10
► Dr. Li. A lumbar puncture was performed, and his CSF was VDRL positive. This confirmed a diagnosis of neurosyphilis (Table 4). The patient was treated for neurosyphilis with IV penicillin. The patient shared that he had episodes of unprotected oral sexual activity within the past year and approximately 1 year ago, he came in close contact (but no sexual activity) with a person who had a rash consistent with syphilis.Dr. William, syphilis would be a potential unifying diagnosis of his renal and ophthalmologic manifestations. Is syphilis known to cause membranous nephropathy?
► Dr. William. Though it is uncommon, the nephrotic syndrome is a well-described complication of secondary syphilis.11,12 Syphilis has been shown to cause nephrotic syndrome in a variety of ways. Case reports abound linking syphilis to minimal change disease and other glomerular diseases.13,14 A case report from 1993 shows a membranous pattern of glomerular disease similar to this case.15 As a form of secondary membranous nephropathy, the immunofluorescence pattern can demonstrate staining similar to the “full house” seen in lupus nephritis (IgA, IgM, and C1q, in addition to IgG and C3).16 This explains the initial interpretation of this patient’s biopsy, as lupus nephritis would be a much more common etiology of secondary membranous nephropathy than is acute syphilis with this immunofluorescence pattern. However, the data in this case are highly suggestive of a causal relationship between secondary syphilis and membranous nephropathy.
► Dr. Li. Dr. Strymish, how should this patient be screened for syphilis reinfection, and at what intervals would you recommend?
► Dr. Strymish. He will need follow-up testing to make sure that his syphilis is effectively treated. If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. He will also need follow-up for normalization of his RPR. Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy according to US Centers for Disease Control and Prevention guidelines.9
His treponemal test for syphilis will likely stay positive for life. His RPR should decrease significantly with effective treatment. It makes sense to screen with RPR alone as long as he continues to have risk factors for acquiring syphilis. Routine syphilis testing is recommended for pregnant women, sexually active men who have sex with men, sexually active persons with HIV, and persons taking PrEP (pre-exposure prophylaxis) for HIV prevention. He should be screened at least yearly for syphilis.
► Dr. Li. Over the next several months, the patient’s creatinine normalized and his proteinuria resolved. His vision recovered, and he has had no further ophthalmologic complications.
Dr. William, what is his long-term renal prognosis? Do you expect that his acute episode of membranous nephropathy will have permanent effects on his renal function?
► Dr. William. His rapid response to therapy for neurosyphilis provides evidence for this etiology of his renal dysfunction and glomerulonephritis. His long-term prognosis is quite good if the syphilis is the only reason for him to have renal disease. The renal damage is often reversible in these cases. However, given his prior extensive NSAID exposure and history of hypertension, he may be at higher risk for chronic kidney disease than an otherwise healthy patient, especially after an episode of acute kidney injury. Therefore, his renal function should continue to be monitored as an outpatient.
Acknowledgments
The authors thank this veteran for sharing his story and allowing us to learn from this unusual case for the benefit of our future patients.
1. Rennke H, Denker BM. Renal Pathophysiology: The Essentials. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2014.
2. Maas RJ, Deegens JK, Smeets B, Moeller MJ, Wetzels JF. Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat Rev Nephrol. 2016;12(12):768-776.
3. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21.
4. Rennke HG. Secondary membranoproliferative glomerulonephritis. Kidney Int. 1995;47(2):643-656.
5. Nawaz FA, Larsen CP, Troxell ML. Membranous nephropathy and nonsteroidal anti-inflammatory agents. Am J Kidney Dis. 2013;62(5):1012-1017.
6. Pillay A. Centers for Disease Control and Prevention Syphilis Summit—Diagnostics and laboratory issues. Sex Transm Dis. 2018;45(9S)(suppl 1):S13-S16.
7. Levett PN, Fonseca K, Tsang RS, et al. Canadian Public Health Laboratory Network laboratory guidelines for the use of serological tests (excluding point-of-care tests) for the diagnosis of syphilis in Canada. Can J Infect Dis Med Microbiol. 2015;26(suppl A):6A-12A.
8. Oliver SE, Aubin M, Atwell L, et al. Ocular syphilis—eight jurisdictions, United States, 2014-2015. MMWR Morb Mortal Wkly Rep. 2016;65(43):1185-1188.
9. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recommendations and Reports 2015;64(RR3):1-137. [Erratum in MMWR Recomm Rep. 2015;64(33):924.]
10. US Centers for Disease Control and Prevention. Clinical advisory: ocular syphilis in the United States. https://www.cdc.gov/std/syphilis/clinicaladvisoryos2015.htm. Updated March 24, 2016. Accessed August 12, 2019.
11. Braunstein GD, Lewis EJ, Galvanek EG, Hamilton A, Bell WR. The nephrotic syndrome associated with secondary syphilis: an immune deposit disease. Am J Med. 1970;48:643-648.1.
12. Handoko ML, Duijvestein M, Scheepstra CG, de Fijter CW. Syphilis: a reversible cause of nephrotic syndrome. BMJ Case Rep. 2013;2013:pii:bcr2012008279
13. Krane NK, Espenan P, Walker PD, Bergman SM, Wallin JD. Renal disease and syphilis: a report of nephrotic syndrome with minimal change disease. Am J Kidney Dis. 1987;9(2):176-179.
14. Bhorade MS, Carag HB, Lee HJ, Potter EV, Dunea G. Nephropathy of secondary syphilis: a clinical and pathological spectrum. JAMA. 1971;216(7):1159-1166.
15. Hunte W, al-Ghraoui F, Cohen RJ. Secondary syphilis and the nephrotic syndrome. J Am Soc Nephrol. 1993;3(7):1351-1355.
16. Gamble CN, Reardan JB. Immunopathogenesis of syphilitic glomerulonephritis. Elution of antitreponemal antibody from glomerular immune-complex deposits. N Engl J Med. 1975;292(9):449-454.
*This article has been corrected to include a missing author.
Case Presentation. A 63-year-old male with well-controlled HIV (CD4 count 757, undetectable viral load), epilepsy, and hypertension presented to the VA Boston Healthcare System (VABHS) emergency department with 1 week of bilateral leg swelling and exertional shortness of breath. He reported having no fever, cough, chest pain, pain with inspiration and orthopnea. There was no personal or family history of pulmonary embolism. He reported weight gain but was unable to quantify how much. He also reported flare up of chronic knee pain, without swelling for which he had taken up to 4 tablets of naproxen daily for several weeks. His physical examination was notable for a heart rate of 105 beats per minute and bilateral pitting edema to his knees. Laboratory testing revealed a creatinine level of 2.5 mg/dL, which was increased from a baseline of 1.0 mg/dL (Table 1), and a urine protein-to-creatinine ratio of 7.8 mg/mg (Table 2). A renal ultrasound showed normal-sized kidneys without hydronephrosis or obstructing renal calculi. The patient was admitted for further workup of his dyspnea and acute kidney injury.
► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. William, based on the degree of proteinuria and edema, a diagnosis of nephrotic syndrome was made. How is nephrotic syndrome defined, and how is it distinguished from glomerulonephritis?
► Jeffrey William, MD, Nephrologist, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The pathophysiology of nephrotic disease and glomerulonephritis are quite distinct, resulting in symptoms and systemic manifestations that only slightly overlap. Glomerulonephritis is characterized by inflammation of the endothelial cells of the trilayered glomerular capillary, with a resulting active urine sediment with red blood cells, white blood cells, and casts. Nephrotic syndrome mostly affects the visceral epithelial cells of the glomerular capillary, commonly referred to as podocytes, and hence, the urine sediment in nephrotic disease is often inactive. Patients with nephrotic syndrome have nephrotic-range proteinuria (excretion of > 3.5 g per 24 h or a spot urine protein-creatinine ratio > 3.5 g in the steady state) and both hypoalbuminemia (< 3 g/dL) and peripheral edema. Lipiduria and hyperlipidemia are common findings in nephrotic syndrome but are not required for a clinical diagnosis.1 In contrast, glomerulonephritis is defined by a constellation of findings that include renal insufficiency (often indicated by an elevation in blood urea nitrogen and creatinine), hypertension, hematuria, and subnephrotic range proteinuria. In practice, patients may fulfill criteria of both nephrotic and nephritic syndromes, but the preponderance of clinical evidence often points one way or the other. In this case, nephrotic syndrome was diagnosed based on the urine protein-to-creatinine ratio of 7.8 mg/mg, hypoalbuminemia, and edema.
► Dr. Li. What would be your first-line workup for evaluation of the etiology of this patient’s nephrotic syndrome?
► Dr. William. Rather than memorizing a list of etiologies of nephrotic syndrome, it is essential to consider the pathophysiology of heavy proteinuria. Though the glomerular filtration barrier is extremely complex and defects in any component can cause proteinuria, disruption of the podocyte is often involved. Common disease processes that chiefly target the podocyte include minimal change disease, primary focal and segmental glomerulosclerosis (FSGS), and membranous nephropathy, all by differing mechanisms. Minimal change disease and idiopathic/primary FSGS are increasingly thought to be at differing points on a spectrum of the same disease.2 Secondary FSGS, on the other hand, is a progressive disease, commonly resulting from longstanding hypertension, diabetes mellitus, and obesity in adults. Membranous nephropathy can also be either primary or secondary. Primary membranous nephropathy is chiefly caused by a circulating IgG4 antibody to the podocyte membrane antigen PLA2R (M-type phospholipase A2 receptor), whereas secondary membranous nephropathy can be caused by a variety of systemic etiologies, including autoimmune disease (eg, systemic lupus erythematosus), certain malignancies, chronic infections (eg, hepatitis B and C), and many medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).3-5 Paraprotein deposition diseases can also cause glomerular damage leading to nephrotic-range proteinuria.
Given these potential diagnoses, a careful history should be taken to assess exposures and recent medication use. Urine sediment evaluation is essential in the evaluation of nephrotic syndrome to determine if there is an underlying nephritic process. Select serologies may be sent to look for autoimmune disease, such as systemic lupus erythematosus and common viral exposures like hepatitis B or C. Serum and urine protein electrophoreses would be appropriate initial tests of suspected paraprotein-related diseases. Other serologies, such as antineutrophil cytoplasmic antibodies or antiglomerular basement membrane antibodies, would not necessarily be indicated here given the lack of hematuria and presence of nephrotic-range proteinuria.
► Dr. Li. The initial evaluation was notable for an erythrocyte sedimentation rate > 120 (mm/h) and a weakly positive antinuclear antibody (ANA) titer of 1:40. The remainder of his initial workup did not reveal an etiology for his nephrotic syndrome (Table 3).
Dr. William, is there a role for starting urgent empiric steroids in nephrotic syndrome while workup is ongoing? If so, do the severity of proteinuria and/or symptoms play a role or is this determination based on something else?
► Dr. William. Edema is a primary symptom of nephrotic syndrome and can often be managed with diuretics alone. If a clear medication-mediated cause is suspected, discontinuation of this agent may result in spontaneous improvement without steroid treatment. However,in cases where an etiology is unclear and there are serious thrombotic complications requiring anticoagulation, and a renal biopsy is deemed to be too risky, then empiric steroid therapy may be necessary. Children with new-onset nephrotic syndrome are presumed to have minimal change disease, given its prevalence in this patient population, and are often given empiric steroids without obtaining a renal biopsy. However, in the adult population, a renal biopsy can typically be performed quickly and safely, with pathology results interpreted within days. In this patient, since a diagnosis was unclear and there was no contraindication to renal biopsy, a biopsy should be obtained before consideration of steroids.
► Dr. Li. Steroids were deferred in anticipation of renal biopsy, which showed stage I membranous nephropathy, suggestive of membranous lupus nephritis Class V. The deposits were strongly reactive for immunoglobuline G (IgG), IgA, and complement 1q (C1q), showed co-dominant staining for IgG1, IgG2, and IgG3, and were weakly positive for the PLA2 receptor. Focal intimal arteritis in a small interlobular vessel was seen.
Dr. William, the pathology returned suggestive of lupus nephritis. Does the overall clinical picture fit with lupus nephritis?
► Dr. William. Given the history and a rather low ANA, the diagnosis of lupus nephritis seems unlikely. The lack of IgG4 and PLA2R staining in the biopsy suggests that this membranous pattern on the biopsy is likely to be secondary to a systemic etiology, but further investigation should be pursued.
► Dr. Li. The patient was discharged after the biopsy with a planned outpatient nephrology follow-up to discuss results and treatment. He was prescribed an oral diuretic, and his symptoms improved. Several days after discharge, he developed blurry vision and was evaluated in the Ophthalmology clinic. On fundoscopy, he was found to have acute papillitis, a form of optic neuritis. As part of initial evaluation of infectious etiologies of papillitis, ophthalmology recommended testing for syphilis.
Dr. Strymish, when we are considering secondary syphilis, what is the recommended approach to diagnostic testing?
► Judith Strymish, MD, Infectious Diseases, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The diagnosis of syphilis is usually made through serologic testing of blood specimens. Methods that detect the spirochete directly like dark-field smears are not readily available. Serologic tests include treponemal tests (eg, Treponema pallidum particle agglutination assay [TPPA]) and nontreponemal tests (eg, rapid plasma reagin [RPR]). One needs a confirmatory test because either test is associated with false positives. Either test can be done first. Most laboratories, including those at VABHS are now performing treponemal tests first as these have become more cost-effective.6 The TPPA treponemal test was found to have a lower false negative rate in primary syphilis compared with that of nontreponemal tests.7 Nontreponemal tests can be followed for response to therapy. If a patient has a history of treated syphilis, a nontreponemal test should be sent, since the treponemal test will remain positive for life.
If there is clinical concern for neurosyphilis, cerebrospinal fluid fluorescent (CSF) treponemal antibody needs to be sampled and sent for the nontreponemal venereal disease research laboratory (VDRL) test. The VDRL is highly specific for neurosyphilis but not as sensitive. Cerebrospinal fluid fluorescent treponemal antibody (CSF FTA) may also be sent; it is very sensitive but not very specific for neurosyphilis.
► Dr. Li. An RPR returned positive at 1:512 (was negative 14 months prior on a routine screening test), with positive reflex TPPA (Table 4). A diagnosis of secondary syphilis was made. Dr. Strymish, at this point, what additional testing and treatment is necessary?
► Dr. Strymish. With papillitis and a very high RPR, we need to assume that he has ophthalmic syphilis. This can occur in any stage of syphilis, but his eye findings and high RPR are consistent with secondary syphilis. Ophthalmic syphilis has been on the upswing, even more than is expected with recent increases in syphilis cases.8 Ophthalmic syphilis is considered a form of neurosyphilis. A lumbar puncture and treatment for neurosyphilis is recommended.9,10
► Dr. Li. A lumbar puncture was performed, and his CSF was VDRL positive. This confirmed a diagnosis of neurosyphilis (Table 4). The patient was treated for neurosyphilis with IV penicillin. The patient shared that he had episodes of unprotected oral sexual activity within the past year and approximately 1 year ago, he came in close contact (but no sexual activity) with a person who had a rash consistent with syphilis.Dr. William, syphilis would be a potential unifying diagnosis of his renal and ophthalmologic manifestations. Is syphilis known to cause membranous nephropathy?
► Dr. William. Though it is uncommon, the nephrotic syndrome is a well-described complication of secondary syphilis.11,12 Syphilis has been shown to cause nephrotic syndrome in a variety of ways. Case reports abound linking syphilis to minimal change disease and other glomerular diseases.13,14 A case report from 1993 shows a membranous pattern of glomerular disease similar to this case.15 As a form of secondary membranous nephropathy, the immunofluorescence pattern can demonstrate staining similar to the “full house” seen in lupus nephritis (IgA, IgM, and C1q, in addition to IgG and C3).16 This explains the initial interpretation of this patient’s biopsy, as lupus nephritis would be a much more common etiology of secondary membranous nephropathy than is acute syphilis with this immunofluorescence pattern. However, the data in this case are highly suggestive of a causal relationship between secondary syphilis and membranous nephropathy.
► Dr. Li. Dr. Strymish, how should this patient be screened for syphilis reinfection, and at what intervals would you recommend?
► Dr. Strymish. He will need follow-up testing to make sure that his syphilis is effectively treated. If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. He will also need follow-up for normalization of his RPR. Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy according to US Centers for Disease Control and Prevention guidelines.9
His treponemal test for syphilis will likely stay positive for life. His RPR should decrease significantly with effective treatment. It makes sense to screen with RPR alone as long as he continues to have risk factors for acquiring syphilis. Routine syphilis testing is recommended for pregnant women, sexually active men who have sex with men, sexually active persons with HIV, and persons taking PrEP (pre-exposure prophylaxis) for HIV prevention. He should be screened at least yearly for syphilis.
► Dr. Li. Over the next several months, the patient’s creatinine normalized and his proteinuria resolved. His vision recovered, and he has had no further ophthalmologic complications.
Dr. William, what is his long-term renal prognosis? Do you expect that his acute episode of membranous nephropathy will have permanent effects on his renal function?
► Dr. William. His rapid response to therapy for neurosyphilis provides evidence for this etiology of his renal dysfunction and glomerulonephritis. His long-term prognosis is quite good if the syphilis is the only reason for him to have renal disease. The renal damage is often reversible in these cases. However, given his prior extensive NSAID exposure and history of hypertension, he may be at higher risk for chronic kidney disease than an otherwise healthy patient, especially after an episode of acute kidney injury. Therefore, his renal function should continue to be monitored as an outpatient.
Acknowledgments
The authors thank this veteran for sharing his story and allowing us to learn from this unusual case for the benefit of our future patients.
*This article has been corrected to include a missing author.
Case Presentation. A 63-year-old male with well-controlled HIV (CD4 count 757, undetectable viral load), epilepsy, and hypertension presented to the VA Boston Healthcare System (VABHS) emergency department with 1 week of bilateral leg swelling and exertional shortness of breath. He reported having no fever, cough, chest pain, pain with inspiration and orthopnea. There was no personal or family history of pulmonary embolism. He reported weight gain but was unable to quantify how much. He also reported flare up of chronic knee pain, without swelling for which he had taken up to 4 tablets of naproxen daily for several weeks. His physical examination was notable for a heart rate of 105 beats per minute and bilateral pitting edema to his knees. Laboratory testing revealed a creatinine level of 2.5 mg/dL, which was increased from a baseline of 1.0 mg/dL (Table 1), and a urine protein-to-creatinine ratio of 7.8 mg/mg (Table 2). A renal ultrasound showed normal-sized kidneys without hydronephrosis or obstructing renal calculi. The patient was admitted for further workup of his dyspnea and acute kidney injury.
► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. William, based on the degree of proteinuria and edema, a diagnosis of nephrotic syndrome was made. How is nephrotic syndrome defined, and how is it distinguished from glomerulonephritis?
► Jeffrey William, MD, Nephrologist, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The pathophysiology of nephrotic disease and glomerulonephritis are quite distinct, resulting in symptoms and systemic manifestations that only slightly overlap. Glomerulonephritis is characterized by inflammation of the endothelial cells of the trilayered glomerular capillary, with a resulting active urine sediment with red blood cells, white blood cells, and casts. Nephrotic syndrome mostly affects the visceral epithelial cells of the glomerular capillary, commonly referred to as podocytes, and hence, the urine sediment in nephrotic disease is often inactive. Patients with nephrotic syndrome have nephrotic-range proteinuria (excretion of > 3.5 g per 24 h or a spot urine protein-creatinine ratio > 3.5 g in the steady state) and both hypoalbuminemia (< 3 g/dL) and peripheral edema. Lipiduria and hyperlipidemia are common findings in nephrotic syndrome but are not required for a clinical diagnosis.1 In contrast, glomerulonephritis is defined by a constellation of findings that include renal insufficiency (often indicated by an elevation in blood urea nitrogen and creatinine), hypertension, hematuria, and subnephrotic range proteinuria. In practice, patients may fulfill criteria of both nephrotic and nephritic syndromes, but the preponderance of clinical evidence often points one way or the other. In this case, nephrotic syndrome was diagnosed based on the urine protein-to-creatinine ratio of 7.8 mg/mg, hypoalbuminemia, and edema.
► Dr. Li. What would be your first-line workup for evaluation of the etiology of this patient’s nephrotic syndrome?
► Dr. William. Rather than memorizing a list of etiologies of nephrotic syndrome, it is essential to consider the pathophysiology of heavy proteinuria. Though the glomerular filtration barrier is extremely complex and defects in any component can cause proteinuria, disruption of the podocyte is often involved. Common disease processes that chiefly target the podocyte include minimal change disease, primary focal and segmental glomerulosclerosis (FSGS), and membranous nephropathy, all by differing mechanisms. Minimal change disease and idiopathic/primary FSGS are increasingly thought to be at differing points on a spectrum of the same disease.2 Secondary FSGS, on the other hand, is a progressive disease, commonly resulting from longstanding hypertension, diabetes mellitus, and obesity in adults. Membranous nephropathy can also be either primary or secondary. Primary membranous nephropathy is chiefly caused by a circulating IgG4 antibody to the podocyte membrane antigen PLA2R (M-type phospholipase A2 receptor), whereas secondary membranous nephropathy can be caused by a variety of systemic etiologies, including autoimmune disease (eg, systemic lupus erythematosus), certain malignancies, chronic infections (eg, hepatitis B and C), and many medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).3-5 Paraprotein deposition diseases can also cause glomerular damage leading to nephrotic-range proteinuria.
Given these potential diagnoses, a careful history should be taken to assess exposures and recent medication use. Urine sediment evaluation is essential in the evaluation of nephrotic syndrome to determine if there is an underlying nephritic process. Select serologies may be sent to look for autoimmune disease, such as systemic lupus erythematosus and common viral exposures like hepatitis B or C. Serum and urine protein electrophoreses would be appropriate initial tests of suspected paraprotein-related diseases. Other serologies, such as antineutrophil cytoplasmic antibodies or antiglomerular basement membrane antibodies, would not necessarily be indicated here given the lack of hematuria and presence of nephrotic-range proteinuria.
► Dr. Li. The initial evaluation was notable for an erythrocyte sedimentation rate > 120 (mm/h) and a weakly positive antinuclear antibody (ANA) titer of 1:40. The remainder of his initial workup did not reveal an etiology for his nephrotic syndrome (Table 3).
Dr. William, is there a role for starting urgent empiric steroids in nephrotic syndrome while workup is ongoing? If so, do the severity of proteinuria and/or symptoms play a role or is this determination based on something else?
► Dr. William. Edema is a primary symptom of nephrotic syndrome and can often be managed with diuretics alone. If a clear medication-mediated cause is suspected, discontinuation of this agent may result in spontaneous improvement without steroid treatment. However,in cases where an etiology is unclear and there are serious thrombotic complications requiring anticoagulation, and a renal biopsy is deemed to be too risky, then empiric steroid therapy may be necessary. Children with new-onset nephrotic syndrome are presumed to have minimal change disease, given its prevalence in this patient population, and are often given empiric steroids without obtaining a renal biopsy. However, in the adult population, a renal biopsy can typically be performed quickly and safely, with pathology results interpreted within days. In this patient, since a diagnosis was unclear and there was no contraindication to renal biopsy, a biopsy should be obtained before consideration of steroids.
► Dr. Li. Steroids were deferred in anticipation of renal biopsy, which showed stage I membranous nephropathy, suggestive of membranous lupus nephritis Class V. The deposits were strongly reactive for immunoglobuline G (IgG), IgA, and complement 1q (C1q), showed co-dominant staining for IgG1, IgG2, and IgG3, and were weakly positive for the PLA2 receptor. Focal intimal arteritis in a small interlobular vessel was seen.
Dr. William, the pathology returned suggestive of lupus nephritis. Does the overall clinical picture fit with lupus nephritis?
► Dr. William. Given the history and a rather low ANA, the diagnosis of lupus nephritis seems unlikely. The lack of IgG4 and PLA2R staining in the biopsy suggests that this membranous pattern on the biopsy is likely to be secondary to a systemic etiology, but further investigation should be pursued.
► Dr. Li. The patient was discharged after the biopsy with a planned outpatient nephrology follow-up to discuss results and treatment. He was prescribed an oral diuretic, and his symptoms improved. Several days after discharge, he developed blurry vision and was evaluated in the Ophthalmology clinic. On fundoscopy, he was found to have acute papillitis, a form of optic neuritis. As part of initial evaluation of infectious etiologies of papillitis, ophthalmology recommended testing for syphilis.
Dr. Strymish, when we are considering secondary syphilis, what is the recommended approach to diagnostic testing?
► Judith Strymish, MD, Infectious Diseases, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The diagnosis of syphilis is usually made through serologic testing of blood specimens. Methods that detect the spirochete directly like dark-field smears are not readily available. Serologic tests include treponemal tests (eg, Treponema pallidum particle agglutination assay [TPPA]) and nontreponemal tests (eg, rapid plasma reagin [RPR]). One needs a confirmatory test because either test is associated with false positives. Either test can be done first. Most laboratories, including those at VABHS are now performing treponemal tests first as these have become more cost-effective.6 The TPPA treponemal test was found to have a lower false negative rate in primary syphilis compared with that of nontreponemal tests.7 Nontreponemal tests can be followed for response to therapy. If a patient has a history of treated syphilis, a nontreponemal test should be sent, since the treponemal test will remain positive for life.
If there is clinical concern for neurosyphilis, cerebrospinal fluid fluorescent (CSF) treponemal antibody needs to be sampled and sent for the nontreponemal venereal disease research laboratory (VDRL) test. The VDRL is highly specific for neurosyphilis but not as sensitive. Cerebrospinal fluid fluorescent treponemal antibody (CSF FTA) may also be sent; it is very sensitive but not very specific for neurosyphilis.
► Dr. Li. An RPR returned positive at 1:512 (was negative 14 months prior on a routine screening test), with positive reflex TPPA (Table 4). A diagnosis of secondary syphilis was made. Dr. Strymish, at this point, what additional testing and treatment is necessary?
► Dr. Strymish. With papillitis and a very high RPR, we need to assume that he has ophthalmic syphilis. This can occur in any stage of syphilis, but his eye findings and high RPR are consistent with secondary syphilis. Ophthalmic syphilis has been on the upswing, even more than is expected with recent increases in syphilis cases.8 Ophthalmic syphilis is considered a form of neurosyphilis. A lumbar puncture and treatment for neurosyphilis is recommended.9,10
► Dr. Li. A lumbar puncture was performed, and his CSF was VDRL positive. This confirmed a diagnosis of neurosyphilis (Table 4). The patient was treated for neurosyphilis with IV penicillin. The patient shared that he had episodes of unprotected oral sexual activity within the past year and approximately 1 year ago, he came in close contact (but no sexual activity) with a person who had a rash consistent with syphilis.Dr. William, syphilis would be a potential unifying diagnosis of his renal and ophthalmologic manifestations. Is syphilis known to cause membranous nephropathy?
► Dr. William. Though it is uncommon, the nephrotic syndrome is a well-described complication of secondary syphilis.11,12 Syphilis has been shown to cause nephrotic syndrome in a variety of ways. Case reports abound linking syphilis to minimal change disease and other glomerular diseases.13,14 A case report from 1993 shows a membranous pattern of glomerular disease similar to this case.15 As a form of secondary membranous nephropathy, the immunofluorescence pattern can demonstrate staining similar to the “full house” seen in lupus nephritis (IgA, IgM, and C1q, in addition to IgG and C3).16 This explains the initial interpretation of this patient’s biopsy, as lupus nephritis would be a much more common etiology of secondary membranous nephropathy than is acute syphilis with this immunofluorescence pattern. However, the data in this case are highly suggestive of a causal relationship between secondary syphilis and membranous nephropathy.
► Dr. Li. Dr. Strymish, how should this patient be screened for syphilis reinfection, and at what intervals would you recommend?
► Dr. Strymish. He will need follow-up testing to make sure that his syphilis is effectively treated. If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. He will also need follow-up for normalization of his RPR. Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy according to US Centers for Disease Control and Prevention guidelines.9
His treponemal test for syphilis will likely stay positive for life. His RPR should decrease significantly with effective treatment. It makes sense to screen with RPR alone as long as he continues to have risk factors for acquiring syphilis. Routine syphilis testing is recommended for pregnant women, sexually active men who have sex with men, sexually active persons with HIV, and persons taking PrEP (pre-exposure prophylaxis) for HIV prevention. He should be screened at least yearly for syphilis.
► Dr. Li. Over the next several months, the patient’s creatinine normalized and his proteinuria resolved. His vision recovered, and he has had no further ophthalmologic complications.
Dr. William, what is his long-term renal prognosis? Do you expect that his acute episode of membranous nephropathy will have permanent effects on his renal function?
► Dr. William. His rapid response to therapy for neurosyphilis provides evidence for this etiology of his renal dysfunction and glomerulonephritis. His long-term prognosis is quite good if the syphilis is the only reason for him to have renal disease. The renal damage is often reversible in these cases. However, given his prior extensive NSAID exposure and history of hypertension, he may be at higher risk for chronic kidney disease than an otherwise healthy patient, especially after an episode of acute kidney injury. Therefore, his renal function should continue to be monitored as an outpatient.
Acknowledgments
The authors thank this veteran for sharing his story and allowing us to learn from this unusual case for the benefit of our future patients.
1. Rennke H, Denker BM. Renal Pathophysiology: The Essentials. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2014.
2. Maas RJ, Deegens JK, Smeets B, Moeller MJ, Wetzels JF. Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat Rev Nephrol. 2016;12(12):768-776.
3. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21.
4. Rennke HG. Secondary membranoproliferative glomerulonephritis. Kidney Int. 1995;47(2):643-656.
5. Nawaz FA, Larsen CP, Troxell ML. Membranous nephropathy and nonsteroidal anti-inflammatory agents. Am J Kidney Dis. 2013;62(5):1012-1017.
6. Pillay A. Centers for Disease Control and Prevention Syphilis Summit—Diagnostics and laboratory issues. Sex Transm Dis. 2018;45(9S)(suppl 1):S13-S16.
7. Levett PN, Fonseca K, Tsang RS, et al. Canadian Public Health Laboratory Network laboratory guidelines for the use of serological tests (excluding point-of-care tests) for the diagnosis of syphilis in Canada. Can J Infect Dis Med Microbiol. 2015;26(suppl A):6A-12A.
8. Oliver SE, Aubin M, Atwell L, et al. Ocular syphilis—eight jurisdictions, United States, 2014-2015. MMWR Morb Mortal Wkly Rep. 2016;65(43):1185-1188.
9. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recommendations and Reports 2015;64(RR3):1-137. [Erratum in MMWR Recomm Rep. 2015;64(33):924.]
10. US Centers for Disease Control and Prevention. Clinical advisory: ocular syphilis in the United States. https://www.cdc.gov/std/syphilis/clinicaladvisoryos2015.htm. Updated March 24, 2016. Accessed August 12, 2019.
11. Braunstein GD, Lewis EJ, Galvanek EG, Hamilton A, Bell WR. The nephrotic syndrome associated with secondary syphilis: an immune deposit disease. Am J Med. 1970;48:643-648.1.
12. Handoko ML, Duijvestein M, Scheepstra CG, de Fijter CW. Syphilis: a reversible cause of nephrotic syndrome. BMJ Case Rep. 2013;2013:pii:bcr2012008279
13. Krane NK, Espenan P, Walker PD, Bergman SM, Wallin JD. Renal disease and syphilis: a report of nephrotic syndrome with minimal change disease. Am J Kidney Dis. 1987;9(2):176-179.
14. Bhorade MS, Carag HB, Lee HJ, Potter EV, Dunea G. Nephropathy of secondary syphilis: a clinical and pathological spectrum. JAMA. 1971;216(7):1159-1166.
15. Hunte W, al-Ghraoui F, Cohen RJ. Secondary syphilis and the nephrotic syndrome. J Am Soc Nephrol. 1993;3(7):1351-1355.
16. Gamble CN, Reardan JB. Immunopathogenesis of syphilitic glomerulonephritis. Elution of antitreponemal antibody from glomerular immune-complex deposits. N Engl J Med. 1975;292(9):449-454.
1. Rennke H, Denker BM. Renal Pathophysiology: The Essentials. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2014.
2. Maas RJ, Deegens JK, Smeets B, Moeller MJ, Wetzels JF. Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat Rev Nephrol. 2016;12(12):768-776.
3. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21.
4. Rennke HG. Secondary membranoproliferative glomerulonephritis. Kidney Int. 1995;47(2):643-656.
5. Nawaz FA, Larsen CP, Troxell ML. Membranous nephropathy and nonsteroidal anti-inflammatory agents. Am J Kidney Dis. 2013;62(5):1012-1017.
6. Pillay A. Centers for Disease Control and Prevention Syphilis Summit—Diagnostics and laboratory issues. Sex Transm Dis. 2018;45(9S)(suppl 1):S13-S16.
7. Levett PN, Fonseca K, Tsang RS, et al. Canadian Public Health Laboratory Network laboratory guidelines for the use of serological tests (excluding point-of-care tests) for the diagnosis of syphilis in Canada. Can J Infect Dis Med Microbiol. 2015;26(suppl A):6A-12A.
8. Oliver SE, Aubin M, Atwell L, et al. Ocular syphilis—eight jurisdictions, United States, 2014-2015. MMWR Morb Mortal Wkly Rep. 2016;65(43):1185-1188.
9. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recommendations and Reports 2015;64(RR3):1-137. [Erratum in MMWR Recomm Rep. 2015;64(33):924.]
10. US Centers for Disease Control and Prevention. Clinical advisory: ocular syphilis in the United States. https://www.cdc.gov/std/syphilis/clinicaladvisoryos2015.htm. Updated March 24, 2016. Accessed August 12, 2019.
11. Braunstein GD, Lewis EJ, Galvanek EG, Hamilton A, Bell WR. The nephrotic syndrome associated with secondary syphilis: an immune deposit disease. Am J Med. 1970;48:643-648.1.
12. Handoko ML, Duijvestein M, Scheepstra CG, de Fijter CW. Syphilis: a reversible cause of nephrotic syndrome. BMJ Case Rep. 2013;2013:pii:bcr2012008279
13. Krane NK, Espenan P, Walker PD, Bergman SM, Wallin JD. Renal disease and syphilis: a report of nephrotic syndrome with minimal change disease. Am J Kidney Dis. 1987;9(2):176-179.
14. Bhorade MS, Carag HB, Lee HJ, Potter EV, Dunea G. Nephropathy of secondary syphilis: a clinical and pathological spectrum. JAMA. 1971;216(7):1159-1166.
15. Hunte W, al-Ghraoui F, Cohen RJ. Secondary syphilis and the nephrotic syndrome. J Am Soc Nephrol. 1993;3(7):1351-1355.
16. Gamble CN, Reardan JB. Immunopathogenesis of syphilitic glomerulonephritis. Elution of antitreponemal antibody from glomerular immune-complex deposits. N Engl J Med. 1975;292(9):449-454.
HIV drug may enhance efficacy of chemoradiation in locally advanced lung cancer
Administering an HIV drug concurrently with chemoradiotherapy resulted in promising local control and overall survival in patients with unresectable, locally advanced non–small cell lung cancer, researchers reported.
There was no overt exacerbation of the toxic effects of chemoradiotherapy with the addition of nelfinavir, a protease inhibitor, in the prospective, open-label, phase 1/2 study, the researchers wrote.
Nelfinavir plus chemoradiotherapy yielded a median progression-free survival of 11.7 months and median survival of 41.1 months, while the cumulative local failure incidence was 39% according to their report.
Those outcomes compare favorably with historical data, the investigators wrote in JAMA Oncology.
In benchmark results of the RTOG 0617 study of chemoradiotherapy in locally advanced non–small cell lung cancer, median overall survival was 28.7 months receiving radiotherapy at a standard dose of 60 Gy, and 20.3 months for those receiving high-dose (74 Gy) radiotherapy.
However, a randomized, phase 3 trial is needed to confirm these latest results with a protease inhibitor added to chemotherapy, according to Ramesh Rengan, MD, PhD, of the University of Washington, Seattle, and coinvestigators.
“As nelfinavir is a U.S. Food and Drug Administration–approved oral drug, this treatment approach is feasible and is potentially a readily exportable platform for daily clinical use,” Dr. Rengan and coauthors wrote.
In vitro and in vivo studies have shown that nelfinavir inhibited PI3K and Akt signaling, sensitized tumor cells to ionizing radiation, and improved tumor perfusion in animal models. “We hypothesize that it is these properties that drive the clinical results observed in this study,” Dr. Rengan and coauthors wrote.
They reported on a total of 35 patients with stage IIIA/IIIB non–small cell lung cancer who received nelfinavir at either 625 mg or 1,250 mg twice daily, starting 7-14 days before starting radiotherapy to 66.6 Gy at 1.8 Gy per fraction, and throughout the full course of radiotherapy.
There were no dose-limiting toxic effects observed in the study, and toxic effects were “acceptable,” with no grade 4 nonhematologic toxic effects seen, according to investigators. Leukopenia was the primary grade 3-4 hematologic toxic effect, observed in 2 of 5 patients receiving the lower nelfinavir dose and 18 of 30 at the higher dose.
Beyond non–small cell lung cancer, the efficacy and safety nelfinavir given concurrently with radiotherapy has been looked at in other disease settings. Data from those trials suggest that this protease inhibitor could “augment tumor response” not only in non–small cell lung cancer, but in locally advanced pancreatic cancer and glioblastoma, all of which are relatively radioresistant, according to Dr. Rengan and colleagues.
Study support came from grants from the National Institutes of Health and Abramson Cancer Center, and an American Society for Radiation Oncology training award to Dr. Rengan. Study authors reported disclosures related to Pfizer, 511 Pharma, Progenics Pharmaceuticals, Siemens, Actinium, AstraZeneca, Merck, Bristol-Myers Squibb, and others.
SOURCE: Rengan R et al. JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.2095.
Administering an HIV drug concurrently with chemoradiotherapy resulted in promising local control and overall survival in patients with unresectable, locally advanced non–small cell lung cancer, researchers reported.
There was no overt exacerbation of the toxic effects of chemoradiotherapy with the addition of nelfinavir, a protease inhibitor, in the prospective, open-label, phase 1/2 study, the researchers wrote.
Nelfinavir plus chemoradiotherapy yielded a median progression-free survival of 11.7 months and median survival of 41.1 months, while the cumulative local failure incidence was 39% according to their report.
Those outcomes compare favorably with historical data, the investigators wrote in JAMA Oncology.
In benchmark results of the RTOG 0617 study of chemoradiotherapy in locally advanced non–small cell lung cancer, median overall survival was 28.7 months receiving radiotherapy at a standard dose of 60 Gy, and 20.3 months for those receiving high-dose (74 Gy) radiotherapy.
However, a randomized, phase 3 trial is needed to confirm these latest results with a protease inhibitor added to chemotherapy, according to Ramesh Rengan, MD, PhD, of the University of Washington, Seattle, and coinvestigators.
“As nelfinavir is a U.S. Food and Drug Administration–approved oral drug, this treatment approach is feasible and is potentially a readily exportable platform for daily clinical use,” Dr. Rengan and coauthors wrote.
In vitro and in vivo studies have shown that nelfinavir inhibited PI3K and Akt signaling, sensitized tumor cells to ionizing radiation, and improved tumor perfusion in animal models. “We hypothesize that it is these properties that drive the clinical results observed in this study,” Dr. Rengan and coauthors wrote.
They reported on a total of 35 patients with stage IIIA/IIIB non–small cell lung cancer who received nelfinavir at either 625 mg or 1,250 mg twice daily, starting 7-14 days before starting radiotherapy to 66.6 Gy at 1.8 Gy per fraction, and throughout the full course of radiotherapy.
There were no dose-limiting toxic effects observed in the study, and toxic effects were “acceptable,” with no grade 4 nonhematologic toxic effects seen, according to investigators. Leukopenia was the primary grade 3-4 hematologic toxic effect, observed in 2 of 5 patients receiving the lower nelfinavir dose and 18 of 30 at the higher dose.
Beyond non–small cell lung cancer, the efficacy and safety nelfinavir given concurrently with radiotherapy has been looked at in other disease settings. Data from those trials suggest that this protease inhibitor could “augment tumor response” not only in non–small cell lung cancer, but in locally advanced pancreatic cancer and glioblastoma, all of which are relatively radioresistant, according to Dr. Rengan and colleagues.
Study support came from grants from the National Institutes of Health and Abramson Cancer Center, and an American Society for Radiation Oncology training award to Dr. Rengan. Study authors reported disclosures related to Pfizer, 511 Pharma, Progenics Pharmaceuticals, Siemens, Actinium, AstraZeneca, Merck, Bristol-Myers Squibb, and others.
SOURCE: Rengan R et al. JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.2095.
Administering an HIV drug concurrently with chemoradiotherapy resulted in promising local control and overall survival in patients with unresectable, locally advanced non–small cell lung cancer, researchers reported.
There was no overt exacerbation of the toxic effects of chemoradiotherapy with the addition of nelfinavir, a protease inhibitor, in the prospective, open-label, phase 1/2 study, the researchers wrote.
Nelfinavir plus chemoradiotherapy yielded a median progression-free survival of 11.7 months and median survival of 41.1 months, while the cumulative local failure incidence was 39% according to their report.
Those outcomes compare favorably with historical data, the investigators wrote in JAMA Oncology.
In benchmark results of the RTOG 0617 study of chemoradiotherapy in locally advanced non–small cell lung cancer, median overall survival was 28.7 months receiving radiotherapy at a standard dose of 60 Gy, and 20.3 months for those receiving high-dose (74 Gy) radiotherapy.
However, a randomized, phase 3 trial is needed to confirm these latest results with a protease inhibitor added to chemotherapy, according to Ramesh Rengan, MD, PhD, of the University of Washington, Seattle, and coinvestigators.
“As nelfinavir is a U.S. Food and Drug Administration–approved oral drug, this treatment approach is feasible and is potentially a readily exportable platform for daily clinical use,” Dr. Rengan and coauthors wrote.
In vitro and in vivo studies have shown that nelfinavir inhibited PI3K and Akt signaling, sensitized tumor cells to ionizing radiation, and improved tumor perfusion in animal models. “We hypothesize that it is these properties that drive the clinical results observed in this study,” Dr. Rengan and coauthors wrote.
They reported on a total of 35 patients with stage IIIA/IIIB non–small cell lung cancer who received nelfinavir at either 625 mg or 1,250 mg twice daily, starting 7-14 days before starting radiotherapy to 66.6 Gy at 1.8 Gy per fraction, and throughout the full course of radiotherapy.
There were no dose-limiting toxic effects observed in the study, and toxic effects were “acceptable,” with no grade 4 nonhematologic toxic effects seen, according to investigators. Leukopenia was the primary grade 3-4 hematologic toxic effect, observed in 2 of 5 patients receiving the lower nelfinavir dose and 18 of 30 at the higher dose.
Beyond non–small cell lung cancer, the efficacy and safety nelfinavir given concurrently with radiotherapy has been looked at in other disease settings. Data from those trials suggest that this protease inhibitor could “augment tumor response” not only in non–small cell lung cancer, but in locally advanced pancreatic cancer and glioblastoma, all of which are relatively radioresistant, according to Dr. Rengan and colleagues.
Study support came from grants from the National Institutes of Health and Abramson Cancer Center, and an American Society for Radiation Oncology training award to Dr. Rengan. Study authors reported disclosures related to Pfizer, 511 Pharma, Progenics Pharmaceuticals, Siemens, Actinium, AstraZeneca, Merck, Bristol-Myers Squibb, and others.
SOURCE: Rengan R et al. JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.2095.
FROM JAMA ONCOLOGY
HCV coinfection adds to cardiovascular risk in HIV-infected patients
Hepatitis C virus (HCV) coinfection, as well as an accumulation of viral and bacterial infections, was independently associated with the risk of developing a cardiovascular event in HIV-infected patients, according to the results of a large retrospective analysis.
The study comprised 823 patients at a single institution during 1982-2018. The researchers assessed those patients who had at least two visits to the HIV clinic, data concerning herpes varicella zoster virus (VZV) reactivation, and bacterial infections. Data on HCV coinfection status (as determined by HCV antibodies and qualitative HCV-PCR) were also available, according to Miguel Genebat, MD, of Virgen del Rocío University Hospital, Seville, Spain, and colleagues.
During the observational period, 58 patients (7%) experienced a cardiovascular event at a median age of 47 years. Most of these patients (50, 86%) had effective HIV treatment, with their viral load being persistently undetectable.
In terms of standard cardiovascular disease (CVD) risk factors, hypercholesterolemia was present in 31 patients (53%) and only 11 subjects (19%) had diabetes. This left 24 “low-risk” subjects, 5 of whom (21%) developed recurrent CVD and 8 of whom (33%) died after the development of cardiovascular disease.
The most frequent cardiovascular event was acute coronary syndrome (ACS), developed by 38 patients, with 14 (24%) of these individuals having recurrent CVD events. Among the 58 patients who experienced a cardiovascular event, 21 (36%) died, 17 from cardiovascular disease, 2 from cancer, and 2 each from acute bacterial infection and end-stage liver disease.
The researchers examined other variables potentially associated with the development of cardiovascular disease. They performed a multivariate analysis considering the added burden of infections and found that advanced age at HIV-1 diagnosis (OR, 1.07), a T-CD4 nadir of less than 200 cells/mcL (OR, 2.01), a diagnosis of HIV prior to combined antiretroviral therapy availability in 1996 (OR, 2.35), and cumulative infections greater than 2 (OR, 3.63), were all significantly and independently associated with the risk of developing a cardiovascular event.
They also found that HCV coinfection (OR, 2.84) on its own in simple multivariate analysis increased the risk of developing a CVD event in HIV-infected subjects. There was insufficient power to tease out the individual risk of other infections, such as herpes zoster virus and bacterial infections, hence the use of cumulative infections reported above.
The researchers concluded that potential strategies to minimize cardiovascular risk in these subjects could be treating HCV coinfection in all subjects independently of liver fibrosis stage, starting cART as soon as possible, and immunizing for those infections for which effective vaccine are available.
The authors reported that they had no conflicts of interest.
SOURCE: Genebat M. et al. Antiviral Res. 2019 Sep;169:104527.
Hepatitis C virus (HCV) coinfection, as well as an accumulation of viral and bacterial infections, was independently associated with the risk of developing a cardiovascular event in HIV-infected patients, according to the results of a large retrospective analysis.
The study comprised 823 patients at a single institution during 1982-2018. The researchers assessed those patients who had at least two visits to the HIV clinic, data concerning herpes varicella zoster virus (VZV) reactivation, and bacterial infections. Data on HCV coinfection status (as determined by HCV antibodies and qualitative HCV-PCR) were also available, according to Miguel Genebat, MD, of Virgen del Rocío University Hospital, Seville, Spain, and colleagues.
During the observational period, 58 patients (7%) experienced a cardiovascular event at a median age of 47 years. Most of these patients (50, 86%) had effective HIV treatment, with their viral load being persistently undetectable.
In terms of standard cardiovascular disease (CVD) risk factors, hypercholesterolemia was present in 31 patients (53%) and only 11 subjects (19%) had diabetes. This left 24 “low-risk” subjects, 5 of whom (21%) developed recurrent CVD and 8 of whom (33%) died after the development of cardiovascular disease.
The most frequent cardiovascular event was acute coronary syndrome (ACS), developed by 38 patients, with 14 (24%) of these individuals having recurrent CVD events. Among the 58 patients who experienced a cardiovascular event, 21 (36%) died, 17 from cardiovascular disease, 2 from cancer, and 2 each from acute bacterial infection and end-stage liver disease.
The researchers examined other variables potentially associated with the development of cardiovascular disease. They performed a multivariate analysis considering the added burden of infections and found that advanced age at HIV-1 diagnosis (OR, 1.07), a T-CD4 nadir of less than 200 cells/mcL (OR, 2.01), a diagnosis of HIV prior to combined antiretroviral therapy availability in 1996 (OR, 2.35), and cumulative infections greater than 2 (OR, 3.63), were all significantly and independently associated with the risk of developing a cardiovascular event.
They also found that HCV coinfection (OR, 2.84) on its own in simple multivariate analysis increased the risk of developing a CVD event in HIV-infected subjects. There was insufficient power to tease out the individual risk of other infections, such as herpes zoster virus and bacterial infections, hence the use of cumulative infections reported above.
The researchers concluded that potential strategies to minimize cardiovascular risk in these subjects could be treating HCV coinfection in all subjects independently of liver fibrosis stage, starting cART as soon as possible, and immunizing for those infections for which effective vaccine are available.
The authors reported that they had no conflicts of interest.
SOURCE: Genebat M. et al. Antiviral Res. 2019 Sep;169:104527.
Hepatitis C virus (HCV) coinfection, as well as an accumulation of viral and bacterial infections, was independently associated with the risk of developing a cardiovascular event in HIV-infected patients, according to the results of a large retrospective analysis.
The study comprised 823 patients at a single institution during 1982-2018. The researchers assessed those patients who had at least two visits to the HIV clinic, data concerning herpes varicella zoster virus (VZV) reactivation, and bacterial infections. Data on HCV coinfection status (as determined by HCV antibodies and qualitative HCV-PCR) were also available, according to Miguel Genebat, MD, of Virgen del Rocío University Hospital, Seville, Spain, and colleagues.
During the observational period, 58 patients (7%) experienced a cardiovascular event at a median age of 47 years. Most of these patients (50, 86%) had effective HIV treatment, with their viral load being persistently undetectable.
In terms of standard cardiovascular disease (CVD) risk factors, hypercholesterolemia was present in 31 patients (53%) and only 11 subjects (19%) had diabetes. This left 24 “low-risk” subjects, 5 of whom (21%) developed recurrent CVD and 8 of whom (33%) died after the development of cardiovascular disease.
The most frequent cardiovascular event was acute coronary syndrome (ACS), developed by 38 patients, with 14 (24%) of these individuals having recurrent CVD events. Among the 58 patients who experienced a cardiovascular event, 21 (36%) died, 17 from cardiovascular disease, 2 from cancer, and 2 each from acute bacterial infection and end-stage liver disease.
The researchers examined other variables potentially associated with the development of cardiovascular disease. They performed a multivariate analysis considering the added burden of infections and found that advanced age at HIV-1 diagnosis (OR, 1.07), a T-CD4 nadir of less than 200 cells/mcL (OR, 2.01), a diagnosis of HIV prior to combined antiretroviral therapy availability in 1996 (OR, 2.35), and cumulative infections greater than 2 (OR, 3.63), were all significantly and independently associated with the risk of developing a cardiovascular event.
They also found that HCV coinfection (OR, 2.84) on its own in simple multivariate analysis increased the risk of developing a CVD event in HIV-infected subjects. There was insufficient power to tease out the individual risk of other infections, such as herpes zoster virus and bacterial infections, hence the use of cumulative infections reported above.
The researchers concluded that potential strategies to minimize cardiovascular risk in these subjects could be treating HCV coinfection in all subjects independently of liver fibrosis stage, starting cART as soon as possible, and immunizing for those infections for which effective vaccine are available.
The authors reported that they had no conflicts of interest.
SOURCE: Genebat M. et al. Antiviral Res. 2019 Sep;169:104527.
FROM ANTIVIRAL RESEARCH