Weight starts to weigh in
“I am very mindful of weight gain potential, and I talk to patients about it. It doesn’t determine what regimen I choose for a patient” right now, “but it’s only a matter of time before it starts influencing what we do, particularly if we can achieve efficacy with fewer drugs,” commented Babafemi O. Taiwo, MD, professor of medicine and chief of infectious diseases at Northwestern University in Chicago. “I’ve had some patients show up with a weight gain of 20 kg, and that shouldn’t happen,” he said during a recent online educational session. Dr. Taiwo said his recent practice has been to warn patients about possible weight gain and to urge them to get back in touch with him quickly if it happens.
“Virologic suppression is the most important goal with ART, and the U.S. Department of Health and Human Services currently recommends INSTI-based ART for most PWH [people with HIV],” wrote Dr. Lake in April 2020. “I counsel all PWH initiating ART about the potential for weight gain, and I discuss their current diet and healthy lifestyle habits. I explain to patients that we will monitor their weight, and if weight gain seems more than either of us are comfortable with then we will reassess. Only a small percentage of patients experience excessive weight gain after starting ART.” Dr. Lake also stressed that she had not yet begun to change the regimen a patient is on solely because of weight gain. “We do not know whether this weight gain is reversible,” she noted.
“I do not anticipate that a risk of weight gain at present will dictate a change in guidelines,” said Dr. Geretti. “Drugs such as dolutegravir and bictegravir are very effective, and they are unlikely to cause drug resistance. Further data on the mechanism of weight gain and the reversibility after a change of treatment will help refine drug selection in the near future,” she predicted.
“I consider weight gain when prescribing because my patients hear about this. It’s a side effect that my patients really care about, and I don’t blame them,” said Lisa Hightow-Weidman, MD, a professor and HIV specialist at the University of North Carolina at Chapel Hill, during an on-line educational session. “If you don’t discuss it with a patient and then weight gain happens and the patient finds out [the known risk from their treatment] they may have an issue,” she noted. But weight gain is not a reason to avoid these drugs. “They are great medications in many ways, with once-daily regimens and few side effects.”
Weight gain during pregnancy a special concern
An additional analysis of data from ADVANCE presented at the conference highlighted what the observed weight gain on ART could mean for women who become pregnant while on treatment. Based on a systematic literature review, the ADVANCE investigators calculated the relative risk for six obesity-related pregnancy complications, compared with nonobese women: preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, postpartum hemorrhage, and caesarean delivery. Based on the obesity changes among women on their assigned ART in ADVANCE, the researchers calculated the predicted incidence of these six complications. The analysis showed that for every 1,000 women, those on TAG-DTG-FTC would have an excess of 53 obesity-related pregnancy complications, those on TDF-DTG-FTC would develop 28 excess pregnancy complications, and those on TDG-EFV-FTC would have four excess complications, reported Dr. Hill at the International AIDS conference.
The researchers also ran a similar simulation for the incidence of neonatal complications that could result when mothers are obese because of their ART. The six neonatal complications included in this analysis were small for gestational age, large for gestational age, macrosomia, neonatal death, stillbirth, and neural tube defects. Based on the excess rate of incident obesity, they calculated that for every 1,000 pregnancies women on TAD-DTG-FTC would have 24 additional infants born with one of these complications, women on TDF-DTG-FTC would have an excess of 13 of these events, and women on TDG-EFV-FTC would have an excess of three such obesity-related neonatal complications, Dr. Hill said.
Sorting out the drugs
Results from several additional studies reported at the conference have started trying to discern exactly which ART drugs and regimens pose the greatest weight gain risk and which have the least risk while retaining high efficacy and resistance barriers.
Further evidence implicating any type of ART as a driver of increased weight came from a review of 8,256 adults infected with HIV and members of the Kaiser Permanente health system in three U.S. regions during 2000-2016. Researchers matched these cases using several demographic factors with just under 130,000 members without HIV. Those infected by HIV had half the prevalence of obesity as the matched controls at baseline. During 12 years of follow-up, those infected with HIV had a threefold higher rate of weight gain than those who were uninfected. Annual weight gain averaged 0.06 kg/year among the uninfected people and 0.22 kg/year among those infected with HIV, a statistically significant difference that was consistent regardless of whether people started the study at a normal body mass index, overweight, or obese, reported Michael J. Silverberg, PhD, an epidemiologist with Kaiser Permanente in Oakland, Calif.
Another study tried to focus on the weight gain impact when patients on three-drug ART regimens changed from taking TDF to TAF. This analysis used data collected in the OPERA (Observational Pharmaco-Epidemiology Research & Analysis) longitudinal cohort of about 115,000 U.S. PWH. The observational cohort included nearly 7,000 patients who made a TDF-to-TAF switch, including 3,288 patients who maintained treatment during this switch with an INSTI, 1,454 who maintained a background regimen based on a NNRTI, 1,430 patients who also switched from an INSTI to a different drug, and 747 patients maintained on a boosted dose of a protease inhibitor. All patients were well controlled on their baseline regimen, with at least two consecutive measures showing undetectable viral load.
Patients who maintained their background regimens while changing from TDF to TAF had a 2.0-2.6 kg increase in weight during the 9 months immediately following their switch to TAF, reported Patrick Mallon, MB, a professor of microbial diseases at University College Dublin. Among the patients who both switched to TAF and also switched to treatment with an INSTI, weight gain during the 9 months after the switch averaged 2.6-4.5 kg, depending on which INSTI was started. Patients who switched to treatment with elvitegravir/cobicistat (an INSTI plus a boosting agent) averaged a gain of 2.6 kg during 9 months, those who switched to DTG averaged a 3.1-kg gain, and those who switched to BTG averaged a 4.6-kg increase, Dr. Mallon reported at the conference.
These findings “give us a good sense that the weight gain is real. This is not just overeating or not exercising, but weight changes coincidental with a change in HIV treatment,” commented David Wohl, MD, professor of medicine and site leader of the HIV Prevention and Treatment Clinical Trials Unit at the University of North Carolina at Chapel Hill, during an online educational session.
Contrary to this evidence suggesting a consistent uptick in weight when patients start TAF treatment was a recent report on 629 HIV patients randomized to treatment with TAF-BTG-FTC or abacavir (an NRTI, Ziagen)–DTG-3TC, which found similar weight gains between these two regimens after 144 weeks on treatment (Lancet HIV. 2020 Jun;7[6]:e389-400). This finding had the effect of “strengthening the argument that TAF is simply an innocent bystander” and does not play a central role in weight gain, and supporting the notion that the alternative tenofovir formulation, TDF, differs from TAF by promoting weight loss, Dr. Venter and Dr. Hill suggested in their commentary that accompanied this report.
The new findings from Dr. Mallon raise “serious questions about the way we have moved to TAF as a replacement for TDF, especially because the benefits [from TAF] are for a small subgroup – patients with renal disease or osteoporosis,” Dr. Venter said in an interview. “The question is, will we see weight gain like this” if TAF was combined with a non-INSTI drug? he wondered.
While some study results have suggested a mitigating effect from TDF on weight gain, that wasn’t the case in the AFRICOS (African Cohort Study) study of 1,954 PWH who started treatment with TDF-DTG-FTC (742 patients) or a different three-drug regimen. After a median of 225 days on treatment, those who started on TDF-DTG-FTC had an adjusted, 85% higher rate of developing a high body mass index, compared with patients on a different ART regimen, Julie Ake, MD, reported in a talk at the conference. Her conclusion focused on the possible involvement of DTG: “Consistent with previous reports, dolutegravir was significantly associated with an increased risk of developing high body mass index,” said Dr. Ake, director of the U.S. Military HIV Research Program in Bethesda, Md. and leader of AFRICOS.
A potential workaround to some drugs that cause excessive the weight gain is to just not use them. That was part of the rationale for the TANGO study, which took 741 HIV-infected patients with successful viral suppression on a regimen of TAF-FTC plus one or two additional agents and switched half of them to a TAF-less, two-drug regimen of DTG-FTC. This open-label study’s primary endpoint was noninferiority for viral suppression of the DTG-FTC regimen, compared with patients who stayed on their starting regimen, and the results proved that DTG-FTC was just as effective over 48 weeks for this outcome (Clin Infect Dis. 2020 Jan 6. doi: 10.1093/cid/ciz1243).
At the conference, TANGO’s lead investigator, Jean van Wyk, MD, reported the weight and metabolic effects of the switch. The results showed a similar and small weight gain (on average less than 1 kg) during 48 week follow-up regardless of whether patients remained on their baseline, TAF-containing regimen or switched to DTG-FTC, said Dr. van Wyk, global medical lead for HIV treatment at Viiv Healthcare, the company that markets DTG. About three-quarters of patients in both arms received “boosted” dosages of their drugs, and in this subgroup, patients on DTG-FTC showed statistically significant benefits in several lipid levels, fasting glucose level, and in their degree of insulin resistance. Dr. van Wyk said. These between-group differences were not statistically significant among the “unboosted” patients, and the results failed to show a significant between-group difference in the incidence of metabolic syndrome.
Dr. Venter called these results “exciting,” and noted that he already uses the DTG-FTC two-drug combination “a lot” to treat PWH and renal disease.
A second alternative regimen showcased in a talk at the conference used the three-drug regimen of TDF-FTC plus the NNRTI, DOR (doravirine, Pifeltro). The DRIVE-SHIFT trial enrolled 670 HIV patients with successfully suppressed viral load on conventional regimens who were either switched to TDF-DOR-FTC or maintained on their baseline treatment. After 48 weeks, results confirmed the primary efficacy endpoint of noninferiority for maintenance of suppression with the investigational regimen (J Acquir Immune Defic Syndr. 2019 Aug;81[4]:463-72).
A post-hoc analysis looked at weight changes among these patients after as much as 144 weeks of follow-up. The results showed that patients switched to TDF-DOR-FTC had an average weight increase of 1.2-1.4 kg after more than 2 years on the new regimen, with fewer than 10% of patients having a 10% or greater weight gain with DOR, a “next-generation” NNRTI, reported Princy N. Kumar, MD, professor at Georgetown University and chief of infectious diseases at MedStar Georgetown University Hospital in Washington. “Weight gain was minimal, even over the long term,” she noted.
The tested DOR-based regimen also looks “very exciting,” but the populations it’s been tested have also been largely limited to White men, and limited data exist about the regimen’s performance in pregnant women, commented Dr. Venter. The DRIVE-SHIRT patient cohort was about 85% men, and about three-quarters White.