From the Journals
HIV guidelines: Update recommends immediate treatment, three-drug therapy
AMSTERDAM – A two-drug antiretroviral regimen with an integrase inhibitor was noninferior to a standard three-drug regimen for controlling HIV viral load in a pair of identical, phase 3, multicenter, randomized trials with more than 1,400 patients.
Mitchel L. Zoler/MDedge News
Dr. Pedro Cahn
The efficacy and safety results seen in the two studies at the primary endpoint follow-up of 48 weeks support the tested combination of the integrase inhibitor dolutegravir (Tivicay) plus the nucleoside reverse transcriptase inhibitor (RTI) lamivudine (3TC, Epivir) as an “effective option,” Pedro Cahn, MD, said at the 22nd International AIDS Conference.
The two trials from which he reported results, GEMINI-1 and GEMINI-2, which both compared the dolutegravir (DTG) plus 3TC regimen against DTG plus the nucleotide RTI tenofovir (Viread) and the nucleoside RTI emtricitabine (Emtriva), together showed after 48 weeks on treatment a 91% rate of complete virologic response to DTG plus 3TC with fewer than 50 detectable HIV RNA copies per mL, compared with a 93% complete response among patients on DTG plus tenofovir and emtricitabine. The efficacy of the two-drug regimen fell within the prespecified definition of noninferiority, compared with the three-drug comparator arm, the primary endpoint for both studies, said Dr. Cahn, scientific director of Fundacion Huesped in Buenos Aires, and professor of infectious diseases at Buenos Aires University.
“This is the first time a randomized, controlled trial showed the noninferiority of a two-drug regimen, compared with a three-drug regimen while using an integrase inhibitor as the core drug,” Dr. Cahn said. The goal of cutting the treatment regimen down to two drugs is to “reduce drug burden” and potentially produce fewer adverse effects and reduce cost, he explained.
Integrase strand transport inhibitors like DTG make sense as the core drug because “as a class they quickly reduce viral load” and have several other very attractive properties including good tolerability, a high barrier to resistance mutations, quick recovery of CD4 cell levels, and good adherence by patients, said Dr. Cahn. These advantages apply not only to DTG but also to other drugs in the class: raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Biktarvy). Integrase inhibitors have been specified as part of the preferred anti-HIV regimen for most people starting HIV treatment by public health officials in several countries as well as by the World Health Organization in its 2018 revised HIV treatment recommendations.
But Dr. Cahn put a few qualifications on the findings so far for the combination of DTG and 3TC. Its durability has been tested out only to 48 weeks, although during that time no resistant HIV was seen. The studies will continue to follow the patients on dual treatment for as long as 144 weeks, he said. Also, the two-drug regimen should be considered, for the time being, only for patients who match the enrollment criteria for the GEMINI trials: Patients with a viral load no greater than 500,000 RNA copies/mL, no prior treatment, no evidence of preexisting viral resistance to any anti-HIV drugs, and no hepatitis B virus infection or need for hepatitis C virus treatment. Also there is uncertainty about the risk that women who become pregnant while on DTG have for giving birth to an infant with a neural tube defect. A recent report documented preliminary evidence for an increased risk (N Engl J Med. 2018 Jul 24. doi: 10.1056/NEJMc180765).
In addition to its noninferior efficacy, compared with a triple-drug regimen, the dual regimen showed good safety and tolerance, with a 7% incidence of serious adverse events and a 2% rate of events leading to withdrawal of treatment, rates similar to the triple-drug arm. The dual regimen also showed less evidence for renal damage than the triple regimen, including a statistically significant smaller drop in glomerular filtration rate than the triple regimen and no spikes in urine markers of renal damage as occurred on three drugs. Two drugs also induced no increases in markers of bone metabolism, but this happened with three drugs, Dr. Cahn reported.
The combined data from the two GEMINI studies enrolled 1,433 HIV-infected patients at centers in 21 countries including several U.S. centers. Patients averaged about 33 years old, 85% were men, and more than 90% had a CD4 cell count greater than 200 cell/mL at enrollment. Eighty percent had a viral load of no more than 100,00 RNA copies/mL, and the 20% with higher viral loads were stratified in equal numbers into the two treatment arms.
The 91% and 93% virologic response rates in the two treatment arms came in the intention-to-treat analysis and correlated with similar average rises among patients in the two arms in CD4 cell counts after 48 weeks of 224-228 cell/mm3. In the per protocol analysis the virologic response rates were 93% with the dual regimen and 94% with the triple regimen
SOURCE: Cahn P et al. AIDS 2018, Abstract 13210.