HIV Therapy

Efficacy of a Two-Drug ART Regimen for Initial HIV Therapy

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In a pilot single-arm study, the two-drug regimen dolutegravir + lamivudine achieved viral suppression in 90% of patients at 24 weeks.

Increasing data support use of certain two-drug antiretroviral (ART) regimens for maintenance therapy for select HIV-infected patients suppressed on a standard ART regimen (NEJM JW Infect Dis Jan 2018). Experience with two-drug ART regimens for initial HIV therapy has been less favorable. In this pilot study, the two-drug regimen dolutegravir + lamivudine (3TC) was evaluated in treatment-naive HIV-infected patients without active hepatitis B infection who had HIV RNA levels ≥1000 and <500,000 copies/mL. The planned primary endpoint was the proportion with HIV RNA <50 copies/mL at week 24.

The study enrolled 120 persons at 26 sites in the U.S. (median HIV RNA, 4.6 log10 copies/mL; median CD4 count, 387 cells/mm3; 87% male; 72% nonwhite). At 24 weeks, 108 (90%) of the participants had HIV levels <50 copies/mL; results were similar for those with HIV RNA >100,000 or ≤ 100,000 copies/mL. Three participants met criteria for virologic failure; all had undetectable dolutegravir levels at ≥1 time points and one had M184V and R263R/K integrase mutations identified at time of failure. The regimen was well tolerated, with no treatment discontinuations due to adverse effects. The authors conclude that these results support further evaluation in select treatment-naive patients planned in the currently enrolling phase 3 studies.

Comment

Dolutegravir/3TC is a regimen of interest due to the potency and high barrier to resistance of dolutegravir and the potency, tolerability, and low cost of generic 3TC. Although these results are encouraging from the efficacy standpoint, the development of resistance to dolutegravir is worrisome and has not been generally observed with dolutegravir use as part of initial three-drug therapy. Results of the phase 3 GEMINI-1 and 2 trials comparing dolutegravir/3TC to a standard three-drug regimen for initial treatment (https://clinicaltrials.gov/ct2/show/results/NCT02831764), anticipated in 2018, will provide more definitive data on the potential of this two-drug regimen.

HIV Therapy Switch Tied to Lower Platelet Reactivity

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Virologically suppressed HIV patients who were switched from therapy containing abacavir to another therapy seemed to have lower platelet reactivity to certain types of agonists, a researcher said here.

A substudy of an existing phase III randomized trial examining abacavir/lamivudine (ABC/3TC) and tenofovir alafenamide/emtricitabine (TAF/FTC) found that patients in the TAF/FTC arm had significantly lower platelet reactivity in response to collagen at weeks 4 and 12 compared with patients in the ABC/3TC arm, reported Patrick Mallon, MD, of University College Dublin, and colleagues.

Prior research suggests that people living with HIV are at an increased risk for myocardial infarction, and that increased platelet reactivity is linked with cardiovascular events, the authors said. In addition, investigators in the prominent Data collection on Adverse events of Anti-HIV Drugs (D:A:D) study described a potentially reversible association between abacavir and cardiovascular disease risk.

“We all live in the real world — we’ve been sitting on this problem for the last 10 years, but it’s never been perfectly studied. If we didn’t get that study 10 years ago, we’re not going to get it now,” Mallon said at a press conference at the Conference on Retroviruses and Opportunistic Infections (CROI).

Mallon’s group conducted a 61-person substudy of an existing study that examined four clinical sites in Dublin and London. Patients in the initial study were virologically suppressed, with HIV-1 RNA <50 copies/mL for at least 6 months. The authors hypothesized that patients who switched from the ABC regimen to the TAF regimen would result in decreases in platelet reactivity.

The original study examined virologically suppressed patients on ABC/3TC who were randomized to either switch to TAF/FTC or remain on ABC/3TC while continuing their third agent. This substudy contained 29 patients from the TAF/FTC arm and 32 from the ABC/3TC arm. In the substudy, researchers measured platelet aggregation at baseline in response to increasing concentrations of five agonists: collagen, thrombin receptor-activating peptide, adenosine diphosphate, epinephrine and arachidonic acid.

Mean age of the substudy participants ranged from 49 to 50, about 28% to 31% were women, and 52% were white in the TAF arm versus 60% in the ABC arm. There was a higher portion of patients with hyperlipidemia (41% versus 31%) and hypertension (34% versus 28%) in the ABC/3TC group compared with the TAF/FTC group.

Overall, platelet reactivity was significantly lower in the TAF/FTC group in response to collagen at both the week 4 and week 12 of the substudy. Platelet reactivity was significantly lower in response to thrombin receptor-activating peptide and adenosine diphosphate at week 4, but not week 12 in the TAF/FTC group. However, there were no between-group differences with platelet reactivity in response to epinephrine or arachidonic acid.

Moreover, there was a significant increase in the expression of glycoprotein VI (GPVI), a collagen receptor expressed on platelets, in the TAF/FTC group at week 12 compared to baseline.

Study limitations included the fact that the recruitment target was not achieved. Also, it was not designed to measure clinical cardiovascular events and did not recruit participants with pre-existing renal dysfunction.

CROI press conference moderator Judith Currier, MD, of the University of California Los Angeles, said that this is “really important data and we should do more with it. We need to see how often we see this reactivity in those who are taking the drug.”

Mallon went a step further, saying that this study adds to a “growing body of literature that points to a significant safety signal around this drug. It’s time that this data is taken on board because it is a safety issue and may in some way explain some very important clinical events.”