Dual Therapy for HIV Two-Stepping In

Heather Boerner

July 29, 2019

MEXICO CITY — Two-drug regimens may be as effective and safe as multi-drug therapies, according to investigators evaluating paired down treatment options for HIV.

"I don't mean to say that everyone should be on dual therapy," but it could be the beginning of a new era in HIV treatment, said Pedro Cahn, MD, from the Buenos Aires University Medical School in Argentina.

Previous attempts to treat people living with HIV with only two drugs were found to be ineffective at suppressing the HIV virus and led to drug resistance.

But results from a prespecified secondary analysis of data from the GEMINI studies (NCT02831673 and NCT02831764), presented here at the International AIDS Society (IAS) 2019 Conference on HIV Science, showed that the two-drug regimen of dolutegravir and lamivudine (Dovato, ViiV Healthcare) suppresses HIV in people new to treatment for 96 weeks, with zero drug-resistant mutations.

Also presented at the meeting were results from the TANGO study (NCT03446573), which demonstrated that the combination of dolutegravir and lamivudine is as effective, as durable, and as free of resistance at 48 weeks as traditional triple therapy in people who switch from three-drug regimens, and results from a phase 2b trial of 121 people that showed that islatravir, Merck's investigational agent, plus doravirine is as safe and effective as a three-drug regimen at 48 weeks.

These findings add to the body of evidence established by the SWORD 1 and 2 trials, which showed that dolutegravir plus rilpivirine is effective in people switching from three-drug regimens, as reported by Medscape Medical News.

Together, the findings provide an opportunity "to think about the position of dual therapy in international guidelines," Cahn told Medscape Medical News.

GEMINI and TANGO

This time last year, Cahn was on another stage talking about similar data, as reported by Medscape Medical News. At the time, the 1433 participants in GEMINI 1 and 2 had been on their new regimen for 48 weeks. Rates of viral loads below 50 copies/mL were comparable in patients treated with the two-drug and three-drug regimens in GEMINI 1 (90% vs 93%) and GEMINI 2 (93% vs 94%).

The GEMINI cohort was 85% male and 65% white. None of the participants were coinfected with hepatitis B or resistant to reverse-transcriptase or protease inhibitors. All had baseline HIV viral loads between 1000 and 500,000 copies/mL, and 91% had CD4 T-cell counts above 200 cells/mm³.

At 48 weeks, the rate of viral suppression (<50 copies/mL) was similar in the dolutegravir plus lamivudine group and the dolutegravir plus tenofovir disoproxil fumarate and emtracitabine (Truvada, Gilead Sciences) group (91.5% vs 93.3%).

But when Cahn presented those data last year, there were questions about the durability of the response and whether resistance could develop.

Durable Response

This year, Cahn was able to report that the response is durable and resistance did not develop. The combination of dolutegravir plus lamivudine "has been shown to be as effective as triple therapy," he explained.

In fact, a pooled analysis of 96-week GEMINI results showed that viral suppression was maintained with dual and triple therapy (86.0% vs 89.5%) and that there was no treatment-emergent resistance. Confirmed viral nonsuppression led 11 people in the dual-therapy group and seven in the triple-therapy group to withdraw from the study.

The remaining GEMINI participants will be followed for another year, Cahn said.

Preliminary 48-week results from the phase 3 TANGO study, which is assessing virally suppressed patients who switch to Dovato from a three- or four-drug regimen containing the emtricitabine and tenofovir alafenamide combination (Descovy, Gilead Sciences), were presented by Jean van Wyk, MBChB, from ViiV Healthcare.

The TANGO cohort was 92% male and 79% white. None of the 741 participants were coinfected with hepatitis B, resistant to nucleoside reverse-transcriptase or integrase inhibitors, or had a history of treatment failure. Median CD4 counts at baseline were lower in the Dovato group than in the multi-drug group (682 vs 720 copies/mm³).

At 48 weeks, rates of viral suppression were comparable in the group that switched to Dovato and the group that remained on a multi-drug regimen containing tenofovir alafenamide (93.2% vs 93.0%). Neither regimen led to resistance. The one person who withdrew because of lack of efficacy was on the multi-drug regimen.

"What we found, in short, was that dolutegravir was noninferior to TAF-based three- or four-drug regimens, whether you look at viral failure as the primary end point or virologic success as a secondary end point," van Wyk said.

The data drew praise from Tony Mills, MD, an HIV specialist in Los Angeles, who called the presentations "exciting." He also pointed out that people taking Dovato appeared to have better renal markers than those taking a tenofovir-alafenamide-based regimen.

"We didn't want to overestimate those results, as there was no significant difference in terms of adverse events," Cahn said. "We will see the clinical meaning of that difference in the long run."

But both TANGO and GEMINI drew renewed criticism for their limited participant group.

Where Are the Women?

"These are exciting results but I have to express some concern about the lack of diversity in the enrolled population," said Mark Hubbard, an HIV advocate associated with AVAC.

"I'm going to echo these comments and go a little bit further," said Lena Serghides, PhD, from the University of Toronto. "You had about 100 females. If you have women in the study, can you give us some gender- or sex-based analysis?"

Cahn explained that the participants were chosen to reflect epidemics where the study was conducted, primarily in Europe, Latin America, and North America. However, he reported, a substudy on gender differences will be forthcoming.

There were no medicines for HIV when Myron Cohen, MD, from the University of North Carolina at Chapel Hill, began studying HIV. Over time, though, he has seen HIV treatment move from no treatment and certain death to one treatment, ATZ, which involved multiple pills a day, to three drugs and multiple pills a day, to three drugs combined into one pill.

With the GEMINI and TANGO results, and those from Merck's islatravir plus doravirine phase 2b study, along with the injectable combination of cabotegravir plus rilpivirine, there is a shake-up in HIV treatment.

"We are in a place and time — I don't know how many speakers at IAS this year said the same thing — that with a pill a day, people living with HIV can live a normal life span," Cohen said. And yet, drug makers and researchers are still seeking simpler, better-tolerated treatments. It's pretty impressive," and a real move forward.

TANGO and GEMINI were funded by ViiV Healthcare. Cahn and Serghides have disclosed no relevant financial relationships. van Wyk is an employee of ViiV Healthcare. Cohen reports receiving advisory board honoraria or travel reimbursement from Janssen Global Services, Roche Molecular Systems, and Merck Research.

Editor's note: The text has been changed to clarify that tenofovir alafenamide was used in combination with emtricitabine in the multi-drug regimens.

International AIDS Society (IAS) 2019 Conference on HIV Science: Abstracts WEAB0404LB and WEAB0403LB. Presented July 23, 2019.

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