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CROI 2017: Dual Antiretroviral Regimen Maintains Durable HIV Suppression after Switch

People who switched from standard antiretroviral therapy to a 2-drug regimen of dolutegravir (Tivicay) plus rilpivirine (Edurant) were able to maintain an undetectable viral load for 48 weeks in a pair of late-stage clinical trials, according to a late-breaking report at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Seattle.

As long as people with HIV face the prospect of lifelong treatment, researchers will continue to look for antiretroviral regimens that are easier to take and more affordable, while remaining highly effective and well-tolerated. If this can be accomplished with 2 instead of 3 or more drugs, treatment could be simpler and the cost could be lower. But simplifying therapy too much raises the risk of treatment failure and drug resistance.

Josep Llibre from University Hospital Germans Trias in Barcelona presented findings from the SWORD-1 and -2 trials, which evaluated whether dolutegravir plus rilpivirine could maintain viral suppression in treatment-experienced people who switched from a 3- or 4-drug regimen with undetectable virus.

"It's been a long-term dream to try to find safe strategies that can control the disease with a reduced number of drugs," Llibre said at a CROI press briefing.

ViiV Healthcare's dolutegravir is a potent integrase inhibitor with a high barrier to resistance, making it a good candidate for simplified therapy. Janssen'srilpivirine is a well-tolerated second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI).

Prior studies suggested that this approach is feasible. As reported at the International AIDS Conference last July, the PADDLE pilot study showed that a dual regimen of dolutegravir plus the inexpensive nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (3TC or Epivir) led to sustained viral suppression in most people starting ART for the first time (the Phase 3 GEMINI trials are evaluating this regimen in a larger study). Another small study suggested that dolutegravir alone might be enough to maintain undetectable viral load in some highly treatment-experienced patients. Previous studies looked at monotherapy or dual therapy using boosted protease inhibitors, but these agents have more side effects and drug-drug interactions than integrase inhibitors.

SWORD-1 (NCT02429791) and SWORD-2 (NCT02422797) were identical multicenter randomized trials with enrollment North and South America, Europe, Russia, and Asia. Together the studies included 1024 people with HIV who had been on standard ART with undetectable viral load (HIV RNA <50 copies/mL) for at least a year -- with a median of 4 years -- and had no history of virological failure or evidence of drug resistance.

More than three-quarters were men, most were white, the median age was 43 years, and the baseline CD4 T-cell count was approximately 600 cells/mm³. At study entry they were on regimens containing at least 3 drugs including an integrase inhibitor (20%), NNRTI (54%), or protease inhibitor (26%) plus 2 NRTIs; 73% used tenofovir disoproxil fumarate. People with chronic hepatitis B coinfection were excluded.

Participants in these open-label studies were randomly assigned (1:1) to either switch to the dual regimen of once-daily dolutegravir plus rilpivirine or stay on their current regimen. The primary endpoint was continued undetectable viral load at 48 weeks.

Results

• Most participants in both treatment arms maintained viral suppression.
• 95% of people in the dolutegravir plus rilpivirine arm and 95% in the unchanged regimen arm had HIV RNA below 50 copies/mL at 48 weeks.
• These results showed that switching to the dual regimen was non-inferior to staying on standard therapy.
• Virological failure was rare, <1% in the dual therapy arm and 1% in the unchanged regimen arm.
• Among those who underwent viral sequencing, 1 person taking dolutegravir plus rilpivirine had a NNRTI resistance mutation, but no one in either arm had integrase resistance mutations.
• Treatment was generally safe and well-tolerated, with no unexpected drug-related adverse events.
• Serious adverse events were comparable in both arms, but discontinuations due to adverse events occurred more often in the dual therapy arm (3% vs <1%).
• The most common adverse events were nasopharyngitis (inflammation of the nose and throat), headache, upper respiratory tract infections, and diarrhea.
• Although the frequency of more severe (grade 3-4) adverse events did not differ between the 2 arms, there were more mild to moderate (grade 1-2) events reported in the dolutegravir plus rilpivirine arm (17% vs 2%).
• Switching to the dual regimen had a beneficial on bone biomarkers -- likely because many switched off tenofovir DF, which is known to cause bone loss -- and a neutral effect on blood lipids.

Joseph Eron of the University of North Carolina at Chapel Hill suggested at the press conference that the pattern of side effects may reflect the fact that people who switch drugs often blame any symptoms on their new medications, while those who stay on the same treatment might not bother to report common minor symptoms such as headache or sore throat.

"This is the first time we can prove [a 2-drug regimen] is non-inferior in a once-daily regimen with no booster, no protease inhibitor and no NRTIs." Dr Llibre concluded.

The SWORD studies are continuing follow-up through 148 weeks. A new trial will assess a fixed-dose coformulation of dolutegravir plus rilpivirine -- described as a very small pill -- as once-daily single-tablet regimens are now the standard of care for a majority of people with HIV. This study will enroll some people with pre-existing drug resistance, to better reflect a "real world" patient population.

2/14/17

Sources

JM Llibre, C-C Hung, C Brinson, et al. Phase III SWORD 1&2: Switch to DTG+RPV Maintains Virologic Suppression Through 48 Wks. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 44LB.

ViiV Healthcare. ViiV Healthcare announces detailed positive phase III results for investigational two-drug regimen of dolutegravir and rilpivirine for HIV treatment. Press release. February 13, 2017.