Dolutegravir regimen highly effective in clinical trial for women

A once-daily regimen containing the potent HIV integrase inhibitor dolutegravir worked better than an older atazanavir-containing regimen – with higher rates of viral suppression both overall and across race subgroups – in the ARIA trial, one of the few antiretroviral therapy studies to enrol only women, according to a presentation at IDWeek last week in New Orleans.

Over the course of the HIV/AIDS epidemic white men have been over-represented while women and people of colour have been under-represented in clinical trials of new therapies. But worldwide, women make up about half of all people living with HIV and people of African heritage have the highest burden of disease, and it is important for new treatments to be tested in all the groups that will ultimately use them.

Debbie Hagins of Chatham County Health Department in Savannah, Georgia, presented findings from the ARIA trial, sponsored by ViiV Healthcare, which enrolled 495 previously untreated women in 12 countries.

The study compared a fixed-dose combination of dolutegravir/abacavir/lamivudine (Triumeq) versus ritonavir-boosted atazanavir (Reyataz) plus tenofovir DF/emtricitabine (Truvada). Dolutegravir has been shown to have a high barrier to resistance and is potent enough to be used without a booster.

Nearly a third of trial participants were enrolled in the UK and Europe, a quarter in the US, 13% in South Africa, and the rest in Russia, Argentina, Thailand and Mexico. Just under half (46%) were white, 41% were of African heritage and 13% were of other races/ethnicities, mostly Asian. The median age was 37 years. The median baseline CD4 T-cell count was approximately 350 cells/mm³ and over a quarter had a viral load above 100,000 copies/ml.

Half the women were randomly assigned to receive dolutegravir/abacavir/lamivudine and half to receive atazanavir/ritonavir plus tenofovir/emtricitabine. The study's primary endpoint was the proportion in each arm with viral load below 50 copies/ml after 48 weeks on treatment.

After 48 weeks on treatment, 82% of women taking the dolutegravir regimen and 71% taking the atazanavir regimen achieved viral suppression in an intention-to-treat analysis. The difference was large enough to show that the dolutegravir regimen was not only non-inferior, but also superior to the atazanavir regimen. Response rates were similar when comparing women with baseline viral loads above or below 100,000 copies/ml and CD4 counts above or below 350 cells/mm³.

In a subgroup analysis by race, white women had higher virological response rates on both dolutegravir and atazanavir (86 vs 80%) compared to black women (74 vs 67%), but the difference between the two regimens was similar for both groups.

Half as many women in the dolutegravir arm met the criteria for virological non-response compared to those in the atazanavir arm (6 vs 14% respectively). None of the women who experienced virological failure while on dolutegravir/abacavir/lamivudine developed resistance to these drugs.

The higher response rate in the dolutegravir arm was largely driven by more discontinuations due to adverse events in the atazanavir arm. About 20% of participants in both arms stopped treatment before 48 weeks – including 13 women who became pregnant – but the reasons for doing so differed.

About 80% of women in both treatment arms experienced some adverse events, but those taking dolutegravir were less likely to report moderate-to-severe events (46 vs 55%) and drug-related events (33 vs 49%). Women in the dolutegravir arm had fewer serious adverse events (0 vs 3), drug-related serious adverse events (20 vs 12) and discontinuations due to adverse events (17 vs 10) than those in the atazanavir arm. As expected, women taking atazanavir were more likely to develop jaundice and yellowing of the eyes due to elevated bilirubin. Patterns and frequency of adverse events were similar when comparing black and white women.

Central nervous system side-effects associated with dolutegravir are an emerging concern, but Hagins said that the rate of neuropsychiatric events study were the same in both treatment arms (14% overall, 4% insomnia, 2-3% depression).

Dolutegravir/abacavir/lamivudine "demonstrated superior efficacy and a favourable safety profile compared to atazanavir plus tenofovir/emtricitabine in treatment-naive women after 48 weeks of treatment," the investigators concluded in their study abstract. "Race subgroup analyses were consistent with overall results."