Perspective from Paul E. Sax, MD
July 25, 2019
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Dolutegravir-based regimens noninferior to standard HIV care, studies show

Perspective from Paul E. Sax, MD
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Findings from two phase 3 trials published in The New England Journal of Medicine demonstrated that dolutegravir-based treatment for HIV is noninferior to efavirenz-based regimens, although dolutegravir was associated with excessive weight gain in both studies.

WHO last year recommended dolutegravir (DTG)-based regimens as the preferred treatment for HIV over efavirenz-based regimens, but the recommendation was conditional in pregnant women after findings from the ongoing Tsepamo study in Botswana raised concerns about neural tube defects in infants.

However, additional data from the study presented at the International AIDS Society Conference in Mexico City this week and also published in The New England Journal of Medicine showed the risk was significantly lower than previously thought, and WHO now recommends DTG as a preferred first- and second-line treatment for all populations.

DTG outperforms EFV

In the first of two studies that further confirmed the efficacy of DTG, Charles Kouanfack, MD, PhD, from the Central Hospital of Yaoundé in Cameroon, and colleagues conducted an open-label, multicenter, randomized phase 3 noninferiority trial among 613 ART-naive adults with HIV-1 infection living in Cameroon who had HIV-1 RNA levels of 1,000 copies/mL or more. They were randomly assigned to receive either DTG or a low dose of 400 mg of efavirenz (EFV), both combined with tenofovir disoproxil fumarate (TDF) and lamivudine. The researchers used the percentage of patients with HIV-1 RNA levels less than 50 copies/mL at 48 weeks as the primary endpoint.

At 48 weeks, 74.5% of patients in the DTG arm and 69% of patients in the low-dose EFV group had HIV-1 RNA levels less than 50 copies/mL, a difference of 5.5 percentage points (95% CI, –1.6 to 12.7; P < .001 for noninferiority), according to Kouanfack and colleagues. Among patients who started with a viral load of at least 100,000 copies/mL, the researchers observed a viral load of less than 50 copies/mL in 66.2% of patients in the DTG group and in 61.5% of patients in the EFV group at 48 weeks, a difference of 4.7 percentage points (95% CI, –4.6 to 14). Three patients in the DTG group and in 16 patients in the EFV group experienced virologic failure.

Participants in the DTG-based group experienced a median weight gain of 5 kg vs. 3 kg in the EFV group, and the incidence of obesity also was higher in DTG arm, 12.3% compared with 5.4% in the EFV arm.

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“Follow-up of these participants will be critical, given the potentially important public health consequences that may jeopardize the large-scale use of dolutegravir,” Kouanfack and colleagues wrote.

In a second study, Willem D.F. Venter, FCP(SA), PhD, from Wits Reproductive Health and HIV Institute in Johannesburg, South Africa, and colleagues conducted a phase 3, open-label randomized trial among 1,053 patients aged 12 years or older with HIV-1 RNA levels of 500 copies/mL or more.

The patients were randomly assigned to a triple-therapy combination of emtricitabine (FTC) and DTG plus either tenofovir alafenamide fumarate (TAF) or TDF, or the local standard-care regimen of TDF-FTC-EFV. The researchers used the percentage of patients with HIV-1 RNA levels less than 50 copies/mL at 48 weeks as the primary endpoint.

At 48 weeks, 84% of patients in the DTG and TAF-based group, 85% of patients in the DTG and TDF-based group and 79% of patients in the standard-care group had a viral load of less than 50 copies/mL. The researchers found that the TAF-based regimen had less effect on bone density and renal function than the other regimens, although it was associated with the greatest weight increase at 6.4 kg compared with 3.2 kg in the TDF-based group and 1.7 kg in the standard-care group.

“The increased risk of weight gain with both DTG-containing regimens and the limited knowledge base regarding TAF in pregnancy need to be evaluated against improvements in side-effect profile and adherence, slight reductions in time to virologic control, and effect on bone mineral density and renal function,” Venter and colleagues wrote.

‘We need to accelerate’

In a related editorial, Diane V. Havlir, MD, professor of medicine at the University of California, San Francisco, and Meg C. Doherty, MD, PhD, MPH, an assistant professor of medicine at the Johns Hopkins Bloomberg School of Public Health, described DTG as an imperfect but essential HIV treatment option.

“This recent headwind caused by the imperfections of dolutegravir should not slow down the urgency to deliver lifesaving therapy to millions still in need,” they wrote. “We need to accelerate (not slow) the transition to dolutegravir-based regimens for initial therapy, offer treatment as early as possible, make use of the best currently available treatment options, shore up pharmacovigilance, and continue research at the same time.” – by Joe Gramigna

References:

Havlir DV, Doherty MC. New Engl J Med. 2019;doi:10.1056/NEJMe1909363.

Kouanfack C, et al. New Engl J Med. 2019;doi:10.1056/NEJMoa1904340.

Venter WDF, et al. New Engl J Med. 2019;doi:10.1056/NEJMoa1902824.

WHO. WHO recommends dolutegravir as preferred HIV treatment option in all populations. https://www.who.int/news-room/detail/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations. Accessed July 24, 2019.

Disclosures: Havlir reports grants from the NIH. Kouanfack and Doherty report no relevant financial disclosures. Venter reports grants from Unitaid, USAID, South African Medical Research Council, the Bill and Melinda Gates Foundation and Gilead Sciences, as well as personal fees from Virology Education, Roche, Gilead Sciences, ViiV Healthcare, Merck, Johnson & Johnson, Mylan and Adcock Ingram.