In the JournalsPerspective

Dolutegravir-based regimens noninferior to standard HIV care, studies show

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.

“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.

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.

    Perspective
    Paul E. Sax

    Paul E. Sax

    In the United States, Europe and other parts of the world, we've already moved away from EFV to DTG and other integrase-inhibitor-based initial regimens because of better tolerability, making the use of EFV less common. These studies show that in Africa, just like in the rest of the world, DTG is better tolerated than EFV. They did not demonstrate the superiority of DTG over EFV.

    The ADVANCE study had findings similar to those from past research — patients receiving TAF experience less of an effect on renal and bone biomarkers than patients receiving TDF, but the absolute incidence of clinically significant renal disease in a population like this is still very low. We do not see any differences related to renal discontinuations, which were shown in previous studies that had much longer follow-up periods and larger cohorts.

    An additional finding worth mentioning is that DTG-based regimens have a higher resistance barrier than EFV-based regimens, meaning patients who experience viral failure or rebound on DTG-based regimens are less likely to develop resistance than people on EFV-based regimens.

    Clinicians should certainly take away that these studies confirm the high virologic efficacy of DTG-based regimens and their acceptable tolerability. The NAMSEL study included many patients who had viral loads greater than 100,000 at the beginning, so it provides some context because that is a study population we do not often see in the original registrational trials. Both studies enrolled over 60% women, which is something else we do not see much in registrational studies. Most of the studies conducted in the U.S. and Europe are overwhelmingly composed of male patients. This is a broader population to see the activity of DTG-based regimens.

    An unanticipated finding and one that has been heralded by some observational studies is that DTG-based treatments are clearly associated with greater weight gain than EFV-based treatments. TAF seems to augment this effect. DTG causes greater weight gain than EFV, and TAF causes greater weight gain than TDF. In addition, the effect seems to be greater in women than in men. In particular, the women enrolled in the ADVANCE study who received the DTG plus the TAF regimen experienced a substantial amount of weight gain, a 10-kg increase in body weight on average by week 96, with a substantial fraction of the participants moving into the overweight or obese categories. There did not seem to be any metabolic adverse effects associated with this weight gain, but it is quite alarming and is a noticeable difference between the study arms. One of the key questions is, "What is the mechanism of this weight gain?" There has been some evidence that the first form of TDF might be associated with appetite suppression or weight subtility or even weight loss. A possibility is that there is some sort of off-target toxicity of integrase inhibitors and TAF that we have not yet identified. That is going to be an area of significant research over the coming years because we use these drugs frequently in clinical practice.

    • Paul E. Sax, MD
    • Clinical director, HIV program and division of infectious diseases
      Brigham and Women’s Hospital
      Boston

    Disclosures: Sax reports serving as a scientific advisory board member/consultant for Gilead Sciences, GlaxoSmithKline/ViiV, Janssen and Merck; receiving research support from Gilead, GlaxoSmithKline/ViiV and Merck; and serving in editorial positions at UpToDate, Medscape, NEJM Journal Watch and Open Forum Infectious Diseases.

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