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Dolutegravir-emtricitabine + TAF/TDF combo ADVANCEs as potential HIV-1 treatment

Roshini Claire Anthony
20 Aug 2019

The combination of emtricitabine and dolutegravir with either a tenofovir alafenamide fumarate (TAF) or tenofovir disoproxil fumarate (TDF)-based regimen fared similarly to a TDF-emtricitabine-efavirenz regimen in reducing HIV-1 RNA levels, according to results of the phase III ADVANCE* study presented at IAS 2019.

“[T]reatment with dolutegravir combined with either of two tenofovir prodrugs (TAF and TDF) was noninferior to the standard-of-care (SOC) regimen with respect to the percentage of patients with HIV-1 RNA suppression at week 48,” said the researchers.

Study participants were 1,053 HIV-1-positive** individuals (median age 32 years, 59 percent female, mean CD4 count 337 cells/mm3) from South Africa who were antiretroviral-naïve in the prior 6 months. They were randomized 1:1:1 to receive emtricitabine plus dolutegravir plus either TAF or TDF or the local standard treatment of TDF-emtricitabine-efavirenz (SOC).

At 48 weeks, a similar proportion of patients on TAF, TDF, and SOC had a HIV-1 viral load of <50 copies/mL in both the intention-to-treat (84, 85, and 79 percent, respectively) and per-protocol analyses (96, 95, and 96 percent, respectively). [IAS 2019, abstract WEAB0405LB; N Engl J Med 2019;doi:10.1056/NEJMoa1902824]

Both the TAF- and TDF-based regimens demonstrated noninferiority to SOC in terms of RNA suppression at week 48 (difference, 5.1 percentage points, 98.3 percent confidence interval [CI], -1.9 to 12.2; p=0.08 and difference, 6.3 percentage points, 98.3 percent CI, -0.7 to 13.2; p=0.03, respectively), with little difference between the TAF and TDF regimens (difference, -1.1 percentage points, 98.3 percent CI, -7.7 to 5.4; p=0.68).

“Differences in efficacy between the groups were driven by a higher number of discontinuations in the [SOC] group than in the other two groups,” said the researchers, with 61 discontinuations in the SOC group compared with 41 and 34 in the TAF and TDF groups, respectively.

More TAF and TDF recipients achieved HIV-1 RNA levels of <1000 copies/mL at week 4 than SOC recipients (98, 97, and 90 percent, respectively).

In patients with virologic failure, there was no evidence of resistance to integrase inhibitors among dolutegravir recipients, though one patient demonstrated new resistance to NRTIs or NNRTIs*** as did four efavirenz recipients.

More SOC recipients experienced grade 3–4 weight loss, dizziness, or elevated γ-glutamyltransferase levels than TAF or TDF recipients. Eight efavirenz recipients discontinued treatment due to toxicity (liver dysfunction [n=5], rash [n=2], and neuropsychiatric symptoms [n=1]). There were 15 cases of tuberculosis, four, three, and eight among TAF, TDF, and SOC recipients, respectively.

TAF recipients had the highest incidence of absolute weight gain compared with TDF and SOC recipients (6, 3, and 1 kg, respectively), as well as new-onset obesity (14, 7, and 6 percent, respectively), with weight gain significantly greater among female than male patients, those with higher viral loads, and those with lower CD4 counts. In contrast, new-onset underweight was more common in SOC than TAF/TDF recipients (4 percent vs 1 percent each).

None of the four deaths (one each in the TAF and TDF groups and two in the SOC group) were deemed treatment-related.

Among most patients with persistent viraemia (≥50 copies/mL at week 48), interventions aimed at improving adherence led to viral suppression over a longer follow-up period.

 

Weighing the benefits vs risks

“[D]olutegravir had a better side-effect profile than efavirenz; TAF had modest benefits over TDF with respect to bone density and renal function, findings that are consistent with the results of previous studies,” said Drs Diane Havlir from the University of California, San Francisco, US, and Meg Doherty from the World Health Organization, Geneva, Switzerland, in an editorial. [N Engl J Med 2019;doi:10.1056/NEJMe1909363]

“However, dolutegravir was unequivocally associated with excessive weight gain, particularly with TAF-emtricitabine,” they added.

The researchers further expressed concern regarding the elevations in truncal fat, a cardiovascular risk factor, associated with weight gain. “[I]t is [also] unclear whether TAF amplifies or TDF mitigates the weight-gain effect of dolutegravir,” they added, while Havlir and Doherty pondered whether dolutegravir or its combination with TAF was the cause of metabolic outcomes. 

“[Nonetheless] dolutegravir and other integrase inhibitors represent a substantial advance to our treatment arsenal, outperforming other agents in nearly all studies in terms of the rapidity of viral suppression, side-effect profile, and resilience to HIV resistance,” said Havlir and Doherty, calling for research into examining the mechanisms behind the metabolic complications of dolutegravir.

 

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