In 1987, azidothymidine (later known as zidovudine) was the first FDA-approved medication for the treatment of human immunodeficiency virus (HIV). Since then, advances in antiretroviral therapy (ART) have led to a dramatic increase in the life expectancy of HIV-infected patients. Following the reproductive cycle of the HIV-1 virus is key to understanding the different targets and strategies of ART. Most ART medications target the reverse-transcriptase enzyme that is responsible for converting single-stranded HIV-1 RNA to double-stranded DNA after the virus has entered the host cell. Other targets for ART include integrase, which catalyzes the integration of HIV DNA into the host cell DNA after migration into the nucleus.
The current first-line ART recommended by the World Health Organization (WHO) consists of two nucleoside reverse-transcriptase inhibitors (NRTIs) and an integrase inhibitor. The integrase inhibitor dolutegravir has a high genetic barrier to resistance and its use in ART regimens has been associated with sustained viral suppression and immunological recovery. Therefore, dolutegravir replaced the NRTI efavirenz in 2018 as the first-line therapy alongside two NRTIs and solved the problem of the increase in efavirenz resistance.
Two trials recently published in the NEJM compared dolutegravir-based regimens to efavirenz-based regimens. Both trials demonstrated that dolutegravir-based treatment was noninferior to efavirenz-based treatment. However, both trials also described significant weight gain in patients in the dolutegravir-based treatment group. In an accompanying editorial, editorialists stressed the benefits of dolutegravir in advancing HIV treatment and called for more data to explore the mechanisms and long-term outcomes associated with excessive weight gain in patients treated with dolutegravir.
The following NEJM Journal Watch summary explains the two studies and results in more detail:
Antiretroviral Therapy in 2019: Which Is the Best Regimen for the Global Roll-Out?
Carlos del Rio, MD reviewing N Engl J Med 2019 Jul 24 Venter WDF et al. N Engl J Med 2019 Jul 24 Havlir DV and Doherty MC. N Engl J Med 2019 Jul 24
Two studies done in Sub-Saharan Africa suggest that dolutegravir-based antiretroviral therapy is noninferior to efavirenz–based ART but is clearly associated with significant weight gain, particularly when combined with tenofovir alafenamide fumarate.
Globally, efavirenz–based antiretroviral therapy (ART) has been the most commonly used antiretroviral regimen. Due to concerns about toxicity, dolutegravir-based and low-dose efavirenz–based ART have been proposed as alternatives. Two studies have now tested these alternatives in Sub-Saharan Africa.
In the NAMSAL study conducted in Cameroon, 613 patients (median age, 37 years; 65.9% women; median viral load, 5.3 log10 copies/mL; median CD4 cell count, 281 cells/μL) were randomized to efavirenz 400 mg/day (EFV400) or dolutegravir (DTG), both in combination with tenofovir disoproxil fumarate (TDF)/lamivudine. At 48 weeks, 74.5% of the DTG arm and 69% of the EFV400 arm has a viral load <50 copies/mL, which met the noninferiority criteria. Among persons with viral load >100,000 copies/mL at baseline, a lower percentage achieved viral suppression (66.2% on DTG and 61.5% on EFV400), which also showed noninferiority. Virologic failure was more common with EFV than DTG (16 vs. 3 participants) as was drug resistance, but more weight gain occurred on DTG (median, 5 kg vs. 3 kg), and more women than men experienced weight gain of ≥10% (38.8% vs 22.9%).
In the partially manufacturer-designed ADVANCE study, conducted in South Africa by Venter and colleagues, 1053 patients (mean age, 32 years; 59% female; mean CD4, 337 cells/μL; 78% with viral load <100,000 copies/mL) were randomized to efavirenz/TDF/emtricitabine (standard of care) or one of two DTG-based regimens, one with coformulated tenofovir/emtricitabine (TDF/FTC) and one with coformulated tenofovir alafenamide fumarate/emtricitabine (TAF/FTC). At 48 weeks, a viral load <50 copies/mL was seen in 79% with standard of care, 84% with DTG/TAF/FTC, and 85% in DTG/TDF/FTC — meeting noninferiority criteria. The standard-of-care arm had a higher number of treatment discontinuations. The strongest predictors of vial suppression were older age (>32 years) and employment. The TAF regimen had less impact than the TDF regimen on bone density and renal function but greater weight gain among women (6.4 kg with TAF; 3.2 kg with TDF, and 1.7 kg with standard care).
Comment: As PEPFAR (the U.S. President's Emergency Plan for AIDS Relief) decided to switch to DTG/TDF/3TC as the preferred antiretroviral regimen, concerns about neural tube defects prompted questions about this approach. These two studies compared two DTG-based antiretroviral regimens to EFV, which has been the standard of care globally. In both studies the DTG-based regimens were noninferior but we also learned that DTG is associated with significant weight gain, in particular when combined with TAF and particularly among women, in whom the weight gain does not appear to plateau. What are the implications of these findings? First, that DTG-based ART should move forward as the preferred regimen globally as PEPFAR has decided. Second, DTG does seem to be associated with weight gain but much more significantly when combined with TAF and particularly among women. Clinicians should discuss with their patients the risks versus benefits of any regimen they are starting. Further research is needed to understand the mechanisms of this weight gain and its long-term metabolic implications.
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Ken is a 2019-2020 NEJM Editorial Fellow and a paediatrician working in the National Health Service of the United Kingdom. He graduated from Imperial College School of Medicine and is training in general paediatrics in London.