Updated assessment of risks and benefits of dolutegravir versus efavirenz in new antiretroviral treatment initiators in sub-Saharan Africa: modelling to inform treatment guidelines

Abstract

BackgroundThe integrase inhibitor dolutegravir is being considered in several countries in sub-Saharan Africa instead of efavirenz for people initiating antiretroviral therapy (ART) because of superior tolerability and a lower risk of resistance emergence. WHO requested updated modelling results for its 2019 Antiretroviral Guidelines update, which was restricted to the choice of dolutegravir or efavirenz in new ART initiators. In response to this request, we modelled the risks and benefits of alternative policies for initial first-line ART regimens. MethodsWe updated an existing individual-based model of HIV transmission and progression in adults to consider information on the risk of neural tube defects in women taking dolutegravir at time of conception, as well as the effects of dolutegravir on weight gain. The model accounted for drug resistance in determining viral suppression, with consequences for clinical outcomes and mother-to-child transmission. We sampled distributions of parameters to create various epidemic setting scenarios, which reflected the diversity of epidemic and programmatic situations in sub-Saharan Africa. For each setting scenario, we considered the situation in 2018 and compared ART initiation policies of an efavirenz-based regimen in women intending pregnancy, and a dolutegravir-based regimen in others, and a dolutegravir-based regimen, including in women intending pregnancy. We considered predicted outcomes over a 20-year period from 2019 to 2039, used a 3% discount rate, and a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted.Findings Considering updated information on risks and benefits, a policy of ART initiation with a dolutegravir-based regimen rather than an efavirenz-based regimen, including in women intending pregnancy, is predicted to bring population health benefits (10 990 DALYs averted per year) and to be cost-saving (by $2•9 million per year), leading to a reduction in the overall population burden of disease of 16 735 net DALYs per year for a country with an adult population size of 10 million. The policy involving ART initiation with a dolutegravir-based regimen in women intending pregnancy was cost-effective in 87% of our setting scenarios and this finding was robust in various sensitivity analyses, including around the potential negative effects of weight gain. Interpretation In the context of a range of modelled setting scenarios in sub-Saharan Africa, we found that a policy of ART initiation with a dolutegravir-based regimen, including in women intending pregnancy, was predicted to bring population health benefits and be cost-effective, supporting WHO's strong recommendation for dolutegravir as a preferred drug for ART initiators.Funding Bill & Melinda Gates Foundation.

Cost-Utility Analysis of a Dolutegravir-Based Versus Low-Dose Efavirenz-Based Regimen for the Initial Treatment of HIV-Infected Patients in Cameroon (NAMSAL ANRS 12313 Trial)

“…Most PROs significantly improved over time in both arms, mainly during the first 48 weeks, with no significant changes observed beyond W48 or significant differences between arms at W96 (complete results are available in the Online Resource, p. [13][14][15].…”

“…Despite these challenges, knowledge about the patient and economic values of these two regimens in SSA is limited. Although the cost-effectiveness of a DTG-based first-line regimen in this region has recently been assessed using modelling [13][14][15], no study has compared DTG with EFV400 while taking the patient's point of view into account.…”

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

“…4 Secondly, greater weight gain was observed in patients treated with DTG compared to efavirenz (EFV) in two clinical trials in sub-Saharan Africa, and elsewhere, leading to concerns about long-term effects of obesity with lifelong ART. [5][6][7][8][9] Whilst cost-effectiveness analyses continue to support the use of DTG as rst-line therapy despite these issues, 10 the WHO and others are revisiting targeted use of efavirenz (EFV). Concerns remain about the use of EFV with widespread NNRTI resistance, which exceeds 10-15% in much of sub-Saharan Africa.…”

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

“…Whilst cost-effectiveness analyses continue to support the use of DTG as first-line therapy despite these issues 10 , the WHO and others are revisiting targeted use of efavirenz (EFV). Concerns remain about the use of EFV with widespread NNRTI resistance, which exceeds 10−15% in much of sub-Saharan Africa 11 .…”