Background

The 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.

Methods

We 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.

中文翻译：

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撒哈拉以南非洲地区新的抗逆转录病毒治疗引发剂中多洛格韦和依法韦仑的风险和获益的最新评估：建模以指导治疗指南。

背景

在撒哈拉以南非洲的多个国家/地区，人们开始考虑使用整合酶抑制剂dolutegravir而不是依法韦仑，因为其具有较高的耐受性和较低的耐药性发生风险，因此人们开始使用抗逆转录病毒疗法（ART）。世卫组织要求为其2019年抗逆转录病毒药物指南更新提供更新的建模结果，该结果仅限于在新的ART引发剂中选择dolutegravir或efavirenz。为响应此要求，我们对初始一线抗病毒治疗方案的替代政策的风险和收益进行了建模。

方法

我们更新了现有的基于成人的HIV传播和进展的个体模型，以考虑有关在受孕时服用dolutegravir的女性神经管缺陷风险的信息，以及dolutegravir对体重增加的影响。该模型考虑了确定病毒抑制作用时的耐药性，并对临床结果和母婴传播产生了影响。我们对参数分布进行了采样，以创建各种流行病场景，这反映了撒哈拉以南非洲流行病和规划情况的多样性。对于每种情况，我们都考虑了2018年的情况，并比较了打算妊娠妇女中以依非韦伦为基础的方案，其他方案中以dolutegravir方案和基于dolutegravir方案的ART起始策略，包括打算怀孕的妇女。我们考虑了从2019年到2039年的20年期间的预期成果，使用了3％的折现率，并且每转换一个残疾调整生命年（DALY）的成本效益阈值为500美元。

发现

考虑到有关风险和收益的最新信息，采用基于多洛格韦的方案而非依非韦伦的方案（包括打算怀孕的妇女）开始抗逆转录病毒疗法的政策预计将为人们带来健康益处（每年避免10990个DALY）。节省成本（每年减少2·900万美元），从而使一个成年人口为1000万的国家/地区的总体疾病负担减少了每年16735个DALY。在我们有87％的背景场景中，针对打算怀孕的妇女，采用基于dolutegravir的方案开始抗逆转录病毒疗法的政策具有成本效益，而且这一发现在各种敏感性分析中都非常可靠，包括体重增加的潜在负面影响。

解释

在撒哈拉以南非洲的一系列模式情景中，我们发现以多洛格韦为基础的方案（包括打算怀孕的妇女）启动抗逆转录病毒疗法的政策将带来人口健康的好处，并且具有成本效益，支持WHO强烈推荐dolutegravir作为ART引发剂的首选药物。

资金

比尔和梅琳达·盖茨基金会。