Background

Antiretroviral therapy (ART) scale-up in sub-Saharan Africa combined with weak routine virological monitoring has driven increasing HIV drug resistance. We investigated ART failure, drug resistance, and early mortality among patients with HIV admitted to hospital in Malawi.

Methods

This observational cohort study was nested within the rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalised patients in Africa (STAMP) trial, which recruited unselected (ie, irrespective of clinical presentation) adult (aged ≥18 years) patients with HIV-1 at admission to medical wards. Patients were included in our observational cohort study if they were enrolled at the Malawi site (Zomba Central Hospital) and were taking ART for at least 6 months at admission. Patients who met inclusion criteria had frozen plasma samples tested for HIV-1 viral load. Those with HIV-1 RNA of at least 1000 copies per mL had drug resistance testing by ultra-deep sequencing, with drug resistance defined as intermediate or high-level resistance using the Stanford HIVDR program. Mortality risk was calculated 56 days from enrolment. Patients were censored at death, at 56 days, or at last contact if lost to follow-up. The modelling strategy addressed the causal association between HIV multidrug resistance and mortality, excluding factors on the causal pathway (most notably, CD4 cell count, clinical signs of advanced HIV, and poor functional and nutritional status).

Findings

Of 1316 patients with HIV enrolled in the STAMP trial at the Malawi site between Oct 26, 2015, and Sept 19, 2017, 786 had taken ART for at least 6 months. 252 (32%) of 786 patients had virological failure (viral load ≥1000 copies per mL). Mean age was 41·5 years (SD 11·4) and 528 (67%) of 786 were women. Of 237 patients with HIV drug resistance results available, 195 (82%) had resistance to lamivudine, 128 (54%) to tenofovir, and 219 (92%) to efavirenz. Resistance to at least two drugs was common (196, 83%), and this was associated with increased mortality (adjusted hazard ratio 1·7, 95% CI 1·2–2·4; p=0·0042).

Interpretation

Interventions are urgently needed and should target ART clinic, hospital, and post-hospital care, including differentiated care focusing on patients with advanced HIV, rapid viral load testing, and routine access to drug resistance testing. Prompt diagnosis and switching to alternative ART could reduce early mortality among inpatients with HIV.

Funding

Joint Global Health Trials Scheme of the Medical Research Council, UK Department for International Development, and Wellcome Trust.

中文翻译：

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马拉维入院成人的病毒学失败、HIV-1 耐药性和早期死亡率：一项观察性队列研究。

 背景

撒哈拉以南非洲地区抗逆转录病毒治疗（ART）的扩大，加上常规病毒学监测薄弱，导致艾滋病毒耐药性不断增加。我们调查了马拉维住院的艾滋病毒患者的 ART 失败、耐药性和早期死亡率。

 方法

这项观察性队列研究嵌套在非洲住院患者基于尿液的结核病快速筛查以降低艾滋病相关死亡率 (STAMP) 试验中，该试验招募了未经选择的（即不考虑临床表现）成年（年龄≥18岁）患者入住内科病房时感染 HIV-1。如果患者在马拉维站点（Zomba 中心医院）入组并且入院时接受 ART 至少 6 个月，则患者将被纳入我们的观察性队列研究。符合纳入标准的患者接受了冷冻血浆样本的 HIV-1 病毒载量检测。那些HIV-1 RNA至少为1000拷贝/毫升的人通过超深度测序进行耐药性测试，使用斯坦福HIVDR项目将耐药性定义为中度或高水平耐药性。死亡风险是在入组后 56 天计算的。患者在死亡时、第 56 天或最后一次联系（如果失访）时进行审查。该建模策略解决了 HIV 多药耐药性与死亡率之间的因果关系，排除了因果途径中的因素（最值得注意的是 CD4 细胞计数、晚期 HIV 的临床症状以及功能和营养状况不佳）。

 发现

2015年10月26日至2017年9月19日期间，在马拉维站点参加了STAMP试验的1316名艾滋病毒患者中，786名患者接受了至少6个月的抗逆转录病毒治疗。 786 名患者中有 252 名（32%）出现病毒学失败（病毒载量≥1000 拷贝/毫升）。平均年龄为 41·5 岁 (SD 11·4)，786 名参与者中有 528 名 (67%) 为女性。在 237 名 HIV 耐药患者中，195 名（82%）对拉米夫定耐药，128 名（54%）对替诺福韦耐药，219 名（92%）对依非韦伦耐药。对至少两种药物的耐药性很常见（196 例，83%），这与死亡率增加相关（调整后的危险比 1·7，95% CI 1·2–2·4；p=0·0042）。

 解释

迫切需要采取干预措施，并应针对 ART 诊所、医院和出院后护理，包括针对晚期 HIV 患者的差异化护理、快速病毒载量检测以及常规耐药性检测。及时诊断并转向替代抗逆转录病毒治疗可以降低住院艾滋病毒患者的早期死亡率。

 资金

医学研究委员会、英国国际发展部和威康信托基金联合全球健康试验计划。