Virological failure, HIV-1 drug resistance, and early mortality in adults admitted to hospital in Malawi: an observational cohort study

Abstract

Summary 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.

Phylogenetic and Drug-Resistance Analysis of HIV-1 Sequences From an Extensive Paediatric HIV-1 Outbreak in Larkana, Pakistan

“…A high prevalence of this mutation has been seen previously in ART-experienced PLWH in Pakistan (Shah et al, 2011) and when found in the ART-naïve population, it may be present due to transmission from non-compliant ART-experienced individuals. The presence of DRMs, especially associated with resistance to zidovudine and nevirapine, two out of three that are drugs part of the ART regimen given to the children, may lead to ART failure (correlating with failure to suppress the viral load), and increase the possibility that these individuals may acquire severe form of disease (Gupta-Wright et al, 2020). A second DRM common in the outbreak sequences was the RT:K219N mutation, a thymidine analogue mutation associated with potential low-level resistance against zidovudine (Rhee et al, 2003).…”

Early Empirical Tuberculosis Treatment in HIV-Positive Patients Admitted to Hospital in South Africa: An Observational Cohort Study

“…In this study, 60% of patients were diagnosed with concurrent HIV-associated diagnoses. Our finding of higher mortality in empirically treated patients than among with microbiologically confirmed TB may be partially explained by higher prevalence of TB meningitis, untreated opportunistic infections (particularly central nervous system infections given high prevalence of abnormal CSF results), comorbidities, or HIV drug resistance [ 30 ]. This population could also benefit from enhanced diagnostics beyond TB coinfection alone.…”

Clinical, health systems and neighbourhood determinants of tuberculosis case fatality in urban Blantyre, Malawi: a multilevel epidemiological analysis of enhanced surveillance data

“…Persistently high case fatality for HIV-positive people despite high ART coverage suggests that HIV-positive people have severe acute illness [28], have profound delays in TB diagnosis and treatment initiation [29,30], or have virological failure to HIV treatment, which itself confers a high risk of death. In a study among HIV-positive people taking ART who were admitted to hospital in Zomba District, Malawi (32%) had virological treatment failure, and resistance to first-line ART drugs was near-universal [31]. Improvements in viral load monitoring and rapid treatment changes linked to supportive adherence interventions could reduce the number of patients that present with severe disease at the start of TB treatment and save more lives [31,32].…”