Pre-treatment integrase inhibitor resistance is uncommon in antiretroviral therapy-naive individuals with HIV-1 subtype A1 and D infections in Uganda.

OBJECTIVE: Dolutegravir (DTG) is now a preferred component of first-line antiretroviral therapy (ART). However, prevalence data on natural resistance to integrase inhibitors [integrase strand transfer inhibitors (INSTIs)] in circulating non-subtype B HIV-1 in sub-Saharan Africa is scarce. Our objective is to report prevalence of pre-treatment integrase polymorphisms associated with resistance to INSTIs in an ART-naive cohort with diverse HIV-1 subtypes. DESIGN: We retrospectively examined HIV-1 integrase sequences from Uganda. METHODS: Plasma samples were derived from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort, reflecting enrollment from 2002 to 2010, prior to initiation of ART. HIV-1 integrase was amplified using nested-PCR and Sanger-sequenced (HXB2 4230-5093). Stanford HIVdb v8.8 was used to infer clinically significant INSTI-associated mutations. Human leukocyte antigen (HLA) typing was performed for all study participants. RESULTS: Plasma samples from 511 ART-naive individuals (subtype: 48% A1, 39% D) yielded HIV-1 integrase genotyping results. Six out of 511 participants (1.2%) had any major INSTI-associated mutations. Of these, two had E138T (subtype A1), three had E138E/K (subtype D), and one had T66T/I (subtype D). No participants had mutations traditionally associated with high levels of INSTI resistance. HLA genotypes A∗02:01/05/14, B∗44:15, and C∗04:07 predicted the presence of L74I, a mutation recently observed in association with long-acting INSTI cabotegravir virologic failure. CONCLUSION: We detected no HIV-1 polymorphisms associated with high levels of DTG resistance in Uganda in the pre-DTG era. Our results support widespread implementation of DTG but careful monitoring of patients on INSTI with virologic failure is warranted to determine if unique mutations predict failure for non-B subtypes of HIV-1.

Prevalence and correlates of chronic obstructive pulmonary disease and chronic respiratory symptoms in rural southwestern Uganda: a cross-sectional, population-based study.

BACKGROUND: The global burden of chronic obstructive pulmonary disease (COPD) disproportionately affects resource-limited settings such as sub-Saharan Africa (SSA), but population-based prevalence estimates in SSA are rare. We aimed to estimate the population prevalence of COPD and chronic respiratory symptoms in rural southwestern Uganda. METHODS: Adults at least 18 years of age who participated in a population-wide census in rural southwestern Uganda completed respiratory questionnaires and lung function testing with bronchodilator challenge at health screening events in June 2015. We defined COPD as post-bronchodilator forced expiratory volume in one second to forced vital capacity ratio less than the lower limit of normal. We fit multivariable linear and log binomial regression models to estimate correlates of abnormal lung function and respiratory symptoms, respectively. We included inverse probability of sampling weights in models to facilitate population-level estimates. RESULTS: Forty-six percent of census participants (843/1814) completed respiratory questionnaires and spirometry, of which 565 (67%) met acceptability standards. COPD and respiratory symptom population prevalence were 2% (95% confidence interval (CI) = 1%-3%) and 30% (95% CI = 25%-36%), respectively. Respiratory symptoms were more prevalent and lung function was lower among women and ever-smokers (P < 0.05). HIV serostatus was associated with neither respiratory symptoms nor lung function. CONCLUSIONS: COPD population prevalence was low despite prevalent respiratory symptoms. This work adds to the growing body of literature depicting lower-than-expected COPD prevalence estimates in SSA and raises questions about whether the high respiratory symptom burden in rural southwestern Uganda represents underlying structural lung disease not identified by screening spirometry.

Prevalence and clinical impacts of HIV-1 intersubtype recombinants in Uganda revealed by near-full-genome population and deep sequencing approaches.

OBJECTIVES: HIV-1 subtypes A1 and D cocirculate in a rural community in Mbarara, Uganda. This study examines HIV-1 intersubtype recombination in this community under a full-genome sequencing context. We aim to estimate prevalence, examine time trends, and test for clinical correlates and outcomes associated with intersubtype recombinants. METHODS: Near-full-genome HIV-1 Sanger sequence data were collected from plasma samples of 504 treatment-naïve individuals, who then received protease inhibitor or nonnucleoside reverse transcriptase inhibitor-containing regimens and were monitored for up to 7.5 years. Subtypes were inferred by Los Alamos Recombinant Identification Program (RIP) 3.0 and compared with Sanger/REGA and MiSeq/RIP. 'Nonrecombinants' and 'recombinants' infections were compared in terms of pretherapy viral load, CD4 cell count, posttherapy time to virologic suppression, virologic rebound, first CD4 rise above baseline and sustained CD4 recovery. RESULTS: Prevalence of intersubtype recombinants varied depending on the genomic region examined: gag (15%), prrt (11%), int (8%), vif (10%), vpr (2%), vpu (9%), GP120 (8%), GP41 (18%), and nef (4%). Of the 200 patients with near-full-genome data, prevalence of intersubtype recombination was 46%; the most frequently observed recombinant was A1-D (25%). Sanger/REGA and MiSeq/RIP yielded generally consistent results. Phylogenetic tree revealed most recombinants did not share common ancestors. No temporal trend was observed (all P > 0.1). Subsequent subtype switches were detected in 27 of 143 (19%) study participants with follow-up sequences. Nonrecombinant versus recombinants infections were not significantly different in any pre nor posttherapy clinical correlates examined (all P > 0.2). CONCLUSION: Intersubtype recombination was highly prevalent (46%) in Uganda if the entire HIV genome was considered, but was neither associated with clinical correlates nor therapy outcomes.