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Objective: We aimed to assess the frequency of tenofovir (TDF) resistance in people failing tenofovir/lamivudine or emtricitabine (XTC)/nonnucleotide reverse-transcriptase inhibitor-based first-line antiretroviral treatment (ART) using data from 15 nationally representative surveys of HIV drug resistance conducted between 2014 and 2018 in Cameroon, Guatemala, Honduras, Nicaragua, Senegal, Uganda, Vietnam and Zambia., Methods: Prevalence of nucleoside reverse-transcriptase inhibitor resistance among participants with virological nonsuppression (viral load ≥1000 copies/ml) who had received TDF-based ART for 12-24 months (early ART group) and at least 40 months (long-term ART group) was assessed using Sanger sequencing and resistance was interpreted using the Stanford HIVdb algorithm. For each group, we estimated a pooled prevalence using random effect meta-analysis., Results: Of 4677 participants enrolled in the surveys, 640 (13.7%) had virological nonsuppression, 431 (67.3%) were successfully genotyped and were included in the analysis; of those, 60.3% (260) were participants in the early ART group. Overall, 39.1, 57.9, 38.5 and 3.6% patients in the early ART group and 42.9, 69.3, 42.9 and 10.0% patients on long-term ART had resistance to TDF, XTC, TDF + XTC and TDF + XTC + zidovudine, respectively. Overall, tenofovir resistance was mainly due to K65R or K70E/G/N/A/S/T/Y115F mutations (79%) but also due to thymidine analogue mutations (21%) which arise from exposure to thymidine analogues but causing cross-resistance to TDF., Conclusion: Dual resistance to TDF + XTC occurred in more than 40% of the people with viral nonsuppression receiving tenofovir-based first-line ART, supporting WHO recommendation to optimize the nucleoside backbone in second-line treatment and cautioning against single drug substitutions in people with unsuppressed viral load.

Objectives: To evaluate long-term virological failure (VF) and drug resistance among HIV-infected Ugandan children on first-line ART., Methods: In a multicentre prospective cohort study, viral load (VL) and drug resistance mutations (DRMs) were investigated at baseline and 6 monthly intervals in children (age ≤ 12 years). VF (two consecutive VLs >1000 copies/mL or death after 6 months of ART) was defined as early VF (0-24 months of ART) or late VF (25-48 months of ART). An active regimen was defined as partially active if the genotypic susceptibility score (GSS) was <3., Results: Between 2010 and 2011, 316 children were enrolled. Viral suppression was achieved in 75.8%, 71.5%, 72.6% and 69.2% at 12, 24, 36 and 48 months. VF occurred in 111/286 (38.8%), of which 67.6% was early and 32.4% late VF. Early VF was associated with a partially active regimen at baseline (OR 6.0, 95% CI 1.9-18.5), poor adherence (OR 3.1, 95% CI 1.3-7.4) and immunodeficiency (OR 3.3, 95% CI 1.1-10.2). Late VF was associated with age >3 years (OR 2.5, 95% CI 1.0-6.6) and WHO stage 3/4 (OR 4.2, 95% CI 1.4-13.4). Acquired DRMs were detected in 27.0% before 24 months, versus 14.4% after 24 months (P < 0.001). A total of 92.2% of the children with early VF, versus 56.2% with late VF, had a partially active regimen (P < 0.001)., Conclusions: VF rates were high, occurred predominantly in the first 24 months and appeared to increase again in year four. Risk factors and patterns of early VF/DRMs were different from those of late VF/DRMs. Virological control may improve by close monitoring and prompt switching to second-line therapy in the first 24 months. Late VF may be prevented by early start of ART., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Dried blood spots (DBS) are an alternative specimen type for HIV drug resistance genotyping in resource-limited settings. Data relating to the impact of DBS storage and shipment conditions on genotyping efficiency under field conditions are limited. We compared the genotyping efficiencies and resistance profiles of DBS stored and shipped at different temperatures to those of plasma specimens collected in parallel from patients receiving antiretroviral therapy in Uganda. Plasma and four DBS cards from anti-coagulated venous blood and a fifth card from finger-prick blood were prepared from 103 HIV patients with a median viral load (VL) of 57,062 copies/ml (range, 1,081 to 2,964,191). DBS were stored at ambient temperature for 2 or 4 weeks or frozen at -80 °C and shipped from Uganda to the United States at ambient temperature or frozen on dry ice for genotyping using a broadly sensitive in-house method. Plasma (97.1%) and DBS (98.1%) stored and shipped frozen had similar genotyping efficiencies. DBS stored frozen (97.1%) or at ambient temperature for 2 weeks (93.2%) and shipped at ambient temperature also had similar genotyping efficiencies. Genotyping efficiency was reduced for DBS stored at ambient temperature for 4 weeks (89.3%, P = 0.03) or prepared from finger-prick blood and stored at ambient temperature for 2 weeks (77.7%, P < 0.001) compared to DBS prepared from venous blood and handled similarly. Resistance profiles were similar between plasma and DBS specimens. This report delineates the optimal DBS collection, storage, and shipping conditions and opens a new avenue for cost-saving ambient-temperature DBS specimen shipments for HIV drug resistance (HIVDR) surveillances in resource-limited settings., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background: Earlier antiretroviral therapy initiation can reduce the incidence of HIV-1. This benefit can be offset by increased transmitted drug resistance (TDR). We compared the preventive benefits of reducing incident infections with the potential TDR increase in East Africa., Methods: A mathematical model was constructed to represent Kampala, Uganda, and Mombasa, Kenya. We predicted the effect of initiating treatment at different immunological thresholds (<350, <500 CD4 cells/μl) on infections averted and mutation-specific TDR prevalence over 10 years compared to initiating treatment at CD4 cell count below 200 cells/μl., Results: When initiating treatment at CD4 cell count below 350 cells/μl, we predict 18 [interquartile range (IQR) 11-31] and 46 (IQR 30-83) infections averted for each additional case of TDR in Kampala and Mombasa, respectively, and 22 (IQR 17-35) and 32 (IQR 21-57) infections averted when initiating at below 500. TDR is predicted to increase most strongly when initiating treatment at CD4 cell count below 500 cells/μl, from 8.3% (IQR 7.7-9.0%) and 12.3% (IQR 11.7-13.1%) in 2012 to 19.0% (IQR 16.5-21.8%) and 19.2% (IQR 17.1-21.5%) in 10 years in Kampala and Mombasa, respectively. The TDR epidemic at all immunological thresholds was comprised mainly of resistance to non-nucleoside reverse transcriptase inhibitors. When 80-100% of individuals with virological failure are timely switched to second-line therapy, TDR is predicted to decline irrespective of treatment initiation threshold., Conclusion: Averted HIV infections due to the expansion of antiretroviral treatment eligibility offset the risk of transmitted drug resistance, as defined by more infections averted than TDR gained. The effectiveness of first-line non-nucleoside reverse transcriptase inhibitor-based therapy can be preserved by improving switching practices to second-line therapy.

During 2006-2007, transmitted human immunodeficiency virus (HIV) drug resistance (TDR) among drug-naive women with newly diagnosed HIV infection and likely to be recently infected when attending antenatal clinics in Entebbe was found to be <5% with use of the World Health Organization (WHO) survey method. Using the same method, we attempted to classify TDR among women who seroconverted during 2008-2010 and who were identified from a cohort of recently infected sex workers in Kampala, Uganda. TDR mutations were identified using the 2009 WHO TDR mutations list. The WHO survey method could not be used to classify TDR because the necessary sample size was not reached during the survey period. However, a point prevalence estimate of 2.6% (95% confidence interval, 0.07%-13.8%) nonnucleoside reverse-transcriptase inhibitor TDR was determined.