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Background: High, sustained adherence to HIV antiretroviral therapy (ART) is critical for achieving viral suppression, which in turn leads to important individual health benefits and reduced secondary viral transmission. Electronic adherence monitors record a date-and-time stamp with each opening as a proxy for pill-taking behavior. These monitors can be combined with interventions (eg, data-informed adherence counseling, SMS-based adherence support, and/or alarms) and have been shown to improve adherence in multiple settings. Their use, however, has largely been limited to the research context., Objective: The goal of the research was to use the Consolidated Framework for Implementation Research (CFIR) to understand factors relevant for implementing a low-cost electronic adherence monitor and associated interventions for routine HIV clinical care in Uganda., Methods: We conducted in-depth qualitative interviews with health care administrators, clinicians, and ART clients about likes and dislikes of the features and functions of electronic adherence monitors and associated interventions, their potential to influence HIV care, suggestions on how to measure their value, and recommendations for their use in routine care. We used an inductive, content analysis approach to understand participant perspectives, identifying aspects of CFIR most relevant to technology implementation in this setting., Results: We interviewed 34 health care administrators/clinicians and 15 ART clients. Participants largely saw the monitors and associated interventions as favorable and beneficial for supporting adherence and improving clinical outcomes through efficient, differentiated care. Relevant outside factors included structural determinants of health, international norms around supporting adherence, and limited funding that necessitates careful assessment of costs and benefits. Within the clinic, the adherence data were felt likely to improve the quality of counseling and thereby morale, as well as increase the efficiency of care delivery. Existing infrastructure and care expenditures and the need for proper training were other noted considerations. At the individual level, the desire for good health and a welcomed pressure to adhere favored uptake of the monitors, although some participants were concerned with clients not using the monitors as planned and the influence of poverty, stigma, and need for privacy. Finally, participants felt that decisions around the implementation process would have to come from the Ministry of Health and other funders and would be influenced by sustainability of the technology and the target population for its use. Coordination across the health care system would be important for implementation., Conclusions: Low-cost electronic adherence monitoring combined with data-informed counseling, SMS-based support, and/or alarms have potential for use in routine HIV care in Uganda. Key metrics of successful implementation will include their impact on efficiency of care delivery and clinical outcomes with careful attention paid to factors such as stigma and cost. Further theory-driven implementation science efforts will be needed to move promising technology from research into clinical care., Trial Registration: ClinicalTrials.gov NCT03825952; https://clinicaltrials.gov/ct2/show/NCT03825952., (©Jessica E Haberer, Lindsey Garrison, John Bosco Tumuhairwe, Robert Baijuka, Edna Tindimwebwa, James Tinkamanyire, Bridget F Burns, Stephen Asiimwe. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 10.09.2020.)

The prevalence of HIV pretreatment drug resistance (PDR) is increasing in sub-Saharan Africa. We sought to describe correlates of PDR and evaluate effects of PDR on clinical outcomes in rural Uganda. We analyzed data from the Uganda AIDS Rural Treatment Outcomes study, a cohort of antiretroviral therapy (ART)-naive adults with HIV (2005-2015). We performed resistance testing on pre-ART specimens. We defined PDR as any World Health Organization (WHO) 2009 surveillance drug resistance mutation and classified PDR level using the Stanford algorithm. We fit unadjusted and sex-stratified log binomial regression and Cox proportional hazard models to identify correlates of PDR and the impact of PDR on viral suppression, loss to follow-up (LTFU), and death. We analyzed data from 738 participants (median age 33 years, 69% female). Overall, prevalence of PDR was 3.5% (n = 26), owing mostly to resistance to non-nucleoside reverse transcriptase inhibitors. PDR increased over time in women (1.8% in those enrolling in clinic in 2001-2006, vs. 7.0% in 2007-2013; p = 0.006), but not in men (1.15% vs. 0.72%, p = 0.737). Lower pre-ART log 10 HIV RNA was also associated with higher prevalence of PDR. We identified longer time to viral suppression among those with PDR compared with without PDR (0.5 and 0.3 years, respectively, p = 0.023), but there was no significant relationship with mortality or LTFU (p = 0.139). We observed increasing rates of PDR in women in southwestern Uganda. Implications of this trend, particularly to prevention of mother-to-child transmission programs in the region, require attention due to delayed viral suppression among those with PDR.

Background: Data on pediatric second-line antiretroviral treatment (ART) outcomes are scarce, but essential to evaluate second-line and design third-line regimens., Methods: Children ≤12 years switching to second-line ART containing a protease inhibitor (PI) in Uganda were followed for 24 months. Viral load (VL) was determined at switch to second-line and every 6 months thereafter; genotypic resistance testing was done if VL ≥ 1000 cps/ml., Results: 60 children were included in the analysis; all had ≥1 drug resistance mutations at switch. Twelve children (20.0%) experienced treatment failure; no PI mutations were detected. Sub-optimal adherence and underweight were associated with treatment failure., Conclusions: No PI mutations occurred in children failing second-line ART, which is reassuring as pediatric third-line is not routinely available in these settings. Poor adherence rather than HIV drug resistance is likely to be the main mechanism for treatment failure and should receive close attention in children on second-line ART., (© The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

HIV-1 viral load (VL) monitoring is recommended but seldom performed in resource-constrained countries. An evaluation of patients receiving first-line antiretroviral therapy in a multicountry PEPFAR program (RV288) was performed to determine the rates and predictors of virologic suppression. Resistance data from treatment failures are available from Uganda and Nigeria. Each country enrolled 325 subjects into this cross-sectional study. Subjects on first-line therapy were randomly selected for HIV RNA testing (viral load). Regimens included efavirenz or nevirapine with zidovudine/lamivudine or tenofovir/lamivudine. VL was determined from plasma using the Roche COBAS TaqMan HIV-1 Test, High Pure System v1.0 (47 copies/ml). Genotypic resistance testing was performed on samples with VL>1,000 copies/ml. From Uganda, 85% of subjects were undetectable while 7% (23/325) had VL>1,000 copies/ml. The HIV-1 subtype distribution was as follows: A=47.6%, C=14.3%, and D=38.1%. No resistance mutations were found in 14% of subjects. All subjects with resistance had the M184V mutation. Of subjects failing a zidovudine regimen less than 1 year, 88% (7/8) had no thymidine analogue mutations (TAMs), compared to 50% (4/8) failing greater than 1 year. Four subjects (25%) had more than two mutations from the TAM-1 pathway (41L, 210W, 215Y). In Nigeria, 82% were undetectable while 14% (45/325) had VL>1,000 copies/ml. HIV-1 subtype distribution was as follows: 62.8%=CRF02_AG, 34%=pure G, and 2.8%=A. Of the 35 genotyped subjects, 14% (5/35) had no resistance mutations. Of the remainder, 10% (3/30) had no nucleoside analogue mutations while 33% (10/30) had only M184V along with nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations. Forty percent (10/25) of subjects on zidovudine failed without TAMs. Another 25% (5/25) of subjects failing on zidovudine had more than two TAM-1 mutations. Individuals failing first-line antiretroviral therapy (ART) may retain sensitivity to one or more nucleoside analogues from the regimen. Knowledge of drug resistance patterns allow for selection of drugs that can be recycled in future regimens. Accumulation of resistance mutations may compromise future treatment options.

Background: The HIV Prevention Trials Network (HPTN) 046 trial evaluated the efficacy of extended infant nevirapine (NVP) administration for prevention of HIV transmission through breastfeeding. Infants received daily NVP up to 6 weeks of age. HIV-uninfected infants (the intent-to-treat group) received daily NVP or placebo up to 6 months of age. We analyzed emergence of NVP resistance in infants who acquired HIV infection despite prophylaxis., Methods: HIV genotyping was performed using the ViroSeq HIV Genotyping System. Medians and proportions were used to summarize data. Two-sided Fisher exact tests were used to evaluate associations between categorical variables., Results: NVP resistance was detected in 12 (92.3%) of 13 infants who were HIV-infected by 6 weeks and in 7 (28%) of 25 infants who were HIV-uninfected at 6 weeks and HIV-infected at 6 months of age (6/8 = 75% in the NVP arm, 1/17 = 5.9% in the placebo arm, P = 0.001). Among those 25 infants, 4 had mothers who initiated an antiretroviral treatment regimen by 6 months postpartum. In all 4 cases, the treatment regimen included a non-nucleoside reverse transcriptase inhibitor (NVP or efavirenz). NVP resistance was detected in all 4 of those infants by 6 months of age (4/4 = 100%). In contrast, only 3 (14.2%) of the remaining 21 HIV-infected infants whose mothers did not initiate antiretroviral treatment developed NVP resistance (P = 0.003)., Conclusions: Extended NVP prophylaxis significantly increased the risk of NVP resistance in infants who acquired HIV infection after 6 weeks of age. Treatment of maternal HIV infection was also associated with emergence of NVP resistance in HIV-infected, breastfed infants.

We sought to determine the pattern of resistance-associated mutations (RAMs) among HIV-1-infected children failing first-line antiretroviral therapy (ART) and ascertain their response to second-line regimens in 48 weeks of follow-up. The design involved a cohort study within an HIV care program. We studied records of 142 children on ART with virological failure to first-line ART and switched to second-line ART with prior genotypic resistance testing. The pattern of RAMs was determined in frequency runs and the factors associated with accumulation of≥3 thymidine analogue mutations (TAMs) and K103N were determined using multivariate logistic models. Changes in weight, height, CD4, and viral load at weeks 24 and 48 after switch to second-line therapy were determined using descriptive statistics. The children were mean age 10.9±4.6 years and 55.6% were male. The commonest nucleoside reverse transcriptase inhibitor (NRTI) RAM was M184V in 129/142 (90.8%) children. TAMs,≥3 TAMs, 69 insertion complex, K65R/N, and Q151M were observed in 43.0%, 10.6%, 18.3%, 2.8%, and 2.1% of the children, respectively. The commonest nonnucleoside reverse transcriptase inhibitor (NNRTI) RAM was K103N in 72/142 (50.7%) children. The starting ART regimen was associated with accumulation of both≥3 TAMs (p=0.046) and K103N (p<0.0001), while a history of poor adherence was associated with K103N accumulation (p=0.0388). After 24 weeks and 48 weeks of follow-up on lopinavir-ritonavir based second-line ART, 86/108 (79.6%) and 84.5% (87/103) of the children had viral loads<400 copies/ml, respectively. The mean CD4 absolute count increased by 173 cells/μl and 267cells/μl at weeks 24 and 48, respectively. Increments were also observed in mean weight (1.6 kg and 4.3 kg) and height (1.8 cm and 5.8 cm) at weeks 24 and 48, respectively. Multiple RAMs were observed among HIV-1-infected children with virological failure on first-line ART with M184V and K103N most frequent. The children responded favorably to boosted PI-based second-line ART.

Objective: HIV pathogenesis is characterized by destructive imbalances between virus-mediated immune damage, antiviral immune responses, and immune activation. We characterized the effects of successful antiretroviral therapy (ART) to identify the breadth and patterns of HIV-associated gene expression., Methods: In a prospective observational, longitudinal cohort study of 10 ART-naive Ugandans with AIDS (median 30 CD4/μL), we measured mRNA gene profiles in peripheral blood using Affymetrix U133&#95;Plus2.0 microarrays at 0, 2, 4, 8, and 24 weeks after ART initiation., Results: We identified 160 mRNA transcripts that were consistently down-regulated and 48 that were up-regulated after ART at each point over 24 weeks based on linear regression modeling (adjusted P < 0.05), Of these 208 transcripts, approximately half represent heretofore unrecognized ART-responsive genes and one-third have no known function. The down-regulated genes with known function encoded mediators of innate antiviral responses, including antiviral restriction factors, pattern recognition receptors, and interferon response proteins, and mediators of immune activation, cellular proliferation, and apoptosis., Conclusions: By using ART to block the viral stimulus, we identified transcripts involved in innate antiviral immunity, including antiviral restriction factors and pattern recognition receptors, that were not previously known to be induced by HIV infection.

Objective: To evaluate the safety and virological response to lopinavir/ritonavir containing second-line therapy after failing a first line nonnucleoside reverse transcriptase inhibitor (NNRTI) based regimen., Design: Prospective 36 months cohort study of patients switched to zidovudine/stavudine plus didanosine plus lopinavir/ritonavir capsules as second-line regimen., Methodology: Structured interview, medical examination, and laboratory assessment performed every 6 months., Results: We enrolled 40 patients; 1 died and 3 were lost to follow-up. Median CD4+ count at baseline was 108 cell/microL, median log viral load was 4.8 copies/mL. Sixteen (40%) patients had baseline genotypic resistant test, 14 (87%) had lamivudine resistance mutations, and all had NNRTIs resistance mutations. At month 36, 82% of the patients achieved viral suppression (<400 copies/ mL) and the median increase in CD4+ count was 214 cell/microL, (interquartile range: 128-295). Twenty-five patients (62%) experienced at least one adverse event., Conclusions: Our study confirms lopinavir/ ritonavir-based second-line regimen but with a high rate of toxicities.