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Background: WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine., Methods: In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete., Findings: Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI -3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3-4 adverse event were similar between the dolutegravir (26 [11%]) and darunavir (28 [12%]) groups and between the tenofovir (22 [9%]) and zidovudine (32 [14%]) groups. There were no deaths related to study medication., Interpretation: Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine., Funding: Janssen., Competing Interests: Declaration of interests NIP reports grants paid to his institution and personal fees from Janssen. CK, AL, and HM report grants and the donation of drugs and trial supplies to their institutions from Janssen. AKam reports grants paid to his institution from Janssen. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In the last decade, survival of people living with HIV (PLHIV) has dramatically increased due wide availability of effective antiretroviral therapy. However, PLHIV remain at a comparatively higher risk of non-communicable comorbidities. We sought to determine the burden of COPD and its associations in an urban tertiary HIV clinic in Uganda., Methods and Findings: HIV-infected adults attending the Makerere University Joint AIDS program; aged ≥30 years without acute ailments were screened for COPD using study questionnaires and spirometry (post-bronchodilator FEV1/FVC<0.7). We determined its prevalence and association with demographic characteristics, body mass index (BMI) and known risk factors. Of 288 participants enrolled, 177 (61%) were female; 253 (88%) were from urban residences, median age was 45 years (IQR: 39-51), 71(25%) were 'ever' smokers, 284(99%) reported biomass fuel use and 72(25%) had a history of tuberculosis. All except 1 participant were on antiretroviral therapy, median current CD4 (cells/mm3) was 558 (IQR 402-753) and 275(96%) were virologically suppressed. Nearly half (130/288, 45%) had recurrent respiratory symptoms. The prevalence of COPD was 3.1% (9/288) [95% CI: 1.63-5.92]. COPD was associated with: previous tuberculosis, (adjusted odds ratio (AOR): 6.36, [95% CI 1.64-35.84], P = 0.036), self-reported chronic shortness of breath (AOR: 9.06, [95% CI 1.34-61.10], P = 0.024) and a BMI <21 Kg/m2 (AOR: 10.42 [95% CI: 1.61-100.00], P = 0.013)., Conclusion: In this HIV population, COPD prevalence was low and was associated with previous tuberculosis, self-reported chronic shortness of breath and BMI <21 Kg/m2., Competing Interests: The authors have declared that no competing interests exist

Background: The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine., Methods: In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points)., Results: We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison., Conclusions: Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.)., (Copyright © 2021 Massachusetts Medical Society.)

INTRODUCTION AND OBJECTIVE: In May 2018, the World Health Organization and other regulatory authorities released a safety alert for dolutegravir related to a risk of neural tube defects among women exposed to dolutegravir at the time of conception. Models of how drug safety information can be shared effectively in the shortest time are necessary to prevent interruptions of public health programs. We sought to describe an implementation process to inform and support women already on dolutegravir-based regimens at the time of conception to make informed choices following the safety alert of a potential teratogenicity risk. We describe the choices made by women, as well as determine the factors associated with women's choices to switch off dolutegravir., Methods: A clinic response plan was developed in the first week following the alert and clinic staff were trained on safety guidance. All women aged < 55 years taking dolutegravir were identified from the clinic database and contacted by phone for earlier appointments. Non-menopausal and non-surgically sterilized women were referred for urine pregnancy testing and evaluation of pregnancy intentions in the following 12 months and effective family planning was offered. We describe the coverage of women who received the communication as well as the fidelity to the outlined plan from 21 May to 12 September, 2018. We used modified a Poisson regression analysis to determine factors associated with switching off dolutegravir., Results: Of all active patients in the clinic, 9% (690/7963) were identified as female aged < 55 years taking dolutegravir. Ninety-five percent (656/690) were reviewed by September 2018 and informed of the safety alert, implying a high level of uptake. Fidelity to standard operating procedures was also high at 72%. Twenty-two percent (146/656) of patients were menopausal or surgically sterilized. Five hundred and ten women were of reproductive potential with a median age (interquartile range) of 37 years (30-42 years). Five percent (23/510) were human chorionic gonadotrophin positive and all initial ultrasound reports revealed no deformities. Twenty-one percent (108/510) had intentions to conceive and opted to stop taking dolutegravir with 90% (97/108) switching to efavirenz. Seventy-nine percent (402/510) opted to remain taking dolutegravir. However, only 40% (160/402) chose effective contraceptive methods and 60% (242/402) opted for condoms only/no contraceptive method., Conclusions: A rapid well-coordinated response ensured prompt communication of the dolutegravir safety warning. The process developed by the clinic can act as a model for response during drug safety alerts. Women made informed decisions with most opting to remain taking dolutegravir; however, effective contraception uptake was low.

Background: HIV drug resistance and suboptimal adherence are the main reasons for treatment failure among HIV-infected individuals. As genotypic resistance testing is not routinely available in resource-limited settings such as Uganda, data on transmitted and acquired resistance are sparse., Methods: This observational follow-up study assessed the virological outcomes of patients diagnosed with virological failure or transmitted HIV drug resistance in 2015 at the adults' outpatient clinic of the Infectious Diseases Institute in Kampala, Uganda. Initially, 2430 patients on antiretroviral therapy (ART) underwent virological monitoring, of which 190 had virological failure and were subsequently eligible for this follow-up study. Nine patients diagnosed with transmitted drug resistance were eligible. In patients with a viral load > 1000 copies/mL, genotypic resistance testing was performed., Results: Of 190 eligible patients, 30 (15.8%) had either died or were lost to follow-up. A total of 148 (77.9%) were included, of which 98 had had a change of ART regimen, and 50 had received adherence counseling only. The majority was now on second-line ART (N = 130, 87.8%). The median age was 39 years (interquartile range: 32-46), and 109 (73.6%) were women. Virological failure was diagnosed in 29 (19.6%) patients, of which 24 (82.8%) were on second-line ART. Relevant drug resistance was found in 25 (86.2%) cases, of which 12 (41.3%) carried dual and 7 (24.1%) triple drug resistance., Conclusion: Two years after initial virological failure, most patients followed up by this study had a successful virological outcome. However, a significant proportion either continued to fail or died or was lost to follow-up.

Background: Little is known about prevalence of drug resistance among HIV-infected Ugandans, a setting with over 15 years of public sector access to antiretroviral therapy (ART) and where virological monitoring was only recently introduced., Setting: This study was conducted in the adults' out-patient clinic of the Infectious Diseases Institute, Kampala, Uganda., Methods: HIV genotyping was performed in ART-naive patients and in treatment-experienced patients on ART for ≥6 months with virological failure (≥1000 copies/mL)., Results: A total of 152 ART-naive and 2430 ART-experienced patients were included. Transmitted drug resistance was detected in 9 (5.9%) patients. After a median time on ART of 4.7 years [interquartile range: 2.5-8.7], 190 patients (7.8%) had virological failure with a median viral load of 4.4 log10 copies per milliliter (interquartile range: 3.9-4.9). In addition, 146 patients had a viral load between 51 and 999 copies per milliliter. Most patients with virological failure (142, 74.7%) were on first-line ART. For 163 (85.8%) ART-experienced patients, genotype results were available. Relevant drug-resistance mutations were observed in 135 (82.8%), of which 103 (63.2%) had resistance to 2 drug classes, and 11 (6.7%) had resistance to all drug classes available in Uganda., Conclusion: The prevalence of transmitted drug resistance was lower than recently reported by the WHO. With 92% of all patients virologically suppressed on ART, the prevalence of virological failure was low when a cutoff of 1000 copies per milliliter is applied, and is in line with the third of the 90-90-90 UNAIDS targets. However, most failing patients had developed multiclass drug resistance.

Recent studies have evaluated cumulative human immunodeficiency virus type 1 (HIV-1) viral load (cVL) for predicting disease outcomes, with discrepant results. We reviewed the disparate methodological approaches taken and evaluated the prognostic utility of cVL in a resource-limited setting. Using data on the Infectious Diseases Institute (Makerere University, Kampala, Uganda) cohort, who initiated antiretroviral therapy in 2004-2005 and were followed up for 9 years, we calculated patients' time-updated cVL by summing the area under their viral load curves on either a linear scale (cVL1) or a logarithmic scale (cVL2). Using Cox proportional hazards models, we evaluated both metrics as predictors of incident opportunistic infections and mortality. Among 489 patients analyzed, neither cVL measure was a statistically significant predictor of opportunistic infection risk. In contrast, cVL2 (but not cVL1) was a statistically significant predictor of mortality, with each log10 increase corresponding to a 1.63-fold (95% confidence interval: 1.02, 2.60) elevation in mortality risk when cVL2 was accumulated from baseline. However, whether cVL is predictive or not hinges on difficult choices surrounding the cVL metric and statistical model employed. Previous studies may have suffered from confounding bias due to their focus on cVL1, which strongly correlates with other variables. Further methodological development is needed to illuminate whether the inconsistent predictive utility of cVL arises from causal relationships or from statistical artifacts., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Few studies have prospectively examined sexual behaviors of HIV-infected person on antiretroviral therapy (ART) in sub-Saharan Africa., Methods: Between 2004 and 2005, 559 HIV-infected, ART-naïve individuals initiating ART at an HIV clinic in Kampala, Uganda, were enrolled into a prospective study and followed to 2008. Clinical and sexual behavior information was assessed at enrollment and semiannually for 3 years after ART initiation. Using log-binomial regression models, we estimated prevalence ratios (PRs) to determine factors associated with being sexually active and having unprotected sex over 3 years after initiating ART., Results: Five hundred fifty-nine adults contributed 2594 person-visits of follow-up. At the time of ART initiation, 323 (57.9%) were sexually active of which 176 (54.5%) had unprotected sex at last sexual intercourse. The majority (63.4%) of married individuals were unaware of their partner's HIV status. Female gender (PR, 2.97; 95% confidence interval, 1.85-4.79), being married (PR, 1.48; 95% confidence interval, 1.06-2.06), and reporting unprotected sex before ART (PR, 1.68; 95% confidence interval, 1.16-2.42) were among the factors independently associated with unprotected sex while on ART. Overall, 7.3% of visit intervals of unprotected sex, 1.0% of intervals of sexual activity, occurred when plasma viral load greater than 1500 copies/mL, representing periods of greater HIV transmission risk., Conclusions: Although unprotected sex reduced over time, women reported unprotected sex more often than men. Disclosure of HIV status was low. Integration of comprehensive prevention programs into HIV care is needed, particularly ones specific for women.

Background: A pruritic papular eruption (PPE) is a common skin manifestation observed in 12-46% of persons with HIV infection living in tropical countries., Objective: To determine whether PPE responds to HAART and whether monitoring PPE severity could be used as a clinical marker to predict virological outcome in resource-limited settings where viral load testing is not available., Methods: The study enrolled 53 patients with PPE for at least 1 month before starting a first-line HAART regimen as part of a prospective study. CD4 cell count and viral load were measured at enrolment and every 3 months. A scoring system was developed to evaluate the PPE severity by asking two questions. Over the last month how itchy has your skin been? Over the last month how has itching interfered with your sleep?, Results: Median CD4 cell count was 15 cells/mul and median viral load 268 663 copies/ml. All patients initiated a regimen containing a nonnucleoside reverse transcriptase inhibitor. Mean PPE score declined from 3.9 at enrolment to 0.1 at 24 months. In 37 (86%) of the 43 patients with at least 6 months of follow-up data, the PPE disappeared and never returned. Patients with viral load > 400 copies/ml at months 9 and/or 12 had significantly higher PPE scores at months 9 to 12 than the patients with < 400 copies/ml., Conclusions: In most patients, PPE disappears during HAART and PPE severity scores were higher in patients whose first-line HAART failed to control plasma viral load.

Background: HIV RNA viral load testing is costly and is generally unavailable in resource-limited settings. We identified predictors of viral failure and documented genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART)., Methods: From April 2004 to June 2005, consecutive treatment-naive patients beginning ART at a university clinic in Uganda were enrolled. Clinical information, CD4 cell count, and HIV RNA level were collected at baseline and every 3 to 6 months. Independent predictors of viral failure were identified using multivariate logistic regression. Genotypic drug resistance for 8 patients with viral failure at 12 months was measured at baseline and at 6 and 12 months., Results: Five hundred twenty-six adults and 250 children (0 to 18 years of age) were started on first-line ART regimens and followed for 12 months. Outcomes could not be assessed in 13% of patients (79 died and 21 were withdrawn). Children were almost twice as likely to have viral failure compared with adults (26% vs. 14%; P = 0.0001). In adults, the sole independent predictor of viral failure was treatment with stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) versus zidovudine (ZDV)/3TC/efavirenz (EFV) (odds ratio [OR] = 2.59, 95% confidence interval [CI]: 1.20 to 5.59). In children, independent predictors of viral failure included male gender (OR = 2.44, 95% CI: 1.20 to 4.93), baseline CD4% <5 (OR = 2.69, 95% CI: 1.28 to 5.63), and treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (OR = 2.46, 95% CI: 1.23 to 4.90). All 8 patients with viral breakthrough and genotypic drug resistance results had nonnucleoside reverse transcriptase inhibitor (NNRTI)- and 3TC-associated mutations., Conclusions: These data demonstrate the effectiveness of ART in a low-resource setting. Children and patients of all ages taking the d4T/3TC/NVP regimen were more likely to have viral failure. Our data suggest that viral failure occurring 6 months or more after the start of ART regimens commonly used in Uganda is likely to be associated with NNRTI- and 3TC-resistant virus.

Although recent data suggest high levels of adherence to expanding antiretroviral therapy (ART) programmes in resource-limited settings, the culture-specific barriers to adherence are poorly understood. In a prospective observational study, we found that 1.2% of patients discontinued ART because of a belief in spiritual healing. Spiritual beliefs should be an important part of ART adherence counselling in resource-limited settings, requiring close collaboration between HIV care programmes and religious leaders to identify common goals and ensure successful treatment.

Abstract Background Viral load monitoring (VLM) to identify individuals failing antiretroviral therapy (ART) is not widely available in resource-limited settings. We compared the genotypic resistance patterns between clients with VLM versus immunological monitoring (IM). Methods Between 2004–2008, 559 ART naïve clients were enrolled in a prospective cohort, initiated on ART, and monitored with viral load (VL) and CD4+ cell counts every 6 months (VLM group). From February 2008 through June 2009, 998 clients on ART for 36–40 months (corresponding to the follow-up time of the VLM group) at the same clinic and monitored with CD4+ cell counts every 6 months were recruited into a cross sectional study (IM group). Samples from VLM clients at 12, 24 and 36 months and IM clients at 36–40 months with VL > 2000 copies/ml underwent genotypic drug resistance testing. Results Baseline characteristics were similar. Virologic failure (VL > 400 copies/ml) at 12, 24 and 36 months in the VLM group were 12%, 6% and 8% respectively, and in the IM group 10% at 36–40 months. Samples from 39 VLM and 70 IM clients were genotyped. 23/39 (59%) clients in the VLM group (at 12, 24 or 36 months) compared to 63/70 (90%) in the IM group, (P P (P < 0.0001). Conclusions Routine VL monitoring reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda.