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Background: In 2018, the tuberculosis molecular bacterial load assay (TB-MBLA), a ribosomal RNA-based test, was acknowledged by WHO as a molecular assay that could replace smear microscopy and culture for monitoring tuberculosis treatment response. In this study, we evaluated the accuracy of TB-MBLA for diagnosis and monitoring of treatment response in comparison with standard-of-care tests., Methods: For this longitudinal prospective study, patients aged 18 years or older with presumptive tuberculosis (coughing for at least 2 weeks, night sweats, and weight loss) were enrolled at China-Uganda Friendship Hospital Naguru (Kampala, Uganda). Participants were evaluated for tuberculosis by TB-MBLA in comparison with Xpert MTB/RIF Ultra (Xpert-Ultra) and smear microscopy, with Mycobacteria Growth Indicator Tube (MGIT) culture as a reference test. Participants who were positive on Xpert-Ultra were enrolled on a standard 6-month anti-tuberculosis regimen, and monitored for treatment response at weeks 2, 8, 17, and 26 after initiation of treatment and then 3 months after treatment., Findings: Between Nov 15, 2019, and June 15, 2022, 210 participants (median age 35 years [IQR 27-44]) were enrolled. 135 (64%) participants were male and 72 (34%) were HIV positive. The pretreatment diagnostic sensitivities of TB-MBLA and Xpert-Ultra were similar (both 99% [95% CI 95-100]) but the specificity was higher for TB-MBLA (90% [83-96]) than for Xpert-Ultra (78% [68-86]). Ten participants were Xpert-Ultra trace positive, eight (80%) of whom were negative by TB-MBLA and MGIT culture. Smear microscopy had lower diagnostic sensitivity (75% [65-83]) but higher specificity (98% [93-100]) than TB-MBLA and Xpert-Ultra. Among participants who were smear microscopy negative, the sensitivity of TB-MBLA was 96% (95 CI 80-100) and was 100% (95% CI 86-100) in those who were HIV positive. 129 (61%) participants were identified as tuberculosis positive by Xpert-Ultra and these individuals were enrolled in the treatment group and monitored for treatment response. According to TB-MBLA, 19 of these patients cleared bacillary load to zero by week 2 of treatment and remained negative throughout the 6-month treatment follow-up. Positivity for tuberculosis decreased with treatment as measured by all tests, but the rate was slower with Xpert-Ultra. Consequently, 31 (33%) of 95 participants were still Xpert-Ultra positive at the end of treatment but were clinically well and negative on TB-MBLA and culture at 6 months of treatment. Two patients were still Xpert-Ultra positive with a further 3 months of post-treatment follow-up. The rate of conversion to negative of the DNA-based Xpert-Ultra was 3·3-times slower than that of the rRNA-based TB-MBLA. Consequently for the same patient, it would take 13 weeks and 52 weeks to reach complete tuberculosis negativity by TB-MBLA and Xpert-Ultra, respectively. Participants who were positive on smear microscopy at 8 weeks, who received an extra month of intensive treatment, had a similar TB-MBLA-measured bacillary load at 8 weeks to those who were smear microscopy negative., Interpretation: TB-MBLA has a similar performance to Xpert-Ultra for pretreatment diagnosis of tuberculosis, but is more accurate at detecting and characterising the response to treatment than Xpert-Ultra and standard-of-care smear microscopy., Funding: European and Developing Countries Clinical Trials Partnership, Makerere University Research and Innovation Fund, US National Institutes of Health., Competing Interests: Declaration of interests WSa and SHG provide pro bono advice for LifeArc, a company that is developing TB-MBLA for clinical use. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years)., Methods: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis., Results: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years., Conclusions: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities., Trial Registration Number: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019)., (© 2024. The Author(s).)

Objectives: Due to the paucity of literature on risk factors for tuberculosis (TB)-related death, we determine the sociodemographic and clinical risk factors associated with TB-related deaths among adult pulmonary TB (PTB) patients on treatment in Selangor, Malaysia., Design: Retrospective cohort study., Setting: Routinely collected primary care data from all government TB clinics in Selangor., Participants: Data of 24 570 eligible adult PTB patients from 2013 to 2019 were obtained from Selangor's State Health Department surveillance records. We included PTB patients aged at least 15 years old at the time of diagnosis with complete documentation of the dates of diagnosis, treatment initiation, end of treatment/follow-up and treatment outcomes. We excluded patients whose diagnoses were changed to non-TB, post-mortem TB diagnosis and multidrug-resistant TB (MDR-TB) patients., Primary and Secondary Outcome Measures: TB-related death, determined from the recorded physicians' consensus during the TB mortality meeting., Results: TB-related death was significantly associated with far (adjusted HR (aHR) 9.98, 95% CI 4.28 to 23.28) and moderately advanced (aHR 3.23, 95% CI 1.43 to 7.31) radiological findings at diagnosis; concurrent TB meningitis (aHR 7.67, 95% CI 4.53 to 12.98) and miliary TB (aHR 6.32, 95% CI 4.10 to 9.74) involvement; HIV positive at diagnosis (aHR 2.81, 95% CI 2.21 to 3.57); Hulu Selangor (aHR 1.95, 95% CI 1.29 to 2.93), Klang (aHR 1.53, 95% CI 1.18 to 1.98) and Hulu Langat (aHR 1.31, 95% CI 1.03 to 1.68) residing districts; no formal education (aHR 1.70, 95% CI 1.23 to 2.35); unemployment (aHR 1.54, 95% CI 1.29 to 1.84), positive sputum smear acid-fast bacilli (AFB) at diagnosis (aHR 1.51, 95% CI 1.22 to 1.85); rural residency (aHR 1.39, 95% CI 1.13 to 1.72) and advancing age (aHR 1.03, 95% CI 1.02 to 1.03)., Conclusions: Far and moderately advanced radiological findings, concurrent TB meningitis and miliary TB involvement, HIV positive, Hulu Selangor, Klang and Hulu Langat residing districts, no formal education, unemployment, positive sputum smear AFB, rural residency and advancing age are risk factors of TB-related death. Our findings should assist in identifying high-risk patients requiring interventions against TB-related death., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Previous studies have indicated different immunological recovery trajectories based on CD4 count or CD4/CD8 ratio. However, these immune indicators are interconnected, and relying solely on one indicator may lead to inaccurate estimates. Therefore, it is essential to develop a comprehensive trajectory model that integrates CD4 count, CD8 count and CD4/CD8 ratio., Methods: We utilized a group-based multi-trajectory model to characterize the latent cluster of recovery based on measurements of CD4 count, CD8 count and CD4/CD8 ratio over a period of up to 96 months following ART initiation. Subsequently, we investigated the characteristics associated with trajectory groups, especially sex and age. Cox model and Kaplan-Meier survival curve were employed to assess differences in all-cause, AIDS-related and non-AIDS related mortality between trajectory groups., Results: A total of 14,718 eligible individuals were followed for a median of 55 months. Longitudinal model identified four subgroups: group 1 (32.5%, low CD4 and CD4/CD8 inversion), group 2 (25.9%, high CD8 and CD4/CD8 inversion), group 3 (27.2%, slow recovery of CD4 and CD4/CD8 inversion) and group 4 (14.4%, rapid increase of CD4 and normal CD4/CD8). Immune recovery was slower in male than in female, and in elders than in youngers. Compared to group 2, group 1 (adjusted hazard ratio [aHR]=3.28; 95% CI 2.33-4.60) and group 3 (aHR=1.56; 95% CI 1.09-2.24) had increased risk of all-cause mortality after adjusting for other factors. Besides, group 1 (aHR=2.17) and group 3 (aHR=1.58) had higher risk of non-AIDS related mortality, and group 1 (aHR=5.92) had significantly increased risk of AIDS related mortality., Conclusion: Longitudinal trajectory analysis of multiple immune indicators can be employed to guide targeted interventions among vulnerable populations in clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ma, Wang, Zhu, Li, Wang, Hao, Gao, Ma and Zhang.)

Pharmacy refill records (PRR), are an accessible strategy for estimating adherence in low- and middle-income countries (LMICs). However, the low-cost urine-tenofovir point-of-care test opens up the possibility of an objective metric of adherence that is scalable to LMICs. This study compared adherence to tenofovir-based regimens using urine-tenofovir point-of-care (POC) test with pharmacy refill records in a Nigerian population of HIV-positive persons. This was a cross-sectional study among 94 HIV-positive adults, which was conducted from June to August 2021, in a large outpatient clinic in Lagos, Nigeria. Adherence to pharmacy appointments was automatically calculated using a computerized pharmacy appointment system (FileMaker Pro™). Urine drops on the urine-tenofovir POC test strip developed 2 lines for a negative test (tenofovir absent) and one line for a positive test. Fisher's exact test was used to examine the association between pharmacy refill record and urine-tenofovir point-of-care test. Logistic regression was performed to predict viral suppression (<1000 copies/mL, based on WHO recommendations) using both methods of adherence determination. A Receiver Operating Characteristic (ROC) curve of the association between specificity and sensitivity was generated to evaluate the predictive value of adherence determined using pharmacy-refill record and urine-tenofovir point-of-care test in forecasting viral suppression. The statistical significance level was set at 0.05. Fisher's exact test showed no statistically significant difference in adherence using urine-tenofovir point-of-care test or pharmacy refill record. The logistic regression model showed that an increase in pharmacy-refill record of ≥ 95% was associated with viral suppression (P = .019). From the ROC curve, the sensitivity was same at 95.5% for both methods, but the specificity of the urine-tenofovir point-of-care test was greater (96.6% vs 95.5%) than pharmacy refill record (P = .837). Urine-tenofovir point-of-care test provided equivalent adherence data to pharmacy refill data., Competing Interests: This work was part of E.C.H’s PhD thesis at the University of Lagos, Nigeria. We have no other conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

To curb HIV infection rate in Tanzania, antiretroviral therapy (ART) has been scaled up since 2006, and in 2019, the country shifted to regimen including dolutegravir as a default first line. We assessed the success of ART and the contribution of HIV drug resistance (HIVDR) to unsuppressed viral loads. Between February and May 2023 a cross-sectional survey with random sampling was conducted in the six clinics in an urban cohort in Dar es Salaam. Patients with unsuppresed viral loads (local criteria viral load (VL) ≥ 1000 copies/mL) were tested for HIVDR mutations using the WHO adapted protocol for plasma samples. Mutations were interpreted using the Stanford HIVDR database. In total 600 individuals participated in this survey, the majority were female (76.83%), mean age ([Formula: see text] standard deviation) was 44.0 ([Formula: see text] 11.6) years. The median duration on ART (interquartile range) was 6.5 (3.9-10.2) years. Approximately 99% were receiving tenofovir + lamivudine + dolutegravir as a fixed dose combination. VL testing was successful in 99.67% (598/600) of survey patients and only 33 had VL ≥ 1000 copies/mL, resulting in a viral suppression level of 94.48% (565/598, 95% CI 92.34-96.17%). For 23 samples, protease and reverse transcriptase (RT) genotyping were successful, with 13 sequences containing RT inhibitor surveillance drug resistance mutations (SDRMs) (56.5%). No SDRM against protease inhibitors were detected. Thirty samples were successfully genotyped for integrase with 3 sequences (10.08%) containing integrase strand transfer inhibitor (INSTI) SDRMs. In samples successfully genotyped in the three genetic regions, 68.18% (16/22) had a genotypic susceptibility score (GSS) ≥ 2.5 for the concurrent regimen, implying factors beyond drug resistance caused the unsuppressed viral load. For five patients, GSS indicated that HIVDR may have caused the unsuppressed viral load. All three patients with INSTI resistance mutations were highly resistant to dolutegravir and accumulated nucleoside and non-nucleoside RT inhibitor HIVDR mutations. Although in this cohort the last 95 UNAIDS target was almost achieved, HIVDR mutations, including INSTIs resistance mutations were detected in HIV-positive individuals taking ART for at least one year. We recommend the design and implementation of high-impact interventions to prevent the increase of HIVDR, failure of dolutegravir and address the non-resistance factors in the study area., (© 2023. The Author(s).)

Objective: We sought to evaluate the variability of HIV-1 and its effect on immuno-virological response among adolescents living with perinatally acquired HIV (APHI)., Methods: A cohort study was conducted from 2018-2020 among 311 APHI receiving antiretroviral therapy (ART) in Cameroon. Sequencing of protease and reverse transcriptase regions was performed for participants experiencing virological failure, VF, (Plasma viral load, PVL ≥ 1000 RNA copies/ml). HIV-1 subtypes were inferred by phylogeny; immuno-virological responses were monitored at 3-time points (T1-T3). Cox regression modeling was used to estimate adjusted hazard ratios (aHRs) of progression to: CD4 < 250, and PVL > 5log10, adjusted for acquired drug resistance, gender, ART line, adherence, and duration on treatment; p < 0.05 was considered statistically significant., Results: Of the 141 participants in VF enrolled, the male-female ratio was 1:1; mean age was 15 (±3) years; and median [IQR] duration on ART was 51 [46-60] months. In all phases, 17 viral clades were found with a predominant CRF02&#95;AG (58.2%, 59.4%, and 58.3%). From T1-T3 respectively, there was an increasing CD4 count (213 [154-313], 366 [309-469], and 438 [364-569] cells/mm3) and decline log10 PVL (5.23, 4.43, and 4.43), similar across subtypes. Among participants with CRF02&#95;AG infection, duration of treatment was significantly associated with both rates of progression to CD4 < 250, and PVL > 5log10, aHR = 0.02 (0.001-0.52), and aHR = 0.05 (0.01-0.47) respectively. Moreover, four potential new HIV-1 recombinants were identified (CRF02&#95;AG/02D, CRF02&#95;AG/02A1F2, D/CRF02&#95;AG, and AF2/CRF02&#95;AG), indicating a wide viral diversity., Conclusion: Among APHI in settings like Cameroon, there is a wide genetic diversity of HIV-1, driven by CRF02&#95;AG and with potential novel clades due to ongoing recombination events. Duration of treatment significantly reduces the risk of disease progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Togna Pabo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Ethiopia is among the highly HIV-affected countries, with reported 12,000 and 12,000 AIDS-related deaths and incidents as per reports from 2021. Although the country has made a promising progress in antiretroviral therapy, recent studies have indicated that pretreatment drug resistance (PDR) is alarmingly increasing, which has become a challenge for the effectiveness of HIV treatment. Epidemiologic data on PDR is necessary to help establish ART regimens with good efficacy. Thus, this systematic review aimed to determine the trend analysis of PDR among ART-naïve individuals along with HIV variant dynamics in Ethiopia., Method: HIV-1 pol sequences from studies conducted between 2003 and 2018 among ART-naïve Ethiopian individuals were retrieved from GenBank and analyzed for the presence of PDR mutations (PDRM) along with the analysis of HIV-1 variant dynamics. The Calibrated Population Resistance (CPR) tool Version 8.1 and the REGA HIV-1 Subtyping Tool Version 3 were used to determine the PDRM and HIV-1 genetic diversity, respectively., Result: We identified nine studies and analyzed 1070 retrieved HIV-1 pol sequences in this systematic review. The pooled prevalence of PDR was 4.8% (51/1070), including 1.4% (15/1070), 2.8% (30/1070), and 0.8% (9/1070) for nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI (NNRTI), and protease inhibitor (PI) resistance, respectively. NRTI and NNRTI concurrent PDRM were observed among 0.2% (2/799) of the analyzed sequences. The overall PDR prevalence has been increasing over the years. Though the prevalence of the NNRTI, NRTI, and PI PDR also increased over the years, the NNRTI increment was more pronounced than the others, reaching 7.84% in 2018 from 2.19% in 2003. The majority (97%; 1038/1070) of the genetic diversity was HIV-1 subtype C virus, followed by subtype C' (2%; 20/1038) and other subtypes (1%; 10/1038)., Conclusions: According to this systematic review, the overall pooled prevalence of PDR is low. Despite the low prevalence, there has been an increasing trend of PDR over the years, which implies the need for routine surveillance of PDRMs along with preventive measures. Hence, this supports the recently endorsed transition of ART regimens from NNRTI to integrase strand transfer inhibitor-based regimens recommended by the WHO. In addition, this finding underscores the need for routine baseline genotypic drug resistance testing for all newly diagnosed HIV-infected patients before initiating treatment to halt the upward trend of PDR., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Tuberculosis (TB) continues to be the leading cause of morbidity and mortality among human immunodeficiency virus (HIV) infected individuals in Sub Saharan Africa, including Uganda. Isoniazid prophylaxis therapy (IPT) is a major public health intervention to limit tuberculosis disease among people living with HIV. However, there is limited information about the influence of IPT on TB disease incidence and its associated risk factors among HIV positive patients in Uganda especially at Reach out-Mbuya community health initiative hence the study. A cross sectional study was conducted among HIV positive adult patients who completed a 6-months long daily treatment of Isoniazid preventive therapy. Sputum samples and urine samples were collected and analysed using Gene Xpert and lateral flow urine Lipoarabinomannan (LF-LAM) tests respectively for presence of Tuberculosis disease. Data analysis was performed using STATA (version 14). Bivariate and multivariate logistic regression were performed to assess the risk factors associated with tuberculosis among the study population and significance estimated at 95% confidence level. A total of 103 HIV positive adults was studied. The mean age of the participants was 42.1 (10.5) and median age was 43 (IQR = 16). The prevalence of tuberculosis disease among HIV positive adult patients who completed Isoniazid preventive therapy was 5.8% (6/103). Counselling, the only significant factor, reduced the likelihood of occurrence of TB disease among HIV patients on IPT treatment (aOR:0.028, P-value < 0.001). A low prevalence of TB disease was observed among HIV patients on IPT treatment. Counselling is a protective factor of TB disease among HIV patients on IPT treatment., (© 2023. Springer Nature Limited.)

'Kick and kill' cure strategies aim to induce HIV protein expression in latently infected cells (kick), and thus trigger their elimination by cytolytic T cells (kill). In the Research in Viral Eradication of HIV Reservoirs trial (NCT02336074), people diagnosed with primary HIV infection received immediate antiretroviral therapy (ART) and were randomised 24 weeks later to either a latency-reversing agent, vorinostat, together with ChAdV63.HIVconsv and MVA.HIVconsv vaccines, or ART alone. This intervention conferred no reduction in HIV-1 reservoir size over ART alone, despite boosting virus-specific CD4+ and CD8+ T cells. The effects of the intervention were examined at the cellular level in the two trial arms using unbiased computational analysis of polyfunctional scores. This showed that the frequency and polyfunctionality of virus-specific CD4+ and CD8+ T cell populations were significantly increased over 12 weeks post-vaccination, compared to the ART-only arm. HIV-specific IL-2-secreting CD8+ T cells also expanded significantly in the intervention arm and were correlated with antiviral activity against heterologous HIV in vitro. Therapeutic vaccination during ART commenced in primary infection can induce functional T cell responses that are phenotypically similar to those of HIV controllers. Analytical therapy interruption may help determine their ability to control HIV in vivo., (© 2023. Springer Nature Limited.)

The objective was to evaluate outcomes in a heroin-dependent population 35 years after first enrolment in methadone maintenance treatment (MMT).  An ad hoc protocol was used to assess drug misuse, treatment, and drug-related morbidity in the survivor sample. The standardized mortality ratio (SMR) and 95% confidence interval (CI) were calculated.  A total of 214 heroin-dependent patients entered MMT between 1982 and 1984 in the Asturias Public Health Service. Information was received on 195 subjects, of whom 146 were deceased.  Men accounted for 77.5% of the study cohort. Over the 35-year follow-up period, the SMR was 11.75 (95% CI = 9.95 - 13.77). In the survivor sample, 5.7% were still enrolled in MMT; human immunodeficiency virus (HIV) was diagnosed in 38.77% and hepatitis B/C in 73.46%. No differences were found between sexes in mortality or HIV and hepatitis B/C status. None of the female survivors were using heroin at the 35-year follow-up compared with 5.26% of males. In conclusion, our study confirms the high long-term mortality rate of heroin addicts, even after enrollment in MMT.

Background: Antiretroviral therapy (ART) has led to a decline in human immunodeficiency virus (HIV)-related mortality, but comorbidities, including organ dysfunction, are increasingly the focus of care. Heart transplant (HT) is a very effective therapeutic strategy for end-stage heart failure (HF); however, clinicians may be hesitant due to concerns of complex drug-drug interactions (DDIs) between ART and HT immunosuppressive regimens and the potential impact of ART on long-term HT outcomes. In this report, we describe long-term (76-month) follow-up of a patient with HIV-positive status who underwent orthotopic HT with special emphasis on complex drug interactions., Case Presentation: A 58-year-old man with HIV-1 developed ischemic cardiomyopathy, progressed to end-stage HF and underwent orthotopic HT. To avoid DDIs with planned immunosuppressive therapies, the ART regimen was modified to consist of lamivudine, tenofovir disoproxil fumarate, rilpivirine, and raltegravir. Following HT, the patient's immunosuppression consisted of tacrolimus and mycophenolate mofetil. He has had normal cardiac function and no opportunistic infections and was subsequently switched to tenofovir alafenamide, emtricitabine, and bictegravir in combination for convenience. Serial HIV-1 RNA blood levels were constantly below the limit of quantification, and his CD4 count remained above 200 cells/mm 3 (30-35%). Several DDIs were identified and addressed; however, his long-term post-HT complications included one episode of asymptomatic acute cellular rejection, adenocarcinoma of the prostate, basal cell carcinoma, cardiac allograft vasculopathy, and peripheral neuropathy., Conclusion: The clinical outcome of this case supports the conclusion of previously published reports, summarized here within, demonstrating that HIV-1 positive status should not preclude HT in carefully selected individuals. Both addressing potential DDIs prior to HT and long-term monitoring for routine post-transplant complications and secondary and incidental malignancies are imperative., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Tuberculosis (TB) is a chronic respiratory infection. Co-infection with human immunodeficiency virus (HIV) has been a significant obstacle to TB control. Insufficient attention has been given to TB/HIV, and more information is needed to address this issue. We conducted an observational study to investigate the epidemiological characteristics, treatment outcomes and its associated factors of HIV-positive TB patients in Southeast China., Methods: An observational study was conducted based on data collected directly from China National TB Surveillance System during 2012-2021. Epidemiological characteristics, drug resistance and outcomes were described as frequency (n) and percentage (%). Risk factors for unsuccessful outcomes were determined using univariate (chi-squared) and multivariate logistic regression analysis., Results: A total of 347 TB/HIV cases were included, and the proportion of HIV-positive cases among all TB cases increased significantly from 0.06% to 2012 to 0.40% in 2021. The majority of cases were males (86.5%), non-local household registers (139, 40.1%), farmers or workers (179, 51.6%), and aged 40-59 (142, 40.9%). Of 347 cases, 290 (83.6%) had pulmonary TB (PTB), 10 (2.9%) had extra pulmonary TB (EPTB) and 47(13.5%) had both PTB and EPTB. A total A total of 258 (74.4%) were HIV positive prior to TB diagnosis. 8.0% (4/50) of cases were resistant to rifampicin (RIF) and 274 patients (83.8%) had successful outcomes. Being non-local (AOR = 2.193, 95% CI = 1.196-4.022, P = 0.011) and diagnosed HIV infection after TB (AOR = 2.365, 95% CI = 1.263-4.430, P = 0.007) were independent risk factors for unsuccessful outcomes of anti-TB treatment., Conclusion: During 2012-2021, the proportion of HIV-positive cases among all TB cases increased significantly in Southeast China. HIV-positive TB patients were significantly more likely to develop resistance to RIF and INH and unsuccessful anti-TB treatment. Non-local registration and becoming HIV positive after TB diagnosis were independent risk factors associated with unsuccessful outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: In French Guiana (population 294,000) the prevalence of type 2 diabetes (10%) and of HIV(1.1%) are very high. Our objective was to determine the prevalence of diabetes and its complications in a HIV cohort., Materials and Methods: We enrolled HIV-infected persons followed in Cayenne, Kourou, and Saint Laurent du Maroni hospitals between January 1, 1992 and December 31, 2021 in the French Hospital Database for HIV (FHDH) a national database compiling data from all French regions., Results: There was no difference of diabetes prevalence between men (8.2%) and women (8.8%), P = 0.4. Patients with diabetes were older (56 years ± 13.4) than those without diabetes (44.7 years ± 13.6) and prevalence increased with age. The proportion of persons with diabetes was greater among virologically suppressed persons (10%) than those with a detectable viral load under antiretroviral treatment (5.8%). Persons with diabetes had substantially greater CD4 counts at diagnosis than persons without diabetes. The majority of macro and microvascular complications were observed in people with diabetes. Persons with diabetes and HIV were significantly less likely to have had AIDS (1.6 versus 2.2 per 100 person-years, respectively). Overall, 374 persons living with HIV of 4167 had died (9%) the proportion of persons with diabetes among the dead was greater than those who did not die 11.7% versus 8.1%, respectively, p = 0.017. However, persons with diabetes were older and hence died older, 62.3 years (SD = 1.9) for deceased persons with diabetes versus 50.4 years (SD = 0.8), P < 0.0001. However, using Cox regression to adjust for age, initial CD4 count, country of birth there was no significant difference in the Hazard for death between persons with diabetes and persons without diabetes (aHR = 0.99, 95%CI = 0.65-1.5), P = 0.9., Conclusions: The prevalence of diabetes in our HIV cohort was high. Persons with diabetes had greater CD4 counts, earlier care, and greater virological suppression than persons without diabetes. There were no significant differences between persons with diabetes and without diabetes in terms of survival., (© 2023. The Author(s).)

Background: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data., Methods: The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations., Findings: Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy., Interpretation: These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs., Funding: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests Kelly E Seaton - support for meetings, HIV Vaccine Trials Network (HVTN). M Julianna McElrath - support for Keystone Symposia. Ian Frank - consulting fees from Gilead, ViiV Health Care and grants or contracts from Moderna, Janssen Therapeutics, Pfizer., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: G. D. received honoraria as consultant, lecturer, or advisory board member from Gilead, ViiV Healthcare, Janssens and MSD. All other authors declare no conflict of interests. No funding was obtained for this study.

Some HIV-infected individuals receiving ART develop low-level viremia (LLV), with a plasma viral load of 50-1000 copies/mL. Persistent low-level viremia is associated with subsequent virologic failure. The peripheral blood CD4 + T cell pool is a source of LLV. However, the intrinsic characteristics of CD4 + T cells in LLV which may contribute to low-level viremia are largely unknown. We analyzed the transcriptome profiling of peripheral blood CD4 + T cells from healthy controls (HC) and HIV-infected patients receiving ART with either virologic suppression (VS) or LLV. To identify pathways potentially responding to increasing viral loads from HC to VS and to LLV, KEGG pathways of differentially expressed genes (DEGs) were acquired by comparing VS with HC (VS-HC group) and LLV with VS (LLV-VS group), and overlapped pathways were analyzed. Characterization of DEGs in key overlapping pathways showed that CD4 + T cells in LLV expressed higher levels of Th1 signature transcription factors (TBX21), toll-like receptors (TLR-4, -6, -7 and -8), anti-HIV entry chemokines (CCL3 and CCL4), and anti-IL-1β factors (ILRN and IL1R2) compared to VS. Our results also indicated activation of the NF-κB and TNF signaling pathways that could promote HIV-1 transcription. Finally, we evaluated the effects of 4 and 17 transcription factors that were upregulated in the VS-HC and LLV-VS groups, respectively, on HIV-1 promoter activity. Functional studies revealed that CXXC5 significantly increased, while SOX5 markedly suppressed HIV-1 transcription. In summary, we found that CD4 + T cells in LLV displayed a distinct mRNA profiling compared to that in VS, which promoted HIV-1 replication and reactivation of viral latency and may eventually contribute to virologic failure in patients with persistent LLV. CXXC5 and SOX5 may serve as targets for the development of latency-reversing agents., Competing Interests: Conflict of interest The authors declare no competing conflict of interest., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

Management of heavily treatment experienced (HTE) people with HIV remains a challenge. Tailored antiretroviral therapy (ART) is needed in this fragile population who almost invariably harbor viral quasispecies with resistance-associated mutations (RAMs). The reference method for HIV genotypic resistance testing (GRT) has long been Sanger sequencing (SS), but next-generation sequencing (NGS), following recent progress in workflow and cost-effectiveness, is replacing SS because of higher sensitivity. From the PRESTIGIO Registry, we present a case of a 59-year-old HTE woman who failed darunavir/ritonavir plus raltegravir at low-viremia levels due mainly to high pill burden and poor adherence. NGS-GRT was performed on HIV-RNA at failure and the results were compared to all past SS-GRT data available (historical genotype). In this case, NGS-GRT did not detect any minority drug-resistant variants. After discussing several therapeutic options, the treatment was changed to dolutegravir 50 mg twice daily plus doravirine 100 mg once a day, based on clinical history, adherence issues, and pill burden, as well as the historical SS-GRT and the latest NGS-GRT results. At six months follow-up visit, the patient had HIV-RNA below 30 copies/ml and CD4+ T cell count increased from 673 cells/ mm3 to 688 cells/ mm3. Close follow-up of this patient is ongoing.

Objectives: To examine female participation and the observed efficacy and safety by sex from phase 3 HIV-1 trials submitted to the United States Food and Drug Administration (FDA) to support approval or a major labeling change., Design: Our analyses were based on phase 3 trials in HIV-1 infected treatment-naive adults submitted to FDA since 2010., Methods: We evaluated enrollment of treatment-naive females in 18 clinical trials for HIV-1. Participation to prevalence ratio (PPR) was calculated as the percentage of females among trial participants divided by the percentage of females in the disease population. PPR between 0.8 and 1.2 reflects similar representation of females in the trial and the disease population. Sex differences in efficacy (virologic response rates) and selected safety events were evaluated., Results: United States (US) females, particularly US Black females were not adequately represented in clinical trials. The PPR for US females overall was 0.59 and for US Black females was 0.63. Statistically significant sex differences favoring males were observed for efficacy outcomes in both the global population and US participants. Statistically significant sex differences were observed for some safety outcomes., Conclusions: US females are underrepresented in phase 3 HIV-1 clinical trials. Underrepresentation was not likely due to enrollment criteria. Statistically significant sex differences were noted for efficacy and selected safety outcomes; however, some differences were not clinically relevant. The ability to detect sex differences was hindered by low numbers of female participants overall and within subgroups. Additional research into innovative approaches to recruit and retain females in clinical trials should continue., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

With the widespread use of Integrase strand transfer inhibitors (INSTIs), surveillance of HIV-1 pretreatment drug resistance is critical in optimizing antiretroviral treatment efficacy. However, despite the introduction of these drugs, data concerning their resistance mutations (RMs) is still limited in Ethiopia. Thus, this study aimed to assess INSTI RMs and polymorphisms at the gene locus coding for Integrase (IN) among viral isolates from ART-naive HIV-1 infected Ethiopian population. This was a cross-sectional study involving isolation of HIV-1 from plasma of 49 newly diagnosed drug-naive HIV-1 infected individuals in Addis-Ababa during the period between June to December 2018. The IN region covering the first 263 codons of blood samples was amplified and sequenced using an in-house assay. INSTIs RMs were examined using calibrated population resistance tool version 8.0 from Stanford HIV drug resistance database while both REGA version 3 online HIV-1 subtyping tool and the jumping profile Hidden Markov Model from GOBICS were used to examine HIV-1 genetic diversity. Among the 49 study participants, 1 (1/49; 2%) harbored a major INSTIs RM (R263K). In addition, blood specimens from 14 (14/49; 28.5%) patients had accessory mutations. Among these, the M50I accessory mutation was observed in a highest frequency (13/49; 28.3%) followed by L74I (1/49; 2%), S119R (1/49; 2%), and S230N (1/49; 2%). Concerning HIV-1 subtype distribution, all the entire study subjects were detected to harbor HIV-1C strain as per the IN gene analysis. This study showed that the level of primary HIV-1 drug resistance to INSTIs is still low in Ethiopia reflecting the cumulative natural occurrence of these mutations in the absence of selective drug pressure and supports the use of INSTIs in the country. However, continues monitoring of drug resistance should be enhanced since the virus potentially develop resistance to this drug classes as time goes by., (© 2023. The Author(s).)

Background: Despite substantial antiretroviral therapy (ART) coverage among individuals with human immunodeficiency virus (HIV) infection in Tanzania, viral load suppression (VLS) among HIV-positive children receiving ART remains intolerably low. This study was conducted to determine factors affecting the nonsuppression of VL in children with HIV receiving ART in the Simiyu region; thus, an effective, sustainable intervention to address VL nonsuppression can be developed in the future., Methods: We conducted a cross-sectional study including children with HIV aged 2-14 years who were currently presenting to care and treatment clinics in the Simiyu region. We collected data from the children/caregivers and care and treatment center databases. We used Stata™ to perform data analysis. We used statistics, including means, standard deviations, medians, interquartile ranges (IQRs), frequencies, and percentages, to describe the data. We performed forward stepwise logistic regression, where the significance level for removal was 0.10 and that for entry was 0.05. The median age of the patients at ART initiation was 2.0 years (IQR, 1.0-5.0 years), and the mean age at HIV VL (HVL) nonsuppression was 8.8 ± 2.99 years. Of the 253 patients, 56% were female, and the mean ART duration was 64 ± 33.07 months. In multivariable analysis, independent predictors of HVL nonsuppression were older age at ART initiation (adjusted odds ratio [AOR] = 1.21; 95% confidence interval [CI] 1.012-1.443) and poor medication adherence (AOR, 0.06; 95% CI 0.004-0.867)., Conclusions: This study showed that older age at ART initiation and poor medication adherence play significant roles in HVL nonsuppression. HIV/AIDS programs should have intensive interventions targeting early identification, ART initiation, and adherence intensification., (© 2023. The Author(s).)

Background: Pre-exposure prophylaxis (PrEP) is an emerging biomedical prevention intervention. Documenting PrEP service delivery models (SDMs) that promote linkage to and continuation of PrEP will inform guidelines and maximise roll-out., Objectives: To synthesise and appraise the effectiveness and feasibility of PrEP SDMs designed to promote linkage to PrEP care among adolescent girls and young women (AGYW) and men in sub-Saharan Africa (SSA)., Eligibility Criteria: Primary quantitative and qualitative studies published in English and conducted in SSA were included. No restrictions on the date of publication were applied., Sources of Evidence: Methodology outlined in the Joanna Briggs Institute reviewers' manual was followed. PubMed, Cochrane library, Scopus, Web of Science and online-conference abstract archives were searched., Charting Methods: Data on article, population, intervention characteristics and key outcomes was charted in REDCap., Results and Conclusion: Of the 1204 identified records, 37 (met the inclusion criteria. Health facility-based integrated models of PrEP delivery with family planning, maternal and child health or sexual and reproductive services to AGYW resulted in PrEP initiation of 16%-90%. Community-based drop-in centres (66%) was the preferred PrEP outlet for AGYW compared with public clinics (25%) and private clinics (9%). Most men preferred community-based delivery models. Among individuals who initiated PrEP, 50% were men, 62% were <35 years old and 97% were tested at health fairs compared with home testing. Integrated antiretroviral therapy (ART)-PrEP delivery was favoured among serodiscordant couples with 82.9% of couples using PrEP or ART with no HIV seroconversions. PrEP initiation within healthcare facilities was increased by perceived client-friendly services and non-judgemental healthcare workers. Barriers to PrEP initiation included distance to travel to and time spent at health facilities and perceived community stigma. PrEP SDMs for AGYW and men need to be tailored to the needs and preferences for each group. Programme implementers should promote community-based SDMs to increase PrEP initiation among AGYW and men., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Pneumocystis pneumonia (PCP) is an opportunistic fungal infection that occurs in people with impaired or suppressed immunity such as patients with human immunodeficiency virus or organ transplant. However, the incidence and characteristics of PCP in the population with long-term hemodialysis is poorly described in the literature., Patient Concerns: We present a case of a 50-year-old female patient being transferred to our hospital in February 2022 with a 20-day history of cough and tight breath. She received amoxicillin and cephalosporin anti-infection treatment successively in local hospital but no significant improvement in symptoms. She had a 2-year history of hemodialysis and no relevant transplantation and human immunodeficiency virus infection. She was diagnosed as ANCA associated vasculitis (AAV) and given oral prednisone acetate (20 mg/day) and methotrexate (2.5 mg/week) half a year ago., Diagnoses: Based on the patient's medical history, Lung computerized tomography image, the Next generation sequencing report, the patient was diagnosed with renal failure, anti-neutrophil cytoplasmic antibody associated vasculitis, and Pneumocystis pneumonia., Interventions: The dosage of immunosuppressant was reduced due to leucocyte dripping and fever, and antibiotic and antifungal treatment were also given. The patient's lung condition was getting worse and noninvasive ventilator was required to maintain blood oxygen. Blood filtration is used to remove toxins. Ganciclovir and trimethoprim-sulfamethoxazole was used based on the next generation sequencing report., Outcomes: The patient died of respiratory failure., Lessons: The risk of PCP in hemodialysis patients may be higher than that in ordinary population, and the prognosis of patients with immunosuppression may be worse. Dynamic assessment of vasculitis activity is necessary for hemodialysis patients with AAV because infections may obscure lung symptoms of AAV. It is not recommended that hemodialysis patients with long-term immunosuppression should reduce or stop the dosage of immunosuppressive drugs during the treatment because it may aggravate the condition of PCP. There is still no clear conclusion on whether hemodialysis patients need preventive medicine, but the identification of risk factors and early diagnosis and treatment are important for the prognosis of PCP on hemodialysis population., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The long-term efficacy and safety of the 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) and 3-drug single-tablet regimens recommended for antiretroviral therapy (ART)-naive people with HIV-1 (PWH) have yet to be compared directly in clinical trials. This indirect treatment comparison (ITC) was conducted to compare the durability of efficacy and long-term safety of DTG + 3TC vs second-generation, integrase strand transfer inhibitor (INSTI)-based, 3-drug, single-tablet regimens bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and DTG/abacavir/3TC (DTG/ABC/3TC) at Week 144 after treatment initiation., Methods: A systematic literature review identified 4 trials evaluating the treatment regimens of interest in ART-naive PWH (GEMINI-1, GEMINI-2, GS-US-380-1489, and GS-US-380-1490). Safety, efficacy, and tolerability results were compared using fixed-effects Bucher ITC methodology to calculate relative outcomes., Results: Rates of virologic suppression (HIV-1 RNA < 50 copies/mL, US Food and Drug Administration Snapshot analysis) and virologic failure (HIV-1 RNA ≥ 50 copies/mL) as well as mean change in CD4 + cell count were similar with DTG + 3TC, BIC/FTC/TAF, and DTG/ABC/3TC at Week 144. Serious adverse events occurred less frequently with DTG + 3TC compared with both BIC/FTC/TAF (odds ratio [OR], 0.51; 95% CI 0.29-0.87; P = 0.014) and DTG/ABC/3TC (OR, 0.38; 95% CI 0.19-0.75; P = 0.006). Discontinuations and overall adverse events were similar across all 3 regimens., Conclusions: These results suggest that the 2-drug regimen DTG + 3TC offers comparable and durable efficacy with fewer serious adverse events vs BIC/FTC/TAF and DTG/ABC/3TC through 144 weeks of treatment in ART-naive PWH. These long-term comparative data support the therapeutic value of DTG + 3TC for PWH., (© 2023. The Author(s).)

There has been a surge in the emergence of HIV-1 drug resistance in Low and Middle-Income Countries (LMICs) due to poor drug-adherence and limited access to viral load testing, the current standard for treatment-monitoring. It is estimated that only 75% of people living with HIV (PLWH) worldwide have access to viral load testing. In LMICs, this figure is below 50%. In a recent WHO survey in mostly LMICs, 21 out of 30 countries surveyed found HIV-1 first-line pre-treatment drug resistance in over 10% of study participants. In the worst-affected regions, up to 68% of infants born to HIV-1 positive mothers were found to harbour first-line HIV-1 treatment resistance. This is a huge public health concern. Greater access to treatment-monitoring is required in LMICs if the UNAIDS "third 95" targets are to be achieved by 2030. Here, we review the current challenges of viral load testing and present the case for greater utilization of Laboratory-based assays that quantify intracellular HIV-1 RNA and/or DNA to provide broader worldwide access to HIV-1 surveillance, drug-resistance monitoring, and cure-research., (© 2023. The Author(s).)

Background: In Zimbabwe, children, adolescents and young adults living with HIV (CALWH) who are on public health antiretroviral therapy (ART) have inadequate viral load (VL) suppression. We assessed whether a clinic-based VL monitoring could decrease 12-month virologic failure rates among these CALWH., Methods: The study was registered on ClinicalTrials.gov: NCT03986099. CALWH in care at Chidamoyo Christian Hospital (CCH) and 8 rural outreach sites (ROS) on long-term community-based ART were randomized (1:1) to 6 monthly VL monitoring by COBAS®Ampliprep®/Taqman48® HIV-1 at the provincial referral laboratory (PRL) as per standard of care (SOC) or by the clinic-based SAMBA II assay, Diagnostics for the Real World, at CCH. VL suppression, turn-around-time (TAT) for VL results, drug switching and drug resistance in second-line failure were assessed at 12 months., Results: Of 390 CALWH enrolled 347 (89%) completed 12 months follow-up. Median (IQR) age and ART duration were 14.1 (9.7-18.2) and 6.4 (3.7-7.9) years, respectively. Over half (57%) of the participants were female. At enrolment, 78 (20%) had VL ≥1,000 copies/ml and VL suppression of 80% was unchanged after 12 months, with no significant difference between the SOC (81%) and the clinic-based (80%) arms (p = 0.528). Median (IQR) months to confirmatory VL result at CCH vs PRL was 4.0 (2.1-4.4) vs 4.5 (3.5-6.3) respectively; p = 0.027 at 12 months. Drug switching was documented among 26/347 (7%) participants with no difference between the median (IQR) time to switch in SOC vs clinic-based arms (5.1 (3.9-10.0) months vs 4.4 (2.5-8.4) respectively; p = 0.569). Out of 24 confirmed second-line failures, only 4/19 (21%) had protease inhibitor resistance., Conclusion: In rural Zimbabwe, the clinic-based SAMBA II assay was able to provide confirmatory VL results faster than the SOC VL assay at the PRL. However, this rapid TAT did not allow for a more efficient drug switch among these CALWH., Competing Interests: At the time of the study, DI and MB were paid employees of Gilead Sciences Inc. There are no patents, products in development or marketed products to declare. This does not alter our adherence to policies on sharing data and materials., (Copyright: © 2023 Kouamou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Doravirine has a unique resistance profile but how this profile might increase its usefulness beyond first-line therapy in persons with susceptible viruses has not been well studied. We sought to determine scenarios in which doravirine would retain activity against isolates from ART-naïve persons with transmitted drug resistance (TDR) and to identify gaps in available doravirine susceptibility data., Methods: We analyzed published in vitro doravirine susceptibility data and applied the results to 42,535 RT sequences from ART-naïve persons published between 2017 and 2021. NNRTI drug resistance mutations (DRMs) were defined as those with a Stanford HIV Drug Resistance Database doravirine penalty score either alone or in combination with other mutations., Results: V106A, Y188L, F227C/L, M230L, and Y318F were associated with the greatest reductions in doravirine susceptibility. However, several NNRTI DRMs and DRM combinations lacking these canonical resistance mutations had > tenfold reduced susceptibility including G190E, one isolate with G190S, three isolates with L100I + K103N, one isolate with K103N + P225H, and isolates with L100I + K103N + V108I and K101E + Y181C + G190A. Of the 42,535 ART-naïve sequences, 3,374 (7.9%) contained a NNRTI DRM of which 2,788 (82.6%) contained 1 DRM (n = 33 distinct mutations), 426 (12.6%) contained 2 DRMs (79 distinct pairs of mutations), and 143 (4.2%) contained ≥ 3 DRMs (86 distinct mutation patterns). Among the 2,788 sequences with one DRM, 112 (4.0%) were associated with ≥ 3.0-fold reduced doravirine susceptibility while 2,625 (94.2%) were associated with < 3.0-fold reduced susceptibility. Data were not available for individual NNRTI DRMs in 51 sequences (1.8%). Among the 426 sequences with two NNRTI DRMs, 180 (42.3%) were associated with ≥ 3.0 fold reduced doravirine susceptibility while just 32 (7.5%) had < 3.0 fold reduced susceptibility. Data were not available for 214 (50.2%) sequences containing two NNRTI DRMs., Conclusions: First-line therapy containing doravirine plus two NRTIs is expected to be effective in treating most persons with TDR as more than 80% of TDR sequences had a single NNRTI DRM and as more than 90% with a single DRM were expected to be susceptible to doravirine. However, caution is required for the use of doravirine in persons with more than one NNRTI DRM even if none of the DRMs are canonical doravirine-resistance mutations., (© 2023. The Author(s).)

Background: HIV-1 infections initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis than those initiated with single founder variants, yet little is known about the routes of exposure through which transmission of multiple founder variants is most probable. Here we used individual patient data to calculate the probability of multiple founders stratified by route of HIV exposure and study methodology., Methods: We conducted a systematic review and meta-analysis of studies that estimated founder variant multiplicity in HIV-1 infection, searching MEDLINE, Embase, and Global Health databases for papers published between Jan 1, 1990, and Sept 14, 2020. Eligible studies must have reported original estimates of founder variant multiplicity in people with acute or early HIV-1 infections, have clearly detailed the methods used, and reported the route of exposure. Studies were excluded if they reported data concerning people living with HIV-1 who had known or suspected superinfection, who were documented as having received pre-exposure prophylaxis, or if the transmitting partner was known to be receiving antiretroviral treatment. Individual patient data were collated from all studies, with authors contacted if these data were not publicly available. We applied logistic meta-regression to these data to estimate the probability that an HIV infection is initiated by multiple founder variants. We calculated a pooled estimate using a random effects model, subsequently stratifying this estimate across exposure routes in a univariable analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the exposure routes. This study is registered with PROSPERO, CRD42020202672., Findings: We included 70 publications in our analysis, comprising 1657 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0·25 (95% CI 0·21-0·29), with moderate heterogeneity (Q=132·3, p<0·0001, I 2 =64·2%). Our multivariable analysis uncovered differences in the probability of multiple variant infection by exposure route. Relative to a baseline of male-to-female transmission, the predicted probability for female-to-male multiple variant transmission was significantly lower at 0·13 (95% CI 0·08-0·20), and the probabilities were significantly higher for transmissions in people who inject drugs (0·37 [0·24-0·53]) and men who have sex with men (0·30 [0·33-0·40]). There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0·21 [0·14-0·31]), post-partum transmission (0·18 [0·03-0·57]), pre-partum transmission (0·17 [0·08-0·33]), and intra-partum transmission (0·27 [0·14-0·45])., Interpretation: We identified that transmissions in people who inject drugs and men who have sex with men are significantly more likely to result in an infection initiated by multiple founder variants, and female-to-male infections are significantly less probable. Quantifying how the routes of HIV infection affect the transmission of multiple variants allows us to better understand how the evolution and epidemiology of HIV-1 determine clinical outcomes., Funding: Medical Research Council Precision Medicine Doctoral Training Programme and a European Research Council Starting Grant., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 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.)

Background: We studied the pharmacokinetics (PK) and safety of 100-mg doravirine and doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination (100/300/300 mg DOR FDC) treatment in adolescents with HIV-1., Methods: Adolescents ages 12 to younger than 18 years were enrolled in 2 sequential cohorts. Cohort 1 evaluated intensive PK and short-term safety of 100-mg single-dose doravirine in adolescents ≥35 kg. Cohort 2 participants either initiated treatment with DOR FDC (antiretroviral (ARV)-naïve) or switched to DOR FDC from a previous ARV regimen (virologically suppressed). The first 10 Cohort 2 participants had intensive PK evaluations, and safety, sparse PK, and HIV RNA were assessed through week 24., Results: Fifty-five adolescents, median age 15.0 years and baseline weight 51.5 kg, were enrolled. Nine participants completed Cohort 1 PK assessments (8 of the 9 participants weighed ≥45 kg) and 45 initiated study drug in Cohort 2. The doravirine geometric mean (GM) AUC 0-∞ was 34.8 μM∙hour, and the GM C 24 was 514 nM after a single dose, with a predicted steady-state GM C 24,ss,pred of 690 nM. Cohort 2 enrolled adolescents weighing ≥45 kg. Plasma concentrations of doravirine, tenofovir, and lamivudine achieved by Cohort 2 participants were similar to those reported in adults. No drug-related serious or grade 3 or 4 adverse events occurred. Forty-two of 45 participants (93.3%; 95% CI: [81.7, 98.6]) achieved or maintained HIV-1 RNA <40 copies/mL., Conclusions: Doravirine and DOR FDC achieved target PK in adolescents with HIV-1. DOR FDC was well-tolerated and maintained excellent virologic efficacy through 24 weeks, offering a favorable option for adolescents., Competing Interests: K.L.Y., H.W., H.T. (now retired), and H.C. hold stock and are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) [license holder Pifeltro and Delstrigo]. P.F. participates on a Merck safety monitoring committee for non-HIV drugs. For the remaining authors, no conflicts of interest were disclosed., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Allergic drug eruptions (ADE) remain a challenge in people living with HIV (PLWH), requiring more studies to guide clinical approaches. While cotrimoxazole is widely used as prophylaxis in PLWH, relationship between client characteristics toward the occurrence of cotrimoxazole ADEs is still poorly understood.A retrospective cohort study followed PLWH initiated with antiretroviral therapy (ART) in St. Carolus Hospital between January 2009 to December 2021. ADE occurrence due to cotrimoxazole were tested for significance using Pearson's Chi-square and Fisher's Exact Test (significant outcome measured as p < 0.05) against CD4 levels at very low (0-100 cells/ul) and low (101-200 cells/ul) groups, comorbidities, and retention status.Cotrimoxazole-related ADEs occurred in 258 (14%) of 1789 subjects with CD4 levels ≤200 cells/ul. Comorbidities of Hepatitis B, Hepatitis C, and M. tuberculosis infections were found in 11, 4, and 95 subjects respectively. 151 (59%) of ADE group had very low CD4 levels (p value  >  0.05). No significant difference was found in ADE incidence between age groups, genders, CD4 levels, comorbidities, and ART retention.Cotrimoxazole-induced ADE is unrelated to CD4 levels, and ART retention was not affected. ADE severity ranges from mild to serious manifestations, and close monitoring is crucial to ensure ADEs are treated ART are well-maintained.

Preventing new HIV infections remains a global challenge. Young women continue to bear a disproportionate burden of infection. Oral pre-exposure prophylaxis (PrEP), offers a novel women-initiated prevention technology and PrEP trials completed to date underscore the importance of their inclusion early in trials evaluating new HIV PrEP technologies. Data from completed topical and systemic PrEP trials highlight the role of gender specific physiological and social factors that impact PrEP uptake, adherence and efficacy. Here we review the past and current developments of HIV-1 prevention options for women with special focus on PrEP considering the diverse factors that can impact PrEP efficacy. Furthermore, we highlight the importance of inclusion of female scientists, clinicians, and community advocates in scientific efforts to further improve HIV prevention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Karim, Archary, Barré-Sinoussi, Broliden, Cabrera, Chiodi, Fidler, Gengiah, Herrera, Kharsany, Liebenberg, Mahomed, Menu, Moog, Scarlatti, Seddiki, Sivro and Cavarelli.)

The objective of this study was to determine the rates of virological failure (VF) and HIV drug resistance (HIVDR) amongst adolescents on antiretroviral Therapy (ART). A retrospectively designed study was conducted in 10 healthcare centers for adolescents living with HIV (ALHIV) in the two main cities of Cameroon (Yaoundé and Douala), from November 2018 to May 2019. Sociodemographic, clinical, therapeutic and laboratory parameters were collected from medical records. All enrolled ALHIV had viral load (VL) measurements following the national guidelines. All patients with a VL ≥ 1000 copies/ml were called to perform genotyping tests. The chi-square test was used to determine the factors associated with VF. Out of the 1316 medical records of ALHIV, we included 1083 ALHIV having a VL result. Among them, 276 (25.5%) were experiencing VF, and VF was significantly higher in ALHIV with suboptimal adherence (p<0.001), older adolescents (p<0.05), those who lived outside the city where they were receiving ART (p<0.006), severely immunocompromised (p<0.01) and started ART at infancy (p<0.02). Among the 45/276 (16.3%) participants with an available genotyping resistance testing (GRT) result, the overall rate of HIVDR was 93.3% (42/45). The most common mutations were K103N (n = 21/42, 52.3%) resulting in high-level resistance to Efavirenz and Nevirapine, followed by M184V (n = 20/42, 47.6%) and thymidine analog mutations (n = 15/42, 35.7%) associated with high-level resistance to Lamivudine and Zidovudine respectively. The high rate of VF and HIVDR among ALHIV regularly followed in health facilities in Cameroon highlights the need to develop interventions adapted to an adolescent-centered approach to preserve future ART options., Competing Interests: The authors have declared that no competing interests exist.

Background: The application time of dolutegravir (DTG) is relatively short, and the treatment experience is insufficient. Therefore, evidence is required to shed more light on the effectiveness and safety issues of DTG in China., Objectives: To assess the effectiveness and safety of a DTG vs. efavirenz (EFV) antiviral regimens (the current mainstream regimen)., Methods: This was a retrospective cohort study. Data of people with HIV (PWH), who started initial DTG-based or EFV-based antiretroviral therapy at the Chengdu Public Health Clinical Medical Center from January 2018 to October 2020, were collected. Effectiveness indicators such as CD4+ T-cell recovery and HIV viral suppression, and safety indicators, including blood routine, liver and kidney function, and occurrence of abnormal blood lipids after DTG vs. EFV-based antiviral regimen treatments, were analyzed., Results: A total of 656 patients were eligible, of which 611 patients were included in the study. Most of the PWHs in our center were young men (86.25%). Nearly one-third of the participants were coinfected with syphilis. The median baseline HIV viral load was 4.70 log10 copies/mL. The median CD4+ T-cell count was 254 cells/mm3. More participants started on EFV-based regimens than DTG-based regimens (82.32% vs. 17.67%). The time to reach the target value (CD4 > 350 cells/mm3) in the DTG group was shorter than that in the EFV group (408 days vs. 522 days), and the percentage of reaching the CD4 target value of the DTG group was higher than that of the EFV group (41.04% vs. 33.76%) in 1 year. The effect of virologic suppression (<50 copies/mL) in the DTG group was superior to that in the EFV group. The use of DTG-containing treatment regimens was significantly related to a quicker virologic suppression (hazard ratio, 1.76; 95% confidence interval of 1.40-2.21, P < 0.0001). The safety data analysis of laboratory indicators showed that there was no significant difference in the incidence of adverse events between the 2 groups., Conclusions: A DTG-based regimen may be more conducive to the CD4 recovery than the EFV-based regimen. The virologic suppression of the DTG group may be superior to that of the EFV group. DTG-based regimens might be the preferred treatment option for people with HIV for initial HIV treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Some inpatients with HIV-RNA ≥500,000 copies/mL in China need to use 2-drug regimen for some reasons, although limited data are available for dolutegravir plus lamivudine (3TC) in those patients with ultra-high viral loads., Methods: We conducted a single-center retrospective-prospective study in China and enrolled 42 ART-naive HIV-infected inpatients who use a once-daily 2-drug regimen because of various reasons (drug interaction, renal impairment, age, and other related comorbidities).They were divided into 2 groups, low viral load group (baseline viral load <500,000 copies/mL, n = 20) and high viral load group (baseline viral load ≥500,000 copies/mL, n = 22). All patients were followed up for 48 weeks., Results: The median of baseline viral load was 5.74 log10 copies/mL and CD4+ T-cell count was 59 cells/μL. At week 48, there was no significant difference (P = 0.598) in proportions of participants with HIV-1 RNA <50 copies/mL [90%, 95% confidence interval (CI) (75.6% to 104.4%) in low viral load groups vs 95.5%, 95% CI (86.0% to 104.9%) in high viral load groups]. No differences were found in mean increase of CD4+ T-cell count from baseline between 2 groups (218 ± 122 vs 265 ± 127 cells/μL, P = 0.245). There is no grade 3 or higher treatment-related adverse events and none discontinued treatment because of adverse events., Conclusions: The results of our study in real world support dolutegravir + 3TC dual regimen as a promising therapy option for treatment-naive HIV-infected patient with baseline viral load ≥500,000 copies/mL., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pretreatment HIV drug resistance (PDR) undermines individual treatment success and threatens the achievement of UNAIDS 95-95-95 targets. In many African countries, limited data are available on PDR as detection of recent HIV infection is uncommon and access to resistance testing is limited. We describe the prevalence of PDR among South African women with recent HIV infection from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial., Methods: HIV-uninfected, sexually active women, aged 18-35 years, and seeking contraception were enrolled in the ECHO Trial at sites in South Africa, from 2015 to 2018. HIV testing was done at trial entry and repeated quarterly. We tested stored plasma samples collected at HIV diagnosis from women who seroconverted during follow-up and had a viral load >1000 copies/mL for antiretroviral resistant mutations using a validated laboratory-developed population genotyping assay, which sequences the full protease and reverse transcriptase regions. Mutation profiles were determined using the Stanford Drug Resistance Database., Results: We sequenced 275 samples. The median age was 23 years, and majority (98.9%, n = 272) were infected with HIV-1 subtype C. The prevalence of surveillance drug resistance mutations (SDRMs) was 13.5% (n = 37). Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations were found in 12.4% of women (n = 34). Few women had NRTI (1.8%, n = 5) and protease inhibitor (1.1%, n = 3) mutations. Five women had multiple NRTI and NNRTI SDRMs., Conclusions: The high levels of PDR, particularly to NNRTIs, strongly support the recent change to the South African national HIV treatment guidelines to transition to a first-line drug regimen that excludes NNRTIs., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Broadly neutralizing monoclonal antibodies (bNAbs) suppress HIV-1 RNA and may deplete residual viral reservoirs. We evaluated the safety and pharmacokinetics (PK) of dual intravenous VRC01LS and 10-1074 in very early-treated children with HIV-1 on suppressive antiretroviral treatment (ART)., Setting: Botswana., Methods: Children with HIV-1 (median age 3.1 years) on ART from <7 days old were enrolled. In phase A, 6 children received 10-1074 (30 mg/kg at day 0, 28, and 56) and 6 children received VRC01LS (30 mg/kg at day 0, 10 mg/kg at days 28 and 56) by intravenous infusion. In phase B, 6 children received the 2 bNAbs combined (with higher VRC01LS maintenance dose, 15 mg/kg) every 4 weeks for 32 weeks with PK evaluations over 8 weeks. Population PK models were developed to predict steady-state concentrations., Results: BNAb infusions were well tolerated. There were no infusion reactions nor any bNAb-related grade 3 or 4 events. The median (range) first dose Cmax and trough (day 28) combined from both phases were 1405 (876-1999) μg/mL and 133 (84-319) μg/mL for 10-1074 and 776 (559-846) μg/mL and 230 (158-294) μg/mL for VRC01LS. No large differences in bNAb clearances were observed when given in combination. The estimated VRC01LS half-life was shorter than in adults. Predicted steady-state troughs [median (90% prediction interval)] were 261 (95-565) and 266 (191-366) μg/mL for 10-1074 and VRC01LS, respectively, when given in combination., Conclusions: 10-1074 and VRC01LS were safe and well-tolerated among children receiving ART. Troughs exceeded minimal targets with every 4-week administration of 10-1074 at 30 mg/kg and VRC01LS at 15 mg/kg., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Results from both clinical trials and real-world observational studies suggest that lamivudine plus dolutegravir (3TC + DTG) dual therapy has excellent virological efficacy and safety in HIV-1-infected patients. However, there is still no relevant study related to this dual therapy reported in China., Methods: In this multicenter, retrospective, observational study that included HIV-1-infected patients in China, baseline and follow-up data were collected to analyze the virological suppression rate, immune restoration, and adverse events during follow-up in HIV-1-infected patients who switched to the 3TC + DTG dual therapy., Results: This study recruited 112 HIV-1-infected patients, including 101 men (90.2%), with a median age of 44.0 years (IQR: 33.00-57.75) and median CD4+ T-cell count of 432.13 cells/μL (IQR: 237.75-578.50). The overall virological suppression rate was 94.5% at the 24-week follow-up. However, the virological suppression rates of men who have sex with men patients and patients with CD4+ T-cell count of <350 cells/μL were higher than the baseline value (P < 0.05) at week 24. The results of Cox regression analysis showed that the baseline CD4+ T-cell count was an independent determinant of immune restoration in patients, and patients with baseline CD4+ T-cell count of 350-500 cells/μL outperformed patients with baseline CD4+ T-cell count of <350 cells/μL in immune restoration (hazard ratio: 4.469, 95% confidence interval: 1.801 to 11.091, P = 0.001). Adverse events were reported in 5 patients (incidence rate of 4.5%); among them, 3 patients developed neuropsychiatric symptoms. Results from the laboratory data analysis showed that patients with grade 1 and 2 adverse events had elevated levels of low-density lipoprotein cholesterol and total bilirubin. Furthermore, grade 3 and 4 adverse events were associated with the elevation of blood glucose level in 4 patients., Conclusions: Thus, the 3TC + DTG dual therapy displayed an excellent virological efficacy against HIV-1 infections and had an acceptable safety profile, with predominantly mild adverse events in HIV-1-infected patients in China., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: HIV drug resistance increased with the widespread use of antiretroviral drugs, and posed great threat to antiretroviral therapy (ART). Pu'er Prefecture, lying in the southwest of Yunnan Province, China, borders Myanmar, Laos and Vietnam, is also the area where AIDS was discovered earlier, however, in which there has been no information on HIV drug resistance., Methods: A cross-sectional survey of pretreatment drug resistance (PDR) was conducted in Pu'er Prefecture in 2021. Partial pol gene sequences were obtained to analyze drug resistance and construct genetic transmission network. HIV drug resistance was analyzed using the Stanford University HIVdb algorithm., Results: A total of 295 sequences were obtained, among which 11 HIV-1 strain types were detected and CRF08&#95;BC (62.0%, 183/295) was the predominant one. Drug resistance mutations (DRMs) were detected in 42.4% (125/295) of the sequences. The prevalence of PDR to any antiretroviral drugs, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 10.8% (32/295), 9.5% (28/295), 1.0% (3/295) and 0.3% (1/295), respectively. The risk of PDR occurrence was higher among individuals with CRF01&#95;AE strain types. HIV-1 molecular network was constructed, in which 56.0% (42/75) of links were transregional, and 54.7% (41/75) of links were associated with Lancang County. Among the sequences in the network, 36.8% (35/95) harbored DRMs, and 9.5% (9/95) were drug resistance strains. Furthermore, 8 clusters had shared DRM., Conclusion: The overall prevalence of PDR in this study was in a moderate level, but NNRTIs resistance was very approaching to the threshold of public response initiation. PDR was identified in the transmission network, and DRMs transmission was observed. These findings suggested that the consecutive PDR surveillance should be conducted in this region., (© 2022. The Author(s).)

Introduction: The CUSTOMIZE hybrid III implementation-effectiveness study evaluated implementation of once-monthly long-acting (LA) cabotegravir + rilpivirine in diverse US healthcare settings. Here, we report patient participant perspectives after 12 months in CUSTOMIZE., Methods: CUSTOMIZE was a phase IIIb, 12-month study conducted from July 2019 to October 2020 at eight diverse US HIV clinics that enrolled virologically suppressed people living with HIV-1 (PLHIV) on a stable oral regimen to receive monthly cabotegravir + rilpivirine LA injections after a 1-month oral lead-in. Participants were administered quantitative surveys before injections at months 1 (baseline), 4 and 12. A randomly selected subset of participants was interviewed at baseline and month 12. Data collection at month 12 was completed by October 2020 (during the COVID-19 pandemic)., Results: At baseline, 109 and 34 participants completed surveys and interviews, respectively; 87% were male; 35% were Black or African American. All participants who remained in the study at month 12 (n = 102) maintained HIV-1 RNA <50 copies/ml; two participants withdrew due to injection-related reasons. Mean total scores measuring acceptability and appropriateness of cabotegravir + rilpivirine LA were high at baseline (4.5-4.6 out of 5) and month 12 (4.7-4.9). At month 12, 74% of participants reported nothing interfered with receiving LA injections; injection pain or soreness was the most common concern (15%). Time spent in the clinic and coming to the clinic for monthly injections was very or extremely acceptable after 12 months for most participants (93% and 87%, respectively), with 64% reporting having spent ≤30 minutes in the clinic for injection visits. At month 12, 92% of participants preferred LA injections to daily oral tablets (3%); 97% plan to continue LA treatment going forward. In month 12 interviews, 24 (77%) of 31 participants reported the COVID-19 pandemic did not impact their ability to receive treatment., Conclusions: Once-monthly cabotegravir + rilpivirine LA was highly acceptable among PLHIV who were virologically suppressed on a stable antiretroviral regimen and interested in trying LA therapy, with few participants reporting challenges receiving LA injections. Implementation data from CUSTOMIZE suggest that monthly LA injections provide a convenient and appealing treatment option for PLHIV., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Human immunodeficiency virus (HIV) remains a global health threat, especially in developing countries. The successful scale-up of antiretroviral therapy (ART) programs to address this threat is hindered by a high proportion of patient loss to follow-up (LTFU). LTFU is associated with poor viral suppression and increased mortality. It is particularly acute among adolescents, who face unique adherence challenges. Although LTFU is a critical obstacle on the continuum of care for adolescents, few regional-level studies report the proportion of LTFU among adolescents receiving ART. Therefore, a systematic review and meta-analysis were conducted to estimate the pooled LTFU in ART programs among adolescents living with HIV in sub-Saharan Africa (SSA)., Methods: We searched five databases (PubMed, Embase (Elsevier), PsycINFO, CINAHL, and Scopus) for articles published between 2005 and 2020 and reference lists of included articles. The PRISMA guidelines for systematic reviews were followed. A standardised checklist to extract data was used. Descriptive summaries were presented using narrative tables and figures. Heterogeneity within the included studies was examined using the Cochrane Q test statistics and I2 test. Random effect models were used to estimate the pooled prevalence of LTFU among ALHIV. We used Stata version 16 statistical software for our analysis., Results: Twenty-nine eligible studies (n = 285,564) were included. An estimated 15.07% (95% CI: 11.07, 19.07) of ALHIV were LTFU. Older adolescents (15-19 years old) were 43% (AOR = 0.57, 95% CI: 0.37, 0.87) more likely to be LTFU than younger (10-14 years old) adolescents. We find an insignificant relationship between gender and LTFU (AOR = 0.95, 95% CI: 0.87, 1.03). A subgroup analysis found that regional differences in the proportion of adolescent LTFU were not statistically significant. The trend analysis indicates an increasing proportion of adolescent LTFU over time., Conclusions and Recommendations: The proportion of LTFU among HIV-positive adolescents in SSA seems higher than those reported in other regions. Older adolescents in the region are at an increased risk for LTFU than younger adolescents. These findings may help policymakers develop appropriate strategies to retain ALHIV in ART services. Such strategies could include community ART distribution points, appointment spacing, adherence clubs, continuous free access to ART, and community-based adherence support., Competing Interests: The authors have declared that no competing interests exist.

Current antiretroviral therapy (ART) guidelines recommend treating all children with HIV-1 infection. This has changed from the broader use of ART to treat children to improve morbidity and minimise mortality. However, prior to current recommendations, not everyone with HIV-1 received timely treatment. What happens to the paediatric immune system when HIV-1 replication is not appropriately supressed remains unclear. 11 samples from adolescents with HIV-1 on ART and uninfected controls in the UK, aged 12-25 years, were examined; overall, adolescents with CD4 + counts > 500/μl and a viral load < 50 copies/ml were compared with adolescents with CD4 + counts < 500/μl and a viral load > 50 copies/ml at time of sampling. Measurements of thymic output were combined with high throughput next generation sequencing and bioinformatics to systematically organize CD4 + and CD8 + T cell receptor (TCR) repertoires. TCR repertoire diversity, clonal expansions, TCR sequence sharing, and formation of TCR clusters in HIV-1 infected adolescents with successful HIV-1 suppression were compared to adolescents with ineffective HIV-1 suppression. Thymic output and CD4 + T cell numbers were decreased in HIV-1 infected adolescents with poor HIV-1 suppression. A strong homeostatic TCR response, driven by the decreased CD4 + T cell compartment and reduced thymic output was observed in the virally uncontrolled HIV-1-infected adolescents. Formation of abundant robust TCR clusters and structurally related TCRs were found in the adolescents with effective HIV-1 suppression. Numerous CD4 + T cell numbers in the virally controlled adolescents emphasize the importance of high thymic output and formation of robust TCR clusters in the maintenance of HIV-1 suppression. While the profound capacity for immune recovery in children may allow better opportunity to deal with immunological stress, when ART is taken appropriately, this study demonstrates new insights into the unique paediatric immune system and the immunological changes when HIV-1 replication is ongoing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sandgaard, Gkouleli, Attenborough, Adams, Gibbons, Holm, Eisen, Baxendale, De Rossi, Pahwa, Chain, Gkazi and Klein.)

Background: Sichuan province is one of the highest AIDS epidemic provinces in China, with a large number of floating population. The annual number of cases of HIV/AIDS reported in Sichuan has been the highest province in China for several successive years. There is a lack of widespread and representative data on the distribution of HIV genotypes in Sichuan. We aim to investigate the characteristics of HIV-1 molecular epidemiology and transmitted drug-resistance in newly diagnosed HIV-infected patients in Sichuan, China., Method: Archived plasma samples (n = 1524) from HIV-1 newly-diagnosed individuals in April 2019 were selected by cross-sectional investigation from all 21 cities in Sichuan province. Phylogenetic relationship, transmission cluster, and genotypic drug resistance analyses were performed using HIV-1 polymerase (pol) gene sequences. We also analysed the association of demographic and virological factors with transmitted drug-resistance (TDR) and transmission clusters., Results: Partial pol gene sequences were obtained from 1297 cases. HIV-1 epidemic strains in Sichuan province: the majority of genotypes were circulating recombinant form (CRF) 07&#95;BC (675, 52.04%), CRF01&#95;AE (343, 26.45%), CRF08&#95;BC (115, 8.87%), CRF85&#95;BC (67, 5.17%), subtype B (33, 2.54%), the other genotypes only accounted for 4.93%, and unique recombinant forms (URFs) (23, 1.77%) were observed in the study, and the difference of age, ethnicity, education, occupation, region and transmission pathway of different genotypes were statistically significant. According to WHO HIVDR surveillance threshold, the level of TDR has reached a medium level, with 72 of 1297 (5.55%) cases carrying drug-resistance mutation sites, TDR mutation frequency to nonnucleoside reverse transcriptase inhibitors (NNRTIs, 3.85%) was much higher than nucleoside reverse transcriptase inhibitors (NRTIs, 0.31%) and protease inhibitors (PIs, 1.70%), and CRF08&#95;BC was a risk factor for TDR (odds ratio, 8.32; 95% CI 4.38-15.80 for CRF07&#95;BC, P < 0.05). The most common drug resistance HIV-1 mutation pattern for NNRTI was V106 (1.31%, 17/1297) and E138 (1.16%, 15/1297), and for PI was M46 (0.69%, 9/1297). A total of 205 (15.8%) pol sequences were involved in the genetic transmission network clusters, CRF01&#95;AE (odds ratio, 2.369; 95% CI 1.659-3.382; P < 0.05), subtype B (odds ratio, 13.723; 95% CI 6.338-29.71; P < 0.05), drug resistance (odds ratio, 0.306; 95% CI 0.106-0.881; P < 0.05) and different levels of education (P < 0.05) were significantly associated to be in clusters., Conclusion: The distribution of HIV-1 genotypes in Sichuan is more diverse and complex, and the Men who have sex with men (MSM) is underrated, arguing for behavior scaling up intervention in this specific population besides the elderly people with heterosexual transmission risk groups. The risk of TDR mutation frequency increased in newly diagnosed patients highlights the significance of genotypic drug resistance monitoring and molecular surveillance of pretreatment HIV-1 drug resistance. The regimen composed of TDF, 3TC and EFV was still currently the preferred solution used free first-line therapy., (© 2022. The Author(s).)

Introduction: HIV incidence remains high among African adolescent girls and young women (AGYW). The primary objective of this study is to assess pre-exposure prophylaxis (PrEP) initiation, use, persistence and HIV acquisition among African AGYW offered PrEP in order to inform PrEP scale-up., Methods: POWER was a prospective implementation science evaluation of PrEP delivery for sexually active HIV-negative AGYW ages 16-25 in family planning clinics in Kisumu, Kenya and youth and primary healthcare clinics in Cape Town and Johannesburg, South Africa. Follow-up visits occurred at month 1 and quarterly for up to 36 months. PrEP users were defined based on the month 1 refill. PrEP persistence through month 6 was assessed using Kaplan-Meier survival analysis among AGYW with a month 1 visit, defining non-persistence as an ≥15 day gap in PrEP availability for daily dosing. PrEP execution was evaluated in a subset with PrEP supply from the prior visit sufficient for daily dosing by measuring blood tenofovir diphosphate (TFV-DP) levels., Results: From June 2017 to September 2020, 2550 AGYW were enrolled (1000 in Kisumu, 787 in Cape Town and 763 in Johannesburg). Median age was 21 years, 66% had a sexual partner of unknown HIV status, and 29% had chlamydia and 10% gonorrhoea. Overall, 2397 (94%) initiated PrEP and 749 (31%) had a refill at 1 month. Of AGYW who could reach 6 months of post-PrEP initiation follow-up, 128/646 (20%) persisted with PrEP for 6 months and an additional 92/646 (14%) had a gap and restarted PrEP. TFV-DP levels indicated that 47% (91/193) took an average of ≥4 doses/week. Sixteen HIV seroconversions were observed (incidence 2.2 per 100 person-years, 95% CI 1.2, 3.5); 13 (81%) seroconverters either did not have PrEP dispensed in the study interval prior to seroconversion or TFV-DP levels indicated <4 doses/week in the prior 6 weeks., Conclusions: In this study of PrEP integration with primary care and reproductive health services for African AGYW, demand for PrEP was high. Although PrEP use decreased in the first months, an important fraction used PrEP through 6 months.  Strategies are needed to simplify PrEP delivery, support adherence and offer long-acting PrEP options to improve persistence and HIV protection., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Prolonged virologic failure on 2nd-line protease inhibitor (PI)-based antiretroviral therapy (ART) without emergence of major protease mutations is well recognized and provides an opportunity to study within-host evolution in long-term viremic individuals. Using next-generation sequencing and in silico haplotype reconstruction, we analyzed whole-genome sequences from longitudinal plasma samples of eight chronically infected HIV-1-positive individuals failing 2nd-line regimens from the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) trial. On nonsuppressive ART, there were large fluctuations in synonymous and nonsynonymous variant frequencies despite stable viremia. Reconstructed haplotypes provided evidence for selective sweeps during periods of partial adherence, and viral haplotype competition, during periods of low drug exposure. Drug resistance mutations in reverse transcriptase (RT) were used as markers of viral haplotypes in the reservoir, and their distribution over time indicated recombination. We independently observed linkage disequilibrium decay, indicative of recombination. These data highlight dramatic changes in virus population structure that occur during stable viremia under nonsuppressive ART. IMPORTANCE HIV-1 infections are most commonly initiated with a single founder virus and are characterized by extensive inter- and intraparticipant genetic diversity. However, existing literature on HIV-1 intrahost population dynamics is largely limited to untreated infections, predominantly in subtype B-infected individuals. The manuscript characterizes viral population dynamics in long-term viremic treatment-experienced individuals, which has not been previously characterized. These data are particularly relevant for understanding HIV dynamics but can also be applied to other RNA viruses. With this unique data set we propose that the virus is highly unstable, and we have found compelling evidence of HIV-1 within-host viral diversification, recombination, and haplotype competition during nonsuppressive ART.

Background: Regimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear., Methods: This retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings., Results: There were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44-64] vs 42 years [IQR 35-50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5-8] vs 5 [IQR 4-6]), more co-medications (median 6 [IQR 4-11] vs 3 [IQR 2-7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%)., Conclusion: The profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities., Competing Interests: This study is a company sponsored study, employed authors DJR, NK, NO, MK, MY received salaries and the manuscript was reviewed by company to meet scientific criteria and meet with our areas of interest as a company. SO received research budget from ViiV healthcare and Gilead Sciences, and honorarium for lectures from ViiV Healthcare, Gilead Sciences, and MSD K.K.. Authors contribution for authors employed by the funding organization is described in "Author Contributions". The funding organization did not interfere with study design, data collection and analysis, nor the decision to publish and has an ethical guideline to always publish after a study has been conducted regardless of the outcome of the results. This does not alter our adherence to PLOS ONE policies on sharing data and materials

Background: Moringa oleifera Lam. is known to be of high nutritional and medicinal importance and has been demonstrated to possess a variety of biological activities., Objective: This study investigated the beneficial role of M. oleifera (moringa) supplementation in HIV positive subjects receiving antiretroviral drugs., Methods: Adult HIV positive individuals (104) attending the medical outpatient clinic in a tertiary health institution in Nigeria receiving highly active anti-retroviral therapies (HAARTs) were recruited in a randomized fashion for the study. Half of the subjects received moringa supplement (20 mg daily) additionally, while the others received only HAART and represented the control group. All subjects were monitored for 3 months during which their immunological status (CD4 counts and TNF-α), and hematological abnormalities at pre (baseline) and post study periods were determined., Results: Baseline levels of CD4 increased while TNF-α decreased significantly in control and moringa supplemented groups (p < 0.01). However, the post study CD4 values in the moringa group were higher and TNF-α values were lower compared to the control group (p < 0.01). In addition, baseline hematological abnormalities (anemia, thrombocytopenia, leucopenia, lymphopenia, and neutropenia) were improved but most significantly in the moringa supplemented subjects., Conclusion: The results suggest that moringa has immune-beneficial properties and improved hematological abnormalities in HIV positive individuals receiving antiretroviral therapy., (© 2022 Aprioku JS et al.)

Introduction: Pretreatment drug resistance (PDR) prevalence in sub-Saharan Africa is rising, but evidence of its impact on efavirenz (EFV)-based antiretroviral treatment (ART) is inconclusive. We determined the impact of PDR on outcomes of EFV-based ART in a subanalysis of a randomized clinical trial comparing different ART monitoring strategies implemented at a rural treatment facility in Limpopo, South Africa., Methods: Participants initiating EFV-based first-line ART (2015-2017) were enrolled and received 96 weeks follow-up. Resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and non-NRTI's (NNRTIs) was retrospectively assessed by population-based sequencing. Virological failure was defined as a viral load of at least 1000 copies/ml after at least 24 weeks of ART., Results: A total of 207 participants were included, 60.4% (125/207) of whom were female. Median age was 38.8 (interquartile range: 31.4-46.7) years. Median CD4+ cell count was 191 (interquartile range: 70-355) cells/μl. PDR was detected in 12.9% (25/194) of participants with available sequencing results; 19 had NNRTI-resistance, and six had NRTI- and NNRTI-resistance. 26.0% of participants (40/154) with sequencing results and virological follow-up developed virological failure. PDR was independently associated with failure (adjusted hazard ratio: 3.7 [95% confidence interval: 1.68.5], P = 0.002). At failure, 87.5% (7/8) of participants with PDR harboured dual-class resistant virus, versus 16.7% (4/24) of participants without PDR (P = 0.0007). Virological resuppression after failure on first-line ART occurred in 57.7% (15/26) of participants without PDR versus 14.3% (1/7) of participants with PDR (P = 0.09)., Conclusion: PDR was detected in 13% of study participants. PDR significantly increased the risk of virological failure of EFV-based ART. Accumulation of resistance at failure and inability to achieve virological resuppression illustrates the profound impact of PDR on treatment outcomes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To evaluate the effectiveness of three models for pre-exposure prophylaxis (PrEP) service delivery to HIV-1 serodiscordant couples in Nigeria., Methods: 297 heterosexual HIV-1 serodiscordant couples were recruited into three PrEP delivery models and followed up for 18 months. The models were i) Outpatient clinic model providing PreP in routine outpatient care; ii) Antiretroviral therapy (ART) clinic model providing PrEP in ART clinics; and iii) Decentralized care model providing PrEP through primary and secondary care centres linked to a tertiary care centre. The primary effectiveness endpoint was incident HIV-1 infection. The HIV incidence before and after the study was compared and the incidence rate ratio computed for each model. Survival analysis was conducted, Cox regression analysis was used to compare the factors that influenced couple retention in each of the models. Kaplan-Meier survival analysis was used to estimate the median retention time (in months) of the study participants in each of the study models, and log-rank test for equality of survival functions was conducted to test for significant differences among the three models., Results: There was no significant difference (p>0.05) in the couple retention rates among the three models. At months 3, 6 and 9, adherence of the HIV-1-infected partners to ART was highest in the decentralized model, whereas at months 9 and 12, the outpatient model had the highest proportion of HIV-1- uninfected partners adhering to PrEP (p<0.001). The HIV incidence per 100 person-years was zero in the general outpatient clinic and ART clinic models and 1.6 (95% CI: 0.04-9.1) in the decentralized clinic model. The difference in the observed and expected incidence rate was 4.3 (95% CI: 0.44-39.57) for the decentralized clinic model., Conclusion: Although incidence of HIV seroconversion was highest in the decentralized clinic model, this difference may be due to the higher sexual risk behavior among study participants in the decentralized model rather than the type of service delivery. The study findings imply that any of the models can effectively deliver PrEP services., Competing Interests: The authors have declared that no competing interests exist.

HIV-1 pol sequences from antiretroviral therapy (ART)-naive and ART-experienced people living with HIV-1 are fundamental to understanding the genetic correlates and epidemiology of HIV-1 drug resistance (HIVDR). To assess the public availability of HIV-1 pol sequences and ART histories of the individuals from whom sequenced viruses were obtained, we performed a systematic review of PubMed and GenBank for HIVDR studies published between 2010 and 2019 that reported HIV-1 pol sequences. 934 studies met inclusion criteria, including 461 studies of ART-naive adults, 407 of ART-experienced adults, and 66 of ART-naive and ART-experienced children. Sequences were available for 317 (68·8%) studies of ART-naive individuals, 190 (46·7%) of ART-experienced individuals, and 45 (68·2%) of children. Among ART-experienced individuals, sequences plus linked ART histories were available for 82 (20·1%) studies. Sequences were available for 21 (29·2%) of 72 clinical trials. Among journals publishing more than ten studies, the proportion with available sequences ranged from 8·3% to 86·9%. Strengthened implementation of data sharing policies is required to increase the number of studies with available HIVDR data to support the enterprise of global ART in the face of emerging HIVDR., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)