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Introduction: Novel point‐of‐care assays which measure urine tenofovir (TFV) concentrations may have a role in improving adherence monitoring for people living with HIV (PLHIV) receiving antiretroviral therapy (ART). However, further studies of their diagnostic accuracy, and whether results are associated with viraemia and drug resistance, are needed to guide their use, particularly in the context of the global dolutegravir rollout. Methods: We conducted a cross‐sectional evaluation among PLHIV receiving first‐line ART containing tenofovir disoproxil fumarate at enrolment into a randomized trial in two South African public sector clinics. We calculated the diagnostic accuracy of the Abbott point‐of‐care immunoassay to detect urine TFV compared to liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). We evaluated the association between point‐of‐care urine TFV results and self‐reported adherence, viraemia ≥1000 copies/ml and HIV drug resistance, among people receiving either efavirenz or dolutegravir‐based ART. Results: Between August 2020 and March 2022, we enrolled 124 participants. The median age was 39 (IQR 34–45) years, 55% were women, 74 (59.7%) were receiving efavirenz and 50 (40.3%) dolutegravir. The sensitivity and specificity of the immunoassay to detect urine TFV ≥1500 ng/ml compared to LC‐MS/MS were 96.1% (95% CI 90.0−98.8) and 95.2% (75.3−100.0), respectively. Urine TFV results were associated with short (p<0.001) and medium‐term (p = 0.036) self‐reported adherence. Overall, 44/124 (35.5%) had viraemia, which was associated with undetectable TFV in those receiving efavirenz (OR 6.01, 1.27−39.0, p = 0.014) and dolutegravir (OR 25.7, 4.20−294.8, p<0.001). However, in those with viraemia while receiving efavirenz, 8/27 (29.6%) had undetectable urine TFV, compared to 11/17 (64.7%) of those receiving dolutegravir. Drug resistance was detected in 23/27 (85.2%) of those receiving efavirenz and only 1/16 (6.3%) of those receiving dolutegravir. There was no association between urine TFV results and drug resistance. Conclusions: Among PLHIV receiving ART, a rapid urine TFV immunoassay can be used to accurately monitor urine TFV levels compared to the gold standard of LC‐MS/MS. Undetectable point‐of‐care urine TFV results were associated with viraemia, particularly among people receiving dolutegravir. Trial registration: Pan‐African Clinical Trials Registry: PACTR202001785886049. [ABSTRACT FROM AUTHOR]

Background: HIV self-testing (HIVST) is one of the recommended approaches for HIV testing services, particularly for helping reach populations who would not normally access facility-based HIV testing. Key stakeholder engagement is paramount in tailoring health interventions to ensure uptake by target populations. Objective: The main objective of this study was to collaborate with key stakeholder in the co-creation of an acceptable HIVST delivery strategies to help improve urban men's engagement with HIV services. Methods: We invited key stakeholders for urban men's HIV services to participate in a co-creation workshop aimed at developing HIVST delivery approaches for urban men, using eThekwini municipality as a study setting. We conducted purposive sampling to include health care users and health care providers, representing a range of views across the public sector and voluntary sector. We employed the nominal group technique (NGT) method for data collection. The NGT workshop was conducted in two consecutives: phase 1 was focused on determining barriers for men's engagement with the current/facility-based HIV testing services; phase 2 was aimed at determining HIVST delivery strategies. Results: Participants identified the following factors as the most important barriers to uptake of HIV testing services by urban men: stigma, ignorance about the importance of testing, and testing process as well as fear of positive test results. Key stakeholders suggested internal motivation strategies as a potentially effective approach to support HIVST delivery strategy. Guided by the NGT results, we designed a HIVST delivery strategy that is supported by a risk communication approach. Conclusion: The NGT enabled successful collaboration with key stakeholders in the co-creation of HIVST delivery strategies to guide implementation and strategy improve urban men's engagement with HIV services. A follow-up study to evaluate the feasibility of implementing these approaches is recommended. [ABSTRACT FROM AUTHOR]

Background: Introduction of tenofovir (TDF) plus lamivudine (3TC) and dolutegravir (DTG) in first- and second-line HIV treatment regimens in South Africa warrants characterization of acquired HIV-1 drug resistance (ADR) mutations that could impact DTG-based antiretroviral therapy (ART). In this study, we sought to determine prevalence of ADR mutations and their potential impact on susceptibility to drugs used in combination with DTG among HIV-positive adults (≥ 18 years) accessing routine care at a selected ART facility in KwaZulu-Natal, South Africa. Methods: We enrolled adult participants in a cross-sectional study between May and September 2019. Eligible participants had a most recent documented viral load (VL) ≥ 1000 copies/mL after at least 6 months on ART. We genotyped HIV-1 reverse transcriptase and protease genes by Sanger sequencing and assessed ADR. We characterized the effect of ADR mutations on the predicted susceptibility to drugs used in combination with DTG. Results: From 143 participants enrolled, we obtained sequence data for 115 (80%), and 92.2% (95% CI 85.7–96.4) had ADR. The proportion with ADR was similar for participants on first-line ART (65/70, 92.9%, 95% CI 84.1–97.6) and those on second-line ART (40/44, 90.9%, 95% CI 78.3–97.5), and was present for the single participant on third-line ART. Approximately 89% (62/70) of those on first-line ART had dual class NRTI and NNRTI resistance and only six (13.6%) of those on second-line ART had major PI mutations. Most participants (82%) with first-line viraemia maintained susceptibility to Zidovudine (AZT), and the majority of them had lost susceptibility to TDF (71%) and 3TC (84%). Approximately two in every five TDF-treated individuals had thymidine analogue mutations (TAMs). Conclusions: Susceptibility to AZT among most participants with first-line viraemia suggests that a new second-line regimen of AZT + 3TC + DTG could be effective. However, atypical occurrence of TAMs in TDF-treated individuals suggests a less effective AZT + 3TC + DTG regimen in a subpopulation of patients. As most patients with first-line viraemia had at least low-level resistance to TDF and 3TC, identifying viraemia before switch to TDF + 3TC + DTG is important to avoid DTG functional monotherapy. These findings highlight a need for close monitoring of outcomes on new standardized treatment regimens. [ABSTRACT FROM AUTHOR]

An editorial is presented on Cryptococcal meningitis is one of the most common and serious human immunodeficiency virus (HIV)-related opportunistic infections among adults in sub-Saharan Africa. Topics include results of a multicenter clinical trial conducted in five African countries that evaluated a simpler treatment regimen; and modified the induction phase of the all-oral regimen used in the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial.

Background We aimed to estimate the prevalence of and explore risk factors for Mycobacterium tuberculosis infection among adolescents in a high tuberculosis (TB) and human immunodeficiency virus (HIV) prevalence setting. Methods A cross-sectional study of adolescents (10–19 years) randomly selected from a demographic surveillance area (DSA) in rural KwaZulu-Natal, South Africa. We determined M tuberculosis infection status using the QuantiFERON-TB Gold-plus assay. We used HIV data from the DSA to estimate community-level adult HIV prevalence and random-effects logistic regression to identify risk factors for TB infection. Results We enrolled 1094 adolescents (548 [50.1%] female); M tuberculosis infection prevalence (weighted for nonresponse by age, sex, and urban/rural residence) was 23.0% (95% confidence interval [CI], 20.6–25.6%). Mycobacterium tuberculosis infection was associated with older age (adjusted odds ratio [aOR], 1.37; 95% CI, 1.10–1.71, for increasing age-group [12–14, 15–17, and 18–19 vs 10–11 years]), ever (vs never) having a household TB contact (aOR, 2.13; 95% CI, 1.25–3.64), and increasing community-level HIV prevalence (aOR, 1.43 and 95% CI, 1.07–1.92, for increasing HIV prevalence category [25%–34.9%, 35%–44.9%, ≥45% vs <25%]). Conclusions Our data support prioritizing TB prevention and care activities in TB-affected households and high HIV prevalence communities. [ABSTRACT FROM AUTHOR]

Objectives: Optimising medication adherence is one of the essential factors in reversing the tide of a TB-HIV syndemic in sub-Saharan Africa, especially South Africa. Impairment in key neurocognitive domains may impair patients' ability to maintain adherence to treatment, but the level of cognition and its relationship to HIV status has not been examined in individuals with drug-resistant TB. We therefore investigated performance on several key neurocognitive domains in relationship to HIV status in a multidrug-resistant tuberculosis patients (MDR-TB) sample.Methods: We enrolled microbiologically confirmed MDR-TB inpatients at a TB-specialist referral hospital in KwaZulu-Natal province, South Africa. We collected cross-sectional data on sociodemographic, clinical and neurocognitive function (e.g. attention, memory, executive functioning, language fluency, visual-spatial, eye-hand coordination). For the primary analysis, we excluded participants with major depressive episode/substance use disorder (MDE/SUD). We fitted adjusted Poisson regression models to explore the association between HIV and neurocognitive function.Results: We enrolled 200 people with MDR-TB; 33 had MDE/SUD, and data of 167 were analysed (151 HIV+, 16 HIV-). The mean age of participants was 34.2 years; the majority were female (83%), and 53% had not completed secondary school. There was evidence of impaired neurocognitive functioning across all domains in both HIV+/- study participants. Based on the regression analyses, individuals with co-infection (MDR-TB/HIV+), as well as those who had longer duration of hospital stays experienced significantly lower cognitive performance in several domains. Poor cognitive performance was significantly related to older age and lower educational attainment. The presence of major depression or substance use disorders did not influence the significance of the findings.Conclusions: Adults with MDR-TB have significant neurocognitive impairment, especially if HIV positive. An integrated approach is necessary in the management of MDR-TB as cognitive health influences the ability to adhere to chronic treatment, clinical outcomes and functionality. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis drug resistance is a threat to global tuberculosis (TB) control. Comprehensive and timely drug susceptibility determination is critical to inform appropriate treatment of drug-resistant tuberculosis (DR-TB). Phenotypic drug susceptibility testing (DST) is the gold standard for M. tuberculosis drug resistance determination. M. tuberculosis whole genome sequencing (WGS) has the potential to be a one-stop method for both comprehensive DST and epidemiological investigations. We discuss in this review the tremendous opportunities that next-generation WGS presents in terms of understanding the molecular epidemiology of tuberculosis and mechanisms of drug resistance. The potential clinical value and public health impact in the areas of DST for patient management and tracing of transmission chains for timely public health intervention are also discussed. We present the current challenges for the implementation of WGS in low and middle-income settings. WGS analysis has already been adapted routinely in laboratories to inform patient management and public health interventions in low burden high-income settings such as the United Kingdom. We predict that the technology will be adapted similarly in high burden settings where the impact on the epidemic will be greatest. [ABSTRACT FROM AUTHOR]

Background: Data are required regarding the feasibility of conducting a randomized trial of point-of-care viral load (VL) testing to guide management of HIV viremia and to provide estimates of effect to guide potential future trial design. Setting: Two public South African clinics during the dolutegravir-based antiretroviral therapy (ART) rollout. Methods: We randomized adults receiving first-line ART, with recent VL ≥1000 copies/mL, in a 1:1 ratio to receive point-of-care Xpert HIV-1 VL versus standard-of-care laboratory VL testing after 12 weeks. Feasibility outcomes included proportions of eligible patients enrolled and completing follow-up and VL process outcomes. Estimates of effect were assessed using the trial primary outcome of VL <50 copies/mL after 24 weeks. Results: From August 2020 to March 2022, we enrolled 80 eligible participants, an estimated 24% of those eligible. 47 of 80 (58.8%) were women, and the median age was 38.5 years (interquartile range [IQR], 33–45). 44 of 80 (55.0%) were receiving dolutegravir, and 36 of 80 (465.0%) were receiving efavirenz. After 12 weeks, point-of-care participants received VL results after median 3.1 hours (IQR 2.6–3.8), versus 7 days (IQR 6–8, P < 0.001) in standard of care. Twelve-week follow-up VL was ≥1000 copies/mL in 13 of 39 (33.3%) point-of-care participants and in 16 of 41 (39.0%) standard-of-care participants; 11 of 13 (84.6%) and 12 of 16 (75.0%) switched to second-line ART. After 24 weeks, 76 of 80 (95.0%) completed follow-up. 27 of 39 (69.2% [95% CI: 53.4 to 81.4]) point-of-care participants achieved VL <50 copies/mL versus 29 of 40 (72.5% [57.0 to 83.9]) standard-of-care participants. Point-of-care participants had median 3 (IQR, 3–4) clinical visits versus 4 (IQR, 4–5) in standard-of-care participants (P < 0.001). Conclusions: It was feasible to conduct a trial of point-of-care VL testing to manage viremia. Point-of-care VL lead to quicker results and fewer clinical visits, but estimates of 24-week VL suppression were similar between arms. Trial Registration: Pan African Clinical Trials Registry: PACTR202001785886049. [ABSTRACT FROM AUTHOR]

Near-perfect adherence to antiretroviral therapy (ART) is required to achieve the best possible prevention and treatment outcomes. Yet, there have been particular concerns about the challenges of adherence among patients living in resource-limited settings in sub-Saharan Africa. The primary objective of this study was to explore adherence in a low-resourced, rural community of high HIV prevalence in South Africa and to identify specific individual and structural factors that can either challenge or support adherence in this context. We applied digital stories as a qualitative research tool to gain insights into personal contexts of HIV and ART adherence. Through an inductive thematic analysis of twenty story texts, soundtracks and drawings, we explored experiences, understandings, and contexts of the participants and identified potential barriers and facilitators for those on lifelong treatment. We found that many of the stories reflected a growing confidence in the effectiveness of ART, which should be viewed as a key facilitator to successful adherence since this attitude can promote disclosure and boost access to social support. Nevertheless, stories also highlighted the complexity of the issues that individuals and households face as they deal with HIV and ART in this setting and it is clear that an overburdened local healthcare system has often struggled to meet the demands of a rapidly expanding epidemic and to provide the necessary medical and emotional support. Our analysis suggests several opportunities for further research and the design of novel health interventions to support optimal adherence. Firstly, future health promotion campaigns should encourage individuals to test together, or at least accompany each other for testing, to encourage social support from the outset. Additionally, home-based testing and ART club interventions might be recommended to make it easier for individuals to adhere to their treatment regimens and to provide a sense of support and solidarity. [ABSTRACT FROM AUTHOR]

Little is known about outcomes after transfer out (TFO) and loss to follow-up (LTF) and how differential outcomes might bias mortality estimates, as analyses generally censor or exclude TFOs/LTF. Using data linked to the National Population Register, we explored mortality among TFO and LTF patients compared with patients who were retained and investigated how linkage impacted on mortality estimates.A cohort analysis of routine data on adults with civil identification numbers starting antiretroviral therapy (ART) 2004-2009 in 4 large South African ART cohorts. The number, proportion, timing, and mortality of TFOs and LTF were reported. Mortality was compared using Kaplan-Meier curves, Cox's proportional hazards, and competing risks regression.Before linkage, 1207 patients (6%) had died, 2624 (13%) were LTF, 1067 (5%) were TFO and 14,583 (75%) were retained. Compared with retained, mortality risk was 3 times higher among TFO patients [adjusted hazard ratio (aHR), 3.11; 95% confidence interval (CI): 2.42 to 3.99] and 20 times higher among LTF patients (aHR, 22.03; 95% CI: 20.05 to 24.21). Excluding early deaths after TFO or LTF, the risk was comparable among TFOs and retained (aHR, 0.75; 95% CI: 0.54 to 1.03) and higher among LTF (aHR, 2.85; 95% CI: 2.43 to 3.33). After linkage, corrected mortality was higher than site-reported mortality. Censoring did not, however, lead to substantial underestimation of mortality among TFOs.Although TFO and LTF predicted mortality, the lower incidence of TFO and subsequent death compared with LTF meant that censoring TFOs did not bias mortality estimates. Future cohort analyses should explicitly consider proportions of TFO/LTF and mortality event rates. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) stigma is a barrier to active case finding and delivery of care in fighting the TB epidemic. As part of a project exploring different models for delivery of TB contact tracing, we conducted a qualitative analysis to explore the presence of TB stigma within communities across South Africa. Methods: We conducted 43 in-depth interviews with 31 people with TB and 12 household contacts as well as five focus group discussions with 40 ward-based team members and 11 community stakeholders across three South African districts. Results: TB stigma is driven and facilitated by fear of disease coupled with an understanding of TB/HIV duality and manifests as anticipated and internalized stigma. Individuals are marked with TB stigma verbally through gossip and visually through symptomatic identification or when accessing care in either TB-specific areas in health clinics or though ward-based outreach teams. Individuals’ unique understanding of stigma influences how they seek care. Conclusion: TB stigma contributes to suboptimal case finding and care at the community level in South Africa. Interventions to combat stigma, such as community and individual education campaigns on TB treatment and transmission as well as the training of health care workers on stigma and stigmatization are needed to prevent discrimination and protect patient confidentiality. [ABSTRACT FROM AUTHOR]

Background Antiretroviral drug resistance is becoming increasingly common with the expansion of human immunodeficiency virus (HIV) treatment programmes in high prevalence settings. Genotypic resistance testing could have benefit in guiding individual-level treatment decisions but successful models for delivering resistance testing in low- and middle-income countries have not been reported. Methods An HIV Treatment Failure Clinic model was implemented within a large primary health care HIV treatment programme in northern KwaZulu-Natal, South Africa. Genotypic resistance testing was offered to adults (=16 years) with virological failure on first-line antiretroviral therapy (one viral load >1000 copies/ml after at least 12 months on a standard first-line regimen). A genotypic resistance test report was generated with treatment recommendations from a specialist HIV clinician and sent to medical officers at the clinics who were responsible for patient management. A quantitative process evaluation was conducted to determine how the model was implemented and to provide feedback regarding barriers and challenges to delivery. Results A total of 508 specimens were submitted for genotyping between 8 April 2011 and 31 January 2013; in 438 cases (86.2%) a complete genotype report with recommendations from the specialist clinician was sent to the medical officer. The median turnaround time from specimen collection to receipt of final report was 18 days (interquartile range (IQR) 13-29). In 114 (26.0%) cases the recommended treatment differed from what would be given in the absence of drug resistance testing. In the majority of cases (n = 315, 71.9%), the subsequent treatment prescribed was in line with the recommendations of the report. Conclusions Genotypic resistance testing was successfully implemented in this large primary health care HIV programme and the system functioned well enough for the results to influence clinical management decisions in real time. Further research will explore the impact and costeffectiveness of different implementation models in different settings. [ABSTRACT FROM AUTHOR]

Substantial amounts of data have been generated from patient management and academic exercises designed to better understand the human immunodeficiency virus (HIV) epidemic and design interventions to control it. A number of specialized databases have been designed to manage huge data sets from HIV cohort, vaccine, host genomic and drug resistance studies. Besides databases from cohort studies, most of the online databases contain limited curated data and are thus sequence repositories. HIV drug resistance has been shown to have a great potential to derail the progress made thus far through antiretroviral therapy. Thus, a lot of resources have been invested in generating drug resistance data for patient management and surveillance purposes. Unfortunately, most of the data currently available relate to subtype B even though >60% of the epidemic is caused by HIV-1 subtype C. A consortium of clinicians, scientists, public health experts and policy markers working in southern Africa came together and formed a network, the Southern African Treatment and Resistance Network (SATuRN), with the aim of increasing curated HIV-1 subtype C and tuberculosis drug resistance data. This article describes the HIV-1 data curation process using the SATuRN Rega database. The data curation is a manual and time-consuming process done by clinical, laboratory and data curation specialists. Access to the highly curated data sets is through applications that are reviewed by the SATuRN executive committee. Examples of research outputs from the analysis of the curated data include trends in the level of transmitted drug resistance in South Africa, analysis of the levels of acquired resistance among patients failing therapy and factors associated with the absence of genotypic evidence of drug resistance among patients failing therapy. All these studies have been important for informing first- and second-line therapy. [ABSTRACT FROM AUTHOR]

To explore the impact of expanded eligibility criteria for antiretroviral therapy (ART) on median CD4+ cell count at ART initiation and early mortality on ART.Analyses included all adults (≥16 years) initiated on first-line ART between August 2004 and July 2012. CD4+ cell count threshold 350 cells per microliter for all adults was implemented in August 2011. Early mortality was defined as any death within 91 days of ART initiation. Trends in baseline CD4+ cell count and early mortality were examined by year (August to July) of ART initiation. Competing risks analysis was used to examine early mortality.A total of 19,080 adults (67.6% female) initiated ART. Median CD4+ cell count at ART initiation was 110-120 cells per microliter over the first 6 years, increasing marginally to 145 cells per microliter in 2010-2011 and more significantly to 199 cells per microliter in 2011-2012. Overall, there were 875 deaths within 91 days of ART initiation; early mortality rate was 19.4 per 100 person-years [95% confidence interval (CI) 18.2 to 20.7]. After adjustment for sex, age, baseline CD4+ cell count, and concurrent tuberculosis (TB), there was a 46% decrease in early mortality for those who initiated ART in 2011-2012 compared with the reference period 2008-2009 (subhazard ratio, 0.54; 95% CI: 0.41 to 0.71).Since the expansion of eligibility criteria, there is evidence of earlier access to ART and a significant reduction in early mortality rate in this primary health care programme. These findings provide strong support for national ART policies and highlight the importance of earlier ART initiation for achieving reductions in HIV-related mortality. [ABSTRACT FROM AUTHOR]

Objective To determine rates of, and factors associated with, disengagement from care in a decentralised antiretroviral programme. Methods Adults (≥16 years) who initiated antiretroviral therapy ( ART) in the Hlabisa HIV Treatment and Care Programme August 2004-March 2011 were included. Disengagement from care was defined as no clinic visit for 180 days, after adjustment for mortality. Cumulative incidence functions for disengagement from care, stratified by year of ART initiation, were obtained; competing-risks regression was used to explore factors associated with disengagement from care. Results A total of 4,674 individuals (median age 34 years, 29% male) contributed 13 610 person-years of follow-up. After adjustment for mortality, incidence of disengagement from care was 3.4 per 100 person-years (95% confidence interval ( CI) 3.1-3.8). Estimated retention at 5 years was 61%. The risk of disengagement from care increased with each calendar year of ART initiation ( P for trend <0.001). There was a strong association between disengagement from care and higher baseline CD4+ cell count (subhazard ratio ( SHR) 1.94 ( P < 0.001) and 2.35 ( P < 0.001) for CD4+ cell count 150-200 cells/μl and >200 cells/μl respectively, compared with CD4 count <50 cells/μl). Of those disengaged from care with known outcomes, the majority (206/303, 68.0%) remained resident within the local community. Conclusions Increasing disengagement from care threatens to limit the population impact of expanded antiretroviral coverage. The influence of both individual and programmatic factors suggests that alternative service delivery strategies will be required to achieve high rates of long-term retention. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa. Design: Cross-sectional study nested within HIV treatment programme. Methods: Adult (≥18 years) HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART) regimen and with evidence of virological failure (one viral load >1000 copies/ml) were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms. Results: A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%); and stavudine, lamivudine and nevirapine (24%). Median duration of ART was 42 months (interquartile range (IQR) 32–53) and median duration of antiretroviral failure was 27 months (IQR 17–40). One hundred and ninety one (86%) had at least one drug resistance mutation. For 34 individuals (15%), the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI) substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR) 5.70, 95% confidence interval (CI) 2.60–12.49). Conclusions: There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis control in sub-Saharan Africa has long been hampered by poor diagnostics and weak health systems. New molecular diagnostics, such as the Xpert® MTB/RIF assay, have the potential to improve patient outcomes. We present a cluster randomised trial designed to evaluate whether the positioning of this diagnostic system within the health system has an impact on important patient-level outcomes. Methods/Design: This pragmatic cluster randomised clinical trial compared two positioning strategies for the Xpert MTB/RIF system: centralised laboratory versus primary health care clinic. The cluster (unit of randomisation) is a 2- week time block at the trial clinic. Adult pulmonary tuberculosis suspects with confirmed human immunodeficiency virus infection and/or at high risk of multidrug-resistant tuberculosis are enrolled from the primary health care clinic. The primary outcome measure is the proportion of culture-confirmed pulmonary tuberculosis cases initiated on appropriate treatment within 30 days of initial clinic visit. Univariate logistic regression will be performed as the primary analysis using generalised estimating equations with a binomial distribution function and a logit link. Conclusion: Diagnostic research tends to focus only on performance of diagnostic tests rather than on patientimportant outcomes. This trial has been designed to improve the quality of evidence around diagnostic strategies and to inform the scale-up of new tuberculosis diagnostics within public health systems in high-burden settings. [ABSTRACT FROM AUTHOR]

The limitations of existing tuberculosis diagnostic tools are significantly hampering tuberculosis control efforts, most noticeably in areas with high prevalence of human immunodeficiency virus (HIV) infection and antituberculosis drug resistance. However, renewed global interest in tuberculosis research has begun to bear fruit, with several new diagnostic technologies progressing through the development pipeline. There are significant challenges in building a sound evidence base to inform public health policies because most diagnostic research focuses on the accuracy of individual tests, with often significant limitations in the design, conduct, and reporting of diagnostic accuracy studies. Diagnostic accuracy studies may not be appropriate to guide public health policies, and clinical trials may increasingly be required to determine the incremental value and cost-effectiveness of new tools. The urgent need for new diagnostics should not distract from pursuing rigorous scientific evaluation focused on public health impact. [ABSTRACT FROM AUTHOR]

Objective: To assess whether treatment outcomes vary with age for adults receiving antiretroviral therapy (ART) in a large rural HIV treatment cohort. Design: Retrospective cohort analysis using data from a public HIV Treatment & Care Programme. Methods: Adults initiating ART 1st August 2004 - 31st October 2009 were stratified by age at initiation: young adults (16-24 years) mid-age adults (25-49 years) and older ($50 years) adults. Kaplan-Meier survival analysis was used to estimate mortality rates and age and person-time stratified Cox regression to determine factors associated with mortality. Changes in CD4 cell counts were quantified using a piecewise linear model based on follow-up CD4 cell counts measured at sixmonthly time points. Results: 8846 adults were included, 808 (9.1%) young adults; 7119 (80.5%) mid-age adults and 919 (10.4%) older adults, with 997 deaths over 14,778 person-years of follow-up. Adjusting for baseline characteristics, older adults had 32% excess mortality (p = 0.004) compared to those aged 25-49 years. Overall mortality rates (MR) per 100 person-years were 6.18 (95% CI 4.90-7.78); 6.55 (95% CI 6.11-7.02) and 8.69 (95% CI 7.34-10.28) for young, mid-age and older adults respectively. In the first year on ART, for older compared to both young and mid-aged adults, MR per 100 person-years were significantly higher; 0-3 months (MR: 27.1 vs 17.17 and 21.36) and 3-12 months (MR: 9.5 vs 4.02 and 6.02) respectively. CD4 count reconstitution was lower, despite better virological response in the older adults. There were no significant differences in MR after 1year of ART. Baseline markers of advanced disease were independently associated with very early mortality (0-3 months) whilst immunological and virological responses were associated with mortality after 12months. Conclusions: Early ART initiation and improving clinical care of older adults are required to reduce high early mortality and enhance immunologic recovery, particularly in the initial phases of ART. [ABSTRACT FROM AUTHOR]

To determine retention in HIV care for individuals not yet eligible for antiretroviral therapy (ART) and to explore factors associated with retention in a rural public health HIV program.HIV-infected adults (≥16 years) not yet eligible for ART, with CD4 cell count >200 cells per microliter from January 2007 to December 2007 were included in the analysis. Retention was defined by repeat CD4 count within 13 months. Factors associated with retention were assessed using logistic regression with clustering at clinic level.Four thousand two hundred twenty-three were included in the analysis (83.9% female). Overall retention was 44.9% with median time to return 201 days [interquartile range (IQR): 127-274]. Retention by initial CD4 count 201-350, 351-500, and >500 cells per microliter was 51.6% [95% confidence interval (CI): 49.1 to 54.0], 43.2% (95% CI: 40.5 to 45.9), and 34.9% (95% CI: 32.4 to 37.4), respectively. Compared with CD4 201-350 cells per microliter, higher initial CD4 count was significantly associated with lower odds of retention [CD4: 351-500 cells/μL adjusted odds ratio (aOR): 0.72, 95% CI: 0.62 to 0.84; CD4 >500 cells/μL aOR: 0.51, 95% CI: 0.44 to 0.60]. Male sex was independently associated with lower odds (aOR: 0.80, 95% CI: 0.67 to 0.96), and older age with higher odds of retention (for each additional year of age aOR: 1.03, 95% CI: 1.03 to 1.04).Retention in HIV care before eligibility for ART is poor, particularly for younger individuals and those at an earlier stage of infection. Further work to optimize and evaluate care and monitoring strategies is required to realize the full benefits of the rapid expansion of HIV programs in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Objective To describe the scale-up of a decentralized HIV treatment programme delivered through the primary health care system in rural KwaZulu-Natal, South Africa, and to assess trends in baseline characteristics and outcomes in the study population. Methods The programme started delivery of antiretroviral therapy (ART) in October 2004. Information on all patients initiated on ART was captured in the programme database and follow-up status was updated monthly. All adult patients (≥16 years) who initiated ART between October 2004 and September 2008 were included and stratified into 6-month groups. Clinical and sociodemographic characteristics were compared between the groups. Retention in care, mortality, loss to follow-up and virological outcomes were assessed at 12 months post-ART initiation. Findings A total of 5719 adults initiated on ART were included (67.9% female). Median baseline CD4+ lymphocyte count was 116 cells/μl (interquartile range, IQR: 53.173). There was an increase in the proportion of women who initiated ART while pregnant but no change in other baseline characteristics over time. Overall retention in care at 12 months was 84.0% (95% confidence interval, CI: 82.6.85.3); 10.9% died (95% CI: 9.8.12.0); 3.7% were lost to follow-up (95% CI: 3.0.4.4). Mortality was highest in the first 3 months after ART initiation: 30.1 deaths per 100 person.years (95% CI: 26.3.34.5). At 12 months 23.0% had a detectable viral load (> 25 copies/ml) (95% CI: 19.5.25.5). Conclusion Outcomes were not affected by rapid expansion of this decentralized HIV treatment programme. The relatively high rates of detectable viral load highlight the need for further efforts to improve the quality of services. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) household contact tracing is a form of targeted active case-finding for which community health workers ('outreach teams') in South Africa are primarily responsible for its implementation. We conducted an exploratory qualitative study to understand the role of outreach teams in delivering TB household contact tracing. Methods: The study took place in three districts of South Africa between May 2016 and February 2017. We conducted 78 in-depth interviews (IDI) (comprising 35 key stakeholders, 31 TB index patients and 12 HHCs) and five focus group discussions (FGD) (40 outreach team members in four FGDs and 12 community stakeholders in one FGD). Results: Outreach teams contributed positively by working across health-related programmes, providing home-based care and assisting with tracing of persons lost to TB care. However, outreach teams had a limited focus on TB household contact tracing activities, likely due to the broad scope of their work and insufficient programmatic support. Outreach teams often confused TB household contact tracing activities with finding persons lost to TB care. The community also had some reservations on the role of outreach teams conducting TB household contact tracing activities. Conclusions: Creating awareness among outreach workers and clinic personnel about the importance of and activities related to TB household contact tracing would be required to strengthen the delivery of TB household contact tracing through the community-based primary health care teams. We need better monitoring and evaluation systems, stronger integration within a realistic scope of work, adequate training on TB household contact tracing and TB infection prevention control measures. Involving the community and educating them on the role of outreach teams could improve acceptance of future activities. These timely results and lessons learned should inform contact tracing approaches in the context of COVID-19. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 70-year-old woman with advanced human immunodeficiency virus (HIV) infection in KwaZulu-Natal, South Africa, experiencing cough, shortness of breath, and malaise. Topics discussed include the patient's HIV treatment history, co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Mycobacterium tuberculosis, and the challenges in managing her symptoms.

Background We aimed to compare clinical outcomes after viremia between dolutegravir vs efavirenz-based first-line antiretroviral therapy (ART) as evidence is lacking outside clinical trials in resource-limited settings. Methods We conducted a retrospective cohort analysis with routine data from 59 South African clinics. We included people with HIV aged ≥15 years receiving first-line tenofovir disoproxil fumarate, lamivudine, dolutegravir (TLD) or tenofovir disoproxil fumarate, emtricitabine, efavirenz (TEE) and with first viremia (≥50 copies/mL) between June and November 2020. We used multivariable modified Poisson regression models to compare retention in care and viral suppression (<50 copies/mL) after 12 months between participants on TLD vs TEE. Results At first viremia, among 9657 participants, 6457 (66.9%) were female, and the median age (interquartile range [IQR]) was 37 (31–44) years; 7598 (78.7%) were receiving TEE and 2059 (21.3%) TLD. Retention in care was slightly higher in the TLD group (84.9%) than TEE (80.8%; adjusted risk ratio [aRR], 1.03; 95% CI, 1.00–1.06). Of 6569 participants retained in care with a 12-month viral load, viral suppression was similar between the TLD (78.9%) and TEE (78.8%) groups (aRR, 1.02; 95% CI, 0.98–1.05). However, 3368 participants changed ART during follow-up: the majority from TEE to first-line TLD (89.1%) or second-line (TLD 3.4%, zidovudine/emtricitabine/lopinavir-ritonavir 2.1%). In a sensitivity analysis among the remaining 3980 participants who did not change ART during follow-up and had a 12-month viral load, viral suppression was higher in the TLD (78.9%) than TEE (74.9%) group (aRR, 1.07; 95% CI, 1.03–1.12). Conclusions Among people with viremia on first-line ART, dolutegravir was associated with slightly better retention in care and similar or better viral suppression than efavirenz. [ABSTRACT FROM AUTHOR]

A case of multidrug-resistant tuberculosis is presented. It highlights the role of whole-genome sequencing, expanded phenotypic drug susceptibility testing, and enhanced case management, offering a more complete understanding of drug susceptibility to Mycobacterium tuberculosis. This approach guides an effective individualized treatment strategy that results in rapid sustained culture conversion. [ABSTRACT FROM AUTHOR]

Objectives: To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (LA-DRVs) on virological failure (VF) among HIV-1/TB-co-infected individuals treated with NNRTI first-line ART.Methods: We conducted a case-control study of 170 adults with HIV-1/TB co-infection. Cases had at least one viral load (VL) ≥1000 RNA copies/mL after ≥6 months on NNRTI-based ART, and controls had sustained VLs <1000 copies/mL. We sequenced plasma viruses by Sanger and MiSeq next-generation sequencing (NGS). We assessed drug resistance mutations (DRMs) using the Stanford drug resistance database, and analysed NGS data for DRMs at ≥20%, 10%, 5% and 2% thresholds. We assessed the effect of pretreatment drug resistance (PDR) on VF.Results: We analysed sequences from 45 cases and 125 controls. Overall prevalence of PDR detected at a ≥20% threshold was 4.7% (8/170) and was higher in cases than in controls (8.9% versus 3.2%), P = 0.210. Participants with PDR at ≥20% had almost 4-fold higher odds of VF (adjusted OR 3.7, 95% CI 0.8-18.3) compared with those without, P = 0.104. PDR prevalence increased to 18.2% (31/170) when LA-DRVs at ≥2% were included. Participants with pretreatment LA-DRVs only had 1.6-fold higher odds of VF (adjusted OR 1.6, 95% CI 0.6-4.3) compared with those without, P = 0.398.Conclusions: Pretreatment DRMs and LA-DRVs increased the odds of developing VF on NNRTI-based ART, although without statistical significance. NGS increased detection of DRMs but provided no additional benefit in identifying participants at risk of VF at lower thresholds. More studies assessing mutation thresholds predictive of VF are required to inform use of NGS in treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral drug resistance is becoming increasingly common with the expansion of human immunodeficiency virus (HIV) treatment programmes in high prevalence settings. Genotypic resistance testing could have benefit in guiding individual-level treatment decisions but successful models for delivering resistance testing in low- and middle-income countries have not been reported.Methods: An HIV Treatment Failure Clinic model was implemented within a large primary health care HIV treatment programme in northern KwaZulu-Natal, South Africa. Genotypic resistance testing was offered to adults (≥16 years) with virological failure on first-line antiretroviral therapy (one viral load >1000 copies/ml after at least 12 months on a standard first-line regimen). A genotypic resistance test report was generated with treatment recommendations from a specialist HIV clinician and sent to medical officers at the clinics who were responsible for patient management. A quantitative process evaluation was conducted to determine how the model was implemented and to provide feedback regarding barriers and challenges to delivery.Results: A total of 508 specimens were submitted for genotyping between 8 April 2011 and 31 January 2013; in 438 cases (86.2%) a complete genotype report with recommendations from the specialist clinician was sent to the medical officer. The median turnaround time from specimen collection to receipt of final report was 18 days (interquartile range (IQR) 13-29). In 114 (26.0%) cases the recommended treatment differed from what would be given in the absence of drug resistance testing. In the majority of cases (n = 315, 71.9%), the subsequent treatment prescribed was in line with the recommendations of the report.Conclusions: Genotypic resistance testing was successfully implemented in this large primary health care HIV programme and the system functioned well enough for the results to influence clinical management decisions in real time. Further research will explore the impact and cost-effectiveness of different implementation models in different settings. [ABSTRACT FROM AUTHOR]

The article discusses a study by M. T. Gler and colleagues conducted to evaluate the efficacy and safety of delaminid in the treatment of multidrug-resistant pulmonary tuberculosis. Topics include comparison between randomised clinical trial and placebo administered trial, use of electrocardiography (ECG), and HIV-infected patients. The results indicate efficacy of Delaminid for improved treatment of drug-resistant tuberculosis.

The global pandemic caused by SARS-CoV-2 has increased the demand for scalable sequencing and diagnostic methods, especially for genomic surveillance. Although next-generation sequencing has enabled large-scale genomic surveillance, the ability to sequence SARS-CoV-2 in some settings has been limited by the cost of sequencing kits and the time-consuming preparations of sequencing libraries. We compared the sequencing outcomes, cost and turn-around times obtained using the standard Illumina DNA Prep kit protocol to three modified protocols with fewer clean-up steps and different reagent volumes (full volume, half volume, one-tenth volume). We processed a single run of 47 samples under each protocol and compared the yield and mean sequence coverage. The sequencing success rate and quality for the four different reactions were as follows: the full reaction was 98.2%, the one-tenth reaction was 98.0%, the full rapid reaction was 97.5% and the half-reaction, was 97.1%. As a result, uniformity of sequence quality indicated that libraries were not affected by the change in protocol. The cost of sequencing was reduced approximately seven-fold and the time taken to prepare the library was reduced from 6.5 hours to 3 hours. The sequencing results obtained using the miniaturised volumes showed comparability to the results obtained using full volumes as described by the manufacturer. The adaptation of the protocol represents a lower-cost, streamlined approach for SARS-CoV-2 sequencing, which can be used to produce genomic data quickly and more affordably, especially in resource-constrained settings. [ABSTRACT FROM AUTHOR]

Introduction: In South Africa, Community Caregivers (CCGs) visit households to provide basic healthcare services including those for tuberculosis and HIV. However, CCG workloads, costs, and time burden are largely unknown. Our objective was to assess the workloads and operational costs for CCG teams operating in different settings in South Africa. Methods: Between March and October 2018, we collected standardized self-reported activity time forms from 11 CCG pairs working at two public health clinics in Ekurhuleni district, South Africa. CCG workloads were assessed based on activity unit times, per-household visit time, and mean daily number of successful household visits. Using activity-based times and CCG operating cost data, we assessed CCG annual and per-household visit costs (USD 2019) from the health system perspective. Results: CCGs in clinic 1 (peri-urban, 7 CCG pairs) and 2 (urban, informal settlement; 4 CCG pairs) served an area of 3.1 km2 and 0.6 km2 with 8,035 and 5,200 registered households, respectively. CCG pairs spent a median 236 minutes per day conducting field activities at clinic 1 versus 235 minutes at clinic 2. CCG pairs at clinic 1 spent 49.5% of this time at households (versus traveling), compared to 35.0% at clinic 2. On average, CCG pairs successfully visited 9.5 vs 6.7 households per day for clinics 1 and 2, respectively. At clinic 1, 2.7% of household visits were unsuccessful, versus 28.5% at clinic 2. Total annual operating costs were higher in clinic 1 ($71,780 vs $49,097) but cost per successful visit was lower ($3.58) than clinic 2 ($5.85). Conclusions: CCG home visits were more frequent, successful, and less costly in clinic 1, which served a larger and more formalized settlement. The variability in workload and cost observed across pairs and clinics suggests that circumstantial factors and CCG needs must be carefully assessed for optimized CCG outreach operations. [ABSTRACT FROM AUTHOR]

Ethiopia is the second most populous country in Africa and the sixth most affected by COVID-19 on the continent. Despite having experienced five infection waves, >499,000 cases, and ~7500 COVID-19-related deaths as of January 2023, there is still no detailed genomic epidemiological report on the introduction and spread of SARS-CoV-2 in Ethiopia. In this study, we reconstructed and elucidated the COVID-19 epidemic dynamics. Specifically, we investigated the introduction, local transmission, ongoing evolution, and spread of SARS-CoV-2 during the first four infection waves using 353 high-quality near-whole genomes sampled in Ethiopia. Our results show that whereas viral introductions seeded the first wave, subsequent waves were seeded by local transmission. The B.1.480 lineage emerged in the first wave and notably remained in circulation even after the emergence of the Alpha variant. The B.1.480 was outcompeted by the Delta variant. Notably, Ethiopia's lack of local sequencing capacity was further limited by sporadic, uneven, and insufficient sampling that limited the incorporation of genomic epidemiology in the epidemic public health response in Ethiopia. These results highlight Ethiopia's role in SARS-CoV-2 dissemination and the urgent need for balanced, near-real-time genomic sequencing. [ABSTRACT FROM AUTHOR]

A 22-year-old woman with uncontrolled advanced human immunodeficiency virus (HIV) infection was persistently infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) beta variant for 9 months, the virus accumulating >20 additional mutations. Antiretroviral therapy suppressed HIV and cleared SARS-CoV-2 within 6 to 9 weeks. Increased vigilance is warranted to benefit affected individuals and prevent the emergence of novel SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis control in sub-Saharan Africa has long been hampered by poor diagnostics and weak health systems. New molecular diagnostics, such as the Xpert® MTB/RIF assay, have the potential to improve patient outcomes. We present a cluster randomised trial designed to evaluate whether the positioning of this diagnostic system within the health system has an impact on important patient-level outcomes.Methods/design: This pragmatic cluster randomised clinical trial compared two positioning strategies for the Xpert MTB/RIF system: centralised laboratory versus primary health care clinic. The cluster (unit of randomisation) is a 2-week time block at the trial clinic. Adult pulmonary tuberculosis suspects with confirmed human immunodeficiency virus infection and/or at high risk of multidrug-resistant tuberculosis are enrolled from the primary health care clinic. The primary outcome measure is the proportion of culture-confirmed pulmonary tuberculosis cases initiated on appropriate treatment within 30 days of initial clinic visit. Univariate logistic regression will be performed as the primary analysis using generalised estimating equations with a binomial distribution function and a logit link.Conclusion: Diagnostic research tends to focus only on performance of diagnostic tests rather than on patient-important outcomes. This trial has been designed to improve the quality of evidence around diagnostic strategies and to inform the scale-up of new tuberculosis diagnostics within public health systems in high-burden settings.Trial Registration: Current Controlled Trials ISRCTN18642314; South African National Clinical Trials Registry DOH-27-0711-3568. [ABSTRACT FROM AUTHOR]

Background Medication adherence is known to challenge treatment of human immunodeficiency virus (HIV)/AIDS and multidrug-resistant tuberculosis (MDR-TB). We hypothesized that adherence using electronic dose monitoring (EDM) would identify an antiretroviral therapy (ART) adherence threshold for emergent ART resistance and predict treatment outcomes in patients with MDR-TB and HIV on ART and bedaquiline-containing TB regimens. Methods A prospective cohort of adults with MDR-TB and HIV on ART and initiating MDR-TB treatment with bedaquiline were enrolled at a public hospital in KwaZulu-Natal, South Africa (PRAXIS Study). Participants received separate EDM devices that measure adherence to bedaquiline and ART (nevirapine or lopinavir/ritonavir). Adherence was calculated cumulatively over 6 months. Participants were followed through completion of MDR-TB treatment. HIV genome sequencing was performed at baseline and 2 and 6 months on samples with HIV RNA ≥1000 copies/mL. Results From November 2016 through February 2018, 198 persons with MDR-TB and HIV were enrolled and followed (median, 17.2 months; interquartile range, 12.2–19.6). Eleven percent had baseline ART resistance mutations, and 7.5% developed emergent ART resistance at 6 months. ART adherence was independently associated with ART resistance and mortality. Modeling identified a significant (P <.001), linear association between ART adherence and emergent resistance, suggesting a strong association without a specific threshold. Conclusions Our findings highlight the need for ART resistance testing, especially in patients with MDR-TB and HIV, which is currently not the standard of care in resource-limited settings. Despite short follow-up duration, reduced ART adherence was significantly associated with emergent resistance and increased mortality. Clinical Trials Registration NCT03162107. [ABSTRACT FROM AUTHOR]

The limitations of existing tuberculosis diagnostic tools are significantly hampering tuberculosis control efforts, most noticeably in areas with high prevalence of human immunodeficiency virus (HIV) infection and antituberculosis drug resistance. However, renewed global interest in tuberculosis research has begun to bear fruit, with several new diagnostic technologies progressing through the development pipeline. There are significant challenges in building a sound evidence base to inform public health policies because most diagnostic research focuses on the accuracy of individual tests, with often significant limitations in the design, conduct, and reporting of diagnostic accuracy studies. Diagnostic accuracy studies may not be appropriate to guide public health policies, and clinical trials may increasingly be required to determine the incremental value and cost-effectiveness of new tools. The urgent need for new diagnostics should not distract from pursuing rigorous scientific evaluation focused on public health impact. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Curbing the Liver Cancer Epidemic in Africa" by P. Hainaut and P. Boyle in the February 2, 2008 issue.

Supplemental Digital Content is Available in the Text. Background: We aimed to evaluate the analytic performance of 3 rapid HIV viral load assays: the novel Xpert HIV-1 VL XC (Xpert XC), Xpert HIV-1 VL (Xpert VL), and m-PIMA HIV-1/2 VL (m-PIMA). Setting: Two South African clinics. Methods: We conducted a prospective diagnostic accuracy study. Site-laboratory technicians and nurses used the Xpert XC, Xpert VL, and m-PIMA to test plasma samples from people with HIV receiving antiretroviral therapy. We compared results with the Roche cobas HIV-1 reference assay. We determined accuracy to detect viraemia at the World Health Organization (WHO) failure threshold of 1000 copies/mL on all 3 assays, and 50 and 200 copies/mL on the Xpert assays. We assessed the agreement using Bland–Altman plots. Results: We enrolled 140 participants (98 [70%] women, median age 37 years), who provided 189 paired samples at one or more timepoints. We tested 174 samples with the Xpert XC, 188 with the Xpert VL, and 128 with the m-PIMA. At 1000 copies/mL, sensitivity and specificity (95% confidence intervals) were 97% (82 to 100) and 98% (93 to 99) (Xpert XC), 100% (87 to 100) and 96% (91 to 98) (Xpert VL), and 92% (72 to 99) and 99% (93 to 100) (m-PIMA) respectively. At 50 copies/mL, sensitivity and specificity were 93% (81 to 98) and 96% (91 to 99) (Xpert XC), and 95% (84 to 99) and 95% (90 to 98) (Xpert VL) respectively. Mean bias was −0.10 (−0.54 to 0.34) log10 copies/mL (Xpert XC), 0.07 (−0.37 to 0.52) log10 copies/mL (Xpert VL), and −0.26 (−0.83 to 0.31) log10 copies/mL (m-PIMA). Conclusions: In these South African clinics, the accuracy of all 3 assays was clinically acceptable to detect viraemia at the WHO failure threshold, whereas both Xpert assays were also accurate at detecting low-level viraemia. [ABSTRACT FROM AUTHOR]

HIV drug resistance (HIVDR) can become a public health concern, especially in low- and middle-income countries where genotypic testing for people initiating antiretroviral therapy (ART) is not available. For first-line regimens to remain effective, levels of transmitted drug resistance (TDR) need to be monitored over time. To determine the temporal trends of TDR in Mozambique, a search for studies in PubMed and sequences in GenBank was performed. Only studies covering the pol region that described HIVDR and genetic diversity from treatment naïve patients were included. A dataset from seven published studies and one novel unpublished study conducted between 1999 and 2018 were included. The Calibrated Population Resistance tool (CPR) and REGA HIV-1 Subtyping Tool version 3 for sequences pooled by sampling year were used to determine resistance mutations and subtypes, respectively. The prevalence of HIVDR amongst treatment-naïve individuals increased over time, reaching 14.4% in 2018. The increase was most prominent for non-nucleoside reverse transcriptase inhibitors (NNRTIs), reaching 12.7% in 2018. Subtype C was predominant in all regions, but a higher genetic variability (19% non-subtype C) was observed in the north region of Mozambique. These findings confirm a higher diversity of HIV in the north of the country and an increased prevalence of NNRTI resistance among treatment naïve individuals over time. [ABSTRACT FROM AUTHOR]

COVID-19 was first diagnosed in Egypt on 14 February 2020. By the end of November 2021, over 333,840 cases and 18,832 deaths had been reported. As part of the national genomic surveillance, 1027 SARS-CoV-2 near whole-genomes were generated and published by the end of July 2021. Here we describe the genomic epidemiology of SARS-CoV-2 in Egypt over this period using a subset of 976 high-quality Egyptian genomes analyzed together with a representative set of global sequences within a phylogenetic framework. A single lineage, C.36, introduced early in the pandemic was responsible for most of the cases in Egypt. Furthermore, to remain dominant in the face of mounting immunity from previous infections and vaccinations, this lineage acquired several mutations known to confer an adaptive advantage. These results highlight the value of continuous genomic surveillance in regions where VOCs are not predominant and the need for enforcement of public health measures to prevent expansion of the existing lineages. [ABSTRACT FROM AUTHOR]

Background People living with HIV (PLWH) have been reported to have a higher risk of more severe COVID-19 disease and death. We assessed the ability of the Ad26.CoV2.S vaccine to elicit neutralizing activity against the Delta variant in PLWH relative to HIV-negative individuals. We also examined effects of HIV status and suppression on Delta neutralization response in SARS-CoV-2—infected unvaccinated participants. Methods We enrolled participants who were vaccinated through the SISONKE South African clinical trial of the Ad26.CoV2.S vaccine in healthcare workers (HCWs). PLWH in this group had well-controlled HIV infection. We also enrolled unvaccinated participants previously infected with SARS-CoV-2. Neutralization capacity was assessed by a live virus neutralization assay of the Delta variant. Results Most Ad26.CoV2.S vaccinated HCWs were previously infected with SARS-CoV-2. In this group, Delta variant neutralization was 9-fold higher compared with the infected-only group and 26-fold higher relative to the vaccinated-only group. No decrease in Delta variant neutralization was observed in PLWH relative to HIV-negative participants. In contrast, SARS-CoV-2—infected, unvaccinated PLWH showed 7-fold lower neutralization and a higher frequency of nonresponders, with the highest frequency of nonresponders in people with HIV viremia. Vaccinated-only participants showed low neutralization capacity. Conclusions The neutralization response of the Delta variant following Ad26.CoV2.S vaccination in PLWH with well-controlled HIV was not inferior to HIV-negative participants, irrespective of past SARS-CoV-2 infection. In SARS-CoV-2—infected and nonvaccinated participants, HIV infection reduced the neutralization response to SARS-CoV-2, with the strongest reduction in HIV viremic individuals. [ABSTRACT FROM AUTHOR]

Background Better understanding of drug resistance patterns in HIV-infected children on antiretroviral therapy (ART) is required to inform public health policies in high prevalence settings. The aim of this study was to characterise the acquired drug resistance in HIV-infected children failing first-line ART in a decentralised rural HIV programme. Methods Plasma samples were collected from 101 paediatric patients (⩽15 yrs of age) identified as failing ART. RNA was extracted from the plasma, reverse transcribed and a 1.3 kb region of the protease gene was amplified and sequenced using Sanger sequencing protocols. Sequences were edited in Geneius and drug resistance mutations were identified using the RegaDB and the Stanford, Rega and ANRS resistance algorithms. The prevalence and frequency of mutations were analysed together with selected clinical and demographic data in STATA v11. Results A total of 101 children were enrolled and 89 (88%) were successfully genotyped; 73 on a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen and 16 on a protease inhibitor (PI)-based regimen at the time of genotyping. The majority of patients on an NNRTI regimen (80%) had both nucleoside reverse-transcriptase inhibitor (NRTI) and NNRTI resistance mutations. M184V and K103N were the most common mutations amongst children on NNRTI-based and K103N among children on PI-based regimens. 23% had one or more thymidine analogue mutation (TAM) and 6% had ⩾3 TAMs. Only one child on a PI-based regimen harboured a major PI resistance mutation. Conclusions Whilst the patterns of resistance were largely predictable, the few complex resistance patterns seen with NNRTI-based regimens and the absence of major PI mutations in children failing PI-based regimens suggest the need for wider access to genotypic resistance testing in this setting. [ABSTRACT FROM AUTHOR]

There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (Beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV-negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes. [ABSTRACT FROM AUTHOR]

Background: South Africa remains the country with the greatest burden of HIV-infected individuals and the second highest estimated TB incidence per capita worldwide. Within South Africa, KwaZulu-Natal has one of the highest rates of TB incidence and an emerging epidemic of drug-resistant tuberculosis. Methods: Review of records of consecutive HIV-infected people initiated onto ART between 1st January 2005 and 31st March 2006. Patients were screened for TB at initiation and incident episodes recorded. CD4 counts, viral loads and follow-up status were recorded; data was censored on 5th August 2008. Geographic cluster analysis was performed using spatial scanning. Results: 801 patients were initiated. TB prevalence was 25.3%, associated with lower CD4 (AHR 2.61 p = 0.01 for CD4 <50 cells/μl) and prior TB (AHR 1.58 p = 0.02). Incidence was 6.89 per 100 person-years from 81 cases over 1175 person-years analysis time and was highest in the first 3 months after ART initiation; associated with male sex and higher log HIV RNA. Prevalent and incident TB were significantly associated with mortality (OR 1.81 p = 0.01 and 2.02 p = 0.01 respectively). Incident TB was associated with a non-significant trend towards viral load >25 copies/ml (OR 1.75 p = 0.11). A low-risk cluster for incident TB was identified for patients living near the local hospital in the geospatial analysis. Conclusion: There is a large burden of TB in this population. Rate of incident TB stabilises at a rate higher than that of the overall population. These data highlight the need for greater research on strategies for active case finding in rural settings and the need to focus on strengthening primary health care. [ABSTRACT FROM AUTHOR]

The article discusses a study which describes the genomic epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a dataset of genomes from several African countries and overseas territories. Topics include a brief background on the spread of the coronavirus which originated in Wuhan, China in 2019, an overview of the genomic surveillance efforts in Africa from the onset of the pandemic, and data on Africa's contribution to the international spread of the virus.

The rapid identification and isolation of infected individuals remains a key strategy for controlling the spread of SARS-CoV-2. Frequent testing of populations to detect infection early in asymptomatic or presymptomatic individuals can be a powerful tool for intercepting transmission, especially when the viral prevalence is low. However, RT-PCR testing—the gold standard of SARS-CoV-2 diagnosis—is expensive, making regular testing of every individual unfeasible. Sample pooling is one approach to lowering costs. By combining samples and testing them in groups the number of tests required is reduced, substantially lowering costs. Here we report on the implementation of pooling strategies using 3-d and 4-d hypercubes to test a professional sports team in South Africa. We have shown that infected samples can be reliably detected in groups of 27 and 81, with minimal loss of assay sensitivity for samples with individual Ct values of up to 32. We report on the automation of sample pooling, using a liquid-handling robot and an automated web interface to identify positive samples. We conclude that hypercube pooling allows for the reliable RT-PCR detection of SARS-CoV-2 infection, at significantly lower costs than lateral flow antigen (LFA) tests. [ABSTRACT FROM AUTHOR]

• The early COVID-19 epidemic in South Africa was highly heterogeneous looking at the epidemiological progression between major provinces. • Early transmission in KwaZulu-Natal (KZN) was associated with multiple international introductions of SARS-CoV-2. • The dominating lineages during this time of the epidemic were B.1 and B, which mainly originated from Europe. • Evidence for transmission clusters during the first month of the epidemic suggested locally acquired infection. • A clustered outbreak was linked to a major hospital outbreak in Durban, which inflated the early mortality in KZN. The Network for Genomic Surveillance in South Africa (NGS-SA) was formed to investigate the introduction and understand the early transmission dynamics of the SARS-CoV-2 epidemic in South-Africa. This paper presents the first results from this group, which is a molecular epidemiological study of the first 21 SARS-CoV-2 whole genomes sampled in the first port of entry – KwaZulu-Natal (KZN) – during the first month of the epidemic. By combining this with calculations of the effective reproduction number (R), it aimed to shed light on the patterns of infections in South Africa. Two of the largest provinces – Gauteng and KZN – had a slow growth rate for the number of detected cases, while the epidemic spread faster in the Western Cape and Eastern Cape. The estimates of transmission potential suggested a decrease towards R = 1 since the first cases and deaths, but a subsequent estimated R average of 1.39 between 6–18 May 2020. It was also demonstrated that early transmission in KZN was associated with multiple international introductions and dominated by lineages B1 and B. Evidence for locally acquired infections in a hospital in Durban within the first month of the epidemic was also provided. The COVID-19 pandemic in South Africa was very heterogeneous in its spatial dimension, with many distinct introductions of SARS-CoV2 in KZN and evidence of nosocomial transmission, which inflated early mortality in KZN. The epidemic at the local level was still developing and NGS-SA aimed to clarify the dynamics in South Africa and devise the most effective measures as the outbreak evolved. [ABSTRACT FROM AUTHOR]

Participatory visual research can offer critical insight into the experiences of those most affected by health issues. As these methods are increasingly used to research sensitive topics, there is a need for a clear ethical framework to guide best practice on the part of researchers and research ethics committees. Here we reflect on a project where we used digital storytelling as a participatory visual methodology to explore HIV treatment adherence in rural South Africa, with a focus on the ethical issues we encountered during the lifetime of the project. To ground our reflections, we use the framework for ethical research developed by Emanuel et al., and the adaptation of this framework for social science proposed by Wassenaar and Mamotte. We suggest that fellow PVM practitioners and REC members draw on this holistic framework to support the optimal application of PVM in health research. [ABSTRACT FROM AUTHOR]