Repeating an intervention strategy consistent with the chronic disease care model has been demonstrated to be efficacious in improving cessation outcomes among smokers. However, evidence is lacking for repeat treatment outcomes among people with HIV (PWH) who smoke in low-resource settings. We evaluated outcomes among participants (n = 384) who were provided a second round of treatment after initial treatment failure in a randomized controlled trial of behavioral counseling (BC) with or without combination nicotine replacement therapy (nicotine patches and gum, cNRT). The primary outcome was self-reported smoking abstinence at 6 months after repeat treatment, biochemically verified using exhaled breath carbon monoxide (CO) and urine cotinine test. Secondary outcomes include smoking abstinence at 2 months after repeat treatment and smoking reduction, measured by changes in exhaled breath CO at 2 months and 6 months after repeat treatment. Overall, 35 (9

BACKGROUND:Despite the expansion of antiretroviral treatment programmes, the incidence and mortality of HIV-associated cryptococcal meningitis remain high in Africa. Cryptococcal antigen (CrAg) in the blood precedes meningitis. CrAg screening of individuals with advanced HIV disease, combined with pre-emptive fluconazole treatment, reduces the risk of cryptococcal meningitis and associated mortality. However, mortality among individuals with antigenaemia treated with fluconazole is higher than that of CD4-matched individuals with a CrAg-negative test. Autopsy studies have found that cryptococcal disease remains an important cause of death in people with antigenaemia despite pre-emptive antifungal treatment. This suggests a need for more potent treatment for antigenaemia. Flucytosine, combined with fluconazole, is an effective and safe oral treatment for cryptococcal meningitis, and flucytosine has become more widely available as a generic formulation. This trial aims to determine whether combination treatment of fluconazole plus flucytosine is superior to fluconazole monotherapy in reducing all-cause mortality among adults with antigenaemia without evidence of meningitis. METHODS:This multi-centre, open-label phase III randomised-controlled trial embedded in routine CrAg screening programmes in South Africa and Tanzania will compare 14 days of fluconazole (1200 mg/day) plus flucytosine (100 mg/kg/day) to fluconazole (1200 mg/day) alone for the treatment of adults with advanced HIV disease, a blood CrAg-positive test and without evidence of meningitis. Following this 2-week induction therapy, all participants are given fluconazole consolidation and maintenance therapy per local guidelines. The primary endpoint is all-cause mortality at 6 months (superiority analysis). Secondary endpoints include time to all-cause mortality, cryptococcal meningitis-free survival and incidence of symptomatic cryptococcal meningitis, proportion of participants with grade 3 or 4 adverse events, efficacy outcomes by baseline CrAg titre/CrAg semi-quantitative assay score, and health service and household costs per life year saved. A total of 600 participants will be enrolled, 300 per arm, sufficient to detect a 40% relative reduction in mortality with 91% power. DISCUSSION:An all-oral combination regimen of flucytosine with fluconazole, tested in adults with early cryptococcal disease across a range of baseline CrAg titres, could be an easy-to-administer, safe, and implementable alternative if found to be superior to the current World Health Organization recommended standard of fluconazole monotherapy. TRIAL REGISTRATION:ISRCTN30579828, registered 04 March 2021, and SANCTR DOH-27-122021-6511, registered 06 December 2021.

BACKGROUND:Nonpharmaceutical interventions, implemented during the COVID-19 pandemic, affected the transmission of other respiratory pathogens. METHODS:Systematically collected respiratory illness surveillance data and consistent case definitions were used to describe changes in influenza and respiratory syncytial virus (RSV)-associated outpatient visits and hospitalisations in South Africa during the first 3 years of the COVID-19 pandemic relative to a pre-COVID-19 pandemic period (2017-2019). RESULTS:In 2020, influenza circulation almost ceased. In 2021 an out-of-season circulation was observed with a return to prepandemic timing, albeit with a higher peak in 2022. During the pandemic period, influenza-associated influenza-like illness (ILI) was more common in those aged ≥ 5 years compared to < 6 months. Patients with influenza-associated severe respiratory illness (SRI) were less likely to be ≥ 45 years versus < 6 months and less likely to be admitted to ICU (aOR 0.2, 95% CI 0.04-0.8). RSV circulation declined at the start of the pandemic, with an out-of-season spring resurgence in 2020 followed by a return to prepandemic timing in 2021 and a higher peak in 2022. During the pandemic, compared to the prepandemic period, patients with RSV-associated SRI were more likely to be aged 1-4 years (aOR 1.5, 95% CI 1.2-1.8) versus < 6 months and less likely to be admitted to ICU (aOR 0.5, 95% CI 0.3-0.8). CONCLUSION:We report low levels of influenza circulation and out-of-season RSV circulation in 2020 with changes in the age distribution of cases and risk of ICU admission. Return to prepandemic timing was earlier for RSV, with higher seasonal peaks for influenza-associated ILI and RSV-associated SRI in 2022.

Abstract Despite suppressive antiretroviral therapy (ART), HIV persists in the central nervous system (CNS) and contributes to HIV-associated neurocognitive disorder (HAND), but cell type–specific effects remain poorly defined. Using fluorescence-activated nuclei sorting of postmortem brain tissue of aviremic and viremic deceased people with HIV (DPWH) and HIV-negative individuals, we quantified the size of the HIV CNS reservoir and transcriptional alterations. Microglia were identified as the dominant CNS reservoir, harboring 10³–10⁴ HIV DNA copies per million cells by ddPCR-LTR assay in both aviremic and viremic DPWH. Bulk RNA-sequencing revealed immune pathway upregulation specifically in microglia, and downregulation of synaptic and homeostatic pathways across cell-types in viremic compared to aviremic individuals. ART partially mitigated microglial transcriptional dysregulation, but transcriptional profiles did not restore profiles to HIV-negative levels. Notably, persistent microglial infection was associated with transcriptional changes in other cell-types, underscoring microglia as a key therapeutical target for CNS-directed HIV cure strategies.

Background Community-acquired pneumonia (CAP) is a major cause of hospitalisation. In South Africa 74% of adults hospitalised with CAP are patients living with HIV (PLWH). Streptococcus(S) pneumoniae remains a leading cause of CAP in PLWH. Rapid and accurate pathogen identification has significant management implications. The objectives of the study is to: describe respiratory pathogens detected by the BioFire® FilmArray® multiplex PCR pneumonia panels (MPPP) and compare S. pneumoniae detection with standard diagnostics in adults admitted with CAP. Secondary objectives were to stratify pathogens by HIV status and assess length of stay (LOS) and mortality risk. Methods Stored sputum specimens from the PotPrev trial collected between August to December 2019, pre-covid era, were analysed using MPPP. S. pneumoniae identification was made by three separate methods: multiplex PCR (mPCR) on sputum, single-plex PCR on nasopharyngeal swab (NPS) and blood. Results In 146 samples analysed, MPPP detected 275 pathogens in 119 patients (81.5%). Seven organisms accounted for 80% of pathogens: Streptococcus pneumoniae (24.7%), Haemophilus influenzae (17.8%), Staphylococcus aureus (9.1%), Mycobacterium tuberculosis (9.1%), Moraxella catarrhalis (8.4%), Rhinovirus (5.5%) and Influenza virus (4.4%). Among 68 S. pneumoniae cases, NPS lytA PCR had the highest sensitivity (91.2%), followed by mPCR (67.6%) and blood lytA PCR (27.9%). Of note, mPCR detected 7.4% additional cases. Concordance between NPS lytA PCR and mPCR was 61.3%, and blood lytA PCR 24.6%. Among PLWH, a wider spectrum of pathogens was observed, with Pneumocystis jirovecii pneumonia accounting for a high proportion of cases (8.7%). There were no differences in bacterial (p = 0.37), viral (p = 0.5), mortality (p = 0.6), or length of stay (median six days, p = 0.96) in PLWH. Survivors and non-survivors had similar LOS (p = 0.68). Low oxygen saturation was associated with reduced survival (p = 0.039). Conclusion MPPP in addition to standard diagnostics increases pathogen detection in hospitalized CAP. PLWH had distinct aetiology with a higher pathogen burden. These findings support the value of molecular diagnostics and context-specific approaches in high HIV-burden settings.

Background:The World Health Organization recommends dolutegravir (DTG) as the anchor antiretroviral therapy (ART) drug for children with HIV. Methods:The ODYSSEY randomized trial evaluated DTG-based ART vs non-DTG standard of care (SOC) over 96 weeks in children starting first-line ART or switching to second-line. Participant follow-up was extended to 240 weeks; ART in extended follow-up was per national guidelines. Flexible parametric survival models estimated the proportion of participants with treatment failure on randomized allocation, accounting for treatment switches through censoring and inverse probability of censoring weights. Adverse events were analyzed in the intention-to-treat population. Results:ODYSSEY enrolled 792 participants (392 DTG, 400 SOC): 311 started first-line (SOC, 92% efavirenz) and 396 second-line (SOC, 98% ritonavir-boosted protease inhibitors). The median (range) age at enrollment was 11.4 years (0.1-18.0); weight was 28.7 kg (3.4-85.0); and 89% were from Africa. Median follow-up on randomized allocation was 286 weeks (IQR, 230-310) for DTG and 204 weeks (168-240) for SOC. Among SOC participants, 23% switched to DTG before 192 weeks, 65% before 240 weeks. By 240 weeks, 74 participants on DTG and 131 on SOC had treatment failure (estimated, 19% vs 34%; difference [DTG-SOC], -15%; 95% CI, -21% to -9%; P < .001). Treatment effects were similar between first- and second-line (P = .10). The proportions of participants with serious adverse events (52 DTG vs 53 SOC, P = .92) or grade ≥3 adverse events (98 DTG vs 121 SOC, P = .09) were similar by arm over 192 weeks. Conclusions:DTG showed superior efficacy vs SOC over 240 weeks in children, with no safety concerns.

BACKGROUND:Data on predictors of treatment failure in children starting antiretroviral therapy (ART) are limited, particularly on dolutegravir-based regimens (DTG). METHODS:ODYSSEY demonstrated superior efficacy of DTG versus standard-of-care (SOC). We assessed predictors at ART initiation of treatment failure by 96 weeks. RESULTS:Three hundred and eighty-one children started first-line ART (82% African). At ART-initiation, median age was 10.5 years (IQR: 6.5, 14.0, 67 < 3 years), CD4% 20% (IQR: 12, 28), BMI-for-age Z-score -.58 (IQR:-1.48, +.25). One hundred and eighty-nine children started DTG, 192 started SOC (91% ≥3 years started efavirenz; 79% <3 years started lopinavir). Seventy-five children experienced treatment failure (24 DTG, 51 SOC). Failure risk was lower on DTG than SOC (hazard ratio [HR] = 0.47, 95% CI: 0.29-0.77, P = .002). Lower BMI-for-age Z-score (HR = 0.82 for each unit gain, 95% CI: 0.70-0.96, P = .01) and being at an African site (HR = 2.09, 95% CI: 0.82-5.31, P = .09) were associated with higher failure risk. Risk was also higher at younger ages with the steepest increase in the youngest children and increased at lower CD4%, with a stronger CD4% effect at younger ages. At CD4% = 20, HRs relative to age 10 years were 2.40 (95% CI: 1.58-3.65) at age 1 year, 1.30 (95% CI: 1.15-1.48) at age 5 years, and 0.80 (95% CI: 0.72-0.89) at age 18 years. At age 1 year, HRs relative to CD4% = 20 were 1.39 (95% CI: 1.16-1.66) at CD4% = 15, and 0.52 (95% CI: 0.36-0.75) at CD4% = 30; at age 10, corresponding estimates were 1.07 (95% CI: 0.94-1.20) at CD4% = 15, and 0.88 (95% CI: 0.69-1.13) at CD4% = 30. CONCLUSIONS:Young age, low BMI-for-age, and low CD4% at ART initiation predicted higher risk of treatment failure and can guide targeted support.

BACKGROUND:Combined therapy with delamanid, bedaquiline, and quabodepistat (DBQ) showed potent early bactericidal activity and was well tolerated in a phase 2a, 14-day early bactericidal activity trial in participants with drug-susceptible pulmonary tuberculosis. This subsequent proof-of-concept trial evaluated the efficacy and safety of a 4-month, three-dose level regimen of DBQ in participants with drug-susceptible pulmonary tuberculosis compared with 6 months of the standard of care. METHODS:This open-label, randomised, proof-of-concept, non-inferiority, phase 2b/c trial was conducted at six clinical research sites in South Africa. Adults aged 18-65 years with newly diagnosed, drug-susceptible pulmonary tuberculosis were recruited by research sites from community tuberculosis clinics. Participants were randomly assigned (1:2:2:1) by balanced block randomisation (block size six) to receive oral delamanid (300 mg once a day) and bedaquiline (400 mg once a day for 2 weeks then 200 mg three times a week) plus quabodepistat at once-daily doses of 10 mg (DBQ10 group), 30 mg (DBQ30 group), or 90 mg (DBQ90 group) for 4 months; or 6 months of RHEZ (rifampicin, isoniazid, ethambutol, and pyrazinamide for 8 weeks followed by 18 weeks of rifampin and isoniazid). All drugs were administered orally. Masking procedures were not used, although microbiology laboratory staff were masked to treatment assignment. The primary endpoints were the proportion of participants reaching sputum culture conversion by the end of the treatment period in the modified intention-to-treat (mITT) analysis set and safety in the safety analysis set. Non-inferiority, with a margin of 12%, was assessed for the primary endpoint in the mITT analysis set, comparing the pooled DBQ group and the RHEZ group using a two-sided 80% CI. This study was registered at ClinicalTrials.gov, NCT05221502, and is complete. FINDINGS:Between April 12, 2022, and May 19, 2024, 306 individuals were screened, of whom 122 were enrolled and randomly assigned: 20 to the DBQ10 group, 42 to the DBQ30 group, 39 to the DBQ90 group, and 21 to the RHEZ group. 121 participants received at least one dose of study drug and comprised the mITT analysis set. At the end of the treatment period, the proportion of participants with sputum culture conversion was 100·0% (95% CI 83·2-100·0, all 20 participants) in the DBQ10 group, 92·9% (80·5-98·5, 39 of 42 participants) in the DBQ30 group, 97·4% (86·2-99·9, 37 of 38 participants) in the DBQ90 group, 96·0% (90·1-98·9, 96 of 100 participants) in the pooled DBQ group, and 100·0% (83·9-100·0, all 21 participants) in the RHEZ group. The comparison between the pooled DBQ group and the RHEZ group met non-inferiority for the primary endpoint (difference -4·0% [80% CI -7·4 to 3·4]). Adverse events were mostly mild to moderate, with no serious adverse events or discontinuations attributed to trial medications. Rates of adverse events of grade 3 or higher were 20% (four of 20 participants) in the DBQ10 group, 14% (six of 42 participants) in the DBQ30 group, 11% (four of 38 participants) in the DBQ90 group, and 5% (one of 21 participants) in the RHEZ group. One participant (in the DBQ90 group) died after worsening pulmonary tuberculosis with pneumonia, which was assessed as not related to study treatment. 105 (87%) of 121 participants had at least one treatment-emergent adverse event: 17 (85%) of 20 in the DBQ10 group, 37 (88%) of 42 in the DBQ30 group, 30 (79%) of 38 in the DBQ90 group, and all 21 (100%) participants in the RHEZ group. The most common treatment-emergent adverse events in the total population of 121 participants were upper respiratory tract infection (n=36, 30%), headache (n=24, 20%), and diarrhoea (n=12, 10%). INTERPRETATION:In this proof-of-concept study, 4 months of DBQ showed a promising end-of-treatment non-inferiority signal versus 6 months of RHEZ and was generally well tolerated. Our results support further studies of quabodepistat as a potential component of new treatment-shortening regimens for tuberculosis. FUNDING:Otsuka Pharmaceutical Development & Commercialization, with partial funding from the Gates Foundation.

BACKGROUND:Two-drug regimen dolutegravir/lamivudine (DTG/3TC) is recommended as an alternative to standard three-drug regimens in adult treatment guidelines. This nested pharmacokinetic sub-study within the D3/Penta 21 randomised trial (#NCT04337450) assessed DTG and 3TC concentrations and safety in virologically-suppressed children, switching to once-daily DTG/3TC fixed-dose formulations. METHODS:Children aged 2-<15 years received either 5/30 mg DTG/3TC dispersible tablets (DT) or 50/300 mg film-coated tablets (FCT), using WHO weight band (WB)-aligned dosing: 10-<14 kg 4 DTs; 14-<20 kg 5 DTs; 20-<25 kg 6 DTs or 1 FCT; 25-<40 kg 1 FCT. A minimum of 8-evaluable pharmacokinetic curves per WB/formulation were targeted for 24 h pharmacokinetic profiling (t = 0, 1, 2, 3, 4, 6, and 24 h post-dosing) at steady state. The number of children with DTG Ctrough <0.32 mg/L (EC90) and <0.064 mg/L (PA-IC90) were summarised. Safety was evaluated through 48 weeks in eligible children consented to the pharmacokinetic sub-study. FINDINGS:Between 11th May 2022 and 31st May 2023, 82 children consented for the sub-study. Seventy-two were included in the pharmacokinetic analysis; median (IQR) age was 7.1 (4.9-10.0) years and weight 21.6 (17.7-24.8) kg. DTG geometric mean (GM) (%CV) Ctrough and AUC0-24 h were 0.82 (54) mg/L and 66.2 (35) h∗mg/L. 3TC GM-AUC0-24 h was 16.2 (45) h∗mg/L. Three children had DTG Ctrough<0.32 mg/L, all had DTG Ctrough ≥0.064 mg/L. In children weighing 20-<25 kg WB and taking 1 FCT (50/300 mg) 3TC GM AUC0-24 h was 19% higher than in children ≥25 kg (1 FCT). Of 82 children, 3 had 4 serious adverse events (SAEs) and 5 had 6 grade ≥3 adverse events (AEs). No AEs were related to DTG/3TC or resulted in treatment discontinuation. No 3TC-related AEs or laboratory abnormalities were observed in children taking FCT in the 20-<25 kg WB. PK parameters were comparable to historical paediatric data from ODYSSEY (DTG) and IMPAACT2019 (3TC) trials. INTERPRETATION:The study demonstrated adequate DTG and 3TC exposures with reassuring safety profiles using WB-based dosing, supporting licencing applications for dispersible and film-coated DTG/3TC formulations for paediatric use. FUNDING:The D3/Penta 21 trial is sponsored by Fondazione Penta Onlus ETS (Penta) and funded by ViiV Healthcare.

OBJECTIVE:The purpose of this study was to evaluate the efficacy of combination nicotine replacement therapy (c-NRT) for smoking cessation among people with HIV (PWH) in South Africa. DESIGN:We conducted an open-label, individually randomized clinical trial. METHODS:Using a two-armed approach, PWH who smoke were randomized to receive either intensive antismoking behavioral counselling or intensive antismoking behavioral counseling plus c-NRT (nicotine patches augmented by nicotine gum). Self-reported smoking abstinence was biochemically validated with exhaled breath carbon monoxide (CO) and urine cotinine at 6 months. Recruitment, provision of trial interventions, and follow-up of participants took place in March 2014 through June 2016. RESULTS:We randomly assigned 280 participants to the behavioral counseling arm and 281 participants to the behavioral counseling + c-NRT arm. Four hundred and thirty-eight (78%) participants were men and 123 (22%) were women. For our primary outcome of biochemically verified abstinence at 6 months, 41 (15%) were quit in the behavioral counseling + c-NRT arm vs. 28 (10%) in the behavioral counseling arm, resulting in a 5% [95% confidence interval (CI) -1 to 10%] absolute difference in relative risk and an adjusted odd ratio of 1.47 (95% CI 0.86-2.52) comparing the behavioral counseling + c-NRT to the behavioral counseling arm. CONCLUSION:Although our results did not reach statistical significance, we found augmentation of behavioral counseling with c-NRT to increase smoking abstinence at 6 months, which is consistent with performance in the general population. PWH in low-resource settings may benefit from the addition of c-NRT to existing tobacco cessation interventions.

The nicotine metabolite ratio (NMR) has been informative in selecting treatment choices for nicotine dependence and increasing treatment efficacy in Western settings; however, the clinical utility of the NMR among smokers in low-resource settings remains unclear. Prospective analysis was conducted using data from a randomized controlled trial of smoking cessation among adults living with HIV, to examine the association between the NMR and response to smoking cessation treatment. NMR was assessed using bio-banked urine samples collected at baseline. Self-reported smoking at 6 months was verified using a urine cotinine test and exhaled breath carbon monoxide (CO). We found no associations between the NMR and smoking abstinence (adjusted risk ratio (aRR) = 0.82; 95% CI: 0.45, 1.49; p = 0.53). No evidence of effect modification by treatment conditions was observed on the multiplicative scale (aRR = 1.17; 95% CI: 0.32, 4.30; p = 0.81) or additive scale (adjusted relative excess risk due to interaction (aRERI) = 0.10; 95% CI: −1.16, 1.36; p = 0.44). Our results suggest that the NMR may not be a viable approach for selecting smoking cessation treatment in this setting, given the minimal variability in our sample and racial/ethnic makeup of this population.

OBJECTIVES:An increasing proportion of hospitalized persons with HIV (PWH) in South Africa are virally suppressed. This study aimed to characterize causes of hospitalization, the burden of advanced HIV disease (AHD), and 30-day postdischarge mortality among this patient population. METHODS:We conducted a prospective observational study of adult PWH with a viral load <1000 copies/ml admitted to a public tertiary hospital in Klerksdorp, South Africa from October 2023 to September 2024. Demographic, clinical, and laboratory data were collected, and 30-day follow-up was conducted to assess mortality. AHD was defined as a CD4 count <200 cells/mm 3 or WHO stage 3 or 4 disease based on presence of an AIDS-defining illness. Comparisons between participants hospitalized with AIDS-defining conditions vs. other causes, as well as between decedents and survivors, were conducted using Wilcoxon rank sum and Fisher's exact tests. RESULTS:Of 1245 hospitalized patients screened, 99 virally suppressed PWH were enrolled. Median age was 45 years; 56% were female. AIDS-defining illnesses, primarily tuberculosis (TB), accounted for 27.3% of hospitalizations. Forty-four participants (44%) met criteria for AHD. Thirty-day mortality was 12.1% (6 in-hospital, 6 postdischarge). Most decedents were <50 years of age and had undetectable viral loads. Factors significantly associated with 30-day mortality included >10 years since HIV diagnosis and initial hemoglobin <12 g /dl. CONCLUSIONS:Despite virologic suppression, PWH who are hospitalized remain at high risk for death-particularly from TB and other AIDS-related illnesses. Strengthening early TB detection, expanding preventive therapy, and improving postdischarge care are critical to improving outcomes in this population.

Background: Mortality among people living with HIV (PLWH) in developing settings remains elevated, despite high coverage with antiretroviral therapy (ART), with 70% – 80% being virally suppressed (VS). Objectives: This study aimed to determine cause-specific mortality in PLWH in South Africa. Method: An autopsy study with detailed medical record review was undertaken in PLWH dying in hospital. Minimally invasive autopsies were performed on 38 VS and 21 unsuppressed PLWH (≥ 18 years) dying in hospital between May 2018 and April 2022. We assessed clinical and histological findings to determine underlying, contributing, and immediate causes of death (CODs). Results: Median CD4 counts were 180 and 42 cells/mm3 in patients with and without VS respectively. Leading immediate CODs in both VS and unsuppressed PLWH were respiratory failure, sepsis, and septic shock; leading contributing CODs in decreasing order of frequency in both groups were acute kidney injury (AKI), bacterial pneumonia, immunological failure, gastroenteritis and current tuberculosis. Leading underlying CODs in both groups were hypertension, current tuberculosis, malignancies, and chronic obstructive pulmonary disease. VS was associated with lower risk of septic shock and AKI. Conclusion: VS on ART appeared to reduce risk of death from specific pathologies. However, infections, multi-organ failure, non-AIDS-defining malignancies, and metabolic diseases remain important CODs. Incomplete immune reconstitution appears to be a key contributor to premature death.

Hyperkalaemia is a medical emergency that may manifest with a spectrum of cardiac conduction abnormalities and, if not promptly managed, can progress to cardiac arrest. While standard management typically involves stat doses of insulin to lower serum potassium, the optimal dosing regimen remains controversial. Patients whose serum potassium exceeds the upper normal limit by more than 1 mmol/L often require repeated conventional management to shift potassium intracellularly – usually every 2 to 4 h. Although dialysis is indicated in patients with concomitant renal dysfunction, its availability in resource-constrained settings is limited. We present three cases of symptomatic hyperkalaemia successfully managed with continuous insulin infusions, thereby obviating the need for dialysis. These cases underscore the potential role of continuous insulin infusions as an alternative strategy for correcting hyperkalaemia in settings where dialysis is not immediately available.

With the highest global burden of HIV, South Africa initiates HIV treatment using first line antiretroviral therapy (AR ) regimens in newly diagnosed patients. Antiretroviral (ARV) associated nephrotoxicity has been observed in 10% of South African patients newly receiving first line AR , as well as in patients who have extensively received TDF-based ART regimens, and this can progress to acute kidney injury (A I). o identify potential biomarkers that will improve the detection of ARV associated nephrotoxicity, proteomic analysis was performed using the sequential window acquisition of all theoretical mass spectra (SWATH MS) data acquisition method on the plasma of the case group (AKI) and the control group (non AKI). Data are available via ProteomeXchange with identifier PXD054218. Evaluation of the results identified thirty four proteins that showed a significant change in abundance, with three proteins showing increased abundance, while thirty one proteins showed decreased abundance between the A I and non A I groups. Machine learning was also used to evaluate the results and showed twenty ranked proteins that contributed to distinguishing between the AKI and non AKI groups. The majority of the proteins of significant differential abundance and those ranked by the machine learning model participate in enriched biological processes that correspond to known pathophysiological and cellular mechanisms that contribute to AKI, suggesting that those proteins can serve as potential biomarkers to be further verified and validated for AKI diagnosis. Comparison of the plasma and previously generated urinary proteome profiles showed five proteins with significant differences in abundance that overlapped both proteomes providing evidence for the renal physiological dynamics of these proteins in renal injury and disease. Significance: Improving the detection of ARV associated nephrotoxicity is challenging because current serum creatinine (srCr) based equations used to estimate the glomerular filtration rate (eGFR) for assessing kidney function have been reported to overestimate the eGFR in the South African population and changes in srCr measurements also reflect a delayed response to the initial structural injury of the kidney. his hinders the timeous detection of ARV associated nephrotoxicity which can lead to irreversible renal damage and can compromise the continuation of treatment in P HIV, thus emphasising the need to introduce novel AI biomarkers to mitigate ARV associated nephrotoxicity in at risk P HIV in South Africa. ### Competing Interest Statement Ireshyn Govender is an employee of ReSyn Biosciences, the proprietor of MagReSyn HILIC technology.

Background: Liver disease is the leading cause of non-AIDS-related mortality in people living with HIV (PLWH). Steatotic liver disease (SLD) is increasingly recognised as an important aetiological factor in liver dysfunction in PLWH.Objectives: This study aimed to determine the post-mortem prevalence and severity of SLD and determine HIV- and non-HIV-related risk factors associated with it.Method: We conducted a retrospective cross-sectional study in which liver histology from 59 deceased people who were infected with HIV was assessed for steatosis, and findings correlated with clinical, epidemiological, and biochemical data.Results: Decedents were predominantly men (33/59); 63% (37/59) were virologically supressed. Median CD4+ T-cell count was 139 cells/µL (interquartile range [IQR]: 47–344). Steatosis was present in 39% (23/59) of decedents: 74% mild, 9% moderate, and 17% severe steatosis. There were no cases of steatohepatitis, and one case with mild fibrosis. Factors associated with SLD were: CD4 T-lymphocyte count 200 cells/µL (odds ratio [OR]: 3.69; 95% confidence interval [CI]: 1.19–11.44), female sex (OR: 8.5; 95% CI: 2.57–28.17), hypertension (OR: 6.5; 95% CI: 2.05–21.00), and being normal or overweight (OR: 6.75; 95% CI: 1.12–40.56). Virological suppression and duration of antiretroviral drug use were not associated with steatosis.Conclusion: We found a high proportion of SLD with heterogeneous causes in deceased people who were infected with HIV, exceeding previously reported prevalences from elsewhere in Africa. A preserved CD4 count and being female conferred the highest risk for steatosis, underscoring the need for screening in this subgroup and further research to delineate risks in a Southern African population.

Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.

Identifying risk factors for respiratory syncytial virus (RSV)–associated severe acute respiratory illness (SARI) will assist with targeting vaccine interventions. Using surveillance data from South Africa (2012–2018), we compared the characteristics of individuals with RSV-associated influenza-like illness (ILI) (reference group) to those with RSV-associated SARI to describe factors associated with SARI using a multivariable analysis. RSV was detected in 6 Not applicable, this is not a clinical trial.