Perinatal HIV Research Unit

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%) participants were abstinent at 6 months post-repeat treatment, including 15 (8%) participants in the repeat BC group compared to 20 (11%) participants in the repeat BC + cNRT group. There was no significant difference in abstinence rates between repeat treatment groups (Chi Squared (χ2) = 0.23; p = 0.63), including after adjusting for potential confounders [adjusted risk ratio (aRR) = 1.16, 95% CI 0.39, 3.47; p = 0.79]. Although augmenting repeat treatment of BC with cNRT may not provide additional benefits for PWH with prior treatment failure in this population, PWH in this setting may benefit from a repeat treatment strategy of BC with or without cNRT.

Abstract Pretomanid is a key component of the bedaquiline, pretomanid, linezolid with or without moxifloxacin (BPaL/M)regimen recommended for treatment of rifampicin-resistant tuberculosis (RR-TB). To support dose optimization and efficacy interpretation, we developed a pretomanid population pharmacokinetic (PK) model and evaluated exposure and probability of target attainment (PTA). Ninety-four RR-TB patients received daily oral pretomanid at 200 mg, and plasma samples were collected at multiple time points. Pretomanid concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry and PK modeling was performed using nlmixr2 in R. A one-compartment model with first-order absorption and elimination, and fat free mass allometric scaling best described the data. Typical clearance was 3.10 L/h, median AUC₀₋₂₄ was 63,733 μg·h/L, and median trough concentration was 1,965 μg/L. Pretomanid MICs for Mycobacterium tuberculosis in the TB-PRACTECAL trial were consistently below the provisional critical concentration, with a median of 0.125 mg/L. PK-Pharmacodynamic (PD) simulations indicated that nearly all participants achieved drug exposures exceeding %fT>MIC, supporting the regimen’s efficacy across the study population. We developed a pretomanid population PK model and facilitated exploring robust PK-PD targets for PTA that remain valuable to support dose optimisation. There is an urgent need for further research to identify the optimal clinically relevant PK-PD index for pretomanid, especially within the context of combination therapy.

ABSTRACT HIV transmission among adolescents remains a pressing public health challenge in South Africa. Onward HIV disclosure to sexual partners can reduce transmission, but disclosure is low among adolescents. Adherence to hegemonic masculine norms may create a barrier to disclosure among boys. Repeated measures designs are necessary to more accurately capture disclosure, which is an ongoing behavior shaped by multiple processes. 251 South African adolescent boys living with perinatally-acquired HIV and in an intimate relationship were enrolled between 2020–2023. They completed a survey capturing their adherence to masculine norms and their HIV disclosure self-efficacy. They then completed brief mobile surveys weekly for the following year, reporting their recent HIV disclosure behavior. Using mixed effects models, we found that adherence to hegemonic masculine norms at baseline was associated with significantly lower odds of onward HIV disclosure to a sexual partner over the study year. Adherence to hegemonic masculine norms was also associated with lower HIV disclosure self-efficacy at two timepoints. This study confirms a quantitative association between hegemonic masculinity and disclosure and extends the literature to an understudied population. To prevent new HIV infections among South African adolescents, it will be important to develop and adapt interventions that address hegemonic masculinity.

ABSTRACT The prevalence of behavioral problems in children and adolescents living with HIV is high. We investigate associations between oral microbiota and behavioral problems in children living with HIV (CLWH) and children who are HIV-uninfected (CHU). Oral swab samples, assessment of behavioral functioning using the Strengths and Difficulties Questionnaire (SDQ), and clinical and social data were collected from 477 CLWH and 123 CHU at two sites in Johannesburg, South Africa. DNA was extracted from oral swab samples and the V4 amplicon of the 16S rRNA gene sequenced. Behavioral problems were more prevalent in CLWH than in CHU, and in boys than in girls. Oral microbiota diversity and taxa abundances in CLWH did not differ between those with and without behavioral problems. In contrast, in CHU, those with behavioral problems had higher alpha diversity indices and lower abundances of Rothia and Schaalia than those without behavioral problems. Behavioral problems in CLWH were associated with being male, lower Tanner stage, less maternal education, and dental caries. Markers of poor oral health were associated with behavioral problems in CLWH, and oral microbiota profile correlated with behavioral problems in CHU. Oral health may be a preventable factor that could help reduce behavior problems in CLWH.

IntroductionData on the burden of SARS-CoV-2 infections by age group and for different severity levels are lacking. We estimated the South African SARS-CoV-2 disease burden and severity, describing changes in the shape of the disease burden pyramid with successive waves.MethodsWe estimated SARS-CoV-2 medically and non-medically attended illness stratified by severity (mild, severe non-fatal and fatal) during the initial five waves, spanning 1 March 2020 through 13 August 2022. We used individual-level national surveillance, healthcare utilisation and serosurvey data to estimate wave-specific hospitalisation-fatality (HFR) and infection-fatality ratios. We estimated wave-specific incidence rates per 100 000 population with 95% CIs derived from bootstrapping the individual-level data.ResultsOn 13 August 2022, the estimated cumulative number of SARS-CoV-2 infections in South Africa was 104.6 million, of which 399 900 (0.38%) were severe non-fatal and 258 800-289 000 (0.25 - 0.28%) fatal. 29% of severe non-fatal illness and 55 - 60% of deaths occurred outside the hospital. The highest burden of severe and fatal illness was during the Delta wave (wave 3), and the HFR across the initial three waves was similar (range 31–34%). Although there were more infections during the Omicron BA.1 wave (wave 4), there was a substantial reduction in HFR (14%). Successive waves saw a reduction in the rate of increase in mortality and hospitalisations with increasing age.ConclusionsThe substantial South African national burden of SARS-CoV-2 for the initial five waves contradicts the belief of minimal impact in Africa. A high proportion of severe non-fatal and fatal illness occurred outside of the hospital, highlighting the importance of studies of health-seeking and vital registration systems to document the full burden of illness. The highest burden of severe illness and death was in the Delta wave. Following the Omicron emergence, severe illness reduced, and with successive waves, proportionately more children were infected and became ill, suggesting a transition to a more endemic pattern.

Background/Objectives: Tuberculosis (TB) and SARS-CoV-2 share similar symptoms and transmission routes. In early 2021, USAID and Stop TB Partnership recommended an integrated approach for simultaneous COVID-19 and TB testing in high TB burden countries for individuals with respiratory symptoms. In this evaluation, we tested a single sputum for both SARS-CoV-2 and Mycobacterium tuberculosis complex (MTBC) from participants at two healthcare facilities in South Africa. The diagnostic accuracy of the Xpert Xpress SARS-CoV-2 (Xpress) assay using a sputum swab capture method was assessed by comparing the results with routine SARS-CoV-2 testing, while also determining the prevalence of TB and TB-COVID-19 co-infection in the study population. Methods: A total of 2274 individuals were screened for enrolment. Eligibility included the presence of respiratory symptoms, close contact with a person with TB, TB diagnosis in the last two years or a person living with HIV. Sputum from 1032 participants was tested on the Xpress assay using a swab capture method while residual sputum was tested on the Xpert MTB/RIF Ultra assay for MTBC and rifampicin-resistance detection. Concordance between the Xpress assay and routine SARS-CoV-2 testing was assessed. Results: The Xpress assay detected SARS-CoV-2 in 183/1032 (18%) participants, TB was detected in 35/1032 (3%) participants and 10/1032 (1%) participants were co-infected with TB and COVID-19. The Xpress assay showed substantial agreement with routine testing (Kappa: 0.755). Conclusions: The study findings underscore a substantial identification of TB and rifampicin-resistant TB that would have been missed if bi-disease testing was not performed. In addition, the sputum swab capture method demonstrated reliable performance for SARS-CoV-2 detection.

Recent evidence indicates that levofloxacin (LFX) is effective in preventing TB in individuals exposed to multidrug-resistant TB (MDR-TB). Despite the need for pediatric formulations, the 250 mg adult LFX formulation is affordable and widely used for TB treatment and prevention in children. TB-CHAMP (Tuberculosis Child Multidrug-resistant Preventive Therapy ISRCTN92634082) was a trial of MDR-TB preventive treatment, comparing levofloxacin to placebo in children with MDR-TB exposure. Acceptability questionnaires were administered to caregivers at six timepoints during the 24-week treatment phase. Likert scales were used to grade 6 domains of acceptability, and a composite acceptability (CA) outcome was generated. Factors associated with acceptability were assessed using modified Poisson regression models to estimate risk ratios (RRs). Overall, 922 children were randomised, 453 to LFX and 469 to placebo. By Week 8, 25.1% of children on LFX had poor CA versus 6.2% receiving placebo (Weeks 0-24: RR 3.43, 95% CI 2.69-4.37). Acceptability in the LFX arm improved from 36.8% poor CA at baseline to 12.9% at Week 24. Only 11.7% of children swallowing tablets whole/halved had poor CA outcomes at Week 8, compared to 34.4% swallowing crushed/softened tablets. LFX 250 mg tablets have reasonable acceptability and could be used as an alternative to dispersible formulations, especially in children able to swallow tablets.

Abstract Question addressed by the studyA radiological index capable of quantifying pulmonary tuberculosis (TB) disease progression on standard Chest X-Ray (CXR) could enhance clinical management and inform therapeutic decision-making. Our objectives were: to develop a radiological index that quantitatively assesses the progression of pulmonary TB in patients over the course of treatment and follow-up, to evaluate its usefulness by using CXRs from a cohort of TB patients, and to validate it with CXRs from an independent cohort of TB patients.Materials/patients and methodsAn index was developed to identify and classify patterns of radiological findings of both active and inactive pulmonary TB. This index was evaluated in a first cohort comprising a pseudonymized sample of serial CXRs from 21 TB patients at the Perinatal HIV Research Unit (PHRU) in South Africa and validated in a second, larger, independent cohort comprising 50 treated TB patients from the National Institute of Allergy and Infectious Diseases (NIAID) TB Data Portals. The relationship between index values for activity markers and patients’ clinical characteristics was also analysed.ResultsA radiological index, the RUTI-TB Evolution Score (RTBES), was created and validated in two cohorts, achieving 95.96% interobserver agreement (±2 points). In both cohorts, RTBES for active TB signs decreased over follow-up. Higher baseline RTBES correlated with male sex, higher bacterial loads, and extensive pulmonary involvement (including cavitation and pleural effusions). Baseline RTBES≥2 predicted unfavourable outcomes; 80% of failures/deaths occurred above this threshold.Answer to the questionRTBES effectively quantified pulmonary TB severity and tracked treatment evolution on standard CXRs, showing promise as a prognostic tool to inform clinical decision-making.

There are currently at least 70 characterised lysosomal storage diseases (LSD) resultant from inherited single-gene defects. Of these, at least 30 present with central nervous system (CNS) neurodegeneration and overlapping aetiology. Substrate accumulation and dysfunctional neuronal lysosomes are common denominator, but how variants in 30 different genes converge on this central cellular phenotype is unclear. Equally unresolved is how the accumulation of a diverse spectrum of substrates in the neuronal lysosomes results in remarkably similar neurodegenerative outcomes. Conversely, how is it that many other monogenic LSDs cause only visceral disease? Lysosomal substance accumulation in LSDs with CNS neurodegeneration (nLSD) includes lipofuscinoses, mucopolysaccharidoses, sphingolipidoses and glycoproteinoses. Here, we review the latest discoveries in the fundamental biology of four classes of nLSDs, comparing and contrasting new insights into disease mechanism with emerging evidence of unifying convergence.