Growth Profiles of Children and Adolescents Living with and without Perinatal HIV Infection in Southern Africa: A Secondary Analysis of Cohort Data.

Impaired linear growth and slower pubertal growth can be associated with perinatal HIV infection. We characterised growth relative to population norms, among the full adolescent period in southern Africa to better understand processes leading to morbidity in adulthood. We conducted a secondary analysis of 945 adolescents aged 8-20 years from urban Malawi and Zimbabwe; we included children with HIV (CWH), an uninfected comparison group from a cohort study, and CWH with co-morbid chronic lung disease (CLD) from a randomised controlled trial. We used latent class analysis of anthropometric Z-scores generated from British 1990 reference equations at two annual time-points, to identify growth trajectory profiles and used multinomial logistic regression to identify factors associated with growth profiles. Growth faltering (one or more of weight-for-age, height-for-age, or BMI-for-age Z-scores < -2) occurred in 38% (116/303) of CWH from the cohort study, 62% (209/336) of CWH with CLD, and 14% (44/306) of HIV-uninfected participants. We identified seven different growth profiles, defined, relatively, as (1) average growth, (2) tall not thin, (3) short not thin, (4) stunted not thin, (5) thin not stunted, (6) thin and stunted and (7) very thin and stunted. Females in profile 3 exhibited the highest body fat percentage, which increased over 1 year. Males at older age and CWH especially those with CLD were more likely to fall into growth profiles 4-7. Improvements in height-for-age Z-scores were observed in profiles 6-7 over 1 year. Interventions to target those with the worst growth faltering and longer-term follow-up to assess the impact on adult health are warranted.

Trial-of-antibiotics to assist tuberculosis diagnosis in symptomatic adults in Malawi (ACT-TB study): a randomised controlled trial.

BACKGROUND: Clinical practice and diagnostic algorithms often assume that tuberculosis can be ruled out in mycobacteriology-negative individuals whose symptoms improve with a trial-of-antibiotics. We aimed to investigate diagnostic performance, clinical benefit, and antimicrobial resistance using a randomised controlled trial. METHODS: In this three-arm, individually randomised, open-label, controlled trial, we enrolled Malawian adults (aged ≥18 years) attending primary care who reported being unwell for at least 14 days (including cough) with no immediate indication for hospitalisation at Limbe and Ndirande Health Centres in Blantyre. Participants were randomly allocated (1:1:1) to azithromycin (500 mg taken once per day for 3 days), amoxicillin (1 g taken three times per day for 5 days), or standard of care with no immediate antibiotics, stratified by study site. Sputum at enrolment and day 8 was tested for tuberculosis (microscopy, Xpert MTB/RIF, and culture). The primary efficacy outcome was day 8 specificity (percentage with symptom improvement among mycobacteriology-negative participants), and day 29 clinical outcome (death, hospitalisation, or missed tuberculosis diagnosis) among all randomised participants. This study is registered with ClinicalTrials.gov, NCT03545373. FINDINGS: Between Feb 25, 2019, and March 14, 2020, 5825 adults were screened and 1583 (mean age 36 years; 236 [14·9%] HIV positive) were randomly assigned to standard of care (530 participants), azithromycin (527 participants), or amoxicillin (526 participants) groups. Overall, 6·3% (100 of 1583 participants) had positive baseline sputum mycobacteriology. 310 (79·1%) of 392 patients receiving standard of care reported symptom improvement at day 8, compared with 340 (88·7%) of 383 patients receiving azithromycin (adjusted difference 8·6%, 95% CI 3·9-13·3%; p<0·0004) and 346 (89·4%) of 387 receiving amoxicillin (adjusted difference 8·8%, 4·0-13·6%; p=0·0003). The proportion of participants with day 29 composite clinical outcomes was similar between groups (standard of care 1% [7 of 530 participants], azithromycin 1% [6 of 527 participants], amoxicillin 2% [12 of 526 participants]). INTERPRETATION: Routine outpatient trial-of-antibiotics during tuberculosis investigations modestly improved diagnostic specificity for mycobacteriologically confirmed tuberculosis but had no appreciable effect on death, hospitalisation, and missed tuberculosis diagnosis. These results confirm the limited benefit of trial-of-antibiotics, presenting an opportunity for discontinuation of trial-of-antibiotics and improved antimicrobial stewardship during tuberculosis screening, without affecting clinical outcomes. FUNDING: Northern Norway Regional Health Authority (Helse Nord RHF), Commonwealth Scholarship Commission in the UK, Wellcome Trust, UK Medical Research Council, and the UK Department for International Development.

Waning of antibody levels induced by a 13-valent pneumococcal conjugate vaccine, using a 3 + 0 schedule, within the first year of life among children younger than 5 years in Blantyre, Malawi: an observational, population-level, serosurveillance study.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) induce serotype-specific IgG antibodies, effectively reducing vaccine-serotype carriage and invasive pneumococcal disease (IPD). IgG production wanes approximately 1 month after vaccination in absence of serotype-specific exposure. With uncertainty surrrounding correlate of protection (CoP) estimates and with persistent vaccine-serotype carriage and vaccine-serotype IPD after PCV13 introduction, we aimed to profile population-level immunogenicity among children younger than 5 years in Blantyre, Malawi. METHODS: For this serosurveillance study, we used a random subset of samples from a prospective population-based serosurvey in Blantyre, Malawi, done between Dec 16, 2016, and June 27, 2018. Sample selection was based on age category optimisation among children younger than 5 years, adequate sample volume, and available budget. We measured serotype-specific IgGs against the 13 vaccine serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) and two non-vaccine serotypes (12F and 33F), as well as IgGs against three pneumococcal proteins (PsaA, NanA, and Ply), using ELISA and a direct-binding electrochemiluminescence-based multiplex assay. We estimated population-level, serotype-specific immunogenicity profiles using a linear spline regression model. Analyses included samples stratified to 20 3-month age strata (eg, age <3 months to 57-59 months). FINDINGS: We evaluated 638 plasma samples: 556 primary samples and 82 unique secondary samples (each linked to one primary sample). Immunogenicity profiles revealed a consistent pattern among vaccine serotypes except serotype 3: a vaccine-induced IgG peak followed by waning to a nadir and subsequent increase in titre. For serotype 3, we observed no apparent vaccine-induced increase. Heterogeneity in parameters included age range at post-vaccination nadir (from 11·2 months [19A] to 27·3 months [7F]). The age at peak IgG titre ranged from 2·69 months (5) to 6·64 months (14). Titres dropped below CoPs against IPD among nine vaccine serotypes (1, 3, 4, 5, 6B, 7F, 9V, 18C, and 23F) and below CoPs against carriage for ten vaccine serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F). Increasing antibody concentrations among older children and seroincident events were consistent with ongoing vaccine-serotype exposure. INTERPRETATION: A 3 + 0 PCV13 schedule with high uptake has not led to sustained population-level antibody immunity beyond the first year of life. Indeed, post-vaccine antibody concentrations dropped below putative CoPs for several vaccine serotypes, potentially contributing to persistent vaccine-serotype carriage and residual vaccine-serotype IPD in Malawi and other similar settings. Policy decisions should consider alternative vaccine strategies, including a booster dose, to achieve sustained vaccine-induced antibody titres, and thus control. FUNDING: Bill & Melinda Gates Foundation, Wellcome UK, and National Institute for Health and Care Research.

Adherence to additional medication for management of HIV-associated comorbidities among older children and adolescents taking antiretroviral therapy.

BACKGROUND: Management of co-morbidities among persons living with HIV is an emerging priority, which may require additional medication over and above life-long antiretroviral therapy (ART). We explored factors associated with adherence to the trial drug among children and adolescents with perinatally acquired HIV taking antiretroviral therapy (ART) in the Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-Infected Children (BREATHE) trial. METHODS: The BREATHE trial recruited 6-19 year olds with perinatally acquired HIV and co-morbid chronic lung disease as measured by FEV1. This two-site trial was individually randomised (1:1), double-blind and placebo-controlled. Participants received a once-weekly weight-based dose of 1-5 tablets of azithromycin (AZM: 250mg) or placebo, taken orally. We used pharmacy dispensing records and count of returned pills to measure adherence to study medication. Logistic regression was used to explore factors associated with adherence coverage. Poisson regression with Lexis expansion for time was used to explore whether adherence modified the effect of azithromycin on the incidence of acute respiratory exacerbation, a secondary outcome of the trial. Trial registration: ClinicalTrials.gov NCT02426112. RESULTS: The 347 participants (median age 15.3, 51% male) consumed 14,622 doses of study medication over 16,220 person-weeks under study. Adherence was higher for those randomised to AZM (73.4%) than placebo (68.4%) and declined over the 48 weeks of the study (Score test for trend <0.02). Those with unsuppressed HIV viral load at baseline had 2.08 (95% CI: 1.19, 3.63) times the odds of non-adherence than those with viral suppression. Differences were also observed between trial sites. CONCLUSION: The majority of children and adolescents tolerated the addition of a once-weekly dose of medication to their pill burden. Barriers in adhering to treatment for co-morbid conditions are likely common to barriers in adhering to ART. Control of co-morbidities will therefore present additional challenges in HIV care.

SARS-CoV-2 exposure in Malawian blood donors: an analysis of seroprevalence and variant dynamics between January 2020 and July 2021.

BACKGROUND: By August 2021, the COVID-19 pandemic has been less severe in sub-Saharan Africa than elsewhere. In Malawi, there have been three subsequent epidemic waves. We therefore aimed to describe the dynamics of SARS-CoV-2 exposure in Malawi. METHODS: We measured the seroprevalence of anti-SARS-CoV-2 antibodies amongst randomly selected blood transfusion donor sera in Malawi from January 2020 to July 2021 using a cross-sectional study design. In a subset, we also assessed in vitro neutralisation against the original variant (D614G WT) and the Beta variant. RESULTS: A total of 5085 samples were selected from the blood donor database, of which 4075 (80.1%) were aged 20-49 years. Of the total, 1401 were seropositive. After adjustment for assay characteristics and applying population weights, seropositivity reached peaks in October 2020 (18.5%) and May 2021 (64.9%) reflecting the first two epidemic waves. Unlike the first wave, both urban and rural areas had high seropositivity in the second wave, Balaka (rural, 66.2%, April 2021), Blantyre (urban, 75.6%, May 2021), Lilongwe (urban, 78.0%, May 2021), and Mzuzu (urban, 74.6%, April 2021). Blantyre and Mzuzu also show indications of the start of a third pandemic wave with seroprevalence picking up again in July 2021 (Blantyre, 81.7%; Mzuzu, 71.0%). More first wave sera showed in vitro neutralisation activity against the original variant (78% [7/9]) than the beta variant (22% [2/9]), while more second wave sera showed neutralisation activity against the beta variant (75% [12/16]) than the original variant (63% [10/16]). CONCLUSION: The findings confirm extensive SARS-CoV-2 exposure in Malawi over two epidemic waves with likely poor cross-protection to reinfection from the first on the second wave. The dynamics of SARS-CoV-2 exposure will therefore need to be taken into account in the formulation of the COVID-19 vaccination policy in Malawi and across the region. Future studies should use an adequate sample size for the assessment of neutralisation activity across a panel of SARS-CoV-2 variants of concern/interest to estimate community immunity.

Prevalence and antimicrobial resistance profiles of respiratory microbial flora in African children with HIV-associated chronic lung disease.

BACKGROUND: HIV-associated chronic lung disease (CLD) is common among children living with HIV (CLWH) in sub-Saharan Africa, including those on antiretroviral therapy (ART). However, the pathogenesis of CLD and its possible association with microbial determinants remain poorly understood. We investigated the prevalence, and antibiotic susceptibility of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) among CLWH (established on ART) who had CLD (CLD+), or not (CLD-) in Zimbabwe and Malawi. METHODS: Nasopharyngeal swabs (NP) and sputa were collected from CLD+ CLWH (defined as forced-expiratory volume per second z-score < - 1 without reversibility post-bronchodilation with salbutamol), at enrolment as part of a randomised, placebo-controlled trial of azithromycin (BREATHE trial - NCT02426112 ), and from age- and sex-matched CLD- CLWH. Samples were cultured, and antibiotic susceptibility testing was conducted using disk diffusion. Risk factors for bacterial carriage were identified using questionnaires and analysed using multivariate logistic regression. RESULTS: A total of 410 participants (336 CLD+, 74 CLD-) were enrolled (median age, 15 years [IQR = 13-18]). SP and MC carriage in NP were higher in CLD+ than in CLD- children: 46% (154/336) vs. 26% (19/74), p = 0.008; and 14% (49/336) vs. 3% (2/74), p = 0.012, respectively. SP isolates from the NP of CLD+ children were more likely to be non-susceptible to penicillin than those from CLD- children (36% [53/144] vs 11% [2/18], p = 0.036). Methicillin-resistant SA was uncommon [4% (7/195)]. In multivariate analysis, key factors associated with NP bacterial carriage included having CLD (SP: adjusted odds ratio (aOR) 2 [95% CI 1.1-3.9]), younger age (SP: aOR 3.2 [1.8-5.8]), viral load suppression (SP: aOR 0.6 [0.4-1.0], SA: 0.5 [0.3-0.9]), stunting (SP: aOR 1.6 [1.1-2.6]) and male sex (SA: aOR 1.7 [1.0-2.9]). Sputum bacterial carriage was similar in both groups (50%) and was associated with Zimbabwean site (SP: aOR 3.1 [1.4-7.3], SA: 2.1 [1.1-4.2]), being on ART for a longer period (SP: aOR 0.3 [0.1-0.8]), and hot compared to rainy season (SP: aOR 2.3 [1.2-4.4]). CONCLUSIONS: CLD+ CLWH were more likely to be colonised by MC and SP, including penicillin-non-susceptible SP strains, than CLD- CLWH. The role of these bacteria in CLD pathogenesis, including the risk of acute exacerbations, should be further studied.

Chronic lung disease in children and adolescents with HIV: a case-control study.

OBJECTIVE: To describe the features of HIV-associated chronic lung disease (CLD) in older children and adolescents living with HIV and to examine the clinical factors associated with CLD. This is a post hoc analysis of baseline data from the BREATHE clinical trial (ClinicalTrials.gov, NCT02426112). METHODS: Children and adolescents aged 6-19 years were screened for CLD (defined as a FEV1 z-score <-1 with no reversibility post-bronchodilation with salbutamol) at two HIV clinics in Harare, Zimbabwe, and Blantyre, Malawi. Eligible participants with CLD (cases) were enrolled, together with a control group without CLD [frequency-matched by age group and duration on antiretroviral therapy (ART)] in a 4:1 allocation ratio. A clinical history and examination were undertaken. The association between CLD and a priori-defined demographic and clinical covariates was investigated using multivariable logistic regression. RESULTS: Of the 1585 participants screened, 419 (32%) had a FEV1 z-score <-1, of whom 347 were enrolled as cases [median age 15.3 years (IQR 12.7-17.7); 48.9% female] and 74 with FEV1 z-score >0 as controls [median age 15.6 years (IQR 12.1-18.2); 62.2% female]. Among cases, current respiratory symptoms including cough and shortness of breath were reported infrequently (9.3% and 1.8%, respectively). However, 152 (43.8%) of cases had a respiratory rate above the 90th centile for their age. Wasting and taking second-line ART were independently associated with CLD. CONCLUSIONS: The presence of CLD indicates the need to address additional treatment support for youth living with HIV, alongside ART provision, to ensure a healthier adulthood.

OBJECTIF: Décrire les caractéristiques de la maladie pulmonaire chronique (MPC) associée au VIH chez les enfants plus âgés et les adolescents vivant avec le VIH et examiner les facteurs cliniques associés à la MPC. Il s'agit d'une analyse post-hoc des données de référence de l'essai clinique BREATHE (ClinicalTrials.gov, NCT02426112 ). MÉTHODES: Les enfants et adolescents âgés de 6 à 19 ans ont été dépistés pour la MPC (défini comme un score z FEV1 <-1 sans réversibilité post-bronchodilatation avec du salbutamol) dans deux cliniques VIH à Harare, au Zimbabwe et à Blantyre, au Malawi. Les participants éligibles atteints de MPC (cas) ont été inscrits, ainsi qu'un groupe témoin sans MPC (fréquence appariée par groupe d'âge et durée sous ART) dans un rapport d'allocation de 4:1. Une histoire clinique et un examen ont été entrepris. L'association entre la MPC et les covariables démographiques et cliniques définies a priori a été étudiée en utilisant une régression logistique multivariable. RÉSULTATS: Sur les 1.585 participants dépistés, 419 (32%) avaient un score z FEV 1 <-1, dont 347 étaient inscrits comme cas (âge médian 15,3 ans [IQR 12,7 -17,7]; 48,9% de sexe féminin), et 74 avec un score z FEV1 >0 comme témoins (âge médian 15,6 ans [IQR 12,1 -18,2]; 62,2% de sexe féminin). Parmi les cas, les symptômes respiratoires en cours, y compris la toux et l'essoufflement, n'ont pas été rapportés fréquemment (9,3% et 1,8%, respectivement). Cependant, 152 (43,8%) des cas avaient une fréquence respiratoire supérieure au 90e centile pour leur âge. L'émaciation et la prise d'un traitement antirétroviral (ART) de deuxième intention étaient indépendamment associées à la MPC. CONCLUSIONS: La présence de MPC indique la nécessité d'un soutien thérapeutique supplémentaire aux jeunes vivant avec le VIH, à côté de à la fourniture de l'ART, pour assurer un âge adulte en meilleure santé.