HIV-endemic Settings Research Articles

Hodgkin lymphoma: the role of EBV plasma viral load testing in an HIV-endemic setting

South Africa has a high burden of human immune deficiency virus (HIV)-associated Hodgkin lymphoma (HL) which is typically Epstein–Barr virus (EBV) infected, detected by histological stains. Circulating plasma EBV derived from apoptotic EBV infected tumour cells is a potential biomarker. This study aimed to evaluate the role of plasma EBV load testing in newly diagnosed HL patients and correlate pretreatment plasma EBV levels, HIV status and EBV tumour status with overall survival (OS). Untreated HL patients were prospectively included. Polymerase chain reaction measured EBV plasma viral loads. Kaplan–Meier curves with log-rank tests estimated the impact of HIV, EBV tumour status and plasma EBV viral loads on OS. Multivariable analysis was performed using a Cox proportional hazards model. Receiver operative characteristic curve analysis determined cutoff plasma EBV DNA levels with optimal sensitivity, specificity and concordance with tumour EBV status. The 68 patients included 21 (31%) HIV +ve and 33 (49%) EBV tumour +ve. EBV plasma ≥ 10 000 IU/ml (P = 0.008), EBV +ve tumour (P = 0.014), HIV +ve status (P = 0.009) and age ≥ 45 years (P = 0.018) predicted poorer OS on univariate analysis. Plasma EBV levels > 762 IU/ml had 89.29% sensitivity and 96.77% specificity for detecting EBV +ve HL. High plasma EBV levels ≥ 10 000 IU/ml, HIV +ve status and EBV tumour +ve status predicted poorer OS. Plasma EBV levels > 762 IU/ml predicted EBV +ve tumour status with high sensitivity and specificity. Plasma EBV viral DNA testing is a promising biomarker for EBV +ve HL.

Diagnostic accuracy of Truenat MTB Plus, Truenat MTB Ultima and Xpert MTB/RIF Ultra for the diagnosis of pulmonary TB in an HIV-endemic setting.

Truenat MTB Plus (MTB Plus) and MTB Ultima (Ultima) are World Health Organization-endorsed low-complexity tuberculosis (TB) tests, however, performance data are scarce. Adults (≥18 years; n=498) self-presenting with symptoms to primary care clinics in Cape Town, South Africa (19/02/2016-22/02/2023) provided sputa. We evaluated the accuracy of MTB Plus and Ultima, with Xpert MTB/RIF Ultra (Ultra) as a comparator, vs. a single culture (TB reference standard) or MTBDRplus on an isolate (rifampicin susceptibility reference standard). The proportion of MTB Plus and Ultima unsuccessful results was 20% (95% confidence interval 17, 23) and 14 (11, 16), respectively, with ≥half resolving upon retesting the same eluate. In a three-way analysis, MTB Plus, Ultima and Ultra had sensitivities of 84% (78, 88), 90% (85, 93), and 92% (87, 95), and specificities of 95% (92, 97), 85% (80, 88) and 95% (92, 97) for TB. The proportion of unsuccessful results for MTB-RIF Dx done the same day as DNA extraction was 9% (3, 16; MTB Plus-positives) and 18% (10, 26; Ultima-positives) [if after day-of-extraction, these were 27% (18, 35) and 44% (35, 51)]. Same-day rifampicin susceptibility testing was often unsuccessful in samples with "very low" load [73% (58, 89) MTB Plus, 75% (65, 86) Ultima] but had 100% (40, 100) sensitivity and 99% (96, 100) specificity (for both MTB Plus- or Ultima-positive DNA). Lot variation in unsuccessful and false-positive results was observed. Ultima showed comparable sensitivity to Ultra but specificity, lot variation, and, like MTB-RIF Dx, unsuccessful result rates were suboptimal. European & Developing Countries Clinical Trials Partnership, and South African Medical Research Council.

Developing an integrated HIV clinical and population database in rural south Africa

BackgroundHIV cohort data are crucial for understanding the effects of HIV infection and treatment. Linkage between HIV clinical and population records unlocks potential to understand the cause and consequences of social-economic factors on HIV-care seeking behaviors and mortality outcomes. We created HIV data infrastructure by linking HIV treatment records with routinely collected records. MethodsWe linked HIV cohort data(n=119,434) to Health and Demographic Surveillance(n=256,425), laboratory tests(n=617,314), clinic visits and hospital admissions(n=170,325) from KwaZulu-Natal, an HIV-endemic setting in rural South Africa. We used graph-based probabilistic record linkage algorithm to link the data for HIV patients accessing care at 17 clinics within the Hlabisa sub-district. Africa Health Research Institute (AHRI) has collected health and demographic surveillance data since 2000. AHRI has set up a hospital information system in the district to capture ICD-10 code admissions and discharges. ResultsFrom the 5% sample of 462,524 linkage clusters, the computed F-score was 0.88, sensitivity was 88% and positive predictive value was 91%. 38.5% of the patient ID clusters contained records linked across multiple databases. 36% of the HIV patient ID clusters contained records linked with laboratory tests. 19.5% of the HIV patient ID clusters contained data on demographic surveillance. 12.5% of the HIV patient ID clusters contained records linked with clinic visits and hospital admissions. 4% of patient IDs contained records across all four databases. ConclusionWe have successfully created a cross-sectorial HIV cohort through probabilistic record linkage methods. The cohort provides a platform to answer policy-relevant questions.

First-Line Antituberculosis Drug Challenge Reactions in Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome in an HIV Endemic Setting

BackgroundIn high HIV prevalence settings, first line anti-tuberculosis drug (FLTD)-associated DRESS poses therapeutic challenges. Sequential and additive drug challenge (SADC) of FLTDs best identifies offending drug(s), avoids unnecessary exclusions, and optimises re-initiation of non-offending drugs. However, SADC-associated reaction complexities limit its utility. ObjectiveWe aimed to describe characteristics of FLTD-associated DRESS patients, their treatment-limiting SADC reactions and related outcomes. MethodsPatients hospitalized with FLTD-associated DRESS from 2013–2023 in a South African tertiary hospital and enrolled (retrospectively or prospectively) in an existing registry were eligible. ResultsSADC was undertaken in 41 patients. Overall, 47 classifiable reactions occurred, 34/47(72%) in 29/41(71%) patients, were treatment-limiting and 12/41(29%) reinitiated FLTDs uneventfully. Fifteen single and eight multiple drug-reactors were identified. Rifampicin, in 13/23(57%) reactors was the commonest individual offender. Ethambutol was most frequently involved in multiple drug-reactors. Median(IQR) time to a detectable reaction was 24(12-120) hours, 6/34(18%) being immediate (<6hours). Itch (65%), eosinophilia (56%), fever (41%), atypical lymphocytosis (41%), rash (38%), transaminitis (32%) and facial oedema (18%), singly or in combination were commonest features. Three reactions, one epidermal necrolysis and two liver derangements, were CTCAE grade 4 (life-threatening) events. No predictors of multiple drug-reactivity were identified, but multiple reactors were hospitalised significantly longer, 125(100-134) versus 60(45-80) days. ConclusionsSADC optimises FLTD reinitiation. However, timing, clinical presentation and severity of SADC-associated reactions following FLTD-associated DRESS is markedly heterogenous. Additionally, multiple drug-reactors are a complex group requiring longer hospitalisation, and without routine biomarkers to differentiate true multiple drug hypersensitivity from non-specific flare-ups and guide long-term drug avoidance strategies.

Mortality among extrapulmonary tuberculosis patients in the HIV endemic setting: lessons from a tertiary level hospital in Mbeya, Tanzania

Extrapulmonary tuberculosis (EPTB) has received less attention than pulmonary tuberculosis due to its non-contagious nature. EPTB can affect any organ and is more prevalent in people living with HIV. Low- and middle-income countries are now facing the double burden of non-communicable diseases (NCDs) and HIV, complicating the management of patients with symptoms that could be compatible with both EPTB and NCDs. Little is known about the risk of death of patients presenting with symptoms compatible with EPTB. We included patients with a clinical suspicion of EPTB from a tertiary level hospital in Mbeya, Tanzania, to assess their risk of dying. A total of 113 (61%) patients were classified as having EPTB, and 72 (39%) as having non-TB, with corresponding mortality rates of 40% and 41%. Associated factors for mortality in the TB groups was hospitalization and male sex. Risk factors for hospitalization was having disease manifestation at any site other than lymph nodes, and comorbidities. Our results imply that NCDs serve as significant comorbidities amplifying the mortality risk in EPTB. To strive towards universal health coverage, focus should be on building robust health systems that can tackle both infectious diseases, such as EPTB, and NCDs.

Hematological Complications of Human Immunodeficiency Virus (HIV) Infection: An Update From an HIV-Endemic Setting.

Medical professionals, particularly in regions with a high burden of human immunodeficiency virus (HIV), should be alert to the hematological complications of HIV, which may include cytopenias, malignancy, and coagulation disturbances. Patients may present with these conditions as the first manifestation of HIV infection. Hematological abnormalities are often multifactorial with opportunistic infections, drugs, malignancy, and HIV infection itself contributing to the clinical presentation, and the diagnosis should consider all these factors. Life-threatening hematological complications requiring urgent diagnosis and management include thrombotic thrombocytopenic purpura, superior mediastinal syndrome, spinal cord compression, and tumor lysis syndrome due to aggressive lymphoma. Antiretroviral therapy is the therapeutic backbone, including for patients with advanced HIV, in addition to specific therapy for the complication. This article reviews the impact of HIV on the hematological system and provides a clinical and diagnostic approach, including the role of a bone marrow biopsy, focusing on perspectives from sub-Saharan Africa.

“So that’s why I found PrEP to be safest way to protect yourself”: exploring IPV experiences and impact on HIV prevention among pregnant and postpartum women in Cape Town, South Africa

Intimate partner violence (IPV) occurs at alarmingly high rates towards pregnant women in South Africa. Experiences of emotional, physical, and sexual IPV in pregnancy can adversely impact the health and safety of mother and fetus. Furthermore, IPV is associated with increased risk of HIV, exacerbating the public health impact of violence among pregnant women in this HIV endemic setting. In-depth understanding of cultural and contextual drivers of experiences of IPV is a critical precursor to development of interventions effectively addressing this issue among pregnant women in South Africa. The present study examines factors contributing to IPV among pregnant women to identify potential points of intervention. We conducted twenty in-depth interviews with postpartum women who used oral pre-exposure prophylaxis (PrEP) in pregnancy and reported recent experiences of IPV and/or ongoing alcohol use in a township near Cape Town, South Africa that experiences a heavy burden of both HIV and IPV. Interpretive thematic analysis was used. Several patterns of IPV during pregnancy were identified and violence was frequently described as co-occurring with male partner alcohol use. A majority of women referenced oral PrEP as their preferred method for HIV prevention, highlighting the agency and discretion it provided as beneficial attributes for women experiencing IPV. Fear of judgement from peers for remaining with an abusive partner and a lack of clear community messaging around IPV were identified as barriers to disclosure and support-seeking. Addressing the lack of social support received by women experiencing IPV during pregnancy in South Africa is essential to comprehensive IPV programming.

Diagnostic Accuracy of Computer-Aided Detection During Active Case Finding for Pulmonary Tuberculosis in Africa: A Systematic Review and Meta-analysis.

Computer-aided detection (CAD) may be a useful screening tool for tuberculosis (TB). However, there are limited data about its utility in active case finding (ACF) in a community-based setting, and particularly in an HIV-endemic setting where performance may be compromised. We performed a systematic review and evaluated articles published between January 2012 and February 2023 that included CAD as a screening tool to detect pulmonary TB against a microbiological reference standard (sputum culture and/or nucleic acid amplification test [NAAT]). We collected and summarized data on study characteristics and diagnostic accuracy measures. Two reviewers independently extracted data and assessed methodological quality against Quality Assessment of Diagnostic Accuracy Studies-2 criteria. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines were followed. Of 1748 articles reviewed, 5 met with the eligibility criteria and were included in this review. A meta-analysis revealed pooled sensitivity of 0.87 (95% CI, 0.78-0.96) and specificity of 0.74 (95% CI, 0.55-0.93), just below the World Health Organization (WHO)-recommended target product profile (TPP) for a screening test (sensitivity ≥0.90 and specificity ≥0.70). We found a high risk of bias and applicability concerns across all studies. Subgroup analyses, including the impact of HIV and previous TB, were not possible due to the nature of the reporting within the included studies. This review provides evidence, specifically in the context of ACF, for CAD as a potentially useful and cost-effective screening tool for TB in a resource-poor HIV-endemic African setting. However, given methodological concerns, caution is required with regards to applicability and generalizability.

Perinatal HIV exposure and infection and caregiver depressive symptoms

ABSTRACT Survival is possible for children perinatally exposed to or infected by HIV in the post-combined antiretroviral therapy era and identifying factors affecting children’s ability to thrive has public health significance. Caregiver mental health is one such factor to consider given its impact on child development, but previous work has not included a full complement of HIV exposure/infection groups within HIV-endemic settings. We compared depressive symptoms among caregivers of 3 groups of 6-10-year-olds in Uganda: children with perinatally acquired HIV infection (CPHIV, n = 102), children with perinatal HIV exposure, but no infection (CPHEU, n = 101), and children without perinatal HIV exposure or infection (CHUU, n = 103). The Hopkins Symptom Checklist was used to assess caregiver depressive symptoms. Generalized linear models were used to estimate group mean differences. Adjusted models included caregiver demographics, social support, and lifetime trauma. Depression symptoms were higher among CPHEU compared to CPHIV caregivers (model coefficient [B] = −3.5, 95%CI −5.3, −1.8). This finding was minimally attenuated following adjustment for covariates (B = −2.2, 95%CI −4.1, −0.4) and among biological mothers. At lower levels of social support and wealth, CPHEU caregivers reported higher levels of depression symptoms than CPHIV caregivers. Our findings point to unmet mental health needs among CPHEU caregivers.

Upper Aero-Digestive Tract Malignancies in Botswana: Clinicopathological Features and Human Papillomavirus Genotypes in an Hiv-Endemic Setting

Upper Aero-Digestive Tract Malignancies in Botswana: Clinicopathological Features and Human Papillomavirus Genotypes in an Hiv-Endemic Setting

Improved diagnosis of extrapulmonary tuberculosis in adults with and without HIV in Mbeya, Tanzania using the MPT64 antigen detection test.

Extrapulmonary tuberculosis (EPTB) in People Living with HIV (PLWHIV) is a diagnostic challenge. Our immunochemistry based MPT64 antigen detection test has shown improved sensitivity compared to current laboratory tests in the resource limited diagnostic setting. The aim of this study was to validate the implementability and diagnostic performance of the test in PLWHIV and HIV negative adults in a HIV endemic Tanzanian setting. Adult (>18 y) presumptive EPTB patients were prospectively enrolled at Mbeya Zonal Referral Hospital and followed to the end of treatment or until an alternative diagnosis was reached. Suspected sites of infection were sampled and were subject to routine diagnostics, GeneXpert MTB/RIF assay and the MPT64 test. The performance of the diagnostics tests was assessed using a composite reference standard that included clinical suspicion, mycobacterial culture, response to anti-tuberculosis (TB) therapy, cytological and radiological findings. Patients (N = 168) were categorized as 21 confirmed TB, 23 probable TB and 44 possible TB cases, 69 patients were categorized as non-TB cases and 11 were uncategorized. In the TB group, the three most common infections were adenitis (41%), peritonitis (19%) and pleuritis (14%). The TB and non-TB groups did not differ in HIV seropositivity (46% vs 42%) Among HIV negative and PLWHIV, the MPT64 test had a sensitivity of (91% vs 78%), specificity (75% vs 86%), positive predictive value (80% vs 88%), negative predictive value (89% vs 74%), and accuracy (84% vs 81%), respectively. Performance was not significantly reduced in PLWHIV, and sensitivity was higher than in the currently used tests, including the GeneXpert MTB/RIF assay. The MPT64 test improved the diagnosis of EPTB, irrespective of HIV status. The test performed better than currently used diagnostic test. The test was implementable in a tertiary level hospital with basic pathology services in a HIV endemic Tanzanian setting.

Psychosocial Support Programme Improves Adherence and Health Systems Experiences for Adolescents on Antiretroviral Therapy in Mpumalanga Province, South Africa.

(1) Background: Psychosocial support (PSS) plays a significant role in persistent adherence to and retention in antiretroviral therapy (ART) for adolescents living with the human immunodeficiency virus (ALHIV). This paper qualitatively explores the experiences of ALHIV on ART, who participated in a PSS programme in five public primary healthcare facilities in Mpumalanga Province in South Africa during the COVID-19 pandemic. (2) Methods: Data were collected through 24 focus group discussions with 173 ALHIV on ART and subjected to inductive thematic analysis. Informed consent was obtained before all data collection. (3) Results: The PSS programme facilitated the process of full HIV disclosure to these adolescents with the support of parents/guardians while motivating adherence through peer support groups and health education for improved treatment literacy. Participants reported positive health systems experiences, improved healthcare provider-client relations, and prompt access to health services. (4) Conclusions: The PSS programme successfully kept ALHIV engaged in ART care despite the health service disruptions encountered during the COVID-19 pandemic. We recommend rigorous evaluation of the effects of the PSS intervention on adherence to and retention in ART among ALHIV in HIV-endemic settings.

Alignment of PrEP adherence with periods of HIV risk among adolescent girls and young women in South Africa and Zimbabwe: a secondary analysis of the HPTN 082 randomised controlled trial

Adolescent girls and young women in southern and eastern Africa have adherence challenges with daily oral HIV pre-exposure prophylaxis (PrEP). High adherence is most important during periods of HIV risk (prevention-effective adherence). We aimed to describe HIV risk behaviour and to understand patterns in PrEP adherence during periods of risk among adolescent girls and young women from sub-Saharan Africa. We did a secondary analysis of the HPTN 082 trial, an open-label, interventional, randomised controlled trial of sexually active adolescent girls and young women (aged 16-25 years) testing negative for HIV in Johannesburg and Cape Town, South Africa, and in Harare, Zimbabwe. The primary outcomes were high cumulative PrEP adherence, dichotomised as intracellular tenofovir diphosphate concentrations of at least 700 fmol/punch in dried blood spots at weeks 13, 26, and 52, and high recent PrEP adherence, dichotomised as plasma tenofovir concentrations of at least 40 ng/mL at weeks 13, 26, and 52, among participants who accepted PrEP. We collected data on sexual behaviour every 3 months. We categorised visits into a binary variable of any HIV risk based on condomless sex, more than one sexual partner, primary partner's HIV status and antiretroviral use, transactional sex, drug or alcohol use around sexual activity, and laboratory-diagnosed STIs. We used generalised estimating equations to evaluate associations between HIV risk (reflecting behaviour during the previous 3 months) and high cumulative and recent adherence to PrEP and any PrEP use (quantifiable drug concentrations). The trial is registered with ClinicalTrials.gov, NCT02732730. Between Oct 12, 2016, and Oct 25, 2018, 451 women were recruited, and 427 participants (median age 21·0 years [IQR 19·0-22·0]) were eligible for inclusion in this analysis. The proportion of participants reporting at least one HIV risk factor decreased significantly over follow-up, from 364 (85%) participants at enrolment, 226 (60%) at week 13, and 243 (65%) at week 26, to 224 (61%) at week 52 (p<0·0001). Any HIV risk was significantly associated with high PrEP adherence, measured by both tenofovir diphosphate concentrations of at least 700 fmol/punch (adjusted relative risk 1·57 [95% CI 1·09-2·25]; p=0·014) and plasma tenofovir concentrations of at least 40 ng/mL (1·36 [1·11-1·65]; p=0·0025). Any HIV risk was also associated with quantifiable concentrations of tenofovir diphosphate (1·15 [1·03-1·29]; p=0·013) and tenofovir (1·27 [1·09-1·49]; p=0·0022). We observed significant dose-response relationships between number of HIV risk factors and PrEP drug concentrations. The association between any HIV risk and high PrEP adherence suggests that adolescent girls and young women were able to use PrEP during periods of risk, an indicator of prevention-effective PrEP adherence. Our findings support a shift in the PrEP framework to acknowledge prevention-effective adherence practices, which might improve PrEP delivery and adherence support for adolescent girls and young women in HIV-endemic settings. US National Institutes of Health.

Piloting and validating the linkage of routine ART and laboratory records in an HIV endemic setting.

ObjectivesIntegrating clinical and laboratory data systems offers opportunities to understand disease aetiology and improve patient outcomes. We developed and piloted a data linkage algorithm to link HIV patient treatment records with routine laboratory service records in an HIV endemic setting in rural South Africa. ApproachWe used data from the South Africa’s National Health Laboratory Service (NHLS) and Three Integrated Electronic Registers (TIER.Net) databases for 17 primary healthcare clinics from uMkhanyakude district, South Africa. The two databases contained data on key demographic variables such as patient first name, surname, date of birth, sex, and health facility, and national ID numbers for a subset of the data. We adapted a probabilistic record linkage algorithm we previously developed for linkage of laboratory results. We trained and validated our algorithm using two approaches: 1) firstly, we constructed a quasi-gold standard based on manual review of potential matches for 1,061 randomly selected patients; 2) secondly, we constructed a quasi-gold standard based on records that contained national ID numbers. We calculated the probabilities that the algorithm could correctly identify a true match (sensitivity) and the probabilities that the match identified by the algorithm was truly a match (positive predictive value) using the two approaches. ResultsBetween 2015 and 2020, 55,077 patients were recorded in the HIV treatment database and 386,577 laboratory tests were recorded in the laboratory service database. The sensitivity and positive predictive value in the manually reviewed data were estimated to be 94.4% and 81.2% respectively. The sensitivity and positive predictive value in the matched individual identifiers were estimated to be 99.6% and 99.7% respectively. ConclusionsRecords can be linked successfully, but estimated performance of record linkage depends on the validation set used. Manually reviewed data contain noise and may underestimate performance, while national ID numbers may overestimate performance due to non-random patterns of missingness.

Expression of mycobacterium tuberculosis induced SOCS3 and STAT3 and the implications on innate immunity in TB patients vs healthy contacts in high TB/HIV endemic setting: A cross-sectional analytical study.

BackgroundMycobacterium tuberculosis (TB) remains a disease of global health concern and a leading cause of mortality arising from an infectious agent. Protective immunity to TB remains unclear. Suppressor of cytokine signaling-3 (SOCS3) and signal transduction and activator of transcription-3 (STAT3) genes have shown potential to influence innate immunity. We, therefore, explored the expression of SOCS3 and STAT3 and their implications on the innate immunity in TB patients and their healthy close contacts.MethodsWe recruited 72 TB patients and 62 healthy contacts from a high TB and HIV endemic setting (Lusaka, Zambia). We used RT-PCRT and flow cytometry to quantify the expression of SOCS, STAT3 and cytokines respectively. Data was analysed Stata version 14.0 and figures were developed in GraphPad prism version 9.1.0 (221). Assessment for associations for categorical and continuous variables was analysed using the Chi-square test and Mann-Whitney test respectively. Spearman’s rank correlation was used to evaluate the relationship between SOCS3 and IL-6. A p-value < 0.05 was considered statistically significant.ResultsHealthy contacts markedly expressed SOCS3 in both unstimulated and stimulated whole blood in comparison to TB patients (p <0.0001). STAT3 was elevated in TB patients in TB patients in stimulated blood only. IL-6 (P = < 0.0001) and IL-10 (P = <0.0001), were significantly expressed in Healthy contacts in comparison to TB patients. TNF-α (p = 0.044) were markedly elevated in TB patients in comparison to healthy contacts. IL-6 and SOCS3 correlated significantly in healthy contacts only (r = 0.429, p = 0.02).ConclusionsBoth SOCS3 and STAT3 are genes of importance in mounting protective innate immunity against TB. We propose that SOCS3 stimulation and inhibition of STAT3 as possible approaches in gene therapy and vaccine development for TB.

Assessment of tuberculosis disease activity in people infected with Mycobacterium tuberculosis and living with HIV: A longitudinal cohort study.

SummaryBackgroundEarly detection of asymptomatic incipient tuberculosis (TB) could improve clinical outcomes and reduce the spread of Mycobacterium tuberculosis (MTB) infection, particularly in HIV endemic settings. This study assessed TB disease activity over 5 years in people living with HIV co-infected with MTB using a surrogate biomarker.MethodsBetween Jan 1, 2013 and Aug 31, 2018, 2014 people living with HIV were screened annually for active TB using the Xpert MTB/RIF diagnostic assay in 11 clinics in Kenya, Tanzania, Uganda, and Nigeria. Longitudinal blood mononuclear cell samples from 46 selected patients with active and recurrent tuberculosis, latent infection, or incipient TB were further analysed for MTB-specific T-cell activation (defined by CD38 expression) as a well-defined surrogate marker for TB disease covering a total of 1758 person-months.FindingsMTB-specific CD4 T-cell activation differentiated active, Xpert MTB/RIF positive TB from latent TB with a sensitivity and specificity of 86% and was reduced upon TB treatment initiation. Activated MTB-specific T cells were present in 63% and 23% of incipient TB cases 6 and 12 months before diagnosis of active disease, respectively. Transient increases of MTB-specific T cell activation were also observed in individuals with latent infection, while persistent activation was a hallmark of recurrent TB after the end of treatment.InterpretationIn most cases, progression to active TB disease started 6–12 months before diagnosis by clinical symptoms and sputum occurrence of bacilli. Blood biomarkers could facilitate early detection of incipient TB, improve clinical outcomes, and reduce the transmission of MTB.FundingThis work was supported by the President's Emergency Plan for AIDS Relief via a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense [W81XWH-11-2-0174, W81XWH-18-2-0040] and by the Bundesministerium für Bildung und Forschung (BmBF) through funding of the Deutsches Zentrum für Infektionsforschung (DZIF, TTU-TB personalized medicine TTU 02_813).

The relationship between adverse childhood experiences and common mental disorders among pregnant women living with HIV in Malawi

IntroductionAdverse childhood experiences (ACEs) have been linked to common mental disorders (CMDs) such as anxiety and depressive thoughts. We examined the prevalence of ACEs and their association with CMDs among pregnant women living with HIV (PWLHIV) in Malawi—an HIV endemic resource-limited setting. MethodsThis is a cross-sectional study of 798 PWLHIV enrolled in the VITAL Start trial in Malawi (10/2018 to 06/2021) (NCT03654898). ACE histories were assessed using WHO's Adverse Childhood Experiences International Questionnaire (ACE-IQ) tool. Depressive symptoms (somatic complaints, reduced vital energy, anxiety, and depressive thoughts) were assessed using WHO's Self Reporting Questionnaire 20-Item (SRQ-20) tool. Log-binomial regressions were used to examine the association between cumulative ACEs and each depressive symptom, as well as identify ACEs driving this association. ResultsThe mean age of our sample was 27.5 years. Over 95 % reported having experienced ≥1 ACE. On average, each participant reported four ACEs; 11 % reported sexual abuse. About 52 % and 44 % reported anxiety and depressive thoughts, respectively. In regressions, cumulative ACE scores were significantly associated with depressive symptoms—even after adjusting for multiple testing. This association was primarily driven by reports of sexual abuse. LimitationsData on maternal ACEs were self-reported and could suffer from measurement error because of recall bias. ConclusionsACEs are widespread and have a graded relationship with depressive symptoms in motherhood. Sexual abuse was found to be a primary driver of this association. Earlier recognition of ACEs and provision of trauma-informed interventions to improve care in PWLHIV may reduce negative mental health sequelae.

IFN-γ ELISpot in Severe Cutaneous Adverse Reactions to First-Line Antituberculosis Drugs in an HIV Endemic Setting

Severe cutaneous adverse reactions related to first-line antituberculosis drugs are associated with high mortality and long-term morbidity. Oral sequential drug challenge, as a form of drug provocation testing, helps to salvage therapy by identifying culprit drugs but is associated with risk and is costly. IFN-γ enzyme-linked immune absorbent spot (ELISpot), an adjunctive invitro diagnostic tool, may help to guide risk-stratification approaches. To determine the diagnostic accuracy of IFN-γ ELISpot against full-dose sequential drug challenge, we analyzed samples collected prospectively at multiple time points in 32 patients with first-line antituberculosis drug‒associated severe cutaneous adverse reaction (81% HIV infected, 25 with drug reaction with eosinophilia and systemic symptoms, and 7 with Stevens‒Johnson syndrome/toxic epidermal necrolysis). Sensitivity of IFN-γ ELISpot was 33% (4 of 12), 13% (1 of 8), 11% (1 of 9), and 0% (0 of 4) for rifampicin, isoniazid, pyrazinamide, and ethambutol, respectively (positivity threshold ≥50 spot forming units/million cells). Specificity was 100% for all the four drugs. Rifampicin IFN-γ ELISpot sensitivity increased to 58% (7 of 12) if a threshold of 20 spot forming units was used and to 75% (3 of 4) when restricted to samples <12 weeks after acute severe cutaneous adverse reaction event; specificity remained 100% for both. IFN-γ ELISpot offers adequate risk stratification of rifampicin severe cutaneous adverse reaction using acute samples and lowered threshold for positivity. Given the low sensitivity of IFN-γ ELISpot for other first-line antituberculosis drugs, additional optimization is needed to improve risk-stratification potential.

Isoniazid and Rifampicin Tuberculosis Drug Resistance in HIV Endemic Region of Western Kenya

Background: Tuberculosis drug resistance is often associated with inadequate anti-tuberculosis treatment regimen resulting to mutations that confers resistance to anti-tuberculosis agents. This is aggravated by synergetic relationship between Tuberculosis and HIV (Human Immunodeficiency Virus). Over 25% of Global Tuberculosis deaths occur in Africa and Kenya is one of the 30 high burden countries that together account for more than 80% of the world’s TB cases. According to World Health Organization, in 2018, Multi drug resistant Tuberculosis prevalence in Kenya was 1.3% in new cases and 4.4% in retreatment cases. Kisumu County recorded the second highest HIV prevalence at 18.6% against the national prevalence of 4.5% in 2020. The extent of regional burden of DR-TB and HIV co-infection has not been exactly well-defined in Western Kenya. Methods: This was a prospective cross sectional study that aimed to explore the association between Tuberculosis drug resistance and HIV status among new and previously treated pulmonary tuberculosis cases in Kisumu County, Kenya. Tuberculosis clinical suspects were recruited into the study and classified as HIV positive or negative based on their clinical data. Sputum samples from tuberculosis clinical suspects were subjected to fluorescent microscopy, phenotypic culture and line probe assay. Results: Out of a sample of 256, response rate was 216 of which HIV positive cases were 119(55.1%) and negative were 97 (44.9%). The study found that out of 11 that were phenotypic Isoniazid resistance 8(6.7%) were from HIV positive cases while 3 (3.2%) were from HIV negative cases. Phenotypic rifampicin resistance among the HIV positive were 8 (6.7%) while HIV negative were 2 (2.1%). All the 2(1.7%) MDR cases were from HIV positive participants. The study found out that HIV status and Tuberculosis cases were significantly associated at p&lt;.05. HIV positive cases were more likely associated with retreatment cases (OR=1.4,95CI:1.00-1.90) compared to new cases. The study found out that the common mutant probe among the HIV positive was katG MUT1 4(2.6%), while mutant probes among the HIV negative were in hA MUT1 1(0.7%), katG MUT1 1(0.7%) and roB MUT2A 1(0.7%). Wild type gene deletion among the HIV positive cases were observed in probes katG WT 3(2.1%), roB WT7, katG WT 1(0.7%) while wild type gene deletion among the HIV negative cases were inhA WT1 1(0.7%), in hA WT1/inhAWT2 1(0.7%), katG WT 1(0.7%). Conclusion: Interventions specific to HIV-endemic areas are urgently needed to block tuberculosis drug resistance transmission. Development and improvement of the efficacy of interventions will require a greater understanding of the transmission of multidrug-resistant tuberculosis in HIV-endemic settings like Kisumu County, Western Kenya.

Leading causes of death and high mortality rates in an HIV endemic setting (Kisumu county, Kenya, 2019).

In resource-limited settings, underlying causes of death (UCOD) often are not ascertained systematically, leading to unreliable mortality statistics. We reviewed medical charts to establish UCOD for decedents at two high volume mortuaries in Kisumu County, Kenya, and compared ascertained UCOD to those notified to the civil registry. Medical experts trained in COD certification examined medical charts and ascertained causes of death for 456 decedents admitted to the mortuaries from April 16 through July 12, 2019. Decedents with unknown HIV status or who had tested HIV-negative >90 days before the date of death were tested for HIV. We calculated annualized all-cause and cause-specific mortality rates grouped according to global burden of disease (GBD) categories and separately for deaths due to HIV/AIDS and expressed estimated deaths per 100,000 population. We compared notified to ascertained UCOD using Cohen's Kappa (κ) and assessed for the independence of proportions using Pearson's chi-squared test. The four leading UCOD were HIV/AIDS (102/442 [23.1%]), hypertensive disease (41/442 [9.3%]), other cardiovascular diseases (23/442 [5.2%]), and cancer (20/442 [4.5%]). The all-cause mortality rate was 1,086/100,000 population. The highest cause-specific mortality was in GBD category II (noncommunicable diseases; 516/100,000), followed by GBD I (communicable, perinatal, maternal, and nutritional; 513/100,000), and III (injuries; 56/100,000). The HIV/AIDS mortality rate was 251/100,000 population. The proportion of deaths due to GBD II causes was higher among females (51.9%) than male decedents (42.1%; p = 0.039). Conversely, more men/boys (8.6%) than women/girls (2.1%) died of GBD III causes (p = 0.002). Most of the records with available recorded and ascertained UCOD (n = 236), 167 (70.8%) had incorrectly recorded UCOD, and agreement between notified and ascertained UCOD was poor (29.2%; κ = 0.26). Mortality from infectious diseases, especially HIV/AIDS, is high in Kisumu County, but there is a shift toward higher mortality from noncommunicable diseases, possibly reflecting an epidemiologic transition and improving HIV outcomes. The epidemiologic transition suggests the need for increased focus on controlling noncommunicable conditions despite the high communicable disease burden. The weak agreement between notified and ascertained UCOD could lead to substantial inaccuracies in mortality statistics, which wholly depend on death notifications.