Browsing by Author "Joska, John"

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    A cross-sectional study of the association between cognitive impairment and haemoglobin levels in HIV-infected South Africans established on antiretroviral therapy
    (2019) Vermaak, John-Randel; Joska, John; Decloedt, Eric
    Background Sub-Saharan Africa, the epicenter of the global population of people living with HIV (PLHIV), is estimated to have more than 25 million PLHIV. In the era before the widespread availability of antiretroviral therapy (ART), anaemia (low serum haemoglobin) was a common clinical finding that was seen as a potential risk factor for HIV-associated neurocognitive impairment. The association between haemoglobin levels and neurocognitive function has not been assessed in a Sub-Saharan study population in the era of ART. Methods A cross-sectional secondary data analysis was performed to assess the association between serum haemoglobin level and neurocognitive function in 129 participants who had both neurocognitive test (global deficit score) and full blood count results performed as part of a randomised placebo controlled trial that evaluated the efficacy of lithium carbonate for the treatment of HIV associated neurocognitive disorders. Results The majority of our participants were female (87%) with a mean age of 37 ±7.78 years. Participants were all established on ART with a median CD4 count of 495 cells/µL (IQR=315- 629). The median haemoglobin level was 12.2 (IQR=11.6-13.00) and anaemia was present in 8.5%. Serum haemoglobin level was not associated with global deficit scores (GDS) and fewer years of education was the only independent risk association for GDS-defined neurocognitive impairment. Conclusion We found that in South Africans, who are established on ART, anaemia is less common than in the pre-ART era and importantly, that low-normal serum Hb levels do not present a risk for GDS-defined neurocognitive impairment. These findings are relevant as they show that aggressive management of low-normal Hb levels is not necessary provided individuals are otherwise clinically well and virally suppressed.
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    An assessment of external HIV-related stigma in South Africa: implications for interventions
    (2021) Mehlomakulu, Vuyelwa; Simbayi, Leickness C; Joska, John; Nyasulu, Peter
    Background Globally, external HIV-related stigma is a major threat to all HIV prevention, care and treatment interventions including the recently launched Universal Test and Treat (UTT) strategy in South Africa and the 90-90-90 targets set by UNAIDS for the global response by 2020. The 90-90-90 targets are put in place to track the progression from HIV testing to durable viral load suppression among people living with HIV. The targets guide HIV programmes to achieve 90% known HIV status, to access 90% antiretroviral therapy and to suppress 90% viral loads (UNAIDS, 2017). Achievement of the 90-90-90 targets has since become a part of South Africa's National Strategic Plan for HIV, TB and STIs 2017-2022. External HIV-related stigma in this study was defined as the presence of one or more of the following attitudes and behaviours: rejection, avoidance, intolerance, stereotyping, discrimination, and physical violence towards people living or perceived as having HIV. There have not been many efforts to attenuate HIV-related stigma in South Africa, as it continues to exist. There has been a scale up of other HIV responses, such as HIV Counselling and Testing (HCT) and treatment, with the argument made that in scaling up these biomedical approaches, stigma would disappear. Furthermore, its exact magnitude, trends over the years and correlates have not been explored fully at national level, hence the present study known as Stigma Assessment Study in South Africa (SASSA). SASSA is based on the Institutional Social Construction theory framework. It explores the external HIV-related stigma magnitude and its trends between 2005 and 2012, as well as the associated factors which influence its prevalence in South Africa at a national level. The study further explores the mediating and moderating factors of external HIV-related stigma and tries to explore external HIV-related stigma by viewing individuals with HIV living in families, societies and structures, with the hope of contributing to the development of new systematic HIV-related stigma interventions in South Africa as well as, strengthening existing ones. Methodology The project used secondary data obtained from three South African national population HIV surveys which were conducted in 2005, 2008 and 2012 by a research consortium led by the Human Sciences Research Council. Sub-samples of the original surveys consisting of respondents aged 15 years and older who had responded to the stigma questions in the three surveys were extracted and included in the SASSA analysis. A nationally representative sample of a total of 16 140 individual respondents from the 2005 survey, 13 134 from the 2008 survey and 30 748 from the 2012 survey was used in the study. Two different measures of external HIV stigma are used in this analysis, one is a summary measure from the latest survey data, i.e. 2012, which was used to do a regression analysis. The summary measure was regarded as reliable to use for the regression analysis as it provides crude effect of the exposure factors on external HIV stigma. However, this summary measure was not included in the previous surveys, i.e. 2005 and 2008, and therefore could not be used for trends analysis. We therefore used 4 individual stigma items for the trends analysis as these were included in all 3 surveys. The use of 4 individual stigma items was important because when data from a variety of sources or categories have been joined together, the meaning of the data can be difficult to see. It was therefore considered ideal to assess the performance of the individual constructs on their individual contribution to the impact on HIV external stigma. Furthermore, analysis using individual constructs provided an opportunity to see specific patterns which could have remained obscure in crude analysis. The first measure of external HIV-related stigma used in the regression analysis was measured by five individual items which elicited attitudes towards people living with HIV (PLHIV). The five items were based on a 9-item scale that was originally developed and tested in a South African population, and the 9-item scale was found to be internally consistent (alpha = 0.75) and reliable (r = 0.67). The 5 items were (1) People who have AIDS are dirty; (2) People who have AIDS are cursed; (3) People who have AIDS should be ashamed; (4) People with AIDS must expect some restrictions on their freedom; (5) A person with AIDS must have done something wrong and deserves to be punished. As explained above, the specific external HIV stigma patterns second measure, which was utilized to explore stigma trends over the years 2005, 2008 and 2012, consists of four individual stigma items which elicited attitudes towards PLHIV. The four individual stigma items included: (1) If you knew that a shopkeeper or food seller had HIV, would you buy food from them? (2) Would you be willing to care for a family member with AIDS? (3) Is it a waste of money to train or give a promotion to someone with HIV/AIDS? (4) Would you want to keep the HIV positive status of a family member a secret? Findings Overall, external HIV-related stigma was found to exist among 38.3% of adult South Africans in 2012. Multiple regression analysis showed that predictors of external HIV-related stigma were race, sex, education level, self-perceived risk of HIV infection and HIV knowledge (p< 0.01). Females were less likely to report external HIV-stigma than males (AOR = 0.9, P< 0.001). Those who perceived themselves to be at high risk of HIV infection were less likely to display some stigma than those who believed they were at low risk (AOR = 0.89, p < 0.01). The study did not find any significant associations between HIV testing or awareness of HIV status, with external HIV-related stigma in this study. Looking at the individual external HIV stigma items used to measure trends, the study reveals a slight decrease in the reporting of stigma over the three time periods (2005 vs 2008 vs 2012) on responses for two of the stigma items (Q1: If you knew that a shopkeeper or food seller had HIV, would you buy food from them, and Q2: Would you be willing to care for a family member with AIDS). While an increase was observed in the reporting of stigma over the three years on responses for two of the stigma items (Q3: Is it a waste of money to train or give a promotion to someone with HIV/AIDS, and Q4: Would you want to keep the HIV positive status of a family member a secret). The structural equation modelling (SEM) showed likelihood ratio test results with a p-value greater than 0.05, a root mean square error of approximation (RMSE) of 0.008 and Tucker–Lewis index (TLI) value of 0.985. The model fit assessment results allow us to accept that an hypothesized model of the study is not far from a perfect model. The SEM results also showed a direct effect of sex on HIV knowledge statistically significant at p < 0.001, with race having an effect of 3.3% and education a direct effect of 9.5%, and both of these showed a statistically significant effect (p < 0.001) respectively. HIV knowledge showed to have a statistically significant inverse relationship on external HIV stigma of -10.4% (95% CI: -12.3-0.09) p< 0.001. Awareness of HIV status had the highest positive direct effect on external stigma of 10% (95% CI: 4.41-15.67%) p<0.001. With regard to indirect effects, sex, race, and education had minimal negative indirect effects on external stigma, which was statistically significant for all the three covariates. With the said effects of external HIV-related stigma, it was found that HIV knowledge independently mediates the relationship between Level of Education, Awareness of HIV status, Race, HIV testing history, and Sex, with External HIV-related stigma. Conclusion External HIV-related stigma still exists in South Africa despite previous success in massive ART rollout, HTC campaigns, and most recently test-and-treat programmes, which were arguably thought to have a parallel effect in the decrease of HIV related stigma. The focus on individualistic health structural approaches that do not generally have stigma-reduction as a specific aim, as discussed, is likely to undermine the successes achieved in the fight against HIV thus far. There is a need to develop innovative holistic interventions which are specifically intended for HIV stigma reduction. These should be inclusive of both social institutional elements and health structural elements to address the challenge of external HIV-related stigma.
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    An Evaluation of the Psychometric Properties of the Montreal Cognitive Assessment Tool when Administered in a Memory Clinic At Groote Schuur Hospital, Cape Town, South Africa
    (2022) Thungana, Yanga; Joska, John; Thomas, Kevin
    Worldwide, the population is aging, and the prevalence of neurocognitive disorders is expected to rise exponentially. Therefore, early detection of dementia is favorable for the patient and may even be of greater significance if disease-modifying treatments are discovered. The Montreal Cognitive Assessment (MoCA) is a reliable and valid cognitive screening tool but is sensitive to several sociodemographic factors, including language, culture, and quality of education. This underscores the need for cognitive screening scales validated in the culturally diverse South African setting. Aim. The purpose of this study was to investigate the utility of the MoCA as a brief cognitive screening tool in a specialized clinical South African sample. Methods. A retrospective medical folder review of 162 patients seen at Groote Schuur Hospital Memory Clinic for the first time between January 2014 and August 2021. Results. The median age of participants was 67 years (IQR 58-73). Most were females (63%, n =102), and had dementia (58%, n = 94); more than half (51%, n = 78) had at least 12 years of formal education. Older age and lower levels of education were associated with lower MoCA scores (p < 0.001). Conclusion. In a specialized South African clinical setting, the MoCA demonstrated good psychometric properties as a screening tool for evaluating different levels of cognitive impairment. However, to our knowledge, this is the first South African study to assess the factor structure of the MoCA in a clinical setting. More comprehensive and larger studies should evaluate the validity of our findings.
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    An investigation of a neuro-inflammatory profile of HIV-associated neurocognitive disorders
    (2021) Williams, Monray Edward; Naude, Pieter; Joska, John; Stein, Dan
    Background HIV-associated neurocognitive disorder (HAND) is the consequence of the effects of HIV-1 within the central nervous system (CNS). HIV-associated neurocognitive impairment differs in severity with milder forms presenting in 50% of people living with HIV (PLWH), regardless of treatment status. Chronic immune dysregulation has been associated with HAND; in particular, it has been noted that inflammation persists despite the successful treatment with antiretroviral therapy (ART). However, the nature to which (neuro)inflammation influences cognitive performance and brain integrity remain unclear. Further, it is not clear how sequence variation in neurotoxic viral proteins, including Tat, affects inflammation in PLWH. This study aimed to 1) perform a systematic review of the existing literature to identify changes in peripheral immune markers that are associated with HAND in ART-experienced PLWH, 2) determine the association of blood peripheral immune markers with domain-based neurocognitive performance and structural brain changes in South African PLWH, and 3) lastly, to evaluate the possible influence of Tat sequence variation on a dysregulated immune profile in HIV-1C infection (i.e. Tat-C). Methods A systematic review of the published literature was performed to identify the most common markers associated with HAND in the ART-era. A panel of markers was measured in a treatment naïve South African cohort by enzyme-linked immunosorbent assays (ELISA). Cognitive performance was established using a battery of tests sensitive to HIV-associated neurocognitive impairment, with domain based scores utilized in analysis. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3T. Markers were correlated with neurocognitive performance and cortical thickness and surface area. Further, a prospective review of the literature was performed to determine the association between Tat sequence variation and underlying mechanisms (and inflammation) of HAND. The HIV-1 was genotyped and the influence of Tat sequence variation on immune marker levels was evaluated in a subset of South African participants. Results A systematic review of the existing literature suggested that peripheral immune markers of monocyte activation (sCD14 and sCD163) and inflammation (IL-18 and IP10) were associated with HAND in the majority of studies. Evaluation of blood immune markers in a treatment naïve South African cohort showed that thymidine phosphorylase (TYMP) and neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher, while matrix metalloproteinase (MMP)9 levels were significantly lower in PLWH. The results further showed that in PLWH, worse psychomotor processing speed was associated with higher TYMP and NGAL levels and worse motor function was associated with higher NGAL levels. Further, in imaging analysis, it was reported that higher NGAL levels were associated with the reduced thickness of the bilateral orbitofrontal cortex. The association of NGAL withworse motor function was mediated by the cortical thickness of the bilateral orbitofrontal cortex. The associations between higher NGAL and TYMP levels with cortical thickness were largely found in the regions of the frontal cortex. A review of the literature suggests that key protein signatures (C31S and R57S) present in the Tat protein from HIV-1 subtype C (Tat-C) infection may contribute to the lowered inflammation. Supporting this hypothesis, the results from this thesis showed that HIV-1C participants with the R57S mutation had lower peripheral TYMP levels. Conclusions Current literature supports the premise that chronic inflammation may be an important contributor to the development of the milder forms of HAND. For patients on ART, other strategies are required to address the ongoing peripheral inflammation, in addition to simply suppressing the viral load. In a South African context, TYMP and NGAL may be promising markers for their involvement in HAND. Patients were largely treatment-naïve; therefore, these markers may represent HIV related effects without the potential confounding effects of ART. Therefore, these findings may represent long-standing effects which might persist in treatment experienced participants. In HIV-1C infection, the level of certain inflammatory markers may be influenced by the R57S Tat protein signature. To our best knowledge, this is the first thesis to report the association of these markers with HAND. These immune markers need to be investigated for their potential role in the underlying mechanisms of HAND.
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    The association between aids related stigma and major depressive disorder among HIV-positive individuals in Uganda
    (Public Library of Science, 2012) Akena, Dickens; Musisi, Seggane; Joska, John; Stein, Dan J
    BACKGROUND: Major depressive disorder in people living with HIV/AIDS (PLWHA) is common and may be associated with a number of factors, including AIDS-related stigma, decreased CD4 levels, increased opportunistic infections and sociodemographic variables. The extent to which AIDS-related stigma is associated with major depressive disorder among PLWHA has not been well studied in sub-Saharan Africa. The objective of this study was to examine the associations between major depressive disorder, AIDS-related stigma, immune status, and sociodemographic variables with the aim of making recommendations that can guide clinicians. METHODS: We assessed 368 PLWHA for major depressive disorder, as well as for potentially associated factors, including AIDS-related stigma, CD4 levels, presence of opportunistic infections, and sociodemographic variables. RESULTS: The prevalence of major depressive disorder was 17.4%, while 7.9% of the participants had AIDS related stigma. At multivariable analysis, major depressive disorder was significantly associated with AIDS-related stigma [OR = 1.65, CI (1.20-2.26)], a CD4 count of ≥200 [OR 0.52 CI (0.27-0.99)], and being of younger age [0.95, CI (0.92-0.98). CONCLUSIONS: Due to the high burden of major depressive disorder, and its association with AIDS related stigma, routine screening of PLWHA for both conditions is recommended. However, more research is required to understand this association.
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    Baseline concussion assessments can identify mental disorders: the SCAT-5 Symptom Evaluation compared to other screening tools in South African club rugby
    (2023) Burger, James; Joska, John; Andersen, Lena
    Mental disorders are common in athletes, but often go undiagnosed. Although mental health screenings are not routinely conducted in rugby, the Sport Concussion Assessment Tool – Fifth Edition (SCAT-5) is widely performed and measures affective, cognitive, sleep, and physical symptoms. This study investigated the psychometric properties of the SCAT-5 to explore its potential as a mental health screening tool. During preseason for the 2021 Western Province Super League A in South Africa, clinicians conducted mental health assessments of 71 adult male rugby union players. The SCAT-5 Symptom Evaluation, Baron Depression Screener for Athletes (BDSA), Athlete Psychological Strain Questionnaire (APSQ), Center for Epidemiologic Studies–Depression (CES-D), and Generalised Anxiety Disorder-7 (GAD-7) were compared to each other and to fully-structured diagnostic interviews by mental health professionals using the Mini International Neuropsychiatric Interview (MINI) 7.0.2. Lifetime MINI-defined mental disorders were common, being identified in 33.8% (95%CI 22.79 to 46.17%). Only 4.29% of these had a previous diagnosis. Exploratory Factor Analysis indicated a mental health construct of depression/anxiety being measured by the SCAT-5. The SCAT-5 had strong internal consistency ( = 0.94) and showed moderate convergent validity with the CES-D (r = 0.34; p = 0.008) and GAD-7 (r = 0.49; p < 0.0001). The area under the curve for identifying current disorders was 0.87 (p = 0.003). Since the SCAT-5 has the potential to identify depression and anxiety, it may allow mental health screening without the need for additional measures. Follow-up studies should further explore its discriminative ability in larger samples.
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    Blood and Lumbar Fluid Biomarker Changes in Patients with HIV-Associated Neurocognitive Impairment Treated with Lithium: Analysis from a Randomised Placebo-Controlled Trial
    (2022) Thela, Lindokuhle; Joska, John; Decleodt, Eric
    HIV-associated neurocognitive disorders (HAND) persist in the era of antiretroviral therapy (ART). Thus, ART does not completely halt or reverse the pathological processes behind HAND. Adjuvant mitigating treatments are therefore prudent. Lithium treatment is known to promote neuronal brain-derived neurotrophic factors (BDNF). Lithium is also an inhibitor of glycogen synthase kinase-3 beta (GSK-3-β). We analyzed biomarkers obtained from participants in a randomized placebo-controlled trial of lithium in ART-treated individuals with moderate or severe HAND. We assayed markers at baseline and 24 weeks across several pathways hypothesized to be affected by HIV, inflammation, or degeneration. Investigated biomarkers included dopamine, BDNF, neurofilament light chain, and CD8+ lymphocyte activation (CD38+ HLADR+). Alzheimer's Disease (AD) biomarkers included soluble amyloid precursor protein alpha and beta (sAPPα/β), Aβ38, 40, 42, and ten other biomarkers validated as predictors of mild cognitive impairment and progression in previous studies. These include apolipoprotein C3, pre-albumin, α1-acid glycoprotein, α1-antitrypsin, PEDF, CC4, ICAM-1, RANTES, clusterin, and cystatin c. We recruited 61 participants (placebo = 31; lithium = 30). The age baseline mean was 40 (±8.35) years and the median CD4+ T-cell count was 498 (IQR: 389 – 651) cells/μL. Biomarker concentrations between groups did not differ at baseline. However, both groups' blood dopamine levels decreased significantly after 24 weeks (adj. p< 002). No other marker was significantly different between groups, and we concluded that lithium did not confer neuroprotection following 24 weeks of treatment. However, the study was limited in duration and sample size.
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    Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence
    (BioMed Central Ltd, 2013) Rao, Vasudev; Neogi, Ujjwal; Talboom, Joshua; Padilla, Ligia; Rahman, Mustafizur; Fritz-French, Cari; Gonzalez-Ramirez, Sandra; Verma, Anjali; Wood, Charles; Ruprecht, Ruth; Ranga, Udaykumar; Azim, Tasnim; Joska, John; Eugenin, Eliseo; Shet, Anita; B
    BACKGROUND: HIV-1 Clade C (Subtype C; HIV-1C) is responsible for greater than 50% of infections worldwide. Unlike clade B HIV-1 (Subtype B; HIV-1B), which is known to cause HIV associated dementia (HAD) in approximately 15% to 30% of the infected individuals, HIV-1C has been linked with lower prevalence of HAD (0 to 6%) in India and Ethiopia. However, recent studies report a higher prevalence of HAD in South Africa, Zambia and Botswana, where HIV-1C infections predominate. Therefore, we examined whether Southern African HIV-1C is genetically distinct and investigated its neurovirulence. HIV-1 Tat protein is a viral determinant of neurocognitive dysfunction. Therefore, we focused our study on the variations seen in tat gene and its contribution to HIV associated neuropathogenesis. RESULTS: A phylogenetic analysis of tat sequences of Southern African (South Africa and Zambia) HIV isolates with those from the geographically distant Southeast Asian (India and Bangladesh) isolates revealed that Southern African tat sequences are distinct from Southeast Asian isolates. The proportion of HIV1C variants with an intact dicysteine motif in Tat protein (C30C31) was significantly higher in the Southern African countries compared to Southeast Asia and broadly paralleled the high incidence of HAD in these countries. Neuropathogenic potential of a Southern African HIV-1C isolate (from Zambia; HIV-1C1084i), a HIV-1C isolate (HIV-1IndieC1) from Southeast Asia and a HIV-1B isolate (HIV-1ADA) from the US were tested using in vitro assays to measure neurovirulence and a SCID mouse HIV encephalitis model to measure cognitive deficits. In vitro assays revealed that the Southern African isolate, HIV-1C1084i exhibited increased monocyte chemotaxis and greater neurotoxicity compared to Southeast Asian HIV-1C. In neurocognitive tests, SCID mice injected with MDM infected with Southern African HIV-1C1084i showed greater cognitive dysfunction similar to HIV-1B but much higher than those exposed to Southeast Asian HIV1C. CONCLUSIONS: We report here, for the first time, that HIV-1C from Southern African countries is genetically distinct from Southeast Asian HIV-1C and that it exhibits a high frequency of variants with dicysteine motif in a key neurotoxic HIV protein, Tat. Our results indicate that Tat dicysteine motif determines neurovirulence. If confirmed in population studies, it may be possible to predict neurocognitive outcomes of individuals infected with HIV-1C by genotyping Tat.
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    Comparing dedicated and designated models of integrating mental health into chronic disease care: study protocol for a cluster randomized controlled trial
    (BioMed Central, 2018-03-16) Myers, Bronwyn; Lund, Crick; Lombard, Carl; Joska, John; Levitt, Naomi; Butler, Christopher; Cleary, Susan; Naledi, Tracey; Milligan, Peter; Stein, Dan J; Sorsdahl, Katherine
    Background In low- and middle-income countries (LMIC), it is uncertain whether a “dedicated” approach to integrating mental health care (wherein a community health worker (CHW) has the sole responsibility of delivering mental health care) or a “designated” approach (wherein a CHW provides this service in addition to usual responsibilities) is most effective and cost-effective. This study aims to compare the effectiveness and cost-effectiveness of these two models of service integration relative to treatment as usual (TAU) for improving mental health and chronic disease outcomes among patients with HIV or diabetes. Methods/Design This is a cluster randomised trial. We will randomise 24 primary health care facilities in the Western Cape Province of South Africa to one of three study arms. Within each cluster, we will recruit 25 patients from HIV and 25 from diabetes services for a total sample of 1200 participants. Eligible patients will be aged 18 years or older, take medication for HIV or diabetes, and screen positive on the Alcohol Use Disorder Identification Test for hazardous/harmful alcohol use or depression on the Centre for Epidemiology Scale on Depression. Participants recruited in clinics assigned to the designated or dedicated approach will receive three sessions of motivational interviewing and problem-solving therapy, while those recruited at TAU-assigned clinics will be referred for further assessment. Participants will complete an interviewer-administered questionnaire at baseline, and at 6 and 12 months post-enrolment to assess change in self-reported outcomes. At these end points, we will test HIV RNA viral load for participants with HIV and HbA1c levels for participants with diabetes. Primary outcomes are reductions in self-reported hazardous/harmful alcohol use and risk of depression. Secondary outcomes are improvements in adherence to chronic disease treatment, biomarkers of chronic disease outcomes, and health-related quality of life. Mixed-effect linear regression models will model the effect of the interventions on primary and secondary outcomes. The cost-effectiveness of each approach will be assessed using incremental cost-effectiveness ratios. Discussion Study findings will guide decision-making around how best to integrate mental health counselling into chronic disease care in a LMIC setting. Trial registration Pan African Clinical Trials Registry, Trial registration number: ACTR201610001825403 . Registered 17 October 2016.
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    Comparing the accuracy of brief versus long depression screening instruments which have been validated in low and middle income countries: a systematic review
    (BioMed Central Ltd, 2012) Akena, Dickens; Joska, John; Obuku, Ekwaro; Amos, Taryn; Musisi, Seggane; Stein, Dan
    BACKGROUND: Given the high prevalence of depression in primary health care (PHC), the use of screening instruments has been recommended. Both brief and long depression screening instruments have been validated in low and middle income countries (LMIC), including within HIV care settings. However, it remains unknown whether the brief instruments validated in LMIC are as accurate as the long ones. METHODS: We conducted a search of PUBMED, the COCHRANE library, AIDSLINE, and PSYCH-Info from their inception up to July 2011, for studies that validated depression screening instruments in LMIC. Data were extracted into tables and analyzed using RevMan 5.0 and STATA 11.2 for the presence of heterogeneity. RESULTS: Nineteen studies met our inclusion criteria. The reported prevalence of depression in LMIC ranged from 11.1 to 53%. The area under curve (AUC) scores of the validated instruments ranged from 0.69-0.99. Brief as well as long screening instruments showed acceptable accuracy (AUC[greater than or equal to]0.7). Five of the 19 instruments were validated within HIV settings. There was statistically significant heterogeneity between the studies, and hence a meta-analysis could not be conducted to completion. Heterogeneity chi-squared = 189.23 (d.f. = 18) p<.001. CONCLUSION: Brief depression screening instruments in both general and HIV-PHC are as accurate as the long ones. Brief scales may have an edge over the longer instruments since they can be administered in a much shorter time. However, because the ultra brief scales do not include the whole spectrum of depression symptoms including suicide, their use should be followed by a detailed diagnostic interview.
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    Correlates of Attention Deficit/Hyperactivity Disorder (ADHD) among children in a clinical psychiatric center in Northern Nigeria
    (2011) Sale, Shehu; Joska, John
    This study primarily aims at determining the correlates of Attention Deficit Hyperactivity Disorder (ADHD) among children and adolescents in Northern Nigeria. The secondary aims of the study include a comparison of the identified correlates with results from other developing countries and the developed nations. The results would also provide a rational basis for advocating preventive measures for targeted problems associated with ADHD in the study.
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    Does distress predict central sensitisation in people living with HIV?
    (2023) Mqadi, Luyanduthando; Joska, John
    Background Persistent pain is a frequent complaint associated with compromised mental health in many people with HIV (PWH). Central sensitisation (CS) is a hallmark of most persistent pain conditions. Pain and psychosocial distress (PSD) appear to have a bidirectional relationship. Therefore, it is plausible that PSD contributes to pain by increasing central sensitisation (CS), thus maintaining pain in PWH; however, this hypothesis has not been tested. Experimentally induced secondary hyperalgesia (SH) has been used in the laboratory study of other pain conditions (e.g., neuropathic pain) to increase understanding of CS mechanisms. Therefore, the model of SH is useful for investigating pain related to CS, such as pain associated with HIV. NMDA antagonists are often used to prevent and treat pain associated with CS based on the evidence from animal and human pain studies. Evidence suggests that NMDA antagonists likely target mechanisms underlying clinical pain, specifically wind-up, allodynia and hyperalgesia. However, the effect of NMDA antagonists on SH is under-recognised and poorly understood. Understanding the effect of NMDA antagonists on SH would help to inform the appropriate matching of treatment to individuals. We conducted two studies. First, a systematic review according to PRISMA guidelines on the existing evidence that targeting the NMDA system alters experimentally induced SH, in healthy human participants. Second, we conducted an experimental study to investigate whether distress predicted central sensitisation in people living with HIV (PWH). Methods Systematic review: The influence of NMDA targeting pharmacological manipulations on experimentally induced SH in healthy human adults without clinical pain We identified studies that recruited healthy, pain-free human participants and experimentally induced SH (magnitude of SH, surface area of SH) and used a pharmacological method known to target the NMDA system to manipulate SH. Studies were identified by searching various electronic databases (conducted on the 24th of June 2019, updated on the 29th of September 2022). We also checked reference lists and contacted experts in the field, including authors who have recently published narrative reviews on experimental induction and manipulation of SH, to identify studies missed through electronic searching. We included studies that were published and in-press or accepted records with titles, abstracts, and full-text versions available in English. Authors were asked to provide missing data where necessary. Two or more reviewers assessed the risk of bias, extracted data, and judged the quality of evidence (GRADE) of the included studies. Data analysis was performed by narrative summary, and if more than two studies were available for a given manipulation, data were included in the meta-analysis. Data were pooled in subgroups by study design and the type of manipulation (e.g., ketamine) for each outcome (magnitude of secondary hyperalgesia, area of secondary hyperalgesia, or both). We generated funnel plots to examine publication bias. Experimental study: Does distress predict central sensitisation in PWH? We aimed to investigate the relationships between PSD, SH (a known human surrogate model of CS), and persistent pain in PWH. We recruited consenting adults with well controlled HIV, reporting either persistent pain or no pain (assessed using a modified Brief Pain Inventory). Participants provided self-reports of PSD severity (on the Hopkins 25-item scale). We used high-frequency electrical stimulation to induce SH on one pain-free forearm and assessed the surface area (primary outcome) and magnitude (secondary outcome) of SH using a von Frey filament and ‘pinprick' rods, respectively. It was hypothesised that the surface area and magnitude of experimentally induced SH would be positively associated with PSD severity (hypothesis 1) and that the persistent pain group would have a greater surface area and magnitude of experimentally induced SH than the group without pain (hypothesis 2). Results Systematic review: The influence of NMDA targeting pharmacological manipulations on experimentally induced SH in healthy human adults without clinical pain Twenty-nine records were included in this review. Some records reported multiple manipulation methods, so each yielded multiple datasets. Therefore, the 29 records yielded 52 datasets. The effect of NMDA antagonists on experimentally induced SH was assessed by change in magnitude of SH in three records (4 of 52 studies) and assessed by surface area of SH in 20 records (37 of 52 studies). Six records (11 of 52 studies) assessed by change in surface area of SH. Six records (11 of 52 studies) assessed both the change in magnitude and surface area of SH in response to NMDA antagonist administration. Narrative summary Twelve studies manipulated the magnitude of SH using ketamine alone (n = 10) or combined with alfentanil (n = 2). Seven reported no effect, and three found a decrease in the magnitude of SH. Combining ketamine and alfentanil had no effect on the magnitude of SH. Thirty-five studies manipulated the surface area of SH using ketamine alone (n = 31) or combined with alfentanil (n =2), morphine (n = 1) or remifentanil (n = 1). Of those using ketamine alone, fifteen reported no effect, and sixteen found a decrease in the surface area of SH. Combining ketamine with alfentanil or morphine had no effect on the surface area of SH; however, the combination of ketamine and remifentanil decreased the surface area of SH. Ten studies manipulated the surface area of SH using dextromethorphan alone (n = 8) or combined with morphine (n = 2). Four of those using dextromethorphan alone reported no effect, and the rest reported a decrease in the surface area of SH. Those who combined dextromethorphan with morphine reported no effect (n=1) or a decrease (n=1) in the surface area of SH. Studies that used CH3381 (n = 1) or neramexane (n = 1) reported a decrease in the surface area of SH. One study that used magnesium sulphate found no effect of magnesium on the surface area of SH. Meta-analysis Forty studies (seven assessing the magnitude of SH) were included in the meta-analysis. Ketamine had no effect on the magnitude of SH. Similarly, ketamine, CHF3381, and dextromethorphan had no effect on the surface area of SH. Experimental study: Does distress predict central sensitisation in PWH? There was a positive relationship between PSD severity and the surface area of SH; however, the surface area was not predicted by pain status. There was no relationship between PSD severity and the magnitude of SH. Our plots suggested that the ‘pain' group had a stronger positive relationship between PSD and the magnitude of SH than the ‘no pain' group. However, we couldn't confirm this because we couldn't find a suitable statistical model. The proportion of participants reporting pain developed a greater magnitude of SH than those without pain. In contrast, the proportion of participants without pain developed a greater surface area of SH than those with pain. Conclusion Systematic review: The influence of NMDA targeting pharmacological manipulations on experimentally induced SH in healthy human adults without clinical pain The results of this study indicate that NMDA antagonists have no effect on the surface area or magnitude of experimentally induced SH. These findings carry important implications for clinical practice, highlighting the limited efficacy of NMDA antagonists in modulating SH. Future studies should explore alternative pharmacological and non-pharmacological interventions to assess their potential in modulating SH and optimising patient outcomes. Experimental study: Does distress predict central sensitisation in PWH? Psychosocial distress predicted the surface area but not the magnitude of SH in individuals living with HIV, independent of pain status. The positive relationship between the surface area of SH and PSD may support targeting of PSD to reduce pain. Specifically, interventions aimed at reducing PSD may hold therapeutic potential in addressing SH. Future studies should explore the effects of distressreducing therapy on clinical SH.
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    Factors associated with psychological distress among youth and adults living with HIV in South Africa
    (2023) Ncitakalo, Nolusindiso; Joska, John
    Background Mental disorders represent a growing public health challenge globally. Evidence shows that mental disorders like depression and anxiety are more prevalent in people living with HIV (PLHIV) than in the general population. South Africa carries the world's heaviest burden with 7.9 million people (14% of the population) living with HIV in 2017. However, there is limited literature on mental health disorders among PLHIV in South Africa particularly populationbased cross-sectional studies, as most available evidence of mental disorders among PLHIV is from small-scale studies. Studies have shown the relationship between mental disorders and HIV to be complex and bidirectional. The bidirectional nature of the relationship between mental disorders and HIV implies a complex relationship between factors associated with both health conditions where they co-exist. Improved understanding of the relationship between mental disorders, HIV and associated factors is important for designing interventions to mitigate the impact of both conditions among coinfected individuals. In epidemiological surveys, the presence of common mental disorders may be measured in terms of caseness or through a set of defined questions known as an instrument or scale. While there is a relationship between psychological distress, depressive and the anxiety symptoms, psychological distress scales are usually slightly broad but capture construct. Studies that are attempting to describe the prevalence of anxiety and depression sometimes use measures of psychological distress as a proxy. In large epidemiological surveys, psychological distress measures are used, as opposed to smaller and clinical studies. Similarly for this study, psychological distress was measured by both depressive and anxiety symptoms. Aim and objectives The aim of this study was to explore the extent and effect of psychological distress among youth and adults with HIV in South Africa. The specific objectives were as follows: 1) To conduct a systematic review and meta-analysis of studies on prevalence and correlates of depressive and anxiety symptoms among PLHIV in Southern Africa; 2) To determine the prevalence of depressive and anxiety symptoms and associated risk factors among PLHIV in South Africa; 3) To explore the relationship between HIV-related stigma and psychological vi distress among PLHIV in South Africa; 4) To explore the complex pathways linking HIV status as a mediator in the relationship of psychological distress with socio‑demographic and health related factors in South Africa. Methodology Different sub-samples were used for each paper, depending on the focus or aim of the paper. For the first objective, the systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. To fulfil the second objective, descriptive statistics were used to summarize background characteristics of the study sample and the prevalence of psychological distress. Bivariate logistic regression analysis were used to assess the relationship between psychological distress and each explanatory variable. Additionally, statistically significant variables were entered into a multivariate logistic regression analysis to identify factors independently associated with psychological distress. For the third objective, bivariate and multivariate logistic regression models were used to identify factors associated with stigma among PLHIV with psychological distress. Lastly, generalised structural equation modelling (G-SEM) path analysis was used to explore the direct and indirect relationships of socio-demographic, health and HIV-related factors with psychological distress using HIV status as a mediator. Findings The results of this study were published in four papers, which constitute Chapters 2, 3, 4 and 5. Chapter 2, in the systematic review a total of 27 articles met the eligibility criteria out of the 467 articles. The overall pooled prevalence for depression was 23%, and anxiety was 15%. Prevalence of depressive and anxiety symptoms was significantly higher among females, separated or widowed, unemployed and older age. Additionally, depressive and anxiety symptoms were significantly associated with low income, low education, urban residence, low physical activity, violence and/or partner conflict exposure, lack of social support, stigma and alcohol in PLHIV. In Chapter 3, the prevalence of psychological distress was significantly higher among females (38.2%) than males (28.5%). Psychological distress was significantly associated with being female, low socio-economic conditions, low educational attainment, marital status (being divorced/ separated), unemployment, having chronic conditions, hazardous alcohol drinking and low social support. In Chapter 4, the findings showed that psychological distress among HIV positive individuals was 34.4% and of these, 37.9% vii experienced high levels of HIV-related stigmatizing attitudes. Stigmatizing attitudes among PLHIV were significantly associated with no schooling/primary level education, incorrect knowledge about HIV and myths about HIV and never testing for HIV. In Chapter 5, the HIV positive status was shown to be a mediating factor. Psychological distress was significantly associated with female gender, not being married, having no education/primary level education, reproductive age group 25–49 years, 50 years and older, residing in urban areas, high risk drinkers, hazardous drinkers, ever testing for HIV and reporting of fair /poor selfrated health. Conclusion The systematic review and secondary analysis of the nationally representative populationbased household survey confirmed that psychological distress, as measured by depressive and anxiety symptoms was associated with specific socio-demographic, socio-behavioural and HIV-related factors including stigma among PLHIV in South Africa. The findings also suggest that HIV positive status was a mediating factor in the relationship between psychological distress and identified covariates. These findings highlight the importance of integrated screening and management of psychological distress and HIV. Furthermore, the findings underscore the need for highly targeted interventions tailored for identified groups of PLHIV. Lastly, more longitudinal studies are needed to track changes and trends over time on factors associated with mental disorders and HIV and the impact of respective interventions.
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    Integrating HIV-associated neurocognitive impairment screening and health services within primary healthcare facilities in South Africa
    (2023) Munsami, Adele Delysia; Joska, John; Nightingale Sam
    Despite widespread availability of effective antiretroviral therapy (ART), people living with HIV (PWH) remain at risk of developing comorbidities including HIV-associated neurocognitive impairment (H-NCI). These individuals may then be at an increased risk for treatment non-adherence, which leads to poor quality of life and early mortality. Despite this risk, there is a paucity in trained professionals in low- and middle-income countries with appropriate knowledge and skills to identify H-NCI and make appropriate referrals for additional confirmatory testing or intervention, depending on the severity and context of the screening. General medical doctors, nurses and adherence counsellors provide most HIV related healthcare services at a primary healthcare level in South Africa. However, awareness of the clinical presentation of H-NCI, and their current screening practices among these cadres, is unclear. To address these knowledge gaps this thesis set out to explore the following aims (1) examine existing H-NCI knowledge and practices among healthcare workers delivering HIV services in South Africa, (2) develop an appropriate H-NCI training programme for primary healthcare workers, and (3) lastly, pilot the H-NCI training to determine whether H-NCI screening would be feasible at a primary healthcare level in South Africa. Methods To achieve these objectives, the study was divided into two phases. In phase one, a scoping review identified and summarised published studies addressing brain and/or behaviour training approaches, including H-NCI, targeting frontline HIV healthcare workers in Africa. An online survey was developed and administered to examine existing H-NCI knowledge and current practices among healthcare workers providing HIV services in South Africa. Focus group discussions and in-depth interviews were then conducted to explore knowledge gaps, previous H-NCI training and healthcare workers' perspectives of screening at a primary healthcare level. In phase two, an H-NCI training curriculum was developed and a work-integrated H-NCI training programme targeting primary healthcare workers was piloted. The pilot training assessed knowledge of H-NCI signs and symptoms, healthcare workers' attitude toward and comfort with H-NCI screening tools and healthcare workers ability to accurately administer an H-NCI screening tool. The assessments were repeated two months post-training to evaluate retention of knowledge and skills. Results The scoping review of the existing literature suggested that there were few brain and/ or behaviour training programs targeting healthcare workers providing HIV services in Africa. Of the ten studies identified in the scoping review, one study included H-NCI in the training curriculum. The online survey found that H-NCI knowledge was limited and screening practices virtually non-existent among healthcare workers providing HIV care in South Africa. Qualitative data gathered during the focus group discussions and the in-depth interviews provided greater insight on the existing knowledge and practices gaps as well as highlighting that healthcare workers had not received training on H-NCI. The results from the qualitative investigations showed that primary healthcare workers were in favour of receiving such training. Overall, knowledge of H-NCI improved among primary healthcare workers following the work-integrated H-NCI training programme. The training demonstrated that primary healthcare workers providing clinical services, such as medical doctors or professional nurses were able to administer an H-NCI screening tool. Although knowledge of the clinical presentation of H-NCI improved among adherence counsellors, these healthcare workers experienced challenges in administering the H-NCI screening tool. Conclusion As a body of work, the findings from this thesis suggest that healthcare professionals providing HIV services in South Africa have limited knowledge to identify H-NCI, and screening practices are uncommon. Although training revealed differences between cadres in administering screening tools, healthcare workers providing clinical care, including general medical doctors and professional nurses, may be able to provide H-NCI screening at routine annual visits. Although adherence counsellors are ideally situated in the clinic flow to provide targeted screening by flagging clinical presentation of H-NCI among PWH accessing care, this cadre will require additional training, mentorship and support to successfully administer H-NCI screening tools. However, the feasibility of H-NCI screening at a primary healthcare, timing and nature of any screening remains to be explored. This body of work is a step toward increasing the availability of skilled healthcare workers with appropriate knowledge and skills to screen and identify H-NCI in low- and middle-income countries. The work presented in this thesis provides a foundation for further development of the H-NCI training module and future investigations examining targeted screening strategies at a primary healthcare level, feasibility and access to existing interventions post-screening
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    Neuropsychiatric profile of a cohort of perinatally infected HIV positive children after one year of antiretroviral medication
    (2012) Nassen, René; Joska, John; Ward, Catherine L
    The Highly Active Antiretroviral Therapy (HAART) era in the mid-nineties signalled a dramatic change in the long-term outcome of Human Immunodeficiency Virus (HIV). Many children have shown significant neurologic benefit, and in particular, a decline in the incidence of HIV encephalopathy. As increasing numbers of children have survived into adolescence and early adulthood new challenges have arisen, such as the detection and characterization of milder forms of HIV-associated neurocognitive deficits in children previously thought to be asymptomatic...
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    Neuropsychological outcomes in adults commencing highly active anti-retroviral treatment in South Africa: a prospective study
    (BioMed Central Ltd, 2012) Joska, John; Westgarth-Taylor, Jennifer; Hoare, Jacqueline; Thomas, Kevin; Paul, Robert; Myer, Landon; Stein, Dan
    BACKGROUND:Infection with HIV may result in significant neuropsychological impairment, especially in late stage disease. To date, there have been no cohort studies of the impact of highly active anti-retroviral treatment (HAART) in South Africa where clade C HIV is predominant. METHODS: Participants in the current study were recruited from a larger study of HIV-associated neurocognitive disorders (HAND) and included a group of individuals commencing HAART (n = 82). Baseline and one-year neuropsychological function was assessed using a detailed battery, and summary global deficit scores (GDS) obtained. Associations with change in GDS were calculated. RESULTS: Participants had a median CD4 cell count of 166 at baseline and 350 at follow-up. There were significant difference across groups of GDS severity at baseline with respect to level of education and GDS change at one year (p = 0.00 and 0.00 respectively). Participants with severe impairment at baseline improved significantly more than those with lesser degrees of impairment. Significant improvements were observed in the domains of attention, verbal fluency, motor function, and executive functions. There were unadjusted associations between GDS change and male gender, lower levels of education, baseline CD4 count and baseline GDS severity. In an adjusted model, only baseline GDS severity (p = 0.00) remained significant, with a lower level of education nearing significance (p = 0.05). The overall model was highly significant (p = 00; r-squared = 0.58).DISCUSSION:In individuals in late stage HIV commencing HAART in South Africa, those with severe baseline neuropsychological impairment improved significantly more than those less impaired. While improvement across a number of neuropsychological domains was observed, high rates of impairment persisted. CONCLUSIONS: The effects of HAART and participant variables, such as test experience, require clarification. Studies with larger comparison groups, and where HIV disease characteristics are needed to establish whether the trends we identified are clinically meaningful.
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    Normative scores for a brief neuropsychological battery for the detection of HIV-associated neurocognitive disorder (HAND) among South Africans
    (BioMed Central Ltd, 2010) Singh, Dinesh; Joska, John; Goodkin, Karl; Lopez, Enrique; Myer, Landon; Paul, Robert; John, Sally; Sunpath, Henry
    BACKGROUND:There is an urgent need to more accurately diagnose HIV-associated neurocognitive disorder (HAND) in Africa. Rapid screening tests for HIV-associated dementia are of limited utility due to variable sensitivity and specificity. The use of selected neuropsychological tests is more appropriate, but norms for HIV seronegative people are not readily available for sub-Saharan African populations. We sought to derive normative scores for two commonly used neuropsychological tests that generate four test scores -- namely the Trail-Making Test (Parts A and B) and the Digit Span Test [Forward (DSF) and Backward (DSB)]. To assess memory and recall, we used the memory item of the International HIV Dementia Scale (IHDS).FINDINGS:One hundred and ten HIV seronegative participants were assessed at McCord Hospital, Durban, South Africa between March 3rd and October 31st, 2008. We excluded people with major depressive disorder, substance use abuse and dependence and head injuries (with or without loss of consciousness). All the participants in this study were African and predominantly female with an average age of 28.5 years and 10 years of education. Age and gender influenced neuropsychological functioning, with older people performing worse. The effect of gender was not uniform across all the tests. CONCLUSION: These two neuropsychological tests can be administered with the IHDS in busy antiretroviral clinics. Their performance can be measured against these norms to more accurately diagnose the spectrum and progression of HAND.
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    Simulating therapeutic drug monitoring results for dose individualisation to maintain investigator blinding in a randomised controlled trial
    (BioMed Central, 2017-06-07) Lesosky, Maia; Joska, John; Decloedt, Eric
    Background: Therapeutic drug monitoring (TDM) is essential practice when dosing drugs with a narrow therapeutic index in order to achieve a plasma drug concentration within a narrow target range above the efficacy concentration but below the toxicity concentration. However, TDM with dose individualisation is challenging during a double-blind clinical trial with laboratory staff and investigators blinded to treatment arm allocation. Methods: Drug concentrations were simulated for participants in the placebo arm by an unblinded independent statistician, utilising the measured values from the treatment arm participants. Simulated and actual concentrations were re-blinded and passed on to a dose-adjusting investigator, who made dose adjustment recommendations but was not directly responsible for clinical care of participants. Results: A total of 257 sham lithium plasma concentrations were simulated utilising 242 true lithium plasma concentrations in real time as the trial progressed. The simulated values had a median (interquartile range) of 0.59 (0.46, 0.72) compared to 0.53 (0.39, 0.72) in the treatment arm. Blinding of the laboratory staff and dose-adjusting investigator was maintained successfully. Conclusions: We succeeded in simulating sham lithium plasma concentrations while maintaining blinding. Our simulated values have a smaller range than the observed data, which can be explained by the challenges with respect to drug adherence and dose timing that were experienced. Trial registration: Pan African Clinical Trials Registry, PACTR201310000635418. Registered on 30 August 2013.
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    Task sharing of a psychological intervention for maternal depression in Khayelitsha, South Africa: study protocol for a randomized controlled trial
    (BioMed Central, 2014-11-21) Lund, Crick; Schneider, Marguerite; Davies, Thandi; Nyatsanza, Memory; Honikman, Simone; Bhana, Arvin; Bass, Judith; Bolton, Paul; Dewey, Michael; Joska, John; Kagee, Ashraf; Myer, Landon; Petersen, Inge; Prince, Martin; Stein, Dan J; Thornicroft, Graham; Tomlinson, Mark; Alem, Atalay; Susser, Ezra
    Background: Maternal depression carries a major public health burden for mothers and their infants, yet there is a substantial treatment gap for this condition in low-resourced regions such as sub-Saharan Africa. To address this treatment gap, the strategy of “task sharing” has been proposed, involving the delivery of interventions by non-specialist health workers trained and supervised by specialists in routine healthcare delivery systems. Several psychological interventions have shown benefit in treating maternal depression, but few have been rigorously evaluated using a task sharing approach. The proposed trial will be the first randomised controlled trial (RCT) evaluating a task sharing model of delivering care for women with maternal depression in sub-Saharan Africa. The objective of this RCT is to determine the effectiveness and cost-effectiveness of a task sharing counseling intervention for maternal depression in South Africa. Methods/Design: The study is an individual-level two-arm RCT. A total of 420 depressed pregnant women will be recruited from two ante-natal clinics in a low-income township area of Cape Town, using the Edinburgh Postnatal Depression Scale to screen for depression; 210 women will be randomly allocated to each of the intervention and control arms. The intervention group will be given six sessions of basic counseling over a period of 3 to 4 months, provided by trained community health workers (CHW)s. The control group will receive three monthly phone calls from a CHW trained to conduct phone calls but not basic counseling. The primary outcome measure is the 17-Item Hamilton Depression Rating Scale (HDRS-17). The outcome measures will be applied at the baseline assessment, and at three follow-up points: 1 month before delivery, and 3 and 12 months after delivery. The primary analysis will be by intention-to-treat and secondary analyses will be on a per protocol population. The primary outcome measure will be analyzed using linear regression adjusting for baseline symptom severity measured using the HDRS-17. Discussion: The findings of this trial can provide policy makers with evidence regarding the effectiveness and cost-effectiveness of structured psychological interventions for maternal depression delivered by appropriately trained and supervised non-specialist CHWs in sub-Saharan Africa. Trial registration Clinical Trials (ClinicalTrials.gov): NCT01977326 , registered on 24/10/2013; Pan African Clinical Trials Registry ( http://www.pactr.org ): PACTR201403000676264 , registered on 11/10/2013.