Barriers and Facilitators to Effective Implementation of the NAMWEZA Intervention in Dar es Salaam, Tanzania.

The NAMWEZA intervention was implemented, using a ten-session group format, to build skills targeting psychosocial vulnerabilities and enhancing HIV prevention among people living with HIV (PLH) and their social networks. The overall goal of this intervention is to improve psychological wellbeing and reduce HIV risk behaviours. These analyses aim to describe the barriers and facilitators of implementing the NAMWEZA intervention from the perspective of participants and trained peer group facilitators. Twenty-four in-depth interviews were conducted with NAMWEZA participants, and 50 pooled peer facilitator self-assessment reports were obtained from 16 trained peers. Participants identified personal and structural barriers, including fear of inadvertent HIV status disclosure, time constraints, level of participant reimbursements, and limited space available for group sessions. Factors facilitating effective implementation included perceived benefits of the program, such as reduction in HIV-related risk behaviours, increased self-esteem, and improvement in confidence in HIV prevention communications. Scaling up the NAMWEZA intervention to other areas of Tanzania or regionally should take into account these facilitators and barriers to implementation.

Rigorous Clinical Trial Design in Public Health Emergencies Is Essential.

Randomized clinical trials are the most reliable approaches to evaluating the effects of new treatments and vaccines. During the 2014-2015 West African Ebola epidemic, many argued that such trials were neither ethical nor feasible in an environment of limited health infrastructure and severe disease with a high fatality rate. Consensus among the numerous organizations providing help to the affected areas was never achieved, resulting in fragmented collaboration, delayed study initiation, and ultimately failure to provide definitive evidence on the efficacy of treatments and vaccines. Randomized trials were in fact approved by local ethics boards and initiated, demonstrating that randomized trials, even in such difficult circumstances, are feasible. Improved planning and collaboration among research and humanitarian organizations, and affected communities, in the interepidemic periods are needed to ensure that questions regarding the efficacy of vaccines and treatments can be definitively answered during future public health emergencies.

Building clinical pharmacology laboratory capacity in low- and middle-income countries: Experience from Uganda.

Background: Research and clinical use of clinical pharmacology laboratories are limited in low- and middle-income countries. We describe our experience in building and sustaining laboratory capacity for clinical pharmacology at the Infectious Diseases Institute, Kampala, Uganda. Intervention: Existing laboratory infrastructure was repurposed, and new equipment was acquired. Laboratory personnel were hired and trained to optimise, validate, and develop in-house methods for testing antiretroviral, anti-tuberculosis and other drugs, including 10 high-performance liquid chromatography methods and four mass spectrometry methods. We reviewed all research collaborations and projects for which samples were assayed in the laboratory from January 2006 to November 2020. We assessed laboratory staff mentorship from collaborative relationships and the contribution of research projects towards human resource development, assay development, and equipment and maintenance costs. We further assessed the quality of testing and use of the laboratory for research and clinical care. Lessons learnt: Fourteen years post inception, the clinical pharmacology laboratory had contributed significantly to the overall research output at the institute by supporting 26 pharmacokinetic studies. The laboratory has actively participated in an international external quality assurance programme for the last four years. For clinical care, a therapeutic drug monitoring service is accessible to patients living with HIV at the Adult Infectious Diseases clinic in Kampala, Uganda. Recommendations: Driven primarily by research projects, clinical pharmacology laboratory capacity was successfully established in Uganda, resulting in sustained research output and clinical support. Strategies implemented in building capacity for this laboratory may guide similar processes in other low- and middle-income countries.

Infectious Diseases Institute at Makerere University College of Health Sciences: a case study of a sustainable capacity building model for health care, research and training.

The Infectious Diseases Institute (IDI), established in 2001, was the first autonomous institution of Makerere University set up as an example of what self-governing institutes can do in transforming the academic environment to become a rapidly progressive University addressing the needs of society This paper describes the success factors and lessons learned in development of sustainable centers of excellence to prepare academic institutions to respond appropriately to current and future challenges to global health. Key success factors included a) strong collaboration by local and international experts to combat the HIV pandemic, along with b) seed funding from Pfizer Inc., c) longstanding collaboration with Accordia Global Health Foundation to create and sustain institutional strengthening programs, d) development of a critical mass of multi-disciplinary research leaders and managers of the center, and e) a series of strong directors who built strong governance structures to execute the vision of the institute, with subsequent transition to local leadership. Conclusion: Twenty years of sustained investment in infrastructure, human capital, leadership, and collaborations present Makerere University and the sub-Saharan Africa region with an agile center of excellence with preparedness to meet the current and future challenges to global health.

A CD4(+) T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease.

Many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection. Here we report a peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease. The assay detects interferon-gamma-secreting CD4(+) T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR types. The correlation was observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells. These findings provide direct evidence for a protective role for CD4(+) T cells in humans, and a precise target for the design of improved vaccines against P. falciparum.

A Focus on the Reminiscence Bump to Personalize Music Playlists for Dementia.

PURPOSE: Music and memory are inextricably linked, and the recollection of music varies according to age. In order to create personalized music playlists tailored for people living with dementia, this study aimed to determine the age at which healthy individuals could best recall music that was popular at the time. METHODS: A survey was designed asking participants to identify the number of songs they recalled from a random selection of 10 from the 100 most popular songs from each year, presented in random order of years, from 1945 to 2015. Of the 311 individuals born between 1929 and 2002, who responded to the survey, 157 met the inclusion criteria. RESULTS: The median peak of recollection was between the ages of 13 and 19 across all age-cohorts, with participants recalling a maximum median number of 6-8 songs in all of the age-cohorts. There was no evidence of a difference in the peak age of recollection between those who recognized seven or more songs in at least 1 year and those who recognized fewer than seven songs in all years. CONCLUSION: The peak of recollection of popular music occurs in the teenage years, regardless of era of birth. Music from this "reminiscence bump" provides a rich source of retained music that should be tapped when creating playlists of meaningful music for people living with dementia.

Evaluating spillover of HIV knowledge from study participants to their network members in a stepped-wedge behavioural intervention in Tanzania.

OBJECTIVES: We aim to describe the social network members of participants of a behavioural intervention, and examine how the effects of the intervention may spillover among network members. DESIGN: Secondary analysis of a step-wedge randomised controlled trial. SETTING: Change agents (CAs) were recruited from waiting rooms of HIV treatment facilities in Dar es Salaam, Tanzania, and their network members (NMs) were recruited directly by CAs. PARTICIPANTS: We enrolled 662 CAs in an HIV behavioural intervention. They, along with 710 of their NMs, completed baseline and follow-up interviews from 2011 to 2013. PRIMARY AND SECONDARY OUTCOMES: The primary outcome of this study was change in NMs' HIV knowledge, and the secondary outcome was whether the NM was lost to follow-up. RESULTS: At baseline, many characteristics were different between NMs and CAs. We found a number of NM characteristics significantly associated with follow-up of NMs, particularly female gender (OR=1.64, 95% CI: 1.02 to 2.63) and HIV knowledge (OR=20.0, 95% CI: 3.70 to 125); only one CA variable was significantly associated with NM follow-up: having a private source of water (OR=2.17, 95% CI: 1.33 to 3.57). The 14.2% increase in NMs' HIV knowledge was largely due to CAs feeling empowered to pass on prior knowledge, rather than transmitting new knowledge to their NMs. CONCLUSIONS: Characteristics of social network members of persons living with HIV persons living with HIV may play a role in study retention. Additionally, the HIV knowledge of these NMs increased largely as a function of CA participation in the intervention, suggesting that intervening among highly-connected individuals may maximise benefits to the potential population for whom spillover can occur. TRIAL REGISTRATION NUMBER: Clinical Trial: NCT01693458; Post-results.

Agents of change: Comparing HIV-related risk behavior of people attending ART clinics in Dar es Salaam with members of their social networks.

The aim of the study is to compare sociodemographic characteristics, psychosocial factors, HIV knowledge and risk behaviors of people living with HIV (PLH) and their social network members (NMs) to inform HIV prevention programs that engage PLH as prevention educators in their communities. We compared baseline characteristics of PLH enrolled in an intervention to become HIV prevention Change Agents (CAs) (n = 458) and 602 NMs they recruited. CAs and NMs responded to questionnaires through a computer-driven interface with Audio Computer-Assisted Self Interview (ACASI) software. Although NMs scored higher on socio-economic status, self-esteem and general self-efficacy, they had lower HIV knowledge (AOR 1.5; 95% CI: 1.1-2.1), greater inconsistent condom use (AOR 3.2; 95% CI: 2.4-4.9), and recent experience as perpetrators of physical (AOR 2.5; 95% CI: 1.2-5.1) or sexual (AOR 4.1; 95% CI: 1.4-12.7) intimate partner violence; and as victims of physical (AOR 1.5; 95% CI: 1.0-2.3) or sexual (AOR 2.2; 95% CI: 1.3-3.8) forms of violence than CAs. Higher HIV knowledge and lower sexual risk behaviors among CAs suggest PLH's potential as communicators of HIV prevention information to NMs. CAs' training should also focus on improving self-esteem, general self-efficacy and social support to increase their potential effectiveness as HIV prevention educators and enhance their own overall health and well-being.

Training needs assessment for clinicians at antiretroviral therapy clinics: evidence from a national survey in Uganda.

BACKGROUND: To increase access to antiretroviral therapy in resource-limited settings, several experts recommend "task shifting" from doctors to clinical officers, nurses and midwives. This study sought to identify task shifting that has already occurred and assess the antiretroviral therapy training needs among clinicians to whom tasks have shifted. METHODS: The Infectious Diseases Institute, in collaboration with the Ugandan Ministry of Health, surveyed health professionals and heads of antiretroviral therapy clinics at a stratified random sample of 44 health facilities accredited to provide this therapy. A sample of 265 doctors, clinical officers, nurses and midwives reported on tasks they performed, previous human immunodeficiency virus training, and self-assessment of knowledge of human immunodeficiency virus and antiretroviral therapy. Heads of the antiretroviral therapy clinics reported on clinic characteristics. RESULTS: Thirty of 33 doctors (91%), 24 of 40 clinical officers (60%), 16 of 114 nurses (14%) and 13 of 54 midwives (24%) who worked in accredited antiretroviral therapy clinics reported that they prescribed this therapy (p<0.001). Sixty-four percent of the people who prescribed antiretroviral therapy were not doctors. Among professionals who prescribed it, 76% of doctors, 62% of clinical officers, 62% of nurses and 51% of midwives were trained in initiating patients on antiretroviral therapy (p=0.457); 73%, 46%, 50% and 23%, respectively, were trained in monitoring patients on the therapy (p=0.017). Seven percent of doctors, 42% of clinical officers, 35% of nurses and 77% of midwives assessed that their overall knowledge of antiretroviral therapy was lower than good (p=0.001). CONCLUSION: Training initiatives should be an integral part of the support for task shifting and ensure that antiretroviral therapy is used correctly and that toxicity or drug resistance do not reverse accomplishments to date.

Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis.

RATIONALE: Tuberculosis remains a major cause of morbidity and mortality in the developing world. A better understanding of the mechanisms of disease protection could allow novel strategies to disease management and control. OBJECTIVES: To identify human genomic loci with evidence of linkage to tuberculosis susceptibility and, within these loci, to identify individual genes influencing tuberculosis susceptibility. METHODS: Affected sibling pair analysis in South African and Malawian populations. Independent case-control study in West Africa. MEASUREMENTS AND MAIN RESULTS: Two novel putative loci for tuberculosis susceptibility are identified: chromosome 6p21-q23 and chromosome 20q13.31-33--the latter with the strongest evidence for any locus reported to date in human tuberculosis (single point LOD score of 3.1, P = 10(-4), with a maximum likelihood score [MLS] of 2.8). An independent, multistage genetic association study in West African populations mapped this latter region in detail, finding evidence that variation in the melanocortin 3 receptor (MC3R) and cathepsin Z (CTSZ) genes play a role in the pathogenesis of tuberculosis. CONCLUSIONS: These results demonstrate how a genomewide approach to the complex phenotype of human tuberculosis can identify novel targets for further research.

Agents of change among people living with HIV and their social networks: stepped-wedge randomised controlled trial of the NAMWEZA intervention in Dar es Salaam, Tanzania.

INTRODUCTION: NAMWEZA is a novel intervention that focuses on preventing HIV and promoting sexual and reproductive health and rights by addressing underlying factors related to vulnerability of acquiring HIV, such as depression, intimate partner violence (IPV) and stigma. The goal of the study was to evaluate the effect of the NAMWEZA intervention on risk behaviour as well as factors potentially contributing to this vulnerability for people living with HIV and their network members. METHODS: A stepped-wedge randomised controlled trial was conducted from November 2010 to January 2014 among people living with HIV and their network members in Dar es Salaam, Tanzania. 458 people living with HIV were randomised within age/sex-specific strata to participate in the NAMWEZA intervention at three points in time. In addition, 602 members of their social networks completed the baseline interview. Intention-to-treat analysis was performed, including primary outcomes of uptake of HIV services, self-efficacy, self-esteem, HIV risk behaviour and IPV. RESULTS: For people living with HIV, a number of outcomes improved with the NAMWEZA intervention, including higher self-efficacy and related factors, as well as lower levels of depression and stigma. IPV reduced by 40% among women. Although reductions in HIV risk behaviour were not observed, an increase in access to HIV treatment was reported for network members (72% vs 94%, p=0.002). CONCLUSION: These results demonstrate the complexity of behavioural interventions in reducing the vulnerability of acquiring HIV, since it is possible to observe a broad range of different outcomes. This study indicates the importance of formally evaluating interventions so that policymakers can build on evidence-based approaches to advance the effectiveness of HIV prevention interventions. TRIAL REGISTRATION NUMBER: NCT01693458.

HIV progression and predictors of mortality in a community-based cohort of Zambian adults.

This article describes immunological HIV progression, mortality, and its predictors in 974 Zambian adults. During 3138 person-years of follow-up, 281 deaths occurred, and the overall mortality rate was 9.0 per 100 person-years. Thirty-six percent of patients were dead within 5 years of enrollment. The median survival in patients with baseline CD4 count ≥500 cells/mm³ was 5.62 years, with CD4 count between 200 and 499 cells/mm³ 5.46 years, and with CD4 count <200 cells/mm³ 3.89 years. The mortality rate increased significantly with older age (6.9 in patients <25 years, 9.3 in individuals aged 25-39 years, 10.2 in patients ≥40 years) and was higher in women (rate ratio 1.29). The median annual change of progression markers was -29.6 cells/mm³ for CD4 count, -3.0% for CD4 count percentage, 1.2 nmol/L for neopterin, -1.9 g/L for hemoglobin, and -70 cells/mm³ for total lymphocyte count. Hemoglobin and neopterin were as accurate as CD4 count to predict mortality.

Longitudinal assessment of an ELISPOT test for Mycobacterium tuberculosis infection.

BACKGROUND: Very little longitudinal information is available regarding the performance of T cell-based tests for Mycobacterium tuberculosis infection. To address this deficiency, we conducted a longitudinal assessment of the enzyme-linked immunosorbent spot test (ELISPOT) test in comparison to the standard tuberculin skin test (TST). METHODS AND FINDINGS: In tuberculosis (TB) contacts we repeated ELISPOT tests 3 mo (n = 341) and 18 mo (n = 210) after recruitment and TSTs at 18 mo (n = 130). We evaluated factors for association with conversion and reversion and investigated suspected cases of TB. Of 207 ELISPOT-negative contacts, 51 (24.6%) had 3-mo ELISPOT conversion, which was associated with a positive recruitment TST (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.0-5.0, p = 0.048) and negatively associated with bacillus Calmette-Guérin (BCG) vaccination (OR 0.5, 95% CI 0.2-1.0, p = 0.06). Of 134 contacts, 54 (40.2%) underwent 3-mo ELISPOT reversion, which was less likely in those with a positive recruitment TST (OR 0.3, 95% CI 0.1-0.8, p = 0.014). Between 3 and 18 mo, 35/132 (26.5%) contacts underwent ELISPOT conversion and 28/78 (35.9%) underwent ELISPOT reversion. Of the 210 contacts with complete results, 73 (34.8%) were ELISPOT negative at all three time points; 36 (17.1%) were positive at all three time points. Between recruitment and 18 mo, 20 (27%) contacts had ELISPOT conversion; 37 (50%) had TST conversion, which was associated with a positive recruitment ELISPOT (OR 7.2, 95% CI 1.4-37.1, p = 0.019); 18 (32.7%) underwent ELISPOT reversion; and five (8.9%) underwent TST reversion. Results in 13 contacts diagnosed as having TB were mixed, but suggested higher TST sensitivity. CONCLUSIONS: Both ELISPOT conversion and reversion occur after M. tuberculosis exposure. Rapid ELISPOT reversion may reflect M. tuberculosis clearance or transition into dormancy and may contribute to the relatively low reported ELISPOT conversion rate. Therefore, a negative ELISPOT test for M. tuberculosis infection should be interpreted with caution.

Mature CD8(+) T lymphocyte response to viral infection during fetal life.

Immunization of newborns against viral infections may be hampered by ineffective CD8(+) T cell responses. To characterize the function of CD8(+) T lymphocytes in early life, we studied newborns with congenital human cytomegalovirus (HCMV) infection. We demonstrate that HCMV infection in utero leads to the expansion and the differentiation of mature HCMV-specific CD8(+) T cells, which have similar characteristics to those detected in adults. High frequencies of HCMV-specific CD8(+) T cells were detected by ex vivo tetramer staining as early as after 28 weeks of gestation. During the acute phase of infection, these cells had an early differentiation phenotype (CD28(-)CD27(+)CD45RO(+), perforin(low)), and they acquired a late differentiation phenotype (CD28(-)CD27(-)CD45RA(+), perforin(high)) during the course of the infection. The differentiated cells showed potent perforin-dependent cytolytic activity and produced antiviral cytokines. The finding of a mature and functional CD8(+) T cell response to HCMV suggests that the machinery required to prime such responses is in place during fetal life and could be used to immunize newborns against viral pathogens.

ESAT-6 and CFP-10 can be combined to reduce the cost of testing for Mycobacterium tuberculosis infection, but CFP-10 responses associate with active disease.

Commercial tests measuring IFN-gamma responses to ESAT-6 and CFP-10 are available for diagnosing Mycobacterium tuberculosis infection. Measures that minimize cost and complexity will facilitate their application in less-developed countries. We investigated whether overlapping peptides representing both ESAT-6 and CFP-10 are required to detect M. tuberculosis infection in a high TB-burden country, and whether they can be combined in a single pool. ESAT-6 and CFP-10 peptides were compared in IFN-gamma enzyme-linked immunospot (ELISPOT) in 183 HIV-negative smear-positive TB cases and 1673 HIV-negative household contacts. Separate peptide pools for each antigen were compared with a combined pool in 498 contacts. Forty per cent of responsive contacts recognized both antigens, 51% only ESAT-6 and 10% only CFP-10, whereas 56% of responsive cases recognized both antigens, 30% only ESAT-6 and 13% only CFP-10. Accordingly, CFP-10 response rates were higher for TB cases (odds ratio 2.409, P<0.001). Low purified protein derivative response rates indicated that responses to CFP-10 only were non-specific in contacts. Agreement between peptides in separate versus combined pools was good (kappa=0.758, r=0.840). Therefore a combined ESAT-6/CFP-10 peptide pool provided maximum sensitivity and efficiency, but CFP-10 was mainly required to detect active disease.

Screening for tuberculosis among 2381 household contacts of sputum-smear-positive cases in The Gambia.

Contact investigation is a key component of tuberculosis (TB) control in developed, but not developing, countries. We aimed to measure the prevalence of TB among household contacts of sputum-smear-positive TB cases in The Gambia and to assess the sensitivity of an enzyme-linked immunospot (ELISPOT) assay in this regard. Household contacts of adult smear-positive TB patients were assessed by questionnaire, purified protein derivative (PPD) skin test, ELISPOT assay, physical examination, chest X-ray and sputum/gastric aspirate. Thirty-three TB cases were identified from 2174 of 2381 contacts of 317 adult smear-positive pulmonary TB patients, giving a prevalence of 1518/100000. The cases identified tended to have milder disease than those passively detected. The sensitivity of ESAT-6/CFP-10 ELISPOT test as a screening test for TB disease was estimated as 71%. Fifty-six per cent of contacts with a PPD skin test result >or=10mm induration had detectable responses to ESAT-6/CFP-10 by ELISPOT; 11% with a negative PPD skin test (<10mm) had a positive ESAT-6/CFP-10 response. Active screening for TB among contacts of TB patients may have a role in TB control in The Gambia. These individuals are a high-risk group, and the disease identified is less advanced than that found through passive case detection. An ELISPOT assay was relatively insensitive as a screening test for TB.