Stroke characteristics and outcomes in urban Tanzania: Data from the Prospective Lake Zone Stroke Registry.

BACKGROUND: Stroke is a second leading cause of death globally, with an estimated one in four adults suffering a stroke in their lifetime. We aimed to describe the clinical characteristics, quality of care, and outcomes in adults with stroke in urban Northwestern Tanzania. METHODS: We analyzed de-identified data from a prospective stroke registry from Bugando Medical Centre in Mwanza, the second largest city in Tanzania, between March 2020 and October 2022. This registry included all adults ⩾18 years admitted to our hospital who met the World Health Organization clinical definition of stroke. Information collected included demographics, risk factors, stroke severity using the National Institutes of Health Stroke Scale, brain imaging, indicators for quality of care, discharge modified Rankin Scale, and in-hospital mortality. We examined independent factors associated with mortality using logistic regression. RESULTS: The cohort included 566 adults, of which 52% (294) were female with a mean age of 65 ± 15 years. The majority had a first-ever stroke 88% (498). Premorbid hypertension was present in 86% (488) but only 41% (200) were taking antihypertensive medications before hospital admission; 6% (32) had HIV infection. Ischemic strokes accounted for 66% (371) but only 6% (22) arriving within 4.5 h of symptom onset. In-hospital mortality was 29% (127). Independent factors associated with mortality were severe stroke (adjusted odds ratio (aOR) = 1.81, 95% confidence interval (CI) = 1.47-2.24, p < 0.001), moderate to severe stroke (aOR = 1.49, 95% CI = 1.22-1.84, p < 0.001), moderate stroke (aOR = 1.80, 95% CI = 1.52-2.14, p < 0.001), leukocytosis (aOR = 1.19, 95% CI = 1.03-1.38, p = 0.022), lack of health insurance coverage (aOR = 1.15, 95% CI = 1.02-1.29, p = 0.025), and not receiving any form of venous thromboembolism prophylaxis (aOR = 1.18, 95% CI = 1.02-1.37, p = 0.027). CONCLUSION: We report a stroke cohort with poor in-hospital outcomes in urban Northwestern Tanzania. Early diagnosis and treatment of hypertension could prevent stroke in this region. More work is needed to raise awareness about stroke symptoms and to ensure that people with stroke receive guidelines-directed therapy.

Awareness, Willingness and Use of HIV Pre-Exposure Prophylaxis Among Female Sex Workers Living in Dar-es-Salaam, Tanzania.

Tanzania is in the final stages to roll out pre-exposure prophylaxis (PrEP) to Female Sex Workers (FSWs) so as to reduce new infections. PrEP demonstration projects support programming through gaining first experiences.We analyzed data from a cohort of 700 HIV negative FSWs in Dar-es-Salaam to determine proportions of FSWs who were aware, willing and used PrEP. We compared proportions at cohort enrolment and after 12 months. Logistic regression was used to determine factors associated with PrEP use. PrEP awareness increased from 67% to 97% after 12 months. Willingness was high at both time points (98% versus 96%). Only 8% (57/700) had used PrEP. Being married/cohabiting or separated/divorced/widowed and having sex with a HIV infected partner were independently associated with PrEP use. The PrEP program should focus on scaling up access as willingness to use PrEP is high.

Burden of active pulmonary tuberculosis among patients with diabetes in Dar es Salaam, Tanzania: a cross-sectional study.

OBJECTIVES: We aimed to determine the prevalence, associated factors and describe the chest radiographic findings for active pulmonary tuberculosis (TB) among patients with diabetes mellitus (DM) attending a diabetic clinic in Tanzania. DESIGN: Cross-sectional study. SETTING: A diabetic clinic at Temeke Regional Referral Hospital in Dar es salaam, Tanzania. PARTICIPANTS: Patients with diabetes. MAIN OUTCOME MEASURES: The prevalence and factors associated with active TB in patients with DM. RESULTS: Among 623 patients with DM screened, 11 (1.8%); 95% CI 0.9 to 3.1, had active TB of which 6 (54.5%) were GeneXpert positive and 5 (45.5%) were diagnosed based on clinical symptoms and suggestive chest radiographs. The risk of active TB was lower in patients aged 45-64 years compared with age below 45 years (adjusted prevalence ratio (aPR) 0.39, 95% CI (0.11 to 0.42), p=0.001) and in patients with normal chest examination findings compared with patients with crackles or bronchial breathing sounds (aPR 0.02, 95% CI (0.01 to 0.15), p<0.01). The predominant chest radiographic findings were opacification 100% mainly in the upper and mid-lung zones. CONCLUSION: Diabetics should be screened for pulmonary TB, particularly among individuals aged 45 years and below with crackles or bronchial breathing on auscultation of the chest. High index of suspicion could help in the early detection and control of TB.

Personal experiences following acquiring HIV infection while volunteering in Phase I/II HIV vaccine trials: A qualitative study from Tanzania.

BACKGROUND: Participation in HIV vaccine trials is an essential step towards development of an effective preventive vaccine. A Phase I/II HIV vaccine trial enrolls volunteers at low risk of acquiring HIV infection, however a few may still become infected. Understanding the experiences of volunteers who acquired HIV infection while participating in such trials is essential for future research. Here, we describe experiences of HIV infected volunteers in Phase I/II HIV vaccine trials conducted in urban Tanzania. MATERIALS AND METHODS: We used a case study design. In-depth interviews were conducted with four participants who became HIV infected during long follow-up visits after completion of vaccination schedules in a Phase I/II trial. Between 3 and 8 years after HIV positive diagnosis, each participant was interviewed at three time points within a two-year interval so as to allow for accumulation of experiences and cross-checking the emerging constructs. Data was analyzed using a qualitative data analysis framework. RESULTS: Analysis revealed that participation in HIV vaccine trials involves balancing controversies and the spirit of informed decision. The participants declared that they did not acquire HIV from the experimental vaccine. Disclosure of HIV status within the family was gender specific. Men were hesitant to disclose their HIV status to their sexual partners fearing for the consequences. Women's attempt to disclose their HIV status yielded negative reactions from the sexual partners. The acquired knowledge from the HIV vaccine research enabled the participants to cope with the uncertainties and their health status. CONCLUSIONS: The knowledge acquired during the Phase I/II HIV vaccine trial appears to be an essential resource to cope with uncertainties post research. The HIV vaccine trial implementers need to understand the challenges the volunteers may confront after the trial while coping with their health status. Longitudinal studies are essential to trace the effects of uncertainties to the individual participants.

The Prevalence, Incidence, and Risk Factors for HIV Among Female Sex Workers-A Cohort Being Prepared for a Phase IIb HIV Vaccine Trial in Dar es Salaam, Tanzania.

BACKGROUND: A cohort of female sex workers (FSWs) was established to determine HIV prevalence and incidence, and associated factors in preparation for a phase IIb HIV vaccine and pre-exposure prophylaxis trial (PrEPVacc). SETTING: A cohort of FSWs in Dar es Salaam, Tanzania. METHODS: FSWs aged 18-45 years were recruited using a respondent-driven sampling method. Social demographic data, HIV risk behavioral assessments, and blood samples for testing of HIV, syphilis, hepatitis B (HBV), and hepatitis C (HCV) infections were collected at baseline and then at 3, 6, 9, and 12 months. Poisson regressions were used to estimate the prevalence ratios for factors associated with HIV prevalence and to estimate the 12-month HIV incidence rate. RESULTS: Between October and December 2018, a total of 773 FSWs were screened for eligibility and 700 were enrolled. The baseline prevalence of HIV, syphilis, HBV, and HCV was 7.6%, 1.2%, 1.7%, and 1.0%, respectively. HIV prevalence was associated with older age, using illicit drugs, and being infected with syphilis, HBV, or HCV. Attendance at 12 months was 80% (562/700). Twenty-one FSWs seroconverted during follow-up, giving a 12-month HIV incidence rate of 3.45 per 100 person-years at risk (95% CI; 2.25-5.28/100 person-years at risk). The HIV incidence rate was higher among FSWs aged 18-24 years, FSWs who used drugs, and those diagnosed with syphilis, HBV, or HCV. CONCLUSION: The high HIV incidence rate and retention rate among FSWs enrolled into the cohort demonstrate that this population is suitable for participation in HIV prevention trials.

Ischemic Stroke at a Tertiary Academic Hospital in Tanzania: A Prospective Cohort Study With a Focus on Presumed Large Vessel Occlusion.

Background: Large vessel ischemic strokes account for more than one-third of all strokes associated with substantial morbidity and mortality without early intervention. The incidence of large vessel occlusion (LVO) is not known in sub-Saharan Africa (SSA). Definitive vessel imaging is not routinely available in resource-limited settings. Aims: We aimed to investigate the burden and outcomes of presumed LVO among patients with ischemic stroke admitted to a large tertiary academic hospital in Tanzania. Methods: This cohort study recruited all consenting first-ever ischemic stroke participants admitted at a tertiary hospital in Tanzania. Demographic data were recorded, and participants were followed up to 1 year using the modified Rankin Scale (mRS). A diagnosis of presumed LVO was made by a diagnostic neuroradiologist and interventional neurologist based on contiguous ischemic changes in a pattern consistent with proximal LVO on a non-contrast computed tomography head. We examined factors associated with presumed LVO using logistic regression analysis. Inter-observer Kappa was calculated. Results: We enrolled 158 first-ever ischemic strokes over 8 months with a mean age of 59.7 years. Presumed LVO accounted for 39.2% [95% confidence interval (CI) 31.6-47.3%] and an overall meantime from the onset of stroke symptoms to hospital arrival was 1.74 days. Participants with presumed LVO were more likely to involve the middle cerebral artery (MCA) territory (70.9%), p < 0.0001. Independent factors on multivariate analysis associated with presumed LVO were hypertension [adjusted odds ratio (aOR) 5.74 (95% CI: 1.74-18.9)] and increased waist-hip ratio [aOR 7.20 (95% CI: 1.83-28.2)]. One-year mortality in presumed LVO was 80% when compared with 73.1% in participants without presumed LVO. The Cohen's Kappa inter-observer reliability between the diagnostic neuroradiologist and interventional neurologist was 0.847. Conclusion: There is a high burden of presumed LVO associated with high rates of 1-year morbidity and mortality at a tertiary academic hospital in Tanzania. Efforts are needed to confirm these findings with definitive vessel imaging, promoting cost-effective preventive strategies to reduce the burden of non-communicable diseases (NCDs), and a call for adopting endovascular therapies to reduce morbidity and mortality.

Body mass index, proteinuria and total lymphocyte counts in predicting treatment responses among ART naïve individuals with HIV initiated on antiretroviral treatment in Dar es Salaam, Tanzania, 2019: a cohort study.

OBJECTIVES: To explore the potential use of body mass index (BMI), proteinuria and total lymphocyte count changes in predicting immunological and virological response in individuals with HIV initiated on antiretroviral treatment (ART). DESIGN: Prospective cohort study. SETTING: Three urban HIV care and treatment centres in Dar es Salaam. PARTICIPANTS: Individuals with HIV initiating ART. OUTCOME MEASURES: HIV viral load ≥1000 copies/mL (viral non-suppression) at 6 months after ART initiation. RESULTS: Of 215 (out of 220 enrolled) participants who returned for evaluation at 6 months, 147 (66.8%) were women. At 6 months of follow-up, 89.4% (76/85) of participants with sustained weight gain were virally suppressed compared with 31.8% (7/22) with sustained loss, p<0.001. In participants who were lymphopaenic at baseline, an increase to normal total lymphocyte counts at 6 months was associated with an increase in CD4 count compared with participants who remained lymphopaenic, 96.2% (50/52) versus 54.8% (17/31), p<0.001. At baseline, 50.0% (110/220) had proteinuria. In participants without proteinuria from baseline to 6 months, 89.8% (79/88) were virally suppressed compared with participants with proteinuria at baseline and/or 3 months, 85.6% (77/90), those with persistent proteinuria, 30.8% (8/26), and proteinuria at 6 months only, 45.5% (5/11), p<0.001. In modified Poisson regression, the independent predictors other than CD4 cell counts for viral non-suppression at 6 months among individuals with HIV initiating on ART were BMI loss >5% from baseline to 6 months (adjusted RR 2.73, 95% CI (1.36 to 5.47)), lymphopaenia at 6 months (adjusted RR=4.54, 95% CI (2.19 to 9.39)) and proteinuria at 6 months (adjusted RR=2.63, 95% CI (1.25 to 5.54)). CONCLUSIONS: Change in BMI, total lymphocyte count and presence of proteinuria can monitor and predict ART response and may be particularly helpful in settings when CD4 counts and viral load monitoring are unavailable.

Serial T-SPOT.TB responses in Tanzanian adolescents: Transient, persistent and irregular conversions.

BACKGROUND: Prospective studies of interferon-gamma release assays (IGRA) on healthy subjects in tuberculosis-endemic regions have not examined the long-term variability of serial assays. This issue is relevant to the interpretation of tuberculosis (TB) vaccine trials based on prevention of infection. METHODS: T-SPOT.TB assays were performed manually on healthy adolescents during a tuberculosis vaccine trial in Tanzania at 5 intervals over 3 years. Assay results were defined as negative, positive, borderline or invalid. Subsequently, microtiter plates were analyzed by an automated reader to obtain quantitative counts of spot forming cells (SFCs) for the present analysis. RESULTS: 3387 T-SPOT.TB samples were analyzed from 928 adolescents; manual and automated assay results were 97% concordant. Based on the quantitative results 143 (15%) participants were prevalent IGRA-positives at baseline, were ineligible for further study. Among the remaining IGRA-negative participants, the annual rate of IGRA conversion was 2·9%. Among 43 IGRA converters with repeat assays 12 (28%) were persistent converters, 16 (37%) were transient converters, and 15 (35%) comprised a new category defined as irregular converters (≥2 different subsequent results). ESAT-6 and CFP-10 responses were higher in prevalent than incident positives: 53 vs 36 for CFP-10 (p < 0·007); 44 vs 34 for ESAT-6 (p = 0·12). CONCLUSIONS: Definitions of IGRA conversion, reversion, and persistence depend critically on the frequency of testing. Multiple shifts in categories among adolescents in a TB-endemic country may represent multiple infections, variable host responses in subclinical infection, or assay variation. These findings should to be considered in the design and interpretation of TB vaccine trials based on prevention of infection. Household contact studies could determine whether even transient IGRA conversion might represent exposure to an active case of M. tuberculosis disease.

Systematic comparison of HIV-1 Envelope-specific IgG responses induced by different vaccination regimens: Can we steer IgG recognition towards regions of viral vulnerability?

Immunogens and vaccination regimens can influence patterns of immune-epitope recognition, steering them towards or away from epitopes of potential viral vulnerability. HIV-1 envelope (Env)-specific antibodies targeting variable region 2 (V2) or 3 (V3) correlated with protection during the RV144 trial, however, it was suggested that the immunodominant V3 region might divert antibody responses away from other relevant sites. We mapped IgG responses against linear Env epitopes in five clinical HIV vaccine trials, revealing a specific pattern of Env targeting for each regimen. Notable V2 responses were only induced in trials administering CRF01_AE based immunogens, but targeting of V3 was seen in all trials, with the soluble, trimeric CN54gp140 protein eliciting robust V3 recognition. Strong V3 targeting was linked to greater overall response, increased number of total recognised antigenic regions, and where present, stronger V2 recognition. Hence, strong induction of V3-specific antibodies did not negatively impact the targeting of other linear epitopes in this study, suggesting that the induction of antibodies against V3 and other regions of potential viral vulnerability need not be necessarily mutually exclusive.

The burden, correlates and outcomes of left ventricular hypertrophy among young Africans with first ever stroke in Tanzania.

BACKGROUND: Left ventricular hypertrophy is a pathophysiological response often due to chronic uncontrolled hypertension. Our primary aim was to investigate the magnitude, correlates and outcomes of left ventricular hypertrophy as a surrogate maker for chronic uncontrolled hypertension in young adults ≤ 45 years with stroke. Our secondary aim was to determine the accuracy of electrocardiography using Sokolow-Lyon and Cornell criteria in detecting left ventricular hypertrophy compared to echocardiography. METHODS: This cohort study recruited young strokes who had undergone brain imaging, electrocardiography and transthoracic echocardiography at baseline. The modified Poisson regression model examined baseline correlates for left ventricular hypertrophy. The National Institute of Health Stroke Scale assessed stroke severity and the modified Rankin Scale assessed outcomes to 30-days. Performance of electrical voltage criterions was estimated using receiver operator characteristics. RESULTS: We enrolled 101 stroke participants. Brain imaging revealed ischemic strokes in 60 (59.4%) and those with intracerebral hemorrhage, 33 (86.8%) were localized to the basal ganglia. Left ventricular hypertrophy was present in 76 (75.3%:95%CI 65.7%-83.3%), and 30 (39.5%) and 28 (36.8%) had moderate or severe hypertrophy respectively. Young adults with premorbid or a new diagnosis of hypertension were more likely to have left ventricular hypertrophy, 47 (61.8%), and 26 (34.2%). On multivariable analysis, left ventricular hypertrophy was independently associated with not being on anti-hypertensive medications among hypertensives participants {adjusted risk ratio 1.4 (95%CI:1.04-1.94). The mean National Institute of Health Stroke score was 18 and 30-day mortality was 42 (43.3%). The sensitivity and specificity for Sokolow-Lyon in detecting left ventricular hypertrophy was 27% and 78%, and for Cornell was 32% and 52% respectively. CONCLUSIONS: We identified a high proportion of left ventricular hypertrophy in young adults with stroke associated with chronic undertreated hypertension. While the study methodology does not allow us to determine causation, this association and knowledge of pathophysiological processes supports the notion that chronic hypertension is a major risk factor for young strokes associated with high mortality. Our findings did not support the use of the electrical voltage criteria for detecting left ventricular hypertrophy. We recommend low cost interventions like blood pressure screening and treatment to reduce this burden.

Outcomes within a year following first ever stroke in Tanzania.

BACKGROUND: Stroke contributes to a significant proportion of deaths and disability worldwide, with a high fatality rate within 30 days following a first ever stroke. We describe the outcomes within one year among patients who succumbed a first ever stroke and survived the first 30 days. METHODS: Participants were patients who survived after 30 days from succumbing a first ever stroke admitted at the Muhimbili University of Health and Allied Sciences Academic Medical Center. Stroke survivors or their next of kin were contacted at one year after succumbing a first stroke to determine the outcomes. We assessed participants' vital status and level of disability using the modified Rankin scale. Assessment on utilization of stroke secondary preventive measures among survivors was done by an interviewer-based questionnaire that assessed the number of times participants attended follow up clinics, medication refill and adherence. Participants were examined for waist-hip ratio, body mass index and blood pressure. Cholesterol levels were assessed at one year post first stroke for survivors. Outcomes were summarized as proportions, survival at one year was estimated by using the Kaplan Meier analysis and Cox regression analysis was performed to determine for predictors of mortality. RESULTS: We recruited 130 first stroke survivors. Mortality within one year was 53/130 (40.8%) and disability rate measured by Modified Rankin Scale with scores of 3-5 was 29/77 (37.7%) among survivors. Factors associated with mortality were residual disability HR = 8.60, {95% CI (1.16-63.96)}, severe stroke, HR = 2.67 {95% CI (1.44-4.95)} and residing in Dar-es-Salaam HR = 2.15 {95% (CI 1.06-4.36)}. Non-adherence rates to antihypertensives, antiplatelets and statins was 11/73 (15.1%), 9/23 (39.1%) and 18/22 (81.8%) respectively. Attendance rates of follow-up clinics among all survivors and physiotherapy among survivors with disability are 45/77 (58.4%) and 16/29 (55.2%) respectively. CONCLUSIONS: The mortality and disability rates within a year following a first ever stroke among 30 days stroke survivors is high. Secondary stroke preventive measures should be enhanced to mitigate stroke adverse outcomes. Community outreach programs could be useful interventions in preventing the adverse outcomes of stroke.

"I did not plan to have a baby. This is the outcome of our work": a qualitative study exploring unintended pregnancy among female sex workers.

BACKGROUND: High number of unintended pregnancies-often leading to induced abortions-are reported among female sex workers (FSWs), highlighting a major unmet need for contraception. To better understand barriers to contraceptive use, we explored FSW's pregnancy perceptions and experiences of unintended pregnancy. We hypothesized that sex work exacerbates barriers to contraceptive use and that FSW's pregnancy perceptions and experiences of unintended pregnancy influence future commitment to contraceptive use. METHODS: We conducted in-depth interviews with 11 FSWs (January-June 2019) in Dar es Salaam, Tanzania. We purposively sampled FSWs with a positive pregnancy test from those participating in a HIV vaccine preparedness cohort. We used open ended questions to explore how FSWs make decisions when facing barriers to contraceptive use, dealing with unintended pregnancy and adhering to contraceptive use after experiencing unintended pregnancy. All interviews were conducted in Kiswahili, audio-recorded, transcribed and translated into English. Grounded theory approach was used to analyse transcripts. Open and selective coding was performed using Nvivo software. RESULTS: FSWs reported that sex work impedes good contraceptive behaviour because sex workers felt unable to negotiate consistent condom use, avoided health services due to stigma, missed monthly contraceptive supplies because of inconvenient clinic operating hours or skipped contraceptive pills when intoxicated after taking alcohol. FSWs who perceived pregnancy to be a burden terminated the pregnancy because of fear of loss of income during pregnancy or child rearing expenses in case child support was not assured by their partners. FSWs who perceived pregnancy to be a blessing decided to keep the pregnancy because they desired motherhood and hoped that children would bring prosperity. Family planning counselling and availability of contraceptives during postpartum care influenced the initiation of contraception among FSWs. Financial hardships related to childrearing or painful abortion experiences influenced FSWs' commitment to good contraceptive practices. CONCLUSION: Our results demonstrate that FSWs face barriers to initiating and adhering to contraceptive use because of sex work stigma, inability to negotiate condoms and failure to access medical services at their convenience. Our findings underscore the need to integrate contraceptive services with HIV programs serving FSWs in their areas of work.

Frequent and Durable Anti-HIV Envelope VIV2 IgG Responses Induced by HIV-1 DNA Priming and HIV-MVA Boosting in Healthy Tanzanian Volunteers.

We evaluated antibody responses to the human immunodeficiency virus (HIV) envelope variable regions 1 and 2 (V1V2) in 29 vaccinees who had received three HIV-1 DNA immunizations and two HIV-modified vaccinia virus Ankara (MVA) boosts in the phase I/II HIVIS03 vaccine trial. Twenty vaccinees received a third HIV-MVA boost after three years in the HIVIS06 trial. IgG and IgG antibody subclasses to gp70V1V2 proteins of HIV-1 A244, CN54, Consensus C, and Case A2 were analysed using an enzyme-linked immunosorbent assay (ELISA). Cyclic V2 peptides of A244, Consensus C, and MN were used in a surface plasmon resonance (SPR) assay. Four weeks after the second HIV-MVA, anti-V1V2 IgG antibodies to A244 were detected in 97% of HIVIS03 vaccinees, in 75% three years later, and in 95% after the third HIV-MVA. Anti-CN54 V1V2 IgG was detectable in 48% four weeks after the second HIV-MVA. The SPR data supported the findings. The IgG response was predominantly IgG1. Four weeks after the second HIV-MVA, 85% of vaccinees had IgG1 antibodies to V1V2 A244, which persisted in 25% for three-years. IgG3 and IgG4 antibodies to V1V2 A244 were rare. In conclusion, the HIV-DNA/MVA vaccine regimen induced durable V1V2 IgG antibody responses in a high proportion of vaccinees.

Frequent Anti-V1V2 Responses Induced by HIV-DNA Followed by HIV-MVA with or without CN54rgp140/GLA-AF in Healthy African Volunteers.

Antibody responses that correlated with reduced risk of HIV acquisition in the RV144 efficacy trial were assessed in healthy African volunteers who had been primed three times with HIV-DNA (subtype A, B, C) and then randomized into two groups; group 1 was boosted twice with HIV-MVA (CRF01_AE) and group 2 with the same HIV-MVA coadministered with subtype C envelope (Env) protein (CN54rgp140/GLA-AF). The fine specificity of plasma Env-specific antibody responses was mapped after the final vaccination using linear peptide microarray technology. Binding IgG antibodies to the V1V2 loop in CRF01_AE and subtype C Env and Env-specific IgA antibodies were determined using enzyme-linked immunosorbent assay. Functional antibody-dependent cellular cytotoxicity (ADCC)-mediating antibody responses were measured using luciferase assay. Mapping of linear epitopes within HIV-1 Env demonstrated strong targeting of the V1V2, V3, and the immunodominant region in gp41 in both groups, with additional recognition of two epitopes located in the C2 and C4 regions in group 2. A high frequency of V1V2-specific binding IgG antibody responses was detected to CRF01_AE (77%) and subtype C antigens (65%). In conclusion, coadministration of CN54rgp140/GLA-AF with HIV-MVA did not increase the frequency, breadth, or magnitude of anti-V1V2 responses or ADCC-mediating antibodies induced by boosting with HIV-MVA alone.

DAR-901 vaccine for the prevention of infection with Mycobacterium tuberculosis among BCG-immunized adolescents in Tanzania: A randomized controlled, double-blind phase 2b trial.

BACKGROUND: SRL172 prevented disease due to Mycobacterium tuberculosis in a Phase 3 trial. DAR-901 represents a scalable manufacturing process for SRL172. We sought to determine if DAR-901 would prevent infection with M. tuberculosis among BCG-primed adolescents age 13-15 years in Tanzania. METHODS: Adolescents with a negative T- SPOT.TBR interferon gamma release assay (IGRA) were randomized 1:1 to three intradermal injections of DAR-901 or saline placebo at 0, 2 and 4 months. Repeat IGRAs were performed at 2 months, and at 1, 2, and 3 years. The primary efficacy outcome was time to new TB infection (IGRA conversion to positive); the secondary outcome was time to persistent TB infection (IGRA conversion with repeat positive IGRA). RESULTS: Among 936 participants screened 667 were eligible and randomized to their first dose of vaccine or placebo (safety cohort). At 2 months, 625 participants remained IGRA-negative and were scheduled for the additional two doses (efficacy cohort). DAR-901 was safe and well-tolerated. One DAR-901 recipient developed a vaccine site abscess. Neither the primary nor secondary endpoints differed between the two treatment arms (p = 0.90 and p = 0.20, respectively). DAR-901 IGRA converters had median responses to ESAT-6 of 50.1 spot-forming cells (SFCs) vs. 19.6 SFCs in placebo IGRA converters (p = 0.03). CONCLUSIONS: A three-dose series of 1 mg DAR-901 was safe and well-tolerated but did not prevent initial or persistent IGRA conversion. DAR-901 recipients with IGRA conversion demonstrated enhanced immune responses to ESAT-6. Since protection against disease may require different immunologic responses than protection against infection a trial of DAR-901 to prevent TB disease is warranted. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov as NCT02712424.

Successful implementation of isoniazid preventive therapy at a pediatric HIV clinic in Tanzania.

BACKGROUND: In accordance with international guidance for tuberculosis (TB) prevention, the Tanzanian Ministry of Health recommends isoniazid preventive therapy (IPT) for children aged 12 months and older who are living with HIV. Concerns about tolerability, adherence, and potential mistreatment of undiagnosed TB with monotherapy have limited uptake of IPT globally, especially among children, in whom diagnostic confirmation is challenging. We assessed IPT implementation and adherence at a pediatric HIV clinic in Tanzania. METHODS: In this prospective cohort study, eligible children living with HIV aged 1-15 years receiving care at the DarDar Pediatric Program in Dar es Salaam who screened negative for TB disease were offered a 6-month regimen of daily isoniazid. Patients could choose to receive IPT via facility- or community-based care. Parents/caregivers and children provided informed consent and verbal assent respectively. Isoniazid was dispensed with the child's antiretroviral therapy every 1-3 months. IPT adherence and treatment completion was determined by pill counts, appointment attendance, and self-report. Patients underwent TB symptom screening at every visit. RESULTS: We enrolled 66 children between July and December 2017. No patients/caregivers declined IPT. Most participants were female (n = 43, 65.1%) and the median age was 11 years (interquartile range [IQR] 8, 13). 63 (95.5%) participants chose the facility-based model; due to the small number of participants who chose the community-based model, valid comparisons between the two groups could not be made. Forty-nine participants (74.2%) completed IPT within 10 months. Among the remaining 17, 11 had IPT discontinued by their provider due to adverse drug reactions, 5 lacked documentation of completion, and 1 had unknown outcomes due to missing paperwork. Of those who completed IPT, the average monthly adherence was 98.0%. None of the participants were diagnosed with TB while taking IPT or during a median of 4 months of follow-up. CONCLUSIONS: High adherence and treatment completion rates can be achieved when IPT is integrated into routine, self-selected facility-based pediatric HIV care. Improved record-keeping may yield even higher completion rates. IPT was well tolerated and no cases of TB were detected. IPT for children living with HIV is feasible and should be implemented throughout Tanzania.

Correction to: Successful implementation of isoniazid preventive therapy at a pediatric HIV clinic in Tanzania.

An amendment to this paper has been published and can be accessed via the original article.

The potential of CBC-derived ratios (monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte) to predict or diagnose incident TB infection in Tanzanian adolescents.

BACKGROUND: Ratios of different immune cell populations (i.e., monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte ratios) have been studied as a means of predicting future tuberculosis (TB) disease risk or to assist in the diagnosis of incident TB disease. No studies to-date, however, have evaluated the potential of these ratios to predict or assist in the diagnosis of incident TB infection - the first step in the natural history of TB disease. METHODS: In this prospective study, we evaluated the complete blood count (CBC)-derived metrics of monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) as predictors of future TB infection risk or aids in the diagnosis of TB infection among 145 Tanzanian adolescents enrolled in the DAR-901 vaccine trial, using paired CBCs and interferon-gamma release assays (IGRAs) obtained at 0, 60 and 720 days after study enrollment. RESULTS: At baseline, there were no significant differences between study participants who remained persistently IGRA negative throughout the study period and those who subsequently converted to IGRA positive with respect to MLR (0.18 vs 0.17, p = 0.10), NLR (0.88 vs 1.02, p = 0.08), or PLR (115 vs 120, p = 0.28). Similarly, no significant differences were noted with respect to MLR, NLR, and PLR between IGRA converters and time-matched negative controls at the time of IGRA conversion. With respect to other blood cell measures, however, there were modest but significant differences between IGRA negatives and IGRA converters with respect to red blood cell count (4.8 vs 4.6 ×  106 cells/mcL, p = 0.008), hemoglobin (12.6 vs 12.3 g/dL, p = 0.01), and hematocrit (38.8 vs 37.8%, p = 0.005). CONCLUSIONS: In contrast to prior studies that have suggested that the ratios of different immune cell populations are associated with development of TB disease, our present findings do not demonstrate an association between these ratios and the development of TB infection. However, decreased red blood cell measures were associated with the subsequent development of TB infection, suggesting either that dysregulation of iron metabolism may play a role in TB pathogenesis or that following TB infection, iron dysregulation may precede IGRA positivity. TRIAL REGISTRATION: Clinicaltrials.gov NCT02712424 . Date of registration: March 14, 2016.

Stroke mimics in patients clinically diagnosed with stroke at a tertiary teaching hospital in Tanzania: a prospective cohort study.

BACKGROUND: Stroke mimics account for up to one-third of acute stroke admissions and are a heterogeneous entity which pose diagnostic challenges. Diagnosing such patients is however crucial to avoid delays in treatment and potentially harmful medication prescription. We aimed at describing the magnitude, clinical characteristics and short-term outcomes of stroke mimics in patients clinically diagnosed with a stroke. METHODS: This prospective study enrolled patients admitted with a World Health Organization clinical criteria for stroke at a tertiary hospital in Tanzania. Baseline data was collected and the simplified version of the FABS scale was used to determine its usefulness in predicting stroke mimics. The National Institute of Health Stroke Scale and Modified Rankin Scale were used to assess for admission stroke severity and outcomes respectively. RESULTS: Among 363 patients with suspected stroke on admission, the final diagnosis was stroke mimics in 24 (6.6%) who had a mean age of 65.8 ± 15 years. Patients with stroke mimics were less likely to have cardiovascular risk factors for stroke including premorbid hypertension (7 (29.2%) vs 263 (77.6%), p < 0.001) and increased waist-hip ratio (9 (37.5%) vs 270 (79.6%) p < 0.001) for mimics and true strokes respectively. Clinical findings such as hypertension and the presence of cortical features in neurological examination occurred less in patients with stroke mimics. The simplified FABS score of ≥3 could identify patients with stroke mimics with a sensitivity and specificity of 38 and 80% respectively. The most common causes of mimics were brain tumors 6 (25%), meningoencephalitis 4 (16.7%) and epileptic seizures 3 (12.5%). The majority of patients with stroke mimics had severe disease on admission and the 30-day mortality in these patients was 54.5%. CONCLUSIONS: In the present study, the proportion of stroke mimics among patients clinically diagnosed with stroke was 6.6% and brain tumors was a common etiology. Stroke mimics were less likely to have cardiovascular risk factors and cortical signs during evaluation. We recommend further studies that can help develop clinical scales used for predicting stroke mimics in an African population.

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS:We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38­52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63­87), increasing to 89% (80­94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05­3·08) but not after 30 days (1·25, 0·84­2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16­8·84). INTERPRETATION:In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients