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Introduction: Monitoring HIV viral load (VL) in people living with HIV (PLHIV) on antiretroviral therapy (ART) is recommended by the World Health Organization. Implementation of VL testing programs have been affected by logistic and organizational challenges. Here we describe the VL monitoring cascade in a rural setting in Tanzania and compare turnaround times (TAT) between an on-site and a referral laboratory. Methods In a nested study of the prospective Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) we included PLHIV aged ≥ 15 years, on ART for ≥ 6 months after implementation of routine VL monitoring in 2017. We assessed proportions of PLHIV with a blood sample taken for VL, whose results came back, and who were virally suppressed (VL

Background Patients with clinically suspected tuberculosis are often treated empirically, as diagnosis - especially of extrapulmonary tuberculosis - remains challenging. This leads to an overtreatment of tuberculosis and to underdiagnosis of possible differential diagnoses. Methods This open-label, parallel-group, superiority randomized controlled trial is done in a rural and an urban center in Tanzania. HIV-positive and -negative adults (≥18 years) with clinically suspected extrapulmonary tuberculosis are randomized in a 1:1 ratio to an intervention- or control group, stratified by center and HIV status. The intervention consists of a management algorithm including extended focused assessment of sonography for HIV and tuberculosis (eFASH) in combination with chest X-ray and microbiological tests. Treatment with anti-tuberculosis drugs is started, if eFASH is positive, chest X-ray suggests tuberculosis, or a microbiological result is positive for tuberculosis. Patients in the control group are managed according national guidelines. Treatment is started if microbiology is positive or empirically according to the treating physician. The primary outcome is the proportion of correctly managed patients at 6 months (i.e patients who were treated with anti-tuberculosis treatment and had definite or probable tuberculosis, and patients who were not treated with anti-tuberculosis treatment and did not have tuberculosis). Secondary outcomes are the proportion of symptom-free patients at two and 6 months, and time to death. The sample size is 650 patients. Discussion This study will determine, whether ultrasound in combination with other tests can increase the proportion of correctly managed patients with clinically suspected extrapulmonary tuberculosis, thus reducing overtreatment with anti-tuberculosis drugs. Trial registration PACTR, Registration number: PACTR201712002829221, registered December 1st 2017.

Background Patients with suspected extrapulmonary tuberculosis are often treated empirically. We hypothesized that extended focused assessment with sonography for human immunodeficiency virus (HIV) and tuberculosis (eFASH), in combination with other tests, would increase the proportion of correctly managed patients with suspected extrapulmonary tuberculosis. Methods This trial in adults with suspected extrapulmonary tuberculosis was performed in a rural and an urban hospital in Tanzania. Participants were randomized 1:1 to intervention or routine care, stratified by site and HIV status. All participants underwent clinical evaluation, chest radiography, and testing with sputum Xpert MTB/RIF and urine Xpert MTB/RIF Ultra assays. The intervention was a management algorithm based on results of eFASH plus microbiology, adenosine deaminase (ADA), and chest radiography. The primary outcome was the proportion of correctly managed patients. The presence of positive microbiological or ADA results defined definite tuberculosis. An independent end-point review committee determined diagnoses of probable or no tuberculosis. We evaluated outcomes using logistic regression models, adjusted for randomization stratification factors. Results From September 2018 to October 2020, a total of 1036 patients were screened and 701 were randomized (350 to the intervention and 351 to the control group). Of participants in the intervention group, 251 (72%) had a positive eFASH outcome. In 258 (74%) of the intervention and 227 (65%) of the control participants antituberculosis was initiated treatment at baseline. More intervention participants had definite tuberculosis (n = 124 [35%]), compared with controls (n = 85 [24%]). There was no difference between groups for the primary outcome (intervention group, 266 of 286 [93%]; control group, 245 of 266 [92%]; odds ratio, 1.14 [95% confidence interval: .60–2.16]; P = .68). There were no procedure-associated adverse events. Conclusions eFASH did not change the proportion of correctly managed patients but increased the proportion of those with definite tuberculosis. Clinical Trials Registration Pan African Registry: PACTR201712002829221.

Background: HIV-related stigma is a major barrier to the timely linkage and retention of patients in HIV care in sub-Saharan Africa, where most people living with HIV/AIDS reside. In this implementation study we aim to evaluate the effect of stigma-directed services on linkage to care and other health outcomes in newly diagnosed HIV-positive patients. Methods: In a nested project of the Kilombero and Ulanga Antiretroviral Cohort in rural Tanzania, we conduct a prospective observational pre-post study to assess the impact of a bundle of stigma-directed services for newly diagnosed HIV positive patients. Stigma-directed services, delivered by a lay person living with HIV, are i) post-test counseling, ii) post-test video-assisted teaching, iii) group support therapy and group health education, and iv) mobile health. Patients receiving stigma services (enrolled from 1st February 2020 to 31st August 2021) are compared to a historical control receiving the standard of care (enrolled from 1st July 2017 to 1st February 2019). The primary outcome is ‘linkage to care’. Secondary endpoints are retention in care, viral suppression, death and clinical failure at 6-12 months (up to 31st August 2022). Self-reported stigma and depression are assessed using the Berger Stigma scale and the PHQ-9 questionnaire, respectively. The sample size calculation was based on cohort data from 2018. Assuming a pre-intervention cohort of 511 newly diagnosed adults of whom 346 (68%) were in care and on antiretroviral treatment (ART) at 2 months, a 10% increase in linkage (from 70 to 80%), a two-sided type I error rate of 5%, and 90% power, 321 adults are required for the post-implementation group. Discussion: We expect that integration of stigma-directed services leads to an increase of proportions of patients in care and on ART. The findings will provide guidance on how to integrate stigma-directed services into routine care in rural sub-Saharan Africa.

Background The extent to which drug–drug interactions (DDIs) between antiretrovirals (ARVs) and co-medications are recognized and managed has not been thoroughly evaluated in limited-resource settings. Objectives This prospective questionnaire-based study aimed to determine the prevalence and risk factors for unrecognized/incorrectly managed DDIs in people living with HIV followed-up at the Chronic Diseases Clinic of Ifakara (CDCI) and enrolled in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO). Methods We prospectively included ARV-treated adults receiving ≥1 co-medication coming for a follow-up visit at the CDCI between March and July 2017. Using a structured questionnaire, physicians were requested to identify potentially clinically significant DDIs in the prescribed treatment, to provide recommendations for their management and to indicate any hurdles to implement the recommendations. Prescriptions were subsequently screened for DDIs using the Liverpool DDIs database. Identified clinically significant DDIs and their recommended management according to the DDIs database were compared with the information provided in the questionnaires. Results Among 334 participants, the median age was 47 years (IQR = 40–56 years), 69% were female and 82% had ≥1 non-communicable disease (NCD). Overall, 129 participants had ≥1 clinically relevant DDI, which was not recognized and/or incorrectly managed in 56 participants (43%). Of those, 6 (11%) were due to limited monitoring options or medication affordability issues. In the multivariable logistic regression, the presence of ≥1 NCD was associated with an increased risk for unrecognized/incorrect DDI management (OR = 15.8; 95% CI = 1.8–139.6). Conclusions Recognition/appropriate management of DDIs is suboptimal, highlighting the need for educational programmes, pharmacovigilance activities and increased access to medications and monitoring options. This should become a focus of HIV programmes given the increasing burden of NCDs in sub-Saharan Africa.

Background In sub-Saharan Africa, diagnosis and management of extrapulmonary tuberculosis (EPTB) in people living with HIV (PLHIV) remains a major challenge. This study aimed to characterize the epidemiology and risk factors for poor outcome of extrapulmonary tuberculosis in people living with HIV (PLHIV) in a rural setting in Tanzania. Methods We included PLHIV >18 years of age enrolled into the Kilombero and Ulanga antiretroviral cohort (KIULARCO) from 2013 to 2017. We assessed the diagnosis of tuberculosis by integrating prospectively collected clinical and microbiological data. We calculated prevalence- and incidence rates and used Cox regression analysis to evaluate the association of risk factors in extrapulmonary tuberculosis (EPTB) with a combined endpoint of lost to follow-up (LTFU) and death. Results We included 3,129 subjects (64.5% female) with a median age of 38 years (interquartile range [IQR] 31–46) and a median CD4+ cell count of 229/μl (IQR 94–421) at baseline. During the median follow-up of 1.25 years (IQR 0.46–2.85), 574 (18.4%) subjects were diagnosed with tuberculosis, whereof 175 (30.5%) had an extrapulmonary manifestation. Microbiological evidence by Acid-Fast-Bacillus stain (AFB-stain) or Xpert® MTB/RIF was present in 178/483 (36.9%) patients with pulmonary and in 28/175 (16.0%) of patients with extrapulmonary manifestations, respectively. Incidence density rates for pulmonary Tuberculosis (PTB and EPTB were 17.9/1000person-years (py) (95% CI 14.2–22.6) and 5.8/1000 py (95% CI 4.0–8.5), respectively. The combined endpoint of death and LTFU was observed in 1058 (33.8%) patients, most frequently in the subgroup of EPTB (47.2%). Patients with EPTB had a higher rate of the composite outcome of death/LTFU after TB diagnosis than with PTB [HR 1.63, (1.14–2.31); p = 0.006]. The adjusted hazard ratios [HR (95% CI)] for death/LTFU in EPTB patients were significantly increased for patients aged >45 years [HR 1.95, (1.15–3.3); p = 0.013], whereas ART use was protective [HR 0.15, (0.08–0.27); p

Background Patients with suspected tuberculosis are often overtreated with antituberculosis drugs. We evaluated the diagnostic value of the focused assessment with sonography for HIV-associated tuberculosis (FASH) in rural Tanzania. Methods In a prospective cohort study, the frequency of FASH signs was compared between patients with confirmed tuberculosis and those without tuberculosis. Clinical and laboratory examination, chest x-ray, Xpert MTB/RIF assay, and culture from sputum, sterile body fluids, lymph node aspirates, and Xpert MTB/RIF urine assay was done. Results Of 191 analyzed patients with a 6-month follow-up, 52.4% tested positive for human immunodeficiency virus, 21.5% had clinically suspected pulmonary tuberculosis, 3.7% had extrapulmonary tuberculosis, and 74.9% had extrapulmonary and pulmonary tuberculosis. Tuberculosis was microbiologically confirmed in 57.6%, probable in 13.1%, and excluded in 29.3%. Ten of eleven patients with splenic or hepatic hypoechogenic lesions had confirmed tuberculosis. In a univariate model, abdominal lymphadenopathy was significantly associated with confirmed tuberculosis. Pleural- and pericardial effusion, ascites, and thickened ileum wall lacked significant association. In a multiple regression model, abnormal chest x-ray (odds ratio [OR] = 6.19; 95% confidence interval [CI], 1.96–19.6; P < .002), ≥1 FASH-sign (OR = 3.33; 95% CI, 1.21–9.12; P = .019), and body temperature (OR = 2.48; 95% CI, 1.52–5.03; P = .001 per °C increase) remained associated with tuberculosis. A combination of ≥1 FASH sign, abnormal chest x-ray, and temperature ≥37.5°C had 99.1% sensitivity (95% CI, 94.9–99.9), 35.2% specificity (95% CI, 22.7–49.4), and a positive and negative predictive value of 75.2% (95% CI, 71.3–78.7) and 95.0% (95% CI, 72.3–99.3). Conclusions The absence of FASH signs combined with a normal chest x-ray and body temperature

Background It has been hypothesized that schistosomiasis negatively influences immune reconstitution in people living with HIV starting antiretroviral therapy (ART). In this study, we investigated the effect of schistosomiasis on the course of HIV infection in patients starting ART in a rural part of Tanzania. Methodology Retrospective study including patients prospectively enrolled in a HIV cohort in Ifakara, south-central Tanzania between January 1, 2013 and April 1, 2015. Schistosomal circulating anodic antigen (CAA) was assessed in pre-ART cryopreserved plasma. Regression models were utilized to estimate the effect of CAA positivity on virological and immunological failure and a composite outcome of death/loss to follow-up (LFU). Principal findings At ART-initiation 19.1% (88/461) of patients were CAA-positive. A tendency of higher CD4 increases was seen in CAA-positive patients (+182 cells/μl, interquartile range (IQR), 87–285 cells/μl) compared to CAA-negative patients (+147 cells/μl, IQR, 55–234 cells/μl, p = 0.09) after 10 months of follow-up. After adjustment for baseline risk factors, CAA-positivity showed no association with virological or immunological failure. In CAA-positive patients, 22.7% (20/88) died or were LFU, compared to 29.5% (110/373) of CAA-negative patients (hazard ratio (HR): 0.76, 95% confidence interval (CI), 0.47–1.22, p = 0.25). After adjustment for age, sex, body mass index, educational attainment, WHO-stage, tuberculosis status, and year of ART initiation, CAA-positivity showed a trend of a decreased hazard of death/LFU (HR: 0.58, 95% CI: 0.32–1.05, p = 0.07), while CD4 count at baseline (HR: 0.86, 95% CI: 0.76–1.00, p = 0.02) and MXD (sum of eosinophils, basophils, and monocytes counts) >1,100 cells/μl (HR: 0.56, 95% CI: 0.34–0.93, p = 0.03) were identified as independently protective factors. Conclusions/Significance Schistosomiasis is prevalent in this HIV cohort and may be beneficial for immunological reconstitution, while no effect on virological failure was apparent. A positive effect of schistosomiasis-induced immunomodulation on survival and retention in care needs confirmation in future studies., Author summary Infections with HIV and blood flukes (Schistosoma) both exert chronic modulatory effects on the host’s immune system. Coinfections, meaning the host is simultaneously infected with both pathogens, are common in sub-Saharan Africa. In this situation the induced immune modulation of one pathogen may affect the course of the disease induced by the other pathogen. One study showed that coinfection with Schistosoma in people living with HIV who begin antiretroviral therapy (ART) may have deleterious effects on the reconstitution of the HIV-induced immunosuppression. In the current study, we investigated the effect of Schistosoma coinfection on the recovery of the patient’s immune system, on the efficacy of ART to suppress HIV replication, and on a combined endpoint of lost to follow-up or death. We found that schistosomiasis may have beneficial effects on immune reconstitution, while no deleterious effect was detected on HIV-suppressive efficacy of ART. Surprisingly, our data suggest that schistosomiasis-induced immunomodulatory effects might be beneficial for survival and retention in care. Future studies are warranted to confirm these findings. In the era of increasing access to ART in sub-Saharan Africa, the issue of schistosomiasis-HIV coinfection may have major consequences on the outcome of HIV treatment programs.

Background Differences in rural and urban settings could account for distinct characteristics in the epidemiology of tuberculosis (TB). We comparatively studied epidemiological features of TB and helminth co-infections in adult patients from rural and urban settings of Tanzania. Methods Adult patients (≥ 18 years) with microbiologically confirmed pulmonary TB were consecutively enrolled into two cohorts in Dar es Salaam, with ~ 4.4 million inhabitants (urban), and Ifakara in the sparsely populated Kilombero District with ~ 400 000 inhabitants (rural). Clinical data were obtained at recruitment. Stool and urine samples were subjected to diagnose helminthiases using Kato-Katz, Baermann, urine filtration, and circulating cathodic antigen tests. Differences between groups were assessed by χ2, Fisher’s exact, and Wilcoxon rank sum tests. Logistic regression models were used to determine associations. Results Between August 2015 and February 2017, 668 patients were enrolled, 460 (68.9%) at the urban and 208 (31.1%) at the rural site. Median patient age was 35 years (interquartile range [IQR]: 27–41.5 years), and 454 (68%) were males. Patients from the rural setting were older (median age 37 years vs. 34 years, P = 0.003), had a lower median body mass index (17.5 kg/m2 vs. 18.5 kg/m2, P