Transitioning to Dolutegravir in a Programmatic Setting: Virological Outcomes and Associated Factors Among Treatment-Naive Patients With HIV-1 in the Kilombero and Ulanga Antiretroviral Cohort in Rural Tanzania.

BACKGROUND Virological outcome data after programmatic transition from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based to dolutegravir (DTG)-based antiretroviral therapy (ART) regimens in sub-Saharan Africa (SSA) outside of clinical trials are scarce. We compared viral suppression and associated factors in treatment-naïve people living with HIV (PLHIV) starting DTG- based versus NNRTI-based ART. METHODS We compared virological suppression at 12 months, after treatment initiation in the two cohorts of participants aged ≥15 years, initiating DTG- and NNRTI-based ART. Drug resistance was assessed among participants with viremia ≥50 copies/mL on DTG. RESULTS Viral suppression was achieved for 165/195 (85%) and 154/211 (73%) participants in the DTG- and NNRTI- cohorts, respectively (P = 0.003). DTG-based ART was associated with >2 times the odds of viral suppression versus NNRTI-based ART (adjusted odds ratio, 2.10 [95% confidence interval {CI}, 1.12-3.94]; adjusted risk ratio, 1.11 [95% CI, 1.00-1.24]). HIV-1 genotypic resistance testing (GRT) before ART initiation was done in 14 of 30 viremic participants on DTG, among whom nucleoside reverse transcriptase inhibitor (NRTI), NNRTI, and protease inhibitors resistance was detected in 0 (0%), 2 (14%) and 1 (7%), respectively. No resistance was found in the 2 of 30 participants with available GRT at the time of viremia ≥50 copies/mL. CONCLUSIONS Virological suppression at 1 year was higher in participants initiating DTG- versus NNRTI-based ART. In those with viremia ≥50 copies/mL on DTG-based ART, there was no pretreatment or acquired resistance to the DTG co-administered NRTIs, although the number of samples tested was small

A Bundle of Services Increased Ascertainment of Tuberculosis among HIV-Infected Individuals Enrolled in a HIV Cohort in Rural Sub-Saharan Africa

OBJECTIVES: To report on trends of tuberculosis ascertainment among HIV patients in a rural HIV cohort in Tanzania, and assessing the impact of a bundle of services implemented in December 2012, consisting of three components:(i)integration of HIV and tuberculosis services; (ii)GeneXpert for tuberculosis diagnosis; and (iii)electronic data collection. DESIGN: Retrospective cohort study of patients enrolled in the Kilombero Ulanga Antiretroviral Cohort (KIULARCO), Tanzania.). METHODS: HIV patients without prior history of tuberculosis enrolled in the KIULARCO cohort between 2005 and 2013 were included.Cox proportional hazard models were used to estimate rates and predictors of tuberculosis ascertainment. RESULTS: Of 7114 HIV positive patients enrolled, 5123(72%) had no history of tuberculosis. Of these, 66% were female, median age was 38 years, median baseline CD4+ cell count was 243 cells/microl, and 43% had WHO clinical stage 3 or 4. During follow-up, 421 incident tuberculosis cases were notified with an estimated incidence of 3.6 per 100 person-years(p-y)[95% confidence interval(CI)3.26-3.97]. The incidence rate varied over time and increased significantly from 2.96 to 43.98 cases per 100 p-y after the introduction of the bundle of services in December 2012. Four independent predictors of tuberculosis ascertainment were identified:poor clinical condition at baseline (Hazard Ratio (HR) 3.89, 95% CI 2.87-5.28), WHO clinical stage 3 or 4 (HR 2.48, 95% CI 1.88-3.26), being antiretroviralnaive (HR 2.97, 95% CI 2.25-3.94), and registration in 2013(HR 6.07, 95% CI 4.39-8.38). CONCLUSION: The integration of tuberculosis and HIV services together with comprehensive electronic data collection and use of GeneXpert increased dramatically the ascertainment of tuberculosis in this rural African HIV cohort

High failure rates of protease inhibitor-based antiretroviral treatment in rural Tanzania - a prospective cohort study

Poor adherence to antiretroviral drugs and viral resistance are the main drivers of treatment failure in HIV-infected patients. In sub-Saharan Africa, avoidance of treatment failure on second-line protease inhibitor therapy is critical as treatment options are limited.; In the prospective observational study of the Kilombero & Ulanga Antiretroviral Cohort in rural Tanzania, we assessed virologic failure (viral load ≥1,000 copies/mL) and drug resistance mutations in bio-banked plasma samples 6-12 months after initiation of a protease inhibitor-based treatment regimen. Additionally, viral load was measured before start of protease inhibitor, a second time between 1-5 years after start, and at suspected treatment failure in patients with available bio-banked samples. We performed resistance testing if viral load was ≥1000 copies/ml. Risk factors for virologic failure were analyzed using logistic regression.; In total, 252 patients were included; of those 56% were female and 21% children. Virologic failure occurred 6-12 months after the start of a protease inhibitor in 26/199 (13.1%) of adults and 7/53 of children (13.2%). The prevalence of virologic failure did not change over time. Nucleoside reverse transcriptase inhibitors drug resistance mutation testing performed at 6-12 months showed a positive signal in only 9/16 adults. No cases of resistance mutations for protease inhibitors were seen at this time. In samples taken between 1-5 years protease inhibitor resistance was demonstrated in 2/7 adults. In adult samples before protease inhibitor start, resistance to nucleoside reverse transcriptase inhibitors was detected in 30/41, and to non-nucleoside reverse-transcriptase inhibitors in 35/41 patients. In 15/16 pediatric samples, resistance to both drug classes but not for protease inhibitors was present.; Our study confirms high early failure rates in adults and children treated with protease inhibitors, even in the absence of protease inhibitors resistance mutations, suggesting an urgent need for adherence support in this setting

Cryptococcal Antigenemia in Immunocompromised Human Immunodeficiency Virus Patients in Rural Tanzania: A Preventable Cause of Early Mortality

Background. Cryptococcal meningitis is a leading cause of death in people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome. The World Health Organizations recommends pre-antiretroviral treatment (ART) cryptococcal antigen (CRAG) screening in persons with CD4 below 100 cells/microL. We assessed the prevalence and outcome of cryptococcal antigenemia in rural southern Tanzania. Methods. We conducted a retrospective study including all ART-naive adults with CD4 <150 cells/microL prospectively enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2008 and 2012. Cryptococcal antigen was assessed in cryopreserved pre-ART plasma. Cox regression estimated the composite outcome of death or loss to follow-up (LFU) by CRAG status and fluconazole use. Results. Of 750 ART-naive adults, 28 (3.7%) were CRAG-positive, corresponding to a prevalence of 4.4% (23 of 520) in CD4 <100 and 2.2% (5 of 230) in CD4 100-150 cells/microL. Within 1 year, 75% (21 of 28) of CRAG-positive and 42% (302 of 722) of CRAG-negative patients were dead or LFU (P<.001), with no differences across CD4 strata. Cryptococcal antigen positivity was an independent predictor of death or LFU after adjusting for relevant confounders (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.29-4.83; P = .006). Cryptococcal meningitis occurred in 39% (11 of 28) of CRAG-positive patients, with similar retention-in-care regardless of meningitis diagnosis (P = .8). Cryptococcal antigen titer >1:160 was associated with meningitis development (odds ratio, 4.83; 95% CI, 1.24-8.41; P = .008). Fluconazole receipt decreased death or LFU in CRAG-positive patients (HR, 0.18; 95% CI, .04-.78; P = .022). Conclusions. Cryptococcal antigenemia predicted mortality or LFU among ART-naive HIV-infected persons with CD4 <150 cells/microL, and fluconazole increased survival or retention-in-care, suggesting that targeted pre-ART CRAG screening may decrease early mortality or LFU. A CRAG screening threshold of CD4 <100 cells/microL missed 18% of CRAG-positive patients, suggesting guidelines should consider a higher threshold

Prevention of mother-to-child transmission of HIV Option B+ cascade in rural Tanzania: The One Stop Clinic model

BACKGROUND: Strategies to improve the uptake of Prevention of Mother-To-Child Transmission of HIV (PMTCT) are needed. We integrated HIV and maternal, newborn and child health services in a One Stop Clinic to improve the PMTCT cascade in a rural Tanzanian setting. METHODS: The One Stop Clinic of Ifakara offers integral care to HIV-infected pregnant women and their families at one single place and time. All pregnant women and HIV-exposed infants attended during the first year of Option B+ implementation (04/2014-03/2015) were included. PMTCT was assessed at the antenatal clinic (ANC), HIV care and labour ward, and compared with the pre-B+ period. We also characterised HIV-infected pregnant women and evaluated the MTCT rate. RESULTS: 1,579 women attended the ANC. Seven (0.4%) were known to be HIV-infected. Of the remainder, 98.5% (1,548/1,572) were offered an HIV test, 94% (1,456/1,548) accepted and 38 (2.6%) tested HIV-positive. 51 were re-screened for HIV during late pregnancy and one had seroconverted. The HIV prevalence at the ANC was 3.1% (46/1,463). Of the 39 newly diagnosed women, 35 (90%) were linked to care. HIV test was offered to >98% of ANC clients during both the pre- and post-B+ periods. During the post-B+ period, test acceptance (94% versus 90.5%, p<0.0001) and linkage to care (90% versus 26%, p<0.0001) increased. Ten additional women diagnosed outside the ANC were linked to care. 82% (37/45) of these newly-enrolled women started antiretroviral treatment (ART). After a median time of 17 months, 27% (12/45) were lost to follow-up. 79 women under HIV care became pregnant and all received ART. After a median follow-up time of 19 months, 6% (5/79) had been lost. 5,727 women delivered at the hospital, 20% (1,155/5,727) had unknown HIV serostatus. Of these, 30% (345/1,155) were tested for HIV, and 18/345 (5.2%) were HIV-positive. Compared to the pre-B+ period more women were tested during labour (30% versus 2.4%, p<0.0001). During the study, the MTCT rate was 2.2%. CONCLUSIONS: The implementation of Option B+ through an integrated service delivery model resulted in universal HIV testing in the ANC, high rates of linkage to care, and MTCT below the elimination threshold. However, HIV testing in late pregnancy and labour, and retention during early ART need to be improved

Absence of hepatitis delta infection in a large rural HIV cohort in Tanzania

OBJECTIVES: The epidemiological and clinical determinants of hepatitis delta virus (HDV) infection in Sub-Saharan Africa are ill-defined. The prevalence of HDV infection was determined in HIV/hepatitis B virus (HBV) co-infected individuals in rural Tanzania. METHODS: All hepatitis B virus (HBV)-infected adults under active follow-up in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) were screened for anti-HDV antibodies. For positive samples, a second serological test and nucleic acid amplification were performed. Demographic and clinical characteristics at initiation of antiretroviral therapy (ART) were compared between anti-HDV-negative and positive patients. RESULTS: Among 222 HIV/HBV co-infected patients on ART, 219 (98.6%) had a stored serum sample available and were included in the study. Median age was 37 years, 55% were female, 46% had World Health Organization stage III/IV HIV disease, and the median CD4 count was 179 cells/mul. The prevalence of anti-HDV positivity was 5.0% (95% confidence interval 2.8-8.9%). There was no significant predictor of anti-HDV positivity. HDV could not be amplified in any of the anti-HDV-positive patients and the second serological test was negative in all of them. CONCLUSIONS: No confirmed case of HDV infection was found among over 200 HIV/HBV co-infected patients in Tanzania. As false-positive serology results are common, screening results should be confirmed with a second test

The epidemiology of residual Plasmodium falciparum malaria transmission and infection burden in an African city with high coverage of multiple vector control measures.

BACKGROUND In the Tanzanian city of Dar es Salaam, high coverage of long-lasting insecticidal nets (LLINs), larvicide application (LA) and mosquito-proofed housing, was complemented with improved access to artemisinin-based combination therapy and rapid diagnostic tests by the end of 2012. METHODS Three rounds of city-wide, cluster-sampled cross-sectional surveys of malaria parasite infection status, spanning 2010 to 2012, were complemented by two series of high-resolution, longitudinal surveys of vector density. RESULTS Larvicide application using a granule formulation of Bacillus thuringiensis var. israelensis (Bti) had no effect upon either vector density (P = 0.820) or infection prevalence (P = 0.325) when managed by a private-sector contractor. Infection prevalence rebounded back to 13.8 % in 2010, compared with <2 % at the end of a previous Bti LA evaluation in 2008. Following transition to management by the Ministry of Health and Social Welfare (MoHSW), LA consistently reduced vector densities, first using the same Bti granule in early 2011 [odds ratio (OR) (95 % confidence interval (CI)) = 0.31 (0.14, 0.71), P = 0.0053] and then a pre-diluted aqueous suspension formulation from mid 2011 onwards [OR (95 % CI) = 0.15 (0.07, 0.30), P ≪ 0.000001]. While LA by MoHSW with the granule formulation was associated with reduced infection prevalence [OR (95 % CI) = 0.26 (0.12, 0.56), P = 0.00040], subsequent liquid suspension use, following a mass distribution to achieve universal coverage of LLINs that reduced vector density [OR (95 % CI) = 0.72 (0.51, 1.01), P = 0.057] and prevalence [OR (95 % CI) = 0.80 (0.69, 0.91), P = 0.0013], was not associated with further prevalence reduction (P = 0.836). Sleeping inside houses with complete window screens only reduced infection risk [OR (95 % CI) = 0.71 (0.62, 0.82), P = 0.0000036] if the evenings and mornings were also spent indoors. Furthermore, infection risk was only associated with local vector density [OR (95 % CI) = 6.99 (1.12, 43.7) at one vector mosquito per trap per night, P = 0.037] among the minority (14 %) of households lacking screening. Despite attenuation of malaria transmission and immunity, 88 % of infected residents experienced no recent fever, only 0.4 % of these afebrile cases had been treated for malaria, and prevalence remained high (9.9 %) at the end of the study. CONCLUSIONS While existing vector control interventions have dramatically attenuated malaria transmission in Dar es Salaam, further scale-up and additional measures to protect against mosquito bites outdoors are desirable. Accelerated elimination of chronic human infections persisting at high prevalence will require active, population-wide campaigns with curative drugs

The Influence of Physiological Status on age Prediction of Anopheles Arabiensis Using Near Infra-red spectroscopy

Determining the age of malaria vectors is essential for evaluating the impact of interventions that reduce the survival of wild mosquito populations and for estimating changes in vectorial capacity. Near infra-red spectroscopy (NIRS) is a simple and non-destructive method that has been used to determine the age and species of Anopheles gambiae s.l. by analyzing differences in absorption spectra. The spectra are affected by biochemical changes that occur during the life of a mosquito and could be influenced by senescence and also the life history of the mosquito, i.e., mating, blood feeding and egg-laying events. To better understand these changes, we evaluated the influence of mosquito physiological status on NIR energy absorption spectra. Mosquitoes were kept in individual cups to permit record keeping of each individual insect’s life history. Mosquitoes of the same chronological age, but at different physiological stages, were scanned and compared using cross-validations. We observed a slight trend within some physiological stages that suggest older insects tend to be predicted as being physiologically more mature. It was advantageous to include mosquitoes of different chronological ages and physiological stages in calibrations, as it increases the robustness of the model resulting in better age predictions. Progression through different physiological statuses of An. arabiensis influences the chronological age prediction by the NIRS. Entomologists that wish to use NIR technology to predict the age of field-caught An. gambiae s.l from their study area should use a calibration developed from their field strain using mosquitoes of diverse chronological ages and physiological stages to increase the robustness and accuracy of the predictions.\u

Cohort profile: the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO): a prospective HIV cohort in rural Tanzania

The Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) is a single-site, open and ongoing prospective cohort of people living with human immunodeficiency virus (PLWHIV) established in 2005 at the Chronic Diseases Clinic of Ifakara (CDCI), within the Saint Francis Referral Hospital (SFRH) in Ifakara, Tanzania. The objectives of KIULARCO are to (i) provide patient and cohort-level information on the outcomes of HIV treatment; (ii) provide cohort-level information on opportunistic infections and comorbidities; (iii) evaluate aspects of human immunodeficiency virus (HIV) care and treatment that have national or international policy relevance; (iv) provide a platform for studies on improving HIV care and treatment in sub-Saharan Africa; and (v) contribute to generating local capacity to deal with the challenges posed by the HIV/AIDS pandemic in this region. Moreover, KIULARCO may serve as a model for other healthcare settings in rural sub-Saharan Africa. Since 2005, all patients diagnosed with HIV at the Saint Francis Referral Hospital are invited to participate in the cohort, including non-pregnant adults, pregnant women, adolescents, children and infants. The information collected includes demographics, baseline and follow-up clinical data, laboratory data, medication history, drug toxicities, diagnoses and outcomes. Real-time data are captured during the patient encounter through an electronic medical record system that allowed transition to a paperless clinic in 2013. In addition, KIULARCO is associated with a biobank of cryopreserved plasma samples and cell pellets collected from all participants before and at different time-points during antiretroviral treatment. Up to the end of 2016, 12 185 PLWHIV have been seen at the CDCI; 9218 (76%) of whom have been enrolled into KIULARCO and 6965 (76%) of these have received ART from the clinic. Patients on ART attend at least every 3 months, with laboratory monitoring every 6 months. KIULARCO data have been used to generate relevant information regarding ART outcomes, opportunistic infections, non-AIDS comorbidities, prevention of mother-to-child transmission of HIV, paediatric HIV, and mortality and retention in care. Requests for collaborations on analyses can be submitted to the KIULARCO scientific committee. KIULARCO provides a framework for improving the quality of care of people living with HIV in sub-Saharan Africa, to generate relevant information to evaluate ART programmes and to build local capacity to deal with HIV/AIDS. The comprehensiveness of the data collected, together with the biobank spanning over ten years has created a unique research platform in rural sub-Saharan Africa

Prevalence and Outcomes of Hepatitis B Co-infection and Associated Liver Disease Among Antiretroviral Therapy-Naive Individuals in a Rural Tanzanian Human Immunodeficiency Virus Cohort

Background. We evaluated the prevalence of chronic hepatitis B virus (HBV) infection and liver fibrosis/cirrhosis in human immunodeficiency virus (HIV)-infected individuals enrolled in a rural Tanzanian prospective cohort and assessed hepatic fibrosis progression 12–24 months after antiretroviral treatment (ART) initiation. Methods. All ART-naive HIV-infected adults ≥15-year-old enrolled in the Kilombero and Ulanga Antiretroviral Cohort who started ART between 2005 and 2015 were included. Pre-ART factors associated with significant liver fibrosis (aspartate aminotransferase-to-platelet ratio index [APRI] >1.5) and cirrhosis (APRI > 2.0) were identified using logistic regression. Results. Of 3097 individuals screened, 227 (7.3%; 95% CI, 6.4–8.2) were hepatitis B surface antigen (HBsAg) positive. Before ART initiation, 9.1% individuals had significant liver fibrosis and 5.3% had cirrhosis. Human immunodeficiency virus/HBVcoinfected individuals were more likely to have an APRI score indicating significant fibrosis (14.2% vs 8.7%, P = .03) and cirrhosis (9.2% vs 4.9%, P = .03) than HBV-uninfected patients. CD4 cell count <200 cell/μL and alcohol consumption were independently associated with pre-ART APRI score, indicating significant fibrosis and cirrhosis in multivariable analyses. Among individuals with elevated APRI measurements pre- and 12–24 months post-ART initiation, 53 of 57 (93.0%) of HIV-monoinfected and 4 of 5 (80.0%) of HIV/HBV-coinfected had a regression to APRI < 1.5. Conclusions. Hepatic fibrosis and cirrhosis were common in our cohort, especially among HIV/HBV-coinfected individuals. The APRI improved in most patients. Pre-ART HBsAg screening and early onset of tenofovir-based ART for HIV/HBV-coinfection should be prioritized in sub-Saharan Africa