Immune reconstitution inflammatory syndrome associated with dermatophytoses in two HIV-1 positive patients in rural Tanzania: a case report

Immune reconstitution inflammatory syndrome associated with dermatophytoses (tinea-IRIS) may cause considerable morbidity. Yet, it has been scarcely reported and is rarely considered in the differential diagnosis of HIV associated cutaneous lesions in Africa. If identified, it responds well to antifungals combined with steroids. We present two cases of suspected tinea-immune reconstitution inflammatory syndrome from a large HIV clinic in rural Tanzania.; A first case was a 33 years-old female newly diagnosed HIV patient with CD4 count of 4 cells/μL (0 %), normal complete blood count, liver and renal function tests was started on co-formulated tenofovir/emtricitabine/efavirenz and prophylactic cotrimoxazole. Two weeks later she presented with exaggerated inflammatory hyperpigmented skin plaques with central desquamation, active borders and scratch lesions on the face, trunk and lower limbs. Tinea-IRIS was suspected and fluconazole (150 mg daily) and prednisolone (1 mg/Kg/day tapered down after 1 week) were given. Her symptoms subsided completely after 8 weeks of treatment, and her next CD4 counts had increased to 134 cells/μL (11 %). The second case was a 35 years-old female newly diagnosed with HIV. She had 1 CD4 cell/μL (0 %), haemoglobin 9.8 g/dl, and normal renal and liver function tests. Esophageal candidiasis and normocytic-normochromic anaemia were diagnosed. She received fluconazole, prophylactic cotrimoxazole and tenofovir/emtricitabine/efavirenz. Seven weeks later she presented with inflammatory skin plaques with elevated margins and central hyperpigmentation on the trunk, face and limbs in the frame of a good general recovery and increased CD4 counts (188 cells/μL, 6 %). Tinea-IRIS was suspected and treated with griseofulvin 500 mg daily and prednisolone 1 mg/Kg tapered down after 1 week, with total resolution of symptoms in 2 weeks.; The two cases had advanced immunosuppression and developed de-novo exaggerated manifestation of inflammatory lesions compatible with tinea corporis and tinea facies in temporal association with antiretroviral treatment initiation and good immunological response. This is compatible with unmasking tinea-IRIS, and reminds African clinicians about the importance of considering this entity in the differential diagnosis of patients with skin lesions developing after antiretroviral treatment initiation

Mortality in a cohort of people living with HIV in rural Tanzania, accounting for unseen mortality among those lost to follow-up

Mortality assessment in cohorts with high lost to follow-up (LTFU) is challenging in settings with limited civil registration systems. We aimed to assess mortality in a clinical cohort (KIULARCO) of HIV-infected persons in rural Tanzania, accounting for unseen deaths among participants LTFU. We included adults enrolled in 2005-2015 and traced a non-random sample of those LTFU. We estimated mortality using Kaplan-Meier methods with: A) routinely-captured data; B) crudely incorporating tracing data; C) weighting using tracing data to crudely correct for unobserved deaths among participants LTFU; and D) weighting using tracing data accounting for participant characteristics. We investigated associated factors using proportional hazards models. Among 7460 adults, 646 (9%) died, 883 (12%) transferred clinics, and 2911 (39%) were LTFU. Of 2010 (69%) traced participants, 325 (16%) were found: 131 (40%) died and 130 (40%) transferred. Five-year mortality estimates were A) 13.1%; B) 16.2%; C) 36.8%; D) 35.1%. Higher mortality was associated with male sex, referral as hospital in-patient, living close to the clinic, lower body mass index, more advanced WHO stage, lower CD4 count, and less time since antiretroviral therapy initiation. Adjusting for unseen deaths among participants LTFU approximately doubled the five-year mortality estimates. Our approach is applicable to other cohorts adopting targeted tracing

Body mass index trends and its impact of under and overweight on outcome among PLHIV on antiretroviral treatment in rural Tanzania: a prospective cohort study

INTRODUCTION: Increased body weight is an important risk factor for cardiovascular disease and is increasingly reported as a health problem in people living with HIV (PLHIV). There is limited data from rural sub-Saharan Africa, where malnutrition usually presents with both over- and undernutrition. We aimed to determine the prevalence and risk factors of underweight and overweight/obesity in PLHIV enrolled in a cohort in rural Tanzania before the introduction of integrase inhibitors. METHODS: This nested study of the prospective Kilombero and Ulanga Antiretroviral Cohort included adults aged ≥19 years initiated on antiretroviral therapy between 01/2013 and 12/2018 with follow-up through 06/2019. Body Mass Index (BMI) was classified as underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), or overweight/obese (≥25.0 kg/m2). Stratified piecewise linear mixed models were used to assess the association between baseline characteristics and follow-up BMI. Cox proportional hazard models were used to assess the association between time-updated BMI and death/loss to follow-up (LTFU). RESULTS: Among 2,129 patients, 22,027 BMI measurements (median 9 measurements: interquartile range 5-15) were analysed. At baseline, 398 (19%) patients were underweight and 356 (17%) were overweight/obese. The majority of patients were female (n = 1249; 59%), and aged 35-44 years (779; 37%). During the first 9 months, for every three additional months on antiretroviral therapy, BMI increased by 2% (95% confidence interval 1-2%, p<0.0001) among patients underweight at baseline and by 0.7% (0.5-0.6%, p 2 times the hazard of death/LTFU compared to participants with normal BMI. CONCLUSION: We found a double burden of malnutrition, with underweight being an independent predictor of mortality. Monitoring and measures to address both states of malnutrition among PLHIV should be integrated into routine HIV care

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

Prospective assessment of loss to follow-up: incidence and associated factors in a cohort of HIV-positive adults in rural Tanzania

Lifelong antiretroviral therapy (ART) improves health outcomes for HIV-positive individuals, but is jeopardized by irregular clinic attendance and hence poor adherence. Loss to follow-up (LTFU) is typically defined retrospectively but this may lead to biased inferences. We assessed incidence of and factors associated with LTFU, prospectively and accounting for recurrent LTFU episodes, in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) of HIV-positive persons in rural Tanzania.; We included adults (≥15 years) enrolled in 2005 to 2016, regardless of ART status, with follow-up through April 2017. LTFU was defined as >60 days late for a scheduled appointment. Participants could experience multiple LTFU episodes. We performed analyses based on the first (prospective) and last (retrospective) events observed during follow-up, and accounting for recurrent LTFU episodes. Time to LTFU was estimated using cumulative incidence functions. We assessed factors associated with LTFU using cause-specific proportional hazards, marginal means/rates, and Prentice, Williams and Peterson models.; Among 8087 participants (65% female, 60% aged ≥35 years, 42% WHO stage 3/4, and 47% CD4 count <200 cells/mm; 3; ), there were 8140 LTFU episodes, after which there were 2483 (31%) returns to care. One-year LTFU probabilities were 0.41 (95% confidence interval 0.40, 0.42) and 0.21 (0.20, 0.22) considering the first and last events respectively. Factors associated with LTFU were broadly consistent across different models: being male, younger age, never married, living far from the clinic, not having an HIV-positive partner, lower BMI, advanced WHO stage, not having tuberculosis, and shorter time since ART initiation. Associations between LTFU and pregnancy, CD4 count, and enrolment year depended on the analysis approach.; LTFU episodes were common and prompt tracing efforts are urgently needed. We identified socio-demographic and clinical characteristics associated with LTFU that can be used to target tracing efforts and to help inform the design of appropriate interventions. Incidence of and risk factors for LTFU differed based on the LTFU definition applied, highlighting the importance of appropriately accounting for recurrent LTFU episodes. We recommend using a prospective definition of LTFU combined with recurrent event analyses in cohorts where repeated interruptions in care are common

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

Prevalence, incidence and predictors of renal impairment in persons with HIV receiving protease-inhibitors in rural Tanzania

OBJECTIVE: Ritonavir-boosted protease inhibitors (bPI) in people living with HIV (PLWH) have been associated with renal impairment. Limited data are available from rural sub-Saharan Africa. METHODS: Using data from the Kilombero and Ulanga Antiretroviral Cohort Study (KIULARCO) in rural Tanzania from 2005-01/2020, we assessed the prevalence of renal impairment (estimated glomerular filtration rate <60 mL/min/1.73m2) at the time of switch from first-line antiretroviral treatment (ART) to bPI-regimen and the incidence of renal impairment on bPI. We assessed risk factors for renal impairment using logistic and Cox regression models. RESULTS: Renal impairment was present in 52/687 PLWH (7.6%) at the switch to bPI. Among 556 participants with normal kidney function at switch, 41 (7.4%) developed renal impairment after a median time of 3.5 (IQR 1.6-5.1) years (incidence 22/1,000 person-years (95%CI 16.1-29.8)). Factors associated with renal impairment at switch were older age (adjusted odds ratio (aOR) 1.55 per 10 years; 95%CI 1.15-2.11), body mass index (BMI) /=18kg/m2; 95%CI 1.28-6.14) and arterial hypertension (aOR 2.33; 95%CI 1.03-5.28). The risk of renal impairment was lower with increased duration of ART use (aOR 0.78 per one-year increase; 95%CI 0.67-0.91). The renal impairment incidence under bPI was associated with older age (adjusted hazard ratio 2.01 per 10 years; 95%CI 1.46-2.78). CONCLUSIONS: In PLWH in rural sub-Saharan Africa, prevalence and incidence of renal impairment among those who were switched from first-line to bPI-regimens were high. We found associations between renal impairment and older age, arterial hypertension, low BMI and time on ART

The Chronic Diseases Clinic of Ifakara (CDCI)- establishing a model clinic for chronic care delivery in rural sub-Saharan Africa

The rollout of antiretroviral drugs in sub-Saharan Africa to address the huge health impact of the HIV pandemic has been one of the largest projects undertaken in medical history and is an unprecedented medical success story. However, the path has been and still is characterized by many far reaching implementational challenges. Here, we report on the building and maintaining of a role model clinic in Ifakara, rural Southwestern Tanzania, within a collaborative project to support HIV services within the national program, training for staff and integrated research to better understand local needs and improve patients' outcomes

Failure to return pillbox is a predictor of being lost to follow-up among people living with HIV on antiretroviral therapy in rural Tanzania

OBJECTIVES: Pill count is used to assess drug adherence in people living with HIV (PLHIV). Carrying a pillbox is associated with fear of concealment and stigma and might indicate poor adherence and predict someone who will be lost to follow-up (LTFU). We therefore assessed the association between pillbox return and being LTFU in rural Tanzania. METHODS: This is a nested study of the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO). We included PLHIV aged >/= 18 years enrolled in KIULARCO between January 2013 and March 2019 with follow-up through January 2020, who were on antiretroviral treatment (ART) for >/= 6 months. Baseline was defined as the latest ART initiation or KIULARCO enrolment. We determined the association between time-dependent failed pillbox return updated at every visit and LTFU using Kaplan-Meier estimation and Cox models. RESULTS: Among 2552 PLHIV included in the study, 1735 (68.0%) were female, 959 (40.3%) had a WHO stage III/IV and 1487 (66.4%) had a CD4 cell count < 350 cells/microL. The median age was 38.4 years [interquartile range (IQR): 31.7-46.2]. During a median follow-up of 33.1 months (IQR: 17.5-52.4), 909 (35.6%) participants were LTFU, 43 (1.7%) died and 194 (7.6%) had transferred to another clinic. The probability of being LTFU was higher among PLHIV with failed pillbox return than among those who returned their pillbox [30.0%, 95% confidence interval (CI): 26.8-33.2% vs. 19.4%, 95% CI: 17.4-21.6%, respectively, at 24 months (hazard ratio = 1.67, 95% CI: 1.46-1.90; p < 0.001)]. CONCLUSIONS: Failed pillbox return was associated with a higher risk of being LTFU and could be used as a simple tool to identify PLHIV for appropriate interventions to reduce their chance of being LTFU