Optimization of HIV and tuberculosis co-treatment in Tanzania : drug-drug interactions and clinical outcomes

Background: Sub-Saharan Africa has been greatly affected by the HIV epidemic, with an estimated 23.5 million people living with HIV/AIDS (PLWHA) residing within this region by the end of 2011, being the leading course of morbidity and mortality. Tanzania is one of the countries in this region with an HIV prevalence of 5.7% i.e approximately 2.7 million PLWHA. The most common opportunistic infection in sub-Saharan Africa is tuberculosis (TB). Currently HIV and TB are the leading cause of morbidity and mortality in Tanzania. The management of these two infections in individuals with the dual infection is challenging due to drug-drug interactions that could potentially lead to toxicities or ineffective treatment outcomes for one or both diseases. This thesis aims to describe the socio-demographic and clinical characteristics as well as the clinical outcomes of treatment. Methods: We first performed a baseline study of a clinical HIV infected population enrolled at the HIV care and treatment centre (CTC) at Muhimbili National Hospital between June 2004 and September 2008. Based on this clinical experience, a cohort of HIV infected patients, with or without TB who were HAART naïve with CD4 cell counts <200cells/ μL were recruited and followed up for 48 weeks after HAART initiation. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of HAART therapy. Plasma efavirenz concentrations and CYP2B6*6, CYP3A5*3,*6 and *7, ABCB1 and SLCO1B1 genotypes were determined. A 29-item questionnaire on neuropsychiatric manifestations was collected up to week 16 of follow up. Results: Most patients presenting to the CTC had advanced immune deficiency. Significantly higher proportions were female patients. With the free access to HAART in the later years, patients presented earlier to the CTC in the course of HIV disease. For the co-infection cohort study a total of 255 HIV only patients and 231 HIV-TB patients were recruited. The HIV-TB patients had significantly lower body mass index, Karnofsky scores and haemoglobin compared to those with HIV only, despite similar baseline CD4 cell counts. Mortality was similar in both the HIV only and those with HIV-TB, being 10.9% (16 deaths/100person years) and 11.3% (17 deaths/100py) respectively with the predictors for mortality being advanced disease such as low CD4 counts, low baseline WBC, oral candidiasis and Kaposis sarcoma. HIV only patients had significantly higher plasma efavirenz concentrations compared to the HIV-TB patients 4 weeks after HAART initiation indicating an interaction with rifampicin. Female gender and those with CYP2B6*6/*6 genotype also had significantly higher plasma efavirenz concentrations. Pharmacogenetic variants play a role in plasma efavirenz concentrations and long-term efavirenz autoinduction. The proportion of patients with efavirenz concentrations below the therapeutic range (<1μg/ml) at week 16 was higher compared to the concentrations at week 4 predominantly affecting extensive metabolizers showing that efavirenz autoinduction continues up to week 16. The incidence of drug induced liver injury (DILI) was 7.8% being non-significantly higher in the HIV-TB patients compared to those with HIV only. The median time to DILI was 2 weeks and the predictors for DILI included CYP2B6*6/*6 genotype and a positive antibody result to hepatitis C infection, but not efavirenz concentrations. The overall incidence of neuropsychiatric manifestations was 57% and these were higher in the HIV only compared to those with HIV-TB (66.7% vs 47.4%). The HIV only patients were more symptomatic, with proportionately higher grades of manifestations compared to those with HIV-TB. The risk of neuropsychiatric manifestations was 3 times higher in HIV only compared to those with HIV-TB. There were comparable increases in the median body weight and median CD4 cell counts towards the end of the study between the HIV only and those with HIV-TB. A total of 11.7% (11 HIV only and 8 HIV-TB) of the patients were defined to have treatment failure. Conclusion: Patients enrolled at the CTCs are predominantly females, and present with advanced immune deficiency that ultimately puts them at a higher risk of dying. Pharmacogenetic variants influence efavirenz concentrations where slow metabolizers are at a higher risk of presenting with higher efavirenz concentrations, DILI and neuropsychiatric manifestations. The DILI seen in our setting is mild, transient and does not require treatment interruption. Patients using efavirenz alone are at a higher risk of developing neuropsychiatric manifestations compared to those who concomitantly use rifampicin. The WHO recommended efavirenz dosage of 600mg daily can be used with rifampicin among Tanzanian patients without compromise to their treatment outcomes

A Case-Control Study of Factors Associated with Non-Adherent to Antiretroviral Therapy Among HIV Infected People in Pwani Region, Eastern Tanzania

Non-adherence is one of the major causes of treatment failure which leads to increased morbidity and mortality caused by opportunistic infections. Optimal anti-retroviral therapy (ART) adherence is essential for maximal suppression of viral replication and long term survival of patients. In order to develop effective public health interventions in the context of scaling ART services to peripheral areas, it is important to evaluate factors associated with non-adherence among HIV-infected individuals in Pwani Region. The purpose of this study was to identify factors related to non-adherence to ART among HIV infected people in Pwani Region eastern of Tanzania. A case-control study was carried out at Tumbi Hospital and Chalinze Health Centre in Pwani Region in eastern Tanzania. A structured questionnaire was used to assess non-adherence and adherence to doses instruction and time schedule. Patients with less than 95% adherence were defined as cases while those with more than 95% adherence became controls. A structured questionnaire containing factors known to be associated with non-adherence to ART in similar settings was administered. Univariate and multivariate conditional logistic regression was performed to identify factors associated with non-adherence. A total of 79 cases and 237 controls matched by age and sex were studied. A high proportion of cases and controls (77.2% and 84.8%) had good knowledge of ART benefits, adherence and eligibility. Majority of cases (73.3%) and controls (69.2%) used public transport to access ART services. More than half of cases (53.2%) missed clinic appointments due to lack of bus fare or other reasons and was associated with ART non adherence (mOR 4.2, 95%CI, 2.2-8.1 and 2.1,95%CI 1.2-4.2). Disclosure to confidants only and failure to disclose HIV-test positive status were associated with non adherence (mOR 3.3, 95%CI 1.3-8.5 and 2.3, 95%CI 1.2-7.1). Alcohol use was associated with non adherence to ART (mOR 1.9, 95%CI 1.4-3.7). Patients who were not satisfied with providers were more likely to be non adherence to ART (mOR 2.0, 95%CI 1.2-3.8). In conclusion, these findings show that adherence is a process which is depended on local specific adherence factors. Adherence improvement strategies need to consider site specific adherence determinants, patient experiences and concern

Risk Factors for Anaemia Among HIV Infected Children Attending Care and Treatment Clinic at Muhimbili National Hospital in Dar es Salaam, Tanzania

There is paucity of data describing the risk factors for anaemia among HIV infected children in Tanzania. This cross sectional study was carried out to determine the contributing factors for anaemia among HIV-infected children attending Muhimbili National Hospital in Dar es Salaam. Both univariate and multivariate logistic regression analyses were performed to identify possible factors associated with anaemia in HIV-infected children. A total of 75 (44%) patients among 167 recruited HIV-infected children aged 6 months to 59 months of were found to be anaemic (Hg<11g/dl). Multivariate logistic regression demonstrated that not being on HAART (OR 3.40, 95%CI (1.20-9.60), having CD4% <25% (OR 2.30, 95%CI (1.20-34.60), having a history of tuberculosis (TB) (OR 3.23, 95%CI (1.10-9.70) and having hookworm infestation (OR 5.97, 95%CI (1.92-18.4) were independent risk factors for anaemia among HIV infected children. The analyses also showed that being HIV positive for ≥ 2.5 years resulted into a low risk of severe anaemia compared to being HIV positive for < 2.5 years. Taking multivitamins (OR 0.07, 95%, CI (0.020-0.30) and antihelminthics (OR 0.27, 95%CI (0.10-0.74) were also protective against anaemia in children. Similar factors (with exception of using antihelmintics) were associated with severe anaemia. In conclusion the factors associated with anaemia in HIV infected children were multifactorial in nature. Efforts to correct anaemia in HIV infected children should include use of HAART and treatment of infections such as TB and hookworms

Prevalence and risk factors for obstructive sleep apnoea in Dar es Salaam, Tanzania

Background: Obstructive sleep apnoea (OSA) is a common cause of daytime sleepiness, a condition associated with accidents, antisocial behaviour, mood disturbances, cognitive dysfunctions and inefficiency at work. This study was carried out to determine the prevalence and risk factors for obstructive sleep apnoea in Dar es Salaam, Tanzania.Methods: Multistage random sampling of households was done. Eligible members were interviewed and underwent anthropometric measurements. Epiworth sleepiness scale was used to asses one’s likelihood of daytime sleepiness. OSA was defined as the presence of 2 of the following: symptoms of obstructive sleep apnoea, a Body Mass Index (BMI) ≥ 28 kg/ m² and a total Epworth score≥ 15.Results: A total of 1249 people were involved in the study. Of these, 65.2% were females. Night snoring was reported by 9.3% of the respondents. The prevalence of OSA was 11.5% (144/1249). OSA was significantly more common among females (12.9%) (p = 0.038) than males. OSA prevalence increased significantly with increasing age (p &lt;0.001) and increasing BMI (p- value &lt; 0.001).  Respondents with hypertension, central obesity and those who snored at night significantly presented with high prevalence of OSA, being 26.5%, 34% and 29.3%, respectively (p- value &lt;0.001 for each). OSA was found in 26.3% of diabetics (p= 0.042). The odds of OSA were significantly higher among females, OR (95% CI) = 2.0 (1.2-3.2), among age group 45-54 years, OR (95% CI) = 2.2 (1.1-4.3), among those with central obesity OR (95% CI) = 3.4 (2.1- 5.4) and among night snorers OR (95% CI) = 2.8(1.7-4.6). Socio-economic status, cigarette smoking, alcohol consumption, hypertension and diabetes mellitus could not predict OSA.Conclusions: OSA is prevalent among residents of Dar es Salaam and significantly associated with age 45 years or older, female gender, high socioeconomic status, obesity and overweight and night snoring. Predictors of OSA were female sex, age above 45 years, central obesity, and night snoring. Clinicians should therefore actively look for OSA in patients with these characteristics.

Vitamin D Status and TB Treatment Outcomes in Adult Patients in Tanzania: A Cohort Study.

Vitamin D is an immunomodulator and can alter response to tuberculosis (TB) treatment, though randomised trials have been inconclusive to date. We present one of the first comprehensive analysis of the associations between vitamin D status and TB treatment, T-cell counts and nutritional outcomes by HIV status. Cohort study. Outpatient clinics in Tanzania. 25-hydroxyvitamin D levels were assessed in a cohort of 677 patients with TB (344 HIV infected) initiating anti-TB treatment at enrolment in a multivitamin supplementation (excluding vitamin D) trial (Clinicaltrials.gov identifier: NCT00197704). Information on treatment outcomes such as failure and relapse, HIV disease progression, T-cell counts and anthropometry was collected routinely, with a median follow-up of 52 and 30 months for HIV-uninfected and HIV-infected patients, respectively. Cox and binomial regression, and generalised estimating equations were used to assess the association of vitamin D status with these outcomes. Mean 25-hydroxyvitamin D concentrations at enrolment were 69.8 (±21.5) nmol/L (27.9 (±8.6) ng/mL). Vitamin D insufficiency (<75 nmol/L) was associated with a 66% higher risk of relapse (95% CI 4% to 164%; 133% higher risk in HIV-uninfected patients). Each unit higher 25-hydroxyvitamin D levels at baseline were associated with a decrease of 3 (p=0.004) CD8 and 3 (p=0.01) CD3 T-cells/µL during follow-up in patients with HIV infection. Vitamin D insufficiency was also associated with a greater decrease of body mass index (BMI; -0.21 kg/m(2); 95% CI -0.39 to -0.02), during the first 8 months of follow-up. No association was observed for vitamin D status with mortality or HIV disease progression. Adequate vitamin D status is associated with a lower risk of relapse and with improved nutritional indicators such as BMI in patients with TB, with or without HIV infection. Further research is needed to determine the optimal dose of vitamin D and effectiveness of daily vitamin D supplementation among patients with TB

A Trial of the Effect of Micronutrient Supplementation on Treatment Outcome, T Cell Counts, Morbidity, and Mortality in Adults with Pulmonary Tuberculosis.

Tuberculosis (TB) often coincides with nutritional deficiencies. The effects of micronutrient supplementation on TB treatment outcomes, clinical complications, and mortality are uncertain. We conducted a randomized, double-blind, placebo-controlled trial of micronutrients (vitamins A, B complex, C, and E, as well as selenium) in Dar es Salaam, Tanzania. We enrolled 471 human immunodeficiency virus (HIV)-infected and 416 HIV-negative adults with pulmonary TB at the time of initiating chemotherapy and monitored them for a median of 43 months. Micronutrients decreased the risk ofTB recurrence by 45% overall (95% confidence interval [CI], 7% to 67%; P = .02) and by 63% in HIV-infected patients (95% CI, 8% to 85%; P = .02). There were no significant effects on mortality overall; however, we noted a marginally significant 64% reduction of deaths in HIV-negative subjects (95% CI, -14% to 88%; P = .08). Supplementation increased CD3+ and CD4+ cell counts and decreased the incidence of extrapulmonary TB and genital ulcers in HIV-negative patients. Micronutrients reduced the incidence of peripheral neuropathy by 57% (95% CI, 41% to 69%; P < .001), irrespective of HIV status. There were no significant effects on weight gain, body composition, anemia, or HIV load. Micronutrient supplementation could improve the outcome in patients undergoing TB chemotherapy in Tanzania

Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-group Prospective Cohort Study in two sub-Saharan Africa Populations.

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations

The prevalence and pattern of antibiotic prescription among insured patients in Dar es Salaam Tanzania

Introduction:&nbsp;high prevalence of antibiotic prescriptions may contribute to the problem of antibiotic resistance. Understanding the pattern of antibiotic prescriptions in a country may inform monitoring and stewardship activities, which are crucial in the fight against antibiotic resistance. We aimed to determine the prevalence and describe the pattern of antibiotic prescriptions among National Health Insurance Fund (NHIF) insured patients receiving treatment at health facilities in Ilala Municipality, Dar es Salaam, Tanzania. Methods:&nbsp;a cross-sectional analysis of claim forms of NHIF insured patients. A data extraction form was used to capture data for September, 2019 submitted to the Ilala NHIF offices. Results:&nbsp;among 993 insured patients (mean [±SD] age 36.3 [±23.2] years; 581 [58.5%] females; 535 [53.9%] adults) a total of 357 (46.4%, 95% CI, 42.8-50.0) received an antibiotic prescription. Of the 357 patients who received an antibiotic prescription, 71(19.9%) received more than one antibiotic prescription. The most common antibiotic prescribed was amoxicillin/clavulanate (17.1%) followed by amoxicillin (16.5%) whereas the most commonly prescribed antibiotic class was the penicillins (51.3%) followed by the nitroimidazoles (14.0%). Among patients who received more than one antibiotic, the most commonly co-prescribed antibiotics were Ampicillin/Cloxacillin plus Metronidazole (11.4%) followed by Amoxicillin plus Metronidazole (7.1%). According to 2019 WHO Access, Watch, Reserve (AWaRe) Classification of antibiotics, 60.8% of patients received the access antibiotics, 33.3% received the watch antibiotics whereas 17.4% of patients received antibiotics that were not recommended. No patient received an antibiotic from the reserve group. Conclusion:&nbsp;the prevalence of antibiotic prescriptions in Tanzania is high and some antibiotics not recommended by the WHO are still prescribed. We recommend revision of the current Tanzania treatment guideline on antibiotics to reflect WHO recommendations, and further research to address local factors influencing antibiotic prescriptions is warranted

Management of HIV and AIDS at lower primary health care facility in Chalinze, eastern Tanzania

Implementation of Antiretroviral Therapy (ART) services at health centres in Tanzania were delayed due to several reasons including shortage of qualified staff, inadequate infrastructure and logistics problems. However, patients from peripheral areas experienced difficulties in accessing ART services due to long distances from clinics. National AIDS Control Programme (NACP) and Non-Governmental Organizations (NGOs) embarked on ART services scale-up programme aimed at improved ART availability and accessibility. Through this programme ART services were established at health centres and selected dispensaries. However, no previous documented experiences existed at country level to guide provision of services. Therefore, this study was designed to gather experiences and share lessons learnt with other health care providers and programme implementing partners. This was a descriptive cross-sectional study involved patients enrolled to ART services between May 2007 and April 2009. Data collection involved observation of health providers’ performance and retrospective ART and care patients’ registers review. During the study period, 611 care and 284 ART patients were attended. Majority of patients (85.1%; 762/895) were adults aged 25-45 years. In total 61.5% (550/895) of the patients had CD4+T lymphocytes ≤350/µl the cut-off point for initiating ART. The frequency of symptoms was noted to significantly decrease with increasing CD4 counts (

Lung functions among patients with pulmonary tuberculosis in Dar es Salaam – a cross-sectional study

Background Approximately 40–60 % of patients remain sufferers of sequela of obstructive, restrictive or mixed patterns of lung disease despite treatment for pulmonary tuberculosis (PTB). The prevalence of these abnormalities in Tanzania remains unknown. Methods A descriptive cross-sectional study was carried out among 501 patients with PTB who had completed at least 20 weeks of treatment. These underwent spirometry and their lung functions were classified as normal or abnormal (obstructive, restrictive or mixed). Logistic regression models were used to explore factors associated with abnormal lung functions. Results Abnormal lung functions were present in 371 (74 %) patients. There were 210 (42 %) patients with obstructive, 65 (13 %) patients with restrictive and 96 (19 %) patients with mixed patterns respectively. Significant factors associated with abnormal lung functions included recurrent PTB (Adj OR 2.8, CI 1.274 - 6.106), Human Immunodeficiency Virus (HIV) negative status (Adj OR 1.7, CI 1.055 - 2.583), age more than 40 years (Adj OR 1.7, CI 1.080 - 2.804) and male sex (Adj OR 1.7, CI 1.123 - 2.614). Conclusion The prevalence of abnormal lung functions is high and it is associated with male sex, age older than 40 years, recurrent PTB and HIV negative status