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

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

Drug resistance testing through remote genotyping and predicted treatment options in human immunodeficiency virus type 1 infected Tanzanian subjects failing first or second line antiretroviral therapy

Antiretroviral therapy (ART) has been successfully introduced in low-middle income countries. However an increasing rate of ART failure with resistant virus is reported. We therefore described the pattern of drug resistance mutations at antiretroviral treatment (ART) failure in a real-life Tanzanian setting using the remote genotyping procedure and thereafter predicted future treatment options using rule-based algorithm and the EuResist bioinformatics predictive engine. According to national guidelines, the default first-line regimen is tenofovir + lamivudine + efavirenz, but variations including nevirapine, stavudine or emtricitabine can be considered. If failure on first-line ART occurs, a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and boosted lopinavir or atazanavir is recommended

Risk Factors for Mortality among HIV-Positive Patients with and Without Active Tuberculosis in Dar es Salaam, Tanzania.

The aim of this study was to describe risk factors for mortality and clinical characteristics of HIV-infected patients with and without tuberculosis (TB) coinfection. A cohort of HIV-infected patients with CD4(+) T-cell counts of ≤200 cells/μl was recruited, consisting of 255 HIV-infected patients without active TB and 231 patients with active TB. All received a well-supervised treatment with an efavirenz-based HAART, and those coinfected with TB received appropriate anti-TB treatment. They were followed up for 48 weeks after HAART initiation. Common presenting symptoms in HIV-only patients were fever (36.5%), headache (34.5%), skin rash (34.5%) and weight loss (32%), while in HIV-TB patients the symptoms were weight loss (58%), cough (57.6%), night sweats (44.6%) and fever (34.2%). HIV-TB patients had significantly lower body mass index, Karnofsky scores and haemoglobin levels compared to those infected with HIV only, despite similar baseline CD4(+) T-cell counts. Overall, 12 (4.7%) HIV patients developed TB and 7 (3%) HIV-TB patients had worsening of their TB symptoms during the study period. Mortality was similar in the two groups, being 10.9% (16 deaths per 100 person years) and 11.3% (17 deaths per 100 person years) in HIV-only and HIV-TB patients, respectively. Overall, more males (13.1%) died compared to females (9.6%). Predictors of mortality were presence of oral candidiasis, Kaposi's sarcoma, low Karnofsky score, and low baseline white blood cell and CD4(+) T-cell counts. The outcomes following well-supervised treatment of HIV-TB patients are similar to those in patients with HIV alone. Predictors of mortality were those of advanced disease

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

Liver Enzyme Abnormalities and Associated Risk Factors in HIV Patients on Efavirenz-Based HAART with or without Tuberculosis Co-Infection in Tanzania.

To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection. A total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7 per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI. Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians

Effect of Improved access to Antiretroviral Therapy on clinical characteristics of patients enrolled in the HIV care and treatment clinic, at Muhimbili National Hospital (MNH), Dar es Salaam, Tanzania

\ud Sub-Saharan Africa has been severely affected by the HIV and AIDS pandemic. Global efforts at improving care and treatment has included scaling up use of antiretroviral therapy (ART). In Tanzania, HIV care and treatment program, including the provision of free ART started in 2004 with a pilot program at Muhimbili National Hospital in Dar es Salaam. This study describes the socio-demographic and clinical features of patients enrolled at the care and treatment clinic at MNH, Dar es Salaam, Tanzania. A cross-sectional study looking at baseline characteristics of patients enrolled at the HIV clinic at MNH between June 2004-Dec 2005 compared to those enrolled between 2006 and September 2008. Of all enrolled patients, 2408 (58.5%) were used for analysis. More females than males were attending the clinic. Their baseline median CD4 cell count was low (136 cells/microl) with 65.7% having below 200 cells/microl. Females had higher CD4 cell counts (150 cells/microl) than males (109 cells/microl) p < 0.001). The most common presenting features were skin rash and/or itching (51.6%); progressive weight loss (32.7%) and fever (23.4). Patients enrolled earlier at the clinic (2004-5) were significantly more symptomatic and had significantly lower CD4 cell count (127 cells/microl) compared to CD4 of 167 cells/microl in those seen later (2006-8) (p < 0.001). Patients enrolled to the MNH HIV clinic were predominantly females, and presented with advanced immune-deficiency. Improved access to HIV care and treatment services seems to be associated with patients' early presentation to the clinics in the course of HIV disease.\u

Variability of efavirenz plasma concentrations among pediatric HIV patients treated with efavirenz based combination antiretroviral therapy in Dar es Salaam, Tanzania

Abstract Background Children are subject to varying drug pharmacokinetics which influence plasma drug levels, and hence treatment outcomes especially for drugs like efavirenz whose plasma concentrations are directly related to treatment outcomes. This study is aimed at determining plasma efavirenz concentrations among Tanzanian pediatric HIV-1 patients on efavirenz-based combination antiretroviral therapy (cART) and relating it to clinical, immunological and virologic treatment responses. Methods A cross sectional study involving pediatric HIV patients aged 5–15 years on efavirenz-based cART for ≥ 6 months were recruited in Dar es Salaam. Data on demographics, cART regimens, efavirenz dose and time of the last dose were collected using structured questionnaires and checklists. Venous blood samples were drawn at 10–19 h post-dosing for efavirenz plasma analysis. Results A total of 145 children with a mean ± SD age of 10.83 ± 2.75 years, on cART for a mean ± SD of 3.7 ± 2.56 years were recruited. Median [IQR] efavirenz concentration was 2.56 [IQR = 1.5–4.6] μg/mL with wide inter-patient variability (CV 111%). Poor virologic response was observed in 70.8%, 20.8% and 15.9% of patients with efavirenz levels  4 μg/mL respectively. Patients with efavirenz levels of < 1 μg/mL were 11 times more likely to have detectable viral loads. Immunologically, 31.8% of children who had low levels (< 1 μg/mL) of efavirenz had a CD4 count of < 350 cells/μL. Conclusion Wide inter-individual variability in efavirenz plasma concentrations is seen among Tanzanian children in routine clinical practice with many being outside the recommended therapeutic range. Virologic failure is very high in children with sub-therapeutic levels. Concentrations outside the therapeutic window suggest the need for dose adjustment on the basis of therapeutic drug monitoring to optimize treatment

Molecular epidemiology of pregnancy using omics data: advances, success stories, and challenges.

Multi-omics approaches have been successfully applied to investigate pregnancy and health outcomes at a molecular and genetic level in several studies. As omics technologies advance, research areas are open to study further. Here we discuss overall trends and examples of successfully using omics technologies and techniques (e.g., genomics, proteomics, metabolomics, and metagenomics) to investigate the molecular epidemiology of pregnancy. In addition, we outline omics applications and study characteristics of pregnancy for understanding fundamental biology, causal health, and physiological relationships, risk and prediction modeling, diagnostics, and correlations