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.

List of scientific papers

I. Mugusi SF, Mwita JC, Francis JM, Aboud S, Bakari M, Aris EA, Swai AB, Mugusi FM, Pallangyo K, Sandstrom E. 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. BMC Public Health. 2010 May 28;10:291.
https://doi.org/10.1186/1471-2458-10-291

II. Mugusi SF, Ngaimisi E, Janabi MY, Mugusi FM, Minzi OM, Sasi PG, Bakari M, Lindquist L, Aklillu E, Sandstrom EG. Risk factors for mortality among HIV-positive patients with and without active tuberculosis in Dar es Salaam, Tanzania. Antivir Ther. 2012;17(2):265-74.
https://doi.org/10.3851/IMP1956

III. Ngaimisi E, Mugusi S, Minzi OM, Sasi P, Riedel KD, Suda A, Ueda N, Janabi M, Mugusi F, Haefeli WE, Burhenne J, Aklillu E. Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients. Clin Pharmacol Ther. 2010 Nov;88(5):676-84.
https://doi.org/10.1038/clpt.2010.172

IV. Mugusi S, Ngaimisi E, Janabi M, Minzi O, Bakari M, Riedel KD, Burhenne J, Lindquist L, Mugusi F, Sandstrom E, Aklillu E. Liver enzyme abnormalities and associated risk factors in HIV patients on efavirenz-based HAART with or without tuberculosis co-infection in Tanzania. PLoS One. 2012;7(7):e40180.
https://doi.org/10.1371/journal.pone.0040180

V. Mugusi S, Ngaimisi E, Janabi M, Mugusi F, Minzi O, Aris E, Bakari M, Bertilsson L, Burhene J, Sandstrom E, Aklillu E. Neuropsychiatric manifestations among HIV-1 infected African patients receiving Efavirenz based HAART with or without Tuberculosis treatment containing Rifampicin. [Manuscript]