Optimization of TB/HIV co-treatment in Ethiopian patients

Abstract: Tuberculosis (TB) and HIV infection act with deadly synergy. HIV is the most important risk factor for latent TB reactivation and active TB progression following exposure or reinfection while TB accelerates HIV progression. TB is the most frequent cause of morbidity and mortality in HIV infection. Anti-TB therapy (ATT) must precede initiation of combination Antiretroviral Therapy (cART), TB being the most immediate threat. Undoubtedly cART benefits; however, important clinical challenges emerge when cART is initiated during TB therapy. Optimization TB and HIV cotreatment is therefore required. Paper II: We hypothesized that by initiating efavirenz (EFV)-based cART earlier than the second week of ATT in patients with CD4 counts < 200 cells/ µL; overall survival can be improved at 48 weeks. The study hypothesis was tested with randomized, open-label, clinical trial comparing efficacy and safety of EFV-based cART one week, four weeks and eight weeks after ATT in coinfected patients with baseline CD4 count < 200 cells/µL. The results showed that cART one week after TB therapy doesn’t improve overall survival at 48 weeks. All-cause mortality in subgroups with CD4 count below 50 cells/µL versus above was lowest in week one. However, compared with week four and eight, first line ATT interruption from severe Drug-Induced Liver Injury (DILI) was highest in week one deaths (P=0.03) and in the CD4 subgroup < 50 cells/µL (P=0.02). The key question for CD4 category < 50 cells/µL is striking the optimal balance between the potential survival benefits if cART is initiated one week after TB therapy as opposed to the increased morbidity and mortality due to DILI and risk of ATT interruption. Paper I and IV: We investigated DILI during TB/HIV cotreatment and HIV-treatment with EFV-based cART. DILI is the most important treatment limiting factor for continuation of both ATT and/or cART. Multiple evidences show that TB/HIV coinfected patients experience higher rate of adverse drug reactions than those without HIV. Both are prospective cohort studies and analysis was made with multivariate Cox regression model. Outcome measures were incidence rates for DILI, ATT and/or cART interruptions as well as assessment of risk factors. Paper I on EFV-based cART in HIV-infected patients with baseline CD4 counts < 200 cells/µL revealed high plasma EFV levels and CYP 2B6'6 genetic polymorphism predict DILI events in addition to baseline transaminitis, low CD4 count, low serum albumin and platelet values. Paper IV specifically addressed severe form of DILI during TB/HIV cotreatment compared with only TB treatment in HIV-negative patients as well as EFV-based cART in HIV-infected patients with baseline CD4 counts < 200 cells/µL inclusive of isoniazid preventive therapy. The findings from this study are: severe DILI risk is increased several folds with TB/HIV coinfection whereas concurrent cART timing doesn’t alter the risk. Incidence rate of ATT interruption is higher with CD4< 50 cells/µL. Independent risk factors for severe DILI in addition to TB/HIV coinfection were abnormal alanine aminotransferase and bilirubin values at baseline, CD4 < 50 cells/µL and positive HCV antibody result. In summary, the result concur earlier initiation of EFV-based cART during TB/HIV coinfection, though DILI remains as the most important challenge. It is more related to ATT than EFV-based cART and not affected by the timing of EFV-based cART within the first 8 weeks of TB therapy. Paper III evaluated Ethiopian HIV-1 subtype C virus (HIV-1CET) at near full length genome level for phylogenetic analysis, genotypic drug resistance and viral tropism. The results showed high diversity among HIV-1CET strains compared to other geographical locations suggesting introduction of HIV-1C in the country occurred in early phase of HIV- 1C epidemic. Primary drug resistant mutations were identified in < 5% of the cases and 95% of the viral strains had R-5 tropism.