Yimam Getaneh Misganie

Title : Highly Active Antiretroviral Treatment (HAART) Induced hepatotoxicity among HIV Positive Population: Systematic Review

Abstract:

Background: The advent of HAART dramatically reduced the clinical impact of HIV infection.  Dual Nucleoside Reverse Transcriptase Inhibitors (NRTIs) with either protease inhibi­tors (PI) or Non-nucleotide/s Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are the backbones of antiret­roviral therapy regimens. HAART-induced liver injury has appeared as a primary cause of death in HIV infected patient as a result of the high HIV prevalence and due to the late HIV diagnosis and late initiation of HAART. The high rate of HBV and HCV co-infection in sub-Saharan African countries could hinder the treatment outcome of HAART. This review considers hepatotoxic effects of the different classes of HAARTs and assesses the risk factors associated with hepatotoxicity in HAART treated patients. 

Method: A three-step search strategy was utilized in this review. Initial search of Pub Med central and Google scholar was undertaken, this search was to address published studies with key words antiretroviral therapy, liver, toxicity and HIV positive. A second search using all identified keywords including biomarkers of hepatotoxicity (ALT, AST, Creatinine, ADR). Thirdly, the reference list of all identified reports and articles were searched for additional studies. People living with HIV with intervention HAART and a control group of HAART Naïve population while the outcome was organ toxicity. We considered 22 qualitative and 47 quantitative studies included for this review.  Qualitative data was extracted from papers included in the review.

Result: A study conducted in Debrebirhan Hospital, Ethiopia, revealed, 25% of clients in HAART treated groups and 9.2% of treatment naïve controls had showed liver enzyme changes while other study reported no significant variation  (20.1% Vs. 22.0%) among HAART experienced and HAART na¨ıve patients. In a study conducted in US, the incidence of HAART-related severe hepatotoxicity is estimated at 10% and a report from Latin American children estimated 3.2% in children on non-PI regimens and 1.5% among children receiving PI-based HAART. In Asian children 2.68% had FIB-4 score >1.3 prior to HAART and 0.73% developed FIB-4>1.3 during HAART follow-up. Mitochondrial toxicity is a prevailing explanation for hepatotoxicity among patients treated with NRTIs (stavudine, didanosine and zalcitabine). Hypersensitivity reaction associated with Abacavir may be accompanied by liver failure. In vitro study revealed toxicity zalcitabine≥didanosine>stavudine>lamivudine>zidovudine>abacavir.  NNRTIs are associated with higher incidence of hepatotoxicity in patients treated with NVP as com­pared with EFZ. One study found a higher incidence of severe hepatotoxicity in patients on ritonavir (OR, 6.2; 95% CI, 2.8-13.7). Other study revealed ritonavir was associated with a significantly higher incidence of severe hepatotoxicity versus other PIs in the first 6 months of therapy. Study of 1,325 patients confirmed the association of indinavir use with severe hyperbilirubinemia at 6 months, 12 months, and 24 months of ART. Ritonavir was associated with a significantly higher incidence of severe hepatotoxicity versus other protease inhibitors. Combination of ritonavir with coinfection HBV or HCV was a 2.78 and 2.46 fold increased risk for liver toxicity. HAART induced hepatotoxicity were associated with recent discontinuation of lamivudine (OR=6.8; 95%CI=2.1-22.7), recent start of nevirapine (OR=9.6; 95%CI=3.2-28.3) recent start of ritonavir (OR=4.9; 95%CI=2.0-12.1). Other risk factors for hepatotoxicity were older age, female gender, African American ethnicity, CD4 count of <200 cells/mm³ and co-infection.

Conclusion: Evidence on the impact of HAART on hepatotoxicity was controversial. However, predominant and wider scope studies concluded certain classes of antiretroviral cause hepatotoxic reactions. Liver function should therefore be monitored on a regular basis in patients with HIV receiving any antiretroviral agent. Close monitoring of co-infected patients could contribute to better out come from HAART. There were limited studies among children and adolescent while the available ARV drugs were not validated on the safety and efficacy for this group of population.  Validation of combination therapies on safety and efficacy prior to use could be important.

Biography:

Dr. Yimam Getaneh is currently a PhD fellow in Biomedical Science from Universitas Airlangga, Surabaya Indonesia, also MSc graduate in Biomedical Science from Bahir Dar University Ethiopia. He is also currently working for the Ethiopian Public Health Institute as senior researcher. Since 2013, Dr. Yimam concluded and published more than 32 nationally representative research projects specific to HIV drug resistance. His PhD project is also on toxicity and HIV drug resistance among people taking antiretroviral therapy in Ethiopia.