The impact of lamivudine-based antiretroviral therapy on hepatitis B virus (HBV) genetic evolution among HIV-HBV co-infected patients

Résumé

The Hepatitis B Virus (HBV) affects mainly to the liver, infecting the hepatocytes, and it can be either acute or chronic. Globally, it is estimated that 2 billion of people are infected with HBV and 350-400 million people suffer chronic infection. Furthermore, more than 600.000 HBV carriers die every year from end-stage liver diseases including fulminant hepatitis, cirrhosis or hepatocellular carcinoma (HCC) caused by HBV infection and hence it represents a major global health problem. HBV prevalence is higher in low-income countries including Africa, the middleeast and Asia than in western world, where horizontal transmission of HBV is the most common route. Conversely, in western countries, sexual and parenteral (intravenous drug used) are the main routes of transmission. Furthermore, as HBV shares the routes of infection with Human Immunodeficiency Virus (HIV), co-infection is relatively frequent. Among 36 million people living with HIV worldwide and approximately 4 million people (~10%) are chronically co-infected with HBV. Similarly, the prevalence of this coinfection is higher in Africa and Asia (up to 20% in some regions) than in western countries (<10%). HBV is characterized by an extraordinary genetic variability mainly due to its reverse transcriptase, which lacks of proof-reading activity producing a high mutation rate. The high genetic variability allows HBV the ability to develop drug resistance mutations to evade pharmacological pressure. Additionally to Interferon ?, there are 5 nucleoside/nucleotide analogues approved for HBV treatment (lamivudine, telvibudine, entecavir, adefovir, and tenofovir). Nowadays, tenofovir (TDF) is one of the most widely nucleotide analogue used for the treatment of HBV infection, which is also active against HIV and is commonly used in western countries for the treatment of HIV/HBV co-infected patients due to its high antiviral efficacy and high genetic barrier for resistance. However, in low-income countries, the use of this drug is still restricted because its high cost and lamivudine (3TC) is still the most nucleoside analogue used against HBV infection included within the HIV antiretroviral therapy because is cheaper and also active against HIV. As consequence of this regimen, HBV drug resistance is expected among these patients since the long-term exposure to 3TC monotherapies is associated with high rates of HBV drug resistance in both HBV monoinfected and HIV/HBV co-infected patients. HIV/HBV co-infected patients show higher HBV DNA levels and lower serum alanine aminotransferase (ALT) levels than those infected with HBV alone. Moreover, liver fibrosis tends to be more advance and the risk of end-stage liver disease is increased. Nevertheless, there is scarce information regarding how HIV could drive the HBV genetic evolution. In this thesis, two HIV/HBV co-infected cohorts under 3TCbased treatment have been studied from two different endemic countries, Ghana and Malawi. The genetic variability within the genes that encodes the polymerase and the Hepatitis B Surface Antigen (HBsAg) was assessed. The Ghana cohort was under longterm treatment and three clinically different cohorts were evaluated at genetic level to evaluate how HIV drives HBV evolution (HIV/HBsAg positive, HIV/HBsAg negative and HBV monoinfected). In Malawi, the rates and predictors of virological responses in HIV/HBV co-infected patients under 3TC-based regimens were evaluated after 48 weeks of 3TC-based therapy. Additionally, the genetic evolution of both polymerase and HBsAg were also assessed.