Impact of hepatitis B co-infection in patients starting antiretroviral therapy
Lead Research Organisation:
University College London
Department Name: Infection and Population Health
Abstract
Worldwide, hepatitis B virus (HBV) infection is ten times as common as HIV. Interactions between HIV and the hepatitis viruses, HBV in particular, increase rates of liver disease and have not been investigated in Africa where HBV is common. In countries where highly active antiretroviral therapy (HAART) is used extensively to treat HIV, liver disease is an increasingly important cause of death.
A trial of HAART in Zimbabwe and Uganda provides a unique opportunity to investigate the efficacy and safety of HAART in hepatitis co-infected patients. Two of the drugs used (tenofovir and lamivudine) have activity against HBV, and another (nevirapine) may cause liver disease in HIV/HBV co-infection.
Stored pre-treatment samples will be tested for HBV and subsequent samples from HIV/HBV co-infected individuals will be tested for the level of hepatitis B virus. Samples from patients failing HBV treatment will be tested for drug-resistant strains of HBV, by sequencing of the HBV genome.
We intend to determine how common HBV is in HIV-positive patients and the benefits and risks associated with treating HIV. We will also examine HBV resistance which is particularly important if the resistant virus is not protected against by current vaccines.
A trial of HAART in Zimbabwe and Uganda provides a unique opportunity to investigate the efficacy and safety of HAART in hepatitis co-infected patients. Two of the drugs used (tenofovir and lamivudine) have activity against HBV, and another (nevirapine) may cause liver disease in HIV/HBV co-infection.
Stored pre-treatment samples will be tested for HBV and subsequent samples from HIV/HBV co-infected individuals will be tested for the level of hepatitis B virus. Samples from patients failing HBV treatment will be tested for drug-resistant strains of HBV, by sequencing of the HBV genome.
We intend to determine how common HBV is in HIV-positive patients and the benefits and risks associated with treating HIV. We will also examine HBV resistance which is particularly important if the resistant virus is not protected against by current vaccines.
Technical Summary
Aims
The hypothesis is that hepatitis B virus (HBV) infection status should be determined before starting antiretroviral treatment to reduce morbidity and mortality in HIV-infected adults in Africa.
Objectives
To determine:
1. The prevalence of HBV co-infection in a strategy trial of highly active antiretroviral therapy (HAART) in Africa.
2. The HBV genotypes of those co-infected, and whether this is related to HBV or HIV outcomes (viral suppression, disease progression or safety).
3. The rate and duration of HBV viral suppression in co-infected patients given lamivudine-based or lamivudine/tenofovir-based HAART.
4. Baseline characteristics that may predict the development of exacerbations of inflammatory liver disease (liver flares), or disease progression.
5. The incidence of liver events in those taking nevirapine.
6. The HBV resistance patterns in cases of HBV viral rebound or failure to suppress.
Design
A cohort study based on a population recruited to a clinical trial of HIV management strategy - DART (Development of Antiretroviral Therapy), in which patients have been randomised to full laboratory monitoring (including HIV viral load and CD4 count), or clinical monitoring only.
Methodology
Baseline blood samples from the DART population (n=3300, CD4<200 at entry) will be tested for HBV and hepatitis C virus (HCV) serology and viral load, and follow-up samples for HBV viral load. The virus will be sequenced in cases of virological failure or non-response to detect baseline and treatment-emergent mutations. These data will be correlated with clinical and treatment data.
Outcomes will be compared between those individuals taking HAART regimens containing lamivudine (3TC) as the only HBV-active drug, with individuals taking both 3TC and tenofovir (TDF), which also has HBV activity. Liver disease events will also be studied in patients taking nevirapine (NVP), comparing those with and without HBV co-infection.
Scientific and Medical Opportunities
In the developed world, where HAART is used widely, chronic liver disease caused by HBV or HCV causes an increasing proportion of HIV-related deaths, as overall mortality rates decline. Hepatitis-HIV interactions have not been studied in Africa where most HBV infections are acquired in early life, with a different host-parasite relationship and distribution of genotypes. A trial of HAART in Zimbabwe and Uganda (DART) provides a unique opportunity to investigate the consequences of HBV infection in HIV positive individuals starting HAART including the development of HBV resistance mutations. The findings may have important implications for developing strategies for roll-out of HAART and for future antiviral resistance in HBV
The hypothesis is that hepatitis B virus (HBV) infection status should be determined before starting antiretroviral treatment to reduce morbidity and mortality in HIV-infected adults in Africa.
Objectives
To determine:
1. The prevalence of HBV co-infection in a strategy trial of highly active antiretroviral therapy (HAART) in Africa.
2. The HBV genotypes of those co-infected, and whether this is related to HBV or HIV outcomes (viral suppression, disease progression or safety).
3. The rate and duration of HBV viral suppression in co-infected patients given lamivudine-based or lamivudine/tenofovir-based HAART.
4. Baseline characteristics that may predict the development of exacerbations of inflammatory liver disease (liver flares), or disease progression.
5. The incidence of liver events in those taking nevirapine.
6. The HBV resistance patterns in cases of HBV viral rebound or failure to suppress.
Design
A cohort study based on a population recruited to a clinical trial of HIV management strategy - DART (Development of Antiretroviral Therapy), in which patients have been randomised to full laboratory monitoring (including HIV viral load and CD4 count), or clinical monitoring only.
Methodology
Baseline blood samples from the DART population (n=3300, CD4<200 at entry) will be tested for HBV and hepatitis C virus (HCV) serology and viral load, and follow-up samples for HBV viral load. The virus will be sequenced in cases of virological failure or non-response to detect baseline and treatment-emergent mutations. These data will be correlated with clinical and treatment data.
Outcomes will be compared between those individuals taking HAART regimens containing lamivudine (3TC) as the only HBV-active drug, with individuals taking both 3TC and tenofovir (TDF), which also has HBV activity. Liver disease events will also be studied in patients taking nevirapine (NVP), comparing those with and without HBV co-infection.
Scientific and Medical Opportunities
In the developed world, where HAART is used widely, chronic liver disease caused by HBV or HCV causes an increasing proportion of HIV-related deaths, as overall mortality rates decline. Hepatitis-HIV interactions have not been studied in Africa where most HBV infections are acquired in early life, with a different host-parasite relationship and distribution of genotypes. A trial of HAART in Zimbabwe and Uganda (DART) provides a unique opportunity to investigate the consequences of HBV infection in HIV positive individuals starting HAART including the development of HBV resistance mutations. The findings may have important implications for developing strategies for roll-out of HAART and for future antiviral resistance in HBV
