Natural history of HIV and Hepatitis Coinfection

Natural history of chronic hepatitis C in HIV-infected patients

Dr Stanislas Pol (Necker-Cochin Hospital, Paris, France) remarked how the decrease in mortality conferred by the use of highly active antiretroviral therapy (HAART) has allowed the expression of liver-related complications associated with HCV chronic infection. Liver disease is now one of the leading causes of morbidity and mortality in coinfected patients [1].

HIV infection results in decreased spontaneous recovery after acute HCV infection, increased HCV viremia by 2- to 8- fold, increased infectivity (perinatal from 5% to 20 %, and sexual from <1% to 1-2%), and accelerated progression to advanced degrees of fibrosis and cirrhosis. Decreased CD4 counts are associated with increased liver disease progression.

Some studies have suggested that HAART, especially protease inhibitors (PI) may decrease the severity of liver disease and liver-related mortality [2]. However other studies have found decreased necro-inflammatory activity but similar degrees of fibrosis in HAART-treated patients [3].

Dr. Pol stated that steatosis and other factors present such as alcohol and drug use, and HAART hepatotoxicity, may overshadow the potentially beneficial effect of HAART on the liver in HIV/HCV-coinfection. Prospective studies are needed to analyze morbidity and mortality in HIV/HCV-coinfected patients, and to evaluate the impact of HAART on the liver.

Natural history of chronic hepatitis B in HIV-infected patients (Massimo Puoti, University of Brescia, Italy)

HIV infection increases the levels of HBV viral replication, fibrosis progression, cirrhotic decompensations and liver-related mortality, and decreases spontaneous clearance after acute HBV infection, anti-HBe seroconversion and necro-inflammatory activity. Older age, low CD4 counts, HBeAg persistence, and high HBV DNA levels are negative prognostic factors in HIV/HBV-coinfected individuals [4,5]

Dr. Puoti underscored that HAART-induced immune restoration is a double edged sword for HBV infection. Thus, improvement in the immune responses may trigger spontaneous anti-HBe and anti-HBs seroconversions, and even a better control of the HBV replication, but they also favor flares of necro-inflammatory activity.

The significance and prevalence of occult HBV infection in HIV-infected cohorts is unclear, and it should be analyzed with standardized methods. Other research requirements include assessing the impact of HBV genotypes, of HIV-induced changes in immune responses to HBV and of modifications in anti-HBV immune responses induced by HAART on the pathogenesis of HBV-induced liver damage/disease progression, and assessing the natural history of HBV infection under HAART with anti-HBV activity.

Influence of viral hepatitis on HIV infection and disease. (Dr. Jürgen Rockstroh University of Bonn, Germany)

Some early cohort studies reported that HCV and HBV increased the risk of progression to AIDS and death in HIV-infected patients. However, subsequent studies, after controlling for confounding factors such as baseline CD4 counts and HIV viral loads, use of HAART, age, race, and transmission risk factors for HIV did not confirm previous results.

Dr. Rockstroh presented data on the EuroSIDA cohort analysis, which found no difference between HCV-positive and HCV-negative patients initiating HAART, neither in the time to achieve undetectable HIV viral load, nor in the time needed to increase CD4+ counts by 50%, supporting findings of other studies. As for HBV, no differences in response to HAART and HIV disease progression between HBsAg-positive and HBsAg-negative patients were seen in the HIV-NAT cohort [6].

Nevertheless, there is an increased risk of liver disease-related morbidity and mortality, as well as of global mortality in hepatitis coinfected HIV patients in the EuroSIDA cohort. In addition, coinfected subjects have more hepatotoxicity under antiretroviral treatment regimens.

According to Dr. Rockstroh, future research needs focus on the assessment of the outcome of subjects with high HBV viral load, of the long-term impact of HAART plus anti-HBV drugs in HIV/HBV-coinfection, and of the impact of HCV genotypes and HCV viremia on the outcome of HIV/HCV-coinfected population.

Tolerance and management of HAART in patients coinfected with chronic hepatitis (Dr. Marina Núñez, Hospital Carlos III, Madrid, Spain)

HAART-related hepatotoxicity and drug discontinuation are significantly increased in patients coinfected by HCV and/or HBV. Another predictor factor of liver toxicity is the use of certain antiretroviral drugs, such as full dose ritonavir (RTV) and nevirapine (NVP). Non-nucleoside reverse transcriptase inhibitors (NNRTI) seem to be more hepatotoxic than the newer protease inhibitors (PI) lopinavir (LPV) and atazanavir (ATV), even though they are boosted by low doses of RTV.

This author highlighted the multiplicity of mechanisms of liver toxicity in patients taking HAART (figure 1) [7]. The disorders in the fat and carbohydrate metabolism, which may be associated with liver steatosis are being recognized as relevant factors which may contribute to enhance the liver damage caused by HCV and HBV in HAART-treated patients.


Figure 1. Mechanisms of HAART-related hepatotoxicity and concurrent factors

Although higher levels of antiretrovirals pertaining to the three major families have been proven in subjects with advanced cirrhosis, the clinical consequences are uncertain. Regarding correlation between drug levels and hepatotoxicity, results have been negative for all PI studied, and conflicting for NVP.

Studies are needed to compare liver safety of currently used antiretrovirals stratifying by detectable HCV RNA, to assess the long-term clinical consequences of mild-to-moderate hepatotoxicity, to genetically identify individuals at higher risk, as well as to determine the role of therapeutic drug monitoring.

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