Antiretroviral therapy does not fully reverse impact of HIV on hepatitis C-related cirrhosis

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In a meta-analysis of over 3500 patients co-infected with HIV and hepatitis C, Canadian researchers have found that the risk of hepatitis C-related cirrhosis has fallen since effective antiretroviral therapy became available. However, the report, published in the October 1st edition of AIDS, also notes that antiretroviral therapy does not fully counter the harmful impact HIV has on the liver of co-infected individuals.

HIV and hepatitis C virus are both spread through blood-to-blood contact, and so co-infection can be common, especially among certain groups such as injecting drug users. The risk of hepatitis C transmission during sex is low, though outbreaks of co-infection have been seen in large urban centres in western Europe among gay men who practise rough sex. Mother-to-child transmission of hepatitis C is also uncommon, but the risk is increased in the presence of HIV co-infection.

Hepatitis C targets the liver, which becomes progressively damaged through fibrosis (moderate scarring). Cirrhosis (severe scarring) normally takes several years to develop, but there is evidence that being co-infected with HIV increases the risk of developing advanced liver disease. In people who only have hepatitis C and not HIV (hepatitis C mono-infection), the average time to liver disease is about 30 years. Studies in co-infected people report average times of 15 to 25 years. The cause of this hastened fibrosis is not clear, but may be linked to the immunosupression caused by HIV.

Glossary

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

fibrosis

Thickening and scarring of connective tissue. Often refers to fibrosis of the liver, which can be caused by an inflammatory reaction to long-term hepatitis infection. See also ‘cirrhosis’, which is more severe scarring.

meta-analysis

When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.

toxicity

Side-effects.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

Antiretroviral therapy can effectively suppress HIV replication and leads to improvements in the immune function in HIV-positive people. It remains unclear whether or not effective HIV treatment has blunted the impact that HIV has on hepatitis C disease. In meta-analysis, performed before effective antiretroviral therapy became available, co-infection was associated with a 2.9-fold increase in risk of cirrhosis compared with hepatitis C mono-infection. More recent studies have provided conflicting results on the benefits of HIV treatment. Antiretroviral therapy has been linked to lower liver-related death rates, but it is not clear that it slows fibrosis.

To address this question, investigators at the University of Toronto conducted two meta-analyses of studies of co-infection published between 1990 and 2007. In the first, they used 17 studies of co-infected people from the US and Western Europe to estimate rates of disease progression. In the second, they collected data from 27 studies of both hepatitis C mono-infected and HIV/hepatitis C co-infected people and assessed the risk of cirrhosis and the impact of antiretroviral therapy on this risk.

To get a sense of how quickly liver disease progresses in co-infected people, the investigators analysed data from over 3500 co-infected people, over 80% of whom had contracted hepatitis C through injecting drug use. They found that the proportion of co-infected people who had cirrhosis was 21% after 20 years, and 49% after 30 years. This finding is similar to some 20-year estimates from some studies of hepatitis C mono-infection (22% to 24%), but much higher than estimates from other studies (4% to 7%), they write.

The investigators then turned their attention to the impact of antiretroviral therapy on hepatitis C-related liver disease. Using the second data set of 27 studies including over 7600 people, they calculated and compared the risk of developing cirrhosis between HIV/hepatitis C co-infected (2636 patients) and hepatitis C mono-infected (4970 individuals) groups. They also evaluated the impact of antiretroviral therapy on the risk of cirrhosis.

The investigators found significant variations in the relative risks reported in the studies, but overall, outcomes were worse among co-infected people compared to those with hepatitis C alone. The estimated risk of cirrhosis was 2.11-fold higher (95% CI 1.51 – 2.96) with co-infection than with hepatitis C mono-infection. The risk was 2.49-fold higher (95% CI, 1.81 – 3.42) in co-infected people not taking antiretroviral therapy and 1.72-fold higher (95% CI, 1.06 – 2.80) in those on HIV treatment.

“Over the period studied, HAART [highly active antiretroviral therapy] did not appear to fully correct the adverse effect of HIV infection on [hepatitis C virus] prognosis,” the investigators write. They note that only about three-quarters of people included in the on-antiretroviral therapy analysis had been on treatment for over a year and thus, the risk estimates may be based on a suboptimal response to such therapy. “In addition,” they offer, “HAART may have dual effects, producing slower fibrosis progression as a result of immune reconstitution, but also inducing liver toxicity, which may lead to an enhancement of fibrogenesis.”

In a final analysis, the investigators tested the assumption that the rate of fibrosis progression remains constant over time in co-infected people. This assumption has weakened estimates of progression rate and made comparison between studies difficult. The investigators calculated the annual probability of transitioning through the different stages of fibrosis. Using two different statistical analyses, they concluded that in co-infected individuals, the rate of progression is constant, with an estimated weighted mean transition probability between 0.11 and 0.12 per year at any stage of fibrosis.

Concluding, the investigators offer that their findings provide insight to some very practical questions about caring for a HIV/hepatitis C co-infected population. “These estimates,” they write, “should provide more accurate information for the prediction of [hepatitis C] disease burden, economic evaluation of antiviral therapies and preventive strategies, and healthcare policy decision-making among the injecting drug user population.”

References

Thien HH, et al. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS 22:1979 – 1991, 2008.