A prospective study of patients co-infected with HIV and hepatitis C has found significant progression of liver fibrosis in a quarter of the cohort over a span of three years, despite little or no evidence of fibrosis at the beginning of the study.
HIV disease state, HIV treatment, and hepatitis C virus (HCV) treatment were found to play little or no role in the risk of progression of fibrosis: analysis identified only elevations of serum aspartate aminotransferase (AST) as a significant predictor of progression.
The findings, from a research team at Baltimore's Johns Hopkins University School of Medicine, headed by Mark Sulkowski, were published in the October 2007 issue of AIDS.
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.
A procedure to remove a small sample of tissue so that it can be examined for signs of disease.
An extension of multivariable analysis that is used to model two or more outcomes at the same time.
The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).
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.
The short-term goal of hepatitis C treatment is sustained virologic response (SVR): prolonged undetectable HCV viral load after the course of treatment is concluded. However, SVR rates are often low, especially in HIV/HCV co-infection. Studies have reported conflicting results as to the effect of virologically unsuccessful HCV treatment on the progression of liver disease, and on the impact of HAART on hepatitis C disease.
Sulkowski's research team has been following a prospective cohort of HIV/HCV co-infected adults, using repeat liver biopsies to measure the progression of fibrosis, to determine the impacts of HAART and HCV treatment, and assess the risk factors for progression. Data on 61 people from this cohort were presented previously at the Twelfth Conference on Retroviruses and Opportunistic Infections (CROI) in 2005 and again at the Thirteenth CROI in February 2006.
The published cohort consisted of 184 adults with HIV and HCV infection, who had had at least two liver biopsies between January 1998 and July 2006, and who did not have cirrhosis of the liver at the first biopsy. The cohort was largely African-American (86%) and people with a history of injection drug use (80%); most were men (74%) with a median age of 44 years.
HIV disease was well-controlled in most: the median CD4 cell count was 379 cells/mm3, 60% had a viral load of less than 400 copies/ml, 83% had received antiretroviral therapy, and 62% were on HAART at the time of the first biopsy.
Nearly all (95%) had HCV genotype 1; the median HCV RNA level was 573,000 at first biopsy and very few (1.7%) had received HCV treatment at or before this time.
This study used the Ishak modified scale to measure fibrosis: biopsy findings were graded as stage F0 to F6. At the time of first biopsy, 136 patients (77%) had minimal or no fibrosis (F0 or F1), 9% had stage F2, and 11% had "bridging" (stage F3 or F4) fibrosis. (Ten patients were excluded due to cirrhosis - stage F5 or higher.)
"Significant progression" between biopsies was defined as an increase of at least two stages. By this definition, 41 (24%) of the patients were "progressors", who experienced a significant increase in fibrosis between their first and second biopsy – a median interval of 2.9 years. (The greatest number (48%) had no change in fibrosis score over that time; 22% had a one-stage (less than significant) increase.)
Of the 136 who had no or minimal fibrosis at the first biopsy, 32% were progressors, including 14% who progressed to stage F3, F4, or even the cirrhotic stages F5 or F6. Among the progressors, the median rate of progression was 0.83 units per year.
The research team then compared the characteristics of the progressors with those of the non-progressors. Surprisingly, very few factors were found to differ between the two groups, especially after multivariate analysis. None of the following factors were found to be significant predictors: age, sex, race, CD4 cell count, HIV viral load, length of ART exposure, antiretroviral drug class used, or length of exposure to individual antiretroviral drugs, HCV genotype, or HCV RNA level.
Between biopsies, 37 (21%) of the patients received HCV treatment with interferon (standard or pegylated) plus ribavirin. SVR rates were extremely low: only three patients (2.7%) achieved sustained HCV suppression; all three were non-progressors.
Significant fibrosis progression was more common in those who received HCV treatment (35% vs. 20%), but those who were treated were more likely to already have had significant fibrosis at the first biopsy, and had higher ALT and AST levels between biopsies.
In multivariate analysis, the difference due to HCV treatment disappeared: the only risk factor associated with progression of fibrosis was elevated AST level between biopsies. ("Elevated" in this case was taken to be 2.5 or more times the upper limit of normal, 37 U/l.) Elevated ASTs were found in 25% of progressors vs. 12% of non-progressors (p = 0.03); by multivariate analysis the odds ratio was 3.4 (95% confidence interval, 1.4 – 7.9).
The researchers note several key conclusions. Firstly, their finding of significant fibrosis progression in a quarter of the cohort is significantly greater than that reported in many HCV-monoinfected cohorts, and "was unexpected in this cohort of [co-infected] patients with minimal liver disease on initial biopsy."
Secondly, they found little or no effect of either antiretroviral or HCV treatment on the progression of fibrosis. These data "suggest that the effect of ART on hepatic fibrogenesis is likely to be modest over a 3-year period".
Other studies have reported that HCV treatment is associated with stable or improved hepatic fibrosis (Rodriguez-Torres 2007). In contrast, the Johns Hopkins team "failed to detect a beneficial effect of HCV treatment on fibrosis progression in the absence of SVR," although they "can not exclude a modest effect of HIV and HCV treatment", and note that "the non-random selection of patients to receive HCV treatment may … introduce bias and randomized controlled trials are needed." Alcohol use (which was self-reported) may have been "incompletely assessed". As most patients were already on HAART at the time of first biopsy, the effects of HAART may have been underestimated, and the extremely low response rates to HCV treatment may have limited the observed treatment effect.
