CROI: Liver fibrosis and noninvasive monitoring tools in HIV/HCV coinfected patients

Several research teams presented data on liver fibrosis progression and the use of noninvasive monitoring tests in HIV/HCV coinfected patients at the Thirteenth Conference on Retroviruses and Opportunistic Infections, held February 6-9 in Denver. Although research to date has produced mixed results, numerous studies suggest that liver damage related to hepatitis C progresses more rapidly in coinfected individuals.

HCV treatment linked to reduced fibrosis

In a poster presentation, Pablo Barreiro and colleagues from Madrid offered evidence that successful hepatitis C treatment can slow down and even reverse liver damage in HIV/HCV coinfected individuals. Standard treatment for both coinfected and monoinfected patients consists of pegylated interferon (Pegasys, Peg-Intron or Viraferon Peg) plus ribavirin for 24 (HCV genotypes 2 or 3) or 48 (genotype 1) weeks. Most studies indicate that coinfected patients are less likely to clear HCV with therapy; in the APRICOT trial, for example, 62% of coinfected genotype 2/3 patients and 29% with genotype 1 achieved sustained virological response, compared with about 80% and 45%, respectively, in studies of HCV monoinfected individuals.

In the current study, the researchers sought to determine whether liver fibrosis improves in coinfected patients who achieve sustained response, as it does in HCV monoinfected individuals. They analysed data from 112 coinfected participants who completed a full course of treatment with conventional or pegylated interferon with or without ribavirin. Most (76%) were men, with a mean age of 36 years; 70% had genotype 1, 24% had genotype 3, and 6% had genotype 4. About 70% were on HAART, 63-72% had undetectable HIV viral load (below 50 copies/ml), and the median CD4 cellcount was above 600 cells/mm³. Before starting HCV therapy, all had elevated liver enzymes and some degree of fibrosis, as determined by liver biopsy. After completing treatment, 44 achieved sustained virological response, whilst 68 were nonresponders or relapsers. Demographic features of the sustained virological response and nonresponder/relapser groups were comparable.

The researchers measured post-treatment fibrosis an average of 2.5 years after HCV therapy using the FibroScan elastometry test, which assesses the rigidity of the liver. They found that the sustained virological response group was more likely to have low fibrosis scores (F0-F1) than the nonresponders/relapsers (59% vs 44%, respectively). Conversely, moderate to severe fibrosis was more common among the nonresponders/relapsers (14% vs 7% for stage F3; 7% vs 10% for F4), with an odds ratio (OR) of 2.6 (p = 0.04). In the sustained virological response group, patients with stage F0-F1 fibrosis had a longer lag between the end of HCV therapy and elastometry evaluation than those with stage F2-F4 fibrosis (38 vs 22 months; p = 0.06), suggesting that fibrosis improved over time. All three patients who had cleared HCV for ten or more years had stage F0-F1 fibrosis.

The researchers concluded that sustained virological response after interferon-based therapy “may lead to regression of HCV-related liver fibrosis in HIV coinfected patients,” but “long periods of time seem to be required to show this benefit.”

Noninvasive testing useful in coinfected patients

Barreiro’s study confirmed that the noninvasive FibroScan test is useful for coinfected individuals as well as those with HCV alone. Other researchers also presented posters demonstrating the value of noninvasive fibrosis tests in the coinfected population.

Mark Sulkowski and colleagues analysed factors associated with fibrosis progression in 218 coinfected patients treated at the Johns Hopkins HIV clinic. Most were male (67%) and of African descent (83%); the mean age was 49 years. A majority (76%) had a history of injecting drug use, and 40% had a past or present diagnosis of alcohol abuse. The median HIV viral load was 309 copies/ml and the median CD4 count was 345 cells/mm³. One quarter (25%) had “significant fibrosis” (Ishak stage F3 or higher), while the remainder were classified as having “minimal fibrosis” (stage F2 or lower).

The presence of “significant fibrosis” was associated with plasma aspartate aminotransferase [AST] levels 1.25 or more times the upper limit of normal (OR = 4.2; 95% confidence interval [CI] 1.8-10.0), platelet counts below 150,000 cells/mm³ (OR = 3.7; 95% CI 1.6-8.6), plasma albumin below 3.5 g/dL (OR = 2.3; 95% CI 1.0-5.2), and alcohol abuse (OR = 3.5; 95% CI 1.7-7.6). Worse fibrosis was not, however, linked to age, sex, hyperglycemia, CD4 cell count, HIV viral load, or use of antiretroviral therapy.

The researchers also found that the Johns Hopkins Fibrosis Index – comprising history of alcohol use and laboratory measures of AST, platelet count, and albumin – predicted fibrosis better than the AST-to-Platelet Ratio Index (APRI) or the “FIB-4” index (which takes into account AST and alanine aminotransferase [ALT] levels, platelet count, and patient age). Area under the receiver operating characteristic curves for the three indices were 0.79, 0.76, and 0.74, respectively. The authors concluded that assessment of routine laboratory parameters and clinical data on alcohol abuse “accurately predicted significant fibrosis in HCV-infected adults,” adding that such noninvasive indices “may have a role in identifying patients with significant liver disease in settings in which access to liver biopsy is limited.”

In a related study, Huda Al-Morhi from McGill University in Montreal and colleagues used the APRI in a cross-sectional analysis of factors associated with fibrosis in 162 coinfected patients followed for an average of one year (35 were excluded due to missing data or undetectable HCV RNA). Most (81%) were men, 70% had genotype 1 HCV, and the mean age was 43 years. A majority (70%) were on HAART, the mean HIV viral load was 2.6 log₁₀ copies/ml, and the mean CD4 cell count was 378 cells/mm³. The mean time since estimated exposure to HCV was 17 years; 7% also showed evidence of triple infection with hepatitis B virus (HBV). About one third (35%) were injecting drug users at the time of the study, while 79% had a history of injecting. More than half currently used alcohol or marijuana or smoked cigarettes (58%, 54%, and 71%, respectively), while higher proportions had ever used these substances (86%, 85%, and 91%, respectively).

The median APRI score was 0.66 (range 0.16 to 49.5), and 24% had “significant fibrosis” (APRI of 1.5 or higher). In a multivariate analysis (excluding the HBV triple-infected patients), more severe fibrosis was associated with present or past alcohol use (OR = 9.0; 95% CI 0.96-85; p = 0.03), but not with injecting drug use, marijuana, or cigarettes. Higher CD4 cell count was associated with less severe fibrosis (OR = 0.43 per 100 cells; 95% CI 0.2-0.9; p = 0.03), but current HAART use had no significant effect. Interestingly, higher cholesterol levels were also linked to less severe fibrosis (OR = 0.18; 95% CI 0.04-0.85; p = 0.03). The researchers concluded that, as expected, impaired immunity was associated with worse fibrosis. However, while “any amount of alcohol use was associated with fibrosis,” they wrote, “no contribution of other addictions or lifestyle factors was observed.”

Taken together, these data suggest that successful HCV treatment leads to improved liver health in HIV/HCV coinfected as well as HCV monoinfected patients, and that steps can be taken to reduce fibrosis risk – in particular, avoiding alcohol and using HAART to manage HIV. In addition, they show that fibrosis progression can be assessed using noninvasive tools in this population. This is welcome news for coinfected patients who are prone to more rapid liver disease progression, potentially allowing them to avoid frequent invasive liver biopsies to monitor fibrosis.