By Liz Highleyman

Prior studies have indicated that HIV positive individuals coinfected with hepatitis C virus (HCV) tend to experience more rapid and more severe liver disease progression than HIV negative people with HCV alone. Data are mixed, however, and some evidence suggests that HIV-HCV coinfected patients with well-preserved immune function and a high CD4 cell count may fare as well as HCV monoinfected individuals.

Two presentations at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) this week in San Francisco shed further light on fibrosis progression in coinfected individuals.

Fibrosis and Inflammation Progression

Richard Sterling from Virginia Commonwealth University and colleagues conducted a prospective, longitudinal evaluation of paired liver biopsies to assess histological disease progression in a cohort of coinfected patients.

Out of 261 HIV-HCV coinfected individuals who underwent an initial biopsy between 1998 and 2008 at their institution, 47 patients without baseline cirrhosis had at least 2 paired biopsies and were included in the present analysis. Individuals with hepatitis B, heavy alcohol use, or other causes of liver disease were excluded.

Demographic characteristics reflected those of the HIV positive population. Most (70%) were men, 77% were African-American, and the mean age was 42 years. Participants had well-controlled HIV disease, with a mean CD4 count of about 600 cells/mm3. About 80% were on HAART and nearly half had HIV RNA < 400 copies/mL.

Almost all participants (95%) had HCV genotype 1 and about one-third had received interferon-based treatment for chronic hepatitis C; within the latter group, about 25% were non-responders, 2% experienced relapse, and 6% achieved sustained virological response.

Clinical and laboratory data were obtained at the time of biopsy and every 3-6 months thereafter. The mean interval between biopsies was 52 months (about 4 years). Liver histology was assessed using Ishak scores for inflammation (scale of 0-18) and fibrosis (scale of 0-6). Steatosis (fat accumulation in liver cells) and cytologic ballooning were also assessed.

Results

• At baseline, the average inflammation score was 6.4, the average fibrosis scores was 1.5, and 24% of patients had steatosis affecting > 5% of liver cells.

• Between the first and second biopsies, the following changes were observed:

• 34% of patients experienced fibrosis progression (21% by < 2 points, 13% by > 2 points).

• 44% had unchanged fibrosis;

• 21% experienced fibrosis regression or improvement (19% by < 2 points, 2% by > 2 points).

• Changes in inflammation were as follows:

• 55% experienced worsened inflammation (13% by < 2 points, 42% by > 2 points).

• 15% had unchanged inflammation.

• 29% experienced an improvement in inflammation (8% by < 2 points, 21% by > 2 points).

• The annual man rate of fibrosis progression was 0.132 units per year.

• The annual mean inflammation progression rate was 0.174 units/year.

• There was no observed association between liver disease progression and any of the following factors:

• Patient demographics (sex, race, age);

• AST or ALT level;

• CD4 cell count;

• HIV viral load;

• Overall use of HAART;

• Specific use of stavudine (d4T; Zerit) and didanosine (ddI; Videx);

• Use of or response to anti-HCV therapy;

• Baseline FIB-4 (an non-invasive index of biochemical markers of fibrosis);

• Baseline liver histology including inflammation, fibrosis, or steatosis.

These findings led the investigators to conclude, "Significant fibrosis progression (> 2 points) occurred in 13%, and 42% had significant increase in inflammation after a mean interval of 52 months."

"No single factor was predictive of worsening histology," they added. "Therefore, biopsy is required to identify those individuals who have liver disease progression."

In the discussion following the presentation, it was noted that researchers at Johns Hopkins University reported that the rate of significant fibrosis in their HIV-HCV coinfected cohort was about twice as high (25%) as the 13% rate reported here. Dr. Sterling said he could not explain the disparity.

Even though the fibrosis rate in the present study was relatively low, he still recommended that motivated coinfected patients should receive anti-HCV treatment, given that it was impossible at this time to predict which ones would progress.

Virginia Commonwealth University, Richmond, VA.

Normal ALT

In a second study, C. Sagnelli and colleagues assessed liver disease outcomes among HIV-HCV coinfected patients with persistently normal ALT.

ALT (alanine aminotransferase) is an enzyme that indicates liver inflammation. It is often elevated in people with active viral hepatitis, drug-induced hepatoxicity, or other conditions that damage the liver. However, ALT does not necessarily reflect fibrosis, and some people with chronic hepatitis C sustain significant liver disease progression with persistently normal ALT levels.

The Italian investigators studied 34 HIV-HCV coinfected patients with 9 normal aminotransferase level tests over 18 months who underwent liver biopsies. Outcomes in this group were compared with those of 30 HCV monoinfected individuals with persistently normal ALT who received biopsies during the same period.

At the time of liver biopsy, 29 of 34 patients in the former group were on HAART. Overall, this group had well-controlled HIV disease, with a mean CD4 count of about 560 cells/mm3, but just over half had a CD4 cell nadir (lowest-ever level) of 200 cells/mm3 or less. HIV-HCV coinfected individuals were more likely than HCV monoinfected patients to be male (62% vs 43%), to be injection drug users (77% vs 0%), and to be infected with HCV genotypes 3 (38% vs 0%) or 4 (29% vs 0%). None had received hepatitis C treatment prior to biopsy.

Liver biopsies were analyzed for histological activity index (HAI), fibrosis, and steatosis using the Ishak scoring system by a pathologist unaware of clinical and laboratory data. Several types of microlesions (e.g., acidophil bodies, lymphoid follicles, rhomboid hepatocytes, Mallory bodies, germinal centers, etc.) were recorded as present or absent.

Results

• The HAI score was < 8 in the majority of patients in both the HIV-HCV coinfected and HCV monoinfected groups (91% vs 97%).

• The fibrosis score, however, was significantly higher in the HIV-HCV coinfected group compared with the HCV monoinfected group (mean 2.1 vs 1.4; P < 0.05).

• 24% of coinfected patients had a fibrosis score of 3-6, compared with 7% of HCV monoinfected individuals (P < 0.05).

• 32% of coinfected patients had a high degree of steatosis (scores of 3-4) compared with just 3% of HCV monoinfected individuals (P < 0.005).

• Analysis of liver microlesions, however, did not reveal statistically significant differences between the2 groups.

Based on these findings, the researchers concluded, "The data indicate that both HIV-HCV coinfected and HCV monoinfected patients with [persistently normal ALT] show a low degree of necroinflammation."

"Patients with HIV-HCV coinfection frequently show moderate or high liver fibrosis and deserve anti-HCV treatment," they added.

The investigators suggested that the higher degree of cirrhosis in the coinfected group might be attributable to HAART toxicity or to the higher prevalence of HCV genotype 3.

Second University of Naples, Naples, Italy; San Raffaele Hospital, Milan, Italy.

11/07/08

References

RK Sterling, PG Smith, J Wegelin, and others. Prospective evaluation by paired liver biopsy of HCV disease progression in patients (pts) co-infected with HIV. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 27/1931.

C Sagnelli, C Uberti-Foppa, L Galli, and others. Liver Histology in HIV/HCV Coinfected Patients with Persistently Normal Serum Aminotransferases. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 502.