One third of HIV/HCV coinfected patients with normal ALT have advanced fibrosis in Spanish cohort

Maida and colleagues from Hospital Carlos III, Madrid presented results on the degrees of fibrosis in HIV/HCV coinfected patients who have normal ALT levels. In HCV monoinfected patients about 30% of HCV monoinfected patients have ALT levels within normal limits and 11-19% of them show significant histologic liver damage.

They identified patients with detectable plasma HCV RNA who had not been treated for HCV, and who had persistently normal ALT levels throughout the prior 12 months of follow-up (= 4 determinations). Presence and grade of fibrosis was evaluated by FibroScan.

Out of 279 coinfected patients with positive HCV RNA, 25 (8.9%) had persistently normal ALT. Distribution of HCV genotypes was 13 (56.5%), 1 (4.3%), 1 (4.3%) and 8 (34.8%) for genotypes 1, 2, 3 and 4 respectively. FibroScan results were as follows: F1 8 (47.1%), F2 4 (23.5%), F3 2 (11.8%), F4 3 (17.6%).

There was a trend among patients with HCV-4 genotype (50%) to have more often severe fibrosis (F3-F4) compared to genotype HCV-1 (11.1%) (p= 0.07).

The authors concluded that 9% per cent of HIV-infected subjects with detectable HCV RNA present persistently normal transaminase levels, being HCV-1/4 genotypes more frequent than HCV-2/3. In this cohort, nearly one third of HIV-infected patients with chronic HCV infection and persistently normal ALT had advanced degrees of liver fibrosis that would indicate HCV-treatment. HCV-4 genotype showed a trend to higher degrees of fibrosis.

Comment

About a quarter of these patients seem to have relevant fibrosis despite persistent normal ALT, which is higher than the approx. 15% reported by Zeuzem et al in the HCV-monoinfected population. But, these are low numbers (n=25) and coinfected patients represent a population which consumes more alcohol and are on a higher number of medications and this may result in additional liver toxicities.

This adds to existing reports in patients with HCV mono-infection where the phenomenon of advanced fibrosis and even cirrhosis have been reported with normal ALTs (see Shiffman et al, JID, 2000; 182: 155-1601, Puoti et al. J Hepatology, 2002; 37: 117-123). There are a number of issues to consider in appraising this phenomenon.

HCV not only has an effect on hepatocytes (damage of which causes release of the classical liver enzymes, ALT, AST), but may also have a direct effect on the activation and proliferation of hepatic stallete cells, which cause direct hepatic fibrosis, thus causing significant fibrosis in the presence of normal ALT.

It also rasies the issue of the definiton and use of the term normal ALT. There is increasing evidence that values of ALT/AST at the upper end of the normal range may in fact be abnormal or high for some patients and are dependent on sex and body mass index. For example, an ALT of 30 iu/l (normal range 5-40 iu/l for most laboratories) may be normal for an 80kg male, but high for a 50kg female (see Kaplan MM, Ann Intern Med 2003; 137: 49-51).

Furthermore, this abstract illustrates the increasing utility of non-invasive markers/tests for the assessment of hepatic fibrosis. Although these tests are currently being evaluated for their sensitivities and specificities in predicting various stages of fibrosis in HIV-infected patients, as this study shows, there is increasing utility especially in Europe. However, the cut-off values for various stages of fibrosis and their sensitivities and specificities have yet to be defined in large populations with HIV-infection, so one must view these results in that context.

Maida I, Soriano V, Gonzalez G et al. Liver fibrosis stage in HIV/HCV-coinfected patients with persistently normal transaminases levels. Poster H-1483. 45th ICAAC, 16-19 December 2005, Washington.