Factors Affecting Liver Fibrosis in Human Immunodeficiency Virus and Hepatitis C Virus Coinfected Patients: Impact of Protease Inhibitor Therapy


 (HEPATOLOGY August 2001;34:283-287)



Hepatitis C virus (HCV)-related liver fibrosis progression is accelerated in human immunodeficiency virus (HIV)-in-fected patients. The effect of protease inhibitor (PI) therapy on liver fibrosis is unknown. The aim of this work was to analyze the impact of PI therapy on HCV-related liver fibrosis in HIV/HCV coinfected patients. We evaluated in a long-term follow-up retrospective cohort study the influence of antiretroviral therapy containing PI on liver fibrosis in 182 consecutive HIV/HCV coinfected patients. At liver biopsy, 63 patients had received PI and 119 patients had never been treated with PI. Relationships between liver histologic features, age, alcohol consumption, CD4 cell count, HIV-RNA load, and antiretroviral regimens were analyzed. Liver fibrosis stage was lower in patients receiving PIs by comparison with patients who had never received PIs (P =.03). The 5-, 15-, and 25-year cirrhosis rates were 2% versus 5%, 5% versus 18%, and 9% versus 27%, respectively, in patients who had received PIs compared with PI-untreated patients (P =.0006). Multivariate analysis identified 4 independent predictors of progression to cirrhosis: absence of protease inhibitor therapy (relative risk [RR] =4.74, 95% confidence interval [CI], 1.34-16.67), heavy alcohol consumption (50 g daily) (RR =4.71, 95% CI, 1.92-11.57), low CD4 cell count (<200/ uL) (RR =2.74, 95% CI, 1.17-6.41), and age at HCV contamination (>/=20 years) (RR =2.37, 95% CI, 1.04- 5.38). In conclusion, protease inhibitor therapy might not accelerate progression to HCV-related cirrhosis. Further-more, chronic use of antiretroviral therapy containing PI together with reduction of alcohol consumption and main-tenance of high CD4 count could have a beneficial impact on liver fibrosis progression in HIV/HCV coinfected patients.

In Table 1 below you can see that less patients receiving a PI regimen used more than 50 grams per day of alcohol (20.6% vs 31.9%). This difference may not be significant but raises a question. It's possible this could effect the PI recipients in developing less fibrosis or in having a lower rate of liver progression. As well, I mention below how viral load above or below 200 may play a role in progression of liver disease. I spoke to one of the article's author who said viral load was not an independent risk factor. In other words, according to his statistical analysis viral load did not affect progression. I brought attention to this point because at the DDW Conference this past Summer (2001) a study from Sterling suggested that patients with undetectable HIV viral load were more likely to have cirrhosis.

I think that Benhamou's conclusion is a very soft statement, and this is appropriate. The sample size is somewhat small, but more importantly the main problem is that which occurs with retrospective data. There may be some bias that we can't appreciate in the data.

The patient's that had not received PIs had more fibrosis and possibly more inflammation on biopsy than the patients that had received some PI regime but it is impossible to know if this is at all related to the medications. Perhaps the PI based group would have looked healthier regardless. The patients that are more ill from liver disease (appear cirrhotic, complain more of RUQ pain etc) may have been less likely to be placed on a PI based regime because the provider was nervous about the issue of PIs in liver disease. Also, we don't know enough about the cocktails, how they varied. The sample size is not large enough to rule out all of these things.

Having said that, this study was well done, compared to other studies on the same question. Still, in my opinion, none of these studies have been done very well, well enough to reach fairly firm conclusions. HAART may accelerate HCV progression for some individuals and not for others. This may depend on a number of factors we have yet to identify. (see this article) I think that we need to see more data. To better assess the affect of HAART or antiretroviral therapy on HCV disease we need data from trials comparing various treatment combinations and almost every trial requires a biopsy on entry and always a medication history. Therefore, we can see if their HAART correlates with their pre-HCV treatment stage of disease.

A prospective randomized trial would be ideal but probably not practical or ethical. I don't think that you can randomize someone to receive or not receive a certain HAART regime based on their HCV......HIV course drives this decision.

Why Would PI Therapy Slow or Stop Hepatitis Disease Progression

 The mechanisms involved in the beneficial impact of PI therapy on liver fibrosis remained unknown. Improvement of immune functions assessed by increases in CD4 count related to antiretroviral therapy might reduce the liver fibrosis pro-gression rate. However, in the present study, the influence of PI therapy was independent of both the CD4 cell count and HIV plasma load. Nevertheless, numerous immune modifica-tions, other than the increases in CD4 cell count, could have influenced liver fibrosis progression. Changes in intrahepatic cytokine pattern of secretion, related to immune restoration, should reduce or reverse proinflammatory and profibrosing processes and thus improve liver lesions. Another hypothesis is that PIs may have a direct impact on cytokine expression involved in fibrosis matrix synthesis. In-deed, elevated levels of transforming growth factor b1 (TGF-b1), a cytokine involved in the production of liver collagen matrix,24,25 has been found in serum or plasma of HIV-in-fected patients.26 A significant decrease in TGF-b1 splenocyte secretion had been shown in saquinavir-treated mice.27 Whether PIs, such as saquinavir, may have an anti–TGF-b1 activity in human liver remains to be shown. In summary, PI therapy might not worsen HCV-induced liver damages. Furthermore, chronic administration of PI containing antiretroviral therapy together with reduction of alcohol consumption and maintenance of high CD4 count may have a benefic impact on HCV-related liver fibrosis in HIV/HCV coinfected patients.


Undetectable HIV Viral Load May Also Be A Factor in Progression


Tables 3 & 4 show that having HIV viral load <200 may play a role in liver disease progression.




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