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Accelerated Liver Disease Progression in HCV/HIV Coinfection
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"Unexpected Significant Liver Disease Among HIV/HCV Co-infected persons with Minimal Fibrosis on Initial liver Biopsy"
...28% of patients receiving two liver biopsies 2.84 years apart experienced accelerated HCV disease progression... 8% developed cirrhosis...
Reported by Jules Levin
This study reported by Mark Sulkowski at the 12th CROI (Feb 2005) found that HCV in HIV+ individuals may progress more quickly than many had previously thought. I have been saying this for years.
In HCV monoinfection the protocol is to repeat a liver biopsy every 3-5 years to monitor progression, and if there is progression you can catch this and consider starting therapy. In coinfection many doctors have been using this same time-frame for repeating liver biopsies of 3-5 years. I have been saying that in an ideal world biopsies should be repeated every 1 year in coinfection in order to adequately monitor disease progression because HIV accelerates HCV progression. Of course, doing a biopsy every year is unrealistic. Therefore, many doctors will recommend initiatting HCV therapy after the first biopsy if the patient has stage 2 or even stage 1 using system that rates stages 1-4 with 4 being cirrhosis; stage 1 is minimal disease, stage 2 is moderate disease, stage 0 is no disease).
In this study Sulkowski performed 2 liver biopsies separated by only 2.84 years on average. Biopsy results were reported by stage, stages 0 through 6, with 0 meaning no disease (fibrosis) & stage 6 being cirrhosis. He found that 28% of patients experienced accelerated disease progression, that is they saw HCV disease progression of 2 stages or more in 28% of study patients. 14% of patients experienced even more disease progression, they progressed by 3 stages. On the first biopsy, 15% of patients had advanced liver disease (3% had stage 2, & 12% had stage 3 or 4), while on the 2nd liver biopsy 32% of patients had stage 2 or more (10% had stage 2, 14% had stage 3 or 4, & 8% had progressed to stage 5 or 6 (ciirhosis). So, what does this mean?
There were confounding information in this study. Sulkowski reported 28% of the study patients had a history of alcohol use. We don't know a true history of these patients alcohol use & how many of these patients used alcohol excessively. Therefore, we can't evaluate the impact of alcohol on their HCV disease progression. In this study, on average study patients had HCV for 23 years. You would expect disease could accelerate progression more quickly at any time for a patient with disease for so long. The study was not designed to evaluate the affect of ART or HAART on disease progression and the patient sample size was too small to conclude much regarding this. But the data discussed & reported below suggest that patients with well controlled HIV, high CD4 counts & low or undetectable HIV viral load, may have a beneficial affect in slowing disease progression. Several recently published studies & a study reported by Brau at EASL last year suggest this may be true. But there are many variables in disease progression & its difficult to say with the data we have now that this is true, for all patients. For example, alcohol usage greatly affects HCV disease progression. So if you drink excessively having undetectable HIV viral load & 1000 CD4s may not mean very much. There are other variables as well. Some studies find that HAART may accelerate HCV progression. I think we don't know the answer to this question, does well controlled HIV slow disease progression?. One study found that HAART did not accelerate HCV progression, unless there were consistent liver enzyme test values over 150 IU/L. In the end, I think that for coinfected patients it is probably a good idea to consider starting PegIFN/RBV therapy sooner rather than delaying therapy, which could risk accelerated HCV progression. If you are coinfected & your liver biopsy reports minimal or moderate fibrosis, it's time to seriously consider therapy. The treaters I know & respect recommend this. Using a biopsy evaluation scoring of stages 1-4, if your stage is 1 they suggest therapy & if you are stage 2 they recommend therapy. The decision to begin therapy should of course take into consideration other factors in a patient's life. If their situation is unstable or life is chaotic or in some significant way the patient is not ready to begin therapy, then delaying may be better. But be careful, undue delay may result in accelerated disease progression.
There wasn't much in the way of significant new information on HCV at the 12th CROI. What was presented at this conference shows that coinfection still trails monoinfection in a number of ways. There were several interesting reports, however, at the conference. One study found coinfected patients undergoing IFN/RBV therapy and using AZT were more likely to experience anemia. Several previous studies have already reported this, but this is important information. Using EPO or Procrit if you have abnemia on IFN/RBV therapy can be very important. EPO can increase hemoglobin & decrease fatigue. This has the affect of increasing tolerability of RBV & being able to maintain RBV dosing without dose reduction. This should translate into an increased capacity to achieve a sustained viral response to HCV. Two studies at CROI found HCV sexual transmission among men who have sex with men. The oral presentation from the French was more impressive than the poster from the Swiss Cohort. But again, this information, although important, has been presented a number of times before supported by data from studies. Two posters reported on the importance of ribavirin drug levels in achieving a Sustained Viral Response (SVR). This has been reported a number of times over the past few years at liver conferences. Studies have shown that ribavirin adherence is very important during the first 12 weeks of therapy. Studies find that missing ribavirin doses during this early period after starting IFN/RBV therapy contributes to NOT achieving SVR. These studies find that missing ribavirin doses or dose-reducing is more important in contributing to NOT achieving a viral response than if you miss interferon doses or dose-reduce interferon. RBV dose reduction occurs in association with experiencing fatigue and anemia (reduced hemoglobin). We now know that reducing your ribavirin dose or missing doses can reduce your chance of achieving an SVR, and RBV dose reduction or missing doses has more impact than IFN dose reduction or dose missing in your capacity to achieve an SVR.
Mark Sulkowski reported these study results at an oral session at the 12th CROI.
His backgrounder was:
--guidelines recommend liver biopsy prior to HCV treatment to assess the fibrosis stage
--the primary basis for this recommendation is to withhold HCV therapy in persons with little or no fibrosis due to low risk for progression
STUDY OBJECTIVES
Hypothesis:
--HCV/HIV coinfected persons with no or minimal fibrosis on initial biopsy will not experience significant fibrosis progression over a short period of time (about 3 yrs) [ed note: in HCV monoinfection liver biopsy is recommended every 3-5 years to monitor a patient's disease. Since HIV can appreciably accelerate HCV using the same approach in coinfected patients is risky as disease progression may accelerate]
Objective:
--to ascertain the incidence of significant fibrosis progression between liver biopsies among patients with HCV/HIV coinfection
METHODS
Subjects were followed in a prospective cohort of patients receiving medical care in the Johns Hopkins University HIV Clinic
--receiving comprehensive baseline evaluation
--longitudinal data was collectedÑlabs, alcohol & drug use, ART prescription
61 HCV/HIV coinfected , non-cirrhotic patienbts who underwent two liver biopsies were studied for this analysis. 6 patients were excluded due to having cirrhosis on the first biopsy.
The median time between the first & the second biopsy was 2.84 yrs
(2.05-3.41).
Biopsies were simultaneously evaluated by a single pathologist who was blind to biopsy sequence. The biopsies were scored according to the Ishak criteria for fibrosis & activity.
Modified Fibrosis Staging
0 No fibrosis
1 some portal areas
2 most portal areas
3 occasional portal to portal (P-P) bridging
4 marked bridging (P-P) as well as portal to central
5 incomplete cirrhosis
6 cirrhosis
Fibrosis progression (FP) was defined as increase by 2 or more Ishak stages between biopsies 1 & 2.
Primary outcome was incidence of FP.
Sulkowski performed an analysis of characteristics of persons with & without progression.
CHARACTERISTICS AT INITIAL BIOPSY (n=61)
Age: 44 (40-48)
Male sex; 75%
African-American: 86%
IDU ever: 69%
History of alcohol use: 28%
HCV duration, median yrs (IQR): 23.8 (21-27.5)
CD4 count <200: 21%
HIV RNA <400 c/ml: 57%
ART: 82%
Pre-biopsy AST >100 U/L: 15%
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Sulkowski suggested that these data suggest that better control of HIV through ART use (as measured by HIV RNA & CD4 count) may be associated with slowing disease progression, but the sample size in the study may be too small to find significance. 75% of the Cd4 count tests were over 200 for non-progressors vs 64% for progressors; >75% of the viral load tests were undetectable (<400) for 44% of patients with no HCV disease stage change vs 35% for patients with HCV disease progression; 10% of patients with no disease progression had not used ART vs 21% who had HCV disease progression. Sulkowski commented that elevations in AST test results reflected disease progression, suggesting that if your ALT or AST test results are consistently elevated this could be a sign that HCV disease is progressing: more patients had disease progression when >33% (1 of 3) of their AST tests results were >100 U/L values (43% vs 17; significant p value). Sulkowski comments regarding HCV therapy, that there was no difference (22% vs 35%) between progressors & non-progressors based on whether they had HCV therapy. These patients had all been non-responders to HCV therapy & in many cases received less than 16 weeks therapy. Therefore, if interferon would play any role in slowing HCV disease progression, as it is thought that it does, this would not likely be reflected here because 16 weeks therapy is too short a period of time.
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