American Association for the Study of Liver Diseases

American Association for the Study of Liver Diseases (AASLD), 50th Annual Meeting, Dallas

Response to HCV Treatment By African Americans; When Should Individual Begin HCV Treatment

Report 4 from Liver Conference in Dallas, 50th AASLD Meeting, Saturday, Nov 7
I’ve reported two studies yesterday and the day before highlighting the poor response of African Americans to HCV treatment. At the DDW conference in Orlando in May, this subject received a little attention. But at this conference attention has increased as there are a number of studies reported that begin to address this concern. Immediately below is a discussion by me of when to begin therapy. Following are additional reports of studies also addressing the questions of African American responses to HCV treatment

When does a person begin HCV therapy? Individuals may be in a position to consider delaying therapy for better treatments or because they appear stable at this time. Opinions appear mixed if one should treat HCV aggressively. The answer to this question is more complicated when a person is co-infected with HIV. In other words, if a person is co-infected with HCV and HIV, when should they begin therapy? If a person’s situation is poor—biopsy shows fibrosis progressed, their liver is inflamed, ALT is elevated—they may want to begin therapy although some still delay therapy sometimes waiting for new and better treatments. Is it better to treat this disease as early as possible or reasonable? Some doctors would say yes. Other GI doctors would suggest placing a person in a study. And some doctors would suggest delaying treatment. It appears to me that the GI and Hepatologists who’ve traditionally treated hepatitis may be more conservative in their treatment approaches but doctors with experience in HIV appear to me to be more aggressive. Should a person treat their HIV first, and improve CD4s and viral load prior to starting HCV therapy? Some say yes, if possible. Some people experience intolerable increases in liver function tests after starting HAART and are unable to tolerate HAART. Some doctors stop HAART and treat for HCV. Their plan is to place person back on HAART after liver is improved and ALT is under control. One study suggests that person with higher CD4s may respond better to HCV treatment. Its possible that having HIV viral load under control may promote a better response to HCV therapy.

There are several key questions about HCV treatment for person also having HIV. Will the person respond to HCV treatment? I hear mixed opinions and we don’t have study data yet to begin to answer that question, as studies are ongoing, but a few doctors told me their HIV patients can respond well to HCV treatment. One doctor from an urban based clinic in Chicago told me his patients with HIV are African Americans and they don’t respond in general to treatment. But of course being black, having HIV, and because blacks appear to have high incidence of genotype 1 are three reasons for therapy not being successful.

Its very important to remember that in studies patients responses are assessed by two basic parameters—normalization of ALT (liver function tests) and HCV viral load being undetectable. A number of doctors have told me that a person can still benefit from HCV treatment even if their viral load does not go to undetectable. Treatment can reduce liver inflammation, reduce ALT, improve the histology or general condition of the liver, improve how a person feels, and viral load may be reduced although it may be undetectable. These beneficial effects of treatment may be helpful in preserving a person’s health and longevity, but I don’t think studies directly answer this question yet. That is, will these benefits, in the absence of low or undetectable viral load, have long term benefits. An additional point to bear in mind is that research for new HCV drugs are ongoing and new treatments should be available within a few years. Keeping your liver relatively healthy and in a position to respond to new treatment may be important. Another point to consider is cirrhosis. HCV treatment that does not reduce viral load to undetectable may still help delay progression to cirrhosis or hepatocellular carcinoma. If a person has compensated cirrhosis it is difficult to predict when progression to more serious cirrhosis can occur. Biosy is a way to monitor the liver's condition but how many biopsies can you perform?

Its important to find a doctor that is aware and knowledgeable about these issues, and can make better informed treatment decisions with you. Unfortunatly, I think there are not many doctors who have developed this capacity. As well, there is less certainty about how to treat HCV for HIV-infected individuals. There are a number of variables that are not well understood yet. It is also important to remember that a reason HCV is becoming a problem for people with HIV is because of the development of successful HIV treatment. Since HIV treatments are improving longevity a person’s HCV status becomes one that doctors now feel should be addressed. Without successful HIV treatment a person may not have survived so treatment for HCV was less of a concern.

HCV Treatment & African Americans

Kie Lim and Christine Bruno with the Emory University School of Medicine reported on their study showing a poor response to treatment for African Americans. They said likelihood of response to interferon is shown to correlate with several factors including levels of HCV RNA, gender, viral genotype, cirrhosis, and possibly race. The aim of their study was to prospectively look at differences in response to interferon monotherapy between caucasians and African Americans. HCV patients treated with IFN (Intron A) from 1996 to mid 1998 in a large inner city hospital were prospectively enrolled. Information from pre-treatment, a liver biopsy (unless documented cirrhosis) and baseline quantitative HCV RNA by PCR (by Lab Corp) was obtained. Treatment with IFN 3 MIU three times per week was started for a minimum of 3 months and viral response was assessed after this time period. Treatment outcome was analyzed by race, sex, presence of cirrhosis and initial viral load. Response is defined as HCV RNA below 500 copies/ml after a minimum of 3 months therapy.

A total of 55 patients were enrolled: 39 AA and 16 CA (mean age 48 and 45, respectively). 15 patients (11 AA and 4 CA) were excluded from the initial analysis as 9 patients did not complete a minimum of 3 month treatment due to side effects, and 6 patients did not have proper documentation of viral response by PCR although all had persistent abnormal ALT at end of treatment period.

Of the 40 patients they analyzed only 5 of 40 responded to treatment (HCV below 500 copies/ml): 1 of 28 (3%) African Americans, and 4 of 12 (33%) caucasians (p=below 0.001). The AA responder is a 43 year old female without cirrhosis and an initial viral load of 0.003 x 10 to 6th copies/ml (I think this is 3000 copies/ml). If so, it’s a low viral load. The 4 CA responders were all males, one had cirrhosis and all but one had initial viral loads above 2 x 10 to 6th (above 2 million).

Of the 27 AA non-responders, 59% were female, 22% had cirrhosis, and 15% had an initial viral load above 2 million. The authors said the poor response by AA in this study cannot be explained by gender, presence of cirrhosis nor a high baseline viral load. 75% of the caucasians that responded had viral load above 2 million. Conversely, African American non-responders had low viral loads (mean 1.4 x 10 to 6th; I think that’s 1.4 million; median 0.5 x 10 to 6th- 500,000 copies/ml I think) and were more frequently female.

Yesterday NATAP reported on an analysis presented at AASLD of a large study (I think it was a retrospective study) looking at 1744 patients in which 28 blacks received IFN+RBV and 25 received IFN alone. The study authors (McHutchison, Poynard and others) reported 21% (6/28) of AA had a sustained virologic response rate from IFN+RBV and 0% from IFN alone. While caucasians experienced a 37% response rate (346/925) from IFN+RBV and 13% from IFN alone. The authors said that controlling for genotype and other factors indicated that AA had less reduction in viral RNA during treatment. This suggests to them there may be inherent host differences among racial groups.

I’d like to highlight the difference between the results of the study above where 3% of AA had response rate to the following study in which 21% had viral response. The differences may be associated with the settings in which the studies were conducted. In the study reported by Kim and Bruno they said it was conducted in an inner city hospital. In the McHutchison study the investigators were likely to be doctors affiliated with large medical centers. The populations in the 2 studies may have been very different. The McHutchison study suggests to me that 20% of AA are capable of responding to therapy. But as we have seen in HIV the responses observed in well controlled study situations yield response rates different than when the therapies are used in real life situations. Possibly, study participants were more highly selected and received more support in the McHutchison study. This also suggests the 37% response rate in caucasians seen in the McHutchison study may be lower in real-life clinic treatment settings where patients may not receive support needed to optimize their response to therapy. In this study Asians (n=27) had a 53% response rate (11/20), and Hispanics 27% (4/15) to IFN+RBV.

Are African Americans With Chronic HCV More Resistant to Antiviral Therapy?

In another study sponsored by Schering Plough and authored by Cliff Brass of Schering, they surveyed a large number of "diverse investigators" studying the use of Rebetron (interferon alpha-2b + ribavarin) to treat chronic HCV. All responses were gathered in January 1999, and investigators were using standard three times per week interferon dosing or higher/daily dose interferon therapy. During treatment response (DT) is defined as undetectable virus 6 months after cessation of therapy. Authors said the three-fold decrease for AA they observed in during therapy response is particularly striking for both treatment naļve and non-responder populations.

The DT response for naives was 57% (477/849) in caucasians, 17% (20/116) for African Americans, and 63% (22/35) for Asians. The sustained response rate was reported as 54% for treatment-naļve caucasians and 8% (2/24) for treatment-naļve African Americans.

Regarding the non-responder populations, 34% of caucasians had sustained response and 11% (8/75) AA had response. 50% of Asians had response. The during therapy response (DT) was 45% for caucasians, 15% (41/265) for African Americans, 41% for Asians (9/22), and 46% (37/80) for Hispanics.