NATAP - DDW Liver Conference, San Diego, May 21-24 - Report 5
In an oral discussion about HCV/HIV coinfection, Doug Dieterich, a noted hepatologist and HIV/HIV coinfection treating physician, talked about HCV's affect on HIV progression; Improved Histology (Liver Condition) With Detectable HCV-RNA (Maintenance Therapy); Pegasys+Ribavirin: 72 week results from small study; It's readily accepted that HIV can speed HCV progression, but there is controversy about wheher HCV speeds HIV progression. I have seen studies supporting both that HCV speeds HIV progression and that it doesn't. Dieterich showed data from a hemophilia cohort study in the United Kingdom (Sabin C.J Infect Dis 1997; 176: 164). 111 HCV/HIV co-infected patients, of whom 70% had genotype 1 and 27% had genotype 2 or 3. There was increased risk progression to AIDS (RH 3.08) and death (RH 3.4) compared to genotype 2/3. A Kaplan-Meier curve showed dramatically less progression to AIDS or death for genotypes other than one. He said the reasons are unknown. He reviewed data on mother-to-infant transmission. The rate of mother-to-infant transmission of HCV has been observed at about 5% (3-8%), but if the mother has HIV/HCV coinfection the incidence rate of HCV transmission increases to about 17% (7-36%). HCV/HIV coinfection may increase HIV transmission rate from 16.3% when only HIV is present to 26.1% when mother has HCV/HIV. It appears that this data is prior to the use of HAART or may apply when antiretroviral therapy is not used. Nonetheless, the point is that HCV can increase the risk of HIV transmission.
Raj Reddy discussed the response rate to interferon+ribavirin (Rebetron) by African Americans. About 90% or more of African Americans may be genotype 1. In two studies he discussed the response rate to interferon was 2% and 0%, respectively. In the large McHutchison IFN/RBV study of 1600 individuals with chronic HCV, only 53 (3%) were African American and 96% of the African Americans were genotype 1. But for genotype 1 patients the response rates were the same for caucasians (23%) and African Americans (21%). Reddy cautioned that the study was small.
Improved Histology (Liver Condition) With Detectable HCV-RNA
The standard of success in studies is generally how many people were able to reduce their HCV viral load to undetectable (<100 copies/ml). However, obviously many people are unable to achieve this goal. Some people are relapsers, that is their viral load is undetectable during treatment or following the end of treatment. Some people never reach undetectable--either they have minimal viral load reductions or none at all. Several studies have shown that histology can show improvement even if viral load is not reduced to undetectable. Mitch Shiffman's study showed that individual's with a viral load reduction of 1 log or greater had improved fibrosis. The Pegasys study data shows similar results. In the Pegasys study of 271 cirrhotics, 184 received biopsies before and after treatment. 54 percent (37 of 68) of participants who received 180 mcg. of PEGASYS demonstrated a histological response, while 31 percent (17 of 55) of participants in the standard interferon arm demonstrated a similar response.
There are two key questions that need to be answered. Can individuals without any viral load reduction improve their liver condition? Do these improvements reported from Shiffman and the Pegasys studies translate into long term clinical benefit--reduced liver cancer, decompensated cirrhosis and death? Studies are being planned to address these questions but the answers may take time in coming. In the meantime, doctors I've spoken with mostly presume that the short-term improvements in histology are meaningful and ought to drive treatment decisions. For example, they suggest that if a person is unable to achieve undetectable HCV-RNA with IFN+RBV, a long term maintenance therapy of IFN alone should be considered. A low maintenance dose of pegylated or regular interferon can be considered. The beneficial affects of interferon or ribavirin may not always be measureable. For example, if HCV enters the brain as suggested by researchers at DDW and EASL, HCV therapy may improve cerebral function and related symptomology. This was reported by Ludwig Kramer at DDW. For a more detailed report see the DDW NATAP report called HIV and The Brain, which will or should be posted to DDW Reports on the NATAP web site. It's believed that ribavirin may be associated with this improvement because interferon does not appear to be able to enter the brain. Interferon therapy may improve immune response to HCV that is not measureable. Of course, in the end the ultimate evaluation is whether disease progression can be slowed or stopped. The affect of drug therapy is sometimes difficult to assess because some people do not progress without therapy.
This study has been reported on several times but here Mark Sulkowski reported the end-of-followup data on a small open-label phase II study of Pegylated interferon a2a and ribavirin combination therapy for chronic HCV. Twenty patients chronic HCV received subcutaneous PEG IFN a-2a, 180 ug, once weekly plus oral RBV, 1000 mg to 1200 mg, daily (with and 11 without food). Paients with non-1 genotype received 24 weeks treatment. Patients with genotype 1 received 48 weeks of treatment, if HCV-RNA was undetectable by Amplicor Mintor II (sensitivity = 100 copies/ml) at 24 weeks. Sustained virologic response was defined as HCV RNA <100 copies/ml at 24 weeks after treatment stopped.
The mean age of the 20 study participants was 41. The ethnic breakdown was 18 caucasians, 1 African American, and 1 Asian. All patients had noncirrhotic liver disease with persistently elevated serum ALT. 8 of 20 (40%) patients were women. 8 patients had <2 million copies/ml at baseline and 12 had >2 million copies/ml. And all were IFN and RBV treatment na‘ve.
Sixteen patients were HCV genotype 1 and 4 were genotype 2. Mean and median baseline HCV RNA were 7.7 million copies/ml and 7.9 million copies/ml. The incidence of adverse events and the serum concentrations of RBV were similar between fasting and non-fasting patients. The most common adverse events were myalgia (17 patients), fatigue and pyrexia (15), headache (14), irritability and dermatitis (10), insomnia (9), rigors and arthralgia (8), and nausea and vomiting (7).
Mean hemoglobin concentrations were 15.3 g/dL, 13.0 g/dL, 12.5 g/dL, and 12.4 g/dL at weeks 0, 4, 12 and 24, respectively. Neutropenia was observed; cell counts below 1000 cells/mm3 were noted in 7 patients. No patient required discontinuation of either PEG IFN a-2a or RBV because of anemia, thrombocytopenia (low platelets), or neutropenia.
Nine patients had dose adjustments (14 events): anemia (5 patients), neutropenia (3 patients), adverse events (6 patients). There was a mean decrease from baseline at week 24 in hemoglobin of 2.9 g/dL. 7 patients had their lowest ANC <1000 cells/mm3. 2 patients had platelet counts below 75,000 during therapy, but none below 50,000.
This data compares with a 28% response rate for genotype 1 (for those receiving 48 weeks therapy; 16% for those receiving 24 weeks therapy) in the large US IFN+RBV study which used Intron A regular interferon. For other genotypes, the end-of-followup viral response rate was about 67% whether they received 24 or 48 weeks IFN+RBV combination therapy. Overall, 13% receiving 48 weeks interferon monotherapy 3 MIU 3x/week) achieved undetectable HCV-RNA; 6% for those with 24 weeks IFN monotherapy. Most people in the US are genotype 1. Baseline HCV viral load is predictive of viral response. A person with a high baseline viral load (usually considered >2 million copies/ml) has a lower response rate than a person with lower HCV viral load before starting treatment. When to begin therapy is a key and difficult question. The decision should be based on the individual's personal situation and should be based on a discussion between the doctor and patient. Ultimately, it's the patient's decision. There are many factors to consider including: person's liver condition (best evaluated by results of liver biopsy); not everyone's HCV disease progresses, but HIV speeds up HCV progression without HAART therapy; we don't know how much successful HAART may slow HCV progression (this may vary on the individual's situation); it appears that earlier in HCV disease stage a person may be more likely to respond better to therapy.
This is a small study and does not necessarily reflect results expected in a large study of coinfected individuals. Several studies in coinfected individuals are planned or have started. It's expected that a better understanding of response by coinfected individuals will emerge from these studies. One key question is whether AZT and d4T interact with ribavirin. Earlier in vitro studies suggest showed an interaction, but it remains uncertain if there is a clinical affect. An answer to this question is expected from planned studies. Doug Dieterich conducted a study of about 30 coinfected individuals some of whom were taking AZT or d4T and were receiving IFN+RBV. He did not detect an affect on the HIV viral load of those individuals in the study. However, his study was small and I think the question remains unanswered. The larger ACTG study will examine this question more closely with both in vitro and clinical looks.