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Hepatitis C Virus

There are many parallels between hepatitis C and HIV. Hepatitis C is predominantly acquired by parenteral transmission. Injection drug use accounts for 50% or higher for all patients who are HCV infected. The groups that had both HCV and HIV are going to be predominantly injection drug users who are co-infected with the two viruses because sexual transmission of hepatitis C is relatively inefficient, so in gay men who are HIV positive, hepatitis C is present.

Nevertheless, hepatitis C is sexually transmitted and again, when you are counseling your patient who is hep C positive, if they are co-infected you will counsel them for safe sex regardless. But if they are hep C positive alone, the current CDC guidelines are that you should tell that individual that the risk of sexual transmission in a stable, mutually monogamous sexual relationship.

The perinatal transmission of hepatitis C is also well documented and again, very little is understood about the natural history of perinatally acquired hepatitis C. This is an area of active investigation currently. But again, it is relatively inefficiently transmitted perinatally, in contrast to hepatitis B which is very efficiently transmitted perinatally. The risk of transmission, particularly perinatal transmission, appears at least in part to be related to the level of viremia, the hepatitis C viremia in the mother. That also may be true for other modes of transmission such as needle stick exposure and even sexual exposure.

Treatment: there are also, this last week, the hepatologists were officially in the world of combination therapy for treatment of naive individuals. Interferon plus ribavirin was FDA approved for chronic hepatitis C infection. Iíll talk a little bit about this and itís applicability to our patients who are HIV positive.

Thereís a lot of interest now in the hepatitis C protease as a target for antiviral development. Also the hepatitis C polymerase, the HRNA and RNA dependent polymerase. So with that background, it is completely predictable that we will have to move to combination treatments, however we are still very limited in the drugs that are available. They really are still based on interferon.

There are also some clinical parallels between hepatitis C and HIV. There is a lot of morbidity in these infections and this is something that we are just beginning to quantify with quality of life assessments in patients who have hepatitis C. Itís very clear that itís not merely that this disease can kill you, because it is the leading indication for liver transplantation in this country, but this disease causes profound morbidity in many individuals who are infected. Morbidity which can be numbered in the fatigue associated with infection, memory loss associated with infection, some of the extrahepatic manifestations of hepatitis C such as vasculitides, cryoglobulinemia. It has

One of the differences - well, there are many obviously - the natural history is much more aggressive for HIV than it is for hepatitis C. Currently in the natural history studies that we have available for hepatitis C, depending on the age of the cohort that is

Iím going to briefly talk about the natural history of hepatitis C and HIV co-infection and then deal predominantly with the treatment of hepatitis C alone and how we should apply it in clinical trials to the co-infected individual because the data on the use of interferon as a single drug in the co-infected individuals is, A) bad, or inadequate and B) outmoded. And then I am going to talk briefly about hepatitis B because again hepatologists had another drug approved this week - Epivir was

This is a study that we were involved with, and it really compared the safety and efficacy of interferon plus placebo to interferon to ribavirin for patients who had never been treated before for their hepatitis C disease. Ribavirin is, as you probably know, is a nucleoside analogue which was tested actually I think many years ago for HIV infection. It is a guanidine analogue and itís mechanism of action in hepatitis C is actually largely unknown but it may affect GMP pools and it may inhibit an enzyme called inosine monophosphate dehydrogenase which, when inhibited, has both an antiviral effect and also an immunosuppressive effect. The dose of ribavirin was either 1200 mg a day or 1000 mg a day in twice daily doses, divided doses, depending on the weight of the patient. And the dose of interferon was 3 million units three times a week. Patients received either six months of combination therapy versus interferon placebo or a year of combination therapy versus interferon placebo. They were monitored frequently during the study as well as in follow-up. One of the major endpoints of treatment was, histological endpoints, which were a comparison of the liver biopsy six months of treatment versus the pretreatment biopsy. The other primary endpoint was sustained viral clearance. Now the endpoints that we have in hepatitis trials is actually very different to the endpoints that have been developed in HIV in that we aim to be able to stop drug and so patients are treated for a limited period of time and they are followed for six months of therapy and itís the sustained viral clearance by sensitive PCR-base methodologies, which is usually the primary endpoint of our trials.

Secondary endpoints include improvement in liver biopsy and these are often, but not always, concordant with virological response and by chemical endpoints. Normalization of liver enzymes, again taken primarily off drug. We also look at end of treatment response rates but a sustained response rate is what we are trying to achieve with our treatment regimens. And this is the heart of the matter, the meat of the matter. This looks at the sustained virological response rates in patients receiving interferon plus ribavirin, shown here, to 48 weeks versus interferon plus placebo for 48 and that was achievable in 38% of patients. So of all comers treated, 38% were able to lose virus six months off drug and that from other studies has been maintained in the majority of individuals if you can get a patient to be virologically negative six months off treatment.

Interestingly, this was significantly better that just 24 weeks of combination, but I think that our cost-efficacy analyses would have to come up with algorithms for all of us to decide whether itís worth - or which groups of patients should be treated for the full year, because this improvement of 7% comes at a substantial cost, in terms of morbidity to the patient from these drugs, as well as cost to the pharmacy, depending on where you are practicing.

I mentioned at the beginning how poorly we seem to be doing today with interferon, and I think this slide points to that. The interferon plus placebo group that were treated for a year only had a 13% sustained loss of virus, and this used to be - this was what the initial FDA approval was based on, which was interferon as a single drug three times a week for six months - and with that regimen we were able to clear virus in only 6% of patients. So again, itís important for you if you are thinking about your HIV-positive patient who may have contraindications to ribavirin therapy because the major side effect.

Chemical response is actually paralleled by the virological responses with sustained normalization of liver enzymes of treatments and 36% of patients - and that was compared with 37% who sustained virological response rates. And again, significantly better than patients receiving just interferon as a single drug.

Now, I mentioned to you before the genotype of hepatitis C and how it influences therapy. I donít really believe it influences natural history, but it clearly influences therapy. Genotype-1 is present in 70% of all individuals in the United States and also in about the same proportion of those who have HIV/HCV co-infection. The genotype distribution appears to be similar to the HCV group alone. And if you have genotype-1 infection, your response rates with a year of combination is actually 28%.

This slide is relevant to the patient who is HCV/HIV co-infection because high levels of virus, pre-treatment levels of virus that are high, are consistently associated with reduced response rates versus patients with low levels of virus. So 36% of patients responded if they had, with combination for a year, if they had high levels of virus compared to 43%.

Now whatís the problem with ribavirin? Iíve shown you that it works a whole lot better than interferon as a single drug. The big problem is the toxicity of the drug. You get the toxicities of interferon, which is the standard flu-like toxicities, but in addition the major toxicity of ribavirin is anemia and 21%.