Hepatits C

It’s estimated that about 1 million Americans have HIV but that 4 million have hepatitis C (HCV). The incidence of HCV among people with HIV is an emerging concern because people with HIV are living longer healthier lives. The increased longevity allows HCV to become a problem. Its estimated that 40% or more of people with HIV may also have HCV. Mark Sulkowski reported at IDSA that about 50-90% of persons who acquired HIV from injecting drug use are also HCV-infected. He suggested that there may be 300,000 persons co-infected with HCV and HIV in the USA, representing 30% of the estimated 1 million persons with HIV.

Currently, the recommended treatment approach to HCV is combination therapy with interferon and ribavirin. The combination is more effective in reducing or eliminating HCV than monotherapy with interferon which was previously used. The main goals of therapy are to achieve a sustained virological response and a sustained biochemical response 6 months after the cessation of therapy. A sustained virological response (SR) means that HCV viral load is undetectable. A SR 6 months after therapy ended is expected to translate into long term absence of virus.  So far studies show that undetectable HCV viral load sustained after 6 months following stopping therapy can be maintained for 10 years. As a result, some doctors say HCV is curable, unlike HIV. A biochemical response refers to the effect of treatment on certain liver function test—ALT and AST. A good response is normalization of these lab tests. Even if a person does not achieve undetectable HCV viral load, the effects of therapy on liver histology (liver condition) may be enough to result in long term benefit..

Factors Predictive of Therapeutic Success: HCV kinetics, genotype, baseline HCV-RNA, interferon dosing & levels. Data from studies show that combination HCV therapy results in about 40% achieving a sustained virological response. If a person has genotype 2 the response rate reported was 66%. If a person has genotype 1, a virological SR occurs 28% of time after 48 weeks of combination treatment but is only 16% after 6 months of combination treatment. This data is from treatment with interferon 3 times per week with ribavirin. Daily dosing of interferon may improve response rates. Previous to the availability of combination therapy, 10%-20% receiving interferon alone responded with a sustained virological response. A person with a lower HCV viral load at baseline is expected to respond better. A person with early cirrhosis may be less likely to respond well, but it appears can respond. Treatment with pegylated interferon for individuals with compensated cirrhosis was reported at AASLD (see below).  A number of experts feel that the standard recommended dosing of interferon (3 MIU three times per week) is inadequate. Several studies and the viral kinetics of HCV suggest that daily dosing of 3 MIU or more may be preferable and more successful. Preliminary data reported at AASLD meeting on pegylated interferon is promising that it will improve virological and biochemical response over current therapy. See report below.

Complications of HCV/HIV Co-infection. Treating a person co-infected with both HCV and HIV is more complicated than treating a person who has only HCV. HIV affects the immune system. This in turn may affect a person’s response to HCV or HCV therapy. A person is likely to respond better to HCV treatment if their HIV viral load is undetectable and their CD4 is higher. However, some people cannot tolerate HAART due to their underlying liver condition, and may have to be treated first for HCV. People with HIV may have anemia or a tendency to develop anemia, and HCV therapy can be associated with the development of anemia. As well, HCV therapy can cause reduced platelets, another problem people with HIV may experience. Weekly lab tests are drawn after initiating HCV therapy to monitor for anemia, platelets and additional relevant labs. A person’s HIV viral load should be monitored closely after starting HCV therapy to make sure it remains stable. Ribavirin may have an interaction with AZT or d4T in that ribivarin may inhibit blood levels of these 2 NRTis thus potentially reducing their antiviral activity. Reported below are 2 small studies on treating HCV in co-infected individuals.

Cirrhosis has been found to be more frequent (33%) in co-infected individuals than in patients with HCV alone (11%). It appears that HIV can have a negative effect on HCV progression. One study suggested that co-infection with HIV and HCV may increase the death rate compared to infection only with HIV. A pregnant woman with HCV and HIV may be more likely to pass HCV onto her newborn. It appears as though HIV worsens HCV but some have raised the question that its unclear if or how much HCV worsens HIV. I think this is an irrelevant question, but a study discussed below suggests HCV can accelerate HIV clinical progression. To me its clear that co-infection worsens your general health and potential longevity.

The side effects of taking interferon +  ribivarin can be difficult to tolerate. It can cause flu-like symptoms such as fever, achiness, fatigue, dis-orientation or lightheadedness, severe depression, and others. Tolerability can vary by individual but often the person taking HAART for HIV may also be experiencing side effects from HAART. In addition, there is the concern about adherence to medications. Combination HCV therapy requires taking ribivarin pills twice a day and interferon subcutaneous injections either three times per week or more often. Patients must accommodate taking HAART and HCV therapy into their schedules. The advent of once a week administration with pegylated interferon should help adherence and willingness to initiate treatment.

Additional key questions are unanswered. When should a person begin HCV therapy? The answer to this question is controversial. Several factors are considered: the person’s HCV viral load, their genotype, the condition of their liver taken from a biopsy, their ALT and AST. Viral load is different in HCV than in HIV. HCV viral load appears to fluctuate during initial stages of therapy, while in HIV viral load declines below detection limits and is expected to remain there. An HCV viral load of 200,000 copies/ml is considered low. A person with genotype 1 is less likely to achieve a sustained virological response than a person with genotype 2, and in the USA genotype 1 is more common. Although you can monitor your liver condition for progression and intervene with therapy when there is progression, you want to be careful not to delay therapy and allow more severe liver disease to develop unknowingly.

A person with chronic HCV may experience fatigue and malaise. The rate of progression of HCV can be highly variable. Recent data suggest that patients may be slow, intermediate, or rapid "fibrosers". Slow fibrosers may not progress to cirrhosis despite years of infection, whereas rapid fibrosers may progress to cirrhosis in ten to fifteen years. Moderate intake of alcohol may enhance disease progression. Also associated with more severe liver disease are age >40 years at infection, and being male. Once cirrhosis is established, the rate of development to carcinoma may be as high as 1-4% per year. Once patients develop a clinical complication of their cirrhosis, the 5-10 year survival rate is only 50% and 30%, respectively. I think it’s important to consult with a doctor possessing a high level of experience and expertise in treating HCV and in treating co-infection. It may also be helpful to consult with 2 or more liver specialists in conjunction with your HIV doctor.  This may help you in better understanding your situation, in selecting the best treatment approach, and in feeling comfortable with making your treatment decisions.

There are a few additional questions. Several studies reported at AASLD showed a range of 3% to 20% for sustained virologic response rate among African-Americans to combination interferon-ribavirin therapy. Researchers preliminarily think the low virologic response rate may be due to a host or genetic reason. One study showed 96% of African Americans had HCV genotype 1. As mentioned above, although a person may not reduce viral load to undetectable therapy may improve the condition of the liver. It is still uncertain whether long-term benefit will accrue to improvement in the liver condition. A study showed Vitamin E and omega 3 fish oil supplements both can improve liver enzymes. Prior in vitro data suggests that ribavirin may have interaction with AZT or d4T. The Dietrich study below does not detect an effect and begins to address this question, but additional ongoing studies are needed to more comprehensively address it. Individuals with higher CD4s appear to respond better to HCV therapy. So treatment for HIV which gets virus under control and improves CD4s may predispose individuals to a better response to HCV therapy. The preliminary data from pegylated interferon studies promise for improved response rates to HCV therapy, and easier once a week administration (see data below). By taking interferon three times per week, in between dosing the levels of interferon in a person goes down. Taking pegylated interferon once per week appears to maintain stable & adequate interferon levels in the blood until the next dose. If a person has HCV but is negative for hepatitis A they are strongly urged to take the hepatitis A vaccine. Contracting hepatitis A if one has HCV can be severe.

12 Month Update of Interferon-Ribavirin Combination Treatment For Hepatitis C in HIV Co-infected Persons.  This is a 12 month update from Doug Dietrich's 6-month data reported at ICAAC in Sept '99 on HIV-HCV co-infected individuals treated with IFN+RBV. The more detailed original report from ICAAC is available on the NATAP web site (www.natap.org - in the Conference Reports section). In this small study, 20 HIV-infected individuals randomly received either IFN alone or IFN+RBV. Because of the potential inhibition of phosphorylation of AZT and d4T by RBV, this study evaluates the effects of 3 MIU IFN tiw (3x/week) alone and in combination with RBV 1000-1200 mg per day bid.

At baseline, median age was 40, median CD4 was 348, baseline median HIV RNA <400 copies/ml (mean 4,954 copies/ml). 13/24 patients had HIV RNA <400 c/ml. Median HIV RNA was 25,100 c/ml among those with detectable HIV RNA. 19/24 were receiving HAART. 19 were receiving AZT or d4T. Median liver biopsy/fibrosis was 2.1 for both groups.

At ICAAC, Dieterich reported median HCV viral load was 600 copies/ml (5/7 had <400 copies/ml) after 6 months treatment. At 4 months in study those who had received IFN alone (n=10) at baseline crossed over to receive IFN+RBV if their viral load was detectable. Dosages were IFN 3 MIU tiw + RBV 800 mg day.

Dieterich reported at AASLD that after 12 months of therapy, for those who started combination IFN+RBV at beginning of study:

The baseline numbers for the IFN+RBV group was 325,000 HCV-RNA and <400 HIV RNA. Since the HIV-RNA was still <400 at month 12, this suggests that the clinical effect of combining RBV with AZT or d4T may not be harmful for patients.

For the group who started with IFN alone their median baseline HCV-RNA and HIV-RNA was 5 million (and reduced to 98,000 at 12 months) and 1,500 copies/ml, respectively; CD4s were 190. After 3 months, their HCV-RNA and HIV-RNA were 4.35 million and 600 copies/ml, respectively; CD4s were 186. They added RBV at 4 months and at 6 months their HCV-RNA and HIV-RNA were 447,000 and <400, respectively; CD4s were 190. So HCV-RNA was reduced about 1 log after adding RBV. After 9 months their HCV RNA was 176,000, after 12 months it was 98,000. And their HIV-RNA was <400 copies/ml.

Side Effects. After irritability, the most common side of IFN/RBV therapy was anemia (5/11 patients) in the combination arm vs 1/10 in the IFN alone group. All patients with hemoglobin <10 g/dL were treated with 40,000 units of recombinant human erythropoietin (r-HuEPO) for at least 3 months. After 5.5 weeks of r-HuEPO therapy, median hemoglobin was 12.7 g/dL. Hemoglobin >10 g/dL was achieved after 4 weeks of r-HuEPO therapy in 4/5 patients in the IFN/RBV group and after 8 weeks of rHuEPO therapy in the remaining patient. Just 1 patient discontinued IFN/RBV combination therapy because of intractable anemia. The patient in the IFN alone group with hemoglobin < 10 g/dL responded to r-HuEPO therapy after 8 weeks of therapy.

This study and others suggest HIV infected individuals can be treated successfully for HCV. It appears as though HIV-RNA was not effected by potential changes in phosphorylation of AZT and d4T by RBV. However, study was small and Dieterich did not study phosphorylation. A larger study is needed to further explore the potential RBV interaction with d4T and AZT (phosphorylation), and to better characterize and assess co-infection treatment issues. It's important to characterize treatment responses, and when and with what to begin HCV treatment for co-infection.

IFN+RBV Treatment for HCV-HIV Co-infection. In a second study, a French research group (by A.O.L. Landau et al) evaluated the efficacy and safety on IFN+RBV for treating chronic HCV among 20 HCV-HIV co-infected individuals in an open-label multi-center trial. Subjects received 3 MIU tiw IFN in combination with RBV 1000 mg or 1200 mg daily during 12 months. The primary study endpoint was virological response defined as HCV viral load undetectable by PCR at months 3 and 6. It is generally accepted that the goal of HCV treatment is a "sustained virological response" which is defined as an undetectable HCV viral load 6 months after treatment has stopped. So results at 6 months are preliminary because a person can have undetectable HCV viral load after 6 or 12 months of treatment but their HCV viral load can be detectable 6 months after stopping treatment. In which case they are not considered a "sustained virological responder". Again, it is generally accepted that a person can still benefit from HCV treatment even if they are not a sustained virological responder.

Mean HIV viral load and CD4 were 7,600 copies/ml (low) and 350. ALTs and ASTs (liver function tests) were 121 and 75, respectively at baseline. Total Knodell score at baseline was 10.7 with 9 individuals having active cirrhosis (45%). I’m assuming these 9 had early (compensated) cirrhosis. After 6 months of treatment with IFB+RBV, 10 patients (50%) had undetectable HCV viral load. Seven participants became undetectable at month 3 and 3 at month 6. LFTs were in the normal range. There were 5 individuals with genotype 1 (1b=2; 1a=3) and 5 with genotype 3a in the responder group. The study authors concluded that IFN+RBV treatment is safe and effective in co-infected individuals. I think the data is preliminary because both of the studies are short term and small, but they preliminarily suggest co-infected individuals can be treated for HCV with success. Larger and long-term studies are needed and planned to confirm this and to address the questions raised at beginning of this article. 

Preliminary Data on Pegylated Interferon.  Hoffman-La Roche reported data on their pegylated interferon (Pegasys) in combination with Ribavirin in chronic HCV for treatment naïve individuals (phase II open-label study). A once-weekly dose (180 ug s.c.) of Pegasys was administered to 20 patients in combination with 1000-1200 mg oral ribavirin twice daily. Virologic responses were 30% at week 4, 70% at week 12, 80% at week 24, and 70% at week 48. The end-of -treatment (ETR) response (week 48) for patients with genotype 1 was 63% (10/16). HCV genotype 2 had sustained response rate of 100% (4/4) at week 48 (24 weeks of treatment and 24 weeks of follow-up). Biochemical response was 60% at week 4, 70% at week 12, 65% at week 24, and 60% at week 48. Studies in HIV-infected individuals are ongoing and planned.

A total of 12 dose modifications were made in 8 patients due to anemia (4), neutropenia (2), and other AEs ( 6). Mean hemoglobin was 15.3, 13.0, 12.5, and 12.7 g/dL at baseline and weeks 4, 12 and 24. Neutropenia was observed with counts falling below 1000 cells/mm3  in 7 patients. Platelet counts declined until week 12 then stabilized. The lowest count was 68,000 plt/mm3. No patient required discontinuation of either RBV or IFN because of anemia, thrombocytopenia, or neutropenia. 4 patients experienced severe AEs. Roche reported that multiple dosing of PEG-IFN had no significant effect on in vivo metabolism involving the CYP isoenzymes 2C9, 2C19, 2D6, and 3A4. A significant drug interaction is seen with PEG-IFN and drugs metabolized by CYP1A2. Clearance of theophylline is reduced by PEG-IFN but the magnitude of effect is similar to that of IFN. Roche concluded that most marketed drugs that undergo CYP metabolism are unlikely to be affected by concomitant use of PEG IFN.

Schering Plough reported preliminary results from their pegylated interferon. This early open-label, randomized, active controlled study was to assess safety, PK, and efficacy of pegylated IFN + ribavirin in various doses. 72 Patients (20-68 yrs age) with chronic HCV received either PEG IFN 0.35, 0.7, or 1.4 ug/kg s.c. weekly for 24 weeks alone or in combination with ribavirin 600, 800, or 1000-1200 mg oral daily. When looking at the antiviral activity at 24 and 28 weeks of various IFN doses, those individuals receiving the highest dose of 1.4 (ug/kg once weekly) + RBV had 81% undetectable compared to 50% receiving PEG IFN alone (24 weeks). At week 28 (4 weeks of follow-up) 73% receiving IFN+RBV were undetectable and 57% receiving PEG IFN alone were undetectable. The speaker said a higher dose of I think 3.0 ug/kg was being explored and data would be available in 2000.

Jenny Heathcote reported on the efficacy and safety of once-weekly pegylated interferon alone (Roche’s Pegasys) in patients with chronic HCV and compensated cirrhosis. To qualify for the study patients had to have biopsy proven cirrhosis/incomplete cirrhosis, and compensated liver disease (Child-Pugh Class A).  271 IFN-naïve adults were randomized to receive 3 MIU IFN sc tiw or 90 or 180 ug PEG IFN sc once a week for 48 weeks. The study participants were 72% male and 88% caucasian. Median baseline viral loads were 3.2 million in IFN 3 MIU, 2.6 million in PEG-IFN 90 mcg, and 2.3 million in PEG-IFN 180 mcg. Cirrhosis—76% in IFN 3 MIU, 79% in PEG-IFN 90 mcg, and 79% in PEG-IFN 180 mcg. Transitional cirrhosis—24% in 3 MIU group, 20% in PEG-IFN 90 mcg, and 21% in PEG-IFN 180 mcg group. The end-of-treatment response (Amplicor <100 copies/ml) was 13%, 43%, and 43% in the 3MIU tiw, 90 ug and the 180 ug groups (n=87), respectively. At the end of follow-up 8%, 13%, and 29% were undetectable in the 3 groups. Only 10% (n=48) with genotype 1 receiving 180 ug dose had undetectable HCV RNA. Adding ribavirin would be expected to improve response. 5% receiving 90ug and 8% and 0% receiving 3 MIU had response. Individuals with non-genotype 1 had much better response: 53% receiving 180 ug, 25% receiving 90 ug, and 13% - 3 MIU. Individuals with above 2 million viral load at baseline had 23% sustained response while 35% were undetectable with baseline VL below 2 million, in the 180 ug group.

SAFETY. One safety concern going into study was that compensated cirrhosis would turn into decompensated during therapy but Heathcote said she did not observe this. Dose modifications—37% in 180 ug group versus 25% in 90 ug and 29% in 3 MIU groups. Heathcote said dose modification was often for short period of time. Dose modification was required for thrombocytopenia in 6%, 18%, and 19%, and for neutropenia in 14%, 9%, and 11% in the 3 MIU IFN, 90 ug, and 180 ug groups, respectively. The discontinuation for drug intolerance was 10%, 11% and 14%, in the IFN, 90 ug, and 180 ug groups. 2%, 4%, and 2% discontinued due to thrombocytopenia in the 3 groups, respectively.

Incidence of HCV Among Individuals HIV-infected Through IVDU. It has been previously reported by several researchers that a very high percentage of individuals who contracted HIV through IVDU are co-infected with HCV. Dieterich has reported that in NY 40% with HIV have HCV, in Buffalo 42%, and in Boston 56%. Two studies reported at ICAAC on the incidence of HCV among people who contracted HIV through IVDU. M Jara reported that at a time when testing for HCV was not yet routine and the level of documented testing among HIV patients was 71% in Massachusetts, 51% (n=36) were HCV+. AIDS cases with a history of IVDU were significantly more likely to have HCV than cases due to high-risk sexual contact. All available medical records were reviewed for a random sample of male and all female AIDS cases reported to the Massachusetts AIDS Surveillance from 11/93 to 3/97 by a convenience sample of medical facilities statewide (n=307). The study authors recommended testing for HCV should be routine part of HIV care. Ihab Ibraham from Downstate Hospital in Brooklyn, NY reported at IDSA that despite known and perceived HCV/HIV risk factors (IVDU), less than half of their clinic patients were tested for HCV during the past several years. He followed by saying that now patients are referred for testing.

In a second study D Ferris from the St Paul’s Hospital in Vancouver BC, Canada reported on a database they started collecting in their HIV/Hepatitis Clinic. To date they have assessed 31 HIV+ patients with hepatitis (29 male, 2 females) of which 13 are IVDUs and 18 are not.  Excessive alcohol use was more frequent in the IVDU group (54% vs 17%, p=0.03). Notably, HCV was 100% prevalent in the IVDU group and 26.7% in the non-IVDU group. The authors also reported that less IVDUs were using HAART compared to non-IVDUs (46% vs 83%, p=0.03). Because of the greater risks for liver disease in IVDUs, the authors recommend goals of management should focus on removing barriers to HAART and developing treatment strategies for substance abuse and hepatitis C.

At IDSA Catherine Sallenave-Karpman reported that upon review of records for 161 HIV+ patients in rural Vermont Clinic, 63% were screened for HCV by ELISA, HCV serology was positive in 32% of those screened. 75% of those HCV positive had IVDU experience, while only 6.8% in HCV negatives.

HCV speeds HIV clinical progression. L Piroth and others looked at the effect of HCV on clinical and immunological progression of HIV in HIV infected individuals. 812 HIV+ patients were followed in 13 French medical centers since 1985. 89 (11%) were co-infected with HIV and HCV. 9.2% were Ag HBs positive. 465 patients were treated with anti-retroviral therapy: 28% with NRTI monotherapy; 68% with double NRTI therapy. The authors reported that using a statistical analysis (univariate analysis) clinical HIV evolution was significantly faster in the HIV-HCV co-infected group than in the HCV negative group. But immunological evolution was not significantly different. In a multi-variate analysis, clinical HIV progression remained significantly associated with HCV co-infection as gender, age, and lack of treatment by NRTIs did.

HIV Speeds Hepatitis C Progression. Dieterich has reported that preliminary studies show fibrosis is more severe in HIV, and cirrhosis is more frequent in HIV (33%) than in those with HCV alone (11%). As well, recent data suggests increased death rate: 11% in co-infected (40% from liver disease) and 6.8% in HIV alone, and maternal-fetal transmission of HCV increased from 7% to 11-25%. Likewise, HCV may increase the risk of HIV transmission. Barbara McGovern conducted a retrospective of all HIV+ patients who died at her institution in Boston from May ’98 to April ‘99, and reported at IDSA that end-stage liver disease due to HCV/HBV is now the leading cause of death in patients with underlying HIV. 55% of patients who died of end-stage liver disease had undetectable HIV viral load and/or CD4 count >300 prior to death. 32% had to stop HIV therapy secondary to abnormal LFTs. She recommended that patients co-infected with HIV and HCV and/or HBV need careful assessment of the possibility of underlying liver disease prior to the initiation of HIV treatment.

Hepatitis A and HIV. R.E. Berggren and others reported that hepatitis A (HAV) can severely impact HIV+ individuals. 35 individuals co-infected with HAV and HIV were followed. The mean baseline CD4 count was 375. HAV resulted in HAART interruption for a mean 57 days with 4/35 requiring hospitalization (11%) and 8/32 (25%) requiring a prescription change due to failure to suppress HIV viral after resuming HAART. At one year post HAV, the HIV viral load was significantly higher in the HAV cases than the control group. The authors recommended that HIV+ individuals should receive an HAV vaccine.

Effects of HIV therapy on HCV fibrosis progression:

HIV Protease Inhibitor Therapy and Duration of PI Therapy May Be Associated Slower Liver Fibrosis Progression.  Christine Katlama and others in French HIV research group reported here in Dallas and also at ICAAC HIV Conference in September that individuals co-infected with HIV and HCV who receive protease inhibitor therapy for HIV can experience decreased liver fibrosis progression rates. Katlama said HCV related liver fibrosis progression is accelerated in HIV infected patients. The objective of their study is to examine the impact of combination anti-retroviral therapy for HIV including a PI on liver fibrosis progression rates. 162 consecutive HCV-HIV co-infected patients (119 male; 36.7 yrs age) were studied. At liver biopsy, HCV duration was 14.4 years, CD4s were 327, and HIV RNA was performed in 79 patients (17,823 copies/ml). 42 patients had self-recorded alcohol consumption (SRAC above 50g/day). At liver biopsy, 49 patients were receiving PI therapy for 12 months. Estimated FPR (fibrosis progression rate) was defined as ratio between fibrosis stage (METAVIR scoring system) and HCV duration. Since the linearity of liver fibrosis progression remains questionable only non-parametric statistical tests were used for univariate and multivariate analysis.

Patients receiving PI therapy had higher duration of HCV infection and lower HIV viral load than patients who had never received PI treatment (17 vs 14 years, p=0.04; 12,154 vs 22,332 copies/ml, p=0.03). Neither CD4 count nor alcohol consumption showed significant difference between the 2 groups. Patients with high FPR (above 2.0 fibrosis units/year; that is, expected time from HCV infection to cirrhosis below 20 years, n=45) included more patients older than 20 years at HCV infection, with a SRAC (alcohol consumption) above 50 g/day, and with a CD4 count below 200, and less patients treated with a PI compared to patients with low FPR (equal to or below 2.0 fibrosis units/year, n=117). Logistic regression analysis identified 2 independent factors associated

with high FPR: CD4 count below 200 (odds ratio=15; p below 0.0001)) and no previous treatment with PI (odds ratio=3.8, p=0.02). The duration of PI therapy is associated with a low FPR in HCV-HIV co-infected patients. The independent association between PI therapy and liver fibrosis progression is not explained by the studied factors, including the CD4 count. I think its possible that improved CD4s and viral load due to any HAART HIV therapy may be associated with improved fibrosis progression.