There has been some controversy about treating individuals for hepatitis C when they are co-infected with HIV. One important question is—will people with HIV respond as well to hepatitis C (HCV) treatment as people without HIV? Additional issues are –when should a person begin HCV therapy? There are mixed opinions about when to begin HCV therapy. Some treaters are more aggressive and others prefer delaying treatment. There is preliminary in vitro data suggesting that AZT and d4T may interact with ribivarin to reduce the antiviral effectiveness of AZT and d4T. The generally recommended and most effective HCV treatment is ribivarin+interferon and one of the concerning side effects of this 2 drug combination can be anemia. Will people with HIV have a more pronounced problem with anemia due to this HCV treatment? Can people with HIV taking complicated HAART regimens adhere to an additional treatment regimen without missing doses? Is daily interferon dosing rather than 3 times weekly (TIW) more effective? Several studies suggest daily interferon dosing may be more effective in long-term viral suppression of HCV. As a result of these issues and others a number of doctors are uncertain about whether to treat co-infected individuals for HCV and have delayed therapy.

Several of these questions were explored in small studies reported on at ICAAC. A number of additional studies are ongoing or about to begin which will attempt to answer these questions. In the meantime, the health or clinical status of some co-infected people may not be well-served waiting for answers from studies until a year or more has passed. I’ve selected key HCV studies presented at ICAAC to report on.

Two small preliminary studies show HIV+ individuals can respond well to HCV treatment with interferon and ribivarin, and there was no evidence in this preliminary 3-4 month study that potential ribivarin interaction with AZT or d4T increased HIV viral load. Doug Dieterich, MD, treats HIV and hepatitis in New York City and presented preliminary data at ICAAC on 21 individuals with both HIV and HCV and their response to HCV treatment. 19 of 21 were receiving HAART and taking AZT or d4T. To address the question that ribivarin may interact and reduce effectiveness of AZT or d4T, 11 individuals received interferon (IFN) 3 MU three times per week (TIW) alone for 4 months and then ribivarin (1000 mg-1200 mg) was added. Eleven individuals started with both interferon 3 MU TIW and the same dose of ribivarin (RBV).

Median baseline HCV RNA was 5 million in the IFN alone group and 325,000 in the IFN+RBV group. HIV RNA was 1,500 in the IFN alone group and <400 in the IFN+RBV group. CD4s were 211 in the IFN alone group and 529 in the IFN+RBV group.

Results: After 3 months of treatment the HCV viral load in the IFN alone group was much less than the 3 log reduction after 3 months for the group receiving IFN+RBV. Additionally, 4/8 in the IFN+RBV group had undetectable HCV viral load. The two-drug therapy appeared more effective virologically then the IFN monotherapy although the baseline HCV viral load was higher in the IFN alone group. The absolute number of CD4s decreased in the RBV+IFN group from 529 at baseline to 277 after 3 months of treatment but Dieterich reported the CD4 percentage was about the same. In the RBV+IFN group after 6 months treatment the median HCV RNA was 600 copies/ml (5/7 <400).

Essentially, none of the patients in either of the treatment groups had increased HIV viral loads after 3-4 months follow-up. One individual’s baseline HIV viral load was unknown and had about 6,000 copies/ml after 3 months. A second person’s HIV viral load increased from 1500 copies/ml to 5,000 copies/ml. The authors concluded that IFN+RBV therapy results in a large reduction in HCV viral load in co-infected individuals. The results of this study suggest that a potential interaction between AZT or d4T and RBV may not result in an increase in HIV viral load, and it suggests there may not be an interaction between ribivarin and AZT or d4T. But the study follow-up of 3-4 months may be too short as some researchers have said that an interaction could manifest following additional time on therapy. Viral load could rebound with more time. As well, in this study baseline HIV viral loads were low and results might be different in individuals with high HIV viral loads. Also, there was no direct measure in this study of whether RBV actually reduced the antiviral activity of AZT or d4T. Additional larger and longer-term studies are needed and planned to confirm these results. But this data is encouraging about this potential problem of ribivarin reducing the antiviral effect of AZT and d4T.

Adverse Events: The main adverse event was anemia—1 of 10 in the IFN alone group and 5 of 11 (45%) in the RBV+IFN group. Anemia was defined as hemoglobin <10. Irritability was highly reported: 7/10 in the IFN alone group and 6/11 (54%) in the IFN+RBV group.

All patients with hemoglobin <10 were treated with 40,000 units of recombinant human erythropoietin (EPO) for at least 3 months. After 5.5 weeks of EPO median hemoglobin was 12.6. Hemoglobin >10 was achieved after 4 weeks in 4/5 in the IFN+RBV group and after 8 weeks of EPO in the remaining patient. One patient discontinued IFN+RBV because of intractable anemia. The 1 person in the IFN alone group with <10 hemoglobin responded to EPO after 8 weeks of treatment. Two discontinuations were reported in each of the two treatment groups for a total of 4 due to "constitutional symptoms". As you may know interferon can cause flu-like aches and pains and fatigue. The magnitude of the side effects and their tolerability can vary between individuals.

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 MU 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". 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 active cirrhosis (45%). 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.

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. 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.

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.

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.

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.

Commentary: individuals co-infected with HCV and HIV may have a severe response if infected with HAV. It’s recommended that individuals who have HCV and HIV should be tested for HAV and if not infected they should receive HAV vaccine.