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HCV Therapy in HCV/HIV Coinfection
Reported by Jules Levin
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There were a few studies reported today in posters on response to HCV therapy by HCV/HIV coinfected patients. The data is preliminary as I'll explain below but suggest that coinfected patients may not respond as well to therapy as patients with HCV alone. Is this a reason to not treat your HCV? I don't think so. A study was reported by Thierry Poynard showing that interferon+ribavirin appears to improve, slow, or stop liver damage even if there is no viral response (non-responders). And yesterday the Japanese research group reported from a large analysis that interferon improves disease progression. Other studies have suggested that interferon can slow disease progression even if there is little viral load response. In speaking with French researchers here their experience is that coinfected patients respond less by about 5-10% in terms of percent achieving a sustained virologic response. It's my understanding that genotype 1 is less prevalent in Europe (50%) while here in the USA genotype 1 prevalence is 70%. Among IVDUs genotype 1 is reportedly found 80% of the time. While several studies report over 90% of African-Americans have genotype 1. So, one reason coinfected patients don't respond as well is because they have a higher percentage of genotype 1. However, there may be other factors. HIV may impair the immune response. Evaluating a person's immunity by their CD4 count is a crude way to assess the capacity of their immune system. Inside liver cells there are CD4 cells. Researchers have yet to examine inside liver cells in coinfected patients to see if their immune response is impaired. Additionally, the overall immune response in HIV is not well understood. More research is needed to understand the role of HIV in perhaps limiting the response to HCV therapy. Other factors may also be involved such-is the HIV viral load undetectable which may improve response to HCV therapy; alcohol intake; is HAART playing a role; do individual drugs play a role; the length of time a person has had HCV.
PEGASYS
Roche reported very preliminary data on their study of coinfected patients in the USA. 150 coinfected patients are being enrolled in this study to receive Pegasys (pegylated interferon alfa-2a) 180 ug by subcutaneous injection for 48 weeks. Patients receive Pegasys momotherapy for 12 weeks and can add ribavirin if they have detectable viral load at 12 weeks or do not achieve 2 or more log reduction in HCV viral load. Patients could have CD4s as low as 100 for this study and detectable HIV-RNA. 106 patients enrolled; age 44; 82% male (women respond better); ALT 101; 59% had high viral load (6 million); average HCV-RNA 6.3 log IU/mL; 80% genotype 1 (this is a high percentage of genotype 1); average HIV-RNA 2.3 log; 11% cirrhotic.
Cd4 at baseline was 513 and 436 at week 12. 63% had <50 copies/ml HIV-RNA at baseline and 72% at week 12. 19.1% (17/89) had negative HCV-RNA at week 12 (on Pegasys monotherapy). 33.7% (30/89) had a reduction in HCV-RNA of 2 or more log. 9 patients (8.5%) have discontinued therapy: 5 patients (4.7%) because of expected adverse events and 4 because of refusal of treatment or failure to return. The authors reported that no unexpected adverse effects of the study meds were seen. The lowest post-baseline neutrophil count of grade 4 neutropenia (<500/mm3) occurred in 9 patients (8.5%); the lowest post-baseline hemoglobin level grade 1 (8.0-9.4) occurred in 2 patients; and thrombocytopenia (platelet count <20,000 mm3) occurred in 1 patient.
82% of patients experienced at least 1 AE: fatigue 35%; myalgia (muscle aches) 27%; headache 22%; nausea 20%; pyrexia 19%; rigors 18%; arthralgia 12%; injection site inflammation 12%; depression 12%.
These results are obviously preliminary, at week 12. And we look forward to further analysis.
Edmund Bini, from New York City, reported on a small study of coinfected patients receiving standard interferon + ribavirin. Consecutive HIV and HCV coinfected patients were treated with IFN alfa-2b 3 million units three times per week with 800-1200mg/day of RBV. The results in these patients were compared to a matched group (similar characteristics) of patients with HCV alone. The duration of therapy was 24 weeks if genotype 2/3 or up to 48 weeks in those with genotype 1. Sustained virologic response was defined as <100 copies/ml 24 weeks after stopping therapy. In patients with genotype 1, treatment was discontinued if HCV was still detectable at week 24. All data was analyzed by an intent-to-treat analysis. 96 patients were included in the study- 32 with coinfection and 64 with HCV alone.
Bini said there were no significant differences between the coinfected patients and those with HCV alone. Treatment was completed in 75% of the coinfected patients and 83% of those with HCV alone (p=0.37). The coinfected patients had HIV for 7.5 years, on average. CD4 count was 433. Average HIV viral load was <50 copies/ml (range <50 to 83,000). Average number of ART medications was 3. Bini reported 84% had genotype 1in both groups. In both groups, 40% had >2 million viral load. Average HCV-RNA was 1.5 million copies/ml. Histologic Activity Index (0-18) was 6.7 in HIV group and 6.1 in HCV group (NS). Cirrhosis was 22% in each group. Duration of HCV was 16.8 years in HIV group and 19 years in the HCV group. So, these patients had HCV for much longer than they had HIV. 68-73% had IVDU as the risk factor for HCV. 56-65% were African-American. 18-25% were Hispanic. 90% male. Age was 49 on average.
The end-of-treatment viral response was 39% in the HCV alone group and 34% in the coinfected group (p=0.66, NS). So, the 2 groups responded the same. At the end of followup (sustained response) 26.6% in the HCV alone group and 21.9% in the coinfected group (p=0.62, no difference) had a viral response. Response according to genotype: genotype 1: 22% in HCV alone and 18.5% in coinfected; genotype 2/3 50% in HCV group and 40% in the coinfected patients. No coinfected patient with undetectable HIV viral load developed HIV viremia during treatment or follow-up. Treatment with IFN+RBV did not result in a significant CD4 count decrease. There were no serious adverse events. Bini reported there was no difference between the 2 groups in terms of dose reductions and other adverse events. This is unusual. In real life, you would expect coinfected patients to discontinue more often and have higher incidence of reduced hemoglobin. Bini concluded that the response was the same between coinfected patients and those with HCV alone.
The AmFar study in coinfected patients was reported but there are some problems with this study. It was conducted at 21 sites including Puerto Rico. 110 patients received either standard interferon monotherapy 3 million units 3 times per week or IFN+RBV. But, patients in the IFN/RBV arm received IFN monotherapy for 12 weeks and if detectable they could replace RBV placebo with RBV at week 16 (in a blinded fashion). Although it wasn't stated in the poster, I was told that patients who added RBV were still considered non-responders. Patients were somewhat evenly divided between being white, black, or hispanic. 85% were men. 75% had genotype 1 and baseline HCV-RNA was 4.4 million copies/ml. Fibrosis was present in 84% of participants. 15% had cirrhosis. Hepatic necrosis was present in 59%. Median HIV-RNA was 400 copies/ml and mean viral load was 37,000 in the IFN/RBV group. Average CD4 was 500. 56% had undetectable HIV-RNA. 57% were on a PI regimen. 15% were not on any ART. 26% were taking AZT and 54% were taking d4T. ALT was about 100. RESULTS: at week 72, 8% receiving IFN/RBV had undetectable HCV-RNA. But remember patients were initially randomized to 16 weeks of IFN monotherapy. Although it wasn't mentioned in the poster and may not be true, I was told that those who added RBV because they weren't undetectable were considered failures (nonresponders). 0% (0/40) with genotype 1 had a sustained response while 25% with other genotypes had a sustained response. These results are strange. A response rate of 0% in genotype 1 is unexpectly low. 28% were African-American in the study and 36% were white. 21 patients (19%) experienced an undetectable viral load during at least one evaluation during the study. 3 of these patients were taking IFN monotherapy at the time of being undetectable. The authors reported that 50% of patients discontinued study drugs before prematurely. And 20% reported premature discontinuation was due to an adverse event. This is a high discontinuation rate. The most commonly reported adverse events were elevated ALT 32% (???); leukopenia 28%; elevated triglycerides 25%; anemia 24%; asthenia (fatigue 24%. It sounds to me as if patient management was not handled well. 24 patients were reported to have bilirubinemia, 18 with depression. 15 with elevated amylase, 13 elevated lipase, 12 hypoglycemia. The response rate at week 12 was 23% for those receiving IFN/RBV.
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