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PegIntron + Ribavirin in HIV/HCV Coinfected Patients
Reported by Jules Levin
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A French research group reported in an afternoon 4pm oral session on HCV/HIV coinfected patients who received either PegIntron plus ribavirin or interferon plus ribavirin. The preliminary results were poor and may in part be due to increased difficulty for HIV-infected patients in tolerating the therapy, as the discontinuation rate in the study appears high. The investigators did not report on any means used to improve tolerability of therapy. Although the investigators reported the percent of patients with genotype 1, they did not report the baseline HCV viral load for patients.
These were about 400 treatment-naive patients randomized to: PegIntron 1.5 ug/kg/week + ribavirin 800 mg/day or interferon 3 MIU three times per week + ribavirin 800 mg/day. Treatment is for 48 weeks with a 24-week follow-up period, when the sustained viral response will be evaluated. Patients had a liver biopsy before starting therapy, had stable HIV viral load, and Cd4 count >200.
The study is looking at long-term virologic response, safety & tolerability, ALT CD4 count, HIV viral load and liver histology. 148 patients out of the 206 assigned to this arm have been analyzed and 34 patients in the PegIntron arm stopped treatment. In the IFN arm 210 patients were assigned, 152 analyzed in this report, and 34 stopped treatment. In speaking with the study investigators they told me that one of the reasons for the low response rates, which you will see below, is because of the high 20-30% discontinuation rate. In the Pegasys/RBV study reported at EASL the discontinuation rates for patients were 12% and 14% in the PegIntron/RBV study. They also sited the high rate of genotype 1 in this study as another reason for the poor response.
Patients were 39 years old; 70-77% men; 67 kg weight (2.2 lbs per kg). Patients had HIV for 10 years. Cd4 count was good, 500. 70% had <400 copies HIV viral load. For patients with detectable HIV, viral load averaged 3.7 log (under 10,000). 80% were taking HAART.
The duration of HCV infection was reported as 13-14 years. 80% acquired HCV through IVDU. Histology: 40% had F3-F4 (cirrhosis) which is a high rate but surprisingly in the preliminary analysis having crrhosis did not reduce the response rate. 64-69% had genotype 1 or 4. In the US it's estimated that 70-80% of coinfected patients have genotype 1. Average ALT was 2 times the upper limit of normal. 15-19% had normal ALT.
RESULTS
37% (53/143) of patients in the PegIntron/RBV group had a virologic response vs 24% (37/152) in the IFN/RBV group (ITT analysis). They did not report in the slides which viral load test they used but in speaking with the investigators they said they used the sensitive test (100 copies).
25% of patients with genotype 1 or 4 had undetectable viral load at week 48. They did not report results by whether patient had high or low viral load. This is a poor response. In HCV monoinfected studies for patients with high viral load (>2 million) and genotype 1 they had a 29% response rate after 72 weeks in the PegIntron/RBV study and 35% in the Pegasys/RBV study. And of course 25% response rate will decline from 48 weeks to 72 weeks. Additionally, the relapse rate might be greater for coinfected patients, but until we see data from coinfection studies this is speculative. Again, the investigators told me that they feel the low response rate is in part due to higher discontinuation rate than that seen for monoinfected patients.
About 45% of genotype 2/3 patients had undetectable viral load at week 48. This is also much lower than seen in studies of monoinfected patients, where response rates have been 70%+ after 72 weeks. At this point in the analysis of this study they reported that there was no difference in response between patients with cirrhosis (F3-F4) and less advanced disease (F0-F2). Usually, patients with advanced disease don't respond as well.
Although patients received a fixed dose of ribavirin, when looking at whether a patient received more or less than 10.6 mg/kg of RBV there was no difference in response. I surmise this could be due to tolerability problems & discontinuation due to RBV related side effects. I don't think the investigators addressed whether or not they used EPO or any other supportive mechanisms to help patients to deal with therapy side effects. Clearly, coinfected patients may experience more side effects & toxicities due to HCV therapy and will need supportive services.
SIDE EFFECTS
They reported side effects were about the same between the 2 arms. 10-15% of patients reported experiencing diarrhea, anorexia, abdominal pain, or nausea. 33% reported asthenia (fatigue), 20% flu-like symptoms, 10% fever, 20% mylagia & 10% arthralgia (body aches), and 10% headaches. 10-15% reported depression, insomnia, irritability, or anxiety.
There were an equal number of serious adverse events in each group: 23% in the Peg group & 19% in the IFN group. Psychiatric events: 7 Peg, 9 IFN. Hyperlactatemia (>5mM/l): 4 in Peg group, 2 in IFN group. They reported patients who experienced mitochindrial toxicity were on d4T/ddI; odds ratio for ddI 17.
The oral presentation on this study in coinfection did not include a report
on certain toxicities. But the printed program contained this information of
interest:
significant decrease at week 12-
-- in hemoglobin (IFN: -1.5 g/dl; Peg: -1.8 g/dl)
--also in neutrophils (IFN: -693; Peg -1298)
--lymphocytes (IFN: -317; Peg -542; including CD4s -44 & -69 (NS))
--platelets (IFN:-16,000; Peg: -33,000)
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