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PegIntron plus Ribavirin vs Interferon plus Rinavirin in HCV/HIV Coinfected Patients: preliminary week 48 results
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Here is a brief summary of the study results the researchers presented. After 48 weeks treatment the patients receiving PegIntron (pegylated interferon alpha 2b) plus Ribavirin had 38% undetectable HCV compared to 24% for patients receiving interferon plus ribavirin. All patients received a fixed dose of ribavirin (800 mg per day). There was a high rate (35%) of discontinuation from the study, which the study authors said plays key role in low response. For patients with genotype 1, the response rate at the end of 48 weeks treatment was 25% for patients receiving PegIntron plus ribavirin and 10% for patients receiving. Patients with >500 CD4s appeared to respond better than patients with <500 CD4s regardless of whether they received PegIntron or interferon regimen. Patients who had HCV for a shorter time (on average <8
years) and received PegIntron appeared to respod better to therapy than
patients with a longer duration (>8 years on average) of HCV (50% vs 31%). But for patients receiving interferon there did not appear to be a difference in response based on duration of HCV. There was a 20-25% rate of serious adverse events and psychiatric events occurred most often. The usual side effects occurred: depression, weakness, body aches, flu-like symptoms, diarrhea, irritability. More details are reported below.
THE STUDY DETAILS
A French research group reported at an oral HIV session the preliminary 48-week results from the ANRS HCO2 (RIBAVIC) study which examined HCV/HIV coinfected patients receiving either PegIntron 1.5 ug/kg by once weekly subcutaneous injection + ribavirin 800 mg per day or standard interferon a-ab 3 million international units (MIU) 3 times per week by subc injection. The study is for 72 weeks: 48 weeks treatment and 24 weeks of followup. A sustained viral response is evaluated at week 72 and it is the sustained response which is used to predict long-term outcome.
Patients stable and low HIV RNA, were stable on HAART, and had over 200 Cd4s to qualify for this study. Treatment was for 48 weeks. Patients were evaluated for loss of HCV RNA at week 72 (SVR: sustained viral response). As weell, safety, tolerability, ALT, CD4s, HIV RNA, and liver histology were evaluated (first biopsy within 18 months before starting HCV therapy and second biopsy taken at week 72.
442 patients were screened for eligibility (26 excluded: 7 for heamotological disorders). 416 were randomized. Of the 208 randomized to PegIntron+RBV, 157 were analyzed at week 48: were never treated, 3 died, 10 were lost to follow-up, 100 were on treatment and 35 stopped treatment,. So, the discontinuation rate was higher than in non HIV-infected patients due to tolerability and side effects. Of the 210 randomized to IFN+RBV 162 were analyzed at week 48: 6 were never treated, 1 died, 9 were lost to followup, 105 were on treatment and 41 stopped treatment (39% discontinuation rate). Deaths were said not to be related to HCV or HCV treatment.
The baseline characteristics for the patients were well balanced before starting the study; age 39 yrs, 70-77% male, body weight 134 lbs, 10 yrs since seroconverting to HIV+. CD4 count 515. 65-70% had <400 HIV RNA. For patients with >400 copies the average HIV RNA was 5,000 copies. 80% were on HAART. Patients had HCV for on average 13-14 yrs, longer than they had HIV (70% of IVDUs acquire HCV during first year of IVDU). 80% acquired HCV by IVDU. 5-10% blood transfusion. Histology (Metavirscore): a high percentage had cirrhosis: 38-40%. Average fibrosis score was 2.3 and average inflammation 1.7-1.8. Genotype 1: 64-69%. Only 15-19% of patients had sustained ALT below 5 times the upper limit of normal.
RESULTS
Using an ITT analysis at week 48 (end of treatment response) in which they evaluated all patients analyzed at week 48 (n=319: 59/157 (38%) receiving PegIntron had undetectable HCV viral load, vs 39/162 (24%) on IFN (p=0.01).
When analyzing only the patients who were on treatment as defined above (100 on PegIntron and 105 on IFN, 50/100 (51%) on PegIntron had loss of dectable HCV viral load vs 32/105 (31%) on IFN (p=0.01).
The high discontinuation rates due to tolerability and side effects appear to play a key role in response rates lower than that seen in HCV monoinfected patients.
RESPONSE BY GENOTYPE
The key data are the results in genotype 1 patients because 70% of patients in the US are genotype 1, and 80% of coinfected because are genotype 1 and over 90% of African-Americans with HCV are genotype 1. In this study the authors said there was not a statistically significant difference in response between the patients who received PegIntron or IFN for both genotype 1 and 2, but 25% of genotype 1 who received PegIntron had viral response at week 48 compared to 10% of patients who received interferon (I think this was using ITT analysis). The authors did not report the response rates for patients with genotype 1 and high viral load. Although these study results are preliminary, these responses in coinfected patients appear to be lower than that seen in monoinfected patients. In large registrational studies of IFN+RBV response rates after 72 weeks were 38-40%. For patients with genotype 2/3 in this study response rates after 48 weeks were about 45%, which compares to a 75-80% response rate seen in monoinfected patients 6 months after stopping therapy. Why is the response so low? It could be the high discontinuation rate due to more difficulty tolerating the medications and the side effects, and it could also be due to HIV impairing the immune system and thus the response to therapy.
HISTOLOGIC RESPONSE
I think he said there was no siginificant difference between PegIntron & IFN group in improvement of fibrosis, although these 48 week results are preliminary and maybe the difference will be significant with further analysis. About 35% receiving PegIntron or IFN had improved Fibrosis score, and there was no difference whether patients had early disease (F0-F2) or more advanced HCV (F3-F4). 20% of patients receiving IFN had improvement in Fibroisis score if they early HCV disease (F0-F2) and about 25% had improved score if they had more advanced HCV (F3-F4).
RESPONSE BY RIBAVIRIN DOSE
Although the patients in this study received a fixed 800 mg/day dose of RBV, achieving a RBV dose of >10.6 mg/kg did not appear to improve the 48 week response rate in patients receiving PegIntron although it did appear to improve responses in patients receiving IFN (40% vs 20%), and this was similar in patients receiving IFN. More than 80% of patients in the study received more than 10.6 mg/kg of RBV.
RESPONSE BY CD4 COUNT
Patients with >500 CD4s appeared to have a better viral response than patients with <500 CD4s whether they received Peg or IFN, although the difference was not significant at week 48 (38% vs 32% for patients receiving PegIntron; 28% vs 19% for patients receiving IFN).
RESPONSE BY DURATION OF HCV
The longer patients had HCV the worse their response to therapy. For patients
receiving PegIntron the response rate was 50% if they had HCV for less than 8
years vs 31% if they had HCV for longer than 8 years. This difference
appeared to be significant. For patients receiving IFN the difference in
response did not appear to be much whether patients had HCV for more or less
than 8 years (27% for < 8 yrs vs 22% for >8 yrs).
RESPONSE BY VIRAL LOAD BEFORE THERAPY
Although it wasnąt yet a significant difference yet HCV viral load before starting therapy predicted response for patients whether they receieved PegIbtron or IFN: (40% vs 30% for PegIntron; 23% vs 3% for IFN). High viral load was >2 million.
SAFETY AND TOLERABILITY
This analysis looks at 308 patients with an average follow-up of 39 weeks. The authors said the adverse event profile was similar whether patients received PegIntron or IFN. This is the percent of patients reporting the side effect.
Asthenia (weakness) 33%
Flu-like symptoms 22%
Fever 13%
Mylagia 18% (muscle pain)
Arthralgia 12% (joint pain)
Headache 12%
GI Side Effects
Diarrhea 10%
Anorexia 10%
Abdominal pain 10%
Nausea 8%
Psychiatric
Depression 12%
insomnia 11%
irritability 10%
anxiety 8%
Upper and lower respiratory symptoms: 10-15%
Hair loss: 6%
SERIOUS ADVERSE EVENTS
25% of patients receiving PegIntron and 21% of patients receiving IFN reported serious events.
Psychiatric events (12 vs 9 events, PegIntron vs IFN)
Sepsis (2 vs 2 events)
Pneumona (4 vs 4 events)
Hepatic failure ((6 vs 4 events)
Acute pancreatitis (3 vs 3 events)
Hyperlactatemia (>5mM/l) (7 vs 1 events)
Hemotologic disorders (8 vs 1 events)
Mitochondrial toxicity events: most patients were taking d4T+ddI; odds ratio for ddI was 23
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