A substantial proportion of HIV/HCV co-infected patients responded to a second attempt at treatment with pegylated interferon (Pegasys, Peg-Intron) plus ribavirin, according to a study presented on Thursday at the Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco.
Many individuals with chronic hepatitis C virus (HCV) infection do not clear the virus with their first attempt at treatment, whilst others relapse after an initial response. This is especially true if originally treated with the older conventional interferon or if their regimens did not include adequate doses of ribavirin. Previous research has shown that co-infected patients are less likely to respond than individuals with HCV alone, and those with HCV genotypes 1 or 4 respond less well than those with genotypes 2 or 3.
In the PILOT study, investigators at Hospital Carlos III in Madrid, Spain, recruited 51 HIV positive participants who were non-responders or relapsers to previous suboptimal therapy. About three-quarters were prior non-responders and the rest relapsers. Previous regimens consisted of conventional interferon monotherapy (27%), conventional interferon plus ribavirin (29%), or pegylated interferon plus 800 mg/day ribavirin (44%); the mean duration of prior therapy was about five months.
Three-quarters of the participants were men, with a mean age of 41 years. The mean HCV viral load was 5.9 log10; 72% had HCV genotypes 1 or 4, whilst the remainder had genotypes 2 or 3. Degree of liver fibrosis was estimated using hepatic elastometry (FibroScan). At study enrolment, 24% had absent or mild liver fibrosis (stage F0-F1), 18% had stage F2, 5% had stage F3, and 53% had advanced fibrosis or cirrhosis (stage F4). Ninety percent were on HAART, 74% had HIV viral loads below 50 copies/mL, and the mean CD4 cell count was 621 cells/mm3.
Participants were re-treated with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus ribavirin dosed according to body weight (1000 mg/day if less than 75 kg and 1200 mg/day if heavier than 75 kg). The study protocol calls for 48 weeks of therapy; the interim analysis presented at the conference examined response rates through 24 weeks.
After four weeks of therapy, in an intent-to-treat analysis, 33% of prior relapsers with genotypes 1 or 4 and 83% with genotype 2 or 3 experienced rapid virological response (RVR), achieving HCV viral loads below 50 IU/mL. Among prior non-responders, the corresponding rates were 19% for genotypes 1 or 4 and 80% for genotypes 2 or 3.
Looking at early virological response (EVR), defined as a 2 log10 or greater decrease in HCV RNA at Week 12, prior relapsers had particularly high response rates: 93% for genotypes 1 or 4 and 98% for genotypes 2 or 3. EVR rates were considerably lower among prior non-responders: 52% for genotypes 1 or 4 and 75% for genotypes 2 or 3.
After 24 weeks, 65% of genotype 1 or 4 relapsers and 69% of genotype 2 or 3 relapsers had undetectable HCV viral load. For prior non-responders, the corresponding rates were 48% and 75%, respectively. Interestingly, while the response rate declined dramatically from Week 12 to Week 24 in relapsers, it remained stable over time in the prior non-responders.
Participants previously treated with conventional interferon monotherapy were somewhat more likely to respond to re-treatment than those who previously received conventional interferon plus ribavirin or pegylated interferon plus ribavirin, but the difference was not statistically significant. Baseline HCV viral load, degree of fibrosis, and body weight were also associated with treatment response in a univariate analysis.
However, after adjusting for other factors in a multivariate analysis, plasma ribavirin level was the strongest predictor of response. Patients who achieved undetectable HCV RNA at Week 24 had a mean ribavirin level of 3.4 mcg/mL, compared with 1.8 mcg/mL for re-treatment non-responders (p=0.001). The researchers determined that the ribavirin cut-off level that best predicted 24-week response was 2.1 mcg/mL.
With regard to side effects, patients taking AZT (Retrovir) had a greater decrease in haemoglobin levels (a mean decline of 4.5 mg/dL, compared with 2.6 mg/dL in patients not on AZT) -- not surprising, since both AZT and ribavirin can cause anaemia. However, only four participants stopped treatment early (two due to severe anaemia, one due to severe depression, and one lost to follow-up).
The investigators concluded, “Re-treatment of HIV/HCV co-infected patients with [pegylated interferon alfa-2a] plus weight-based ribavirin doses (1,000-1,200 mg/day) provides Week 4, Week 12 and Week 24 virological response in a substantial number of patients.”
They added that this data is “encouraging and warrants further follow-up until completion of therapy.” They also recommended that monitoring of plasma ribavirin levels may be advisable in patients undergoing re-treatment for chronic hepatitis C.
Labarga P et al. Re-treatment with pegylated interferon-a2a plus ribavirin in HIV+ patients with chronic hepatitis C who failed a prior course of suboptimal HCV therapy. Forty-Sixth ICAAC, San Francisco, abstract H-1061, 2006.