12-week response predicts which HIV-HCV coinfected patients will not benefit from continued pegylated interferon plus ribavirin
1 April 2003. Related: Conference reports, Hepatitis coinfection, CROI 10 (Retrovirus) 2003.
Ronald Baker PhD, HIVandHepatits.com
Treatment with pegylated interferon plus ribavirin is producing an average 60% ‘cure’ rate among HCV-monoinfected individuals. At the same time, liver disease caused by HCV infection is a growing cause of concern among HIV-HCV coinfected patients and their caregivers.
The response rates to combination therapy with pegylated interferon/ribavirin appear to be lower in HIV-HCV coinfected patients, while the side effects of treatment are more frequent. This may be due to the interaction between ribavirin and the nucleoside analogue drugs.
In HCV-monoinfected patients, the treatment response at 12 weeks or ‘early virological response’ (EVR) predicts which patients will not benefit from continued therapy with pegylated interferon/ribavirin. A reduction in HCV RNA > 2 logs at 12 weeks predicts a continued benefit.
No data among coinfected patients are available on the validity of this approach.
In the present study, investigators evaluated 89 HIV-HCV coinfected patients who completed a course of anti-HCV therapy. Pegylated interferon was administered to 63 and standard interferon to the remaining patients, all at standard doses. All received ribavirin 400 mg twice daily.
Overall, sustained virological response (SVR) occurred in 29 patients. End-of- treatment response with further relapse was seen in 15. The remaining 45 were non-responders.
A drop in HCV RNA > 2 logs occurred in 38 (43%) and 52 (58%) of patients at four and 12 weeks, respectively. Of those subjects, only 18 (48%) and 29 (56%), respectively, reached SVR. In contrast, SVR occurred in 11 (38%) and 0 patients who did not show a > 2 log drop In HCV RNA at weeks four and 12, respectively.
Thus the negative predictive value (NPV) was 100% at week 12. There were no significant differences between HCV genotypes, baseline HCV RNA and use of either pegylated or regular interferon.
In patients with HCV genotype 2-3, a high rate of relapse in early responders was noted, which suggests that extending treatment beyond six months might have provided a higher SVR rate for them.
The investigators conclude: “The use of an early time decision point at 12 weeks to identify which subjects will not benefit from continuing anti-HCV treatment is valid for HIV positive patients. However, a delayed clearance of HCV RNA in early responders with HIV might account for a higher relapse rate when treatment is stopped prematurely, eg six months in genotypes 2-3.”
M Perez-Omeda et al. Predictive value of early virologic response (12 weeks) to pegylated interferon plus ribavirin in HIV-HCV co-infected patients. 10th CROI, 10–14 February 2003, Boston. Abstract 842.
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This study makes two very important observations in the treatment of chronic HCV in HIV co-infection. Firstly the low rates of SR compared to HCV mono-infected patients even with Pegylated IFN and Ribavirin and secondly the importance of EVR (12 week response) in predicting overall SR.
Two large RCTs presented to date, ANR HCO2-RIBAVIC study (AASLD, 2002) and Voigt et al (Glasgow 2002) have shown overall ETRs of 45% and 38% respectively with PEGIFN-alpha 2b and Ribavirin in HCV/HIV co-infected patients. In both these studies treatment was given for 12 months and ETRs for genotypes 2/3 were much higher at 55% and 72% respectively. The final results from these studies and the multinational APRICOT study (Pegasys and Ribavirn) will give us a better idea of overall SR in co-infected patients and predictors of response (pre-treatment HCV viral loads, CD4 counts, HAART and drug interactions, stage of liver disease etc). It is likely that even in patients with genotype 2/3 HCV co-infection 12 months therapy may be recommended to prevent virological relapse.
These results also confirm the importance of the 12 week response in predicting ETR and SVR. This has been confirmed as a predictor of response with IFN and Ribavirin in co-infected patients (Soriano 2002). High drop-out rates due to intolerance and side-effects are common with IFN and Ribavirin (20-30% in most studies with co-infected patients), and a non-response, or < 2 log drop in viraemia at 12 weeks is predictive of treatment failure. For these reasons it is currently good practice to stop treatment at this stage.
The benefit of possible inhibition of fibrosis progression in (non responding) advanced patients by interferon maintenance has been suggested, but the data supporting this approach are not conclusive and the studies are still ongoing.