Very early prediction of response to HCV treatment with PEG‐IFN‐alfa‐2a and ribavirin in HIV/HCV‐coinfected patients

Abstract

The objective of the present study was to find very early viral kinetic markers to predict nonresponse to HCV therapy in a group of HIV/HCV-coinfected patients. Twenty-six patients (15 HCV genotype-1 and 11 genotype-3) were treated with a 48-week regimen of peginterferon-alfa-2a (PEG-IFN) (180 μg/week) and weight based ribavirin (11mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 hours; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6±0.3 days after initiation of therapy, followed by a 0.3- to 12.9-fold viral rebound until the administration of the second dose of PEG-IFN, which were not associated with SVR or HCV genotype. A viral decline <1.19 log for genotype-1 and <0.97 log for genotype-3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virologic response had a similar positive predictive value (PPV) for SVR as a rapid virologic response at week 4. In addition, a second-phase-viral-decline slope (i.e., measured from day 2 to 29) less than 0.3 log/wk had a NPV=100% for SVR. CONCLUSIONS First phase viral decline at day 2 and second-phase-viral-decline slope (<0.3 log/wk) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of nonresponse in patients with HCV and HIV.

Pharmacodynamics of PEG-IFN-α-2a and HCV Response as a Function of IL28B Polymorphism in HIV/HCV-Coinfected Patients

“…In contrast, we did not identify a significant (p=0.5) difference in IL28B genotype frequencies between African Americans and White patients from Brazil (Table 1). The lack of an association between race and IL28B genotype in our South American patient population might partly explain the lack of association between race/ethnicity and viral kinetic parameters or viral response patterns in our recent reports 16, 17 . Indeed, preliminary results indicate that ~80% (of 353) of HCV-mono-infected individuals in Brazil are TC or TT with a similar distribution of CC/TC/TT genotypes between African Americans and Whites (Araujo et al manuscript in preparation).…”

“…In addition, there was a significantly higher proportion of IL28B genotype-CC in patients infected with HCV-genotype 3 than in patients infected with HCV-genotype 1 (Table S1), in agreement with recent studies that include HIV/HCV-coinfected 25 , and HCV-monoinfected individuals 27 . We previously reported higher first and faster second phase viral declines in genotype-3 compared to genotype-1 HIV/HCV co-infected patients 16 . In the current study, we identified a higher prevalence of IL28B CC-genotype in HCV genotype-3 cases, but no association between IL28B genotype and the second phase viral decline or the loss rate of HCV-infected cells, δ.…”

“…Detailed baseline characteristics, viral response and viral kinetic and pharmacodynamic parameters, estimated via mathematical modeling, were recently studied 16, 17 . The SNP near the IL28B gene, rs12979860, was examined using the 5’ nuclease assay with allele specific PCR probes as recently described 10 .…”

“… * One standard deviation; IQR, interquartile range; V 0 , baseline HCV RNA level; V min , the observed nadir HCV RNA in each patient 16 during the administration of the first dose of PEG-IFN; V 7d , HCV RNA level at day 7 of therapy; δ, death/loss rate of HCV-infected cells; EC 50 , PEG-IFN concentration at which the drug’s effectiveness in blocking viral production is half its maximum; ε 7max , maximum PEG-IFN effectiveness during the first week of therapy; ε 7average , average PEG-IFN effectiveness during the first week of therapy; ε max , maximum PEG-IFN effectiveness from week 4 to week 12 of therapy; ** n=21 for δ, EC 50 , ε 7max , ε 7average , ε max parameters as recently estimated 17 . …”

“…To the best of our knowledge, there is no such information in HIV/HCV co-infected individuals. To determine the relationship between IL28B polymorphisms and viral/host parameters in HIV/HCV co-infected patients, we compared IL28B genotypes with recent results of viral response 16 and estimates of viral kinetic and pharmacodynamic parameters 17 in 26 patients with HIV and HCV who were treated with PEG-IFN-α-2a and ribavirin.…”