Baseline characteristics and viral response
The baseline characteristics of the 26 subjects who were included in the study are presented in . Five patients discontinued therapy by week 12 (one was incarcerated, one died due to a complication not related to liver disease, two asked to stop treatment, and one was lost to follow-up). At the end of therapy, i.e., week 48, 18 (out of 21) achieved an end-of-treatment response (HCV RNA <50 IU/ml), while only seven patients had an SVR (Tables and ). Considering baseline characteristics (), HCV genotype was the only parameter associated with SVR based on intention to treat (ITT) p=0.09 and per protocol (PP) p=0.05 analysis.
Early Viral Kinetic parameters results
Virological response and HCV genotype
Viral kinetic profiles and response
Viral response by genotype is presented in detail at 0-28 days and 0-84 days of therapy for the 21 patients with complete follow-up (). Patients were stratified into three groups based on their viral response (i.e., NR – nonresponders [i.e., detectable HCV RNA at the end of therapy (week 48); REL – relapsers [i.e., negative HCV RNA at week 48 but positive after follow up], SVR [i.e., negative HCV RNA at follow up] (). It is clear that regardless of the genotype, the viral load decay pattern at early on treatment time points distinguished among the SVR, REL and NR groups. There were distinct differences in the response pattern between genotype 1 () and genotype 3 (). Patients infected with HCV genotype 3, including those in the REL group, showed a more rapid and intense initial reduction in viral load than that seen in patients infected with HCV genotype 1. Genotype 1 subjects who achieved an SVR had a fast and marked viral decline, which distinguished them from REL or NR. In genotype 1 patients, a 1.5 log drop at day 15 differentiated SVR from REL (p=0.012) and 1.9 log drop at day 15 distinguished SVR from NR (p=0.008). For genotype 3, a 1.5 log drop by week 4 distinguished between SVR and REL (p=0.014) even though all genotype 3 patients reached cEVR.
Viral kinetic parameters during the first 29 days of therapy in all 26 patients are presented in . Following the first dose of PEG-IFN, viral load dropped to a nadir, Vmin, of 1.3 ± 0.3 log10 from baseline within 1.6 ± 0.3 days (). Thereafter, a 0.3-to 12.9-fold viral rebound was observed before the second dose of PEG-IFN was given at day 7. Following the second dose of PEG-IFN, a slower phase of viral decline was observed (). While baseline viral load, day of Vmin, and viral rebound parameters were similar among the SVR, REL and NR groups, the first phase of viral decline from baseline and the viral slope decline (i.e., following the second dose of PEG-IFN) were significantly (p<0.02) higher in SVR compared to REL and NR ().
Viral kinetic profiles, HCV genotype, race and response
We further analyzed viral response in conjunction with genotype as shown in . First-phase viral decline was significantly higher in genotype 3 compared to genotype 1 patients (median 0.92 vs 1.65 log10, respectively, p=0.009). In addition, the slower-phase viral decline slope measured from day 7 until day 15 (median 1.0 vs 0.35 log/wk, respectively, p=0.031) or from day 7 until day 29 (0.72 vs 0.30 log/wk, respectively, p=0.008), were significantly higher in genotype 3 compared to genotype 1. All rapid viral responder (RVR) subjects were genotype 3 (p=0.007). At week 12, all genotype 3 subjects had a cEVR, while only 20% of genotype 1 (p<0.001) subjects achieved a cEVR. End-of-therapy response and relapse rate were similar by genotype (p=0.3 and p=0.1, respectively), but SVR rate was significantly (p=0.05) greater in genotype 3 patients. Interestingly, viral kinetic parameters and treatment response did not vary by race/ethnicity (White or Black) (not shown).
Finally, the relationship between log10 viral decline at days 2 and 15 per genotype and outcome of therapy is shown in . Patients who achieved an SVR had a profound viral decline (see left lower quadrant of ). In contrast, relapsers (REL) and nonresponders (NR), scattered on the two upper quadrants, which corresponds to a slower pattern of viral decline slope (see also ).
A relationship between viral decline at days 2 and 15 of therapy per genotype and outcome (see also ).
Very early predictors of successful treatment response
Change in HCV RNA level at very early on treatment time points was a strong predictor of SVR. In genotype 1 patients, an HCV RNA decline of 0.75 log10 from baseline at day 1, had good discriminatory ability (AUROC 0.95), a positive predictive value (PPV) of 67% and a negative predictive value (NPV) of 100% for SVR (). In the genotype 3 group, a day 2 HCV RNA decline cutoff value of 0.97 log10, had a good discriminatory ability (AUROC 0.82), with a PPV of 83% and NPV of 100% for the development of SVR (). In both groups, viral decline at day 2 had similar discriminatory ability with the same PPV and NPV to identify likely SVRs as RVR at week 4 (). According to these criteria, 2 out of 3 (67%) genotype-3 subjects and 10 out of 11 (91%) genotype-1 subjects, could have stopped (or extended) therapy based on day 2 HCV RNA decline.
Summary of ROC curve cut-off for selected early points and prediction of therapy outcome by HCV genotype.
Coinfected patients with a slow second phase viral decline slope less than 0.3 log/wk (measured here from day 2 to day 29 using linear regression; ) did not achieve SVR (NPV=100%), in agreement with publications in both HCV genotype 1-monoinfection and HIV/HCV coinfection patients [21
]. However, the positive predictive value for the second phase slope was low in both genotypes (PPV=67% in genotype 1 and PPV=71% in genotype 3), consistent with a recent study in coinfected patients [22
]. According to these criteria, 1 out of 3 (33%) genotype-3 subjects and 10 out of 11 (91%) genotype-1 subjects, could have stopped (or extended) therapy at day 2.