Twenty HIV/HCV-genotype 1 co-infected patients were prospectively included in this study. Demographic, virological, immunological and clinical characteristics are described in . Patients received either PEG-IFN alfa 2a or 2b, depending on the drug provision by the Argentinean Ministry of Health. Ninety percent of the subjects were on HAART, all of them with undetectable HIV viral load. Forty-five percent of them received abacavir-based HAART. A negative drug-drug interaction between abacavir and ribavirin has been postulated by some authors (Vispo et al., 2008
), but this effect seems to be negligible when the ribavirin dose is adjusted to patient’s weight (16 mg/Kg) (Amorosa et al., 2010
; Laufer et al., 2008
; Vispo et al., 2008
Baseline characteristics of the total population and divided according the achievement of cEVR, ETR and SVR.
Only one patient reached rapid virological response. Complete EVR was achieved in 25% of the cases; 25% reached only pEVR but all these patients presented detectable HCV-RNA at week 24 and treatment was stopped. Two patients discontinued treatment prematurely for adverse events (thrombocytopenia).
Sustained virological response was obtained by 15% of the patients and there were no differences regarding baseline CD4+ cell count, age, body weight, years of known HIV or HCV infection, use of abacavir, tenofovir or efavirenz and fibrosis on liver biopsy ().
3.1 HCV 24 hours kinetics
To evaluate the early kinetic of HCV RNA decline, the viral load at 24 hours of treatment initiation was quantified. HCV-VL decay in the first 24 hours of treatment was associated with the achievement of complete early virological response, 24 weeks response and end of treatment response (). No differences were found in baseline characteristics of patients who achieved or not these time points of response ().
HCV 24h viral load decay (mean and SD) according to EVR, 24 weeks response, ETR (48 weeks).
When HCV RNA decay at day 1 was compared between patients who only exhibit a 2log10 reduction in HCV-VL at week 12 (ie: partial EVR) and those with null response (ie: <2log10 reduction in HCV-Vl at week 12) no differences were found (pEVR 0.64log10, SD 0.54 log10 and NR 0.71log10, SD 0.82log10; p=0.79) (). Of note, none of the patients that exhibited only pEVR reached SVR.
HCV 24h viral load decrease (median and range) according to the achievement of RVR, EVR (complete and partial), SVR and null response (NR).
3.2 24h HCV- VL decay as predictor of SVR
Patients who achieved SVR present a 24h a decay in HCV-VL of 1.6log10 (SD 0.28 log10), whereas those who did not achieved SVR reached only a 0.70log10 (SD 0.74log10) reduction in HCV RNA, p=0.04.
The kinetic of HCV RNA decay during treatment according to the achievement of SVR is shown in .
HCV viral load kinetics during treatment with PEG-IFN/RBV divided by viral response.
To assess the predictive value of HCV RNA decay on the first day after treatment initiation with pegylated interferon and ribavirin, we calculated the area under the receiving operating curve (AUROC) of the difference between HCV-VL (log10) at baseline and at 24 hours. We found that AUROC was 0.902 (SD 0.123), 95% confidence interval 0.68-0.98 (p=0.001). A reduction in HCV-VL from baseline to 24h <1.4 had a negative predictive value for achieving SVR of 100% and a positive predictive value of 50%. Using a cut-off value of 1.5 log10 reduction, the negative predictive value decreased to 94.1% whereas the positive one increased to 66.7% (). When the two patients who had to stop treatment prematurely due to adverse events were excluded from the analysis, the cut-off value of 1.4log10 decay as well as the positive and negative predictive value did not change.
Area under the receiver operating characteristic curve, to evaluate the performance of HCV-RNA log10 decay at 24h with sustained virological response as the state variable.
3.3 24 hour HCV viral load decrease and HCV baseline molecular characteristics
Deduced amino acid substitution number of NS5A PKRBD from 19 baseline isolates from the 20 HIV patients were counted and compared with the HCV genotype 1 prototype (M62321) (). We observed that HCV viral isolates, from those patients that exhibited a 24h viral load decrease higher than 1.4 log10 and SVR, presented a higher number of amino acid substitutions in ISDR and PKRBD regions than those who did not achieve these goals. This association was statistically significant (p= 0.02 and 0.03, respectively).
Basal HCV ISDR and PKRBD amino acids sequences of 19 HCV-HIV co-infected patients.
Viral isolates from patients with a decrease higher than 1.4 log at day 1 of treatment, exhibited a mean of 3.1 (SD 1.5) amino acids substitutions in ISDR and 4.8 (SD 2.3) in PKRBD regions and those who presented a lower reduction in HCV-RNA had 1.6 (SD 0.7) and 2.4 (SD1.3) amino acid substitutions, respectively (p=0.02 and 0.03). When the number of substitutions were evaluated in relationship with the achievement or not of SVR the results were: for ISDR region 4 (SD 1.7) vs. 1.7 (SD 0.7), p=0.05 and for PKRBD region 6 (SD 2.6) vs. 2.7 (1.4), (p=0.03).
It was also identified with AUROC (0.885, SD 0.132, 95% CI 0.656-0.981, p=0.0035) that the presence of more than 5 amino acid substitutions in PKRBD region had a 100% positive predictive value and 94.1% negative predictive value for achieving SVR. Regarding mutations in the ISDR region, the same negative and positive predictive values were found when 3 or more substitutions were present (AUROC, 0.865, SD 0.141, 95% CI 0.631-0.974, p=0.0099).