Treatment was prematurely discontinued in 28 (10.1%) patients because of intolerance or adverse events and in 101 (36.3%) additional patients because of null EVR or detectable viral load at treatment week 24 (Fig. 1 and Table 2). Moreover, pegIFN dose was reduced in 61 (21.9%) patients, ribavirin in 42 (15.1%), and both drugs in 17 (6.1%) (Table 2). Rates of treatment discontinuation and dose modification were similar in patients treated with pegIFN alfa-2a and pegIFN alfa-2b (data not shown).
By intention-to-treat (ITT) analysis, 123 patients (44.2%) had undetectable HCV RNA at the end of treatment: 48% of patients treated with pegIFN alfa-2a vs. 39% of those given pegIFN alfa-2b (P = 0.158). Among end-of-treatment responders, 29.3% (36/123) relapsed. Consequently, 31.3% (87/278) of genotype 1 HIV-coinfected patients analyzed in this study achieved an SVR (Fig. 1), with no differences in the SVR rate between pegIFN alfa-2a (30.4%, 49/161) and pegIFN alfa-2b (32.5%, 38/117) (P = 0.717).
Viral eradication was observed in 54.2% (78/144) of patients who completed 80% of the planned therapy. Conversely, the infection was eradicated in only eight out of 134 (6.0%) patients who did not meet the 80/80/80 adherence target.
The probability of eradicating the virus was significantly higher in patients with low baseline AST and HCV RNA levels (Table 1). A trend toward a better response was observed among patients who were not receiving HAART (45.2%, 14/31) compared with those receiving HAART (29.6%, 73/247; P = 0.077) and in those without cirrhosis (34.3%, 49/143) compared with cirrhotic patients (8.8%, 6/32; P = 0.087). By logistic regression analysis, the model that best predicted SVR included no HAART [odds ratio (OR) 2.92, 95% confidence interval (CI) 1.30–6.55; P = 0.009], HCV RNA less than 800 000 (OR 3.18, 95% CI 1.81–5.57, P < 0.001), and normal AST levels (OR 1.92; 95% CI 1.06–3.66, P = 0.046).
Viral response at week 12 of treatment was evaluated in 254 patients, and 182 (71.7%) of them obtained a partial EVR or a complete EVR. Overall, the likelihood to eradicate the virus was 3.32-fold higher (95% CI 1.92–5.74) in patients who achieved a complete EVR than in those showing a partial EVR. Furthermore, the value of EVR to predict long-term outcome varied according to the sensitivity of the test used: 75.4% (52/69) of patients with a complete EVR evaluated by TaqMan vs. 47.3% (26/55) of patients with Monitor-based complete EVR achieved an SVR [risk ratio 1.59, 95% CI 1.17–2.17, P = 0.014]. To further explore this point, treatment week-12 cryopreserved serum samples from 19 of 41 patients who had a complete EVR when formerly evaluated by Monitor (<600 IU/ml) and achieved an end-of-treatment response were retested by TaqMan. Among them, 10 patients were found to have residual viremia at week 12, and seven of these (70%) relapsed, whereas only one of the remaining nine with viral load undetectable by TaqMan (<15 IU/ml) relapsed (risk ratio for relapse among patients with residual viremia 6.30, 95% CI 0.95–41.78, P = 0.038).
By logistic regression analysis, including as binary covariates type of pegIFN used, pegIFN dose reduction, ribavirin dose reduction, pretreatment HCV RNA and week-12 viral response (model 1), HCV RNA 800 000 IU/ml or more, and ribavirin dose reduction were independently associated with a higher risk of relapse, but the strongest predictor of viral relapse was achievement of a partial EVR (Table 3). A further sensitivity analysis (model 2), which included in the previous model the fibrosis score as binary covariate, cirrhosis vs. noncirrhosis (data were missing in 48 of 123 patients with end-of-treatment response), showed that cirrhosis and partial EVR were robust predictors of viral relapse (Table 3).
In the present retrospective analysis, 31% of the patients achieved an SVR. This rate of viral eradication is higher than that of genotype 1 HCV/HIV-coinfected participants in multicenter randomized trials [1–3].
Treatment tolerance was good and the dropout rate was comparable to that observed among HCV-monoinfected patients enrolled in pivotal trials [6,7]. An improvement in the clinical management of HCV/HIV-coinfected patients receiving pegIFN plus ribavirin probably accounts for the low dropout rate observed in the latest reported trials [18,21]. However, in our study, viral response was similar regardless of the treatment-starting year, suggesting that other prognostic factors have a greater impact on treatment outcome than tolerance. High pretreatment HCV RNA, high AST level, and HAART were independent predictors of treatment failure. High viral load, present in almost 70% of our patients, has been consistently associated with poor response in multiple studies [1,2,4,5,11,22–24]. High AST level is a predictor of significant fibrosis  and disease progression  in chronic HCV infection and has been associated with an absence of response to pegIFN plus ribavirin therapy in genotype 1 HCV/HIV-coinfected patients .
A main finding of our study was the high relapse rate of over 60%, which is observed in slow responders after completing 48 weeks of treatment. Moreover, the sensitivity of the test used to evaluate EVR appeared as a valuable prognostic tool for predicting long-term outcome. Seventy percent of patients with a complete EVR by Monitor, who were found to have residual viremia (15–600 IU/ml), when retested by TaqMan, relapsed. In comparison, only 10% of the patients with complete EVR defined by TaqMan relapsed. These data help to refine the predictive value of week-12 response and suggest that viral response at this time point may be useful in clinical practice to guide the duration of treatment for genotype 1 HCV/HIV-coinfected patients. A standard 48-week regimen is sufficient in most patients to achieve a complete EVR, as evaluated by a very sensitive test. Conversely, although conflicting data have been reported in HCV-monoinfected patients [16,17], prolonging treatment duration to 72 weeks might help to reduce the risk of relapse in patients showing a partial EVR who first achieve undetectable viral load at week 24 of treatment.
Whether patients with complete EVR, who require on-treatment dose modifications, particularly those with cirrhosis, benefit from prolonging therapy duration remains to be elucidated.
The main limitation of this study is the retrospective nature of the data analysis. Notwithstanding, we have evaluated a large number of genotype 1 HCV/HIV-coinfected individuals in ‘real-life’ conditions, where criteria to treat patients are not as stringent as in randomized clinical trials. Our results are particularly relevant because no randomized trials addressing the issue of optimal treatment duration are anticipated, and the use of the very promising new anti-HCV agents [33,34] in HIV-coinfected patients is not expected for several years to come.
In conclusion, HCV eradication occurred in 31% of genotype 1 HCV/HIV-coinfected patients treated with pegIFN alfa-2a/2b plus ribavirin for 48 weeks. In contrast with the current recommendation to extend treatment duration for genotype 1 HCV/HIV-coinfected patients who clear the virus later than week 4 of therapy, our data show that week-12 viral response is a strong predictor of long-term outcome in genotype 1 HCV/HIV-coinfected patients. The standard 48-week therapy suffices for most patients with a complete EVR established by a very sensitive test (<15 IU/ml). Slow viral responders, who clear the virus later than treatment week 12, are at a high risk of relapse. The utility of week-12 viral response as a guide to individually tailored treatment duration should be evaluated in well designed prospective trials.
We are indebted to Roche Molecular Diagnostics, Barcelona, Spain, for their technical assistance.
We thank Celine Cavallo for English language editing.
Red Temática Cooperativa de Investigación en SIDA (RIS G03/173-RETIC RD06/006) and Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (Ciberhed, 06/040028).
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