Only nine HCV-1 patients completed the planned 18 months extended duration of treatment. The SVR did not differ significantly in this subset of patients compared with those who were treated for only 12 months (67 versus 42%; P = 0.1). HCV-1 patients with high baseline serum HCV-RNA or with lack of RVR tended to have higher SVR with 18 than 12 months of therapy, however, although these differences did not reach statistical significance probably because of the small size of the study populations: 57 versus 33% (P = 0.2) and 66 versus 28% (P = 0.2), respectively.
In a multivariate logistic regression analysis that included baseline serum HCV-RNA, RVR and treatment duration, RVR and low serum HCV-RNA were significantly associated with SVR. An extended duration of treatment was nearly associated with SVR, but the trend did not reach statistical significance (Table 2).
Hepatitis C virus genotype 3
Overall, 86 (63.7%) had baseline serum HCV-RNA greater than 500 000 IU/ml. RVR was achieved by 41/54 patients (75.9%) with high viraemia and in 33/34 patients (97.1%) with low viraemia (P = 0.08).
In the on-treatment analysis, SVR was achieved in 107/135 patients (79.3%). SVR was higher in patients with baseline serum HCV-RNA less than 500 000 IU/ml than in the rest: 45/49 (92%) versus 62/86 (72%; P = 0.007) and in patients with RVR than in the rest: 67/74 (90%) versus 8/14 (57%; P < 0.001; Fig. 1). The PPV of RVR for SVR was 90% and the NPV was 43%. Baseline serum HCV-RNA levels did not significantly influence the predictive value of SVR in HCV genotype 3 patients (Table 1).
Overall, 90 patients were treated for 6 months and 45 were treated for 12 months. Response rates were similar in both groups (78 versus 82%; P = 0.5) In patients who achieved RVR, SVR was 89% (41/46) and 93% (26/28) in patients treated for 6 and 12 months, respectively (P = 0.7). Among patients without RVR, SVR was achieved in 50% (four out of eight) and 67% (four out of six) of patients treated for 6 and 12 months. Again, no statistically significant differences were found (P = 0.6); however, the small sample number can explain this result.
In the multivariate logistic regression analysis that included baseline HCV-RNA, RVR and length of treatment (24 versus 48 weeks in genotype 3 patients), only RVR was associated with SVR (Table 2).
Hepatitis C virus genotype 4
Overall, 17 patients (45.9%) had baseline serum HCV-RNA greater than 500 000 IU/ml. RVR was obtained by 26.1% of all HCV-4 patients, regardless of baseline HCV load (two out of 10 versus four out of 13 if less or more than 500 000 IU/ml, respectively).
In the on-treatment analysis, SVR was achieved in 15/37 (40.5%) of HCV-4 patients. In contrast with patients infected with HCV genotypes 1 and 3, baseline serum HCV-RNA was not associated with SVR: eight out of 20 (40%) versus seven out of 17 (41%) in patients with less or more than 500 000 IU/ml HCV-RNA (P = 0.1). RVR was, however, significantly associated with SVR in HCV-4 patients: five out of six (83%) versus five out of 17 (30%; P = 0.04; Fig. 1). The PPV and NPV of RVR for SVR in HCV-4 patients was 83.3 and 70.5%, respectively (Table 1).
Baseline serum HCV-RNA predicts SVR to pegIFN plus ribavirin in both HIV-negative and HIV-positive patients with chronic hepatitis C [26,27]. It was the best predictor of SVR in the APRICOT trial, even better than HCV genotype . The overall greater level of serum HCV-RNA in co-infected versus HCV-mono-infected patients (1 log on average) has been postulated to be one of the main reasons to explain the poorer results of HCV therapy in co-infected versus mono-infected patients . Early assessment of HCV kinetics has only recently been accepted as a key predictor of response: HCV-mono-infected patients achieving undetectable viraemia as early as week 4 of treatment is now recognized as one of the most important predictors of SVR regardless of HCV genotype . More importantly, on the basis of RVR, the duration of treatment can be individualized, allowing a shortening of the duration of therapy in patients clearing HCV viraemia as early as at week 4 [1,29]. Our results confirm that this principle can be applied to HCV/HIV-co-infected patients. An important consideration, however, is that baseline serum HCV-RNA seems also to be an independent predictor of SVR in HCV genotype 1 patients. For the rest of the HCV genotypes, clearance of viraemia at week 4 seems to be enough to tailor the duration of therapy. Two recent reports examining only a limited number of HCV genotype 3 patients have already found similar results [30,31].
Although most studies conducted in the past considered a threshold in serum baseline HCV-RNA of 800 000 IU/ml as the best to predict SVR, a lower value of 500 000 IU/ml was the best predictor of SVR in PRESCO . This is in agreement with recent reports from studies conducted in HCV-mono-infected patients treated with pegIFN plus ribavirin, which have highlighted that 400 000 IU/ml seems to be the best threshold to predict SVR, at least in the subset of patients with HCV genotype 1 [32,33].
The PPV of SVR assessing RVR was high for all patients, but for the subset of subjects infected with HCV genotype 1 with high baseline serum HCV-RNA. In this group of patients, who are unfortunately quite common in the co-infected population , alternative treatment strategies should be explored. In HIV-negative patients, extension of treatment to 72 weeks in HCV genotype 1 patients who do not reach undetectable viraemia at week 4 but show more than 2 log declines in HCV-RNA at week 12 was shown to increase the chances of cure [35,36]. Attempts to extend the duration of therapy in co-infected patients have, however, been hampered by high drop-out rates given the poor tolerance of the HCV medication in most patients [24,37,38]. In the analysis per protocol, we did not find a statistically significant difference in SVR rates in HCV genotype 1 patients who received 48 or 72 weeks. In the multivariate analysis a trend towards a better response was, however, observed in the subset of patients treated for a longer time. Clearly, studies specifically designed to test whether HCV-1-co-infected patients with slow virological response might benefit from an extended length of therapy should be conducted. In parallel, strategies to minimize drop-outs during extended therapy should be implemented in this population.
Although the duration of treatment in HIV-positive patients co-infected with HCV genotype 3 has been established in 12 months [21,22], recent reports have shown that treatment may be shortened to 6 months, at least for the subset of patients with RVR [30,31]. In HCV-mono-infected patients, even shorter periods of treatment (12–16 weeks) have proved to be enough [7–9]. It should be emphasized, however, that weight-based ribavirin dosing was used in all these trials. Likewise, patients with HCV genotype 3 in the PRESCO trial also received weight-based ribavirin, and therefore our observation that no further benefit extending treatment from 24 to 48 weeks in HCV-3 patients may only apply when weight-based ribavirin is used and RVR is achieved. Using flat ribavirin doses of 800 mg/day, high relapse rates have been observed in at least two previous trials [19,20]. In contrast with HCV-1 patients, no significant independent influence of baseline HCV-RNA was seen for HCV-3-co-infected patients. The PPV of SVR in patients with RVR was 90% in our study and no further benefit was recognized in extending treatment to 48 weeks. Genotype 3 conclusions can probably be extended to genotype 2-infected patients as HCV-2 carriers respond even better to current anti-HCV therapy. Unfortunately, we were not able to address this issue in PRESCO becausee only three HCV-2- infected patients participated in the trial.
The small subset of co-infected patients with HCV-3 who did not achieve RVR had a relatively low likelihood of reaching SVR (57%). Of note is the fact that this observation was independent of baseline serum HCV-RNA and duration of therapy. Therefore, new strategies should be considered for these patients. Although most of the new antiviral drugs against HCV seem to be quite specific for the more difficult-to-treat HCV genotype 1 patients, some experimental new HCV polymerase inhibitors may be active against HCV-3 and provide hopes for this subset of refractory HCV-3-co-infected patients.
Finally, the achievement of SVR in HCV-4-co-infected patients in our study was mainly driven by the achievement of RVR, with no influence of baseline serum HCV-RNA levels. These results, however, should be interpreted with caution because the number of patients infected with this genotype was relatively small. As for HCV-1, the NPV of RVR for SVR was relatively low in HCV-4, which means that approximately one third of co-infected patients with these genotypes were able to achieve SVR despite not experiencing RVR. This observation was even more pronounced in HCV-3-co-infected patients, in whom the NPV of RVR for SVR was only 43%. Cure was thus obtained in more than half of these patients despite not achieving undetectable viraemia at week 4. Altogether, our results support in co-infection what has already been demonstrated in HCV mono-infection, which in brief is that early virological stopping rules should remain based on the results obtained at week 12 and not shift to earlier time points [1,27,37].
The following are the members of the PRESCO Study Group (in alphabetical order):
Aguirrebengoa K, H. de Cruces, Bilbao; Alcocer F, H. Clínico, Valencia; Álvarez H, H. Arquitecto Marcide, Ferrol; Arazo P, H. Miguel Servet, Zaragoza; Arrobas I, Complejo Hospitalario General, Badajoz; Asensi V, H. General de Asturias, Oviedo; Barberá JR, H. General, Alcazar de San Juan; Barreiro P, H. Carlos III, Madrid; Berdún MA, H. San Jorge, Huesca; Bonet L, H. Son Dureta, Palma de Mallorca; Cadafalch J, H. Sant Pau, Barcelona; Cervantes M, H. Parc Tauli, Sabadell; Cordero M, H. Clínico, Salamanca; Echeverría S, H. Marques de Valdecilla, Santander; Fariña C, H. Marques de Valdecilla, Santander; Fernández-Pelaez JM, H. Virgen de Altagracia, Manzanares; Galindo MJ, H. Clínico, Valencia; García-Samaniego J, H. Carlos III, Madrid; González M, H. Virgen de la Victoria, Málaga; Guardiola JM, H. Sant Pau, Barcelona; Hernández-Burruezo JJ, H. General, Jaén; Jiménez-Nacher I, H. Carlos III, Madrid; López Serrano P, Fundación Alcorcón, Madrid; Losada E, H. Clínico Universitario, Santiago; Mariño A, H. Arquitecto Marcide, Ferrol; Martin-Carbonero L, H. Carlos III, Madrid; Miralles C, H. Xeral-Cíes, Vigo; Núñez M, H. Carlos III, Madrid; Ocampo A, H. Xeral-Cíes, Vigo; Portu J, H. Txagorritxu, Vitoria; Prieto A, H. Clínico Universitario, Santiago; Ramos B, H. Carlos III, Madrid; Rodríguez de Castro E, Hospital Virgen del Toro, Menorca; Romero M, H. Carlos III, Madrid; Samperiz A, H. Reina Sofía, Tudela; Sánchez F, Complejo Hospitalario, Cáceres; San Joaquín I, H. Clínico, Zaragoza; Santos I, H. de la Princesa, Madrid; Sepúlveda MA, Virgen de la Salud, Toledo, Sola J, H. de Navarra, Pamplona; Soriano V, H. Carlos III, Madrid, Spain.
Other members of the Peginterferon Ribavirin ESpaña COinfection (PRESCO) Trial Study Group are listed in the Acknowledgements section.
Sponsorship: This work was partly supported by grants from Fundación Investigacion y Educación en SIDA (IES), Agencia Lain Entralgo, Red de Investigación en SIDA (RIS, ISCIII-RETIC RD06) and the VIRGIL European Network of Excellence on Antiviral Drug Resistance (LSHM-CT-2004-503359).
Conflicts of interest: None.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
hepatitis C virus; HIV; kinetics; pegylated interferon; ribavirin