Bertasso, A

Bhatti, L

Branco, T

Clotet, B

Hassanein, T

Rodriguez-Torres, M

Slim, J

Stancic, S

Sterling, R

Sulkowski, M

Repositório do Hospital Prof. Doutor Fernando Fonseca

Peginterferon alfa-2a (40KD) plus 800 or 1000/1200 mg/day ribavirin in genotype 1 HIV–HCV co-infected patients: early responses to treatment and predictability for SVR in the PARADIGM study  M. Rodriguez-Torres,1 J. Slim,2 L. Bhatti,3 R.K. Sterling,4 T. Hassanein,5 B. Clotet,6 T. Branco,7 A. Bertasso,8 S. Stancic,8 M.S. Sulkowski,9 on behalf of the PARADIGM study investigators   1Fundacion de Investigacion De Diego Santurce, Puerto Rico and Ponce School of Medicine, Santurce, PR, USA; 2St. Michael's Medical Center, Newark, NJ, USA; 3AIDS Healthcare Foundation, LA, CA, USA; 4Virginia Commonwealth University, Richmond, VA, USA; 5University of California San Diego, San Diego, CA, USA; 6Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 7Hospital Fernando da Fonseca, Amadora, Portugal; 8Roche, Nutley, NJ, USA; 9Johns Hopkins University School of Medicine, Baltimore, MD, USA.  INTRODUCTION Among patients with HCV mono-infection, clearance of HCV RNA from serum at week 4 and 12 of treatment with pegylated interferon plus ribavirin is highly predictive of achieving a sustained virological response (SVR).[1, 2] Similar findings have been reported for HIV-HCV co-infected patients[3-5] but there are no data available on the influence of ribavirin dose on the positive predictive value of a negative serum HCV RNA at week 4 or 12.   The objective of the randomised, multinational PARADIGM study was to compare the efficacy and safety of two ribavirin dosage regimens (800 mg/day and 1000/1200 mg/day) administered in combination with peginterferon alfa-2a (40KD) in HIV-HCV co-infected patients. HCV RNA levels were monitored throughout the study, which provides the opportunity to examine the predictive value of early clearance of HCV RNA for SVR.   OBJECTIVE The objective of this analysis is to explore the impact of ribavirin dosing regimen on the time to undetectable HCV RNA and the predictive value of a rapid virological response (RVR) or early virological response (EVR) for SVR.  METHODS Patients Patients eligible for PARADIGM were co-infected with HIV-HCV (genotype 1) infection with a serum HCV RNA titre >600 IU/mL who had not received previous interferon-based therapy for chronic hepatitis C.  Patients were required to have stable HIV disease with a CD4+ cell count ≥100 cells/mm3. Individuals on stable anti-retroviral therapy (ART) and those not requiring ART were both eligible.  Treatment Patients were randomised (1:2) to receive 48 weeks of treatment with oral ribavirin at either a fixed standard dose of 800 mg/day or a higher dose (1000 mg/day for patients with a body weight <75 kg, or 1200 mg/day for those with a body weight ≥75 kg) in combination with subcutaneous peginterferon alfa-2a (40KD) 180 µg/week (Figure 1).  Figure 1. Study design  Outcomes HCV RNA levels were assessed by COBAS® Ampliprep/COBAS® TaqMan® HCV test; detection limit 20 IU/mL, Roche Diagnostics) at baseline, at week 4, 12, 24, and 48 during treatment and after 24 weeks of untreated follow-up (study week 72).   RVR was defined as undetectable HCV RNA in serum at week 4. Complete EVR was defined as undetectable HCV RNA in serum at week 12. Partial EVR was defined as greater than 2-log10 drop in HCV RNA at week 12. SVR was defined as undetectable HCV RNA at the end of untreated follow-up (study week 72).     RESULTS Among the overall population of 410 patients with HIV-HCV co-infection, 80% were male, 64% were Caucasian, 11% had bridging fibrosis or cirrhosis, 80% had an HCV-RNA level >800,000 IU/mL and 89% were receiving ART at baseline (Table 1).  Table 1. Baseline characteristics of patients in PARADIGM    Peginterferon alfa 2a (40KD) plus: ribavirin 800 mg/day  (n=135) ribavirin 1000/1200 mg/day (n=275) Male gender, n (%) 106 (79) 224 (81) Mean age ± SD, years 45.2 ± 8.4 45.5 ± 8.2 Mean weight ± SD, kg 77.2 ±14.1 78.0 ± 17.5 Race/ethnicity, n (%) Non-Hispanic Caucasian 60 (44) 116 (42) Hispanic 33 (24) 76 (28) Hispanic Caucasian 26 (19) 60 (22) Hispanic non-Caucasian 7 (5) 16 (6) Non-Hispanic African American 40 (30) 77 (28) Other 2 (1) 6 (2) Alanine aminotransferase quotient ≤1.5, n (%) 76 (56) 144 (52) Bridging fibrosis/cirrhosis, n (%) 16 (12) 30 (11) Child Pugh score >5, n (%) 2 (1) 6 (2) Mean HCV RNA ±  SD,  log10 IU/mL 6.4 ± 0.82 6.5 ± 0.90 HCV RNA >800,000 IU/mL, n (%) 106 (79) 223 (81) Mean CD4+ cell count  ± SD, cells/mm3 489 ± 243 519 ± 273 CD4+ cell count <200/µl, n (%) 7 (5) 18 (7) On ART, n (%) 120 (89) 241 (88)   SD = standard deviation; ART = anti-retroviral therapy  A total of 120/135 (89%) and 243/275 (88%) patients randomised to 800 mg/day and 1000/1200 mg/day of ribavirin completed the first 12 weeks of treatment.   There was no statistically significant difference in the overall SVR rates between patients randomized to ribavirin 800 mg/day or 1000/1200 mg/day (19% versus 22%, respectively, Figure 2).  Figure 2. Overall SVR rates  Rates of relapse (detectable HCV RNA during 24 weeks untreated follow-up among patients with an undetectable HCV RNA at the end of scheduled treatment) were similar between patients randomized to ribavirin 800 mg/day (32%) and 1000/1200 mg/day (36%).  Among patients randomised to ribavirin 800 mg/day or 1000/1200 mg/day the rates of RVR (8% versus 7%, respectively) and complete EVR (26% in both groups) were similar. In contrast the partial EVR rate was somewhat lower among patients receiving the lower dose of ribavirin (25% versus 35% in patients randomised to 1000/1200 mg/day, Figure 3).    Figure 3. Rates of RVR, complete EVR (cEVR) and partial EVR (pEVR)  In both ribavirin dosage groups, achievement of an RVR or complete EVR was associated with a high probability (positive predictive value; PPV) of achieving an SVR. Conversely, patients with a slow response to treatment (partial EVR) had a low probability of achieving an SVR after 48 weeks of treatment regardless of the dose of ribavirin (Figure 4 and Table 2).   Figure 4. Rates of SVR in patients with an RVR, complete EVR (cEVR) and partial EVR (pEVR)  Failure to achieve an on-treatment response defined as an RVR, cEVR or pEVR was also associated with a high probability of not achieving an SVR defined as the negative predictive value (NPV) (Table 2).     Table 2. Positive and negative predictive values for on-treatment virological responses for SVR On-treatment response category Predictor Ribavirin 800 mg/day Ribavirin 1000/1200 mg/day RVR PPV 64% 75% NPV 85% 82% cEVR PPV 63% 66% NPV 96% 94% pEVR PPV 9% 13% NPV 77% 74% PPV = Positive predictive value defined as the probability a patients with an on-treatment response achieving an SVR NPV = Negative predictive value defined as the probability that a patients without an on-treatment response not achieving an SVR  CONCLUSIONS The use of a higher dose of ribavirin (1000/1200 mg/day) in combination with peginterferon alfa-2a (40KD) did not significantly increase on-treatment virological response rates or SVR rates in HIV-HCV co-infected patients with difficult-to-treat HCV genotype 1 infection in the PARADIGM study.   Consistent with previous reports, achievement of rapid clearance of HCV RNA from serum at week 4 (RVR) and at week 12 (complete EVR) was highly predictive of SVR, regardless of the ribavirin dosing regimen, whereas failure to achieve a cEVR was highly predictive of not achieving an SVR.  Some treatment guidelines recommend a longer 72-week course of treatment among patients with a partial EVR who go on to achieve an undetectable HCV RNA at week 24.[6]       References     1.  Ferenci P, Fried MW, Shiffman ML et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol 2005;43(3):425-433.  2.  Jensen DM, Morgan TR, Marcellin P et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006;43(5):954-960.  3. Núñez M, Miralles C, Berdún MA et al. Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infetced patients : The PRESCO trial. AIDS Research and Human Retroviruses 2007;23(8):972-982.    4. Núñez M, Mariño A, Miralles C et al. Baseline serum hepatitis C virus (HCV) RNA level and response at week 4 are the best predictors of relapse and treatment with pegylated interferon plus ribavirin in HIV/HCV-coinfected patients. J Acquir Immune Defic Syndr 2007; 45(4):439-444.      5. Rodriguez-Torres M, Torriani F, Rockstroh J et al. Degree of viral decline early in treatment predicts sustained virological response in HCV-HIV co-infected patients treated with peginterferon alfa-2a and ribavirin. HIV Clinical Trials 2010 (in Press).    6.  Soriano V, Sulkowski M, Bergin C et al. Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV International Panel. AIDS 2002; 16:813-828.    Presented at the International Liver Congress™ 2010 [45th Annual Meeting of the European Association for the Study of the Liver (EASL)], April 14–18, 2010, Vienna, Austria  This research was funded by Roche, Basel, Switzerland   

Peginterferon alfa-2a (40KD) plus 800 or 1000/1200 mg/day ribavirin in genotype 1 HIV–HCV co-infected patients: early responses to treatment and predictability for SVR in the PARADIGM study

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Peginterferon alfa-2a (40KD) plus 800 or 1000/1200 mg/day ribavirin in genotype 1 HIV–HCV co-infected patients: early responses to treatment and predictability for SVR in the PARADIGM study

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Repositório do Hospital Prof. Doutor Fernando Fonseca