Antiviral Therapy 2014; 19:735–745 (doi: 10.3851/IMP2757)
Original article OPERA: use of pegylated interferon plus ribavirin for treating HCV–HIV coinfection in interferon‑naive patients Giampiero Carosi1, Raffaele Bruno2, Giuseppe Cariti3, Paola Nasta1, Roberto Gulminetti2, Massimo Galli4, Gioacchino Angarano5, Gabriella Verucchi6, Emanuele Pontali7, Amedeo Capetti4, Enzo Raise8, Veronica Ravasio9, Ivana Maida10, Claudio Iannacone11, Antonietta Caputo12, Massimo Puoti13* Institute of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy Department of Infectious Diseases, IRCCS Policlinico San Matteo, Pavia, Italy 3 Infectious Disease Clinic, University of Turin, Turin, Italy 4 Section of Infectious Diseases and Immunohepatology, University Hospital Luigi Sacco, Milan, Italy 5 University Hospital Policlinico, Bari, Italy 6 Operative Unit of Infectious Diseases, University Hospital Policlinico S Orsola Malpighi, Bologna, Italy 7 Galliera Hospital, Genoa, Italy 8 Infectious Diseases Clinic, Dell’Angelo Hospital, Venice, Italy 9 Infectious Diseases Department, Riuniti Hospital, Bergamo, Italy 10 University of Sassari, Sassari, Italy 11 SPARC Consulting Srl, Milan, Italy 12 Roche SpA, Monza, Italy 13 Department of Infectious Diseases, Niguarda Cà Granda Hospital, Milan, Italy 1 2
*Corresponding author e-mail: [email protected]
Background: The Optimized Pegylated interferons Efficacy and anti-Retroviral Approach (OPERA) study aimed to assess the efficacy and safety profile of treatment with pegylated interferons (PEG-IFNs) in interferon-naive patients with chronic HCV and HIV infection in routine clinical practice. Methods: This was a multicentre, prospective observational cohort study conducted at 98 Italian referral centres for the treatment of chronic HCV and HIV coinfection. Adult subjects (n=1,523) with a confirmed diagnosis of HCV and stable HIV coinfection were followed between April 2005 and March 2011; of these, 1,284 were interferon-naive and were the focus of this analysis. Patients received PEG‑IFN-a2a or -a2b plus ribavirin combination therapy. The choice of treatment and dose was at the investigator’s discretion, according to the summary of product characteristics and current guidelines. The
©2014 International Medical Press 1359-6535 (print) 2040-2058 (online)
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primary efficacy end point was sustained virological response (SVR). Secondary end points included rates of rapid viral response, early viral response and response at end of treatment. Results: SVR was achieved by 40.0% of patients; the highest SVR rate was observed in patients with HCV genotypes 2 and 3. More genotype 2 and 3 than genotype 1 and 4 patients achieved rapid and early viral responses, and end of treatment responses. Higher SVR rates were also associated with ≥80% anti-HCV treatment compliance and lower baseline HCV levels. Conclusions: The OPERA study results show that PEG‑IFN plus ribavirin is an effective treatment for HCV–HIV coinfection in interferon-naive patients. Independent predictors of SVR include HCV genotype, undetectable baseline HIV RNA and baseline HCV RNA500,000 copies/ml, n (%) AIDS diagnosis Yes, n (%) No, n (%)
1,284 (100) 967 (75.3) 1,267 (98.7) 7 (0.5) 1 (0.1) 9 (0.7) 42.0 ±6.1 (18–69) 70.0 ±11.9 (45-120) 2 (0.2) 16 (1.2) 165 (12.9) 346 (26.9) 755 (58.8) 3 (0.7) 233 (51.6) 74 (16.4) 95 (21.0) 47 (10.4) 52 (4.0) 337 (26.2) 185 (14.4) 60 (4.7) 496 (38.6) 153 (11.9) 1 (0.1) 574 (44.7) 727 (56.6) 556 (43.3) 22 (1.7) 418 (32.6) 205 (16.0) 639 (49.8) 22 (1.7) 898 (69.9) 336 (26.2) 21 (1.6) 7 (0.5) 453 (35.3) 831 (64.7)
reverse transcriptase inhibitors; 58.7% received protease inhibitors and 32.0% received non-nucleoside reverse transcriptase inhibitors.
Anti-HCV treatment during the study All patients received PEG-IFN treatment; 82.6% received PEG-IFN-a2a and 17.4% received PEG-IFN-a2b. 738
AVT-13-OA-3064_Carosi.indd 738
Starting PEG-IFN-a2a dose was 180 µg/week in 96.3% of patients while an initial mean dose of 1.47 ±0.20 µg (range 0.69–2.50) PEG-IFN-a2b was administered. The initial dose of ribavirin was 800 mg/day in one third of patients (31.3%); the majority (66.2%) received 1,000–1,200 mg/day. Dose did not differ among those with high (>800,000 IU/ml) or low (≤800,000 IU/ml) baseline HCV RNA viral load or those receiving PEGIFN-a2a or -a2b. However, differences were apparent between HCV genotype; the highest dose was administered in 75.4% of genotype 1 and 4 patients and in 54.3% of genotype 2 and 3 patients (P=0.0001). The most appropriate dosage of ribavirin for coinfected patients is still under debate. Registrational trials used ribavirin 800 mg/day for all HCV genotypes [8], and so this dose became the recommended dose upon drug approval for patients receiving PEG-IFN-a2a. Subsequently, based on clinical trials in monoinfected patients [16], the recommended dosage of ribavirin for genotype 1 patients became 1,000 mg/day for patients 75 kg [17]. Based on the results of the PRESCO study [18], weightbased dosing for genotype 1 patients was extended to include coinfected patients receiving PEG-IFN-a2a, and subsequent guidelines recommended that weight-based dosing be adopted for all genotypes [17,19]. Given that the OPERA study was conducted from 2005 to 2011, each centre followed a different approach, including increasing ribavirin dosage according to 2007 guidelines [19]. In OPERA, the highest doses were prescribed in 63.2%, 75.7%, 76.9%, 82.6% and 74.5% of genotype 1 and 4 patients enrolled respectively in 2005, 2006, 2007, 2008 and in 2009 and in 33.9%, 48.7%, 52.7%, 72.6% and 82.9% of genotype 2 and 3 patients enrolled respectively in 2005, 2006, 2007, 2008 and in 2009. Median length of anti-HCV treatment was 44 weeks (IQR 24–54); the number of therapy weeks was greater in patients who experienced an SVR; median weeks of treatment was 53 (IQR 45–60) in patients who achieved an SVR, compared with 30 (IQR 16–50) for those who did not (P48 weeks (45.0%), but only 326 patients (25.4%) were treated for >54 weeks. Of the 1,284 patients, 640 (49.8%) completed the treatment period and follow-up, 19 (1.5%) completed treatment but were lost at follow-up and 625 (48.7%) ©2014 International Medical Press
12/12/2014 11:33:12
PEG-IFN+RBV in HCV–HIV coinfection
discontinued treatment. Reasons for treatment discontinuation were lack of efficacy (n=208, 16.2%), adverse events (190, 14.8%), non-compliance (154, 12.0%), virological breakthrough (55, 4.3%) and other (18, 1.4%). The mean duration of anti-HCV treatment in the 1,072 patients not dropping out for lack of efficacy was significantly different between patients achieving SVR and those not achieving SVR (52 ±17 versus 36 ±23 weeks; P
Original article OPERA: use of pegylated interferon plus ribavirin for treating HCV–HIV coinfection in interferon‑naive patients Giampiero Carosi1, Raffaele Bruno2, Giuseppe Cariti3, Paola Nasta1, Roberto Gulminetti2, Massimo Galli4, Gioacchino Angarano5, Gabriella Verucchi6, Emanuele Pontali7, Amedeo Capetti4, Enzo Raise8, Veronica Ravasio9, Ivana Maida10, Claudio Iannacone11, Antonietta Caputo12, Massimo Puoti13* Institute of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy Department of Infectious Diseases, IRCCS Policlinico San Matteo, Pavia, Italy 3 Infectious Disease Clinic, University of Turin, Turin, Italy 4 Section of Infectious Diseases and Immunohepatology, University Hospital Luigi Sacco, Milan, Italy 5 University Hospital Policlinico, Bari, Italy 6 Operative Unit of Infectious Diseases, University Hospital Policlinico S Orsola Malpighi, Bologna, Italy 7 Galliera Hospital, Genoa, Italy 8 Infectious Diseases Clinic, Dell’Angelo Hospital, Venice, Italy 9 Infectious Diseases Department, Riuniti Hospital, Bergamo, Italy 10 University of Sassari, Sassari, Italy 11 SPARC Consulting Srl, Milan, Italy 12 Roche SpA, Monza, Italy 13 Department of Infectious Diseases, Niguarda Cà Granda Hospital, Milan, Italy 1 2
*Corresponding author e-mail: [email protected]
Background: The Optimized Pegylated interferons Efficacy and anti-Retroviral Approach (OPERA) study aimed to assess the efficacy and safety profile of treatment with pegylated interferons (PEG-IFNs) in interferon-naive patients with chronic HCV and HIV infection in routine clinical practice. Methods: This was a multicentre, prospective observational cohort study conducted at 98 Italian referral centres for the treatment of chronic HCV and HIV coinfection. Adult subjects (n=1,523) with a confirmed diagnosis of HCV and stable HIV coinfection were followed between April 2005 and March 2011; of these, 1,284 were interferon-naive and were the focus of this analysis. Patients received PEG‑IFN-a2a or -a2b plus ribavirin combination therapy. The choice of treatment and dose was at the investigator’s discretion, according to the summary of product characteristics and current guidelines. The
©2014 International Medical Press 1359-6535 (print) 2040-2058 (online)
AVT-13-OA-3064_Carosi.indd 735
primary efficacy end point was sustained virological response (SVR). Secondary end points included rates of rapid viral response, early viral response and response at end of treatment. Results: SVR was achieved by 40.0% of patients; the highest SVR rate was observed in patients with HCV genotypes 2 and 3. More genotype 2 and 3 than genotype 1 and 4 patients achieved rapid and early viral responses, and end of treatment responses. Higher SVR rates were also associated with ≥80% anti-HCV treatment compliance and lower baseline HCV levels. Conclusions: The OPERA study results show that PEG‑IFN plus ribavirin is an effective treatment for HCV–HIV coinfection in interferon-naive patients. Independent predictors of SVR include HCV genotype, undetectable baseline HIV RNA and baseline HCV RNA500,000 copies/ml, n (%) AIDS diagnosis Yes, n (%) No, n (%)
1,284 (100) 967 (75.3) 1,267 (98.7) 7 (0.5) 1 (0.1) 9 (0.7) 42.0 ±6.1 (18–69) 70.0 ±11.9 (45-120) 2 (0.2) 16 (1.2) 165 (12.9) 346 (26.9) 755 (58.8) 3 (0.7) 233 (51.6) 74 (16.4) 95 (21.0) 47 (10.4) 52 (4.0) 337 (26.2) 185 (14.4) 60 (4.7) 496 (38.6) 153 (11.9) 1 (0.1) 574 (44.7) 727 (56.6) 556 (43.3) 22 (1.7) 418 (32.6) 205 (16.0) 639 (49.8) 22 (1.7) 898 (69.9) 336 (26.2) 21 (1.6) 7 (0.5) 453 (35.3) 831 (64.7)
reverse transcriptase inhibitors; 58.7% received protease inhibitors and 32.0% received non-nucleoside reverse transcriptase inhibitors.
Anti-HCV treatment during the study All patients received PEG-IFN treatment; 82.6% received PEG-IFN-a2a and 17.4% received PEG-IFN-a2b. 738
AVT-13-OA-3064_Carosi.indd 738
Starting PEG-IFN-a2a dose was 180 µg/week in 96.3% of patients while an initial mean dose of 1.47 ±0.20 µg (range 0.69–2.50) PEG-IFN-a2b was administered. The initial dose of ribavirin was 800 mg/day in one third of patients (31.3%); the majority (66.2%) received 1,000–1,200 mg/day. Dose did not differ among those with high (>800,000 IU/ml) or low (≤800,000 IU/ml) baseline HCV RNA viral load or those receiving PEGIFN-a2a or -a2b. However, differences were apparent between HCV genotype; the highest dose was administered in 75.4% of genotype 1 and 4 patients and in 54.3% of genotype 2 and 3 patients (P=0.0001). The most appropriate dosage of ribavirin for coinfected patients is still under debate. Registrational trials used ribavirin 800 mg/day for all HCV genotypes [8], and so this dose became the recommended dose upon drug approval for patients receiving PEG-IFN-a2a. Subsequently, based on clinical trials in monoinfected patients [16], the recommended dosage of ribavirin for genotype 1 patients became 1,000 mg/day for patients 75 kg [17]. Based on the results of the PRESCO study [18], weightbased dosing for genotype 1 patients was extended to include coinfected patients receiving PEG-IFN-a2a, and subsequent guidelines recommended that weight-based dosing be adopted for all genotypes [17,19]. Given that the OPERA study was conducted from 2005 to 2011, each centre followed a different approach, including increasing ribavirin dosage according to 2007 guidelines [19]. In OPERA, the highest doses were prescribed in 63.2%, 75.7%, 76.9%, 82.6% and 74.5% of genotype 1 and 4 patients enrolled respectively in 2005, 2006, 2007, 2008 and in 2009 and in 33.9%, 48.7%, 52.7%, 72.6% and 82.9% of genotype 2 and 3 patients enrolled respectively in 2005, 2006, 2007, 2008 and in 2009. Median length of anti-HCV treatment was 44 weeks (IQR 24–54); the number of therapy weeks was greater in patients who experienced an SVR; median weeks of treatment was 53 (IQR 45–60) in patients who achieved an SVR, compared with 30 (IQR 16–50) for those who did not (P48 weeks (45.0%), but only 326 patients (25.4%) were treated for >54 weeks. Of the 1,284 patients, 640 (49.8%) completed the treatment period and follow-up, 19 (1.5%) completed treatment but were lost at follow-up and 625 (48.7%) ©2014 International Medical Press
12/12/2014 11:33:12
PEG-IFN+RBV in HCV–HIV coinfection
discontinued treatment. Reasons for treatment discontinuation were lack of efficacy (n=208, 16.2%), adverse events (190, 14.8%), non-compliance (154, 12.0%), virological breakthrough (55, 4.3%) and other (18, 1.4%). The mean duration of anti-HCV treatment in the 1,072 patients not dropping out for lack of efficacy was significantly different between patients achieving SVR and those not achieving SVR (52 ±17 versus 36 ±23 weeks; P
