Original article OPERA: use of pegylated interferon plus ribavirin for treating HCV HIV coinfection in interferon naive patients

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1 Antiviral Therapy 14; 19: (doi:.3851/imp2757) Original article OPERA: use of pegylated interferon plus ribavirin for treating HCV HIV coinfection in interferon naive patients Giampiero Carosi 1, Raffaele Bruno 2, Giuseppe Cariti 3, Paola Nasta 1, Roberto Gulminetti 2, Massimo Galli 4, Gioacchino Angarano 5, Gabriella Verucchi 6, Emanuele Pontali 7, Amedeo Capetti 4, Enzo Raise 8, Veronica Ravasio 9, Ivana Maida, Claudio Iannacone 11, Antonietta Caputo 12, Massimo Puoti 13 * 1 Institute of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy 2 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 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 *Corresponding author massimo.puoti@ospedaleniguarda.it 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 5 and March 11; 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 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 4.% 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 8% 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 RNA<5, IU/ml. 14 International Medical Press (print) 4-58 (online) 735

2 G Carosi et al. Introduction HCV infection represents a growing burden on health-care systems and the associated mortality rate has eclipsed that of HIV infection. HCV HIV coinfection represents a clinical challenge, as it is associated with lower survival rates than are seen in patients who are HCV monoinfected. HCV is the main reason for liver-related deaths in HIV, while liver mortality ranks second, and in some cases first, among the causes of non-aids-related death in patients with HIV [1 3]. Combination treatment with pegylated interferon-α (PEG-IFN) and ribavirin [4 6], achieves a sustained virological response (SVR) in approximately 4% of treated patients [4,6]. Of the six HCV genotypes, response rates to treatment are higher among genotypes 2, 3, 5 and 6 [4]. Several studies have examined the efficacy of interferon plus ribavirin in patients with HCV HIV, using either PEG-IFN [7,8] or standard interferon [7 ], showing heterogeneous results. Recently, boceprevir and telaprevir two direct-acting antivirals (DAA) have been introduced for the treatment of HCV genotype 1 infection (in addition to PEG-IFN and ribavirin) improving the rate of SVR [11,12]. Preliminary results from two ongoing pilot studies showed that the results of triple therapy with either telaprevir or boceprevir in HCV HIV-coinfected patients are similar to those obtained in HIV uninfected subjects [13,14]. While the advancement of our understanding of drug treatments is based on randomized, prospective clinical trials prior to the approval of a treatment, the wider use of drugs following approval with the collation of real-world data provides a greater understanding of the management of patients and may offer useful information for new treatment strategies based on new anti-hcv DAA. In the field of HCV HIV such data are lacking so the Optimized Pegylated interferons Efficacy and anti-retroviral Approach (OPERA) study was conducted to document routine clinical and treatment data in patients with HCV HIV coinfection. Using a prospective observational design, noninterventional data were collected to provide real-life experimental evidence to further the understanding and continued improvement of the management of patients with HCV HIV coinfection. The objectives of the OPERA study were to evaluate the efficacy and tolerability of PEG-IFNs, as well as monitoring highly active retroviral therapy in interferon-naive patients, among a representative sample of patients with chronic hepatitis C and HIV coinfection under common clinical practice conditions. The focus of the present article is to assess the efficacy and safety profile of treatment with PEG-IFNs in interferon-naive patients with chronic HCV and HIV infection in routine clinical practice. Methods Study design and patients The OPERA study was a multicentre, prospective, observational cohort study conducted at 98 Italian referral centres for the treatment of chronic HCV and HIV coinfection. Eligible patients were adult subjects with a confirmed diagnosis of chronic HCV and HIV infection. They were required to have stable HIV infection (either receiving a stable regimen of combination antiretroviral therapy [cart] defined as 6 weeks of cart with no predictable changes in regimen) and to be willing to use safe contraceptive methods. Main exclusion criteria included pregnancy or lactation, autoimmune hepatitis, severe liver disease (Child-Pugh score 6) or decompensated cirrhosis, history of severe cardiovascular disease, severe psychiatric disease or inability to follow a pattern of clinic visits during observation. All adult HIV HCV patients undergoing HCV treatment at the 98 referral centres during the study period were enrolled as long as they fulfilled the inclusion/ exclusion criteria outlined above and signed written informed consent. The population analysed comprised patients who had not previously received treatment with an interferon (that is, were interferon-naive). Treatment Eligible patients were to start a PEG-IFN-based regimen, either with PEG-IFN-a2a (Pegasys ; Roche, Basel, Switzerland) or PEG-IFN-a2b (PegIntron ; Merck, White House Station, NJ, USA), plus ribavirin, either as capsules (Rebetol ; Merck) or tablets (Copegus ; Roche). The choice of treatment and dose was at the discretion of the investigators, according to the summary of product characteristics and current guidelines. Compliance with anti-hcv therapy was assessed as percentage exposure to anti-hcv therapy, defined as the ratio of cumulative dose (sum of the number of weeks [for PEG-IFN] or days [for ribavirin] multiplied by the dose prescribed during a given time period and throughout the study) to theoretical recommended dose of PEG- IFN or ribavirin during the 48-week treatment period. Assessments A web-based management tool was employed to permit entry of data collected at each centre and downloading of study documents. Baseline assessments included demographic and clinical data, HCV genotype and viral load, HIV RNA viral load and CD4 + T-cell count. Prior anti-hcv and antiretroviral therapy (ART) was recorded as well. Regular clinical and laboratory monitoring was performed at each hospital, in agreement with local procedures. Current ART and other concomitant therapies (if International Medical Press

3 PEG-IFN+RBV in HCV HIV coinfection present) were documented; dose and schedule of PEG- IFN and ribavirin, as well as any medication change occurring during treatment, were tracked. Study end points The primary efficacy end point was SVR, defined as serum HCV RNA level <5 IU/ml (or undetectable when the assay had a different limit of detection) at the end of a 24-week untreated follow-up period. Secondary end points were rates of rapid viral response (RVR), early viral response (EVR) and response at end of treatment (EOT) for patients in which the data were collected. CD4 + T-cell counts at baseline, EOT and end of study (EOS) were also reported. Safety was assessed by laboratory tests and evaluation of clinical adverse events during therapy. Statistical analyses The sample size was calculated in order to estimate the 95% CI for a proportion equal to.5 (maximum variability) with a width equal to.5. To ensure this observational study is considered representative in terms of sample size and study centres, it was planned to include at least 1% of target population and at least % of the sites which manage patients with HCV HIV coinfections. Data analyses were performed on the intent-to-treat (ITT) population, defined as all interferon-naive patients enrolled who took at least one dose of treatment for HCV. Continuous variables were summarized by descriptive statistics and categorical variables were summarized using counts of patients and percentages. Comparisons between groups were carried out using c 2 test or Fisher s Exact test for qualitative variables and the Student s t-test or the non-parametric Mann-Whitney s test for quantitative variables. A multivariate logistic regression analysis was used to assess the factors associated with SVR; 95% CIs were derived from the model using the Wald s method. For continuous variables, for example, age, the odds ratio (OR) for likelihood of SVR was calculated for a defined incremental unit. Patients with a missing HCV RNA level value for any reason at the end of follow-up were considered to be non-responders. Safety data were collected through adverse event records at each visit during treatment and followup the investigator documented any events that were observed, spontaneously reported by the patient or mentioned in response to a direct question. This was complemented by laboratory assessments. Previous diseases, concomitant diseases and adverse events were classified by primary System Organ Class according to the MedDRA thesaurus version 12 [15]. Safety analysis was performed on the safety population, defined as patients enrolled who took at least one dose of the treatment for HCV. All statistical tests were performed at the P.5 level (two-sided). Statistical analyses were carried out using the SAS System version 9.2 (SAS Business Analytics, Cary, NC, USA). Study conduct The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice. The study protocol plus amendments, patient information leaflet and informed consent document were submitted to the Independent Ethics Committee of each centre participating in the study prior to the start of any study-related procedure. Prior to study start, informed consent was sought and obtained from each participating patient. Results The OPERA study was conducted between 8 April 5 and 4 March 11 and included 1,523 patients consecutively enrolled at the 98 referral centres. The mean enrolment rate was 34 patients per year. Of the 1,523 patients in the ITT and safety populations, 1,284 patients had not previously received treatment with an interferon (that is, were interferon-naive) and are reported here. Baseline patient characteristics The main features of the study population (n=1,284) are described in Table 1. Patients had a mean age of 42 years; most patients were male (75.3%) and Caucasian (98.7%). Serum HCV RNA levels were >5, IU/ml in 65.8% of patients and 56.6% were infected with genotype 1 or 4. HIV viral load was undetectable in 69.9% of subjects and the mean ±sd CD4 + T-cell count was ±247.8 cells/µl. At baseline, 276 patients (21.5%) had at least one concomitant disease. The most common (by systemorgan class) were metabolism and nutrition disorders (5.5%; with diabetes mellitus the single most common at 1.9%), followed by psychiatric disorders (4.5%; depression 2.3%). Concomitant medications (at least one excluding ART) were taken by 2 patients (17.1%), with cardiovascular drugs the most common (5.7%; lipid modifying agents 2.1%), followed by nervous system drugs (5.5%; antidepressants 2.6%). The vast majority of patients (n=1,128, 87.9%) received cart for HIV infection at some time in their life either before starting or while receiving anti-hcv therapy (including those who have stopped or have continued taking ART), while 156 (12.1%) never started ART. Of the 983 patients who were receiving cart before starting HCV treatment and continued to take it, or started taking cart after HCV treatment was initiated, almost all (96.3%) received nucleoside Antiviral Therapy

4 G Carosi et al. Table 1. Baseline demographic and clinical data for the subset of interferon-naive patients Characteristic Value Total n (%) 1,284 () Male gender, n (%) 967 (75.3) Race Caucasian, n (%) 1,267 (98.7) Black, n (%) 7 (.5) Asian, n (%) 1 (.1) Other, n (%) 9 (.7) Mean age, years ±sd (range) 42. ±6.1 (18 69) Mean weight, kg ±sd (range [min-max]) 7. ±11.9 (45-1) CD4 + T-cell count class Missing, n (%) 2 (.2) <, n (%) 16 (1.2) 35, n (%) 165 (12.9) , n (%) 346 (26.9) 5, n (%) 755 (58.8) Liver staging (Metavir) Missing, n (%) 3 (.7) F F1, n (%) 233 (51.6) F2, n (%) 74 (16.4) F3, n (%) 95 (21.) F4, n (%) 47 (.4) HCV genotype 1 (unspecified), n (%) 52 (4.) 1a, n (%) 337 (26.2) 1b, n (%) 185 (14.4) 2, n (%) 6 (4.7) 3, n (%) 496 (38.6) 4, n (%) 153 (11.9) 6, n (%) 1 (.1) 1 (total), n (%) 574 (44.7) 1 and 4 (total), n (%) 727 (56.6) 2 and 3 (total), n (%) 556 (43.3) HCV RNA level Not noted, n (%) 22 (1.7) 5, IU/ml, n (%) 418 (32.6) 5,1 8, IU/ml, n (%) 5 (16.) >8, IU/ml, n (%) 639 (49.8) HIV RNA level Not noted, n (%) 22 (1.7) 5 copies/ml, n (%) 898 (69.9) 51, copies/ml, n (%) 336 (26.2),1 5, copies/ml, n (%) 21 (1.6) >5, copies/ml, n (%) 7 (.5) AIDS diagnosis Yes, n (%) 453 (35.3) No, n (%) 831 (64.7) reverse transcriptase inhibitors; 58.7% received protease inhibitors and 32.% 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. Starting PEG-IFN-a2a dose was 18 µg/week in 96.3% of patients while an initial mean dose of 1.47 ±. µg (range ) PEG-IFN-a2b was administered. The initial dose of ribavirin was 8 mg/day in one third of patients (31.3%); the majority (66.2%) received 1, 1, mg/day. Dose did not differ among those with high (>8, IU/ml) or low ( 8, IU/ml) baseline HCV RNA viral load or those receiving PEG- IFN-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=.1). The most appropriate dosage of ribavirin for coinfected patients is still under debate. Registrational trials used ribavirin 8 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, mg/day for patients <75 kg and 1, 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 5 to 11, each centre followed a different approach, including increasing ribavirin dosage according to 7 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 5, 6, 7, 8 and in 9 and in 33.9%, 48.7%, 52.7%, 72.6% and 82.9% of genotype 2 and 3 patients enrolled respectively in 5, 6, 7, 8 and in 9. 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 6) in patients who achieved an SVR, compared with (IQR 16 5) for those who did not (P<.1). The treatment duration was influenced by current guidelines. Later guidelines on anti- HCV treatment during the study period (5 11) suggested a longer treatment duration up to 72 weeks in HCV G1 or 4 patients showing HCV RNA clearance after the first 12 weeks of treatment; in addition, in many centres, 1 year of treatment was given instead of 48 weeks. Overall, 578 patients were treated for >48 weeks (45.%), but only 326 patients (25.4%) were treated for >54 weeks. Of the 1,284 patients, 64 (49.8%) completed the treatment period and follow-up, 19 (1.5%) completed treatment but were lost at follow-up and 625 (48.7%) International Medical Press

5 PEG-IFN+RBV in HCV HIV coinfection discontinued treatment. Reasons for treatment discontinuation were lack of efficacy (n=8, 16.2%), adverse events (19, 14.8%), non-compliance (154, 12.%), virological breakthrough (55, 4.3%) and other (18, 1.4%). The mean duration of anti-hcv treatment in the 1,72 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<.1). This was similar to the significant difference seen between these two groups in the total population. Change in CD4 + T-cell counts after anti-hcv therapy Analysis of CD4 + T-cell counts at baseline, EOT and EOS, showed a significant (P<.1) mean reduction in CD4 + T-cell count between baseline and EOT: ±214.2 cells/µl in the overall population, with a numerically larger reduction in patients achieving an SVR versus those not achieving an SVR (195.8 versus cells/µl); however, the differences in the change in CD4 + T-cell count from baseline to EOT and EOT to EOS, in patients achieving and not achieving an SVR were not statistically significant (P=.579). A major recovery of CD4 + T-cell count from EOT to EOS was observed, almost back to baseline value. Change in HIV RNA after anti-hcv therapy Analysis of HIV RNA showed a significant difference between baseline, EOT and EOS: the proportion of patients with undetectable HIV RNA (<5 copies/ml) was 71.2% at baseline, 79.3% at EOT and 76.8% at EOS (P<.1). HIV RNA was not collected in the case record form as an exact value but the range (< or 5 copies/ml) was recorded at baseline, EOT and EOS in 1,262, 811 and 587 patients, respectively. Virological response The primary outcome, SVR, was achieved by 513 of 1,284 interferon-naive patients, generating an overall SVR rate of 4.%; the highest SVR rate was observed in patients with HCV genotypes 2 and 3 (68.3% and 56.5%, respectively, P=.785 [for difference between genotype 2 and genotype 3]); patients with HCV genotype 1 and 4 had SVR rates of 27.4% and 22.9% respectively (P=.2644; Figure 1A). Of the 683 patients with available HCV RNA test at week 4, a higher proportion of genotype 2 and 3 patients achieved RVR (Figure 1B). The same was observed for EVR, EOT response and SVR (Figure 1B). Infection with HCV genotype 2 and 3, serum HCV RNA<5, IU/ml at baseline and negative serum HCV RNA at week 4 (RVR), as well as undetectable HIV RNA at baseline and compliance to anti-hcv therapy, were all significantly associated with achievement of SVR. Undetectable baseline serum HIV RNA, HCV viral load <5, IU/ml and HCV genotype were identified as independent predictors of SVR at multivariate analysis (Figure 2). The greater sample size of this study and the inclusion of patients not receiving cart or without effective cart, allowed us to estimate the impact of suppressed HIV replication at baseline on the response rate. SVR was similar in the 983 patients either taking cart at baseline or who started cart during the study, compared with patients Figure 1. Response rates according to HCV genotype (G) A Percentage of patients G1 (n=574) 68.3 G2 (n=6) 56.5 G3 (n=496) 22.9 G4 (n=153) B Percentage of patients G1 and G2 and RVR EVR EOT SVR (A) Sustained virological response (SVR) rate 24 weeks after treatment cessation (G1 versus 2 versus 3 versus 4). (B) Rapid virological response (RVR) at 4 weeks (G1 and 4 versus G2 and 3; n=382 and n=1, respectively). Early virological response (EVR) at 12 weeks (n=421 and n=3), response at end of treatment (EOT; n=727 and n=556) and SVR at 24 weeks after treatment (n=727 and n=556). Antiviral Therapy

6 G Carosi et al. Figure 2. Factors predicting sustained virological response Worst chance Better chance Weeks of treatment a Exposure to PEG-IFN Exposure to RBV MDRD-GFR, ml/min/1.73 m 2a γ-gt, U/l a Platelets, 9 /l a ALT, U/l a Triglycerides, mmol/l a Total cholesterol, mmol/l a Glucose, mmol/l a Use of abacavir CD4 + T-cells, number CD4 + T-cells, number RBV, mg/kg a Age, years a Drug addict HIV viral load HCV viral load HCV genotype Gender PEG-IFN <8% <8% Yes <35 <35 No >5 copies/ml >5, IU/ml Female PEG-α2b >8% >8% No 35 5 >5 Yes <5 copies/ml <5, IU/ml G1 and 4 G2 and 3 Male PEG-α2a Odds ratio Metavir staging and virological response at week 4 have not been included because they were available only for a limited number of patients (612 and 683 patients, respectively). a Odds increase per 1 unit. ALT, alanine aminotransferase; γ-gt, gamma glutamyl transferase; PEG-IFN, pegylated interferon; MDRD-GFR, glomerular filtration rate according to Levy s formula; RBV, ribavirin. not treated with cart at any point (39.% versus 43.2%; P=.192), suggesting that SVR was dependent only on cart effectiveness and not on cart exposure. Predictive factors for SVR in interferon-naive patients receiving cart were similar to those in the whole population: namely, baseline HCV RNA 5, IU/ml (P<.17), HCV genotype 2 and 3 (P<.1), undetectable baseline HIV RNA (P<.11) and ribavirin compliance 8% (P=.46). In addition, younger age (P=.147 per year), lower γ-glutamyl transferase levels (P=.31 per 1 mg/dl) and longer duration of anti- HCV therapy (P=. per week) were also predictive for SVR in patients receiving cart. Relapse rates At the end of treatment, 554 patients (43.1%) were considered to be responders, of which 419 (75.6%) reached SVR; the relapse rate from end of treatment to the end of the study was 24.4%. The relapse rate was higher for genotype 1 and 4 (31.7%) compared with genotype 2 and 3 (19.3%). Adverse events Almost half of all dosed patients experienced at least an adverse event for a total of 1,346 events reported (Table 2); of these, 48 were considered mild, 471 moderate, 128 severe and 267 weren t classified. A summary of adverse events occurring in >1% of patients is presented in Table 2. The most frequently reported events were neutropenia (n=252, 19.6%) and anaemia (n=18, 14.%). Neuropsychiatric symptoms (depression, irritability, altered mood and insomnia) were observed in 11.5% of patients. A total of 15 serious adverse events occurring in 14 patients led to dose modification/treatment change while 57 serious adverse events in 54 patients resulted in cessation of treatment. Two deaths occurred during the study and these were considered by the study investigators to be unrelated to treatment (one 38-year old male died from pancytopenia and splenomegaly probably related to no improvement in a diagnosed haematological disease according to the local investigator, while a 45-year old female died from AIDS-related bacterial pneumonia). No other patients International Medical Press

7 PEG-IFN+RBV in HCV HIV coinfection Table 2. Adverse events summary and adverse events occurring in more than 1% of patients n (%) Discontinued, n (%) Adverse event summary Patients who received 1 dose of PEG-IFN, n 1,284 Adverse events, n 1,346 Adverse events considered to be related to treatment, n 1,243 Serious adverse events, n 4 Serious adverse events considered to be related to treatment, n 87 Patients with 1 adverse event 67 (47.3) Patients with 1 adverse event considered related to treatment 589 (45.9) Patients with 1 serious adverse event 93 (7.2) Patient deaths 2 (.2) Adverse event occurring in >1% of patients Neutropenia a 252 (19.6) (1.6) Anaemia a 18 (14.) 46 (3.6) Asthenia 92 (7.2) 29 (2.3) Depression 72 (5.6) 31 (2.4) Thrombocytopenia a 71 (5.5) 13 (1.) Pyrexia 37 (2.9) 16 (1.2) Weight loss 34 (2.6) 9 (.7) Irritability (2.3) 11 (.9) Influenza-like symptoms 28 (2.2) 6 (.5) Altered mood 24 (1.9) 7 (.5) Insomnia 22 (1.7) 1 (.1) Headache 21 (1.6) 4 (.3) Anxiety 19 (1.5) 5 (.4) Pruritus 18 (1.4) 7 (.5) Arthralgia 15 (1.2) 4 (.3) Alopecia 14 (1.1) ( ) Musculoskeletal pain 14 (1.1) 6 (.5) Cough 13 (1.) 3 (.2) a The number of cases of neutropenia, anaemia and thrombocytopenia are derived from the adverse events reported by investigators in the electronic case record adverse event form. There are some discrepancies between these clinically assessed data and those described using laboratory assessments. We reported the data from the adverse event form as even if the laboratory data did not confirm the event (for example, anaemia), from the point of view of the investigator, the event occurred (conservative approach). PEG-IFN, pegylated interferon. experienced any AIDS-related events and no patients with baseline CD4 + T-cell count > and/or undetectable HIV RNA showed CD4 + T-cell count < cells/µl and/or detectable HIV RNA at the end of the follow-up. Hepatic decompensation was observed in one patient and hepatocellular carcinoma was diagnosed in another patient. Both subjects had cirrhosis at baseline. Discussion In this observational study we found that among interferon-naive patients with HCV HIV coinfection, after treatment with PEG-IFN plus ribavirin, an SVR was achieved by 4.% of patients. Higher SVR rates were observed in patients with HCV genotypes 2 and 3; and in patients with lower baseline HCV viral load. Higher SVR rates were also seen in patients with suppressed HIV replication at baseline (<5 copies/ml). As expected, an increased likelihood of achieving an SVR correlated with increased duration of HCV treatment. The treatment duration varied according to treatment centre and was influenced by anti-hcv treatment guidelines in use at the time of treatment. In our study, 45.% received treatment for more than 48 weeks, and a quarter of patients were treated for more than 54 weeks. Analysis of patients not dropping out for lack of efficacy showed that patients achieving SVR had a significantly higher mean duration of treatment than those not achieving SVR. The overall SVR results are consistent with other published major trials; SVR rates observed in this study are compared with other published major studies including more than patients treated with PEG- IFN and ribavirin in Figure 3. The SVR rates of 26% and 58% in patients with HCV genotypes 1 and 4 and genotypes 2 and 3, respectively, observed in the current study were consistent with those reported in other studies (genotype 1: 29% and 34%; genotype 2 or 3, 62% and 58%) [8,]. Other studies by Núñez et al. [18] and Labarga et al. [21] demonstrated SVR rates Antiviral Therapy

8 G Carosi et al. Figure 3. Comparison between OPERA study and published studies including more than HIV HCV-coinfected subjects treated with pegylated interferon plus ribavirin A SVR HCV G1 and 4, % SVR HCV G2 and 3, % B Carrat, 4 [9] 35 Voigt, 6 [24] Torriani, 4 [8] Núñez, 7 [18] Laguno, 9 [25] Berenguer, 12 [] Labarga, 12 [21] OPERA Carrat, 4 [9] Voigt, 6 [24] Torriani, 4 [8] Núñez, 7 [18] Laguno, 9 [25] Berenguer, 12 [] Labarga, 12 [21] OPERA Drop-out (AE), % Drop-out (non-ae a ), % Carrat, 4 [9] Voigt, 6 [24] Torriani, 4 [8] Núñez, 7 [18] Laguno, 9 [25] Berenguer, 12 [] Labarga, 12 [21] OPERA Carrat, 4 [9] Voigt, 6 [24] Torriani, 4 [8] Núñez, 7 [18] Laguno, 9 [25] Berenguer, 12 [] Labarga, 12 [21] OPERA (A) Sustained virological response (SVR). (B) Drop-outs. a Excluding lack of efficacy and virological breakthrough. AE, adverse events; G, genotype. of 35% and 31% in patients with HCV genotype 1 and 4, respectively, and SVR rates of 86% and 82% in patients with HCV genotype 2 and 3. However, these rates were achieved in smaller patient populations and in randomized studies that employed an experimental strategy of increased ribavirin dosing and longer treatment duration in at least one arm. The present data suggest that, in real practice, the effectiveness of PEG- IFN plus ribavirin for the treatment of HCV in persons living with HIV in Italy does not differ from the efficacy data observed in experimental studies. However, although the results in real life are surprisingly similar to those reported in clinical studies, taking into account that less than 5% of treated patients obtained an SVR in our study, there is a need for implementation of new DAAs in the treatment of HCV coinfection in persons with HIV, in order to increase the rate of HCV eradication and, thus, increase coinfected patient survival. Data from Phase II studies with boceprevir and telaprevir added to PEG-IFN and ribavirin in HIV HCV genotype 1 coinfected patients indicate that it International Medical Press

9 PEG-IFN+RBV in HCV HIV coinfection could be possible to achieve SVR rates higher than 5% [22,23]. Common adverse events in this study were consistent with those reported in other studies: that is, neutropenia and anaemia, though the overall rate of adverse events was low compared with the observations of Laguno [] (47.3% versus >9%). The rates of premature withdrawal not related to adverse events or lack of efficacy (approximately 13.3%) were consistent with those observed in a Spanish prospective observational cohort study (11% of responders withdrew) [] and in the Voigt study (9%) [24] but were higher than those observed in another study with a more stringent patient selection (2 6%) []. This confirms that spontaneous withdrawals play an important role in the failure of treatment in the real world. The rate of withdrawal for adverse events (14.8%) was also consistent with most of the multicentre studies, but not with the more recent comparative trials (8 %) [18,21,25], in which the management of side effects were probably better defined. The higher drop-out rate for adverse events in this reallife study in comparison with randomized controlled trials suggests that real-world data will be needed even for new direct-acting anti-hcv antivirals, in order to assess the impact of their introduction into clinical practice. As with other publications, patients with HCV genotypes 2 and 3 were most likely to achieve an SVR compared with 1, 4 or 6, as were those with lower baseline HCV RNA levels [4,7,21,26]. However, in this study, SVR rates were related not only to baseline HCV RNA levels and HCV genotype, but also to undetectable HIV RNA before starting treatment. The positive impact of the suppression of HIV replication on the response to anti-hcv therapy suggests that concurrent effective ART could increase the efficacy of anti-hcv treatment and that this should be initiated and consolidated before starting anti-hcv treatment independently from CD4 + T-cell count as stated in some of the guidelines on anti- HIV therapy [27,28]. However, if this positive impact of HIV suppression on the efficacy of anti-hcv treatment is confirmed in studies of new anti-hcv antivirals, this may result in limiting the combined usage of some antiretroviral agents with directly acting anti HCV antivirals, due to reciprocal drug drug interactions. An alternative explanation for the association between HIV control and improved SVR may be a possible link between compliance with ART and HCV treatments. Although this was not part of this analysis, further analysis is warranted to show whether there is an association between HIV RNA level and compliance with anti-hcv treatment, among patients receiving ART. One of the strengths of the OPERA study was the nature of the data: it was derived from a real-world data set from a large number of study centres. The investigational sites comprised 5% of the Italian sites managing HCV HIV coinfection and enrolled 34 patients per year (17% of the approximately 2, coinfected patients initiated each year on antiviral therapy for HCV infection in Italy), thereby providing sufficient information to form a representative sample. Additionally, the study sample included over 1, patients, considerably larger than prospective randomized trials in the literature [7,18,25,29 33]. While it was prospectively designed, one of the limitations of the study is that it was not specifically conceived to make direct comparisons between treatments. Therefore, the results observed help to contextualize the patient characteristics that are associated with response, but, while there appeared to be a difference between the rates of SVR in patients treated with PEG-IFN-a2a and -a2b, the lack of randomization in this study means that we are not able to draw firm conclusions regarding differences in treatment efficacy. A further characteristic of the study is that the rules followed by investigators for ceasing treatment due to lack of efficacy evolved over time. This reflected the changing practices in the therapeutic area changes that were in the best interests of treatment management and were due to the long period over which the trial was held. With such a trial, it is understandable that such changes may occur. In conclusion, among PEG-IFN-naive patients in Italy, PEG-IFN in combination with ribavirin is an effective management strategy in patients with HCV HIV coinfection. Low baseline HCV viral load, high anti-hcv compliance, HCV genotypes 2 and 3 and an effective concurrent ART are predictors of increased response to treatment. Acknowledgements G Carosi, R Bruno, G Cariti and M Puoti wrote the first draft of the article, contributed to interpretation of data, statistical analysis and model results used in the study. C Iannacone performed the statistical analysis. All authors contributed to and reviewed critically subsequent drafts and approved the final draft of the article. MedDRA is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). The study presented in this article has been sponsored by Roche. The authors would like to thank Matt Weitz, Mary Hines and Sheridan Henness of Springer Healthcare Communications (Auckland, New Zealand) for editorial assistance in the preparation of this manuscript. This assistance was sponsored by Roche. Antiviral Therapy

10 G Carosi et al. Disclosure statement G Carosi has received honorarium as an advisory board member for Bristol Myers Squibb. R Bruno has received support for travel to meetings for this study from Roche, honorarium as an advisory board member from Abbott, Boehringer Ingelheim, Janssen Cilag, Gilead, Merck Sharp & Dohme and payment for lectures from Janssen Cilag and Roche. P Nasta has received grants from Bristol Myers Squibb, Gilead, Merck Sharp & Dohme, Viiv Healthcare, support for travel to meetings from Merck Sharp & Dohme, honorarium as an advisory board member from Gilead, honorarium for expert testimony from Viiv and payment for lectures from Bristol Myers Squibb, Gilead and Merck Sharp & Dohme. R Gulminetti has received a grant through his institution and support for travel to meetings from Roche. M Galli received honorarium as an advisory board member from AbbVie, Bristol Myers Squibb, Gilead, Janssen Cilag, Merck Sharp & Dohme and Viiv. G Angarano has received a grant through his institution from Roche. G Verruchi has received a grant through her institution and support for travel to meetings for this study from Roche, is receiving payment for lectures from Gilead, Merck Sharp & Dohme, Pfizer, Roche and has received support for travel to meetings from Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme and Pfizer. E Pontali has received a grant through his institution, support for travel to meetings for this study, honoraria for participation in review activities, such as data monitoring boards, statistical analysis and end point committees from Roche. I Maida has received support for travel to meetings for this study from and payment for lectures from Roche, honoraria for manuscript preparation from Abbott, Bristol Myers Squibb, Janssen Cilag, Merck Sharp & Dohme and payment for developing educational presentations from Abbott, Bristol Myers Squibb and Gilead. C Iannacone has received consulting fees, fees for providing statistical analysis and payment for reviewing the manuscript from Roche; he is receiving a consultancy honorarium from Amgen, Astra Zeneca, Bayer, Bracco Imaging, Chiesi Farmaceutici, Takeda Italia and payment for manuscript preparation from AstraZeneca, Lundbeck and Takeda Italia. A Caputo is a Roche employee. M Puoti has received honorarium as an advisory board member for Abbott, Abbvie, Bristol Myers Squibb, Boehringer Ingelheim, Gilead, Janssen Cilag, Merck Sharp & Dohme, Roche and Vertex, payment for lectures from Bristol Myers Squibb, Gilead, Merck Sharp & Dohme and Roche. All other authors declare no competing interests. References 1. Price JC, Thio CL. Liver disease in the HIV-infected individual. Clin Gastroenterol Hepatol ; 8: Weber R, Sabin CA, Friis-Moller N, et al. Liverrelated deaths in persons infected with the human immunodeficiency virus: the D:A:D study. 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