Ability of treatment week 12 viral response to predict long-term outcome in genotype 1 hepatitis C virus/HIV coinfected patients
Van den Eynde, Evaa; Tiraboschi, Juan Manuelb; Tural, Cristinac; Solà, Ricardd; Mira, José Antonioe; Podzamczer, Danielb; Jou, Antonic; Cañete, Nuriad; Pineda, Juan Antonioe; Pahissa, Alberta; Crespo, Manuela,f
aInfectious Diseases Service, Hospital Vall d'Hebron, Medicine Department, Universitat Autònoma de Barcelona, Spain
bInfectious Disease Service, Hospital Universitari de Bellvitge, Spain
cHIV Clinical Unit, Internal Medicine Department, Fundació de la Lluita contra la SIDA, University Hospital Germans Trias i Pujol, Spain
dLiver Section, Hospital del Mar, Institut Municipal d'Investigació Médica, Universitat Autònoma de Barcelona, Barcelona, Spain
eUnit of Infectious Diseases, Hospital Universitario de Valme, Sevilla, Spain
fCiber de enfermedades hepáticas y digestivas, Instituto de Salud Carlos III, Barcelona, Spain.
Received 8 October, 2009
Revised 29 October, 2009
Accepted 6 November, 2009
Correspondence to Manuel Crespo, Infectious Diseases Department, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain. Tel: +34 630150090; fax: +34 934282762; e-mail: firstname.lastname@example.org
Objective: Guidelines recommendation to extend treatment duration in genotype 1 hepatitis C virus (HCV)/HIV-coinfected patients who clear the virus later than treatment week 4 is not evidence-based. Our main objective was to study the ability of week 12 viral response [early virologic response (EVR)] to predict long-term outcome in patients treated for 48 weeks.
Design: Multicenter retrospective cohort analysis.
Methods: Genotype 1 HCV treatment-naive, HIV-coinfected adult patients with compensated liver disease who started combination therapy with fixed-dose pegylated-interferon (pegIFN) alfa-2a or weight-based pegIFN alfa-2b plus ribavirin were included. Univariate and forward stepwise logistic regression analysis were used to identify predictors of sustained viral response (SVR) and relapse.
Results: By intention-to-treat analysis, 31.3% (87/278) of patients achieved an SVR. SVR rate was more than three-fold higher in patients who cleared the virus by week 12 of treatment compared with late responders. Among 123 end-of-treatment responders, 36 (29.3%) relapsed. Relapse risk increased in patients with cirrhosis, in those with ribavirin dose reductions and in late responders: more than 65% of patients who cleared the virus between weeks 12 and 24 relapsed following 48 weeks of treatment compared with 10% of those attaining a complete EVR (<15 IU/ml) at treatment week 12 (risk ratio 6.4, 95% confidence interval 2.9–14.4).
Conclusion: Viral response at treatment week 12 is a strong predictor of long-term outcome. Genotype 1 HCV/HIV-coinfected patients who achieve a complete EVR (<15 IU/ml) are at low risk of viral relapse after completing the standard 48 weeks of therapy.
The efficacy of pegylated-interferon (pegIFN) alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C virus (HCV) infection in patients coinfected with HIV varies from 27 to 55% across different randomized trials [1–5]. These rates of viral eradication are lower than those observed in HCV monoinfection [6–8], particularly among genotype 1 HCV/HIV-coinfected patients, in whom sustained viral response (SVR) rates as low as 14% have been reported . More advanced liver fibrosis , prior injection drug use , poor tolerance to treatment [1,9], interference of antiretroviral treatment [1,10,11], and low CD4+ cell counts [11,12] have been associated with lower response in HIV-coinfected patients. However, the reasons for the difference in viral response between HCV-monoinfected and HIV-coinfected patients are poorly understood . Other factors, such as the experience of the treating physician, inadequate management of adverse events, and an insufficient cumulative ribavirin dose [1–3] may also have a negative effect on long-term outcome.
Monitoring of on-treatment viral response has proven useful to improve the individual outcome and has been incorporated into clinical practice . Patients who fail to achieve an early virologic response (EVR), defined as a viral drop of at least to 2 log10 at treatment week 12 have a very low probability of eradicating the virus; hence, treatment in these patients can be confidently discontinued . On the contrary, patients who achieve an EVR and a persistently undetectable viral load at treatment week 24 are advised to complete 48 weeks of therapy . Nonetheless, the magnitude of the week 12 viral response has a considerable impact on the long-term outcome and might be used as a guide to further individualize the duration of treatment. Whereas more than 80% of genotype 1 HCV-monoinfected patients who clear the virus during the first 12 weeks (complete EVR) eventually eradicate the infection, slow responders who clear the virus between treatment weeks 12 and 24 (partial EVR) have a relapse rate of over 65% after completing 48 weeks of therapy . Extension of treatment to 72 weeks might be useful to reduce the risk of relapse in slow responders . However, this strategy failed to improve SVR rates in a recent study conducted on genotype 1 HCV-monoinfected patients, who achieved undetectable viral load between treatment week 12 and 24 .
Although some factors associated with late response and a higher risk of relapse (high viral load, advanced fibrosis, and immunesuppression) are more prevalent among HCV/HIV-coinfected patients, there is little reported data on the association between a late response and the risk of viral relapse in this population , and the current recommendation to extend the duration of treatment of coinfected patients with genotype 1 or 4 who clear the virus later than week 4 of treatment  is not evidence-based.
In the present cohort study, we conducted a retrospective analysis of 278 genotype 1 HCV treatment-naive, HIV-coinfected patients, who were treated with pegIFN alfa-2a or alfa-2b plus ribavirin at five large, university-affiliated hospitals in Spain. We focus on the study of factors associated with SVR and viral relapse after 48 weeks of treatment and specifically determine the ability of week-12 viral response to predict long-term outcome in genotype 1 HCV/HIV-coinfected patients treated according the standard of therapy.
Study design and patients
Retrospective analysis of data collected from all adult genotype 1 HCV treatment-naive, HIV-coinfected patients, who started combination therapy with pegIFN alfa-2a or alfa-2b plus ribavirin at five large, tertiary-care university-affiliated hospitals in Spain. Previously, decompensated cirrhotic patients were excluded from the analysis. All patients provided oral informed consent for their data to be used.
Standard laboratory methods were used for HCV and HIV antibody testing, CD4 cell count and HIV RNA measurement, and liver enzyme testing.
HCV RNA levels were assessed by a qualitative PCR assay (Cobas Amplicor HCV Test v2.0; Roche Molecular Diagnostics, Barcelona, Spain; detection limit 50 IU/ml) and quantified by a PCR assay (Cobas Amplicor HCV Monitor Test v2.0; Roche Molecular Diagnostics, Barcelona, Spain; detection limit 600 IU/ml) or a real-time PCR-based test (Cobas Ampliprep/Cobas TaqMan; Roche Molecular Diagnostics, Barcelona, Spain; detection limit 15 IU/ml).
Liver biopsies were scored at each center by the local pathologist according to the Metavir  or Ishak scoring systems . Fibrosis degree was classified according to the Metavir or Ishak score, respectively, as nonsignificant (F0–1 or F<2), mild-to-moderate (F2–3 or F3–4), and cirrhosis (F4 or F5–6).
The primary efficacy endpoint was SVR, defined as an undetectable viral load 24 weeks after the end of treatment. Treatment duration was initially planned for 48 weeks in all patients. As viral response monitoring was progressively incorporated into clinical practice, therapy could be prematurely stopped in patients who experienced on-treatment early virologic failure, defined as a viral drop of less than 2 log10 units at week 12 or a detectable viral load at week 24.
Viral response at treatment week 12 was divided into three patterns: null EVR, defined as viral decline less than 2 log10 units; partial EVR, defined as a viral drop 2 log10 units but with detectable HCV RNA; and complete EVR, defined as an undetectable viral load at this time point. Viral relapse was calculated as a ratio between the number of patients with detectable viral load at the end of follow-up and the number of patients attaining an end-of-treatment viral response (ETR).
Treatment safety was evaluated at scheduled clinic visits by physical examination, laboratory tests, and recording of clinical adverse events. Stepwise dose reductions of pegIFN and ribavirin for the management of adverse events or treatment intolerance were performed at the discretion of the treating physician.
Data from the patients included in this study were collected by investigators at each center and submitted to the coordinating center for analysis. Categorical variables are reported as absolute numbers and percentages and continuous variables as the median and interquartile range (IQR). Univariate associations of risk factors with SVR and viral relapse were determined using the χ2-test or Fisher exact test for categorical data and the Mann–Whitney U-test for quantitative data. Variables associated with treatment outcome with a P value less than 0.2 were included in a forward stepwise logistic regression analysis to identify independent predictors of SVR and viral relapse. The Hosmer–Lemeshow test was used to evaluate the model's goodness of fit. The percentage of pegIFN and ribavirin dose reduction was calculated as [(cumulative planned dose − cumulative taken dose)/cumulative planned dose] × 100.
Data analyses were performed using SPSS, version 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
Between January 1998 and February 2008, 278 patients treated with pegIFN alfa-2a/2b plus ribavirin met the inclusion criteria for analysis (Fig. 1). As is summarized in Table 1, median age was 39.8 years and the majority of patients were men (76%), former intravenous drug users (85%), receiving highly active antiretroviral treatment (HAART) (89%), and had undetectable HIV RNA (80%). Almost 70% had high pretreatment HCV RNA levels, and 62% of 175 patients who underwent liver biopsy showed bridging fibrosis or cirrhosis.
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.
Predictors of sustained viral response
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).
Predictive value of treatment week-12 response
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).
Predictors of viral relapse
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 .
In agreement with previous results , the SVR rate was lower in patients on HAART than in those without antiretroviral treatment. The concomitant use of ribavirin and didanosine increases the risk of symptomatic mitochondrial toxicity , and the risk of hemoglobin decrease is higher among patients treated with zidovudine [4,29]. Consequently, current guidelines advise against co-administration of these drugs during HCV treatment . Furthermore, treatment with protease inhibitors  and abacavir [10,24] was associated with a poor response to pegIFN plus ribavirin, which raises the concern about interference of some antiretroviral drugs on the activity of pegIFN and/or ribavirin against HCV. In our study, however, no particular antiretroviral drug was associated with treatment outcome. Alternatively, even though the CD4+ cell count was not associated with treatment outcome in our study, HAART can be a surrogate marker of immune dysfunction, as antiretroviral treatment is usually delayed in patients with a preserved immune status. In addition, an increase in the complexity of HCV quasispecies has been observed following the introduction of HAART, and this factor could impair treatment response in these 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.
In keeping with previous data , the risk of relapse was higher in patients with cirrhosis. Furthermore, in agreement with recently reported data , a reduction in the cumulative ribavirin dose was an independent predictor of viral relapse. A limitation of our study is the fact that ribavirin dose was not weight-adjusted in all patients, which could contribute to explain this previous finding. Nevertheless, the starting median ribavirin dose was 14.3 mg/kg per day, and 82% of patients included received a dose of at least 12.3 mg/kg per day. Taken together, these data suggest that maintaining the initial dose of ribavirin for the complete duration of therapy may be crucial for reducing the risk of viral relapse in these very-difficult-to-treat patients.
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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