June 9, 2013

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"To conclude, we found a reduced but persistent long-term risk of developing HCC after achievement of SVR in patients with HCV-related cirrhosis. This risk persisted at least 8 years after SVR had been achieved in some patients. This indicates that continued surveillance for HCC should be maintained during prolonged time periods.....The duration needed for long-term surveillance for HCC after SVR requires further studies"......from jules: it is well considered that if a patient has cirrhosis & then achieves SVR they should receive followup forever every 6 months with an MRI

Clinical Infectious Diseases Advance Access published May 14, 2013

Soo Aleman,1,2 Nogol Rahbin,1 Ola Weiland,2 Loa Davidsdottir,1 Magnus Hedenstierna,2 Nina Rose,1 Hans Verbaan,4 Per Stal,1 Tony Carlsson,2 Hans Norrgren,5 Anders Ekbom,3 Fredrik Granath,3 and Rolf Hultcrantz1

Departments of 1Gastroenterology and Hepatology, 2Infectious Diseases, and 3Clinical Epidemiology, Karolinska Institutet/Karolinska University Hospital, Stockholm; and Departments of 4Medicine and 5Infectious Diseases, Skane University Hospital, Lund, Sweden

Abstract

Background. The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis is not fully known.

Methods. These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up.

Results. Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up.

Conclusions. The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

Hepatitis C virus (HCV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Patients with liver cirrhosis have a higher risk of developing HCC than patients with less advanced fibrosis [1]. Hence, in cirrhotic patients, surveillance for HCC every 6 months by ultrasound is recommended [2].

Since the introduction of standard-of-care therapy with pegylated interferon (peg-IFN) and ribavirin (RBV), the rate of sustained virologic response (SVR) increased compared to earlier treatments and has further improved with the use of first-generation protease inhibitors [3-7]. Studies analyzing the impact of SVR on the risk for developing HCC, liver complications, and liver-related death in cirrhotic patients have included small numbers of patients, and many have been retrospective in design [8-13]. Furthermore, many patients have been lost during follow-up and the follow-up time has often been short. Hence, the remaining long-term risk to develop late complications needs to be better defined in patients with HCV-associated liver cirrhosis after SVR. This will have an impact on the need for HCC surveillance after SVR has been achieved.

The aim of this study was to prospectively evaluate the long-term effect of antiviral therapy on the risk of developing HCC, liver complications, and liver-related death in a cohort of 351 HCV patients with liver cirrhosis. To minimize the loss of patients during follow-up, complementary data from the national registries were used.

PATIENTS AND METHODS

Patients

Members of the Swedish Hepatitis Group were invited to participate in this multicenter study on HCV patients with liver cirrhosis designed to evaluate the risk of developing HCC, liver-related complications, and death. Patients with a diagnosis of HCV-associated liver cirrhosis, without known HCC at the time of diagnosis, were included in the Registry of Hepatitis C Cirrhosis. Patients with a diagnosis of HCC within 6 months after diagnosis of cirrhosis and those with a liver transplant were excluded. In total, 506 patients were consecutively included in the cohort during January 2001-July 2009 from 6 university hospitals in Sweden, with participating departments of gastroenterology and hepatology and infectious diseases at Karolinska University Hospital, Malmo University Hospital, Lund University Hospital, Sahlgrenska University Hospital, and Uppsala University Hospital.

Questionnaires at the time of diagnosis of cirrhosis and at follow-up were collected. The medical history, physical examination, biochemical tests, and virologic data were stored in a central database at the Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm.

All patients were anti-HCV and HCV RNA positive. The cirrhosis diagnosis was based on liver biopsies from 1984 to 2009 (n = 364 [72%]) or a clinical evaluation including biochemical parameters, clinical signs of portal hypertension, and/or radiologic findings consistent with cirrhosis. One hundred eighty-three (38%) patients were diagnosed with cirrhosis prior to 2001.

In total, 351 patients were selected from the Registry of Hepatitis C Cirrhosis for this study. The inclusion criteria were Child-Pugh class A cirrhosis without prior decompensation, defined as a history of ascites, variceal bleeding, and hepatic encephalopathy, at inclusion and no other concomitant liver diseases. Patients who lacked a Child-Pugh classification at the time of inclusion (n = 6), had coinfection with hepatitis B (n = 6) or human immunodeficiency virus (n = 5), had hemochromatosis (n = 4) or autoimmune hepatitis (n = 5), or had a Child-Pugh classification of B (n = 81) or C (n = 26) were excluded, as were Child-Pugh class A patients who had a prior history of decompensation at inclusion (n = 22). The baseline characteristics of the 351 compensated Child-Pugh class A included patients are shown in Table 1. The regional ethics committees in all participating centers approved the study.

Treatment

In Sweden, combination therapy with peg-IFN and RBV was introduced in 2000-2001. Most of our patients treated during the follow-up period thus received peg-IFN alfa-2a or 2b plus RBV according to Swedish consensus [14]. One hundred twenty-three (35%) had previously received antiviral therapy, of whom 23 (7%) had achieved SVR before their inclusion in the study. Prior treatment experience could consist of only IFN injections 3 times per week (n = 35), IFN in combination with RBV (n = 57), or experience of both therapies (n = 31).

SVR was defined as undetectable HCV RNA at end of treatment and follow-up 6 months after treatment end. The clinical routine was to also test HCV RNA at 12-18 months after end of therapy. No patient was HCV RNA positive at this time point.

Among 351 patients in this cohort, 110 (31%) patients achieved SVR, 193 (55%) were treated but failed to achieve SVR ("non-SVR"), and 48 patients remained untreated.

Quantitative and qualitative HCV RNA tests were performed with commercial assays, available at the respective hospital. At Karolinska University Hospital, HCV RNA was assessed with the Amplicor HCV test (Roche Diagnostics, Mannheim, Germany, sensitivity of 50 IU/mL) before 2000; with the Quantiplex HCV-RNA 2.0 test (Bayer Diagnostics, Emeryville, California, lower limit 0.2 mEq/mL) from 2000 to 2001; with the Quantiplex HCV RNA version 3.0 between 2001 and 2006; and with the Roche Ampliprep/Cobas TaqMan test (detection limit 15 IU/mL) after 2006.

Diagnosis of HCC, Follow-up, and Endpoints of the Study

The diagnosis of HCC was confirmed on the basis of a verified focal liver lesion by imaging techniques in accordance with the American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines [2, 15].

The 351 patients were followed up with the start date set as the date of cirrhosis diagnosis, or at the start of this cohort on 1 January 2001, whichever occurred latest. Follow-time at risk was divided into 3 categories: non-SVR, SVR, and untreated person-time. The patients contributed to follow-up time in untreated until the first treatment. Depending on the treatment response, the patients were then contributing to either follow-up time in non-SVR or SVR person-time instead. Because patients could receive >1 treatment during the follow-up period, patients could contribute to different time categories.

The occurrence of death, liver transplant, or the end of the study period (31 July 2009) was set as the endpoint. Liver transplant was considered to be a liver-related death. All endpoint data were obtained from the detailed questionnaires and patient journals and supplemented with information from the registries, described below.

Twenty-four (7%) patients were no longer being followed up at the participating hospital at the end of the follow-up period. For these patients, complementary data on HCC, hospitalizations due to liver-related causes, or death, were retrieved from registries concerning follow-up information. Three (0.8%) patients had moved abroad during the follow-up period and were censored at their last clinical visit.

National Registries

All Swedish residents are assigned a 10-digit personal identification number that is used in all contacts with the healthcare system. To obtain complete information concerning patients no longer being followed up at participating hospitals, we sent the personal identification numbers of our patients to the National Board of Health and Welfare and received data about cancer, date, and cause of death and diagnosis at the time of hospitalization from the Cancer, Causes of Death, and National Patient (Inpatient Registry) Registries, respectively.

Reporting all newly diagnosed malignant tumors to the Cancer Registry is mandatory for both clinicians and pathologists, and >95% of all detected tumors have been reported [16]. The Swedish Registry of Causes of Death contains information on virtually all deceased persons in the country (≥99.5% since 1997), including the date and cause of death. The Swedish National Patient (Inpatient Registry) contains information about all residents who are hospitalized. The completeness of the registry since 1987 is estimated to be 98%-99%.

Statistical Analyses

Continuous variables are presented as mean (SD) or median (range) and categorical variables as frequencies (percentages). Student t test and χ2 test were used. The effect of age (50-59 vs <50 years or >60 vs <50 years), sex, alcohol consumption (<50 or >50 g/day), diabetes, and genotype (genotype 1 vs non-genotype 1) on incidence of HCC or any complication (HCC and liver complications) was tested by Cox regression.

The incidence of HCC, liver-related complications, and disease-free survival in relation to SVR status was estimated as the number of events occurring during non-SVR or untreated time, and SVR time divided by the corresponding person-time at risk in the groups. The effect of SVR was analyzed by Cox regression. The time scale used was calendar time since 1 January 2001 and SVR was considered as a time-dependent covariate. Models were also tested with adjustment for alcohol consumption, age, sex, and diabetes. Results are presented as hazard ratios (HRs) together with 95% confidence intervals, estimated using the profile likelihood method. Survival curves with respect to SVR status were estimated from the cumulative hazard functions for SVR, non-SVR, and untreated follow-up time obtained from the Cox regression models, and significant differences were assessed by testing HR = 1 using Wald tests. The effects of SVR were also analyzed comparing the risks <3 years and >3 years after SVR. All tests were 2-sided and a P value of <.05 was considered statistically significant. Data analysis was performed with SAS 9.2 software (SAS Institute, Cary, North Carolina).

RESULTS

A total of 351 patients with HCV-associated liver cirrhosis were enrolled and followed up for up to 8.6 years (mean, 5.3 [SD, 2.8] years), consisting of 110 patients with SVR and 193 patients with non-SVR and 48 untreated patients.

Incidence of HCC

Six (5%) of the 110 patients with SVR developed HCC during follow-up (after mean 5.4 [SD, 2.6] years of follow-up), corresponding to an incidence of 1.0 per 100 person-years (PY; Table 2). HCC was diagnosed in 2 patients within 1 year after SVR (0.5 and 7.7 months), and the other 4 at 2.4, 7.4, 7.4, and 7.6 years after achieving SVR. HCV RNA was tested at the diagnosis of HCC in 4 of these patients, and they were all negative. None had varices at the time of SVR or developed any other liver complications during follow-up. Among the 6 patients with HCC who had achieved SVR, 5 were male, 3 had diabetes mellitus, and 1 had history of alcohol abuse. Two patients had genotype 1a and 2 had non-genotype 1 (genotype 2 or 3a); the genotype was missing in the remaining 2 patients. One patient underwent liver transplant due to his HCC.

The incidence rate for HCC was significantly higher in non-SVR and untreated person-time with 2.3 and 4.0 per 100 PY, respectively (P = .04 and P = .03, respectively).

Only age and sex were found to be baseline factors significantly affecting the incidence of HCC (age 50-59 vs <50 years: HR, 2.45 [95% confidence interval {CI}, 1.16-5.61], P = .02; age >60 vs <50 years: HR, 3.32 [95% CI, 1.48-7.90], P = .004; male vs female: HR, 2.09 [95% CI, 1.06-4.62], P = .047). For any complication (HCC and liver complication), none of the tested baseline factors were found to significantly affecting the outcome.

Liver-Related Complications

In patients with SVR, 4 (3.6%) developed ascites, 1 (0.9%) hepatic encephalopathy, and none variceal bleeding during follow-up. Ascites was diagnosed 2, 13, 13, and 48 months after SVR had been achieved. None of these patients developed HCC, 3 were males, and none had excessive alcohol consumption or had diabetes mellitus. Two, however, had esophageal varices at the time of inclusion. One patient developed liver encephalopathy 4.1 years after SVR had been achieved.

The risk of developing any liver-related complication was significantly lower in SVR than non-SVR person-time (P = .002) and highest in untreated person-time (P = .04).

The Figure 1 shows the cumulative risk of any complication (HCC and any liver complication). The incidence rate for SVR, non-SVR, and untreated person-time was 1.9, 5.1, and 7.5 per 100 PY, respectively. The risk for any liver complication was significantly lower in SVR person-time and higher in untreated person-time, compared to the risk in non-SVR person-time (P < .0001 and P = .04, respectively).

Liver-Related and Overall Deaths

Eleven (10%) patients with SVR died during follow-up, 4 (3.6%) of liver-related causes with HCC. The causes of death for the other 7 patients were lung cancer (n = 1), pulmonary embolism (n = 1), pneumonia (n = 1), pancreatitis (n = 1), pancreatic cancer (n = 2) and, in 1, unknown. One (0.9%) patient underwent liver transplant due to HCC. Fifty-two (22%) of 241 patients lacking SVR (non-SVR and untreated) died of liver-related causes and 15 (6%) patients of other causes. Liver transplant was performed in 23 patients (10%).

The incidence rate for liver-related death was 0.7 per 100 PY in SVR patients (Table 2), which was significantly lower compared to non-SVR (3.0 per 100 PY; P = .001) or untreated (4.5 per 100 PY; P = .02) patients.

Significantly lower incidence rate for overall death was seen in SVR with 1.9 per 100 PY, compared to 4.1 per 100 PY in non-SVR person-time (P = .003). Thirty-six percent of overall deaths were due to liver-related causes in patients with SVR, whereas the majority of overall deaths (78%) consisted of liver-related causes in patients with non-SVR.

The risks for HCC, any complication, liver-related death, overall death, or any of the mentioned events were analyzed <3 years and compared to those occurring >3 years after SVR had been achieved. The cutoff time point of 3 years was chosen due to the fact that this time point made the distribution of any events similar in the 2 time periods. None of the events were significantly reduced after 3 years of SVR. A trend was noted for a decreased risk of any event, but was not statistically significant (P = .05).

The difference of risk between SVR and non-SVR/untreated person-time in outcomes remained similar when adjusted for alcohol consumption, age, sex, and diabetes mellitus (data not shown).

DISCUSSION

In this study, a total of 351 HCV-infected patients with compensated Child-Pugh class A liver cirrhosis were followed during long-term. This made it possible to evaluate the impact that SVR had on the risk to develop HCC, liver-related complications, and death. This prospectively followed cohort is to our knowledge the largest of cirrhotic HCV-infected patients with or without SVR so far studied. We found that SVR reduced the incidence of these outcomes but that the risk to develop HCC remained during prolonged time after SVR had been achieved, but on a lower level. This highlights the fact that surveillance for HCC needs to be continued during long-term, also in patients who achieve SVR. This is further strengthened by the fact that all patients who died from liver-related causes after having achieved SVR had developed HCC. On the other hand, surveillance with ultrasound is thought to be costly for society and time consuming for the individual. The duration needed for long-term surveillance for HCC after SVR requires further studies.

SVR in cirrhotic patients has generally been 10%-15% lower than in noncirrhotic patients in the pivotal clinical trials and even lower in an everyday clinical setting [17]. Pivotal treatment studies with peg-IFN in combination with RBV have often included patients with advanced fibrosis (F3) and analyzed them together with cirrhotic patients (F4). The risk of liver complications and HCC may differ in these 2 groups, and cirrhotic patients more often fail to achieve SVR than F3 patients [18]. Previous studies on the impact of SVR have often suffered from a retrospective design, included relatively few cirrhotic patients with SVR and suffered from short follow-up periods and/or significant loss of patients during follow-up [8-10, 12, 13]. The effect that SVR has on HCC has therefore yielded diverging results on the reduction of the risk of developing HCC [4-8, 15]. Two studies have shown no significant reduction to develop HCC after SVR [7, 8]. In one prospective study, including both F3 and F4 patients with a mean follow-up time of 3.5 years, the HCC incidence was significantly higher in patients lacking SVR (5.9/100 PY) than in patients with SVR (1.2/100 PY) [12]. We found that the risk of HCC was 1.0 per 100 PY in SVR patients. The risk for HCC was higher in untreated compared to non-SVR time, indicating a beneficial effect despite lack of SVR.

The time point when a new HCC was detected was within 1 year after SVR in 2 of 6 patients, possibly implicating that the cancer was already present but undetected before SVR was reached. In 3 patients, the HCC was detected late, 7 years after SVR. Hence, the risk of developing HCC can persist long-term after SVR. When analyzing the risk for HCC over time after SVR, the risk for HCC was numerically lower >3 years after SVR compared to <3 years after SVR was achieved. This difference, however, was not statistically significant. The lack of significance could have been caused by the low number of events after achievement of SVR, rendering this analysis a low statistical power.

A significantly lower incidence of liver-related complications and liver-related deaths after SVR has been noted in several studies [8-10, 12, 18-21], similar to our study. In meta-analyses with pooled data from both Asian and Western European studies, a reduced risk of HCC, liver-related morbidity, and mortality has been seen in patients with SVR [22, 23]. The risk for overall death was also significantly reduced in patients with SVR in our study, with the majority of deaths non-liver related.

In our study, no patient who achieved SVR developed variceal bleeding. This is in accordance with a prospective study including 34 cirrhotic patients with SVR followed over 12 years, in which none developed de novo esophageal varices during follow-up [11]. Endoscopic surveillance in cirrhotic patients who have achieved SVR is probably not necessary.

A common problem in follow-up studies is the frequent loss of patients during follow-up [12, 18]. In the present study, dropouts were very few (0.8%). This was achieved by using the Swedish registries to clarify the outcome in patients lost from the routine follow-up.

In this study, we do not have sequential measurement of liver fibrosis after achievement of SVR. The importance of fibrosis regression with vanishing cirrhosis seen in the HCV-related cirrhosis after SVR noted in earlier studies could thus not be assessed in our study [24], and the correlation between remaining fibrosis and long-term risk for HCC could not be analyzed.

To conclude, we found a reduced but persistent long-term risk of developing HCC after achievement of SVR in patients with HCV-related cirrhosis. This risk persisted at least 8 years after SVR had been achieved in some patients. This indicates that continued surveillance for HCC should be maintained during prolonged time periods.

Source

Provided by NATAP

Clinical Infectious Diseases Advance Access published May 14, 2013

Oscar Cruz Pereira and Jordan J. Feld
Toronto Western Hospital, University Health Network, Sandra Rotman Centre for Global Health, University of Toronto, Ontario, Canada

"Multiple studies have shown that fibrosis, and even cirrhosis, may regress after SVR. Perhaps an assessment of fibrosis after SVR would allow for better risk stratification....larger studies similar to this effort will be useful to identify high-risk patients who require ongoing HCC screening"

"Although this study focused on the risk of HCC, Hultcrantz et al also found that SVR reduced liver-related complications, liver-related mortality, and all-cause mortality. Combining these data with those from the study by van der Meer et al, as well as other published series, there is now solid evidence that SVR changes the natural history of the disease. SVR can no longer be considered a surrogate endpoint as it truly does indicate a very good long-term prognosis. However, as Hultcrantz and colleagues point out, SVR indicates viral eradication but is not a cure of liver disease. At least for now, even if they achieve SVR, patients with cirrhosis need to keep on screening"

"Hultcrantz and colleagues found that patients who were treated but did not achieve SVR had better outcomes than patients who received no treatment, again raising the question of whether unsuccessful treatment is better than no treatment. Although the rate of HCC was much higher in the untreated population than in those who were treated but did not achieve SVR, it is important to note that this was not a randomized study. Treatment was offered at the discretion of the treating physicians. It is likely that untreated patients had more advanced disease or other comorbidities that influenced both their risk of HCC and the decision to withhold therapy. Notably, they were older and a higher percentage was male and had diabetes, all risk factors for HCC development. Multiple studies have addressed the question of long-term suppressive therapy with discouraging results. Although the HALT-C trial did show a lower incidence of HCC in patients randomized to long-term low-dose peginterferon, the difference only emerged after 5-7 years of follow-up [11]. Given the rapid improvements in HCV therapy, long-term suppressive therapy with interferon to prevent HCC is not a realistic strategy."

Liver cancer is the second most common cause of cancer death worldwide, and the sixth most common in developed countries [1]. Depending on the prevalence of hepatitis C in a region, it can account for 13%-66% of cases of hepatocellular carcinoma (HCC) [2]. HCC occurs almost exclusively in patients with cirrhosis [3]; however, other factors such as the etiology of cirrhosis also play a role. For instance, the risk of HCC in patients with cirrhosis and chronic hepatitis B is 3%-8% per year, but in autoimmune hepatitis the risk is only 1.1% per year or lower [3, 4]. Thus, one would expect that curing hepatitis C might modify the risk of developing HCC.

In this issue of Clinical Infectious Diseases, Hultcrantz and colleagues report on the long-term follow-up of 351 Swedish patients with hepatitis C virus (HCV)-related Child-Pugh class A cirrhosis. All but 48 patients received interferon-based therapy, of whom 110 successfully achieved sustained virologic response (SVR) and were compared to the 193 who did not clear the virus. The authors were able to prospectively collect data during an 8-year study period, even for the 7% who were lost to clinical follow-up. This was thanks to the national registries in Sweden that capture >95% of all cases of cancer and record the cause of >99.5% of all deaths. The incidence of HCC was significantly reduced in patients who achieved SVR (1.0 per 100 person-years [PY]) compared to those who failed treatment (2.3 per 100 PY) or those who were never treated (4.0 per 100 PY). In addition, they found that patients who achieved SVR had fewer liver-related complications, liver-related deaths, and overall deaths (0.9, 0.7, and 1.9 per 100 PY, respectively) than non-SVR (3.2, 3.0, and 4.1 per 100 PY, respectively) or untreated patients (4.9, 4.5, and 5.1 per 100 PY, respectively). They were unable to identify any clear risk factors for the development of HCC or other complications after SVR. Notably, the incidence of HCC was similar in the first 3 years and the subsequent 3 years after viral clearance.

These important data add to the accumulating evidence regarding the significance of SVR. Recently, van der Meer and colleagues reported the results of an international, multicenter, long-term follow-up study of 530 patients with chronic hepatitis C and advanced fibrosis treated with interferon-based regimens [5]. During a median follow-up of 8.4 years, patients who achieved SVR had a lower incidence of HCC (0.55 vs 1.01 per 100 PY), liver failure (0.31 vs 3.62 per 100 PY), liver-related mortality (0.23 vs 3.20 per 100 PY) and, most importantly, all-cause mortality (1.01 vs 2.93 per 100 PY) than patients who did not achieve SVR [5]. The van der Meer study also included patients with only bridging fibrosis. Both studies found that patients who achieved SVR had better outcomes, but they both clearly documented that some patients were still at risk of developing HCC, with an incidence of approximately 0.5%-1% per year.

This raises a challenging issue for clinicians. These findings suggest that we may still need to screen for HCC in patients with cirrhosis even after achieving SVR. However, the reported rates are below the threshold of 1.5% per year for screening to be cost effective [6]. The current American Association for the Study of Liver Diseases (AASLD) guidelines recommend screening all patients with cirrhosis [3] based on a randomized controlled trial showing that surveillance reduced mortality by 37% in Chinese patients with cirrhosis due to hepatitis B [7], and a cost-benefit analysis showing that ultrasound was cost-effective in a mixed population of patients with cirrhosis [8]. Notably, however, although the HALT-C (Hepatitis C Antiviral Long-term Treatment Against Cirrhosis) trial showed that patients with bridging fibrosis had a 0.82% per year risk of developing HCC [9], the AASLD guidelines do not recommend screening such patients because the incidence is below the threshold of 1.5% per year [3]. Thus, although SVR did not eliminate the increased risk of HCC, it may have reduced it to a level at which routine screening of every individual may not be cost effective.

Multiple studies have shown that fibrosis, and even cirrhosis, may regress after SVR. Perhaps an assessment of fibrosis after SVR would allow for better risk stratification. Unfortunately, in the Hultcrantz et al study, fibrosis was not assessed after achieving SVR. However, in a recent long-term follow-up study from the clinical center at the National Institutes of Health, investigators estimated liver fibrosis using transient elastography (TE) in 69 patients who had achieved SVR between 1986 and 2003 [10] and were followed for a mean of 7.5 years. Of those with cirrhosis on biopsy prior to treatment, 14% had TE scores of <7.0 kPa (no significant fibrosis) in their most recent follow-up visit, suggesting that they had significant regression of fibrosis. Notably, a small number of patients (2%) appeared to have progressive disease, with mild fibrosis before treatment and high TE scores (>13.8 kPa) at last follow-up [10]. Although these patients likely had another cause for disease progression, this highlights that fibrosis improvement is not universal. Interestingly, although the distribution of fibrosis scores did not appreciably change after SVR, almost all patients had improvement in parameters of liver synthetic function and portal hypertension, such as bilirubin level and platelet count [10]. The event rate was too low (1 HCC) to determine if fibrosis regression by TE or other parameters would be helpful for risk stratification, but larger studies similar to this effort will be useful to identify high-risk patients who require ongoing HCC screening. This will likely require a collaborative effort from multiple centers to accumulate enough patients who develop HCC after SVR to identify factors and allow for risk stratification. In addition to the degree of regression of fibrosis, factors to look at may include degree of steatosis, comorbidities, and patient demographics as well as time since SVR, even though this did not appear helpful in the Hultcrantz study.

Hultcrantz and colleagues found that patients who were treated but did not achieve SVR had better outcomes than patients who received no treatment, again raising the question of whether unsuccessful treatment is better than no treatment. Although the rate of HCC was much higher in the untreated population than in those who were treated but did not achieve SVR, it is important to note that this was not a randomized study. Treatment was offered at the discretion of the treating physicians. It is likely that untreated patients had more advanced disease or other comorbidities that influenced both their risk of HCC and the decision to withhold therapy. Notably, they were older and a higher percentage was male and had diabetes, all risk factors for HCC development. Multiple studies have addressed the question of long-term suppressive therapy with discouraging results. Although the HALT-C trial did show a lower incidence of HCC in patients randomized to long-term low-dose peginterferon, the difference only emerged after 5-7 years of follow-up [11]. Given the rapid improvements in HCV therapy, long-term suppressive therapy with interferon to prevent HCC is not a realistic strategy.

Although this study focused on the risk of HCC, Hultcrantz et al also found that SVR reduced liver-related complications, liver-related mortality, and all-cause mortality. Combining these data with those from the study by van der Meer et al, as well as other published series, there is now solid evidence that SVR changes the natural history of the disease. SVR can no longer be considered a surrogate endpoint as it truly does indicate a very good long-term prognosis. However, as Hultcrantz and colleagues point out, SVR indicates viral eradication but is not a cure of liver disease. At least for now, even if they achieve SVR, patients with cirrhosis need to keep on screening.

Source

Sofosbuvir and ABT-450: Terminator of hepatitis C virus?

World J Gastroenterol. 2013 June 7; 19(21): 3199-3206.

Published online 2013 June 7. doi: 10.3748/wjg.v19.i21.3199.

©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Qing-Lei Zeng, Ji-Yuan Zhang, Zheng Zhang, Li-Feng Wang and Fu-Sheng Wang.

Qing-Lei Zeng, Fu-Sheng Wang, The Institute of Translational Hepatology, Beijing 302 Hospital, Peking University, Beijing 100039, China

Ji-Yuan Zhang, Zheng Zhang, Li-Feng Wang, Research Center for Biological Therapy, Beijing 302 Hospital, Beijing 100039, China

Author contributions: Zeng QL and Zhang JY contributed equally to this work; Zeng QL and Zhang JY contributed to the study idea, study design, literature search, manuscript writing and final revision of the article; Zhang Z and Wang LF contributed to the manuscript writing and the final revision of the article; Wang FS contributed to the study design, manuscript writing and the final revision of the article.

Correspondence to: Fu-Sheng Wang, MD, PhD, The Institute of Translational Hepatology, Beijing 302 Hospital, Peking University, 100 Xisihuan Middle Road, Beijing 100039, China. fswang302@163.com

Telephone: +86-10-66933332 Fax: +86-10-66933332

Received February 20, 2013; Revised March 31, 2013; Accepted April 17, 2013;

Abstract

Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.

Keywords: Sofosbuvir, ABT-450, Hepatitis C virus, Antiviral therapy, Sustained virologic response

Core tip: We are entering an era in which the development of antiviral agents and successful treatment of chronic hepatitis C is rapidly escalating. In this review, we have summarized the history of anti-hepatitis C virus (HCV) agents from interferon-α (IFN-α) to the latest sofosbuvir- and ABT-450-based therapies. Although a new generation of direct acting anti-HCV agents has largely improved the sustained virologic response rates of patients, many unmet needs and questions remain, such as IFN-free regimens for difficult to treat patients, avoidance of cross-resistance, the role of interleukin-28B status as well as the management of some advanced and co-infected patients.

INTRODUCTION

Chronic hepatitis C virus (HCV) infection is currently a major global health problem that affects 160 million people worldwide and is one of the main causes of chronic liver cirrhosis and hepatocellular carcinoma[1,2]. Compared with the former standard of care (SOC), the current SOC, consisting of peginterferon (pegIFN)-α and ribavirin (RBV) plus telaprevir or boceprevir, achieves higher rates of sustained virologic response (SVR), which is defined as undetectable HCV RNA in the serum for 24 wk after the end of treatment. SVR is associated with a better outcome for chronic hepatitis C (CHC) patients[3,4]. However, not all patients can achieve SVR[5,6]. In addition, triple therapy has many side effects and contraindications that result in a number of eligible patients refusing therapy[7,8].

Based on these complications, pegIFN-α-free regimens could be an alternative for some patients. Several pegIFN-α-free regimens containing sofosbuvir and ABT-450 have shown high SVR rates with only 12 wk of treatment and mild adverse events. These regimens have the potential to be the newest SOC for CHC in the near future. Here, we summarize the clinical development history of anti-HCV agents as well as recent studies of the efficacy and adverse event profile of sofosbuvir and ABT-450 regimens. We also discuss the future focus for HCV studies.

BRIEF DEVELOPMENT HISTORY OF ANTI-HCV AGENTS

IFN era

Anti-HCV therapy is the backbone for the treatment of CHC. Since the late 1980s, IFN-α has gradually become the core of antiviral treatment[9-13]. However, IFN-α monotherapy achieved suboptimal efficacy until combined with RBV[14-22] (Figure 1). PegIFN-α has a higher plasma concentration and half-life than interferon, which results in an improved SVR rate as well as improved patient compliance as the pegylated form can be injected once weekly[23-25]. Higher SVR rates were achieved with combination therapy of pegIFN plus RBV than with pegIFN monotherapy, which has become the SOC during the past decade[26,27]. Meanwhile, the true meaning of SVR was unclear until a large cohort study demonstrated that patients who achieved SVR could be considered cured[28]. Unfortunately, not all patients, especially those infected with genotype 1 and 4 HCV could achieve SVR with the SOC. Furthermore, side effects, long-term treatment, contraindications and poor compliance all spurred the development of new agents with shorter treatment durations, fewer contraindications, oral administration, higher specificity, and fewer side effects.

WJG-19-3199-g001

Figure 1 Brief development history of the anti-hepatitis C virus agents. HCV: Hepatitis C virus; IFN-α: Interferon-α; SVR: Sustained virologic response; pegIFN-α: Peginterferon-α.

Era of direct acting antiviral agents

HCV is classified in the genus hepacivirus of the family flaviviridae. Once the virus is released into the cell, the viral polyprotein is translated and cleaved by host proteases and the viral NS3-4A protease into ten mature proteins. Next, viral RNA is replicated into progeny RNA by the viral NS5B polymerase. Another viral protein, HCV NS5A, is indispensable for viral replication and assembly and could be a nonenzymatic target for therapeutics. With the structures of NS3/4A protease and NS5B polymerase solved and the rapid development of different cell culture models and biotechnology[29], HCV research has been flourishing both on the bench and in industry. In particular, intensive efforts have focused on developing direct acting antiviral agents (DAAs) that can block the activity of viral enzymes.

The serine protease inhibitors telaprevir and boceprevir, approved by the United States Food and Drug Administration in 2011, were the first and currently only DAA to make it to the clinic. Telaprevir is a linear peptidomimetic HCV NS3/4A serine protease inhibitor, and boceprevir is a protease inhibitor that binds to the HCV NS3 active site. Treatment regimens consisting of telaprevir or boceprevir plus pegIFN-α and RBV had significantly higher SVR rates in genotype 1 patients and became the SOC thereafter[30-34]. However, this new SOC has more adverse events and a similar treatment duration when compared with the former SOC[35], and monotherapy with telaprevir or boceprevir was shown to be impractical due to the rapid selection of resistant variants. In 2012, preliminary clinical data showed that combination therapy with the NS5A replication complex inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir could also achieve high efficacy rates after 24 wk of treatment[36], especially in prior null responders. These results showed the potential of a pegIFN-free regimen for 24 wk treatment duration. However, some patients in this study experienced viral breakthrough due to resistant variants, which ultimately resulted in treatment failure.

In January 2013, Gane et al[37] and Poordad et al[38] published clinical data on the efficacy of sofosbuvir- (also known as GS-7977) and ABT-450-based oral treatment regimens for 12 wk treatment duration. The results showed that 100% of genotype 2/3 patients and 93%-95% of genotype 1 patients achieved SVR. The sofosbuvir and ABT-450 studies were open-label clinical studies that assessed various combination and dosages of agents in previously treated and previously untreated patients. Sofosbuvir exhibits a higher barrier to resistance than ABT-450 because its target, the NS5B polymerase is highly conserved, and viral fitness is crippled if variants occur in the polymerase active site. Sofosbuvir also exhibits pan-genotypic antiviral activity compared to genotype-specific agents, such as ABT-450, asunaprevir, telaprevir and boceprevir. Although some mild adverse events were observed, these studies validated the feasibility of achieving extremely high SVR rates with a pegIFN-free regimen and a short treatment duration of 12 wk.

General characteristics of representative DAAs

We summarize representative DAAs from 2011 to January 2013 in Table 1. There have been several treatment evolutions during this timeframe. First, most of these agents were designed for genotype 1 patients, with genotypes 2 and 3 only being considered recently. Second, the treatment period has gradually decreased to 12 wk. Third, dosing frequency has generally improved from three times daily to once daily, which will undoubtedly contribute to better patient compliance. Fourth, combination therapy has gradually shifted away from exclusive combinations with pegIFN-α to trials with and without pegIFN-α to finally pegIFN-α-free regimens. Finally, we found that at least two representative agents were developed from bench to bedside every year. Compared with other DAAs, the sofosbuvir and ABT-450 regimens not only achieve extremely high SVR rates with 12 wk of treatment in treatment-naive patients but are also efficacious in genotype 2 and 3 patients without the need for pegIFN-α.

Table 1
Representative direct acting antiviral agent from 2011 to January, 2013
DAA HCV genotype Course of DAA (wk) Course of therapy (wk) Dose With or without pegIFN-α Published year Ref.
Telaprevir 1a/1b/1c/unknown 12/8 20/24/44/48 750 mg (tid) With 2011 [30-32]
Boceprevir 1a/1b/unknown 24/32/44 28/36/48 800 mg (tid) With 2011 [33-34]
Daclatasvir 1a/1b 24 24 60 mg (qd) With or without 2012 [36]
Asunaprevir 1a/1b 24 24 600 mg (bid) With or without 2012 [36]
Sofosbuvir 1/2/3 8/12 8/12 400 mg (qd) Without 2013 [37]
ABT-450 1a/1b 12 12 250/150 mg (qd) Without 2013 [38]
qd: Once daily; bid: Twice daily; tid: Thrice daily; DAA: Direct acting antiviral agent; HCV: Hepatitis C virus; pegIFN-α: Peginterferon-α.
World J Gastroenterol. 2013 June 7; 19(21): 3199–3206.
Published online 2013 June 7. doi: 10.3748/wjg.v19.i21.3199.

CLINICAL EFFICACY OF SOFOSBUVIR AND ABT-450

Sofosbuvir is a direct acting nucleotide polymerase inhibitor[39], and ABT-450 is a potent macrocyclic HCV NS3 protease inhibitor. Both have been developed as oral therapies for the treatment of chronic HCV infection. Phosphorylated nucleotide analogues, such as sofosbuvir, are converted within the host hepatocyte to the active nucleoside triphosphate, which competes with natural nucleotides, thereby terminating RNA replication in the nascent viral genome. Sofosbuvir acts as a nonobligate chain terminator, targeting the highly conserved active site of the HCV-specific NS5B polymerase[38]. The mechanism of action of NS3 protease inhibitors has been thoroughly reviewed elsewhere[35]. As a potent inhibitor of CYP3A4 (the primary enzyme involved in first-pass metabolism of most protease inhibitors), ritonavir can increase the plasma concentration and half-life of ABT-450, decrease the emergence of resistance mutations in the NS3 gene, and permit once-daily dosing of ABT-450[38,40,41].

Clinical efficacy of sofosbuvir-based therapy

Gane et al[37] published an open-label clinical trial of 95 previously untreated HCV genotype 1/2/3 patients and genotype 1 null responders (Table 2). The patients were divided into 8 groups: sofosbuvir monotherapy and sofosbuvir plus RBV therapy with or without pegIFN-α for 8 or 12 wk. The results showed that 100% of previously untreated genotype 2/3 patients achieved SVR based on sofosbuvir plus RBV. For previously untreated genotype 1 patients, the SVR rate was 84%. Unfortunately, the SVR rate was only 10% for genotype 1 patients who had no response to previous therapy. These results indicate that genotype 2/3 untreated patients can be completely cured with 12 wk of sofosbuvir plus RBV therapy alone.

Table 2

Overview of 95 hepatitis C patients under sofosbuvir regimen
Group n Genotype (n) Status before treatment Therapeutic schedule SVR rate
1 10 2/3 (4/6) Untreated Sofosbuvir + RBV 12 wk 100%
2 9 2/3 (3/6) Untreated (Sofosbuvir + RBV 12 wk) + pegIFNα-2a 4 wk 100%
3 10 2/3 (4/6) Untreated (Sofosbuvir + RBV 12 wk) + pegIFNα-2a 8 wk 100%
4 11 2/3 (4/7) Untreated Sofosbuvir + RBV + pegIFNα-2a 12 wk 100%
5 10 2/3 (3/7) Untreated Sofosbuvir 12 wk 60%
6 10 2/3 (0/10) Untreated Sofosbuvir + RBV + pegIFNα-2a 8 wk 100%
7 10 1a/1b (9/1) No response to prior therapy Sofosbuvir + RBV 12 wk 10%
8 25 1a/1b (22/3) Untreated Sofosbuvir + RBV 12 wk 84%
The dose of sofosbuvir is 400 mg (qd), peginterferon-α (pegIFN-α)-2a is 180 μg (qw), ribavirin (RBV) is 500 mg (bid) for patients with body weight < 75 kg, and RBV is 600 mg (bid) for patients with body weight > 75 kg. qd: Once daily; bid: Twice daily; qw: Once weekly; SVR: Sustained virologic response.

World J Gastroenterol. 2013 June 7; 19(21): 3199–3206.
Published online 2013 June 7. doi: 10.3748/wjg.v19.i21.3199.

Clinical efficacy of ABT-450-based therapy

Poordad et al[38] published an open-label, phase 2a clinical trial of 50 genotype 1 patients, including untreated patients and patients with no or partial response to prior therapy (Table 3). The patients were divided into 3 groups. Patients received a combination of ABT-333 (a nonnucleoside NS5B polymerase inhibitor), RBV and ritonavir plus two different dosages of ABT-450 for 12 wk. The results showed that 93% and 95% of previously untreated genotype 1 patients achieved SVR. Furthermore, 47% prior null and partial responders achieved SVR. These results indicate that almost all untreated patients with genotype 1 can achieve SVR with ABT-450-based regimens, and null and partial responders can achieve higher SVR rates than previously possible.

Table 3

Overview of 50 hepatitis C patients under ABT-450 regimen
Group n Genotype (n) Status before treatment Therapeutic schedule Usage SVR rate2
1 19 1a/1b (17/2) Untreated ABT-450 + ritonavir + ABT-333 + RBV 12 wk ABT-450, 250 mg (qd) 95%
Ritonavir, 100 mg (qd)
ABT-333, 400 mg (bid)
RBV, 1000 or 1200 mg/d1
2 14 1a/1b (11/3) Untreated ABT-450 + ritonavir + ABT-333 + RBV 12 wk ABT-450, 150 mg (qd) 93%
Ritonavir + ABT-333 + RBV Ditto
3 17 1a/1b (16/1) No or partial response to prior therapy ABT-450 + ritonavir + ABT-333 + RBV 12 wk ABT-450, 150 mg (qd) 47%
Ritonavir + ABT-333 + RBV Ditto
1Body weight < 75 kg, 1000 mg/d, divided into doses of 400 and 600 mg, bid; Body weight ≥ 75 kg, 1200 mg/d, 600 mg, bid;
2Sustained virologic response (SVR) in this study was defined as an

World J Gastroenterol. 2013 June 7; 19(21): 3199–3206.
Published online 2013 June 7. doi: 10.3748/wjg.v19.i21.3199.

ADVERSE EVENTS OF SOFOSBUVIR AND ABT-450 REGIMENS

Both sofosbuvir and ABT-450 regimens have various adverse events (Table 4). The most frequent adverse events observed with sofosbuvir-based therapies were headache, fatigue, insomnia, nausea, rash, and anemia[37,42]. For ABT-450-based therapies, the most frequent adverse events were fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting. Some laboratory abnormalities were also observed during the treatment period, including anemia for sofosbuvir-based treatment and hyperbilirubinemia for ABT-450-based therapy. Some laboratory abnormalities were more common among patients receiving pegIFNα-2a. Most adverse events and abnormalities were mild, and none led to treatment interruption.

Table 4

Major adverse events during sofosbuvir and ABT-450 regimens
Adverse events Sofosbuvir regimen ABT-450 regimen1
Headache 32%-90% 14%-26%
Fatigue 10%-70% 35%-47%
Insomnia 10%-67% 0%-26%
Nausea 0%-44% 21%-24%
Rash 10%-60% 6%-21%
Anemia 0%-44% No data
Dizziness 4%-44% 5%-29%
Myalgia 0%-40% No data
Diarrhea 0%-30% No data
Vomiting No data 0%-21%
Irritability 0%-36% No data
Pruritus 0%-33% 0%-21%
Decreased appetite 0%-50% No data
Upper respiratory tract infection 0%-20% No data
Arthralgia 0%-30% No data
Back pain 0%-22% No data
Pyrexia 0%-18% No data
1Adverse events during ABT-450 regimen were only listed those that occurred in more than 20% of patients.

World J Gastroenterol. 2013 June 7; 19(21): 3199–3206.
Published online 2013 June 7. doi: 10.3748/wjg.v19.i21.3199.

INTERLEUKIN-28B POLYMORPHISM IN THE SOFOSBUVIR AND ABT-450 ERA

Genome-wide association studies have demonstrated that single nucleotide polymorphisms near the interleukin-28B (IL-28B) gene that encodes IFN-λ3 are closely associated with spontaneous and treatment-induced HCV clearance[43-46]. The rs12979860 CC genotype is associated with a two-fold greater SVR rate than the TT genotype in European-American individuals. Similar ratios have been observed in both African-American and Hispanic populations of genotype 1 chronic hepatitis C patients. The presence of the C-allele is always accompanied by higher SVR rates, indicating that this allele may favor the clearance of HCV. In studies of sofosbuvir and ABT-450, five groups achieved SVR rates of 100%, independent of IL-28B status (Table 5). Therefore, lower SVR rates may not be primarily due to IL-28B genotypes. Instead, these patients may have acquired resistant variants during treatment. However, it should be noted that the sample size of these studies too small to reach a definitive conclusion on the role of IL-28B. Whether IL-28B genotype will be a predictive marker for treatment response with the new drug regimens requires further investigation with large sample sizes.

Table 5

Interleukin-28B polymorphism in sofosbuvir and ABT-450 era
Group Status before treatment IL-28B CC (n) IL-28B CT (n) IL-28B TT (n) SVR rate
Sofosbuvir
1 Untreated 5 4 1 100%
2 Untreated 4 4 1 100%
3 Untreated 4 4 2 100%
4 Untreated 4 5 2 100%
5 Untreated 2 6 2 60%
6 Untreated 3 6 1 100%
7 No response to prior therapy 2 5 3 10%
8 Untreated 11 12 2 84%
ABT-450
1 Untreated 10/9 7/7 2/2 95%
2 Untreated 5/4 7/7 2/2 93%
3 No or partial response to prior therapy 0/0 12/6 5/2 47%
IL-28B: Interleukin-28B; SVR: Sustained virologic response.

World J Gastroenterol. 2013 June 7; 19(21): 3199–3206.
Published online 2013 June 7. doi: 10.3748/wjg.v19.i21.3199.

PERSPECTIVES

Genotype 1 patients with no or partial response to prior therapy will be the focus of future studies

Currently, the highest SVR rate observed in genotype 1 patients who have no response to prior therapy is 90%, which was achieved with daclatasvir and asunaprevir-based therapy (Table 6). SVR rates in this patient population treated with telaprevir and boceprevir regimens were only 33% and 52%, respectively, which was significantly inferior to the rates in treatment-naive patients. Sofosbuvir plus RBV has achieved an excellent SVR rate in untreated genotype 1 patients compared with genotype 1 patients who had no response to previous treatment. While the ABT-450 regimen achieved high efficacy in genotype 1 patients with no or partial response to prior treatment, the SVR rate was still less than 50%. All of the above-mentioned results suggest that genotype 1 patients with no or partial response should be the focus of further investigation. Furthermore, genotype 1a patients have more opportunities to develop resistance to the DAAs combination from Poordad et al[38]. Genotype 1a accounts for 89%, 8 out of 9 patients with virologic failure in group 3 who have been analyzed for the presence of resistance-associated variants. The genetic barrier to resistance of protease inhibitors is relatively lower for subtype 1a because this subtype only requires one nucleotide substitution to generate resistance, whereas the 1b virus requires two. Accordingly, genotype 1a patients may be more difficult to treat in new DAAs era.

Table 6

Outcome of representative direct acting antiviral agent-based therapy for genotype 1 null responders
Authors n Therapeutic schedule SVR rate
Zeuzem et al[32] 37 (pegIFN-α2a + RBV) 4 wk + (pegIFN-α2a + RBV + telaprevir) 12 wk + (pegIFN-α2a + RBV) 32 wk 33%
Bacon et al[33] 58 (pegIFN-α2b + RBV) 4 wk + (pegIFN-α2b + RBV + boceprevir) 44 wk 52%
Lok et al[36] 11 Daclatasvir + asunaprevir 24 wk 36%
Lok et al[36] 10 Daclatasvir + asunaprevir + pegIFN-α2a + RBV 24 wk 90%
Gane et al[37] 10 Sofosbuvir + RBV 12 wk 10%
Poordad et al[38] 7 ABT-450 + ritonavir + ABT-333 + RBV 12wk 43%
pegIFN-α: Peginterferon-α; SVR: Sustained virologic response; RBV: Ribavirin.

World J Gastroenterol. 2013 June 7; 19(21): 3199–3206.
Published online 2013 June 7. doi: 10.3748/wjg.v19.i21.3199.

DAA combinations with less cross-resistance may be the solution for genotype 1 patients with no or partial response to prior therapy

Although it has not been investigated in a head-to-head study, genotype 1 patients with no or partial response to prior therapy have different SVR rates (10% vs 90%) with different DAA combinations (Table 6)[37,38], indicating that different DAA combinations might be important to successfully treating these types of patients. Various combinations of DAAs are now under investigation[47,48]. However, why a particular combination may lead to an improved SVR rate in these patients remains unclear. It is possible that adding another DAA could complement the mechanisms of action of other agents in the regimen as well as decrease the appearance of cross-resistant variants. As Table 6 shows, 90% of genotype 1 patients with no response to prior therapy can achieve SVR[33], suggesting that a potent DAA combined with pegIFN-α and RBV may be one choice for those patients who can endure the adverse events and long period of treatment.

Combinations with less cross-resistance are the goal for the future

Various DAA combinations have now been investigated, such as asunaprevir plus daclatasvir; sofosbuvir plus RBV; sofosbuvir plus daclatasvir; faldaprevir plus BI207127; ABT-450/ritonavir plus ABT-333; ABT-450, ritonavir plus ABT-072; miracitabine, danoprevir plus ritonavir; and alisporivir plus RBV[47]. DAA combinations not only have the potential to increase antiviral efficacy but also to reduce the risk of viral breakthrough. When combining DAAs, it is important to consider combinations that have a low propensity for cross-resistance. The genetic barriers to resistance of DAAs appear to be an important factor during the development of resistance. When two agents with a low genetic barrier to resistance are combined, breakthrough occurs more quickly[49]. Adding on pegIFN-α or RBV[36] as well as nucleoside analogues with a higher genetic barrier might be better tactics for overcoming resistance[37,50]. For example, 90% of difficult-to-treat patients can achieve SVR with a combination of daclatasvir, asunaprevir, pegIFN-α2a and RBV for 24 wk of treatment[36]. Furthermore, 84%-100% of patients can achieve SVR with a combination of sofosbuvir plus RBV for 12 wk of therapy[37].

PegIFN-α: To be with or not to be with

Whether or not to include pegIFN-α is a key issue in the DAA era. Several years ago, many hepatologists believed that HCV treatment would be IFN free. Now, however, the ability to do away with IFN is not so clear, especially in some difficult-to-treat patients. Although not compared in a head-to-head study, the SVR rate was relatively lower in refractory patients treated with a pegIFN-free regimen, as shown in Table 6. This information indicates that IFN-free regimens may be available for easy-to-treat patients in the near future, whereas IFN might be necessary for difficult-to-treat patients.

Role of IL-28B in reducing treatment duration

In Tables 2 and 5, groups 4 and 6 differ with respect to treatment duration (12 and 8 wk, respectively). In group 4, 81% (9/11) of patients were genotype CC or CT. In group 6, 90% (9/10) of patients were genotype CC or CT. It will be interesting to investigate whether IL-28B polymorphisms could predict treatment duration in the DAA era, especially in patients with the potential to reduce the treatment course.

Other aspects

In addition to above-mentioned situations, results from group 5 patients who received sofosbuvir monotherapy suggested the crucial role of RBV in maintaining an antiviral response (Table 2). However, the exact mechanism by which RBV contributes to SVR in the DAA era remains uncertain. Another area of important research in the future will likely be treatment of patients with cirrhosis, and hepatitis B virus and human immunodeficiency virus co-infected patients. Although the sofosbuvir- and ABT-450-based therapies were well tolerated, the safety profile of other combination treatments remains to be seen.

CONCLUSION

A series of clinical trials have demonstrated that we are currently experiencing a “watershed moment” for the treatment of hepatitis C[51,52]. Despite some unresolved questions, the recent achievements demonstrating DAAs as potent new HCV clearing agents with improved SVR rates appear to be encouraging, and it may be possible to cure nearly all HCV-infected patients in the near future.The progress of new anti-HCV agents might indicate that agents with specificity, sensitivity and a high barrier to resistance are the mainstay for conquering pathogen-related disease. Future studies may focus on the improvement of SVR rates in genotype 1 patients who have no or partial response to prior therapy as well as special patient populations, such as those with cirrhosis or co-infected patients. Furthermore, determining an optimal combination therapy with little cross-resistance and few adverse events as well as better understanding the status of IL-28B polymorphism and the potential mechanism of how RBV may synergize with DAAs are also areas of future study.

Footnotes

Supported by Grants from the National Key Basic Research Program of China, No. 2009CB522507, No. 2012CB519005; and Beijing Nova Program of China, No. Z12110702512071

P- Reviewers Estrabaud E, Quer J S- Editor Wen LL L- Editor A E- Editor Li JY

hepatitis C virus RNA level of less than 25 IU/mL 12 wk after treatment. qd: Once daily; bid: Twice daily; RBV: Ribavirin.

References

Source