My Treatment Approach to Chronic Hepatitis C Virus (Genotypes 1–6)

Article in Press

Mitchell L. Shiffman, MD, April G. Long, NP, Amy James, FNP, Phillip Alexander, NP

Published Online: May 24, 2014

DOI: http://dx.doi.org/10.1016/j.mayocp.2014.04.013

Publication stage: In Press Corrected Proof

Abstract

The treatment of chronic hepatitis C virus (HCV) is evolving rapidly. In 2014, the standard of care and new backbone of HCV treatment is the polymerase inhibitor sofosbuvir (SOF). Our treatment approach in patients with HCV genotype 1 is 12 weeks of SOF, peginterferon (PEGINF), and ribavirin (RBV). In patients with cirrhosis or extrahepatic manifestations of HCV who cannot tolerate PEGINF, we use 12 weeks of SOF and simeprevir. The latter is less costly and more effective than SOF and RBV for 24 weeks. Our treatment approach in all patients with genotype 2 is SOF and RBV for 12 weeks. Hepatitis C virus genotype 3 is now the most costly and difficult to cure. Our approach to treatment-naive patients with genotype 3 is SOF and RBV for 24 weeks. In patients who have previously undergone PEGINF and RBV treatment, we use PEGINF, SOF, and RBV for 12 weeks, which is equally if not more effective and less costly than SOF and RBV for 24 weeks. Patients with cirrhosis who cannot tolerate PEGINF should be treated for 24 weeks with SOF and RBV, although the sustained virologic response is suboptimal.

Chronic hepatitis C virus (HCV) affects an estimated 4 million persons in the United States and 300 million personsworldwide.¹ In the 1960s through the 1980s, most US patients were infected with HCV through the transfusion of blood products and injection drug use. These patients have been infected for 30 to 50 years, and this is the primary driver for the increasing rates of cirrhosis and hepatocellular carcinoma (HCC) in the United States today.² Many of these patients are asymptomatic, and the disease remains undiagnosed. The need to identify these patients is why the US Preventive Services Task Force and the Centers for Disease Control and Prevention have recommended that all persons born between 1945 and 1965 be screened for HCV.^{3, 4}

Long-term studies conducted over the past 2 decades have found that a sustained virologic response (SVR) is long-lasting and that HCV can be “cured.”^{5, 6} Patients who achieve an SVR have improvement in liver histologic features and regression of fibrosis.^{7, 8} Patients with cirrhosis who achieve an SVR rarely experience hepatic decompensation and have a 10-fold decrease in the risk of HCC and a significant reduction in mortality.^{9, 10, 11}

For the past 15 years, interferon and then peginterferon (PEGINF) have been the backbone of HCV treatment on which ribavirin (RBV) and more recently HCV protease inhibitors have been added.¹² In late 2013, the treatment of chronic HCV entered a new era when 2 new oral antiviral agents, simeprevir (SMV) and sofosbuvir (SOF), were approved by the US Food and Drug Administration (FDA). Simeprevir is a protease inhibitor, and its approval by the FDA was based on studies in which it was used with PEGINF and RBV in patients with HCV genotype 1.¹³ Although SMV inhibits the NS3/4A protease like telaprevir (TPV) and boceprevir (BOC), it is taken only once daily, has fewer adverse effects and drug-drug interactions, and appears to have a somewhat higher SVR rate.¹⁴

Sofosbuvir is a polymerase inhibitor that is highly effective in suppressing replication in all HCV genotypes.¹⁵ It is also taken once daily and has few drug-drug interactions and minimal adverse effects. Resistance is extremely rare, and SVR rates of over 90% are achieved in most patients with HCV. In 2014, SOF has become the new backbone of HCV treatment.

The treatment of HCV continues to evolve rapidly. Several pharmaceutical companies have developed and are currently testing combinations of oral antiviral agents for HCV (Table 1).^{16, 17, 18, 19, 20} Two of these treatments have already completed phase 3 clinical trials, and an all-oral antiviral treatment for HCV genotype 1 is expected to be available before the end of 2014. The current dilemma for physicians wanting to treat HCV and patients who want to be cured of this virus is not whether HCV should be treated but rather what agents should be used and when treatment should be initiated. This article summarizes the data that led to the FDA approval of SMV and SOF and describes our treatment approach to patients with chronic HCV in 2014. Given the rapid proliferation of new oral antiviral agent combinations for treatment of HCV, this approach will need to be modified in 2015.

Simeprevir

Simeprevir is a pangenotypic NS3/4A protease inhibitor that is effective in vitro against HCV genotypes 1 through 6.²¹ To date, clinical trials have been completed only in patients with genotype 1. A study in patients with HCV genotype 4 is currently under way. Preliminary data from this study suggest that PEGINF, SOF, and RBV could achieve SVR rates approaching 80%.²² Simeprevir is highly effective and has been approved by the FDA for treatment of patients with chronic HCV genotype 1. Simeprevir binds to the same site as TPV and BOC. It has not been studied in patients in whom TPV or BOC treatment failed or resistance to TPV or BOC developed. Given its mechanism of action, it is unlikely to be effective and should not be used in these patients.¹³

Simeprevir is used as triple therapy with PEGINF and RBV for 12 weeks, followed by an additional 12 weeks of PEGINF and RBV (total duration of therapy, 24 weeks) in all patients who are treatment naive or who have had a relapse while taking PEGINF and RBV, including those with cirrhosis. Approximately 80% of patients achieve a rapid virologic response (RVR), and HCV RNA is undetectable within 4 weeks of initiating treatment. The SVR in these patients is approximately90%.^{23, 24, 25} As opposed to TPV and BOC, for which the duration of therapy is adjusted on the basis of whether an RVR is achieved, response-guided therapy is not necessary with SMV. In patients who have no response to PEGINF and RBV, 12 weeks of SMV, PEGINF, and RBV is followed by 36 weeks of PEGINF and RBV (total duration of therapy, 48 weeks). The SVR rate in these patients is 53% to 65%.²⁶ All patients with HCV RNA levels greater than 25 IU/mL at weeks 4, 12, or 24 should stop treatment. Although controlled clinical trials comparing the SVR rates of the 3 protease inhibitors have not been conducted, each has been evaluated against a placebo control with PEGINF and RBV. Comparison of the improvement in SVR over control for the 3 protease inhibitors suggests that RVR and SVR rates are somewhat higher with SMV compared with TPV or BOC.¹³

Simeprevir offers considerable advantages over TPV and BOC, the most important of which is that SMV does not cause additional anemia compared with PEGINF and RBV.^{23, 24, 25, 26} In phase 2 and 3 clinical trials, patients treated with SMV, PEGINF, and RBV did not have any adverse events with greater frequency than those taking PEGINF and RBV. Simeprevir is taken as a single once-daily tablet, no special diet is required, and far fewer drug-drug interactions have been observed.

The success in patients treated with SMV, like other protease inhibitors, is dependent on an effective interferon response, which is modulated by IL28B genotype.²⁷ In treatment-naive patients, the SVR approaches 90% in patients with IL28BCC genotype and declines in patients with the CT and TT genotypes.^{23, 24} In patients with a previous nonresponse to PEGINF and RBV, the SVR rates during retreatment with SMV triple therapy follow a similar trend of interferon responsiveness: higher rates of SVR with a previous partial response and lower SVR rates in previous nonresponders.²⁶

The primary limitation of SMV is that a sequence variation at the Q80K loci of HCV significantly limits the antiviral efficacy of this protease inhibitor and reduces SVR to values that are similar to that achieved with PEGINF and RBV.^{23, 24, 25, 26}This sequence variation is present in about 40% of patients with HCV genotype 1a. It is not present in HCV genotype 1b. The FDA has suggested that all patients with genotype 1a undergo resistance testing for the presence of the Q80K sequence variation in HCV and that the physician strongly consider using a treatment other than SMV if this sequence variation is present.

The Q80K sequence variation has the greatest impact and considerably lowers SVR in patients who are genetically less sensitive to PEGINF. In contrast, patients with IL28B CC genotype, who are highly sensitive to interferon, have similar SVR rates regardless of the presence or absence of the Q80K sequence variation.^{23, 24, 25, 26} We therefore disagree with the FDA recommendations somewhat and strongly believe that patients with HCV genotype 1a and Q80K who haveIL28B CC genotype could be treated successfully with SMV, PEGINF, and RBV. We do not recommend and we do not treat our patients who have HCV genotype 1 with SMV, PEGINF, and RBV. However, if a physician or payer chooses this regimen, our recommendation would be to test those patients with genotype 1a for IL28B genotype. If the patient hasIL28B CC genotype, then no viral resistance testing is necessary. If the patient has IL28B CC or TT genotype, the patient would then need to be tested for Q80K, and if absent, they could also be treated with SMV, PEGINF, and RBV. In contrast, if the patient has IL28B CT or TT genotype and Q80K sequence variation, we would not recommend SMV.

Sofosbuvir

Sofosbuvir is the first polymerase inhibitor to be approved by the FDA for the treatment of chronic HCV.¹⁵ It is a nucleotide analogue that inhibits the NS5B polymerase and is effective in all HCV genotypes. Sofosbuvir is incorporated into the growing RNA sequence during replication and acts as a chain terminator. A specific sequence variation in the polymerase, S282T, is resistant to SOF by preventing incorporation of the nucleotide analogue into the growing polypeptide chain. However, this sequence variation also impacts the ability of HCV RNA to elongate with normal nucleotides and is therefore a nonviable sequence variation that cannot persist long-term. Resistance to SOF is therefore extremely uncommon and was not observed in any patient treated in the phase 3 clinical trials.^{28, 29, 30} Virtually all patients treated with SOF have undetectable HCV RNA within 2 to 4 weeks of initiating treatment, and all patients are treated for a fixed duration (12 or 24 weeks) on the basis of their genotype.

Sofosbuvir was studied as triple therapy with PEGINF and RBV for just 12 weeks in patients with genotypes 1, 4, 5, and6.²⁸ This was a single-arm study with no comparison with PEGINF and RBV. More than 90% of patients treated with SOF triple therapy had undetectable HCV RNA within 2 weeks, and virtually all patients achieved an RVR. The overall SVR rate was 90%; the SVR rate was 89% in patients with genotype 1 and 96% in patients with genotype 4. In patients with cirrhosis, the SVR rate was 80%. All 7 patients with HCV genotypes 5 and 6 achieved an SVR. Sofosbuvir triple therapy has not been evaluated in patients in whom either PEGINF and RBV or triple therapy with a protease inhibitor failed. However, because protease inhibitors and SOF have a completely different site of action, there is no virologic reason why SOF should not be equally effective in patients in whom treatment with a protease inhibitor failed. In treatment-naive patients with HCV genotype 1 who have the least favorable treatment response characteristics—Metavir fibrosis score of F3 or F4, high viral load, IL28B non-CC genotype—the SVR rate with SOF, PEGINF, and RBV was 71%. In contrast, the SVR rate for patients with these characteristics treated with PEGINF and RBV with or without a protease inhibitor is only 3% to 50%. On the basis of these data, the FDA recommended that all patients with chronic HCV genotypes 1 and 4, regardless of treatment history, could be treated with SOF, PEGINF, and RBV for 12 weeks.

The combination of SOF and RBV represents the first interferon-free regimen approved by the FDA to treat patients with chronic HCV. Sofosbuvir and RBV were studied in 4 clinical trials in patients with genotypes 2 and 3.^{28, 29, 30} In patients with HCV genotype 2, SOF and RBV for only 12 weeks yielded superior SVR rates compared with PEGINF and RBV for 24 weeks. In patients without cirrhosis, SOF and RBV achieved SVR rates of 90% to 97%. In patients with cirrhosis, the SVR ranged from 60% to 94%. The lowest SVR in patients with genotype 2 was observed in a single study that included only 10 patients in whom previous treatment with PEGINF and RBV had failed.²⁹ Extending the duration of SOF and RBV from 12 to 16 weeks in this study yielded an SVR of 78%. Excluding this one study, the SVR in patients with cirrhosis was 90%. The overall SVR rate for all patients with cirrhosis included in all 4 registration studies was 84%; in patients with cirrhosis and previous PEGINF and RBV treatment, the SVR was 82%. On the basis of these data, the FDA recommended that all patients with genotype 2 could be treated with SOF and RBV for 12 weeks.

In patients with genotype 3, treatment with SOF and RBV for 12 weeks yielded an SVR rate of only 61% to 68% in treatment-naive patients without cirrhosis and 21% to 34% in patients with cirrhosis.^{28, 29, 30} These SVR rates are somewhat lower, or at best similar, to that observed with 24 weeks of PEGINF and RBV. In patients in whom previous PEGINF and RBV therapy failed, 12 weeks of SOF and RBV yielded SVR rates of only 19% and 37% in patients with and without cirrhosis, respectively. Extending the duration of SOF and RBV to 16 weeks in patients with previous PEGINF and RBV failure did not significantly change the SVR in patients without cirrhosis but increased the SVR in patients with cirrhosis to 61%. The highest SVR rates in patients with genotype 3 were observed when the duration of SOF and RBV was extended to 24 weeks. In the treatment-naive population, the SVR rate was 92% to 93% in patients with or without cirrhosis. In patients in whom previous treatment with PEGINF and RBV failed, 24 weeks of SOF and RBV achieved an SVR rate of 85% in patient without cirrhosis but only 60% in patients with cirrhosis.³⁰ On the basis of these data, the FDA recommended that all patients with HCV genotype 3 could be treated with SOF and RBV for 24 weeks.

Sofosbuvir and RBV were also studied in patients with genotypes 1, 2, and 3 who had coinfection with human immunodeficiency virus (HIV).³¹ The duration of treatment was 24 weeks for patients with genotypes 1 and 3 and 12 weeks for patients with HCV genotype 2. Sustained virologic response rates of 76%, 88%, and 92% were observed for patients with genotypes 1, 2, and 3, respectively. This study led the FDA to approve SOF and RBV for the treatment of HCV in patients coinfected with HIV. This represents the first antiviral agent to be approved for treatment of HCV-HIV coinfection. The results of this study supported the FDA recommendation to use SOF and RBV for 24 weeks in patients with HCV genotype 1 who had intolerance or contraindications to the use of PEGINF.

Sofosbuvir and RBV have also been studied without PEGINF in patients with HCV and HCC awaiting liver transplant and in patients with post–liver transplant HCV recurrence. The pretransplant HCC study patients who met criteria for the MELD exception were treated with SOF and RBV up until the time they underwent liver transplant.³² Treatment was stopped at the time of the transplant. Overall, 64% of patients did not have HCV recurrence after the transplant. In patients with undetectable HCV RNA for at least 30 days before undergoing transplant, 95% did not experience HCV recurrence. These data led the FDA to approve SOF and RBV for use in patients with HCC awaiting liver transplant.

Two studies have been conducted in the post–liver transplant population.^{33, 34} One study included patients with stable normal graft function at least 6 months after transplant.³³ These patients were treated with SOF and RBV for 24 weeks. Of the 40 patients in this study, 83% had genotype 1. All patients had undetectable HCV RNA within 4 weeks of initiating SOF and RBV. Only data on HCV RNA undetectable 4 weeks after stopping treatment (SVR-4) are available to date, but this level was achieved in 77% of the patients. The other posttransplant study was a compassionate use program for patients with severe HCV recurrence after transplant.³⁴ Most of these patients had either fibrosing cholestatic hepatitis within the first year or had development of decompensated recurrent cirrhosis 2 or more years after their transplant. Of the 20 patients treated with SOF and RBV for 24 weeks, all had undetectable HCV RNA, 64% had clinical improvement, and 60% achieved an SVR; 30% of patients died of complications of their advanced liver disease despite achieving a virologic response.

Sofosbuvir is an extremely safe antiviral agent with minimal adverse effects.¹⁵ In a study in which SOF and RBV were compared with placebo in patients who could not take PEGINF and RBV, the only adverse effects occurring more frequently with SOF and RBV than with placebo were anemia and pruritus, both of which were attributed to RBV.²⁹ In the 5 phase 3 clinical trials, the drop-out rate due to adverse events was greatest in the placebo-treated group (4%); the drop-out rate was only 2% in patients treated with PEGINF, SOF, and RBV for 12 weeks and less than 1% in all SOF and RBV treatment groups.

Combining SOF and SMV in Patients With Genotype 1

The combination of SOF and SMV for either 12 or 24 weeks with or without RBV has been evaluated in 167 patients with HCV genotype 1.³⁵ No single arm of this 2-cohort, 4-arm study had more than 54 patients, and only SVR-4 data are currently available for half the patients. However, the results are extremely noteworthy. Sustained virologic response rates of 93% to 100% were observed in all but one of the groups regardless of whether patients were treated for 12 or 24 weeks and whether they received RBV or not. The lowest SVR (79%) was observed in the group treated with SOF, SMV, and RBV for 24 weeks in which 4 patients had nonvirologic failure. All 14 patients with cirrhosis achieved SVR-4 within just 12 weeks of initiating SOF and SMV. Of the 7 patients with cirrhosis and previous nonresponse, all achieved SVR. In patients with genotype 1a and the Q80K sequence variation, the SVR rate was 90%. In patients without this sequence variation, the SVR rate was 100%.

Adding PEGINF to SOF and RBV in Patients With Genotype 3

Of all patients with HCV, those with genotype 3 have the most difficulty achieving a cure. Many believe this is difficulty is related to the much higher hepatic content of micovesicular steatosis that is unique to patients with HCV genotype 3.³⁶Sustained virologic response in patients with genotype 3 is also negatively impacted by previous nonresponse to PEGINF and RBV. In patients without cirrhosis, a previous nonresponse to PEGINF and RBV is associated with a reduction in SVR from 93% to 85%, and in those with cirrhosis, the SVR is reduced from 92% to 60%.^{28, 29, 30} This negative impact of previous PEGINF and RBV treatment is also observed in patients with genotype 2 but to a far lesser extent. In patients with genotype 2 who have previously undergone PEGINF and RBV treatment, the SVR in response to SOF and RBV is reduced from 97% to 91% in those without cirrhosis and from 100% to 88% in those with cirrhosis.

The SVR in patients with HCV genotype 3, especially patients previously treated with PEGINF and RBV, appears to be enhanced by adding PEGINF to SOF and RBV.³⁷ In a small study of only 24 patients with genotype 3 and previous nonresponse to PEGINF and RBV (half of whom had cirrhosis), 12 weeks of treatment with PEGINF, SOF, and RBV yielded an SVR of 83% in patients with and without cirrhosis. In the same study, 14 patients with HCV genotype 2, cirrhosis, and previous nonresponse to PEGINF and RBV achieved an SVR of 93% when re-treated with PEGINF, SOF, and RBV.

Our Treatment Approach

In January 2014, a joint guideline for treating HCV was issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.³⁸ These recommendations and the FDA recommendations for use of SOF³⁹ are summarized in Table 2. Our treatment approach to chronic HCV at the Liver Institute of Virginia in 2014 is based on the available data and focuses on maximizing SVR while also respecting the cost of treatment (Table 2). In several situations, we believe the American Association for the Study of Liver Diseases/Infectious Diseases Society of America treatment guidelines are overly aggressive, are too costly, and have no clinical trial data to substantiate the recommendation.

Table 2 2014 Treatment Recommendations for Patients With HCV

Variable	AASLD/IDSA	FDA	LIV
Genotype 1: Treatment naive and prior PEGINF and RBV relapse
INF tolerant, no cirrhosis or compensated cirrhosis	PEGINF, SOF, and RBV for 12 wk
INF intolerant, no cirrhosis	SOF and SMV ± RBV for 12 wk	SOF and RBV for 24 wk	Defer treatment
INF intolerant, cirrhosis			SOF and SMV for 12 wk
Genotype 1: Prior PEGINF and RBV nonresponse
INF tolerant, no cirrhosis or compensated cirrhosis	SOF and SMV ± RBV for 12 wk	PEGINF, SOF, and RBV for 12 wk
INF intolerant, no cirrhosis	SOF and SMV ± RBV for 12 wk	SOF and RBV for 24 wk	Defer treatment
INF intolerant, cirrhosis			SOF and SMV for 12 wk
Genotype 1: Prior treatment with PEGINF, RBV, and TPV or BOC
INF tolerant, no cirrhosis or compensated cirrhosis	SOF for 12 wk, PEGINF and RBV for 12-24 wk	PEGINF, SOF, and RBV for 12 wk
INF intolerant, no cirrhosis	NR	SOF and RBV for 24 wk	Defer treatment
INF intolerant, cirrhosis			SOF and SMV for 12 wk
Genotype 2
Treatment naive or PEGINF-RBV relapse, no cirrhosis or compensated cirrhosis	SOF and RBV for 12 wk	SOF and RBV for 12 wk	SOF and RBV for 12 wk
Prior PEGINF-RBV nonresponse, no cirrhosis	SOF and RBV for 12 wk
Prior PEGINF-RBV nonresponse, cirrhosis	SOF and RBV for 12-16 wk
Genotype 3
Treatment naive	SOF and RBV for 24 wk	SOF and RBV for 24 wk	SOF and RBV for 24 wk
Prior PEGINF-RBV, INF tolerant, no cirrhosis or compensated cirrhosis			PEGINF, SOF, and RBV for 12 wk
Prior PEGINF-RBV, INF intolerant, no cirrhosis			Defer treatment
Prior PEGINF-RBV, INF intolerant, cirrhosis			SOF and RBV for 24 wk
Genotype 4
INF tolerant	PEGINF, SOF, and RBV for 12 wk
INF intolerant	SOF and RBV for 24 wk		SOF and SMV for 12 wk
Genotypes 5 and 6
INF tolerant	PEGINF, SOF, and RBV for 12 wk	NA	PEGINF, SOF, and RBV for 12 wk
INF intolerant	NR	NA	SOF and RBV for 24 wk

AASLD = American Association for the Study of Liver Diseases; BOC = boceprevir; FDA = Food and Drug Administration; IDSA = Infectious Diseases Society of America; INF = interferon; LIV = Liver Institute of Virginia; NA = not approved; NR = no recommendation; PEGINF = peginterferon; RBV = ribavirin; SMV = simeprevir; SOF = sofosbuvir; TPV = telaprevir.

Genotypes 1, 4, 5, and 6

Genotype 1 is the most common form of HCV worldwide. Genotype 4 is the dominant genotype in Egypt and the Middle East, genotype 5 is frequent in South Africa, and genotype 6 is common in Vietnam and Cambodia.⁴⁰ In the United States, genotypes 4 through 6 are uncommon and rarely seen except in immigrants from the aforementioned regions of the world.

In patients with genotypes 1, 4, 5, or 6 without cirrhosis, our treatment approach is PEGINF, SOF, and RBV for 12 weeks. The SVR rate is 92% or greater, and less than 2% of these patients will be unable to tolerate this regimen. For patients who have not achieved an SVR during previous treatment with PEGINF and RBV or PEGINF, RBV, and either TPV or BOC, our approach is the same. Patients without cirrhosis who prefer not to be treated with PEGINF or have intolerance or contraindications to PEGINF can defer treatment and wait for an FDA-approved all-oral antiviral combination. Two such regimens are expected to be available before 2015. We do not promote either SOF and RBV for 24 weeks or SOF and SMV for 12 weeks in patients without cirrhosis.

In patients with cirrhosis and genotypes 1, 4, 5, or 6, our approach is still PEGINF, SOF, and RBV for 12 weeks as long as the platelet count and serum albumin level are normal and there is no history of hepatic decompensation or evidence of esophageal varices or subclinical hepatic encephalopathy. In contrast, we would not treat patients with cirrhosis and any of these laboratory or clinical abnormalities with a PEGINF-containing regimen. In a previous study in which patients with these characteristics were treated with PEGINF, RBV, and either TPV or BOC, more than half experienced severe anemia, 25% discontinued treatment, and 1% to 2% died as a result of hepatic decompensation.⁴¹ In our opinion, the risk that this poor outcome could also occur with a 12-week PEGINF and RBV–containing regimen is considerable. In addition, the SVR that could be achieved with PEGINF, SOF, and RBV is reduced to 80% or less in such patients.

In patients with genotype 1 or 4 and cirrhosis who have intolerance or contraindications to PEGINF, our treatment approach is SOF and SMV for 12 weeks. In patients with HCV-induced extrahepatic manifestations such as symptomatic cryoglobulinemia, glomerulonephritis, or B-cell lymphoma, regardless of fibrosis stage, we also use SOF and SMV. We do not believe that testing for the Q80K sequence variation is necessary when treating patients who have genotype 1a with SOF and SMV. The SVR when this sequence variation is present is still 90%, and there is no suggestion from the data that adding RBV or extending the duration of therapy to 24 weeks enhances SVR. We do not recommend 24 weeks of SOF and RBV in these patients; the cost of this regimen is prohibitive, and the SVR rate is estimated to be only in the 70% to 75% range, approximately 20% lower than that observed with SOF and SMV. We also do not recommend deferring treatment in this population, and payers should recognize their need for treatment. These patients have cirrhosis, are at risk for development of severe and life-threatening complications of cirrhosis, and should not have to wait for an alternative all-oral regimen.

In patient with genotypes 5 or 6, cirrhosis, and intolerance or contraindications to PEGINF, we use SOF and RBV for 24 weeks. Although this regimen is costly, this group represents only a limited number of patients with HCV, and no alternative treatment is on the horizon. Simeprevir has activity against HCV genotypes 5 and 6 in vitro, but without any clinical data to support its use, it is difficult to recommend this treatment.

Our treatment approach to patients with HCV genotype 1 does not include TPV, BOC, or SMV in combination with PEGINF and RBV. All of these antiviral agents have a lower SVR rate and require a longer duration of PEGINF and RBV compared with an SOF-containing regimen.¹⁴

Genotype 2

Our treatment approach for all patients with genotype 2, regardless of fibrosis stage, is SOF and RBV for 12 weeks. This group includes patients with cirrhosis in whom PEGINF and RBV failed previously. The SVR rate in this nonresponse subpopulation with cirrhosis is 88% but exceeds 90% in all other subpopulations. A more effective, less costly regimen is unlikely to be developed for patients with HCV genotype 2 in the foreseeable future.

Genotype 3

Patients with genotype 3 are now the most difficult and costly to treat and the most controversial regarding recommendations for treatment. Treatment-naive patients, regardless of the degree of fibrosis, require twice the duration of SOF and RBV (24 weeks) and twice the cost to achieve an SVR of at least 90%. We believe that SOF, RBV, and PEGINF for 12 weeks would yield an SVR of at least 90% and be more cost-effective, but with no data in the treatment-naive population, this approach is difficult to adopt. Therefore, our approach to treatment-naive patients with genotype 3 with or without cirrhosis is SOF and RBV for 24 weeks.

In patients with genotype 3 who have previously undergone PEGINF and RBV treatment and do not have cirrhosis, 24 weeks of SOF and RBV is nearly twice as costly yet offers an SVR similar to 12 weeks of PEGINF, SOF, and RBV (85% vs 83%, respectively). Because only 12 weeks of PEGINF is generally tolerated, we use the cheaper regimen (PEGINF, SOF, and RBV for 12 weeks). Patients with genotype 3 who do not have cirrhosis and are intolerant of PEGINF can defer treatment until a more cost-effective therapy is available. In patients with cirrhosis who do not have contraindications to PEGINF, our approach is to also use PEGINF, SOF, and RBV. The SVR with this treatment is also 83% compared with only 60% for 24 weeks of SOF and RBV. In patients with cirrhosis that is too advanced for PEGINF (see criteria outlined in the “Genotypes 1, 4, 5, and 6” section) and patients with PEGINF intolerance for other reasons, we have no choice but to use the inferior and more costly treatment (SOF and RBV for 24 weeks).

Recommendations

For 2014, SOF has replaced PEGINF as the backbone of HCV therapy. Sofosbuvir is superior to all other currently available antiviral agents with respect to efficacy, adverse effects, drug-drug interactions, viral resistance, and duration of therapy. Peginterferon should still be used in many patients with genotype 1 and in selected patients with genotype 3 because it offers higher efficacy and is less costly than 24 weeks of SOF and RBV. In 2015, another era of HCV treatment will begin, and our need for PEGINF and possibly RBV will no longer exist. Patients with genotype 1 and no cirrhosis may choose to defer treatment until then.

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17. Lawitz, E., Poordad, F.F., Pang, P.S. et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. ([published correction appears in Lancet. 2014;383(9920):870]) Lancet. 2014; 383: 515–523

18. Everson, G.T., Sims, K.D., Rodriguez-Torres, M. et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection.Gastroenterology. 2014; 146: 420–429

19. Lawitz, E, Hezode, C, Gane, E et al. Efficacy and safety of MK-5172 and MK-8742 ± ribavirin in hepatitis C genotype 1 infected patients with cirrhosis or previous null-response: the C-WORTHY Study. J Hepatol. 2014; 60: S25–26

20. Zeuzem, S., Soriano, V., Asselah, T. et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med.2013; 369: 630–639

21. Talwani, R., Heil, E.L., Gilliam, B.L., and Temesgen, Z. Simeprevir: a macrocyclic HCV protease inhibitor. Drugs Today (Barc). 2013; 49: 769–779

22. Moreno C, Hezode C, Marcellin P, et al. Simeprevir with peginterferon/ribavirin in treatment-naïve or -experienced patients with chronic HCV genotype 4 infection: a phase III study. Paper presented at: 14th European AIDs Conference; October 16-19, 2013; Brussels, Belgium.

23. Manns, M., Marcellin, P., Poordad, F.P.F. et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. ([abstract 1413]) J Hepatol. 2013; 58: S568

24. Jacobson, I., Dore, G.J., Foster, G.R. et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-1 a phase III trial. ([abstract 1425]) J Hepatol. 2013; 58: S574

25. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial [published online ahead of print March 3, 2014]. Gastroenterology. http://dx.doi.org/10.1053/j.gastro.2014.02.051.

26. Zeuzem, S., Berg, T., Gane, E. et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014; 146: 430–441

27. Thompson, A.J., Muir, A.J., Sulkowski, M.S. et al. IL28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139: 120–129.e18

28. Lawitz, E., Mangia, A., Wyles, D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368: 1878–1887

29. Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013; 368: 1867–1877

30. Zeuzem, S., Dusheiko, G.M., Salupere, R. et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. ([AASLD abstract 1085]) Hepatology. 2013; 58: 733A

31. Sulkowski, M.S., Rodriguez-Torres, M., Lalezari, J.P. et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). ([AASLD abstract 212]) Hepatology. 2013; 58: 313A

32. Curry, M.P., Forns, X., Chung, R.T. et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. ([AASLD abstract 213]) Hepatology. 2013; 58: 314A

33. Charlton MR, Gane EJ, Manns MP, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study [AASLD abstract LB2]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.

34. Forns, X., Fontana, R.J., Moonka, D. et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. ([AASLD abstract 1084]) Hepatology. 2013; 58:732A

35. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study [AASLD abstract LB3]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.

36. Restivo, L., Zampino, R., Guerrera, B., Ruggiero, L., and Adinolfi, L.E. Steatosis is the predictor of relapse in HCV genotype 3- but not 2-infected patients treated with 12 weeks of pegylated interferon-α-2a plus ribavirin and RVR.J Viral Hepat. 2012; 19: 346–352

37. Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study [AASLD abstract LB4]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.

38.American Association for the Study of Liver Diseases, Infectious Diseases Society of America. Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org/full-report-view. Revised March 21, 2014. Accessed April 19, 2014.

39. Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc; December 2013. http://www.gilead.com/∼/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf.

40. Nguyen, M.H. and Keeffe, E.B. Chronic hepatitis C: genotypes 4 to 9. Clin Liver Dis. 2005; 9: 411–426

41. Hézode, C., Fontaine, H., Dorival, C...., and CUPIC Study Group. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol. 2013; 59: 434–441

Potential Competing Interests: Dr Shiffman has participated in advisor meetings with Achillion Pharmaceuticals, Inc, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead Sciences, Gen-Probe, Inc, Globeimmune Inc, GlaxoSmithKline, Janssen Pharmaceutical Companies, Merck & Co, Inc, Novartis Corp, Genentech, Inc, and Vertex Pharmaceuticals Inc; is on the speakers' bureau for Bayer AG, Gilead Sciences, Janssen Pharmaceutical Companies, Merck & Co, Inc, Genentech, Inc, and Vertex Pharmaceuticals Inc; and receives grant support from Abbott Laboratories, Achillion Pharmaceuticals, Inc, Beckman Coulter, Inc, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead Sciences, Globeimmune Inc, Idenix Pharmaceuticals, Inc, Intercept Pharmaceuticals, Inc, Merck & Co, Inc, Mochida Pharmaceutical Co, Inc, Novartis Corp, and Genentech, Inc. Ms Long has participated in advisor meetings with AbbVie Inc, Gilead Sciences, Janssen Pharmaceutical Companies, Kadmon Pharmaceuticals, Merck & Co, Inc, and Vertex Pharmaceuticals Inc and is on the speakers' bureau for Merck & Co, Inc, GlaxoSmithKline, Kadmon Pharmaceuticals, Salix Pharmaceuticals, Inc, and Vertex Pharmaceuticals Inc. Ms James has participated in advisor meetings with Gilead Sciences and Janssen Pharmaceutical Companies and is on the speakers' bureau for Janssen Pharmaceutical Companies. Mr Alexander has participated in advisor meetings with Gilead Sciences.

© 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

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U.S. FDA Grants Priority Review to AbbVie for Investigational, All-Oral, Interferon-Free Therapy for the Treatment of Genotype 1 Chronic Hepatitis C

Jun 13, 2014

NORTH CHICAGO, Ill., June 13, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced today that the New Drug Application (NDA) for its investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection has been accepted by the U.S. Food and Drug Administration (FDA) and has been granted priority review.

The NDA was submitted on April 21, 2014 and is supported by data from a large clinical program including six Phase III studies of more than 2,300 GT1 patients in over 25 countries. The regimen was granted a Breakthrough Therapy designation by the FDA in May 2013, a status given to investigational treatments for serious or life-threatening conditions with preliminary clinical evidence demonstrating substantial improvement on at least one clinically significant endpoint compared to available therapy.

In May 2014, AbbVie submitted marketing authorization applications (MAAs) for regulatory approval in the European Union.

About AbbVie's Investigational HCV Regimen
The AbbVie investigational regimen consists of ABT-450/ritonavir co-formulated with ombitasvir (ABT-267), and dasabuvir (ABT-333) with or without RBV. The combination of three different mechanisms of action interrupts the hepatitis C virus replication process with the goal of optimizing sustained virologic response rates across different patient populations.

Additional information about AbbVie's Phase III studies can be found on www.clinicaltrials.gov.

AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral regimen with and without ribavirin with the goal of producing high sustained virologic response rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for hepatitis C virus protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2013 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission.

AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

SOURCE AbbVie

For further information: Media: Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com , Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com , Investor Relations: Liz Shea, +1 (847) 935-2211, liz.shea@abbvie.com

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Methadone programs can be key in educating, treating patients with hepatitis C virus infection

Research by Andrew Talal shows that people who inject drugs want to be educated about hepatitis C and are willing to be treated.

More effective, new medications for HCV infection with fewer side effects also are causing a shift in patients’ attitudes

By Ellen Goldbaum

Release Date: May 16, 2014

People who inject drugs and are enrolled in a drug treatment program are receptive to education about, and treatment for, hepatitis C virus, according to a study by researchers at several institutions, including the University at Buffalo.

That finding, published online this week in the Journal of Addiction Medicine will be welcome news to health care providers. The paper notes that injection drug use is a primary mode of infection, making for an HCV infection prevalence as high as 80 percent among people who inject drugs.

"One of the most important findings of this work is that people who inject drugs do want to be educated about the disease and that education is associated with willingness to be treated," says senior author Andrew H. Talal, MD, professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition at UB and adjunct associate professor of medicine at Weill Cornell Medical College. First author is Marija Zeremski, PhD, senior research associate in medicine at Weill Cornell Medical College and research assistant professor of medicine at UB.

Talal and colleagues previously demonstrated that treatment of addiction significantly enhances the ability of people who use drugs to complete HCV therapy.

"These new findings support the premise that addiction-treatment facilities can help provide sustained HCV treatment for this population," Talal says. "These facilities have the added advantage of being able to link HCV care to drug treatment, allowing for closer patient evaluation, which will likely lead to improved adherence to treatment regimens."

HCV infection often is asymptomatic, but 75 to 80 percent of those infected will develop chronic infection that can progress to liver cirrhosis and/or liver cancer, potentially requiring liver transplantation as a life-saving intervention. However, in order to be considered for a liver transplant, people who use drugs must remain "clean" for at least six months.

The study was based on a survey of 320 patients enrolled in a New York City-based methadone treatment program (START Treatment and Recovery Centers). Nearly half of them reported that they had tested positive for HCV infection.

Seventy-eight percent of respondents expressed willingness to participate in HCV-related education and to receive treatment for HCV. More than half of those surveyed correctly responded to at least five of seven questions assessing their knowledge about HCV.

"People who inject drugs have always wanted to be treated for hepatitis C, but there have been a variety of barriers at the patient, provider and institutional levels," says Talal. "Most importantly, there has been a lack of education about the disease, a fear of side effects of interferon, discomfort in conventional health care venues and a lack of awareness of the status of the infection."

In some cases, the percentage of HCV-infected people who use drugs that show up for HCV-related medical appointments is as low as 10 percent, according to Talal.

In the current research, patients cited fear of side effects from interferon, which remains as part of the standard treatment regimen for genotype 1 infection, as a key barrier to their willingness to accept HCV treatment. Interferon can cause multiple side effects, ranging from fatigue, fever, nausea, anorexia, muscle pain and hair loss, to insomnia, depression and irritability. In addition, interferon-based therapies are only effective in eliminating infection in half of those who take it.

"A major change in the attitudes of people who use drugs is due to knowledge about greatly improved treatment efficacy and the ability to provide HCV treatment at the same site as the substance abuse treatment," says Talal.

Talal adds that the New York State law mandating that all individuals born between 1945 and 1965 be offered HCV screening is increasing the number of people diagnosed with the infection, thereby also making them more receptive to HCV education and treatment.

This study, funded by the Viral Hepatitis Action Coalition and performed in collaboration with the Centers for Disease Control and Prevention, documents the initial phase of a project called Prevention, Evaluation and Treatment of Hepatitis C in Opiate Agonist Treatment (PET-C). Led by Talal, the project's goal is to assess how telemedicine can be used to evaluate a model of HCV treatment for people who inject drugs and are enrolled in a drug treatment program.

Talal conducts research on HCV in UB's Clinical and Translational Research Center and he sees patients as a physician with UBMD, the practice plan of the UB School of Medicine and Biomedical Sciences. He previously served on the advisory board for Abbott Molecular, received support from Gilead Sciences and disclosed a prior relationship with Vertex Pharmaceuticals, all of which helped sponsor the study.

Media Contact Information
Ellen Goldbaum Senior Editor, Medicine
Tel: 716-645-4605
goldbaum@buffalo.edu
Twitter: @egoldbaum

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Public health boards fail to prioritise hepatitis C

Alistair Kleebauer

Nursing Standard. 28, 37, 0-0. http://dx.doi.org/10.7748/ns.28.37.0.2837992

Published online: 16 May 2014

Health and wellbeing boards in England are failing to make the hepatitis C virus (HCV) a priority despite an increase in hospital admissions and deaths from the virus, according to the HCV Action network and the charity Hepatitis C Trust.

Both groups said the failure constituted a ‘serious public health issue’ and that their evidence showed just three of the top ten areas with the highest prevalence have a detailed needs assessment of hepatitis C, which is recommended by the National Institute for Health and Care Excellence.

Their report found that 52 per cent of health and wellbeing boards fail to mention hepatitis C at all in their joint strategic needs assessments or in their joint health and wellbeing strategies.

Public Health England (PHE) data show that deaths from hepatitis C-related end-stage liver disease and hepatocellular carcinoma, a hepatitis C-related cancer, are rising year-on-year, from 89 in 1996 to 326 in 2012.

HCV Action’s chair and consultant hepatologist at Nottingham University Hospitals NHS Trust Stephen Ryder said: ‘The report highlights the alarming gap between the prevalence of hepatitis C and the way health and wellbeing boards prioritise the diagnosis and treatment of the virus.’

For read the full report, go to: www.hepctrust.org.uk/Resources/HepC%20New/Documents/Hepatitis%20C%20in%20JSNAs%20Final%20Report%20May%2014%20PDF.pdf

To comment on this story email letters@rcnpublishing.co.uk

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Hepatitis C Virus Therapy in the Direct Acting Antiviral Era

Current Opinion in Gastroenterology

Mitchell L. Shiffman

Curr Opin Gastroenterol. 2014;30(3):217-222.

Abstract and Introduction

Abstract

Purpose of review: The evolution of treatment for patients with chronic hepatitis C virus (HCV) is evolving at a rapid pace. Two new oral antiviral agents, simeprevir and sofosbuvir, have already been approved and are now available for treatment of patients with chronic HCV. Other antiviral agents will be available during 2014.

Recent findings: The protease inhibitor simeprevir was recently approved for use with peginterferon (PEGINF) and ribavirin (RBV) in patients with chronic genotype 1. About 80% of patients achieve a rapid virologic response and can be treated for 24 weeks. The sustained virologic response (SVR) in treatment-naive patients is about 80%. Sofosbuvir, the first polymerase inhibitor, is effective in all HCV genotypes. When utilized with peginterferon and RBV for 12 weeks in treatment-naive patients with genotypes 1, 4, 5 and 6, an SVR of 90% is observed. Sofosbuvir and RBV have also been studied without interferon and represent the first interferon-free therapy for chronic HCV.

Summary: It is now possible to cure chronic HCV in the vast majority of patients with chronic HCV and in many patients without interferon.

Introduction

The treatment of chronic hepatitis C virus (HCV) continues to evolve at an accelerating pace. In 2011, the first two protease inhibitors, telaprevir and boceprevir, were approved to be utilized with peginterferon (PEGINF) and ribavirin (RBV) to treat chronic HCV genotype 1.^[1–5] The addition of a protease inhibitor to PEGINF and RBV represented a huge advance in HCV treatment and increased sustained virologic response (SVR) in the treatment-naive population with HCV genotype 1 from about 40% to 70–75%. The main limitation of these first-generation protease inhibitors was side-effects, particularly anemia, which were more severe than observed with PEGINF and RBV. These adverse events are even more severe and increase the risk of hepatic decompensation in patients with cirrhosis. In a study that included only patients with advanced fibrosis or cirrhosis, many of whom had previously failed PEGINF and RBV, nearly half of all patients treated with either telaprevir or boceprevir developed serious adverse events, 25% discontinued treatment, over half developed severe anemia and required a hematopoetic growth factor and 1–2% died as a result of hepatic decompensation.^[6] The patients at greatest risk to develop hepatic decompensation included those with thrombocytopenia and a low serum albumin.^[7] The SVR in this cohort was only 40%. In the subset of patients with cirrhosis who failed previous therapy, the SVR was under 20%.^[6,7] Results like these caused many physicians who were treating HCV to pause and wait for a better alternative.

In late 2013, another protease inhibitor simeprevir and the first polymerase inhibitor, sofosbuvir, were approved for HCV treatment. These two antiviral agents offer significant advantages compared with telaprevir and boceprevir when treating patients with HCV genotype 1; the duration of therapy is shorter, the adverse effect profile is superior and the SVR is higher. In addition, sofosbuvir is effective against all genotypes and when utilized with RBV represents the first interferon-free treatment for chronic HCV.

During the past few years, several oral antiviral agents, which inhibit various HCV proteins, have been developed at a rapid pace. These include protease inhibitors, nucleotide and nonnucleotide polymerase inhibitors, NS5A inhibitors and cyclophilin inhibitors. Two or more oral antiviral agents from different classes have been combined and their evaluation in phase 3 clinical trials is well underway.^[8–11] During 2015 multiple oral antiviral combinations are expected to be available to treat chronic HCV (Table 1). The rapid evolution of these treatments will make any recommendations for how to treat HCV in 2014 tentative at best. The treatments that will be available during 2014 are illustrated in Fig. 1. The rapid evolution of HCV treatment has also occurred at a pace that far exceeds the appearance of peer-reviewed publications. The vast majority of cited references are therefore abstracts, which have been presented at national and international meetings during 2013.

Figure 1.

Treatment regimens for patients with chronic hepatitis C virus (HCV) utilizing the two newest antiviral agents simeprevir (SPV) and sofosbuvir (SOF). Treatment of patients with HCV genotype 1 includes SPV, peginterferon (PEGINF) and ribavirin (RBV) for 24–48 weeks, SOF, PEGINF and RBV for 12 weeks, SOF plus RBV for 24 weeks or SOF and SPV for 12 weeks. The treatment of patients with HCV genotype 2 is SOF plus RBV for 12 weeks. The treatment of patients with HCV genotype 3 is SOF plus

Simeprevir and Faldaprevir

Both simeprevir and faldaprevir are NS3–4A protease inhibitors.^[12–16] Both act at the same binding site as telaprevir and boceprevir and are only effective in patients with HCV genotype 1. As a result, neither of these agents is likely to be effective in patients with resistance to telaprevir or boceprevir.

Simeprevir was approved for use in patients with HCV genotype 1 in late 2013 and faldaprevir is expected to be approved in early 2014. Both of these protease inhibitors will be utilized as triple therapy with PEGINF and RBV for 12 weeks followed by an additional 12–36 weeks of PEGINF and RBV. In patients who are treatment-naive or who have had prior relapse with PEGINF and RBV, the recommended total duration of therapy when utilizing simeprevir is 24 weeks, that is 12 weeks of simeprevir, PEGINF and RBV followed by an additional 12 weeks of PEGINF and RBV. Approximately, 80% of these patients will achieve a rapid virologic response (RVR) and be HCV RNA undetectable within 4 weeks of initiating treatment. The SVR in these patients is approximately 90%.^[12,13] It is recommended that patients with HCV RNA more than 25 IU/ml at either weeks 4, 12 or 24 stop treatment. In patients with prior nonresponse to PEGINF and RBV, the total duration of therapy is 48 weeks, that is 12 weeks of simeprevir, PEGINF and RBV followed by an additional 36 weeks of PEGINF and RBV. The SVR rate in these patients is 53–65%.^[14] It is recommended that patients with HCV RNA more than 25 IU/ml at either weeks 4, 12 or 24 also stop treatment. It is anticipated that the recommendations for faldaprevir will be quite similar.

Simeprevir and faldaprevir offer significant advantages over telaprevir and boceprevir. The most important of these is that neither of these agents cause additional anemia compared with PEGINF and RBV.^[12–16] All of these agents are dosed as a single once daily tablet, no special diet is required during dosing and no significant drug-drug interactions have been observed. Simeprevir was not noted to have any adverse events with greater frequency than PEGINF and RBV.^[12–14] Faldaprevir was noted to have a slightly higher incidence of rash.^[15,16] However, the rash was graded as only mild or moderate in all cases and no grade 3 rashes were observed. Faldaprevir was also associated with a mild increase in total bilirubin without elevations in liver transaminases or alkaline phosphatase.

Controlled clinical trials comparing the various antiviral agents utilized for treatment of patients with HCV genotype 1 have not been conducted. As such, no direct comparison regarding the relative effectiveness of these agents can be made. Both simeprevir and faldaprevir triple therapies were evaluated against a placebo control with PEGINF and RBV. As a result, the improvement in SVR with the protease inhibitor over control could be compared for all of the available protease inhibitors.^{[1–5,12–16]} Such a comparison suggests that RVR and SVR rates are somewhat higher in patients treated with simeprevir or faldaprevir compared with telaprevir and boceprevir. The high RVR rates observed with simeprevir and faldaprevir allow 80% of patients to be treated for only 24 weeks and lead to the higher SVR rates.

The success of treatment in patients treated with simeprevir or faldaprevir, like other protease inhibitors, is dependent upon an effective interferon response and this is modulated by interleukin-28B genotype. In treatment-naive patients, the SVR approaches 90% in patients with interleukin-28B genotype CC and declines in patients with the CT and TT genotypes.^[12,13,15] In patients with prior nonresponse to PEGINF and RBV, the SVR rates during retreatment with simepreivr or faldaprevir triple therapy follow a similar trend of interferon responsiveness; higher rates of SVR with prior partial response and the lowest SVR rates in prior null responders.^[14,16]

The primary limitation of simeprevir is that a mutation at the Q80K loci of HCV adversely impacts the antiviral efficacy of simeprevir and leads to a significant reduction in SVR.^[12,13,17] This mutation is present in about 40% of patients with HCV genotype 1A. The Q80K mutation is only rarely seen in HCV genotype 1B. The Q80K mutation in HCV has the greatest impact and significantly lowers SVR in patients who are genetically less sensitive to interferon. In contrast, patients with interleukin-genotype CC, who are highly sensitive to interferon, have similar SVR rates even if the HCV Q80K mutation is present.^[12,13] When treating patients with genotype 1A, it is therefore important that the patient is interleukin-28 genotype CC or that HCV does not contain the Q80K mutation. Testing the patient for their IL28B genotype and/or evaluating HCV for the presence of this mutation should be strongly considered if simeprevir is to be utilized. Patients with HCV genotype 1 and the Q80K mutation who are IL28B genotype CT or TT are best treated by an alternative antiviral agent.

Sofosbuvir

Sofosbuvir is the first polymerase inhibitor to be approved for the treatment of chronic HCV. It is a nucleotide analog, which inhibits the NS5B polymerase and is effective in all HCV genotypes. It is incorporated into the growing RNA sequence during replication and acts as a chain terminator. The appearance of resistance to sofosbuvir is extremely limited and when this does occur the viral species is unable to persist.

Sofosbuvir was studied as triple therapy with PEGINF and RBV for just 12 weeks in patients with genotypes 1, 4, 5 and 6^[18**] This was a single arm study with no comparison with PEGINF and RBV because of the marked differences in the duration of treatment. Over 90% of patients treated with sofosbuvir triple therapy were HCV RNA undetectable within 2 weeks and virtually all patients achieved a RVR. The overall SVR rate was 90%: 89% in patients with genotype 1 and 96% in patients with genotype 4. In patients with cirrhosis, the SVR rate was 80%. All seven of the patients with HCV genotypes 5 and 6 achieved SVR. Sofosbuvir triple therapy has not been evaluated in patients who failed either PEGINF and RBV or triple therapy with a protease inhibitor.

The combination of sofosbuvir and RBV represents the first interferon-free regimen approved for use to treat patients with chronic HCV. This combination was initially studied and is approved for use in patients with HCV genotypes 2 and 3.^[18**,19**] In patients with HCV genotype 2, sofosbuvir and RBV yielded superior SVR rates compared with PEGINF and RBV. In treatment-naive patients, 12 weeks of sofosbuvir and RBV achieved SVR rates of 91 and 98% in patients with and without cirrhosis respectively. In patients who had previously failed PEGINF and RBV SVR rates of 96 and 60% were observed with 12 weeks of treatment. Extending the duration of treatment from 12 to 16 weeks did increase the SVR in this subgroup of patients to 78%. The recommended duration of sofosbuvir and RBV for patients with HCV genotype 2 is 12 weeks.

In patients with genotype 3, treatment with sofosbuvir and RBV for 12 weeks yielded an SVR rate of only 61% in patients without cirrhosis and 34% in patients with cirrhosis.^[18**,19**] These SVR rates are very similar to that observed with PEGINF and RBV. Extending the duration of sofosbuvir and RBV to 16 and 24 weeks increased the SVR rate in all patients with genotype 3 to about 62 and 84%, respectively.^[19**,20,21] As a result, the recommended duration of sofosbuvir and RBV for patients with genotype 3 is 24 weeks.

Sofosbuvir and RBV were also studied in patients with genotypes 1, 2 and 3 who had co-infection with HIV.^[22] The duration of treatment for patients with genotypes 1 and 3 was 24 and 12 weeks for patients with HCV genotype 2. SVR rates of 76, 92 and 88% were observed for patients with genotype 1, 2 and 3, respectively. This study led to the approval of sofosbuvir and RBV for the treatment of HCV in patients co-infected with HIV.

Sofosbuvir and RBV have also been studied without interferon in patients with HCV and liver cancer awaiting liver transplant and in patients with post-liver transplant recurrent HCV.^[23,24] The duration of sofosbuvir and RBV in all of these studies was for 24 weeks. SVR rates of about 75% were achieved in each of these populations. These studies led to the recommendation that sofosbuvir and RBV be utilized in patients with HCV genotype 1 who were unable to receive PEGINF. The recommended duration of therapy in these patients was 24 weeks.

Sofosbuvir is a well tolerated antiviral agent with minimal side-effects. In a study in which sofosbuvir and RBV were compared with placebo in patients who could not take PEGINF and RBV, the only side-effects with increased frequency above placebo were anemia and pruritus, both of which were attributed to RBV.^[19**]

Mixing and Matching Antiviral Agents

Both simeprevir and sofosbuvir are currently approved and available for treatment of chronic HCV. The combination of simeprevir and sofosbuvir with or without RBV for either 12 or 24 weeks was evaluated in about 160 patients with HCV genotype 1. Many of these patients had prior nonresponse to PEGINF and RBV and about half had advanced fibrosis or cirrhosis.^[25] Over 93% of all patients achieved SVR. Treating for 24 weeks or using RBV was no more effective than 12 weeks of treatment with just simeprevir and sofosbuvir alone, without RBV. The SVR rate in patients with genotype 1B or genotype 1A without the Q80K mutation was 100%. Patients with genotype 1A and the Q80K mutation had an SVR rate of about 90%. Although the regulatory authorities did not specifically approve the combination of simeprevir and sofosbuvir for the treatment of patients with HCV, the approval by the US Food and Drug Administration states that simeprevir and sofosbuvir are 'indicated for the treatment of chronic HCV infection as part of a combination antiviral regimen'. This opens the door for the use of these agents along to treat patients with HCV genotype 1 and provides a cheaper, shorter and probably superior SVR than 24 weeks of sofosbuvir and RBV.

Identification of Patients With Hepatitis C Virus

An estimated 4 million persons in the United States and 300 million persons worldwide are infected with HCV.^[1] In the United States, the vast majority were infected in the 1960–1980s through the transfusion of blood products and injection drug use. Many of these patients are asymptomatic and have evaded detection for many years. The need to identify these patients is why the Center for Disease Control and the US Preventive Services Task Force has recommended that all persons born between the years of 1945–1965 be screened for HCV.^[26*,27*] If all persons in these birth cohort years were screened, it is estimated that 75% of all persons with HCV in the United States would be identified.

Conclusion

It is now possible to cure HCV in the vast majority of patients with chronic HCV. SVR rates of 80–90% can be routinely achieved in patients with all HCV genotypes in as little as 12–24 weeks. Of the antiviral agents currently available, sofosbuvir appears to be the easiest to manage, the most efficacious and the antiviral agent with the broadest of indications. Patients with HCV genotypes 1, 4, 5 and 6 can be treated with sofosbuvir, PEGINF and RBV for 12 weeks. SVR rates of 90% or better are achieved. Patients with genotype 1 who are unable to tolerate PEGINF and patients with HCV genotype 3 can be treated with sofosbuvir and RBV for 24 weeks. SVR rates in these patients range from 75 to 83%. Patients with genotype 2 can be treated with sofosbuvir and RBV for 12 weeks with an SVR exceeding 90%. Simeprevir offers an SVR of about 80%, but requires 24 weeks of PEGINF and RBV. Patients with HCV genotype 1A and the Q80K mutation have SVR rates that are significantly reduced. Perhaps the best use for simeprevir is with sofosbuvir for 12 weeks in patients with HCV genotype 1. Our ability to eradicate HCV is on the horizon. However, this cannot be achieved unless patients are recognized and this will require screening in those persons at greatest risk, which is now defined by the year of their birth.

References

1. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206.

2. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405–2416.

3. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207–1217.

4. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428; 8.

5. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365:1014–1024.

6. Fontaine H, Hezode C, Dorival C, et al. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non responders treated in the French early access program (anrs co20-CUPIC). J Hepatol 2013; 58 (Suppl 1):S27.

7. Bourlie` re M, Wendt A, Fontaine H, et al. How to optimize HCV therapy in genotype 1 patients with cirrhosis. Liver Int 2013; 33 (Suppl 1):46–55.

8. Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333+/_ ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol 2013; 58 (Suppl; abstr 3).

9. Everson GT, Sims KD, Rodriguez-Torres M, et al. Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. J Hepatol 2013; 58 (Suppl; abstr 1423).

10. Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl j Med 2013; 369:630–639.

11. Gane E, Hyland R, Ding X, et al. ELECTRON: 100% Suppression of Viral Load through 4 Weeks' Posttreatment for Sofosbuvir + Ledipasvir (GS-5885) + RBV for 12 Weeks in Treatment-naive and –experienced Hepatitis C Virus GT 1 Patients. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA, 2013. Abstract 41LB.

12. Manns M, Marcellin P, Poordad FPF, et al. Simeprevir (TMC435) with pegylated interferon/ribavirin for the treatment of chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-2, a phase 3 trial. J Hepatol 2013; 58 (Suppl; abstr 1413).

13. Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatmentnaive patients: results from QUEST-1 a phase III trial. J Hepatol 2013; 58 (Suppl 1):S574.

14. Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: Final SVR24 results of the ASPIRE trial. J Hepatol 37:56. (suppl abstract 2).

15. Sulkowski MS, Asselah T, Lalezari J, et al. Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV: SILEN-C1 trial. Hepatology 2013; 57:2143–2154.

16. Sulkowski MS, Bourlie` re M, Bronowicki JP, et al. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 2013; 57: 2155–2163.

17. Palanisamy N, Danielsson A, Kokkula C, et al. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res 2013; 99:12–17.

18. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887.
**This is the first study to demonstrate the effectiveness of sofosbuvir for the treatment of patients with chronic HCV.

19. Jacobon IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotypes 2 or 3 in patients without treatment options. N Engl J Med 2013; 368:1867–1877.
**This is the first manuscript to demonstrate that an all oral interferon-free regimen can lead to SVR for patients with chronic HCV.

20. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology 2013; 58 (Suppl Abstract 1085).

21. Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study. Hepatology 2013; 58 (Suppl Abstract LB4).

22. Sulkowski MS, Rodriguez-Torres M, Lalezari JP, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected With HIV (PHOTON-1). Hepatology 2013; 58 (Suppl Abstract 212).

23. Curry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology 2013; 58 (Suppl); Abstract 213.

24. Charlton MR, Gane EJ, Manns MP, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study. Hepatology 2013; 58 (Suppl Abstract LB2).

25. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once daily regimen of simeprevir plus sofosbuvir with or without ribavirin in cirrhotic and noncirrhotic HCV genotype treatment naive and prior null-responder patients. The COSMOS study. Hepatology 2013; 58 (Suppl AASLD abstract LB3).

26. Moyer VA, and the U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2013; 159:349–357.
*This study demonstrates the importance of baby boomer cohort screening to detect persons infected with HCV.

27. Smith BD, Morgan RL, Beckett GA, et al. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med 2012; 157:817–822.
* This study demonstrates the importance of baby boomer cohort screening to detect persons infected with HCV.

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Simeprevir approved in the European Union for the treatment of adults with hepatitis C genotype 1 and 4 infection

• OLYSIO™ (Simeprevir) provides a new triple therapy treatment option, as well as the first ever 12-week interferon-free and ribavirin independent treatment regimen, in combination with sofosbuvir, for appropriate patients in Europe

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that simeprevir has been granted marketing authorisation by the European Commission (EC) for the treatment of adults with genotype 1 and 4 chronic hepatitis C in combination with other medicinal products.

“The approval of simeprevir in Europe is a further step in our partner's global strategy to enable an improved treatment for hepatitis C patients. This also means that Medivir will now be able to offer this treatment to patients in the Nordic region, where we have the marketing rights“, says Maris Hartmanis, CEO, Medivir.

This marketing authorisation represents a significant milestone in the development of new triple therapy hepatitis C (HCV) treatment options for genotype 1 and 4 patients. It also includes simeprevir as part of an all oral 12-week interferon-free direct-acting antiviral (DAA) regimen with or without ribavirin (RBV), in genotype 1 or 4 patients, who are intolerant to or ineligible for IFN treatment.

* Treatment-naïve and prior relapse patients with cirrhosis who are co-infected with HIV should receive 48 weeks of treatment. Treatment with simeprevir must be initiated in combination with PegIFN + RBV and administered for 12 weeks and then followed by an additional 36 weeks of PegIFN + RBV.

The EC approval for simeprevir with PegIFN + RBV is based on a clinical trial programme involving three pivotal phase III studies, with over 1000 patients. The trials; QUEST-1, QUEST-2 and PROMISE, explored the use of simeprevir in combination with PegIFN/RBV in treatment-naïve patients and patients who have relapsed after prior interferon-base treatment. All three studies met their primary endpoints and demonstrated that simeprevir in combination with PegIFN/RBV, achieves significant cure rates when compared with PegIFN/RBV alone.

The EC approval for the combination of simeprevir and sofosbuvir also contains the phase II study, COSMOS. This was based upon prior null responder and treatment-naïve patients.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 13.00 CET on 16 May 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S. and in March 2014 in Russia. Following the EMA approval, it is anticipated that simeprevir will be available across a number of European Union countries in conjunction with reimbursement, in the second half of 2014.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

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Helping Patients with Liver Disease Choose Wisely

As in every field of medicine, there are certain tests and procedures that patients with liver disease and their physicians should discuss to ensure they are truly necessary and will improve care. The AASLD is proud to partner with the ABIM Foundation's Choosing Wisely® campaign to identify specific tests, procedures, and treatments that may be unnecessary and may even cause harm.

AASLD has made recommendations on a wide range of liver conditions that affect patients with:

• Cirrhosis and small varices
• Hepatitis encephalopathy
• Hepatitis C virus
• Benign focal liver lesions

View the specific recommendations [PDF]

AASLD's list was developed by a group of experts to broadly represent varying practice settings and subspecialty expertise within the field of hepatology after soliciting the input of the entire AASLD membership. The recommendations that AASLD made are based on the most current evidence found in scientific literature.

Health care in America often includes practices that may provide little, if any, benefit to patients. Some estimate that up to 30 percent of health care spending goes toward duplicative or unnecessary interventions. The Choosing Wisely® campaign of the ABIM Foundation is one way of encouraging conversations between physicians and patients to avoid these unnecessary tests or procedures and improving overall health.

Since launching in April 2012, nearly 100 national, regional and state medical specialty societies, health collaboratives and consumer groups have become Choosing Wisely partners. The campaign has released 54 lists covering more than 250 tests and procedures that the specialty society partners say are overused or inappropriate.

“AASLD is pleased to be working with the ABIM Foundation to help streamline the care of our patients with liver disease and spark conversations with their physicians about the care that is best for them,” said Adrian M. Di Bisceglie, AASLD president.

To view the specific recommendations, click here. [PDF]To learn more about Choosing Wisely and to view the complete lists and additional detail about the recommendations and evidence supporting them, visit www.ChoosingWisely.org.

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About the ABIM Foundation
The mission of the ABIM Foundation is to advance medical professionalism to improve the health care system. We achieve this by collaborating with physicians and physician leaders, medical trainees, health care delivery systems, payers, policy makers, consumer organizations and patients to foster a shared understanding of professionalism and how they can adopt the tenets of professionalism in practice. To learn more about the ABIM Foundation, visit www.abimfoundation.org, read our blog blog.abimfoundation.org, connect with us on Facebook or follow us on Twitter.

About Choosing Wisely®
First announced in December 2011, Choosing Wisely® is part of a multi-year effort led by the ABIM Foundation to support and engage physicians in being better stewards of finite health care resources. Participating specialty societies are working with the ABIM Foundation and Consumer Reports to share the lists widely with their members and convene discussions about the physician's role in helping patients make wise choices. Learn more at www.ChoosingWisely.org.

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U.S. health officials urge use of HIV pill for at-risk individuals

CHICAGO Wed May 14, 2014 7:11pm EDT

(Reuters) - U.S. health officials on Wednesday issued new recommendations urging healthcare workers to consider offering an HIV prevention pill to healthy individuals who are at substantial risk for HIV infection.

The guidelines, issued by the U.S. Centers for Disease Control and Prevention and the U.S. Public Health Service, involve the use of pre-exposure prophylaxis or PrEP, a strategy in which at-risk individuals take a daily dose of an antiretroviral drug to reduce their risk of HIV infection.

The strategy builds on a landmark 2010 study that found Gilead Sciences Inc's Truvada - a pill already widely used to treat the human immunodeficiency virus - was more than 90 percent effective at preventing HIV infections among test subjects who took the drug as prescribed.

According to the new guidelines, healthcare providers should consider PrEP for anyone who meets specific risk criteria, such as being in a relationship with an HIV-infected partner or having sex without condoms with partners known to be at risk for HIV, such as injecting drug users.

The guidelines offer the first comprehensive guidance from the CDC, replacing interim guidance that emerged after studies showed PrEP to be effective in different patient populations.

The CDC now estimates as many as 275,000 uninfected gay men and 140,000 heterosexual couples, in which one partner is HIV-infected, could benefit from PrEP.

Some 1.2 million people in the United States live with HIV, and new infections are estimated at 50,000 each year.

(Reporting by Julie Steenhuysen; Editing by Tom Brown)

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