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editorial

Th e n e w e n g l a n d j o u r n a l o f me dicine

HCV Treatment No More Room for Interferonologists?Joost P.H. Drenth, M.D., Ph.D.

The landscape of therapy for hepatitis C virus

(HCV) infection is changing rapidly. Until recent-

ly, the standard of care for HCV infection was a

combination of peginterferon and ribavirin. Our

increased understanding of the basic biology of

HCV led to the identif ication of specific proteins

involved in the replication of the virus. These

proteins can be targeted by protease and poly-

merase inhibitors.

Two years ago, the advent of protease inhibi-tors, such as telaprevir and boceprevir, profound-ly affected the field.1,2 These agents improvedthe likelihood of cure but came with a numberof inherent limitations. Protease inhibitors do nothave antiviral activity in HCV genotypes otherthan the predominant genotype 1, which leavesat least five other HCV genotypes without cover-age. Moreover, protease inhibitors can promoteviral resistance, which usually signals therapeu-tic failure, and have multiple pharmacokineticinteractions with other drugs. Finally, proteaseinhibitors need to be administered with peginter-feron and ribavirin, two drugs with extensive andwell-established side-effect profiles that are aggra-vated by the addition of telaprevir or boceprevir.

Clinicians who treat patients with HCV infec-tion have learned to accept and treat adverse ef-fects as an integral part of patient care, but theinclusion of protease inhibitors in the therapeutic

arsenal has added a layer of complexity. Indeed,the major challenge of contemporary interferontherapy is adequate management of side effects.Physicians and patients are ready for less toxictherapeutic options.

Two groups of investigators (Jacobson et al.3and Lawitz et al.4) now suggest in the Journalthatchange is about to happen. They describe theuse of sofosbuvir, a novel polymerase inhibitor,in a series of four experimental studies targetingpatients with HCV infection. In three random-

ized trials FISSION, POSITRON, and FUSION investigators focused on patients with HCVgenotype 2 or 3, as seen in everyday clinicalpractice, including patients who had received noprevious treatment, those who were unwilling totake interferon or had unacceptable side effects,

and those who did not have a response to previ-ous therapy. All the studies had a similar endpoint: a sustained virologic response at 12 weeksafter the end of therapy. In addition, in the single-group, open-label NEUTRINO study, investigatorsstudied the use of a sofosbuvir-based regimenin patients with genotype 1, 4, 5, or 6 infection.

The FISSION study examined the efficacy of12 weeks of sofosbuvir plus ribavirin, as com-pared with the standard of care, peginterferonalfa-2a plus ribavirin, administered for 24 weeks.Standard therapy was successful in 78% of pa-tients with genotype 2 infection and 63% ofthose with genotype 3 infection, as comparedwith rates of 97% and 56%, respectively, withthe sofosbuvir-based regimen.

The POSITRON study evaluated a populationthat was not deemed to be eligible for interferon-based therapy and compared 12 weeks of sofos-buvir plus ribavirin with placebo. The primaryreasons for ineligibility were a preexisting psy-chiatric disorder (57%) or autoimmune disorder(19%). None of the patients in the placebo group

achieved the end point, but 93% of those withgenotype 2 infection and 61% of those with geno-type 3 infection had a sustained virologic re-sponse with sofosbuvir plus ribavirin.

The FUSION study, which targeted patientswithout a sustained response to interferon-basedtherapy, compared a 12-week regimen of sofos-buvirribavirin with a 16-week regimen. Four ad-ditional weeks of treatment made a difference,with an increase in the rate of sustained viro-logic response from 86% to 94% in patients with

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editorial

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genotype 2 infection and from 30% to 62% inthose with genotype 3 infection.

Finally, the investigators captured some evi-dence for the pangenotypic anti-HCV propertiesof sofosbuvir. In the NEUTRINO study, patientswith genotype 1 infection (89%), genotype 4 in-fection (9%), or genotype 5 or 6 infection (2%)

who received 12 weeks of treatment with a com-bination of sofosbuvir, peginterferon, and riba-virin had a collective rate of sustained virologicresponse of 90%.

The speed of development of drugs to treatHCV infection is unprecedented. The publicationof clinical data with respect to sofosbuvir comesonly 3 years after the publication of the chemi-cal discovery of the compound.5 Although thedata from the four trials discussed here are en-couraging, the design of the trials may havesuffered from the intense competition that drug

companies face in this market. In the tower ofevidence-based medicine, randomized clinicaltrials are superior to open-label studies. However,of the four studies that are discussed here, onlythree were randomized, and only one was placebo-controlled. In addition, the results for sofosbuvirin these studies falls short of the findings re-ported for the drug in an earlier study by Ganeet al.,6 in which the rate of sustained virologicresponse was 100%. One of the reasons for thedifference may be that the design of the studyby Gane et al. was less rigorous than the de-signs of the studies discussed here. Also of note,the end point that was used in the four studiesdiffered from that used in the study by Ganeet al. The Food and Drug Administration onlyrecently approved an end point of a sustainedvirologic response at 12 weeks (rather than thepreviously approved 24 weeks) as acceptable forHCV trials.7

Our current therapy for HCV infection revolvesaround side-effect management in patients receiv-ing interferon, who require intense monitoring.

Current therapies are typically offered in dedi-cated centers by physicians (aptly termed inter-feronologists) who are well versed in dealing withthe toxic effects of interferon. Without alterna-tives to interferon therapy, we are pushing theenvelope in the acceptance of risks to certainpatients (e.g., those with a psychiatric history).The data from the sofosbuvir trials suggest thata radical change in clinical practice is imminent.But it may be premature to start dismantling thededicated centers now that interferon is in re-

treat, since ribavirin is still part of the mostsuccessful interferon-free regimens. Data fromthe study by Gane et al. suggest that excludingribavirin compromises the efficacy of sofosbuvir.The use of ribavirin has been associated withhemolytic anemia, a condition that requiresclose attention, especially in patients with the

most pressing need for treatment, such as thosewith cirrhosis. Even so, the studies by Jacobsonet al. and Lawitz et al. suggest an acceptablesafety profile for sofosbuvir plus ribavirin, withlow rates of anemia and leukopenia among pa-tients receiving this regimen, as compared withstandard-of-care therapy. On the other hand, anote of caution is appropriate, since long-termdata in larger populations are lacking, and rarebut irreversible adverse events still may emergewith wider use of sofosbuvir.

What are we to conclude from these studies?

The low incidence of side effects, the relativelyshort duration of treatment, and the pangeno-typic properties of the drugs are strong sellingpoints of a sofosbuvirribavirin regimen and willprobably lower the threshold for HCV treatmentfor both patients and physicians. The likely nextstep is to combine sofosbuvir with other direct-acting antivirals to enhance its potency. Is theinterferonologist down and out? I do not thinkso, but it is surely time for reeducation.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

From the Department of Gastroenterology and Hepatology,Radboud University Nijmegen Medical Center, Nijmegen, theNetherlands.

This article was published on April 23, 2013, at NEJM.org.

1. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatmentof HCV infection. N Engl J Med 2011;364:2417-28.2. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for prev i-ously treated chronic HCV genotype 1 infection. N Engl J Med2011;364:1207-17.3. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir forhepatitis C genotype 2 or 3 in patients without treatment op-tions. N Engl J Med 2013. DOI: 10.1056/NEJMoa1214854.4. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previouslyuntreated chronic hepatitis C infect ion. N Engl J Med 2013. DOI:10.1056/NEJMoa1214853.5. Sofia MJ, Bao D, Chang W, et al. Discovery of a -d-2-deoxy-2--fluoro-2--C-methyluridine nucleotide prodrug (PSI-7977)for the treatment of hepatitis C virus. J Med Chem 2010;53:7202-18.6. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide poly-merase inhibitor sofosbuvir plus ribavirin for hepatitis C. N EnglJ Med 2013;368:34-44.7. Chen J, Florian J, Carter W, et al. Earlier sustained virologicresponse endpoints for regulatory approval and dose selection ofhepatitis C therapies. Gastroenterology 2013 March 4 (Epubahead of print).

DOI: 10.1056/NEJMe1303818

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