July 25, 2013

Citations Highlight Promising New Drugs for Hepatitis C Infection


July 2013

by David W. Sharp

The U.S. Centers for Disease Control and Prevention has recently revised its guidance on testing for infection with hepatitis C virus (HCV). Testing for anti-HCV, recommended for known at-risk groups for the past 15 years (and, in 2012, suggested as routine in the birth cohort 1945-65, the so-called “baby boomers”) does not distinguish between past and ongoing infection. The latest guidance includes tests for HCV RNA; these tests do make the distinction. Another reason for the revision is “significant advances in the development of antiviral agents with improved efficacy against HCV” (MMWR 62[18]: 357-61, 2013). Drawing on exclusive citation data from Thomson Reuters Web of Science, a new Top Ten list, with papers #4 and #8, provides the opportunity for an update on those agents.

What’s Hot in Medicine
Rank Paper Citations This Period (Nov-Dec 12) Rank Last Period (Sep-Oct 12)
1 R. Siegel, et al., “The impact of eliminating socioeconomic and racial disparities on premature cancer deaths,” CA-A Cancer J., 61(4): 212-36, Jul-Aug 2011. [American Cancer Soc., Atlanta, GA] 149 1
2 P.B Chapman, et al., “Improved survival with vemurafenib in melanoma with BRAF V600E mutation,” New Engl. J. Med., 364(26): 2507-16,  30 June 2011. [26 institutions worldwide] 121 2
3 M.R. Patel, et al., “Rivaroxaban versus warfarin in nonvalvular atrial fibrillation,” New Engl. Med., 365(10): 883-91, 8 September 2011. [12 institutions worldwide] 77 4
4 F. Poordad, et al., “Boceprevir for untreated chronic HCV genotype 1 infection,” New Engl. J. Med., 364(13): 1195-1206, 31 March 2011. [12 institutions worldwide] 74 9
5 C.R. Smith, et al., “Transcatheter versus surgical aortic-valve replacement in high-risk patients,” New Engl. J. Med., 364(23): 2187-98, 9 June 2011. [12 institutions worldwide] 67 10
6 C.B. Granger, et al., “Apixaban versus warfarin in patients with atrial fibrillation,” New Engl. J. Med., 365(11): 981-92, 15 September 2011. [26 institutions worldwide] 61 7
7 M. Gerlinger, et al., “Intratumor heterogeneity and branched evolution revealed by multiregion sequencing,” New Engl. J. Med., 366(10): 883-92, 8 March 2012. [7 institutions worldwide] 60 +
8 I.M. Jacobson, et al., “Telaprevir for previously untreated chronic hepatitis C virus infection,” New Engl. J. Med., 364(25): 2405-16, 23 June 2011. [22 institutions worldwide] 59 +
9 M.S. Cohen, et al., “Prevention of HIV-1 infection with early antiretroviral therapy,” New Engl. J. Med., 365(6): 493-505, 11 August 2011. [27 institutions worldwide] 57 3
10 E. Scallan, et al., “Foodborne illness acquired in the United States—Major pathogens,” Emerging Infectious Dis., 17(1): 7-15, January 2011. [Ctrs. Disease Control, Atlanta, Ga.] 55 +

SOURCE: Thomson Reuters Web of Science
NB. Only papers indexed by Thomson Reuters since January 2011 are tracked. The “+” sign indicates that the paper was not ranked in the Top Ten during the last period. In the event that two or more papers collected the same number of citations in the most recent bimonthly period, total citations to date determine the rankings

HCV infection is a serious public-health issue. World Health Organization global estimates include 150 million people with chronic HCV infection and 350,000 deaths from HCV-related liver disease and 3 to 4 million new infections annually. Many cases remain undiagnosed; there is currently no vaccine; and available treatments are not ideal. The six known HCV genotypes can respond differently; a mainstay of therapy has been interferon, a tricky drug to manage; and about 60% of patients with HCV genotype 1 infection are not cured by up to 48 weeks of interferon plus ribavirin (J.G. McHutchison et al,  New Engl. J. Med., 361[6]: 580-93, 2009). When ScienceWatch last covered the therapeutic options, the best on offer seemed to be a combination of polyethyleneglycolated interferon (PEG interferon) and the antiviral agent ribavirin. The picture has recently been changing, and rapidly, with the development of compounds that act more directly on HCV. The two current front-runners in terms of both clinical trial activity and publications and citations are boceprevir and telaprevir (#4 and #8, respectively), still given in combination with the former dual therapy, but there is huge interest in second-generation candidates (vaniprevir, sofosbuvir and MK-5172, to name but a few).


There is not yet much long-term clinical experience with any of these new drugs, and issues such as resistance, adverse reactions, and differing response rates for different HCV genotypes will require close attention. However, sustained virologic responses (SVR) are now being reported in 90% or more of patients treated with direct-acting antivirals, and there is the welcome possibility of interferon-free regimens. A New England Journal of Medicine editorial in May of this year, accompanying papers reporting four trials of sofosbuvir, foresaw an imminent radical change in clinical practice, noting that“interferon is in retreat,” although the interferonologist (a reference to the very specialized handling needed for this agent) is not yet down and out (J.P.H. Drenth, New Engl. .J Med., 368[20]: 1931-21, 2013). Other observers, meanwhile, see “the nail in the coffin for HCV” (M.P. Mans., M. Cornberg,, Lancet Infect. Dis., 13[5]: 378-79), or speak of at least interferon-sparing regimens (G. Dusheiko, T. Burney, in a commentary on a phase-2 trial of sofosbuvir published in mid-June [Lancet, 381(9883): 2063-5, 2013). ScienceWatchreaders will want to share this optimism, but while we wait for more evidence on the newest drugs let us focus on the two first-generation agents, both of which have been the subject of large numbers of papers and have been attracting high citation rates in the first half of 2013.


The trial on patients with previously untreated HCV infection (#4) should be considered in parallel with the companion paper on the use of boceprevir in those previously treated (B.R. Bacon, et al,. New Engl. J. Med., 364[13]: 1207-17, 2011; 46 citations this period). With interferon/ribavirin as the standard-of-care control, SVR rates were 21% in previously treated patients and 23% and 40% in black and non-black controls who had not been treated before, compared with the much higher responses found when boceprevir was added of around 60% in treated and untreated depending on the drug regimen used (but lower in blacks). Clinical trials with telaprevir have followed a similar pattern and have similar success in terms of SVR data, and again it is the study in untreated patients (#8) that has been receiving the greater number of citations; the findings from the companion trial here were published in 2010 (J.G. McHutchison, et al., New Engl. J. Med., 362[14]: 1292-303, 2010; a report now too “old” for Hot Papers coverage but cited more than 260 times to date). These findings and others (e.g., S. Zeuzem, et al., New Engl. J. Med., 364[25]: 2417-28, 2011; 37 cites this period) certainly are encouraging, but clinicians may be holding back in the expectation of something even better. In the 12 months following the U.S. Food and Drug Administration’s licensing of these two drugs, only 18.7% of HCV patients were on them, perhaps because of “concerns about side effects and recognition that more effective medications could be available in the future” (E.Y. Chen, et al., Clin. Gastroenterol. Hepatol. April 16, 2013; doi 10.1016/j.cgh.2013.03.032).

A former deputy editor of The Lancet, David W. Sharp, M.A. (Cambridge), is a freelance writer living in Minchinhampton, Gloucestershire, UK.

The data and citation records included in this report are from Thomson Reuters Web of KnowledgeSM. Web of KnowledgeSM is a registered trademark of Thomson Reuters. All rights reserved.



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