Nitazoxanide {NTZ} Novel Agent for Hep C?

Nitazoxanide: Beyond Parasites Toward a Novel Agent for Hepatitis C
Gastroenterology March 2009"numerous questions arise about how best to utilize this oral agent with many similar antiviral effects of interferon. Is there any role for NTZ monotherapy?.....The biggest unanswered question remains as to whether NTZ is sufficiently potent to enhance therapeutic response in patients with difficult-to-treat characteristics, such as genotype 1, high viral levels, African Americans, and previous nonresponders to peginterferon and ribavirin, namely, those frequently found in the US population. Combining NTZ with specific targeted antiviral therapy in HCV (STAT-C agents) is also of interest. Recent in vitro data of NTZ with NS5b polymerase inhibitors and the NS3/4 protease inhibitor telaprevir have yielded promising results.24 NTZ seems to have a high barrier to resistance, synergistic effects on HCV replication when combined with direct antivirals, and some activity against common, drug-resistant variants that form under selective pressure of the polymerase or protease inhibitors.7 Peginterferon and ribavirin remain the cornerstones of therapy, although it is exciting (but a bit premature) to speculate what niche NTZ could potentially fill in future combination therapy. As we continue our quest for an oral “HCV cocktail,” NTZ may find its way into the mix, but first will need to further prove itself in additional, well-designed studies."
Article Outline
See “Improved virologic response in chronic hepatitis C genotype 4 patients given nitazoxanide, peginterferon, and ribavirin” by Rossignol JF, Elfert A, El-Gohary Y, et al on page 856.
Nitazoxanide (NTZ), a thiazolide with activity against anaerobic bacteria, protozoa, and viruses, was the first drug licensed in the United States for the treatment of Cryptosporidium parvum.1 Its antiviral properties against hepatitis B (HBV) and hepatitis C (HCV) were coincidentally discovered when the drug was being evaluated to treat cryptosporidiosis in HIV patients coinfected with HBV or HCV.2 Evaluation of NTZ for chronic HCV was facilitated by studies of the compound for the treatment of infectious diarrhea in Egypt, where there is also very high prevalence of HCV infection, predominantly genotype 4, which resulted from mass immunization for schistosomiasis in the 1950s.3. Although there is substantial literature on NTZ as a safe and effective antiparasitic agent, the initial report of its antiviral properties in HCV-infected patients came in 2008 from Rossignol et al.4 This study was a double-blind, placebo-controlled trial of 50 patients with HCV genotype 4 treated with NTZ monotherapy (500 mg twice daily) for 24 weeks. Remarkably, 7 of 23 patients (30%) had an end-of-treatment response and 4 of 23 (17%) had a sustained virologic response (SVR) compared with none in the placebo arm. Of note, all patients attaining an SVR had a baseline HCV RNA < 400,000 IU/mL. In this issue of Gastroenterology, Rossignol et al5 present the results of a randomized, controlled trial evaluating the efficacy of NTZ in combination with peginterferon and ribavirin. Patients with genotype 4 from 2 Egyptian centers were randomized to receive NTZ monotherapy for 12 weeks followed by either peginterferon plus NTZ (dual therapy) or peginterferon plus ribavirin plus NTZ (triple therapy) for an additional 36 weeks; a control arm received standard dosing of peginterferon and ribavirin for 48 weeks. Rapid virologic response (RVR; undetectable HCV RNA at week 4 of combination therapy) was observed in 38% of the standard of care group, 54% of the dual therapy group, and 64% of the triple therapy group. Complete early virologic response (undetectable HCV RNA at 12 weeks of combination therapy) occurred in 70%, 68%, and 86%, respectively, and the SVR rates at 24 weeks posttreatment were 50%, 61%, and 79%. RVR and SVR rates were significantly higher in patients receiving triple therapy compared with the standard of care. Adverse events were equal among treatment groups except for more anemia noted with ribavirin use. The authors conclude that NTZ with peginterferon and ribavirin increases RVR and SVR rates compared with standard therapy without increasing adverse events. The rationale for the 12-week lead-in phase with NTZ monotherapy is interesting and relates to the proposed mechanism of action of NTZ. Cellular rather than direct antiviral pathways were hypothesized to be affected by NTZ. NTZ effectively inhibits HCV replication in the replicon systems for genotypes 1a and 1b.6 Pretreatment with 3 days of NTZ followed by a combination of NTZ plus interferon resulted in a 3-fold decrease in viral RNA.7 Elazar et al8 have recently proposed that NTZ increases phosphorylation of dsRNA-dependent protein kinase (PKR) and induces eukaryotic initiation factor 2 alpha (eIF2a) which is an important factor in the innate immune response (Figure). Among the molecules with important biological functions induced by type I interferons, PKR plays a critical role in the antiviral defense mechanism of the host. PKR phosphorylates eIF2a in response to viral infection of a cell, which ultimately inhibits translation of viral RNA.9 Several studies have shown that HCV proteins may directly bind to PKR, thereby inhibiting autophosphorylation and obscuring the interferon sensitivity-determining region.10, 11 This proposed virus–host interaction may be important; NTZ seems to improve interferon activity against the virus. We look forward to further elucidation of the role of NTZ in this critical antiviral immune pathway and whether this proposed mechanism is operative in vivo.
Figure. NTZ increases phosphorylation of PKR and induces eIF2a, which ultimately inhibits translation of viral RNA. The authors acknowledge several shortcomings in the present study, including the fact that it was not blinded to physicians or participants and that it was conducted only in genotype 4 patients. Genotype 4 virus, although it is the most genetically diverse of the HCV viruses, is more similar to genotype 1 than to the other genotypes. The SVR rate to peginterferon and ribavirin for patients with genotype 4, ranging between 65% and 79%,3, 12 is intermediate to those reported for genotypes 2 and 3. Middle Eastern patients seem to have a higher response rate of their genotype 4 infections, perhaps related to ethnicity or to the 4a subtype. In the featured study by Rossignol et al,5 the standard of care arm had an SVR of only 50%, which is slightly lower than several series of Middle Eastern patients with genotype 4a infection. Their standard of care group also had a higher body mass index than either the dual or triple therapy groups with NTZ, which can adversely affect response to peginterferon and ribavirin therapy.13. Genotype 1 infection, with an SVR rate of approximately 50%, has remained the major focus of clinical trials utilizing intensified regimens of peginterferon and ribavirin or new classes of drugs. The US population has proven repeatedly to be a more difficult group to treat than many others with lower SVR rates, perhaps due in part to higher body mass indexes and a greater racial variation. African Americans harbor predominantly genotype 1 virus and have remarkably lower overall response rates to peginterferon and ribavirin (approximately 26%–28%) compared with Caucasians..14, 15 Based on data from the Virahep-C study group, African Americans may have “blunted” immune responses to interferon-based therapy when compared with Caucasians.16 As investigations of the role of NTZ in anti-HCV treatment continue, we hope that adequate numbers of African Americans will be recruited to determine whether this drug can improve outcomes in African-American patients with chronic HCV. Overall, only about 5% of patients with advanced fibrosis or cirrhosis were included in the current study. These represent inadequate numbers to comment extensively on the safety and efficacy of NTZ in the setting of cirrhosis. Both of the Phase II studies in genotype 1, treatment-naïve, and nonresponder patients being conducted in the United States will include subjects with well-compensated cirrhosis. This will hopefully provide further safety and efficacy data on this important group of patients who are known to have lower response rates to peginterferon and ribavirin..17, 18 Because NTZ's antiviral properties were first observed in patients coinfected with HCV and HIV and there are long-term safety data in this population, it would also be a logical progression to include this group in a future study. The coinfected population has lower response rates to peginterferon and ribavirin, and often more pronounced side effects,19, 20, 21 so studying NTZ in this population is warranted. A key secondary endpoint in this study was RVR, which revealed that triple therapy had a significantly higher RVR than standard of care (64% vs 38% respectively; P = .048). It is worth noting that during the 12-week NTZ monotherapy lead-in phase, both the double and triple therapy arms had a very modest but significant decrease in viral load from baseline, yet only the triple therapy group, which contained ribavirin, had a significant difference in RVR. Although RVR is a more important predictor of treatment response to peginterferon and ribavirin than is genotype,12 the validity of using it as a predictor after a 12-week lead-in phase (week 16 on treatment) will need to be explored. From this study, it is difficult to ascertain the role of ribavirin as the relapse rates were 15% and 4% in the dual therapy and triple therapy arms, respectively, but significantly higher in the standard of care group at 33%, thereby suggesting that NTZ was associated with reduced relapse rates. Rossignol et al22 recently presented preliminary data from 40 treatment-naïve patients who were all treated with 4 weeks of NTZ followed by 36 weeks of dual therapy with peginterferon alpha 2a and NTZ.22 Utilizing historical controls, SVR rates with the abbreviated lead-in phase and no ribavirin were 80%, comparable with the triple therapy arm from the present study. Based on these data, the lead-in phase in Phase II studies currently underway will be only 4 weeks. As a cautionary note, ribavirin has continued to be necessary to decrease the relapse rate, even in combination with newer direct antivirals like the NS3/4 protease inhibitor telaprevir.23 Clearly, the role of ribavirin in NTZ-containing regimens needs careful evaluation.
Overall, the current study revealed provocative data in genotype 4 HCV infection that will need additional confirmation in larger studies. Thus, NTZ may add to our armamentarium of agents that have activity against HCV, although numerous questions arise about how best to utilize this oral agent with many similar antiviral effects of interferon. Is there any role for NTZ monotherapy? The modest antiviral response to NTZ monotherapy in the present study contrasts sharply with the antiviral response from an earlier study where 30% of patients had undetectable viremia after 24 weeks of NTZ monotherapy.4 It is unlikely that the longer duration of NTZ monotherapy in the earlier study would fully explain these differences and it is unlikely that NTZ monotherapy will be of great benefit for the majority of patients. The more realistic role for NTZ in the near future would be in combination with peginterferon and ribavirin, as is currently being evaluated. Shortened therapy may be possible if the RVR rates continue to be high in subsequent studies. The biggest unanswered question remains as to whether NTZ is sufficiently potent to enhance therapeutic response in patients with difficult-to-treat characteristics, such as genotype 1, high viral levels, African Americans, and previous nonresponders to peginterferon and ribavirin, namely, those frequently found in the US population. Combining NTZ with specific targeted antiviral therapy in HCV (STAT-C agents) is also of interest. Recent in vitro data of NTZ with NS5b polymerase inhibitors and the NS3/4 protease inhibitor telaprevir have yielded promising results.24 NTZ seems to have a high barrier to resistance, synergistic effects on HCV replication when combined with direct antivirals, and some activity against common, drug-resistant variants that form under selective pressure of the polymerase or protease inhibitors.7 Peginterferon and ribavirin remain the cornerstones of therapy, although it is exciting (but a bit premature) to speculate what niche NTZ could potentially fill in future combination therapy. As we continue our quest for an oral “HCV cocktail,” NTZ may find its way into the mix, but first will need to further prove itself in additional, well-designed studies.
References
1. 1Rossignol JF. Nitazoxanide in the treatment of acquired immune deficiency syndrome-related cryptosporidiosis: results of the United States compassionate use program in 365 patients. Aliment Pharmacol Ther. 2006;24:887–894. MEDLINE CrossRef
2. 2Rossignol JF, Keeffe EB. Thiazolides: a new class of drugs for the treatment of chronic hepatitis B and C. Future Microbiol. 2008;3:539–545.
3. 3Kamal SM, Nasser IA. Hepatitis C genotype 4: what we know and what we don't yet know. Hepatology. 2008;47:1371–1383. CrossRef
4. 4Rossignol JF, Kabil SM, El-Gohary Y, et al. Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Aliment Pharmacol Ther. 2008;28:574–580. CrossRef
5. 5Rossignol JF, Elfert A, El-Gohary Y, et al. Improved virologic response in chronic hepatitis C genotype 4 patients given nitazoxanide, peginterferon, and ribavirin. Gastroenterology. 2009;136:856–862. Abstract Full Text Full-Text PDF (487 KB) CrossRef
6. 6Korba BE, Elazar M, Lui P, et al. Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide. Antimicrob Agents Chemother. 2008;52:4069–4071. CrossRef
7. 7Korba BE, Montero AB, Farrar K, et al. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antiviral Res. 2008;77:56–63. CrossRef
8. 8Elazar MLM, McKenna S, et al. Nitazoxanide (NTZ) is an inducer of eIF2a and PKR phosphorylation. Hepatology. 2008;48:1151A.
9. 9Garcia MA, Gil J, Ventoso I, et al. Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev. 2006;70:1032–1060. MEDLINE CrossRef
10. 10Gale MJ, Korth MJ, Tang NM, et al. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology. 1997;230:217–227. MEDLINE CrossRef
11. 11Taylor DR, Shi ST, Romano PR, et al. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science. 1999;285:107–110.. MEDLINE CrossRef
12. 12Fried MW, Shiffman M, et al. Rapid virological response is a more important predictor of sustained virological response (SVR) than genotype in patients with chronic hepatitis C virus infection. J Hepatol. 2008;48:55.
13. 13Bressler BL, Guindi M, Tomlinson G, et al. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology. 2003;38:639–644. MEDLINE CrossRef
14. 14Jeffers LJ, Cassidy W, Howell CD, et al. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology. 2004;39:1702–1708. MEDLINE CrossRef
15. 15Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470–477. Abstract Full Text Full-Text PDF (133 KB) MEDLINE CrossRef
16. 16Rosen HR, Weston SJ, Im K, et al. Selective decrease in hepatitis C virus-specific immunity among African Americans and outcome of antiviral therapy. Hepatology. 2007;46:350–358. CrossRef
17. 17Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982. CrossRef
18. 18Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965. Abstract Full Text Full-Text PDF (110 KB) MEDLINE CrossRef
19. 19Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451–459. CrossRef
20. 20Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839–2848. CrossRef
21. 21Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438–450. CrossRef
22. 22Rossignol JF EA, Keeffe EB. Evaluation of a 4 week lead-in phase with nitazoxanide (NTZ) prior to peginterferon (PegIFN) plus NTZ for treatment of chronic hepatitis C: final report. Hepatology. 2008;48:344A.
23. 23Dusheiko DM, Pol S, et al. Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon-alfa-2a with or without ribavirin: further interim analysis results of the PROVE2 study. J Hepatol. 2008;48:S26. Full-Text PDF (59 KB) CrossRef
24. 24Korba BE EM, Lui P, et al. Potential role for nitazoxanide in combination with STAT-C agents for the inhibition of HCV replication without the development of resistance. Hepatology. 2008;48:356A.