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Sofosbuvir: an antiviral drug with potential efficacy against Zika infection

2016; Elsevier BV; Volume: 55; Linguagem: Inglês

10.1016/j.ijid.2016.12.011

1878-3511

Sandra E. Reznik, Charles R. Ashby,

Malaria Research and Control

•There is an 80% overlap in the amino acids of Zika virus (ZIKV) and hepatitis C virus (HCV) RNA polymerase, which binds sofosbuvir.•It is proposed that the anti-HCV drug, sofosbuvir, be used to treat symptomatic ZIKV infections.•Sofosbuvir (12-week regimen) has a favorable safety profile in HCV patients.•Sofosbuvir has not been reported to produce teratogenic or mutagenic effects in humans.•Sofosbuvir may reduce neurological problems in infants born to symptomatic mothers. Currently, there are no effective licensed vaccines or drugs available for the treatment of Zika virus (ZIKV) infections and financial support for their development is running short. It is suggested that sofosbuvir be considered for Zika infection. Sofosbuvir is used with other drugs for the treatment of hepatitis C virus (HCV) genotypes 1–6 infections. Zika is a member of the Flaviviridae family of viruses, which includes yellow fever virus, West Nile virus, dengue virus, St. Louis encephalitis virus, and HCV.1Weaver S.C. Costa F. Garcia-Blanco M.A. Koop A.I. Ribeiro G.S. Saade G. et al.Zika virus: history, emergence, biology, and prospects for control.Antiviral Res. 2016; 130: 69-80Crossref PubMed Scopus (477) Google Scholar The most common manifestations include a macular or papular rash, fever, arthralgia, retro-orbital pain, conjunctivitis, myalgia, and headache, and these resolve within 2 weeks.2Musso D. Gubler D.J. Zika virus.Clin Microbiol Rev. 2016; 29: 487-524Crossref PubMed Scopus (967) Google Scholar However, ZIKV outbreaks in the Americas and Pacific have been reported to be temporally linked to Guillain–Barré syndrome.2Musso D. Gubler D.J. Zika virus.Clin Microbiol Rev. 2016; 29: 487-524Crossref PubMed Scopus (967) Google Scholar, 3Petersen L.R. Jamieson D.J. Powers A.M. Honein M.A. Zika virus.N Engl J Med. 2016; 374: 1552-1563Crossref PubMed Scopus (885) Google Scholar Also, acute myelitis and meningoencephalitis have occurred in patients infected with ZIKV.2Musso D. Gubler D.J. Zika virus.Clin Microbiol Rev. 2016; 29: 487-524Crossref PubMed Scopus (967) Google Scholar, 3Petersen L.R. Jamieson D.J. Powers A.M. Honein M.A. Zika virus.N Engl J Med. 2016; 374: 1552-1563Crossref PubMed Scopus (885) Google Scholar There is substantial evidence indicating the ZIKV can be transmitted from the mother to the fetus, resulting in adverse fetal effects, including stillbirths, miscarriages, microcephaly, and ocular abnormalities.3Petersen L.R. Jamieson D.J. Powers A.M. Honein M.A. Zika virus.N Engl J Med. 2016; 374: 1552-1563Crossref PubMed Scopus (885) Google Scholar On February 1, 2016, the World Health Organization declared ZIKV to be a public health emergency of international concern. ZIKV, as with other flaviviruses, is an enveloped, single-stranded positive-sense RNA virus.4Cox B.D. Stanton R.A. Schinazi R.F. Predicting Zika virus structural biology: challenges and opportunities for intervention.Antivir Chem Chemother. 2016; 24: 118-126Crossref Scopus (45) Google Scholar It has been hypothesized that ZIKV uses the enzyme RNA-dependent RNA polymerase (RdRp or the non-structural protein, NS5), along with cofactors, to replicate, maintain, and express its RNA genome.4Cox B.D. Stanton R.A. Schinazi R.F. Predicting Zika virus structural biology: challenges and opportunities for intervention.Antivir Chem Chemother. 2016; 24: 118-126Crossref Scopus (45) Google Scholar The three-dimensional structure of flavivirus RdRp resembles that of a cupped right hand and contains a finger, thumb, and palm domain and is conserved.4Cox B.D. Stanton R.A. Schinazi R.F. Predicting Zika virus structural biology: challenges and opportunities for intervention.Antivir Chem Chemother. 2016; 24: 118-126Crossref Scopus (45) Google Scholar Currently, the structure of ZIKV RdRp remains to be elucidated. However, the predicted three-dimensional structure and amino acids for ZIKV RdRp indicates that HCV RdRp (NS5B protein), particularly at the active site, shares many residues in common with ZIKV RdRp.4Cox B.D. Stanton R.A. Schinazi R.F. Predicting Zika virus structural biology: challenges and opportunities for intervention.Antivir Chem Chemother. 2016; 24: 118-126Crossref Scopus (45) Google Scholar Furthermore, the pharmacologically active metabolite of sofosbuvir, 2′-fluoro-2-C-methyl-UTP, which inhibits HCV RdRp, docks into the active site of NS5.4Cox B.D. Stanton R.A. Schinazi R.F. Predicting Zika virus structural biology: challenges and opportunities for intervention.Antivir Chem Chemother. 2016; 24: 118-126Crossref Scopus (45) Google Scholar Thus, it is possible that certain nucleoside and nucleotide compounds that inhibit HCV RdRp may have inhibitory potency against ZIKV. ZIKV RdRp is an excellent pharmacological target as (1) its inhibition will prevent RNA synthesis and decrease viral replication, and (2) there is no similar protein target in human cells. Sofosbuvir is a uridine nucleotide analog that is biotransformed in hepatocytes to a triphosphate metabolite that inhibits HCV RdRp-catalyzed RNA synthesis, thereby inhibiting viral replication and transcription.5Sofia M.J. Nucleotide prodrugs for the treatment of HCV infection.Adv Pharmacol. 2013; 67: 39-73Crossref PubMed Scopus (40) Google Scholar Interestingly, the triphosphate metabolite of the nucleoside analog 7-deaza-2′-C-methyladenosine, which inhibits HCV RdRp in vitro, has been shown to (1) inhibit the in vitro replication of ZIKV, as well as other flaviviruses, and (2) significantly decrease ZIKV viremia and delay morbidity and mortality in ZIKV-infected mice.6Zmurko J. Marques R.E. Schols D. Verbeken E. Kaptein S.J. Neyts J. The viral inhibitor 7-deaza-2′-C-methyladenosine is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model.PLoS Negl Trop Dis. 2016; 10: e0004695Crossref Scopus (221) Google Scholar Congruent with the above findings, certain 2′-C-methylated nucleosides have been shown to inhibit ZIKV replication in cell cultures.7Eyer L. Nencka R. Huvarova I. Palus M. Joao Alves M. Gould E.A. et al.Nucleoside inhibitors of Zika virus.J Infect Dis. 2016; 214: 707-711Crossref PubMed Scopus (136) Google Scholar Two recent studies indicate that sofosbuvir significantly fits or docks into ZIKV RdRp.8Elfiky A.A. Zika viral polymerase inhibition using anti-HCV drugs both in the market and under clinical trials.J Med Virol. 2016; 88: 2044-2051Crossref PubMed Scopus (63) Google Scholar, 9Sacramento C.Q. de Melo G.R. Rocha N. Hoelz L.V.B. Mesquita M. de Freitas C.S. et al.The clinically approved antiviral drug sofosbuvir impairs Brazilian Zika virus replication.BioRxiv. 2016; (http//dx.doi.org/10.1101/061671)Google Scholar Furthermore, there is an 80% overlap in amino acid sequence for the ZIKV and HCV RdRps that bind sofosbuvir.9Sacramento C.Q. de Melo G.R. Rocha N. Hoelz L.V.B. Mesquita M. de Freitas C.S. et al.The clinically approved antiviral drug sofosbuvir impairs Brazilian Zika virus replication.BioRxiv. 2016; (http//dx.doi.org/10.1101/061671)Google Scholar In vitro data indicate that sofosbuvir inhibits (1) Brazilian ZIKV RdRp in a concentration-dependent manner, and (2) Brazilian ZIKV replication in BHK-21 (baby hamster kidney) and SH-Sy5y (human neuroblastoma) cells.9Sacramento C.Q. de Melo G.R. Rocha N. Hoelz L.V.B. Mesquita M. de Freitas C.S. et al.The clinically approved antiviral drug sofosbuvir impairs Brazilian Zika virus replication.BioRxiv. 2016; (http//dx.doi.org/10.1101/061671)Google Scholar Finally, a recent study has shown that BCX4430, an adenosine nucleoside analog, significantly reduces the cytopathic effect of three different ZIKV strains in vitro, decreases mortality in AG129 mice (which lack type I and type II interferon receptors; 300 mg/kg/day), and protects AG129 mice from mortality when given 1 day after ZIKV challenge.10Julander J.G. Siddharthan V. Evans J. Taylor R. Tolbert K. Apuli C. et al.Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model.Antiviral Res. 2017; 137: 14-22Crossref PubMed Scopus (119) Google Scholar It is proposed that prior to clinical trials, the efficacy of sofosbuvir, along with the positive control, 7-deaza-2′-C-methyladenosine, be tested as follows: (1) in vitro against the most common circulating strains of ZIKV to determine whether sofosbuvir inhibits viral replication, and (2) in vivo in AG129 mice infected with ZIKV, where its effect on viremia and morbidity and mortality would be assessed. If these results are positive, the efficacy of sofosbuvir in humans could be tested in randomized controlled trials by recruiting non-pregnant patients (female patients would be tested for pregnancy) aged 18 or older with ZIKV infection proven by RT-PCR of blood or urine and clinical manifestations of the disease present for a minimum of 2 days. Patients would be screened for other arboviruses (notably dengue and chikungunya), as these viruses can elicit similar signs and symptoms as ZIKV. The viral load would be assessed in blood, urine, semen, and vaginal secretions throughout treatment. Based on the hypothesis that sofosbuvir will produce significant attenuation of symptoms as compared to placebo control in at least 50% of patients (with a 95% confidence interval of 40–60%), treatment and placebo control groups of 100 participants each would be sufficient to detect a statistically significant effect of the drug. Sofosbuvir could be administered orally, 400 mg per day for 1 week. If this initial trial were successful, symptomatic pregnant women with proven ZIKV infection could then be recruited for a similar trial of 400 mg of sofosbuvir per day for 1 week. Sofosbuvir has a pharmacokinetic profile that would be suitable for treating the potential variety of patients with ZIKV. For example, at least 80% of a dose of sofosbuvir is absorbed systemically and it can be given without regard to food.11Kirby B.J. Symonds W.T. Kearney B.P. Mathias A.A. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir.Clin Pharmacokinet. 2015; 54: 677-690Crossref PubMed Scopus (183) Google Scholar The primary metabolite of sofosbuvir, GS-331007, is pharmacologically inactive, non-toxic, and primarily excreted unchanged in the urine.11Kirby B.J. Symonds W.T. Kearney B.P. Mathias A.A. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir.Clin Pharmacokinet. 2015; 54: 677-690Crossref PubMed Scopus (183) Google Scholar The kinetics of sofosbuvir are not significantly altered by age (19 to 75 years of age), ethnicity, sex, body mass index, or cirrhosis.11Kirby B.J. Symonds W.T. Kearney B.P. Mathias A.A. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir.Clin Pharmacokinet. 2015; 54: 677-690Crossref PubMed Scopus (183) Google Scholar In addition, sofosbuvir and GS-331007 have linear pharmacokinetics with minimal accumulation after multiple dosing.11Kirby B.J. Symonds W.T. Kearney B.P. Mathias A.A. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir.Clin Pharmacokinet. 2015; 54: 677-690Crossref PubMed Scopus (183) Google Scholar Sofosbuvir has a large volume of distribution (127 liters), thereby increasing the likelihood that sufficient concentrations will be present in potential reservoir areas. Sofosbuvir can be used in patients with severe liver impairment and mild to moderate impairment of renal function.11Kirby B.J. Symonds W.T. Kearney B.P. Mathias A.A. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir.Clin Pharmacokinet. 2015; 54: 677-690Crossref PubMed Scopus (183) Google Scholar Safety would not appear to be of major concern, as the majority of adverse effects reported for 400 mg of sofosbuvir in HCV patients were of grade 1 severity and only 1% of patients discontinued treatment.12Keating G.M. Vaidya A. Sofosbuvir: first global approval.Drugs. 2014; 74: 273-282Crossref PubMed Scopus (78) Google Scholar Nonetheless, if sofosbuvir produced intolerable or severe adverse effects or increased mortality, then treatment would be promptly discontinued. Patients should be screened for HCV, as using sofosbuvir alone for the treatment of HCV would not be considered optimal therapy. Currently, no well-controlled or adequate studies have been done using sofosbuvir in pregnant women. However, to date, no teratogenic effects in humans have been reported. Animal data indicate that at area under the curve exposures far exceeding those seen with normal clinical doses, sofosbuvir does not produce carcinogenesis, mutagenic effects, or an impairment of fertility.13Product information. Sovaldi (sofosbuvir). Foster City, CA: Gilead Sciences, Inc.; 2015 August.Google Scholar In summary, it is proposed that sofosbuvir is a safe pharmacotherapeutic approach for a currently escalating global health threat for which there is currently no effective treatment. If sofosbuvir significantly reduces or eliminates the ZIKV viral load, this approach could (1) eliminate the presence of the virus in plasma, saliva, semen, and other body fluids, as well as the risk of transmission between individuals, in symptomatic cases, and (2) potentially reduce the severe neurological complications currently seen in infants born to symptomatic mothers. The use of sofosbuvir, in combination with other health-related measures (e.g., control of ZIKV vectors), has the potential to attenuate the health problems and consequences associated with ZIKV infection. Note added in proof: During the time our revised manuscript was being reviewed, Bullard-Feibelman et al.14Bullard-Feibelman K.M. Govero J. Zhu Z. Salazar V. Veselinovic M. Diamond M.S. Geiss B.J. The FDA approved drug Sofosbuvir inhibits Zika virus infection.Antiviral Res. 2017; 137: 134-140Crossref PubMed Scopus (180) Google Scholar reported that sofosbuvir: 1) significantly inhibited (EC50 values of 1–5 μM) the replication of 3 strains of Zika virus in multiple human cell lines in vitro; 2) at an oral dose of 33 mg/kg/day for 7 days, protected mice against Zika-induced mortality. In addition, Retallack et al.15Retallack H. Di Lullo E. Arias C. Knopp K.A. Laurie M.T. Sandoval-Espinosa C. et al.Zika virus cell tropism in the developing human brain and inhibition.Proc Natl Acad Sci. 2016; (Nov 29. pii: 201618029. [Epub ahead of print])PubMed Google Scholar reported that in vitro, sofosbuvir (EC50 = 12.4 μM) significantly decreased the infectivity of U87 cells (human primary glioblastoma) by Zika virus. However, it has been reported that 50 μM of sofosbuvir did not significantly alter the cytopathic effect of Zika in Vero cells.16Eyer L. Nencka R. Huvarova I. Palus M. Alves M.J. Gould E.A. et al.Nucleoside inhibitors of Zika virus.J Infect Dis. 2016; 214: 707-711Crossref PubMed Scopus (0) Google Scholar Furthermore, although the active metabolite of sofosbuvir, 2′-F-2′-C-Me-UTP, produced a termination of RNA synthesis, its IC50 value for inhibiting Zika RdRp was 90.76 μM and it was not efficiently incorporated into the RNA chain.17Lu G. Bluemling G.R. Collop P. Hager M. Kuiper D. Gurale B.P. et al.Analysis of ribonucleotide 5′-triphosphate analogs as potential inhibitors of Zika virus RNA-dependent RNA polymerase using non-radioactive polymerase assays.Antimicrob Agents Chemother. 2016; https://doi.org/10.1128/AAC.01967-16Crossref Scopus (40) Google Scholar Given that the aforementioned study was done with purified Zika RdRp, it is possible that the differential findings compared to Retallack et al.15Retallack H. Di Lullo E. Arias C. Knopp K.A. Laurie M.T. Sandoval-Espinosa C. et al.Zika virus cell tropism in the developing human brain and inhibition.Proc Natl Acad Sci. 2016; (Nov 29. pii: 201618029. [Epub ahead of print])PubMed Google Scholar may be due to absence of cellular constituents that alter the sensitivity of RdRp to endogenous substrates and compounds. Funding: None. Conflict of interest: The authors declare that there are no conflicts of interest.