We have previously reported that human adenovirus (HAdV) reference strains clearly show species-dependent resistance to ribavirin, whereas different species of HAdV are equally sensitive to cidofovir. All the serotypes tested were susceptible to cidofovir, whereas only serotypes from species C were sensitive to ribavirin. Here, we aimed to extend these investigations to clinical isolates.
Methods
In vitro, we tested 126 isolates obtained from 65 patients included in a European survey of HAdV infection.
Results
Among the 126 isolates tested, all presented cidofovir 50% inhibitory concentration (IC50) in the same range as the HAdV 5 reference strain. Regarding ribavirin, all isolates from species C (79 tested) showed an IC50 comparable with previously reported results for reference strains; however, 24/32, 2/6 and 3/3 tested isolates from species A, B and D, respectively, were shown to have a ribavirin IC50 comparable with the HAdV 5 reference strain (species C), contrary to previous observations for reference strains of the same species. Among patients who were treated with cidofovir for disseminated HAdV infection, ≥4 sequential isolates could be obtained from 9 patients; no variation in cidofovir susceptibility could be detected.
Conclusions
Cidofovir is active in vitro in all HAdV clinical isolates. Ribavirin was revealed to be active on most HAdV isolates from species A, B and D, and in all isolates from species C. Finally, no resistance to cidofovir became apparent in sequential isolates obtained from treated patients.
References
1.
MorfinF., BoucherA., NajioullahF.Cytomegalovirus and adenovirus infections and diseases among 75 paediatric unrelated allogeneic bone marrow transplant recipients.J Med Virol2004; 72: 257–262.
2.
WallsT., ShankarA.G., ShingadiaD.Adenovirus: an increasingly important pathogen in paediatric bone marrow transplant patients.Lancet Infect Dis2003; 3: 79–86.
3.
IsonM.G.Adenovirus infections in transplant recipients.Clin Infect Dis2006; 43: 331–339.
4.
LenaertsL., NaesensL.Antiviral therapy for adenovirus infections.Antiviral Res2006; 71: 172–180.
5.
Leruez-VilleM., Chardin-OuacheeM., NevenB.Description of an adenovirus A31 outbreak in a paediatric haematology unit.Bone Marrow Transplant2006; 38: 23–28.
6.
RibaudP., ScieuxC., FreymuthF., MorinetF., GluckmanE.Successful treatment of adenovirus disease with intravenous cidofovir in an unrelated stem-cell transplant recipient.Clin Infect Dis1999; 28: 690–691.
7.
CassanoW.F.Intravenous ribavirin therapy for adenovirus cystitis after allogeneic bone marrow transplantation.Bone Marrow Transplant1991; 7: 247–248.
8.
HoffmanJ.A., ShahA.J., RossL.A., KapoorN.Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation.Biol Blood Marrow Transplant2001; 7: 388–394.
9.
LjungmanP., RibaudP., EyrichM.Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.Bone Marrow Transplant2003; 31: 481–486.
10.
NagafujiK., AokiK., HenzanH.Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients.Bone Marrow Transplant2004; 34: 909–914.
11.
MullerW.J., LevinM.J., ShinY.K.Clinical and in vitro evaluation of cidofovir for treatment of adenovirus infection in pediatric hematopoietic stem cell transplant recipients.Clin Infect Dis2005; 41: 1812–1816.
12.
YusufU., HaleG.A., CarrJ.Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients.Transplantation2006; 81: 1398–1404.
13.
NeofytosD., OjhaA., MookerjeeB.Treatment of adenovirus disease in stem cell transplant recipients with cidofovir.Biol Blood Marrow Transplant2007; 13: 74–81.
14.
WallsT., HawramiK., Ushiro-LumbI., ShingadiaD., SahaV., ShankarA.G.Adenovirus infection after pediatric bone marrow transplantation: is treatment always necessary?Clin Infect Dis2005; 40: 1244–1249.
15.
HromasR., ClarkC., BlankeC.Failure of ribavirin to clear adenovirus infections in T cell-depleted allogeneic bone marrow transplantation.Bone Marrow Transplant1994; 14: 663–664.
16.
CrooksB.N., TaylorC.E., TurnerA.J.Respiratory viral infections in primary immune deficiencies: significance and relevance to clinical outcome in a single BMT unit.Bone Marrow Transplant2000; 26: 1097–1102.
17.
LankesterA.C., HeemskerkB., ClaasE.C.Effect of ribavirin on the plasma viral DNA load in patients with disseminating adenovirus infection.Clin Infect Dis2004; 38: 1521–1525.
18.
Arav-BogerR., EchavarriaM., FormanM., CharacheP., PersaudD.Clearance of adenoviral hepatitis with ribavirin therapy in a pediatric liver transplant recipient.Pediatr Infect Dis J2000; 19: 1097–1100.
19.
MiyamuraK., HamaguchiM., TajiH.Successful ribavirin therapy for severe adenovirus hemorrhagic cystitis after allogeneic marrow transplant from close HLA donors rather than distant donors.Bone Marrow Transplant2000; 25: 545–548.
20.
MorfinF., Dupuis-GirodS., MundweilerS.In vitro susceptibility of adenovirus to antiviral drugs is species-dependent.Antivir Ther2005; 10: 225–229.
21.
LangloisM., AllardJ.P., NugierF., AymardM.A rapid and automated colorimetric assay for evaluating the sensitivity of herpes simplex strains to antiviral drugs.J Biol Stand1986; 14: 201–211.
22.
SwensonP.Adenoviruses. In LennetteE.H., SmithT.F., editors. Laboratory diagnosis of viral infections. New York: Marcel Dekker1999; pp. 287–303.
23.
RomanowskiE.G., GordonY.J., Araullo-CruzT., YatesK.A., KinchingtonP.R.The antiviral resistance and replication of cidofovir-resistant adenovirus variants in the New Zealand White rabbit ocular model.Invest Ophthalmol Vis Sci2001; 42: 1812–1815.
24.
FieldH.J.A perspective on resistance to acyclovir in herpes simplex virus.J Antimicrob Chemother1983; 12 Suppl B: 129–135.
25.
StockR., HarsteG., MadischI., HeimA.A rapid quantitative PCR-based assay for testing antiviral agents against human adenoviruses demonstrates type specific differences in ribavirin activity.Antiviral Res2006; 72: 34–41.
26.
SnellN.J.C.Ribavirin – current status of a broad spectrum antiviral agent.Expert Opin Pharmacother2001; 2: 1317–1324.
27.
GraciJ.D., CameronC.E.Mechanisms of action of ribavirin against distinct viruses.Rev Med Virol2006; 16: 37–48.
28.
AllenL.B., BoswellK.H., KhwajaT.A.Synthesis and antiviral activity of some phosphates of the broad-spectrum antiviral nucleoside, 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin).J Med Chem1978; 21: 742–746.
WildnerO., HoffmannD., JoglerC., UberlaK.Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs.Cancer Gene Ther2003; 10: 791–802.
31.
KirsiJ.J., NorthJ.A., McKernanP.A.Broad-spectrum antiviral activity of 2-β-d-ribofuranosylselenazole-4-carboxamide, a new antiviral agent.Antimicrob Agents Chemother1983; 24: 353–361.
32.
BabaM., MoriS., ShigetaS., De ClercqE.Selective inhibitory effect of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine and 2’-nor-cyclic GMP on adenovirus replication in vitro.Antimicrob Agents Chemother1987; 31: 337–339.
33.
NaesensL., LenaertsL., AndreiG.Antiadenovirus activities of several classes of nucleoside and nucleotide analogues.Antimicrob Agents Chemother2005; 49: 1010–1016.
