Direct acting antivirals (DAA) targeting the HCV serine protease and RNA polymerase have recently entered clinical development. Information about primary resistance to these compounds in HIV–HCV-coinfected patients is scarce.
Methods
All individuals newly diagnosed with HIV-1 at several clinics in Madrid between 2000 and 2010 were tested for serum HCV antibody and HCV RNA. The NS3 protease and NS5B polymerase genes were sequenced in all HCV viraemic patients with genotype 1 (G1).
Results
From 1,684 individuals newly diagnosed with HIV-1 during the 10-year study period, 141 (8.4%) were positive for serum HCV RNA. Overall, 58% were infected with G1, being 1a in 64.2% of them. Altogether, 62% of G1a and 30% of G1b harboured HCV drug-resistant changes, with the most common being prQ80K (n=9), prV55A (n=2), polC316Y/N (n=3) and polV499A (n=24). Although no primary resistance mutations were identified for HCV protease inhibitors or nucleoside analogues, mutations C316Y/N and V499A conferring resistance to some non-nucleoside analogues were found in 6% and 51% of G1 patients, respectively.
Conclusions
Natural DAA resistance-associated mutations are frequently seen in HIV–HCV-coinfected individuals. Changes polV499A and prQ80K seem to be natural polymorphisms and their effect on treatment outcomes warrants further examination. However, drug resistance testing in HCV drug-naive individuals coinfected with HIV currently does not seem to be warranted before using HCV protease inhibitors and nucleoside analogues. More information is needed for HCV non-nucleoside analogues.
References
1.
McHutchisonJ.G., EversonG.T., GordonS.C.Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med2009; 360: 1827–1838.
2.
HézodeC., ForestierN., DusheikoG.Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med2009; 360: 1839–1850.
3.
KwoP., LawitzE., McConeJ.Response guided therapy for boceprevir combination treatment? Results from HCV SPRINT-1.60th Annual Meeting of the American Association for the Study of Liver Diseases. 30 October– 3 November 2009, Boston, MA, USA. Abstract 1582.
4.
SorianoV., PetersM., ZeuzemS.New therapies for hepatitis C virus infection. Clin Infect Dis2009; 48: 313–320.
5.
BartelsD.J., ZhouY., ZhangE.Z.Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects. J Infect Dis2008; 198: 800–807.
6.
KuntzenT., TimmJ., BericalA.Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology2008; 48: 1769–1778.
7.
GaudieriS., RauchA., PfafferottK.Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy. Hepatology2009; 49: 1069–1082.
8.
KimA.Y., TimmJ., NolanB.E.Temporal dynamics of a predominant protease inhibitor-resistance mutation in a treatment-naive, hepatitis C virus-infected individual. J Infect Dis2009; 199: 737–741.
9.
ColsonP., BroukN., LemboF., CastellaniP., TamaletC., GerolamiR.Natural presence of substitution R155K within hepatitis C virus NS3 protease from a treatment-naive chronically infected patient. Hepatology2008; 47: 766–767.
10.
Le PogamS., SeshaadriA., KosakaA.Existence of hepatitis C virus NS5B variants naturally resistant to non-nucleoside, but not to nucleoside, polymerase inhibitors among untreated patients. J Antimicrob Chemother2008; 61: 1205–1216.
11.
NetskiD.M., MaoQ., RayS.C., KleinR.S.Genetic divergence of hepatitis C virus: the role of HIV-related immunosuppression. J Acquir Immune Defic Syndr2008; 49: 136–141.
12.
SorianoV., PerelsonA., ZoulimF.Why different dynamics of selection of drug resistance in HIV, hepatitis B and C viruses?J Antimicrob Chemother2008; 62: 1–4.
13.
MorsicaG., BagaglioS., Uberti-FoppaC., GalliL., LazzarinA.Detection of hepatitis C mutants with natural resistance to NS3/4A protease inhibitors in HIV/HCV-coinfected individuals treated with antiretroviral therapy. J Acquir Immune Defic Syndr2009; 51: 106–108.
14.
HirschM.S., GunthardH.F., SchapiroJ.M.Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an international AIDS Society–USA panel. Clin Infect Dis2008; 47: 266–285.
15.
SarrazinC., ZeuzemS.Resistance to direct antiviral agents in patients with HCV infection. Gastroenterology2010; 138: 447–462.
16.
SorianoV., MocroftA., RockstrohJ.Spontaneous viral clearance, viral load and genotype distribution of hepatitis C virus in HIV-infected patients with anti-HCV antibodies in Europe. J Infect Dis2008; 198: 1337–1344.
