Marcadores farmacogenéticos como factores predictivos de respuesta al tratamiento del VHC en pacientes VIH

Abstract

Hepatitis C virus (HCV) affects around 3% of the population worldwide. The standard of care is combination therapy with weekly subcutaneous pegylated interferon and twice daily oral ribavirine (RBV) for one year. Fewer than 50% of patients are cured. HCV infection is one of the most common co-morbid conditions in patients with human immunodeficiency virus (HIV) infection. It occurs in 50% of cases. Cirrhosis develops faster in coinfected patients and end-stage liver disease due to HCV is an important cause of death in HCV/HIV patients. Only 40% of HCV/HIV patient’s response to interferon/RBV (sustained viral response-SVR-). HCV treatment is now changing from double to triple therapy as two new therapies, telaprevir and boceprevir, were approved in 2011. This new triple combined therapy achieves higher percentages of SVR. However, such therapy increases toxicity and is very expensive. New treatment algorithms have not yet been defined. Use of predictive factors for SVR is fundamental to help in selecting the best therapeutic option for our patients. In September 2009 Nature published that some allelic variants in IL28B gene, located at chromosome 19, influence SVR to HCV treatment. In February 2010, the same journal published the beneficial effects of allelic variants of ITPA gene, located at chromosome 20, related to anaemia due to RBV use in HCV treatment. No data are yet available about how these two pharmacogenetic markers influence HCV treatment in HCV/HIV coinfected patients. This thesis analyses the influence of pharmacogenetic markers as predictive factors of SVR and toxicity to HCV treatment in HIV/HCV patients. A total of 73 coinfected patients were analysed and treated for at least 12 weeks. Allelic variants of IL28B (rs12979860) and ITPA genes (rs1127354) were determined in all patients. IL28B gene has three possible genotypes: CC, CT and TT. Forty percent of the population in Europe is CC carriers. This genotype is associated with higher percentages of SVR. ITPA gene also has three possible genotypes: CC, CA and AA. A-allele carriers have less anaemia due to RBV. In our series of coinfected patients the global percentage of SVR was 53%. CC carriers showed percentages of SVR around 70%, while CT/TT carriers only showed 40% (p = 0.04) Anaemia was higher in rs1127354 CC-ITPA gene carriers. Hb decreased from week 1 to week 12 by 23% and 12% for CC and CA/AA carriers, respectively (p>0.001). A-allele carriers showed SVR percentages of 78% while CC carriers showed 38% (p = 0.03) We can conclude that being a CC-IL28B and CA/AA-ITPA carrier correlates strongly with SVR. Moreover, CA/AA ITPA protects from anaemia. Presence of these protective polymorphisms helps select the best HCV therapy for our HIV/HCV coinfected patients.

Date of Award	16 Nov 2011
Original language	Spanish
Supervisor	Pedro Domingo Pedrol (Director)