Treatment of HCV in HIV infected patients
Nisreen F. Bajnaid
Outlines*introduction
*Predictors of response*SOC therapy
*first generation DAA*second generation DAA
*IFN- free regimen
-Chronic HCV infection occurs globally in 20% of HIV seropositive patients
-Sequalaes of HCV/HIV coinfection* higher rate of chronicity
* greater serum HCV-RNA level* accelerated liver fibrosis and faster
decompensation once cirrhosis developed
* higher rate of hepatotoxicity secondary to ART
Which is first ?? HCV or HIV treatment?? Depend on the stage of HIV:
*With CD4 > 500 cell/ml and relatively low plasma HIV RNA ( < 50,000 copes /ml) HCV treatment first
*In advanced cases with higher plasma HIV RNA, uncontrolled HIV replication may have detrimental effect on the efficacy on HCV
therapy treat HIV first
Role of IL28B polymorphism in the treatment of chronic HCV
*4 multicenter studies published between late 2009 and early 2010
*IL28B gene polymorphism rs8099917 and rs12979860 is strongly associated with treatment response
*3 genotypes: CC, CT , TT*predict both the spontaneous recovery as well as
treatment response
Clinical Infectious Diseases 2010; 51(7):788–795
(J Clin Gastroenterol 2013;47:222–227)
Standard of care therapy PEG-IFN + RBV
-co infected patients tend to have lower response rate and more frequent side effect
-in PARADIGM trial ,double blind international trial of HIV/HCV genotype 1 treated with PEG-IFN/RBV reported SVR rate of only 19-22% NOT recommended any more
-standard treatment for genotype 2,3 and 4-response-guided therapy
HIV Clin Trials. 2012;13(3):142–52.
Curr Hepatitis Rep (2013) 12:269–275
Drug –drug interaction* RBV +AZT greater risk of anemia and
neutropenia * RBV + ABC potential antagonism
* RBV + ddi increase risk of lactic acidosis and
pancreatitis
*RBV + atazanavir Hyperbilirubinemia
SVR12 vs SVR24
*FDA has recently accepted SVR at post -treatment week 12 as a primary outcome for clinical trials instead of the previously used SVR24
*data are limited in co-infected population, but this new outcome seems to be acceptable
Gastroenterology 2013;144: 1450–55 e2
J Antimicrob Chemother. 2010;65(10):2063-9.
First Generation DAABOCEPREVIR AND TELAPREVIR
FDA approved 2011
*both improve SVR rate significantly compared with SOC therapy in co infected persons
Which is preferred ?? Telaprevir or boceprevir??- telapriver showed stronger early antiviral activity
- telaprevir is easier to useDrawbacks
*poor safety profile *inconvenient dosing*drug interactions *targeting only genotype 1
*must be given with PEG-IFN/RBV
Telaprevir-NS3/NS4 A protease inhibitor (genotype 1)
-TID dose with meal containing 10-20 g of fat-most common AE : anemia
rash anorectal symptoms
VX08-950-110-Phase 2 a study
-Included 60 co infected treatment naïve patients* 38 patients in T/P/R arm
* 22 in placebo/P/R arm -Acceptable ART regimen : ATZ/r or efevirinz
based treatment -higher dose of telaprevir with efavirinz
-SVR12 : 74 % in T/P/R vs 45 % in P/R
Ann Intern Med 2013; 159: 86–96.
Digestive and Liver Disease 45S (2013) S355–S362
Boceprevir-NS3/NS4 protease inhibitor
-3 times daily ( no fatty meal required)-24 vs 48 weeks depending on
* hx of cirrhosis* previous response to PEG-IFN/RBV
* current response to boceprevir-SE: anemia and dysguesia
AZTNNRTIs
ddI
Lancet Inf Dis. 2013;13(7):597–605.
Lancet Infect Dis 2013; 13: 597–605
Digestive and Liver Disease 45S (2013) S355–S362
Simeprevir-NS3/NS4 protease inhibitor
-has activity against genotype 1, 2, 4 and 6-once daily dose
-transient hyperbilirubinemia
*simeprevir and ART tenofovir , rilpivirine and raltegravir no significant
interactions-NO PIs or Efaverinz
N= 68
N=38
Faldaprevir-NS3/NS4 protease inhibitor
-has activity against genotype 1, 2, 4, 5 and 6-Faldaprevir + deleobuvir (polymerase inhibitor)
+RBV for HCV mono-infected patients -phase IIb trial SVR was achieved by 52–69% of
the patients *The combination is currently being studied in
co-infected patients (NCT01525628)
Sofosbuvir-nucleotide NS5B polymerase inhibitor
-pangenotypic activity-dose: 400 mg once daily
-Sofosbuvir has shown promise as part of IFN-free regimens
- not metabolized by the liver no interaction with ART
Daclatasvir -NS5A inhibitor, active against HCV genotype 1.
-60 mg once daily ( 30 with PIs /90 mg with efavirenz)
Daclatasvir in combination therapy -phase III trial in co-infected patients is ongoing
-HCV genotype 1 naive patients.- Daclatasvir will be administered for 24 weeks and
PEGIFN/ RBV for 24 vs. 48 weeks depending on virological response criteria for shorter therapy
Sofosbuvir in IFN free
regimen
Genotype2SVR 88%
Genotype 3SVR 67%
Genotype 1SVR 76%
*A majority of patients were on ART including efavirenz (34 %), atazanavir/ritonavir (17 %), darunavir/ritonavir (32 %) & raltegravir (16 %).
* 2 patients experienced HIV breakthrough due to poor adherence to ART but NO HCV viral
breakthroughs occurred .*rate of treatment discontinuation (3 %) .
These very promising data suggest that HIV-HCV coinfected patients can achieve high SVR rates with IFN-free
Daclatasvir in combination with sofosbuvir +/- RBV
-achieving SVR12 in >90 % of treatment naïve, genotype 1 patients with 12 weeks of
treatment** -This DAA is in phase II study with simeprevir
-it is being studied in an IFN-free, RBV-free regimen with asunaprevir and BMS-791325.
**63rd Annual Meeting of the American Associationfor the Study of Liver Diseases (AASLD), Boston, MA, November 9-12-2012
Daclatasvir may be co-administered with NRTIs ( ABC , FTC, 3TC, TDF)
NNRTIs (efavirenz, rilpivirine, nevirapine) integrase inhibitors (raltegravir)
entry inhibitors ( maraviroc ) PIs ( boosted atazanavir )
*Higher dose with efavirenz and lower with boosted protease inhibitors
*This agent is currently in Phase III study in HIV/HCV coinfected patients
Conclusion-IL28B is an important predictor of treatment
response -HCV genotype 1 triple therapy
-Studies clearly show that DAAs will change the face of treatment in patients with HIV/HCV coinfection
-Drug–drug interactions are a real issue-IFN-free regimen is a promising approach in
co infected population