treatment of hcv in hiv infected patients
TRANSCRIPT
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Treatment of HCV in HIV infected patients
Nisreen F. Bajnaid
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Outlines*introduction
*Predictors of response*SOC therapy
*first generation DAA*second generation DAA
*IFN- free regimen
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-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
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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
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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
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Clinical Infectious Diseases 2010; 51(7):788–795
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(J Clin Gastroenterol 2013;47:222–227)
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Standard of care therapy PEG-IFN + RBV
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-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.
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Curr Hepatitis Rep (2013) 12:269–275
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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
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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
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J Antimicrob Chemother. 2010;65(10):2063-9.
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First Generation DAABOCEPREVIR AND TELAPREVIR
FDA approved 2011
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*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
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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
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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.
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Digestive and Liver Disease 45S (2013) S355–S362
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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
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AZTNNRTIs
ddI
Lancet Inf Dis. 2013;13(7):597–605.
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Lancet Infect Dis 2013; 13: 597–605
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Digestive and Liver Disease 45S (2013) S355–S362
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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
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N= 68
N=38
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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)
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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
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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
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Sofosbuvir in IFN free
regimen
Genotype2SVR 88%
Genotype 3SVR 67%
Genotype 1SVR 76%
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*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
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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
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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
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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
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