Treatment of hcv in hiv infected patients
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Treatment of hcv in hiv infected patients
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Treatment of hcv in hiv infected patients
- 1. TreaTmenT of HCV in HiV infeCTed paTienTs TreaTmenT of HCV in HiV infeCTed paTienTs Nisreen F. Bajnaid
- 2. Outlines *introduction *Predictors of response *SOC therapy *first generation DAA *second generation DAA *IFN- free regimen
- 3. -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
- 4. 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
- 6. Role of IL28B polymorphism in the treatment of chronic HCV *4multicenter studies published between late 2009 and early 2010 *IL28B gene polymorphism rs8099917 and rs12979860 is strongly associated with treatment response *3genotypes: CC, CT , TT *predict both the spontaneous recovery as well as treatment response
- 7. Clinical Infectious Diseases 2010; 51(7):788–795
- 8. )J Clin Gastroenterol 2013;47:222–227(
- 10. Standard of care therapy PEG-IFN + RBV Standard of care therapy PEG-IFN + RBV
- 11. -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.
- 12. Curr Hepatitis Rep (2013) 12:269–275
- 13. 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
- 14. 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
- 16. First Generation Daa BOCEPREVIR AND TELAPREVIR FDA approved 2011 First Generation Daa BOCEPREVIR AND TELAPREVIR FDA approved 2011
- 17. *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 use Drawbacks *poor safety profile *inconvenient dosing *drug interactions *targeting only genotype 1 *must be given with PEG-IFN/RBV
- 18. 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
- 20. VX08-950-110 -Phase 2 a study -Included 60 co infected treatment naïve patients *38patients in T/P/R arm *22in 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.
- 21. Digestive and Liver Disease 45S (2013) S355–S362
- 22. Boceprevir -NS3/NS4 protease inhibitor -3times daily ( no fatty meal required( -24vs 48 weeks depending on *hx of cirrhosis *previous response to PEG-IFN/RBV *current response to boceprevir -SE: anemia and dysguesia
- 23. AZT NNRTIs ddI Lancet Inf Dis. 2013;13(7):597–605.
- 25. Lancet Infect Dis 2013; 13: 597–605
- 26. Digestive and Liver Disease 45S (2013) S355–S362
- 28. 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
- 29. N= 68 N=38
- 32. 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(
- 36. 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
- 39. Daclatasvir -NS5A inhibitor, active against HCV genotype 1. -60mg once daily )30with 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
- 42. Sofosbuvir in IFN free regimen Sofosbuvir in IFN free regimen Genotype2 SVR 88% Genotype 3 SVR 67% Genotype 1 SVR 76%
- 43. *A majority of patients were on ART including efavirenz (34 %), atazanavir/ritonavir (17 %), darunavir/ritonavir (32 %) & raltegravir (16%(. *2patients 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
- 44. 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 Association for the Study of Liver Diseases (AASLD), Boston, MA, November 9-12-2012
- 45. 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
- 47. 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
Notes de l'éditeur
- -Chronic HCV infection occurs globally in 20% of HIV seropositive patients..the rate is particularly high in HIV patients who acquired the infection parenterally and recently the incidence of HCV is increasing in those MSM population
- With CD4 &gt; 500 cell/ml and relatively low plasma HIV RNA ( &lt; 50,000 copes /ml) HCV treatment first because chronic HCV infection lead to increase risk of transaminitis in patient receiving ART and the tolerance to ART is improved after clearance of HCV e successful therapy
- It is remarkable that HCV subtype 1a viruses respond less well to most of the new agents compared with HCV subtype 1b. As an illustrative example, Baseline polymorphisms at positions associated with is a change at protease resistance to some DAAs may be relevant and influence antiviral responses. An example codon 80, which may compromise the response to low doses of simeprevir (Fig. 3).24 As shown in Table 3, Q80K is present in around 40% of HCV-1a strains.If this variable is proved to influence the response to other antivirals, baseline drug resistance testing may be beneficial as seen with HIV therapy; however, baseline HCV drug resistance testing is currently not recommended
- 4 multicenter studies published between late 2009 and early 2010 addressing host genetic markers that may predict treatment responsiveness in patient with HCV genotype 1 They used genome wide association methodology instead of a candidate gene approach *all studies identified the same gene region near the IL28B gene that is the polymorphism rs8099917 and rs12979860 to be strongly associated with treatment response *ethnic differences in the frequency of these polymorphism can explain the inferior response rate in African Americans compared to Caucasians and increased response in the Asians
- Prediction of response to PEG/IFN and RBV by IL28B gene variation in HIV/HCV co infected patients in SPAIN From oct 2001 –june 2008 . 169 treatment naïve co infected patients SVR 50 % in TT carrier, 29% in TC carrier and 71% in CC carrier The diefference between patients with IL28B genotypes was mainly seen in pt with genotype 1 and 4
- CLINICAL REVIEW Both SPRINT-2 and ADVANCE analyses reveal that over 80% of CC patients are likely to be eligible for shortened duration compared with approximately half of non-CC Patients **An analysis of SPRINT-2 (Serine Protease Inhibitor Therapy 2), the international phase 3 trial of treatment-naive patients, was performed according to IL28B genotype **patients with the favorable CC genotype had similar sustained virologic response (SVR) rates with peginterferon-a and ribavirin with or without boceprevir. Patients with the CT and TT genotypes had substantial increases in SVR with the addition of boceprevir **In the regression analysis of SVR in the SPRINT-2 study, IL28B was an independent predictor of SVR **improved outcomes for all IL28B genotypes ranging from 71% to 90%. The non-CC patients again had substantial increases in SVR rates
- Data from the nucleoside polymerase inhibitor PSI-7977 in combination with peginterferon-a and ribavirin for genotype 1 infection were also presented at the American Association for the Study of Liver Diseases (AASLD) meeting in 2011.19 PSI-7977 in combination with peginterferon-a and ribavirin achieved SVR in 42/48 (88%) of patients in the 200-mg arm and 43/47 (91%) of patients in the 400-mg arm. The full breakdown by IL28B was not presented, but it was reported that 13/13 (100%) of patients with IL28B TT genotype achieved SVR.
- -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% Although patients with HCV genotype 2 or 3 mono-infection may be treated for only 12–24 weeks, there is less evidence for shortened treatment duration in HCV-HIV coinfection and available data suggests that these patients need to be treated for 48 weeks,similar to the treatment of genotype 1 HCVand HIV coinfection Several national and international guidelines indicated response-guided therapy as the best way to optimize treatment with PEG-IFN and ribavirin
- RBV+ ddi increase intracellular concentration increase lactic acidosis and or pancreatitis RBV + AZT ,d4tin vitro antagonism but not clinically significant RBV + ABC potential antagonism Interactions between pegIFNa/RBV and ARVs are relatively limited * Hyperbilirubinemia may be more pronounced in patients taking RBV and atazanavir together
- SVR12 vs. SVR24 The Food and Drug Administration (FDA) has recently accepted a SVR at post-treatment week 12 (SVR12) as a primary outcome for clinical trials instead of the previously used SVR24 (25). In a large cohort of HCV monoinfected patients treated with PEG-IFN/RBV therapy, it has been demonstrated that 12 weeks post-treatment follow-up appears to be as relevant as 24 weeks to define SVR (26). Even if the data are limited, this new outcome also seems to be acceptable in co-infected patients. A retrospective analysis of the results of APRICOT and PARADIGM have shown that only 2/941 patients treated with combination IFN or PEG-IFN/RBV relapsed between post-treatment weeks 12 and 24
- HCV contains a positive-sense RNA genome of 9.6 kb; translation of this genome produces a single polyprotein. Cleavage and processing of this polyprotein results in both structural proteins (core, E1, and E2) and non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) (Fig. 1). The primary targets of DAAs include the serine protease NS3 and its cofactor NS4, the viral RNA-dependent RNA polymerase NS5B, and the nonstructural protein NS5A
- -telaprevir is easier to use ( 3 pills TID for the first 3 months vs 4 pills Q8h during 6-12 months preceded by initial lead in phase of 4 weeks) *higher rate of AE (anemia)
- -NS3/NS4 A PI with activity against genotype 1
- Shorter therapy(24 weeks) in naïve patient and relapsers with undetectable virus at week 4 and week 12 of therapy with no evidence of cirrhosis Shorter therapy has not been studied in phase 2 trial of co infected patients but it is under study in phase 3 trial
- Pt received telaprevir or placebo for 12 weeks in combination with P/R for 48 weeks With efevirinz, the dose of telaprevir is incraesed to 1125 mg TID
- Phase 2 a trial for co infected persons was designed for treatment naïve patients Excluded pt on didianosin ,AZT and NNRTIS
- -improved safety profile (transient hyperbilirubinemia) hyperbilirubinemia (attributed to the drug’s effect on hepatic transport of bilirubin Healthy -volunteer studies suggest simeprevir has no significant drug interactions with tenofovir, rilpivirine, and raltegravir. Simeprevir concentrations were significantly decreased when dosed with efavirenz and significantly increased when dosed with darunavir/ritonavir, resulting in the exclusion of efavirenz and all HIV protease inhibitors from the trial
- Preliminary results were presented in 2013 conference on retroviral and opportunistic infection (CROI) Phase 3 trial designed for co infected ptients with any type of previous treatment response -all patients receive 12 weeks of simeprevir Naïve patients or relapsers witout cirrhosis were treated with peg-ifn/rbv for 24 weeks vs 48 weeks depending on the virologic response -pt with cirrhosis or those with previous partial or no response received 48 weeks of peg-ifn/rbv -allowed ART : truvada, lamuvidine , abacavir, raltegravir , rilpivirine, maraviroc and enfuviritide
- Overall, 106 patients were enrolled in this study. Ontreatment week 4 results are available for 104: 66% ofthe patients were undetectable. As seen in many monoinfected trials, relapse patients had the best response rates (93%) while the rate in non-responders was 37%. SVR4 and SVR12 rates were presented for the subset of patients eligible for 24-week of treatment. Eighty-six percent of these 35 patients achieved SVR4 (na€ıve: 84%, relapsers: 90%) and 77% achieved SVR12 (na€ıve: 75%, relapsers: 80%). No HIV virological failure was reported *Some subgroups had poorer response including: genotype 1a (71 % vs 89 % in genotype 1b); genotype 1a with the Q80K mutation at baseline (67 %); advanced fibrosis or cirrhosis (64 %); and subjects not on ART (62 % vs 75 % of subjects on ART)
- -has been tested in combination with deleobuvir, a non-nucleosidic NS5Bpolymerase inhibitor, and RBV for the treatment of HCV mono-infected patients *There were five arms in this phase IIb trial to explore the impact of the length of treatment, the use of ribavirin and the administration schedule (BID vs TID) of deleobuvir. SVR was achieved by 52–69% of the patients
- *phase III program testing faldaprevir in co-infected patients (including naïve and relapse patients) *acceptable ART are raltegravir, maraviroc, efavirenz, atazanavir/r and darunavir/r *Two doses were tested in this study (120 and 240 mg). ,patients receiving efavirenz were assigned to the 240 mg group while patients receiving darunavir/r or atazanavir were assigned to the 120 mg group. Patients receiving maraviroc or raltegravir were randomized. A total of 308 pts were included in this study, including 17% with cirrhosis. . Preliminary on-treatment results were presented at CROI 2013. At week 12 of treatment, 82% of the previously na€ıve patients and 91% of the previous relapsers had undetectable viral load .
- AE, adverse event; FDV, faldaprevir; HCV, hepatitis C virus; peglFN/RBV, peginterferon/ribavirin; SVR, sustained virologic response. Anton L. Pozniak, MD, FRCP: Interim data were presented at the EACS conference; this slide depicts the sustained virologic response at 4 weeks post treatment SVR4 results. There were very high responses rates with all the different treatment schedules. Of note, response rate at this early time point was similar between cirrhotic and noncirrhotic patients, with 76% and 74% achieving SVR, respectively. SVR4 rates by IL28B genotype, an important marker of success for peginterferon/ribavirin in genotype 1 HCV–infected patients, showed a numerical difference with 89% of patients with the CC genotype achieving SVR4 vs 67% of those with non-CC genotypes. Joseph J. Eron, Jr., MD: When interpreting these results, it is important to remember that these were all HCV treatment–naive patients or previous relapsers (ie, there were no previous null responders or partial responders in the study population) so we should expect that the results may be somewhat better than if other treatment-experienced patients were included. Nevertheless, these results were very promising, since SVR4 is generally predictive of SVR12. I look forward to seeing the SVR 12 primary endpoint data for this study. I think it is encouraging that we are seeing data in coinfected patients earlier and earlier in the development of these agents
- Sofosbuvir is a nucleotide NS5B polymerase inhibitor that is active against all HCV genotypes. It has 2 characteristics that are very important when considering its use in HIV/HCV-coinfected patients: It is not metabolized by the liver so it does not interact with antiretroviral drugs, and resistance to sofosbuvir is very uncommon. This is a small but important study of sofosbuvir plus peginterferon/ribavirin in HIV/HCV-coinfected patients that was presented at IDWeek. This is a single-arm study of 23 HCV treatment–naive patients who all received sofosbuvir 400 mg with peginterferon/ribavirin for 12 weeks. Response rates were in the 90% to 100% range, and the patient’s ART did not affect the HCV outcome. Again, this was a very small study, but these are encouraging results. The FDA is expected to approve sofosbuvir in late 2013. Joel E. Gallant, MD, MPH: With the availability of both sofosbuvir and simeprevir, there is great interest in interferon-sparing regimens. There are some data showing excellent results with the combination of 2 agents without peginterferon in HCV-monoinfected patients.[
- nvestigators included 23 HCV treatment-naïve patients with a HCV genotype between 1 and 4 and no cirrhosis. Patients were given oral sofosbuvir 400mg once daily plus weight-based ribavirin 1000–1200mg/day and subcutaneous peginterferon alfa-2a 180μg/week for 12 weeks. All participants were required to be on a stable antiretroviral regimen for &gt;8 weeks with HIV RNA suppression and have a CD-4 T-cell count &gt;200cells/mm3. The primary efficacy end point was the proportion of patients with SVR 12 weeks after the end of treatment (SVR12). The primary safety and tolerability endpoint included the effect on HIV RNA and CD4 T-cell counts/percentages. Among the patients in this study, 18 (78%) were male; 8 (35%) were black; 15 had a HCV genotype 1a, 4 with genotype 1b, 1 with genotype 2b, 2 with genotype 3a, and 1 with genotype 4a/4b/4c. Five patients (22%) had the IL28b CC genotype. All patients were on a stable antiretroviral treatment regimen, which comprised of tenofovir/emtricitabine plus one of the following: efavirenz (n=7; 30%); ritonavir/atazanavir (n=5; 22%); raltegravir (n=6; 26%); ritonavir/darunavir (n=4; 17%); or rilpivirine (n=1; 4%). “Most patients had rapid on-treatment HCV RNA suppression; 23/23 (100%) had a week 2 HCV RNA below the limit of quantification, and there was no HIV virologic breakthrough at follow-up Week 4,” Dr. Rodriguez-Torres reported. HCV RNA suppression continued throughout the study with 91% of patients (21/23) achieving SVR at week 12. The most frequently reported adverse events were anemia (n=12; 52%) and fatigue (n=8; 35%). Researchers observed a low risk of HIV virologic breakthrough with sofosbuvir plus pegylated interferon/ribavirin therapy. “SVR12 rates were similar to those seen with this regimen in hepatitis C virus mono-infected patients,
- -It was designed to include HCV genotype 1 naive patients.
- Sofosbuvir in IFN free regimen *Interim data for the first IFN-free regimen (sofosbuvir + RBV) studied in HIV-HCV coinfection (PHOTON-1) recently reported excellent response rates for treatment naïve genotype 1, 2, and 3 patients -12 wks of the all-oral therapy in treatment naïve: genotype 2 (N=26) SVR 88% genotype 3 (N=42) SVR 67% - genotype 1 (N=114) patients received 24 weeks of therapy SVR 76%
- *90% of genotype 1 patients completed therapy . *Healthy volunteer drug interaction studies of sofosbuvir with efavirenz, rilpivirine, boosted darunavir, raltegravir, tenofovir, and emtricitabine have not identified clinically significant interactions in IFN-free therapies
- TDF tenofovir The dose may need to be increased when taken with efavirenz and decreased when taken with boosted protease inhibitors This agent is currently in Phase III study in HIV/HCV coinfected patients
- Studies clearly show that DAAs will change the face of treatment in patients with HIV/HCV coinfection.