HCV treatment in HIV-infected patients

Transcription

1 The X Jubilee international conference "White nights of hepatology 2018" HCV treatment in HIV-infected patients Prof. Alexey Kravchenko Federal Scientific and Methodological Center for AIDS Prevention and Control Central Research Institute of Epidemiology Saint-Petersburg - 1 Jun of 2018

2 Настоящим лектор подтверждает, что он(а) получает гонорары за консультационные услуги в области научной и педагогической деятельности (образовательные услуги, научные статьи, участие в экспертных советах, участие в исследованиях и др.) от следующих компаний MSD, BMS, Gilead, Abbvie, Jonson & Jonson, АО Ассоциация-АЗТ, ВИРИОМ, Р-Фарма. By means of this, the speaker confirms that he 9she) receives honoraria for consulting services (educational services, scientific articles, participation in Advisory Boards, clinical trials, other) from the companies as follows MSD, BMS, Gilead, Abbvie, Jonson & Jonson, AZT-Association, VIRIOM, R-Pharma.

3 Wo do we need to treat HCV/HIV coinfection? Overall survival increase Decreased liver mortality Interruption of fibrosis progression Decreased hepatotoxicity risk of ART Operskalski et al. Curr HIV/AIDS rev; 2011; 8; 12-22

4 Proportion of HIV-patients with diagnosed HCV or HBV infection in the Russia 50% 25% 39% 41% 37% 37% 36% 35% 28% 33% 0% HCV infection was diagnosed in 45.2% of patients on dispensary observation ( years) HIV-infected patients died due to terminal stage of liver disease in Russia. 12.1% of patients received HCV treatment. А.В. Кравченко и соавт., 5 ЕЕСААС, По данным учетной формы 61

5 Distribution of patients with HIV / HCV infection according to HCV genotypes Genotype Genotype 2 Genotype Канестри В.Г., Кравченко А.В. и соавт. Эпидемиология и инфекционные болезни, 2001; 1: Кравченко А.В. и соавт. 4 Ежегодный Всероссийский конгресс по инфекционным болезням, Инфекционные болезни, 2012, Т10, Прилож.1, С

6 EACS guidelines on HCV/HIV treatment , V.8.1 Early stages of HIVinfection, CD4 > 500/mkl, fibrosis >F2 HCV infection treatment 200 < CD4 < 500/mkl ART for HCV treatment optimization CD4 < 200/mkl ART for CD4 increase before HCV treatment Guidelines of European AIDS Clinical Society, Version 8.1. October 2016

7 SVR achievement is associated with reduced overall and liver mortality in HCV-infected patients Overall mortality Liver mortality N=695 N=695 SVR achievement is associated with reduced rate of liver fibrosis Berenguer et al. J Acquir Immune Defic Syndr Jul 1;66(3): doi: /QAI

8 Evolution of the therapy efficacy over the past decade in patients with HCV G1 and compensated cirrhosis * pegifn + Rbv BOC or TLV + pegifn-alpha/rbv SMV or SOF + pegifn-alpha/rbv SVR: 1 32% SVR: % SVR: % 1. Marcellin P, et al. Hepatology 2012; 56: ; * SVR rates are presented as range of SVRs for naïve and 2. Poordad F, et al. N Engl J Med 2011; 364: ; experienced patients; 3. Jacobson IM, et al. N Engl J Med 2011; 364: ; SVR rate for GT1/GT4 cirrhotic patients 4. Bacon BR, et al. N Engl J Med 2011; 364: ; treated with SOF + P/R. 5. Zeuzem S, et al. N Engl J Med 2011; 364: ; BOC = boceprevir; TVR = telaprevir; 6. Vierling JM, et al. J Hepatol 2014; doi /j.jhep ; SMV = simeprevir; SOF = sofosbuvir. 7. SOF prescribing information, Dec 2013; 8. SMV prescribing information, Nov 2013; 9. Zeuzem S, et al. Gastroenterol 2014; 146:

9 Treatment algorithm of patients with HCV G1 Э.З. Бурневич, С.Е. Щаницына Клиническая фармакология и терапия,2016, 25(1) с изменениями

10 Triple therapy with SMV is effective in 87-90% naïve and relapsers patients 100% SMV+ПР ПР SVR12 (% пациентов) 75% 50% 25% p<0, % 87% 55% p<0, % 0% Наивные Naïve пациенты patients Пациенты Relapsers с patients рецидивом European population, HCV G1b Foster G, et al. EASL Poster P1127; Forns X, et al. EASL Oral presentation O13

11 Triple therapy with SMV is effective for HCV/HIV patients G1 all G1b 125% SVR12 (% пациентов) 100% 75% 50% 25% 90% 79% 87% 100% 100% 70% 57% 75% 0% Naïve Relapsers Partial Null HIV + HCV co-infection, HCV G1 Failure after previous pegifn + Rbv Dieterich et al. Clin Infect Dis Dec 1;59(11): doi: /cid/ciu675. Epub 2014 Sep 5.

12 SMV + PR for HCV G1 patients with HIV-infection: meta-analysis Frank Andersohn, Anne-Kathrin Claes, Werner Kulp, Jörg Mahlich and Jürgen Kurt Rockstroh Andersohn et al. BMC Infect Dis Jan 11;16:10. doi: /s

13 Comparison of C212 (triple therapy) results and meta-analysis и of trials, when HCV/HIV patients received PR only С212 trial (simeprevir + pegifnα-2а + rbv), n = 106: 1) Adults; 2) HCV G1 + HIV 3) 24 or 48 wks of therapy depending on the response 11 trials, 12 groups(perifnα-2а + ribavirin): 1) Adults; 2) HCV G1 + HIV 3) 12 wks of therapy 4) Clinical or observational trials Meta-analysis* Historical comparison: 1) Efficacy 2) Safety * The efficacy and safety of dual therapy as a result of meta-analysis are combined into randomized and fixed effects in accordance with the Freeman-Tukey double transformation method Andersohn F. et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison. BMC Infectious Diseases, 2016, 16:10

14 Comparison of the SMV + PR and PR therapy results demonstrated significant efficacy of triple therapy 100% % Of patients with SVR 24 weeks after the end of therapy for patients with HIV / HCV co-infection 75% 50% 25% 73% + simeprevir 28% 28% 0% SMV+PR Randomized effects Fixed effects perifnα-2а + rbv Andersohn F. et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison. BMC Infectious Diseases, 2016, 16:10

15 According to the meta-analysis, the addition of simeprevir to dual therapy does not lead to a worsening of the safety profile in patients with HIV infection % patients with AE PR SMV+PR Dscontinuation due to AE 5% 16% at least 1 SAE 10% 17% at least 1 AE 97% 97% 0% 25% 50% 75% 100% Andersohn et al. BMC Infect Dis Jan 11;16:10. doi: /s

16 Conclusion This comparison is the first systematic evidence of the triple therapy superiority over double therapy in patients with HIV/HCV G1 co-infection As a result of the data comparison (C212 study vs studies of dual therapy) the more significant efficacy of triple therapy is fixed Adding simeprevir to dual therapy does not lead to a worsening of the safety profile Andersohn et al. BMC Infect Dis Jan 11;16:10. doi: /s

17 SMV intake always 12 weeks Recommended duration of SMV + PR therapy for patients with HIV / HCV Niave and relapsers F0-F3 SMV + PR PR Niave and relapsers F4 SMV + PR PR Weeks Stopping rule! Stop, if HCV RNA 25 IU/ml Stop, if HCV RNA 25 IU/ml

18 The addition of SMV to PR allows for the majority of patients to reduce viral load significantly by the 4th week of therapy 0 1 SMV 150 мг + ПР плацебо + ПР Время (недели) Mean change of HCV RNA in plasma (lg IU / ml) compared to baseline Fried MW, et al. Hepatology 2013;58:

19 Доля пациентов (%) Management of patients on SMV + therapy according to the stopping rule allows to achieve SVR in most patients, regardless of the stage of liver fibrosis 100 Presence of RGT criteria SVR in this cohort / /173 25/27 23/25 All patients Все пациенты METAVIR F4 RGT (response guided therapy) criteria: HCV RNA <25 IU/ml at 4 wks and <25 IU/ml at 12 wks Relapsers, G1 HCV, European population Forns X, et al. EASL Oral presentation O13

20 Baseline predictors of SVR in patients who received simeprevir plus PR Il28B CC Cirrhosis no Baseline HCV RNA < IU/ml Treatment naïve Prior relapsers Baseline platelet count > 200 х 10^9 1b or 1а without Q80K Baseline albumin > 42 g/l D'Offizi et al. New Microbiol Jan;40(1): Epub 2017 Jan 9.

21 Subgroups of patients with predicted SVR over 80% controlling for other baseline characteristics D'Offizi et al. New Microbiol Jan;40(1): Epub 2017 Jan 9.

22 Observed SVR in treatment naïve and relapsers with GT1b and GT1a without Q80K, METAVIR F0-F2 fibrosis, with RVR D'Offizi et al. New Microbiol Jan;40(1): Epub 2017 Jan 9.

23 Proportion of patients with RAMs (%) NS3/4A RAMs returns to wild type in 50% of patients after 24 wks Median to RAMs loss: 36 wks (31,7 40,9) 24 wks (19,6 36,1) Combined analysis of phase IIb-III SMV studies Lenz et al. J Hepatol May;62(5): Time (wks)

24 NS3/4A RAMs disappear in most patients in 3-year observation study In case of achieving SVR is maintained in 100% of patients for 3 years Zoulim et al. Virol J Jan 30;15(1):26. doi: /s

25 In case of achieved SVR during SMV+PR therapy the majority of patients had regressing liver fibrosis accordingly to the 3 x-year observation SVR + (% patients) No SVR (% patients) 27% 83 % Regress No Regress Zoulim et al. Virol J Jan 30;15(1):26. doi: /s

26 Regimens for HCV G1 treatment with DAAs Genotype 1a and 1b F0-F3 1а F4 comp. 1b F4 comp. Treatment type and durability «3D»* SMV + SOF DCV + SOF 12 wks (+ rbv for 1a) 12 wks 12 wks 24 wks 12 wks with 12 wks + rbv** rbv or 24 wks + rbv 12 wks without rbv 12 wks + rbv *** + rbv - * - «3D» - PTV/RTV/OBV + DSV ** - «3D» + rbv 12 wks could be administered for pts with failure after PR *** - for 1а 24 wks and wihout Q80K mutation Покровский В.В., Юрин О.Г., Кравченко А.В. и соавт. Эпидем. и инфекц. б-ни. Акт. вопросы , Приложение.

27 Possible combinations of АРТ and triple therapy with simeprevir Peg-IFN alfa Ribavirin Simeprevir Abacavir possible interactions possible interactions no interactions Dolutegravir no interactions no interactions no interactions Emtricitabine possible interactions possible interactions no interactions Lamivudine possible interactions possible interactions no interactions Maraviroc no interactions no interactions no interactions Raltegravir no interactions no interactions no interactions Rilpivirine no interactions no interactions no interactions Tenofovir-DF possible interactions possible interactions no interactions

28 Change in the ART regimen before initiating HCV treatment DAA Before the start of HCV treatments, the patient is already receiving effective ART (HIV RNA <50 copies / ml, CD4+> 100 cells / mkl): The treatment regimen for HIV infection (without compromising on the effectiveness of ART) can be changed for the duration of HCV treatment (12 weeks for SMV, weeks for OMV / PTV / RTV). PIs (except for ATV in combination with OMV / PTV / RTV) can at this time be replaced by RAL and probably by DTG (in combination with SMV and OMV / PTV / RTV) or RPV (in combination with DCV or SMV) or ETR. When using the SOF + DCV combination, it is possible not to change the ART regimen that includes HIV's (other than TPV / r) Покровский В.В., Юрин О.Г., Кравченко А.В. и соавт. Эпидем. и инфекц. б-ни. Акт. вопросы , Приложение.