Sofosbuvir plus Peg-Interferon and Ribavirin in Treatment Experienced Patients with Hepatitis C Virus and HIV Co-Infection Mehri Nikbin, MD Infectious Diseases and Tropical Medicine specialist Iran Hepatitis Network (IHN) Middle East Liver Disease (MELD) Email: nikbin_mehri@yahoo.com

HIV / HCV co-infection is double trouble Background HIV / HCV co-infection is double trouble Compared to HIV-negative individuals, those with HIV suffer: Accelerated rate of fibrosis, higher rates of cirrhosis Higher rates of decompensation & higher liver-related mortality Unfortunately these patients have decrease access to liver transplantation compare with mono infected patients To reduce the burden of HIV/HCV co-infection we must screen, test, and treat!

All HIV infected patients should be screened for HCV Background Treatment of HCV in this patients population should have a high priority All HIV infected patients should be screened for HCV

Background Treatment HIV/HCV coinfected patients should be treated and retreated the same as patients without HIV After recognizing and managing interactions with antiretroviral medications and direct acting antivirals (DAAs) Antiretroviral drug switches ,when needed , should be done with goal of maintaining HIV suppression without compromising future options (prior treatment history – response to antiretroviral therapy – resistance profiles – drug tolerance )

(FDA-approved as of February 12), 2016 Treatment of HCV/HIV co-infection, July 2016 Antiviral HCV Treatments Daclatasvir + Sofosbuvir (GT1,3)* Monotherapies IFN-2a IFN-2b PEG-IFN 2a PEG-IFN 2b IFN-2a + Ribavirin IFN-2b + Ribavirin PEG-IFN 2a + Ribavirin* PEG-IFN 2b + Ribavirin PEG-IFN + ribavirin plus either: Boceprevir (GT1) Telaprevir (GT1) Simeprevir (GT1) In combination with other agents: Sofosbuvir Elbasvir + Grazoprevir (FDC) (GT1,4)* Ledipasvir + Sofosbuvir (FDC) (FDC, GT1,4,5,6* Paritaprevir / ritonavir / ombitasvir (FDC) + dasabuvir (GT1) Paritaprevir / ritonavir / ombitasvir (FDC) (GT4 Simeprevir + Sofosbuvir (GT1)

Regimens not recommended for Patients with HIV/HCV Treatment of HCV/HIV co-infection, July 2016 Regimens not recommended for Patients with HIV/HCV Antiretroviral treatment interruption to allow HCV therapy is not recommended Ribavirin should not be used with Didanosine/Stavudine or Zidovudine Sofosbuvir-based regimen should not be used with Tipranavir Should not be used treatment shorter than 12 weeks

Treatment Guidelines: 2014-2015 HCV/HIV treatment EASL guidelines : Sofosbuvir ®+Dacatasvir® Sofosbuvir®+Ledipasvir® Sofosbuvir® +Peginterferon® +Ribaverin® Less emphasis to Sofosbuvir ®+Ribavirin® In genotype 1a,1b,4,5,6 Treatment duration is more systematically extended to 6 months in case of compensated cirrhosis

Sofosbuvir Interactions with Antiretroviral Not metabolized nor induce or inhibit any cytochrome P450 enzyme Drug interaction studies with antiretroviral drugs : no clinically significant interaction with Efavirez, Tenofovir, Emtricitabine, Rilpivirine, Ritonavir- boosted Darunavir, Raltegravir Not recommended for use with Tipranavir

Study Design and Methodology Treatment of HCV/HIV co-infection, July 2016 Study Design and Methodology

Study Design and Methodology Treatment of HCV/HIV co-infection, July 2016 Study Design and Methodology Prospective longitudinal study Twenty patients with chronic HCV coinfected with HIV,undertreat ART and previously treated for HCV (Peginterferon® +Ribavirin®) and no SVR All patients CD4 > 200 HCVRNA viral load :was assessed by Cobas Tagman assey with the low detection of 6 IU/ml HCVRNA viral load : was assessed 4 weeks of therapy , and4 weeks and 12 weeks after end of therapy

Study Design and Methodology Treatment of HCV/HIV co-infection, July 2016 Study Design and Methodology All patients treated with ART continued which contained : NNRT, NRTI,in some patients with PI In two patients Zidovudine® changed All patients treated for chronic HCV : Peginterferon a-2b® (80-150 µg/week) plus oral Ribavirin® 800- 1000 mg(based body weight) and Sofosbuvir® 400 mg/day for 12 weeks

Baseline Characteristics Treatment of HCV/HIV co-infection, July 2016 Baseline Characteristics

Baseline Characteristics Treatment of HCV/HIV co-infection, July 2016   Age (year) 45.15 (6.39) Men 16 (80%) of 20 cases Body-mass index (kg/m2) 25.02 (3.51) Log10 HCV RNA (IU/mL) 5.92 (1.60) HCV genotype 1a 1b 17 (85%) 3 (15%) IL28b CC CT TT 6 (30%) 13 (65%) 1 (5%) Fibroscan F0-F1 F1 F1-F2 F2 F2-F3 F3 F3-F4 F4 4 (20%) 2 (10%) Data are mean (SD) or n (%) unless otherwise stated

Treatment of HCV/HIV co-infection, July 2016 RESULTS

Treatment of HCV/HIV co-infection, July 2016 Results SVR (cutoff HCV RNA :6 IU/ml) 3 months or 12 weeks after end of treatment: 19(95%) RVR : all 19 patients had RVR Non- Response :1(5%) (discontinued treatment due to liver decompensation) Although Tenfovir® was included ART : no rising of BUN –Cr The most common adverse effects : fever , fatigue , anemia (2 patients treated with Eprex® for anemia)

Sofosbuvir for chronic hepatitis C virus infection Treatment of HCV/HIV co-infection, July 2016 Sofosbuvir for chronic hepatitis C virus infection Rodriguez- Torres M,Gaggar A et al. J : acquire immune deific. syndrome , 2015 , 68:543-9 In this single-arm, single-site, open-label trial, 23 HCV/HIV coinfected treatment-naïve patients with genotype 1-4 received the 12- week triple therapy of peginterferon alfa-2a, ribavirin (weight-based), and sofosbuvir. Mean CD4 count was 562 cells/mm3 and all were on antiretroviral therapy (tenofovir-emtricitabine plusone of the following: efavirenz, atazanavir plus ritonavir, darunavir plus ritonavir, rilpivirine,or raltegravir). The overall SVR12 was 91%; of the 19 patients with genotype 1, 89% achieved an SVR12.

Treatment of HCV/HIV co-infection, July 2016 CONCLUSIONS

Treatment of HCV/HIV co-infection, July 2016 Conclusions Peginterferon a2b(80-150µg/week) plus oral Ribavirin® 800- 1000 mg(based body weight) and Sofosbuvir® 400 mg/day for 12 weeks provided high rate of sustained virology response in Iranian patients coinfected with HIV-1 and HCV genotype 1a-1b with compensated cirrhosis who had a history of nonresponse to Peginterferon a-2b. These combination therapy is well tolerated in Iranian patient with coinfected HIV/HCV

Treatment of HCV/HIV co-infection, July 2016 Conclusions At the time of this study ledipasvir +sofobuvir or Daclatasvir ® was not available in Iran.Daclatasvir in combination with Sofosbuvir is first choice for therapy in patients with HIV/HCV. ILB 28 is not important for starting HCV treatment in HIV/HCV coinfected patients

Drug-Drug Interactions Remain Important for: Treatment of HCV/HIV co-infection, July 2016 Drug-Drug Interactions Remain Important for: CAT 1 = no DDI CAT 2 = potential, may require dose reduction or monitoring CAT 3 = contraindicated CAT 4 = unknown interaction Martinello et al, CROI 2016, Abstract 451

Certain Safety Issues Regarding Regimens for HCV Genotype 1 Treatment of HCV/HIV co-infection, July 2016 Certain Safety Issues Regarding Regimens for HCV Genotype 1

Treatment of HCV/HIV co-infection, July 2016 Recommendation HCV treatment in patients with HIV coinfection. AASLD/IDSA Guidance “The guidance from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of Am (IDSA)”. ARV should be consider for most patients with HIV/HCV coinfection regardless of their CD4 count . In naïve patients with CD4>500 ART could be deferred until after treatment of HCV. For those patients whose CD4<200 it may be advisable to first initiate ART and defer HCV therapy