Bruce A. Luxon, MD, Ph.D. Anton and Margaret Fuisz Chair in Medicine Professor and Chair Department of Medicine Georgetown University

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1 Bruce A. Luxon, MD, PhD, FACG Bruce A. Luxon, MD, Ph.D. Anton and Margaret Fuisz Chair in Medicine Professor and Chair Department of Medicine Georgetown University Dr. Luxon is on the speakers p bureau for Merck Pharmaceuticals and is a consultant for Vertex. Dr. Luxon s presentation will include off label uses of FDA approved drugs used to treat hepatitis C. 1

2 Patient is a 49 year old male with hemophilia Past medical history: Multiple transfusions since childhood; anxiety; No ETOH Known HIV and HCV since 1995 HCV Treatment naïve too many side effects ID specialist uncomfortable with liver disease HIV meds Atripla (efavirenz/emtricitabine/tenofovir) Lab values CD4 540 HIV RNA undetectable HCV GT 2 HCV RNA 390,000 IU/ml Alb 4.2 Bilirubin 0.8 Cr AST 66 ALT 78 Plts - 273K Patient has never had a liver biopsy due to hemophilia (and won t get one now) Fibrosure F2 Fibroscan F2-F3 2

3 Patient is a 41 year old AA male fight attendant with HIV HCV co-infection. Risk factor for HIV: needle stick when handling unruly passenger 10 years ago. Diagnosed with HCV 7 years ago; no risk factors. Treated with PEG IFN and ribavirin for 12 weeks Took all medications, including HAART as prescribed CD4-450 HIV RNA undetectable Had flu like symptoms, significant fatigue. Treatment history Had drop in HCV RNA from 4 million to thousands Had drop in Hgb from 14 to 8 Quit after weeks of therapy Labs now HCV RNA 3.4 million IU/ml GT 1b HIV RNA undetectable CD4 540 Cr 0.5 Alb 4.1 Bili 1.0 HIV medications: Reyataz* (atazanavir*) and Truvada (emtricitabine/tenofovir) 3

4 Patient had liver biopsy showing F2-F3 disease with significant inflammation. IL28B testing showed TT Patient really wants treatment Why is this important? Epidemiology Natural history of HCV HIV con-infection Treatment options When is it safe (and necessary) to treat HCV? Current approved HCV therapy Recent trials PEG IFN + ribavirin + PI Future therapies 4

5 Bruce A. Luxon, MD, PhD, FACG HCV co-infection rate exceeds 90% in HIV-infected IVDU patients. Increased lifespan of HIV infected individuals HCV infection with end stage liver disease Accelerated liver fibrosis in uncontrolled HIV disease Accelerated liver fibrosis in controlled HIV disease There are multiple mechanisms for liver damage in co-infected patients. Naggie, Gastro,

6 Annual incidence of acute hepatitis C in HIVpositive men who have sex with men (MSM) Soriano, AIDS Rev,

7 Serial liver biopsy pyin co-infected MSM showed doubling of usual fibrosis. Increase in necro-inflammatory response early in infection sets stage for rapid fibrosis Control of HIV Conflicting gdata regarding ginfluence of HIV medications 7

8 Bruce A. Luxon, MD, PhD, FACG HIV treatment started per guidelines Ave. CD4 before therapy 250; increase in CD4 shown over 8 years Best survival with CD4>550 Acutely infected MSM (HIV positive) with biopsies performed early in disease Fierer, JID,

9 Bruce A. Luxon, MD, PhD, FACG Three year change Macias, Hepatology, 2009 Previous work suggested gg that good g HIV control was needed to maximize HCV treatment success Good control often hard to define and achieve For a while good control defined as CD4 counts > 500 HIV < 400 Now most regimens (except for some resistance patterns) achieve this good control Large studies showed that low CD4 ( ) were NOT predictive of HCV treatment failure 9

10 Mauss, 2005 Two large clinical trials used PEG IFN and ribavirin to treat co-infected patients. Other trials confirmed modest success rates: GT 1 ~ 14 to 36% Not as good as monoinfected but not dismal GT 2/3 ~ 44 to 73% Some co-infected populations p did even more poorly African Americans with GT1: SVR 15% Patients with IL28B TT did poorly Safety issues were not paramount in treating coinfected patients. Naggie, Gastro,

11 Ribavirin needed PEG IFN needed No ribavirin PEG IFN 2a Ribavirin 800 mg/day 48 weeks therapy CD4 counts did NOT influence SVR. HIV levels did NOT influence SVR. 11

12 PEG IFN 2b Ribavirin 800 mg/day 48 weeks therapy Boceprivir and telaprivir became available in May Both are only approved for compensated, mono-infected HCV patients. Both need to be administered with PEG IFN and ribavirin; different treatment regimens. Natural tendency to expand indications HCV-HIV co-infection HCV post liver transplant Not FDA approved 12

13 Bruce A. Luxon, MD, PhD, FACG Clinical trials started almost immediatelyy upon p success of both DAA s (boceprevir & telaprevir) being documented in mono-infected patients. Both DAA s are protease inhibitors which are NOT effective against HIV (good news). Both DAA s interact with CYP3A4 ((bad news)) Can increase or decrease HIV medication levels Can have sub therapeutic levels of DAA caused by HAART Not FDA approved Small phase 2 study, designed g for safety y Treatment of 60 co-infected patients (treatment naïve) PEG IFN + riba + telaprevir vs. PEG IFN + riba Treatment for 48 weeks 12 weeks triple therapy 36 weeks PEG IFN + riba alone Not FDA approved Naggie, Gastro,

14 Bruce A. Luxon, MD, PhD, FACG Small phase 2 study, designed for safety Treatment naive patients (98) PEG IFN + riba + boceprevir vs. PEG IFN + riba Treatment for 48 weeks 4 weeks PEG IFN + riba 44 weeks triple therapy Not FDA approved Naggie, Gastro, 2012 Sulkowski presented data from 60 patients with HCVHIV co-infection who were treated with PEG IFNribavirin-telaprevir. 13 patients were not on HAART (CD4>500) 47 were on HAART (HIV< 50 copies/ml) PART A PART B PEG IFN 2a and ribavirin 800 mg/day were used. HIV medications: Sustiva+Truvada or Atripla Reyataz + Epivir Telaprevir dosed at: Atazanavir (Reyataz): 750 mg TID Efavirenz (Sustiva): 1125 mg TID Not FDA approved 14

15 Total treatment 48 weeks Triple therapy for 12 weeks PEG IFN + ribavirin for 36 weeks Stopping rules HCV> 1000 IU/ml at week 12 HCV detectable at week 24 or 36 Safety: Pruritis (34%) Headache (34%) Nausea (32%) Rash (29%) Dizziness (29%) Anemia equal in both placebo and telaprevir arms CD4 counts fell equally in placebo and telaprevir arms Not FDA approved SVR (Percent t) Triple Dual 0 Total No HAART HAART Not FDA approved 15

16 Both DAA s interact with CYP3A4 Relaltively contraindicated: Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI); AZT; ddi. Small alterations: Isnetress (integrase ihibitor) or HIV protease inhibitors A pharmacokinetic study evaluated drug interactions between boceprevir (Victrelis) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors in healthy volunteers (n=39). In the study, concomitant administration of Victrelis (boceprevir) with ritonavir (Norvir) in combination with atazanavir (Reyataz), darunavir (Prezista), or with lopinavir/ritonavir (Kaletra) resulted in reduced exposures of the HIV medicines and boceprevir. Victrelis reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir, and darunavir by 49, 43 and 59 percent, respectively. Mean reductions of 34 to 44 percent and 25 to 36 percent were observed in area under the curve (AUC) and peak concentration (Cmax) of atazanavir, lopinavir, and darunavir. Co-administration of ritonavirboosted atazanavir with Victrelis did not alter the exposure (AUC) of boceprevir, but co-administration of Victrelis with lopinavir/ritonavir or ritonavir-boosted darunavir decreased the AUC of boceprevir by 45 and 32 percent, respectively. 16

17 New medications are in development for mono-infected HCV patients and will likely be approved in 3-4 years. Whether they are approved for co-infected patients is unknown (similar to the current two DAA s which are not approved for treating co-infected patients). Dietrich presented data on 106 co-infected patients using protease inhibitor simeprivir + PEG IFN + ribavirin. Simeprevir was given once daily. Treatment naïve patients were treated for 12 weeks (triple) then another 12 weeks dual. Previously treated patients were treated for full 48 weeks. Results Treatment naïve patients with initial response stopped therapy at 24 weeks (RGT) and had SVR12 of 77%. Previously treated patients also had good SVR12 (75%). HIV and CD4 counts not affected. Side effects similar to those reported for PEG IFN and ribavirin irin alone (based on interim analysis). 17

18 HCV infection is a very common complication of HIV infection. Liver disease is now the major cause of morbidity and mortality in the HIV infected population (in US and in developed countries). HCV can be treated by PEG IFN and ribavirin with good success rates : GT1 ~ 29% SVR; GT23 ~ 60% SVR. HCV treatment with triple therapy represents an important advance (non FDA approved). Careful selection of HCV treatment regimes, coupled with HIV management, is needed due to drug interactions. HCV induced liver disease is now the most common cause of morbidity and mortality in the HIV infected population. Approved treatment using PEG IFN and ribavirin has success rates of 30% (GT1) and 60% (GT23). Although not yet FDA approved, recent studies have shown that both boceprevir and telaprevir can be used in co-infected patients. Safety issues must be addressed to modify the HIV treatment regime to avoid interactions with the HCV DAA s. 18

19 Patient is a 49 year old male with hemophilia Past medical history: Multiple transfusions since childhood; anxiety; No ETOH Known HIV and HCV since 1995 Since GT 2, I decided to treat him with PEG IFN and ribavirin. Dosed his ribavirin at 800 mg daily. Anticipated 1 year of therapy. Suggested success rate of ~60%. Did NOT change HIV regimen. Currently at month 7; doing well; no bleeds; no anxiety Had RVR; HIV undetectable; CD4 count down proportionately. Patient is a 41 year old AA male fight attendant with HIV HCV co-infection. GT 1b. Previously treated with unknown HCV viral kinetics HIV medications: Reyataz* (atazanavir*) and Truvada (emtricitabine/tenofovir) Changed Reyataz* (atazanavir*) to Isentress (raltegravir); waited 1 month and checked HIV count Started PEG IFN and ribavirin (1200 mg) for 1 month Had RVR Added boceprevir; anticipated triple therapy for 44 weeks Patient had anemia (Hb 11); decreased dose of ribavirin to 800 mg Patient did well: fatigue, decreased exercise tolerance but achieved SVR24 in March 19