Your SlideShare is downloading. ×
New frontiers kostman
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Saving this for later?

Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime - even offline.

Text the download link to your phone

Standard text messaging rates apply

New frontiers kostman

324
views

Published on

Published in: Health & Medicine

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
324
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
10
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • Well, the easy part was to go through some of those data and general considerations. What ’s difficult is to sit down with an individual patient and decide whether or not it is right to treat that patient now with existing therapy, and that requires consideration of a number of factors categorically described in this graph as the competing mortality of HIV, which has fortunately been reduced by ART, AE’s (which for patients with baseline anemia or depression) can be constraining, and the likelihood that that person will respond to treatment, which can be as high as 2/3 chance if you’re genotype 3 in Spain or as low as 10% if you’re genotype 1, high viral load, African-American in Philadelphia. So a lot of the focus then goes to the disease progression and the question is what is the chances of your getting liver failure in the next five years while we wait for better and safer medications, and that unfortunately has been an inexact science.
  • However, HCV genotypes 2 and 3 were found to be more responsive to combination PEG-interferon plus ribavirin (cure rates ~76%) compared to HCV genotype 1 (cure rates ~46%).
  • Background: In an ongoing 1-part, randomized, double-blind, placebo-controlled, parallel-group, phase 2 trial of telaprevir in combination with pegylated interferon-alfa-2a (peg-IFN-a-2a)+ribavirin (RBV) in genotype 1 HCV treatment-naïve HIV+ patients, a week-24 interim analysis was performed. Methods: Patients in each part were randomized into 2 groups: telaprevir 750 mg every 8 hours + pegIFN 180 μg/week + RBV 800 mg/day for 12 weeks followed by 36 weeks of pegIFN+RBV (T/PR group) and placebo + pegIFN+RBV for 48 weeks. The telaprevir dose was 1125 mg every 8 hours when the ART regimen included efavirenz (EFV). In part A, patients had no concurrent ART. In part B, patients were on stable, predefined ART with either an EFV- or an atazanavir (ATV)/ritonavir (r)-based regimen. Results: Of 62 patients randomized, 60 received ≥1 dose, 13 in part A, 47 in part B; 44 patients reached week 24 on the study drug. Mean age was 46 years; 88% were male; 27% were African American; 68% had subtype 1a; 3.3% had cirrhosis. At baseline, 92% and 81% of part A and B patients had HCV RNA ≥800,000 IU/mL, respectively; mean CD4 counts were 690 cells/mm3 and 562 cells/mm3, respectively. Undetectable HCV RNA at week 4, 12, weeks 4 and 12, and week 24 are shown in the table; 2 patients experienced HCV RNA breakthrough on telaprevir (n = 1 EFV, n = 1 ATV/r). There were no HIV RNA breakthroughs. Absolute CD4 counts declined from baseline in both groups, although CD4 percentage remained unchanged. Overall, in the treatment groups compared to placebo, abdominal pain, vomiting, nausea, pyrexia, dizziness, depression, and pruritus occurred ≥10% difference; bilirubin adverse events occurred more frequently in ATV/r patients (27% vs 0%) as did indirect hyperbilirubinemia. No severe rashes were reported. Three treated patients in part B experienced an adverse event (cholelithiasis, jaundice, hemolytic anemia [severe adverse event]) that led to discontinuation of 1 or more study drugs. Telaprevir pharmacokinetics was comparable across ART regimens. The pharmacokinetics of ART when co-administered with telaprevir resulted in changes consistent with prior didanosine (ddI) studies in healthy volunteers. Conclusions: At the week-24 interim analysis, substantially higher on-treatment responses were observed in patients treated with a telaprevir-based regimen than placebo. Overall, undetectable HCV RNA at weeks 4 and 12 was achieved in 63% of treated patients compared to 4.5% on placebo. Bilirubinemia was notable in patients treated with an ATV/r-based regimen; however, safety and tolerability of telaprevir in combination with pegIFN+RBV was comparable to that previously observed in HCV-mono-infected patients.
  • Note the SVR12 rate of the BOC arm is more than double the rate in the P/R arm. Also note that the difference between the 2 arms is similar to the difference between the TVR and P/R arms of the study shown in the prior slide.
  • These are the common AEs reported in these trials where a difference in 10% was seen between the arms. Other AEs were reported, but are not on these lists because there were no differences between the groups. Of note, telapravir is associated with pruritis (especially perianal itching), rash, and fever. Bocepravir is associated with dysgeusia (abnormal/metallic taste), fevers, and cytopenias.
  • 771LB: Background: Boceprevir (BOC) is a potent ketoamide inhibitor of the hepatitis C virus (HCV) NS3 protease that has demonstrated antiviral activity in combination with peg-interferon and ribavirin. HCV co-infection is common among HIV-infected patients and may require co-administration of BOC and ARV drugs. Atazanavir (ATV), lopinavir (LPV), and darunavir (DRV) are among the most frequently prescribed HIV protease inhibitors (HIV-PI). All are given in combination with low-dose ritonavir (r), a potent CYP3A4 inhibitor, which serves as a pharmacokinetic booster. This study was conducted to evaluate the pharmacokinetic interaction of BOC with ATV/r, LPV/r, and DRV/r. Methods: This was a single-center, 3-part, open-label, drug-interaction study in 39 healthy adult subjects. Subjects received BOC (800 mg three times a day) on days 1 to 6. After a 4-day washout, subjects received ATV/r (300/100 mg every day), LPV/r (400/100 mg twice a day), or DRV/r (600/100 mg twice a day) on days 10 to 31. Subjects received concomitant BOC (800 mg three times a day) on days 25 to 31. Blood samples were collected for the pharmacokinetic assessment of HIV-PI, ritonavir, and BOC. Safety assessments included ECG, vital signs, clinical laboratory tests, physical examination, and adverse event monitoring. Results: Co administration of BOC with the HIV-PI/r was generally well tolerated. There were no serious adverse events. Concomitant BOC treatment decreased the exposure of all 3 HIV-PI with AUC0-last, Cmax, and Cmin GMR (90% CI) of ATV 0.65 (0.55 to 0.78), 0.75 (0.64 to 0.88), and 0.51 (0.44 to 0.61); of LPV 0.66 (0.60 to 0.72), 0.70 (0.65 to 0.77), and 0.57 (0.49 to 0.65); and of DRV 0.56 (0.51 to 0.61), 0.64 (0.58 to 0.71), and 0.41 (0.38 to 0.45), respectively. Co-administration with BOC also decreased the exposure of ritonavir in all 3 HIV-PI groups, with ritonavir AUCt decreasing 34%, 22%, and 27% in the ATV, LPV, and DRV cohorts, respectively. Co-administration with ATV/r did not alter BOC AUCt, but co-administration with LPV/r and DRV/r decreased BOC AUCt 45% and 32%, respectively. Conclusions: Concomitant administration of BOC and ATV/r, LPV/r, and DRV/r resulted in reduced steady-state exposures of the HIV-PI, ritonavir, and BOC. 772LB: Background: HIV/hepatitis C virus (HCV) co-infected patients are likely to use both HIV and HCV treatment. HIV guidelines recommend tenofovir (TFV) and emtricitabine (FTA) combined with efavirenz (EFV), atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL) for the initial treatment of HIV infection. Plasma concentrations of the HCV protease inhibitor (PI) boceprevir (BOC) were decreased when BOC was co-administered with EFV or ritonavir. Because no interaction between BOC and RAL is expected, RAL might be a more suitable ARV agent when combined with a BOC-containing HCV treatment. This study was designed to investigate the absence of a drug interaction between BOC and RAL. Methods: This was an open-label, randomized, two-period, cross-over phase I trial in 24 healthy volunteers. All subjects were randomly assigned to: BOC 800 mg three times a day for 10 days plus a single-dose of RAL 400 mg on day 10 followed by a wash-out period and a single-dose of RAL 400 mg on day 38, or the same medication in reverse order. After observed intake of BOC and RAL with a standardized breakfast, blood samples for pharmacokinetics (PK) were collected during an 8-hour and a 12-hour period, respectively. PK parameters were calculated by non-compartmental analysis (WinNonlin version 5.3). Geometric mean ratios (GMR) and 90% confidence intervals (CI) were calculated for RAL AUClast and Cmax after log-transformation of within-subject ratios. A 90%CI within the 0.80 to 1.25 range indicates no clinically meaningful effect of BOC on RAL PK. Results: Twenty-two subjects (10 males) completed the trial. One subject was excluded for non-adherence to the study protocol and another subject because of elevated ALT before receiving BOC. Mean (+range) age and body mass index were 38 (20 to 55) years and 23 (18 to 27) kg/m2, respectively. No serious adverse events were reported. The geometric mean (95%CI) of RAL AUClast and Cmax for RAL+BOC vs RAL alone were 4.27 (3.22 to 5.66) vs 4.22 (3.19 to 5.59) mg.h/L and 1.06 (0.76 to 1.49) vs 0.98 (0.73 to 1.31) mg/L, respectively. GMR (90%CI ) of RAL AUClast and Cmax for RAL+BOC vs RAL alone were 1.01 (0.85 to 1.20) and 1.09 (0.89 to 1.33). Conclusions: BOC did not affect RAL exposure. Due to the absence of a clinically significant drug interaction, RAL can be recommended for combined HIV/HCV treatment including BOC.
  • Background: Sexually transmitted hepatitis C virus (HCV) reinfection has been described in men who have sex with men (MSM) who are co-infected with HIV. Methods: Retrospective analysis from 4 major German HIV and hepatitis care centers (Frankfurt, Hamburg, Berlin, Bonn) on patients with sexually acquired multiple (2 to 4) HCV infections. Patients had either cleared the virus spontaneously or were sustained virological responders (SVR) to HCV therapy after first infection. Reinfection was defined by one of the following conditions: genotype (GT) switch, clade switch, detectable viral load after SVR, or 6 months of undetectability after spontaneous clearance. Results: We identified 45 HIV+ MSM with sexually acquired HCV reinfection: 8 had a third episode, and 1 patient had a fourth infection. At the first HCV episode, median age was 38 years, median HIV viral load was 50 copies/mL (range 20 to 6.15x105), median CD4 lymphocyte count was 490/mm3 (244 to 953); 11 patients had IL28B genotype C/C, 18 had non-C/C (n.a. in 16). Median HCV viral load at first infection was 1.0 x 106 iU/mL, 26 patients had HCV-GT 1, 8 had GT 3, 10 had GT 4. Median alanin aminotransferase was 445 iU/mL, aspartate aminotransferase was 225 iU/mL, gamma-glutamyl transpeptidase was 322 iE/mL. 39 patients responded to treatment, 6 cleared spontaneously. The median delay to the second HCV episode was 34 months. At the second diagnosis, HCV viral load and ALT were not statistically different to the first episode; 18 patients responded to treatment, 7 cleared spontaneously, 6 chronified, results pending in 14, and 24 (55%) patients switched GT. Of the 7 who cleared the second infection spontaneously, 3 had already cleared during the first episode, and 2 patients who cleared during the first episode were re-infected with the same genotype. Conclusions: Sexually acquired HCV re-infections are regularly seen in the setting of HIV co-infection, suggesting the need for enhanced risk behavior counseling. We saw a trend to lower HCV viral load and transaminases during the second infection. Although we saw a high rate of genotype switches, our data do not support the concept of immune protection in HCV re-infections.
  • Transcript

    • 1. Changing Landscape ofHepatitis C Management in 2011:Focus on HIV/HCV Co-Infection Jay Kostman, MD Division of Infectious Diseases Viral Hepatitis Center Perelman School of Medicine of the University of Pennsylvania
    • 2. HCV Genotype Distribution – U.S. General Population1 HIV Coinfection2 NHANES III AACTG Cross-Sectional Analysis (n=250) (n=66) 1 1 74% 83% 3 2 3 7% 15% 9% 6 4 23% 4 2% 6% 1% Alter MJ et al. N Engl J Med 1999;341:556-562. 1 2 Sherman KE et al. Clin Infect Dis 2002;34:831-837.
    • 3. Sources of Infection for Persons with Newly Diagnosed HCV Sexual, 15% Transfusion, 10% (before 7/1992) Injection drug use, 60% Unknown, 10% Other, 5% • Occupational • Hemodialysis • Mother-infant Source: Centers for Disease Control and Prevention
    • 4. Goals of HCV Therapy Eradication Target Virus (Viral Cure) DelayTarget Disease Cirrhosis PreventComplications Prevent Hepatocellular Carcinoma Pearlman BL, Traub N. Clin Infect Dis 2011;52:889-900.
    • 5. Natural History of HCV Infection 55-86%Acute Chronic HepaticHCV HCV Inflammation Alcohol, 14-45% HIV, and hepatitis B Hepatic maySpontaneous Fibrosis accelerate Resolution fibrosis 20% in 20 yrs Cirrhosis 2 – 4% per yr 2 – 5% per yr Hepatocellular Hepatic Carcinoma Decompensation Seeff LB. Hepatology 2002;36 (Suppl 1):S35-46.
    • 6. Staging HCV Liver Fibrosis• Important part of chronic HCV work-up• Identify cirrhosis: ↑ hepatocellular ca risk: need to screen – Monitor for hepatic decompensation – Strongly consider antiviral therapy – Consider liver transplant evaluation• Determine cirrhosis by: – Liver biopsy – Non-invasive tests
    • 7. HCV Treatment in 2011Genotype Therapeutic Options Duration 1 PEG-IFN-2b + ribavirin + boceprevir 24-48 wks* PEG-IFN-2a + ribavirin + telaprevir 24-48 wks* 2, 3 PEG-IFN-2a or -2b + ribavirin 24 wks 4 PEG-IFN-2a or -2b + ribavirin 48 wks PEG-IFN + ribavirin + nitazoxanide^ 48 wks* Duration may depend upon treatment response^ Off-label usage
    • 8. Time Points for Assessment of HCV Virologic Response• Week 4: rapid (RVR) = undetectable HCV• Week 12: – Early virologic response (EVR) = 2 log IU/mL ↓ HCV – Extended RVR (eRVR) = undetectable at wk 4 and 12• Week 24: undetectable HCV• Week 48: end-of-treatment (undetectable)• Week 72: sustained (SVR) = cure
    • 9. Telaprevir Response-Guided Therapy HCV RNA Result* Treatment Treatment Wk 4 Wk 12 Recommendation^ Wk 12 Wk 24 Undetectable Undetectable Telaprevir + TotalPreviously PEG + RBV PEG+RBV 24 wksUntreated Wk 12 Wk 48 Detectable Detectableor Relapse (≤1000 IU/mL) (≤1000 IU/mL) Telaprevir + PEG+RBV Total 48 wks + RBV PEG Wk 12 Wk 48 Prior Null Total or Partial – – Telaprevir + PEG+RBV 48 wks + RBV PEG Response* If HCV RNA >1000 IU/mL at Wk 4 or 12, stop therapy.^ If treatment-naïve and cirrhosis: Consider PEG/RBV x 36 wks, even if undetectable at Wk 4 and 12.
    • 10. SVR Rates with Telaprevir for HCV Genotype 1 Trial Arms* SVR TVR/PRx12 wk  PR x 12 wk 89% ADVANCE (Naïve) TVR/PRx12 wk  PR x 36 wk 75% PR x 48 wk 44% TVR/PRx12 wk  PR x 12 wk 51% PROVE-2 (Prior Rx) TVR/PRx24 wk  PR x 24 wk 53% PR x 48 wk 14%* Note: PEG-IFN alfa-2a used in all arms. TPV = telaprevir; PR = PEG-IFN + ribavirin Jacobson IM et al. N Engl J Med 2011;364:2405-16. Zeuzem S et al. et al. N Engl J Med 2011;364:2417-28.
    • 11. SVR Rates with Boceprevir for HCV Genotype 1 Trial Arms* SVR PRx4 wk  BOC/PRx24 wk  PRx20 63% SPRINT-2 wk (Naïve) PRx4 wk  BOC/PRx44 wk 66% PR x 48 wk 38% PRx4 wk  BOC/PRx32 wk  PRx12 59%RESPOND-2 wk (Prior Rx) PRx4 wk  BOC/PRx44 wk 66% PR x 48 wk 21%* Note: PEG-IFN alfa-2b used in all arms. BOC = boceprevir; PR = PEG-IFN + ribavirin Poordad F et al. N Engl J Med 2011;364:1195-206. Bacon BR et al. N Engl J Med 2011;364:1207-17.
    • 12. Predictors of SVR Host Factors Virus Factors •Younger age• Low HCV RNA level • Female sex • HCV genotype 2, 3 • Absence of HIV SVR • Non-Black • No hepatic steatosis • No insulin resistance • Less fibrosis • Adherence Genetics • Interleukin-28b
    • 13. Interleukin-28b Polymorphism: Strongest Predictor of SVR• Genetic polymorphism – Interleukin-28b gene – Chromosome 19• Homozygous for C allele: – Predicts HCV clearance after acute infection – Genotype 1: predicts SVR • 82% SVR, CC genotype – Genotype 2, 3: less clear Ge D et al. Nature 2009;461:399-401. Thompson AJ et al. Gastroenterology 2010;139:120-9.
    • 14. Toxicities of HCV Therapy• Tend to dominate treatment of HCV• Adverse events affect: – Quality of life – Adherence to antiviral therapy, follow-up• Discontinuation rates in trials: 14% – 22% – Higher in clinical practice
    • 15. Key Toxicities of PEG-IFN + RBV Pegylated Interferon Adverse Effect % Reported Fatigue 54% Influenza-like symptoms 43% Weight loss 39% Depression 22% Dermatitis 21% Thyroid dysfunction 6% Ribavirin Adverse Effect % Reported Hemolytic anemia 22% Fried MW. Hepatology 2002;36 (Supple 1):S237-44.
    • 16. Anemia During HCV Therapy• Due to: – Suppression of erythropoiesis (IFN) – Hemolytic anemia (ribavirin)• Incidence of Hgb <10 gm/dL: 15% - 35%∀ ↓ of ribavirin dose: ↓ likelihood of SVR• Use of erythropoietin: – Halt, reverse anemia during HCV therapy – Allows maintenance of ribavirin dosage – Consider if Hgb <10 gm/dL Mira JA et al. Antivir Ther 2007;12:1225-35.
    • 17. Important Toxicities ofBoceprevir + PEG-IFN + Ribavirin Adverse Effect % Reported Fatigue 57% Anemia 49% Dysgeusia 43% Nausea 43% Insomnia 33% Anorexia 25% Irritability 22% Rash 17% Dry mouth 11% Poordad F et al. N Engl J Med 2011;364:1195-206.
    • 18. Important Toxicities ofTelaprevir + PEG-IFN + Ribavirin Adverse Effect % Reported Rash 56% (severe, 3%) Fatigue 56% Pruritus 47% Nausea 39% Anemia 36% Diarrhea 26% Anorectal discomfort 11% Dysgeusia 10% Anal pruritus 6% Jacobson IM et al. N Engl J Med 2011;364:2405-16.
    • 19. Management of Toxicities• Close follow-up: call with concerning event• Rash: evaluate; antihistamine, topical steroid• Flu-like symptoms: ibuprofen, hydration• Depression: refer; antidepressant• Weight loss: appetite stimulant• Anal discomfort: topical steroid, lidocaine• Anemia: ribavirin dose reduction and erythropoietin
    • 20. Boceprevir vs. Telaprevir: Considerations Boceprevir Telaprevir1. Lead-in: potential to 1. Potential for shorter avoid protease inhibitor treatment duration2. More complex regimen, 2. Simpler regimen, 4 capsules q 8hrs 3 capsules q 8hrs3. Anemia, dysgeusia 3. Rash, anal discomfort4. Drug interactions 4. Drug interactions5. Consider in treatment- 5. Consider in patients naïve, CC genotype previously treated
    • 21. Impact of Chronic HCV in HIV• Chronic HCV is common in HIV pts: – Due to shared routes of transmission – 1/3 of HIV patients coinfected with chronic HCV• Antiretroviral therapy (ART) has ↓ HIV- related complications – Prolonged survival of HIV patients∀ ↑ mortality related to HCV in HIV Lo Re V et al. Clin Liver Dis 2008; 12:587-609.
    • 22. Impact of HIV on HCV Infection∀ ↓ clearance of HCV HCV Exposure∀ ↑ HCV RNA levels Recovery Chronic∀ ↑ fibrosis progression HIV∀ ↑ risk of cirrhosis Cirrhosis∀ ↑ risk of end-stage liver disease (ESLD) HCC ESLD∀ ↑ risk of hepatocellular carcinoma (HCC) Natural History of HCV Benhamou Y et al. Hepatology 1999;30:1054-1058. Graham CS et al. Clin Infect Dis 2001;33:562-569.
    • 23. Which HIV Patients Should be Treated With PEG-IFN/RBV?Disease Progression Adverse Effects of HCV TreatmentTreatment Response Competing Mortality Virologic Histologic
    • 24. SVR Rates for PEG-IFN + RBV Arms of HIV/HCV Treatment Trials Red = Genotype 1 Blue = Genotype 2, 3 Chung RT et al. N Engl J Med 2004;351:451-9. Torriani FJ et al. N Engl J Med 2004;351:438-50.
    • 25. Rare SVR Without EVR in HIV/HCV-Coinfected Patients No. Peg + RBV No EVR SVRAPRICOT1 289 85 2ACTG 50712 106 63 0RIBAVIC3 205 68 1 Torriani FJ et al. N Engl J Med 2004;351:438-50. 1 2 Chung RT et al. N Engl J Med 2004;351:451-9. 3 Carrat F et al. JAMA 2004;292:2839-48.
    • 26. Telaprevir + PEG-IFN/Ribavirin for Genotype 1 HCV/HIV PatientsEligibility 0 wks 12 wks 48 wks• Chronic genotype 1 HCV Telaprevir• HCV treatment-naïve Arm 1 750 mg q8h* PEG-IFN / RBV +• Liver biopsy PEG-IFN / RBV• HIV infection Placebo – No ART Arm 2 + PEG-IFN / RBV PEG-IFN / RBV • CD4 ≥ 500/mm3 *Telaprevir dose 1125 mg q8 with EFV • HIV ≤ 100,000 c/mL – Stable ART Trial Design • ATV/RTV or EFV + TDF/FTC • CD4 ≥ 300/mm3 • HIV ≤ 50 c/mL Sulkowski MS et al. 18th CROI. Abstract 146LB.
    • 27. Telaprevir + PEG-IFN/Ribavirin for Genotype 1 HCV/HIV Patients Undetectable HCV RNA at Week 1259 subjects enrolled:• No ART, n=13• On ART, n=46 – EFV-based, n=22 – ATV/RTV-based, n=24Main telaprevir AEs:• Pruritus: 35%• Nausea: 35% No ART EFV-Based ART ATV-Based ART• Anorexia: 19% Blue = Telaprevir + PEG-IFN + ribavirin Red = PEG-IFN + ribavirin Sulkowski MS et al. 18th CROI. Abstract 146LB.
    • 28. Telaprevir + Peg-IFN and RBV: Sustained Virologic Response (SVR12)Dieterich D, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 46.
    • 29. Dug-Drug Interactions:Telaprevir, Boceprevir, and ARVs• Phase 1 studies in healthy volunteers• Telaprevir drug levels: ↓ 50% w/ LPV/RTV ↓ 30% w/ DRV/RTV, FOS/RTV ↓ with EFV (requires ↑ dosage, 1250 mg TID)• Boceprevir drug levels: ↓ 40% with EFV – No change with PEG-IFN 2b, et al. 18th CROI. Abstract 118. Kasserra C TDF, RTV Van Heeswijk R et al. 18th CROI. Abstract 119.
    • 30. Boceprevir + Peg-IFN and RBV: Sustained Virologic Response (SVR12)Percent with Virologic ResponseSulkowski M, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 47.
    • 31. Notable Adverse Events Seen in HCV PI Trials Telaprevir1 Boceprevir2 TVR+P/R P/R BOC+P/R P/R (N=38) (N=22) (N=64) (N=34) Pruritus 39% 9% Anemia 41% 26% Headache 37% 27% Pyrexia 36% 21% Nausea 3% 23% Asthenia 34% 24% Rash 34% 23% Decreased appetite 34% 18% Pyrexia 21% 9% Depression 21% 9% Diarrhea 28% 18% Neutropenia 24% 23% Dysgeusia 28% 15% Anemia 18% 18% Vomiting 28% 15% Insomnia 13% 23% Flu-like illness 25% 38% Decreased Appetite 11% 18% Neutropenia 19% 6% Weight Decreased 13% 23% Erythropoietin use 38% 21%1. Dieterich D, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 46; 2. Sulkowski M, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 47.
    • 32. Significant Drug-drug interactions between Boceprevir and HIV PIs PK Parameter GM GM GMR 90% CI PI/r or BOC PI/r + BOC ATV AUC (ng●hr/mL) 39,900 26,000 0.65 (0.55, 0.78) ATV/r ATV Cmin (ng/mL) 693 357 0.51 (0.44, 0.61) + BOC BOC AUC (ng●hr/mL) 4,840 4,610 0.95 (0.87, 1.05) BOC Cmin (ng/mL) 106 86.6 0.82 (0.68, 0.98) DRV AUC (ng●hr/mL) 60,300 33,500 0.56 (0.51, 0.61) DRV/r DRV Cmin (ng/mL) 3,220 1,320 0.41 (0.38, 0.45) + BOC BOC AUC (ng●hr/mL) 5,350 3,650 0.68 (0.65, 0.72) BOC Cmin (ng/mL) 94.7 61.5 0.65 (0.56, 0.76) LPV AUC (ng●hr/mL) 117,000 77,000 0.66 (0.60, 0.72) LPV/r LPV Cmin (ng/mL) 6,730 3,800 0.57 (0.49, 0.65) + BOC BOC AUC (ng●hr/mL) 6,040 3,310 0.55 (0.49, 0.61) BOC Cmin (ng/mL) 91.9 39.8 0.43 (0.36, 0.53) No significant drug-drug interactions between boceprevir and raltegravir2Hulskotte E, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 771LB; de Kanter C, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 772LB.
    • 33. Options for Treating HIV/HCV Co- Infected Patients• Dose modification of ARV agents – Limited Data (with efavirenz) – PK interaction may not entirely explain lack of effect – May not be practical (telaprevir “package”)• Modify ARV regimen (raltegravir-no interaction) – Introduce new toxicity – Risk loss of HIV control• Treat HCV without HIV therapy – Risk of HIV disease progression – Decrease chance of HCV response
    • 34. HCV Re-infection Among MSM in Germany Patterns of Re-Infection •Retrospective analysis ofcases of HCV re-infection 45 HIV + MSM with acute HCV infectionin 4 German HIV andhepatitis centers Episode 1 5 SC 40 SVR •Re-infection defined as: •Genotype switch •Detectable VL ≥6 month Episode 2 2 3 SC 4 SC 16 SVR 12 CHC after SVR following (8 pending) SVR HCV therapy •Detectable VL ≥6 month Episode 3 after spontaneous clearance (1 pending) 1 SC 1 SVR 2 SVR 2 CHC •45 cases among MSM,all thought to be sexually Episode 4 1acquired SC SC= spontaneous clearance, SVR=sustained virological response, CHC=Chronic HCVIngiliz P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 752.