Adeel A. Butt, MD * P < % 69% * 70 End of treatment Sustained 39% * 19% IFN a-2a 6/3 MIU PEGASYS™ 180 µg Response (%) Standard Interferon vs. Pegylated Interferon * Intent-to-treat population

Adeel A. Butt, MD Zeuzem et al. NEJM 2000; 343: Standard Interferon vs. Pegylated Interferon Patients with Response (%) 7% 28% IFN  -2a PEG -IFN Genotype 1

Adeel A. Butt, MD Patients with Response (%) 37% 56% IFN  -2a PEG -IFN Zeuzem et al. NEJM 2000; 343: Standard Interferon vs. Pegylated Interferon Genotype 2,3

Adeel A. Butt, MD IFN  -2b + RBV (n = 444) PEG-IFN  -2a + Placebo (n = 224) PEG alone vs. IFN+RBV vs. PEG+RBV PEG-IFN  -2a + RBV (n = 453) Age (mean, y) Male Gender68%73%71% Weight (kg) Genotype 164%64%66% 164%64%66% 2 and 331%33%31% 2 and 331%33%31% HCV RNA Titers (mean, 10 6 c/mL) Cirrhosis15%12%12% Fried MW et al. NEJM 2002

Adeel A. Butt, MD PEG alone vs. IFN+RBV vs. PEG+RBV Sustained Virologic Response n = 224 n = 444 n = % 56% 45% 0% 20% 40% 60% % Patients IFN  -2b + RBV PEG-IFN  -2a + Placebo PEG-IFN  -2a + RBV P = for all comparisons Fried MW et al. NEJM 2002

Adeel A. Butt, MD % of Patients Genotype 1Genotype 2, 3 n = 285 n = % 21% 46% n = 145 n = % 45% 76% n = 69 PEG alone vs. IFN+RBV vs. PEG+RBV Sustained Virologic Response by Genotype PEG-IFN  -2a + Placebo IFN  -2b + RBV PEG-IFN  -2a + RBV P = P = 0.054P = P = P = 0.016

Adeel A. Butt, MD IFN+RBV vs. Low Dose PEG+RBV vs. High Dose PEG+RBV IFN alfa-2b 3 MIU TIW + RBV mg SVR (%) PEG (12 kDa) IFN alfa-2b 1.5 / 0.5  g/kg + RBV mg PEG (12 kDa) IFN alfa-2b 1.5  g/kg + RBV 800 mg P =.01 Manns et al. Lancet. 2001;358: (n = 511)(n = 505)(n = 514) P =.73

Adeel A. Butt, MD

Side Effects of IFN Flu-like symptoms Headache Fatigue or asthenia Myalgia, arthralgia Fever, chills Nausea Diarrhea Alopecia Thyroiditis Psychiatric symptoms Depression Mood lability Injection site reaction Autoimmunity Lab alterations Neutropenia Anemia Thrombocytopenia

Adeel A. Butt, MD Side Effects of RBV Hemolytic anemia Teratogenicity Cough and dyspnea Rash and pruritus Insomnia Anorexia Rebetron  [package insert]. Kenilworth, NJ: Schering Corp; 1999.

Adeel A. Butt, MD PEG (12 kDa) IFN alfa-2b Incidence of Discontinuations Due to Adverse Events IFN = interferon; PEG = polyethylene glycol; RBV = ribavirin. 13 PEG IFN alfa-2b (12 kDa) 1.5 µg/kg + RBV PEG IFN alfa-2b (12 kDa) 1.5/0.5 µg/kg + RBV IFN alfa-2b + RBV Percent

HCV-HIV Co-infection

Adeel A. Butt, MD HCV and HIV - Similarities  + ssRNA – Flavivirus  Virions/d =  Diversity/complexity  Six genotypes  Tropism: hepatocyte  Receptors: LDL, CD81 + ssRNA – Retrovirus Virions/d = Diversity/complexity 11+ clades Tropism: lymphoid Receptors: CD4, CCR5 HIV CCR5 = chemokine receptor 5; CD4 = cluster of deviation 4; CD81 = cluster of deviation 81; LDL = low density lipoprotein; + ssRNA = positive single strand ribonucleic acid. HCV HIV

Adeel A. Butt, MD HCV and HIV Prevalence of HCV in HIV > 10x general population Reported to be between 30-50% ~6% of VA population HCV infected ~35-43% of HIV infected veterans have HCV Greub, Lancet 2000;356:1800-5

Adeel A. Butt, MD Hepatitis C Virus and HIV Liver-Related Mortality UK hemophilia population, Deaths due to liver disease HIV -  16.7-fold HIV +  94.4-fold Risk  after 10 years HIV+ HIV-GP GP = general population; HIV = human immunodeficiency virus; O/E = observed to expected. Deaths Due to Liver Disease (O/E)

Adeel A. Butt, MD Increasing Mortality From ESLD in Patients With HIV One third of 1998 cohort had recent history of discontinuing HAART secondary to hepatotoxicity More than 1/2 who died with ESLD had either NDVL or CD4 >200/mm 3 6 months prior to death ESLD-Related Deaths (%) ESLD = end stage liver disease; NDVL = no detectable viral load.

Adeel A. Butt, MD HCV-HIV Co-infection Progression of liver disease accelerated in HCV-HIV co- infected patients Median time to cirrhosis 7 years in HCV-HIV vs. 23 years in HCV alone Soto, J Hepatol 1997;26:1-5

Adeel A. Butt, MD HCV-HIV Co-infection Generally no increase in HIV progression No difference in survival, progression from HIV to AIDS or AIDS to death or HIV to death Rate of decline of CD4 counts is also similar Dorrucci, JID 1995;172: Staples Clin Infect Dis 1998;29:150-4 Sulkowski JAMA 2002 More AIDS at baseline More progression Decreased CD4 recovery Greub, Lancet 2002 De Luca, Archives 2002 Effect of HCV on HIV Progression CONTROVERSIAL

Adeel A. Butt, MD PEG-IFN + RBV is associated with a superior week 24 virologic response (VR) Overall Wk 24 VR * 10 (15%) 29 (44%) genotype 1**4/52 (7%)17/51 (33%) genotype non-1**6/15 (40%)12/15 (80%)0.06 biochemical response 44% 54% NS IFN + R PEGIFN + R n=67 n=66 p value * intent to treat**Genotype 1 vs. non-1, p < Slide courtesy of R. Chung

Adeel A. Butt, MD A significant portion of virologic nonresponders experience histologic response (HR) Virologic nonresponders 57 (85%) 37 (56%) Wk 24 Bx obtained Histologic response15 (40%) 6 (26%)0.28 Combined virologic and histologic response VR + HR 25 (37%) 35 (53%) 0.08 IFN + R PEGIFN + R n=67 n=66 p value Slide courtesy of R. Chung

Adeel A. Butt, MD Grade 4 events Grade NS Grade 22518NS Grade 32022NS Grade ANC (< 500)37NS gluc (> 500)04NS plt(< 20K)01NS LFTs (> 10x ULN)02NS depression 10NS Premature D/C8 (12%)8 (12%)NS IFN + R PEGIFN + R n = 67 n = 66 p value Slide courtesy of R. Chung

Adeel A. Butt, MD Absolute CD4 fell but CD4% rose Wk 0 CD %CD Wk 24 CD %CD  CD4 W  %CD4 W0-24*+2.5%+3.5%0.14 IFN + R PEGIFN + R p value *overall +3.0%, p = Slide courtesy of R. Chung

Adeel A. Butt, MD There was no adverse effect on HIV-1 control W0W24 undund 59 (50%) 32 (52%)27 (47%)NS unddet 9 (8%) 6 (10%) 3 (5%)NS detund16 (13%) 6 (10%) 10 (5%)NS detdet35 (29%) 18 (29%)17 (30%)NS W0 undetectable 38 (62%) 30 (52%)NS W24 undetectable 38 (62%)37 (65%)NS HIV RNA Total IFN + R PEGIFN + R n = 119 n = 62 n = 57 p Slide courtesy of R. Chung

Adeel A. Butt, MD HCV-HIV Co-infected Patients 51 patients IFN alfa 2b, 3 million units TIW PLUS RBV months 59% genotype 1 Cirrhosis – 55% Mean CD4 = 411 Landau. AIDS 2001;15:

Adeel A. Butt, MD HCV-HIV Co-infected Patients ETVR = 29% SVR = 21% CD4 drop at end of treatment = 51 normalized after 6 months  Treatment discontinuation 29% Landau. AIDS 2001;15:

Adeel A. Butt, MD Hepatotoxicity in Co-infected Patients May be more common in co-infected patients, esp. those on PI based regimens However, overall risk small 88% co-infected patients on HAART had NO toxicity Reversible in those in whom it occurred Difficult to provide guidelines on management: Stop or change therapy if liver enzymes > 3-5 times ULN Sulkowski, JAMA 2000;283:74-80.

Adeel A. Butt, MD Take psychiatric history for depression and mania Develop relationship with mental health providers Treat preexisting depression before starting (PEG) IFN Evaluate patients for development of depression at least every 2 weeks after initiation of IFN therapy Mild depression – evaluate weekly Moderate depression – reduce dose of IFN; consider psychiatric consultation PEG IFN alfa-2a: reduce to 135 µg weekly PEG IFN alfa-2b: reduce dose by 1/2 Severe depression – discontinue IFN/RBV immediately and permanently; obtain immediate psychiatric consult Managing Depression

Adeel A. Butt, MD  Neutropenia  Consider G-CSF 300 µg SC BIW or TIW  No controlled trials demonstrating effectiveness  Clinical experience shows this to be effective  ANC <750 cells/mm 3 – dose reduce IFN  PEG IFN alfa-2a: decrease to 135 µg weekly  PEG IFN alfa-2b: decrease dose by 1/2  ANC <500 cells/mm 3 – discontinue IFN Management of Neutropenia GCSF = granulocyte-colony stimulating factor.

Adeel A. Butt, MD Management of RBV-Induced Anemia Hemoglobin determinations pretreatment, at week 2, week 4, and as needed If >10 g/dL: no action needed If <10 g/dL: reduce RBV dose to 600 mg daily If <8.5 g/dL: stop RBV If decreases by >2 g/dL from starting therapy: reduce dose to 600 mg daily in patients with cardiac history Hemoglobin returns to baseline within 4 weeks after RBV is stopped Cardiac function Anemia may exacerbate symptoms of coronary disease and/or deteriorate cardiac function Recommend stress test for patients aged >50 years Consider epoetin alfa 40,000 IU SC QW

Adeel A. Butt, MD Conclusions HCV is a common disease and a frequent cause of morbidity and mortality in the US and globally Current treatment options can eradicate/cure HCV in a significant proportion of chronically infected patients Very few eligible patients actually receive treatment HCV co-infection is very common in the HIV infected patients Treatment is associated with significant adverse events, especially in the HCV-HIV co-infected patients Benefits of treatment should be weighed against the risks, considering the long natural history of the disease