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Hepatitis C in HIV Ronald D. Wilcox MD FAAP Program Director/PI, Delta AETC Asst Professor of Internal Medicine and Pediatrics, Section of Infectious Diseases Louisiana State University Health Sciences Center DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org www.deltaaetc.org 504-903-0788 LPS Coordinator: Dana Gray DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Create Unique ID Please darken the circles completely No check marks, X’s, or other markings Employment Setting Zip code DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Disclosure • The speaker receives or has received research support from all companies that make HIV medications in the US now or in the past five years • The speaker is NOT on a speakers bureau for any pharmaceutical company DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Polling Question • Please choose which category best describes your profession: – 1. – 2. – 3. – 4. – 5. – 6. Nurse or Advanced Practice Nurse Physician or Physician Assistant Dental professional Pharmacist Case Manager / Social Worker Other medical professional or Administrator DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Polling Question • My current knowledge/experience of Hepatitis C in the setting of HIV most closely resembles which of the following: – 1. I know basically nothing about hepatitis C – 2. I know hepatitis C infects the liver but that is all – 3. I take care of many patients with hepatitis C for their HIV but do not do anything with their hepatitis C – 4. I have a good working knowledge of Hepatitis C and have treated some patients in the past – 5. I am an expert in this field and should actually be giving this talk DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Case • 37 y/o AA male diagnosed 12 years prior with HIV when his lover tested +. Lowest CD4 per pt had been 179. Placed on CombivirTM and abacavir. • Previous meds: indinavir, ddI, AZT, 3TC, nevirapine, and ritonavir. • PMH: syphilis, pneumonia, and + antibodies for hepatitis C and B (HBsAg neg). • SH: Denied IVDU or tobacco. Incarcerated x 12 years • Lab values: AST 131 ALT 147 AlkPO4 75 plts 92,000 HCV RNA PCR 115,000 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Case • Liver biopsy two months after presentation: mild piecemeal necrosis of the parenchyma as well as moderate portal inflammation and bridging fibrosis, compatible with moderate chronic active hepatitis. • 5 months later: acute left hand weakness x 2-3 weeks, facial droop, slurred speech, left foot weakness. MRI consistent with PML; JC virus PCR +. CD4 328, viral load 495. DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Case • HAART changed to d4T, ddI, Efavirenz, and Amprenavir. • Began cidofovir 2 doses one week apart then q3w w/ probenecid . • 6th dose: worsening renal and liver function: ALT 158 AST 207 AlkPO4 209 TB 5.0 Creat 1.5 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Case • Two months later, after 9 doses of cidofovir: AST 390 ALT 162 AlkPO4 193 TB 10.6 PT 14.9 – Pt reported anorexia, diarrhea, and pruritus. – Efavirenz held. • One month later pt died encephalopathic with ESLD 5 days before his parole hearing date. PT one week prior to death 40.9. DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Polling Question • Hepatitis C differs from HIV in all the following ways EXCEPT: – 1. Likelihood of chronicity – 2. Amount of virus production per day in an untreated patient – 3. Ability to integrate into host DNA – 4. Likelihood of cure with therapy – 5. Most common means of transmission when comparing parenteral versus sexual DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org HIV versus Hepatitis C Family # Virions/ day Diversity Chronicity Integration Transmission Hepatitis C HIV Flavivirus 10 (12) Six genotypes Retrovirus 10 (10-11) 11+ clades 80% None 100% Host DNA Parenteral > sexual Sexual > parenteral DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org X 100,000 HIV/HCV Co-infection in the United States 45 40 35 30 25 20 15 10 5 0 Mono-infected Co-infected HCV HIV DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Risk of HIV, HCV, and HBV in IV Drug Users Seroprevalence (%) Baltimore, 1983-1988 100 80 HCV HBV HIV 60 40 20 0 6 12 18 24 30 36 42 48 54 60 66 72 Duration of IVDU (Mos) Garfein et al. Am J Public Health. 1996;86:655-61 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Influence of HIV on Sexual Transmission of HCV • Multi-center cross-sectional study to look at hepatitis C antibody positivity among female sexual partners of hemophiliac men • 3% in partners of co-infected men • 0% in partners of HIV negative men Eyster et al. Ann Inter Med. 1991; 115:764-8 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Perinatal Transmission • Increase risk factors – Maternal HIV – High maternal HCV viral load – Membrane rupture > 6 hours – Internal fetal monitoring • No increase in breast feeding • ? C-section role ? • Testing: Ab after 15 months DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Perinatal Transmission Role of HCV/HIV Co-infection • HIV Co-infection – HCV only – HIV/HCV HCV transmission 5% (3-8%) 17% (7-36%) • HCV co-infection may – HIV only – HIV/HCV HIV transmission 16.3% 26.1% (RO 1.82) Zanetti et al. Lancet. 1995;345:289-91 Hershow et al. J Infect Dis. 1997;176:414-20 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Co-infection HIV Risk Factor Prevalence at Johns Hopkins HIV Clinic 100 90 80 70 Prevalence 60 of HIV/HCV 50 40 (%) 30 20 10 N=1742 0 89 45 Co ho rt 10 En tir e M SM er os ex ua l He t IV DU 14 Sulkowski et al. Hepatology. 2000;32:212A. DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Co-infection HIV Risk Factor Prevalence at the HOP clinic N = 402 w n Un kn o er os ex ua l He m op hi lia Tr an sf us io n He t M SM /I VD U M SM IV DU 45 40 35 30 25 20 15 10 5 0 Data abstracted from the ASD database by Kathleen Welch, PhD DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Polling Question • If someone has chronic hepatitis C, their chance of developing cirrhosis is approximately: – 1. – 2. – 3. – 4. – 5. 5% 20% 35% 50% 65% DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Fibrosis Grade (METAVIR Scoring System) Effect of HCV/HIV Co-infection on Fibrosis Progression Rate 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 HIV+, n=122 HIV– matched controls, n=122 Progression rate was increased in those persons with CD4 < 200 or Ongoing EtOH use 10 20 30 40 HCV Duration, years Benhamou et al. Hepatology. 1999;1054-8. DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Wilcox’s Rules of 20 • Applies to mono-infected patients with Hep C – 15-20% - chronicity – 20% of those with chronic disease develop cirrhosis – Development of cirrhosis occurs in 20-40 years – Of those with cirrhosis, about 5% (1 in 20) develop hepatocellular carcinoma – Chance of perinatal transmission – 1 in 20 (5%) DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Causes of death in HIV+ patients 35 30 25 20 1995 1999 15 10 5 0 PCP BP SEPSIS CANCER ESLD Berggren R. 39th IDSA Conference 2001 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Cause of Death by CD4 count 40 35 30 25 > 200 < 200 20 15 10 5 0 ESLD P<.0001 PCP Sepsis Malig Pneum P=.025 Berggren R. 39th IDSA Conference 2001 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org HCV and HAART • NNRTIs – 20% increase incidence of transaminase elevation – Increased levels of EFV seen with cirrhosis – Once daily nevirapine highest incidence of significant transaminase elevation in class in co-infected • NRTIs – Abacavir may influence chance of cure – mixed results from studies – AZT relatively contra-indicated secondary to anemia – ddI interacts with ribavirin so is absolutely contraindicated DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org HCV and HAART • PIs – Full dose ritonavir probably worse choice – Tipranavir, darunavir have case reports of significant toxicity in co-infected patients – Nelfinavir, atazanavir, fos-amprenavir may be safest choices in co-infected patients • IIs – Case reports of liver toxicity when raltegravir added to a tipranavir-based regimen DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org HAART and Mortality in HCV • SMART Study – “Interruption of antiretroviral therapy is particularly unsafe in persons with hepatitis virus coinfection. Although HCV- and/or HBVcoinfected participants constituted 17% of participants in the SMART study, almost one-half of all non-OD deaths occurred in this population. Viral hepatitis was an unlikely cause of this excess risk” Tedaldi E, Peters L, Neuhaus J et al. Opportunistic disease and mortality in patients coinfected with hepatitis B or C virus in the strategic management of antiretroviral therapy (SMART) study. Clin Infect Dis. 2008 Dec 1;47(11):1468-75 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Polling Question • If an HIV+ patient with + hepatitis C antibody has a normal ALT level, the chance of significant liver disease is the same as in the mono-infected HCV+ patient. – 1. True – 2. False DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org ALT Levels in Chronic HCV • Co-infected patients – 7-9% have consistently normal liver enzymes • 25-40% have significant liver fibrosis on biopsy • 12-14% have cirrhosis – Mono-infected • 10-30% of those with normal enzymes have significant fibrosis – Genotype 3 shown to have faster progression to cirrhosis • Lower ALT – Women – Genotype 4 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Tests to Order Prior to the Liver Biopsy • • • • • • • ANA TSH Alpha-fetoprotein HCV genotype HCV Viral load ART / RPR Ferritin (plus transferrin if elevated) • PT/ PTT • • • • • • • • CBC with plts Chemistry 7 LFTs Uric Acid ECG Stress Test, if indicated Lipid Profile Insulin DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Liver Biopsy • Gold standard, especially in those with genotype 1 – Often by-passed for those with genotypes 2 or 3 • Predictive of outcome and prognosis • Low morbidity/mortality : risk of death 1 per 1012,000 • GI vs. interventional radiology DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Histologic Staging Stage 0 No Fibrosis Stage 1 Stage 2 Few septa Portal Fibrosis Stage 3 Numerous septa Stage 4 Cirrhosis DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Progression of Fibrosis on Biopsy No Fibrosis Stage 1: Fibrous expansion of some portal areas Stage 3: Fibrous expansion of most portal areas with occasional portal to portal bridging Courtesy of Gregory MD. DELTAEverson, REGION Stage 4: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) Stage 5,6: Cirrhosis, probable or defined Cirrhotic liver: Gross anatomy of cadaver AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Non-invasive Procedures to Assess Liver Fibrosis • Elastrometry (ie FibroScan) • Serum Biochemical markers (ie Fibrotest, APRI, SHASTA, FIB-4, Forn’s Index, etc.) – Less accurate in co-infected pts • Good for lack of fibrosis versus advanced disease but less accurate for intermediate stages DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Fig. 1. Main variables to assess in patients considered as candidates for hepatitis C (HCV) therapy. *Low viral load defined as HCV RNA < 500 000–800 000 IU/ml. Ab, antibody. From: Soriano: AIDS, Volume 21(9).May 31, 2007.1073–1089 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Polling Question • When patients have chronic hepatitis, they should be advised to limit acetaminophen use to: – 1. – 2. – 3. – 4. – 5. none at all less than 500 mg per day less than 1000 mg per day less than 2000 mg per day less than 4000 mg per day DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Prevention Practices • Hepatic Diet - balanced • Avoid Alcohol • Immunizations – hepatitis A & B, Pneumovax, Influenza • Limit acetaminophen (Tylenol) < 2 gm/day • Avoid raw seafood, esp from the Gulf DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Nutrition with Hep C • • • • • • Avoid alcohol Avoid crash diets and / or binges Educate self about food pyramid Eat a variety of foods Drink plenty of water If have cirrhosis, need to decrease protein, salt, and iron in diet DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Alcohol Use in HCV • More rapid fibrosis progression • Higher viral loads • 2 schools of thought – No use acceptable – Minimal or special occasion use accepted DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Baseline Screenings Ophthalmologic exam in patients with HTN/DM Alcohol and Depression screen Consider anti-depressant prophylaxis DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Polling Question • The standard therapy for treatment of hepatitis C in HIV is: – 1. – 2. – 3. – 4. – 5. Herbal medications Interferon-alpha plus ritonavir Pegylated-interferon-alpha plus ribavirin Lamivudine plus entacavir Tenofovir plus emtricitabine DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Treatment for Hepatitis C co-infection • Modalities : -- pharmacotherapy : Peg-Interferon alpha (2 choices of formulation) weekly + Ribavirin weight based (usually 1 gm to 1.2 gm daily) -- transplant: referral for MELD score above 25 & end-stage liver disease DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org MELD Score • Three blood tests: – Bilirubin – Prothrombin time (PT) - measured as international normalized ratio (INR) – Creatinine (a measure of kidney function) • 3.8 x log (e) (bilirubin mg/dL) + 11.2 x log (e) (INR) + 9.6 log (e) (creatinine mg/dL) • There are many internet websites that have automatic calculators. All you have to do is to plug in your bilirubin, INR, and creatinine. One such website is the UNOS websitewww.unos.org. • Scores range from 6-40 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Side Effects of Interferon • • • • • • • • Flu-like illness Fatigue Alopecia Weight loss Emotional lability Neutropenia Depression Thrombocytopenia • • • • • • • • Insomnia Thyroid dysfunction Anorexia Retinopathy Neuropathy Diarrhea Hearing loss Rash DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Interferon + RBV in HIV/HCV • Special Toxicity Concerns – Ribavirin • Dose-dependent hemolytic anemia (aggrevated in HIV) • Potential antagonism between AZT, d4T, ddC • Enhancement of ddI levels • Lactic acidosis? • Teratogenicity DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Contra-indications to Treatment with Interferon or Ribavirin • Alcoholics or pts with ongoing IV drug use • Hypersensitivity to either agent • Autoimmune Disease • Decompensated Liver Disease • Pregnancy • Creatinine Clearance < 50 • Hemoglobinopathies or severe anemia • Platelets < 90K (50K) • CD4 < 100 • Unstable Angina • Active Opportunistic Infection • Untreated depression DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Treatment for Hepatitis C Candidates for Treatment Baseline Histology Initial Therapy Maintenance Therapy Mild Individualize No Moderate Yes No Severe Yes No Cirrhosis Yes/Individualize No Decompensated No No DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Sequencing of therapy • If stable on HAART therapy • In treatment-naïve patients: – Usually HAART first* – If liver disease is severe or prevents use of HAART, treat liver disease first – If no need for HAART, treat liver disease first but monitor HIV status closely • *Do NOT start both therapy in same month; wait 23 months to sort out toxicities DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Independent Predictors of Sustained Response • Genotype 2 or 3 • HCV Viral Load < 500,000 – 800,000 IU/ml • Undetectable HCV RNA at week 4 • Gender ( F > M) • White ethnicity • Age < 40 years old • No concurrent ddI or AZT use • No fibrosis or portal involvement only • Low BMI • Higher CD4 counts • No polysubstance abuse or psychiatric disease • Lack of Insulin Resistance DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Clinical and Laboratory Assessments • 2 week intervals first 2-3 months – Depression questionnaire – CBC • 4 week visit – – – – HCV Viral Load* CBC Evaluate weight, adverse events Neurotoxicity rating scale • 12 week intervals – HIV viral load*, CD4 count, HCV Viral Load – Evaluate for drug-drug interactions – TSH to screen DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org How long to treat? Proposed optimal duration of hepatitis C (HCV) therapy in HCV/HIV-coinfected patients. *In patients with baseline low viral load and minimal liver fibrosis. W, week; neg, negative; pos, positive; G, genotype. From: Soriano: AIDS, Volume 21(9).May 31, 2007.1073–1089 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Response to Therapy in Co-Infected – Infectious Diseases Service, Hospital Clínic, Barcelona, Spain. [email protected] – A prospective, randomized, multi-center, open-label clinical trial including 182 human immunodeficiency virus (HIV)-hepatitis C virus (HCV) patients naïve for HCV therapy was performed. – Patients were assigned to PEG 2b (80-150 mug/week; n = 96) or PEG 2a (180 mug/week; n = 86), plus RBV (800-1200 mg/day) for 48 weeks. – The primary endpoint was sustained virological response (SVR: negative HCV-RNA 24 weeks after completion of treatment). – At baseline, both groups were well balanced: 73% male; 63% HCV genotype 1 through 4; 29% had fibrosis index of 3 or greater. –Laguno M, Cifuentes C, Murillas J et al. Randomized trial comparing pegylated interferon alpha-2b versus pegylated interferon alpha-2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients.Hepatology. 2009 Jan;49(1):22-31. DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Response to Therapy in Co-Infected – – – – The overall SVR was 44% (42% PEG 2b versus 46% PEG 2a, P = 0.65). Genotypes 1 and 4, SVRs were 28% versus 32% (P = 0.67) Genotypes 2 and 3, SVRs were 62% versus 71% (P = 0.6) Early virological response (EVR; >or=2 log reduction from baseline or negative HCV-RNA at week 12) was 70% in the PEG 2b group and 80% in the PEG 2a group (P = 0.13), reaching a positive predictive value of SVR of 64% and a negative predictive value of 100% in both arms. – Side effects were present in 96% of patients but led to treatment discontinuation in 10% of patients (8% on PEG 2b and 13% on PEG 2a, P = 0.47). – Conclusion: In patients with HIV, HCV therapy with PEG 2b or PEG 2a plus RBV had no significant differences in efficacy and safety –Laguno M, Cifuentes C, Murillas J et al. Randomized trial comparing pegylated interferon alpha-2b versus pegylated interferon alpha-2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients.Hepatology. 2009 Jan;49(1):22-31. DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Maintenance therapy: HALT • HALT-C study: 1050 non-responders to Treatment with chronic HCV, advanced fibrosis. • Patients randomized to Peg-Ifn versus no treatment for 3.5 years • Mean ALT, inflammatory changes and HCV RNA levels decreased on treatment . • However, no significant difference was observed in any of the primary outcomes including fibrosis Di bisceglie et al. AASLD 2007 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org HIV Co-infection with HBV & HCV • * Epidemiology : up to 9-30 % of HBsAg positive individuals are also HCV seropositive • Fourfold fibrosis progression compared to HBV mono-infected • No guidelines. Based on expert opinion, Management is based on virus predominance DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org HIV co-infection with HepB & HepC Management • Because HCV usually predominates over HBV, most pts will be treated according to HCV recommendations • Individuals with HBV DNA Viral load exceeding 104 IU/ml and undetectable HCV should be treated for HBV predominance • When both viruses are detectable, peg-ifn/ribavarin +/adefovir or entecavir if HBV DNA response is sub-optimal Cheruvu et al. Clinics in liver disease 2007. 917-43 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Summation • Hepatitis C co-infection is fairly common, especially in those with a hx of IVDU • Hepatitis C co-infection should influence choice of HAART • Co-infection increases the progression to cirrhosis • Hepatitis C is curable though and all coinfected patients should be evaluated for treatment. DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Polling question • Compared to your knowledge on this subject before this presentation, your knowledge level now about hepatitis C in HIV is: – 1. Greatly enhanced – 2. Moderately enhanced – 3. Mildly enhanced – 4. I learned nothing new – 5. I am totally confused now and have no interest in dealing with co-infected patients in the future DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org Contact Info • [email protected] • Office: 504-903-7301 • Pager: 504-363-1692 • Cell: 504-491-1219 • Delta AETC: www.deltaaetc.org – 504-903-0788 DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org