DELTA REGION AIDS EDUCATION AND TRAINING CENTER deltaaetc.org Hepatitis C in HIV Ronald D. Wilcox MD...

DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org

Hepatitis C in HIV

Ronald D. Wilcox MD FAAPProgram Director/PI, Delta AETC

Asst Professor of Internal Medicine and Pediatrics, Section of Infectious Diseases

Louisiana State University Health Sciences Center


www.deltaaetc.org 504-903-0788

LPS Coordinator: Dana Gray


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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


Polling Question

• Please choose which category best describes your profession:– 1. Nurse or Advanced Practice Nurse– 2. Physician or Physician Assistant– 3. Dental professional– 4. Pharmacist– 5. Case Manager / Social Worker– 6. Other medical professional or

Administrator


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


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 75plts 92,000HCV RNA PCR 115,000


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.


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 5.0Creat 1.5


Case• Two months later, after 9 doses of

cidofovir: AST 390 ALT 162AlkPO4 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.


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


HIV versus Hepatitis CHepatitis C HIV

Family Flavivirus Retrovirus# Virions/ day 10 (12) 10 (10-11)Diversity Six genotypes 11+ clades

Chronicity 80% 100%Integration None Host DNA

Transmission Parenteral > sexual Sexual > parenteral


HIV/HCV Co-infection in the United States

0

5

10

15

20

25

30

35

40

45

HCV HIV

X 1

00,0

00

Mono-infected

Co-infected


Risk of HIV, HCV, and HBV in IV Drug Users

Baltimore, 1983-1988

0

20

40

60

80

100

6 12 18 24 30 36 42 48 54 60 66 72

Duration of IVDU (Mos)

Ser

op

reva

len

ce (

%)

HCV

HBV

HIV

Garfein et al. Am J Public Health. 1996;86:655-61


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


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


Perinatal TransmissionRole of HCV/HIV Co-infection

• HIV Co-infection HCV transmission– HCV only 5% (3-8%)– HIV/HCV 17% (7-36%)

• HCV co-infection may HIV transmission– HIV only 16.3%– HIV/HCV 26.1% (RO 1.82)

Zanetti et al. Lancet. 1995;345:289-91

Hershow et al. J Infect Dis. 1997;176:414-20


Co-infection HIV Risk Factor Prevalence at Johns Hopkins HIV Clinic

89

14 10

45

0102030405060708090

100

Prevalence of HIV/HCV

(%)

N=1742

Sulkowski et al. Hepatology. 2000;32:212A.


Co-infection HIV Risk Factor Prevalence at the HOP clinic

05

1015202530354045

Data abstracted from the ASD database by Kathleen Welch, PhD

N = 402


Polling Question

• If someone has chronic hepatitis C, their chance of developing cirrhosis is approximately:– 1. 5%– 2. 20%– 3. 35%– 4. 50%– 5. 65%


Effect of HCV/HIV Co-infection on Fibrosis Progression Rate

00.5

11.5

22.5

33.5

44.5

10 20 30 40

HCV Duration, years

Fib

rosi

s G

rad

e (M

ET

AV

IR

Sco

rin

g S

yst

em) HIV+, n=122

HIV– matched controls, n=122

Progression rate was increased in those persons

with CD4 < 200 orOngoing EtOH use

Benhamou et al. Hepatology. 1999;1054-8.


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%)


Causes of death in HIV+ patients

0

5

10

15

20

25

30

35

PCP BP SEPSIS CANCER ESLD

1995

1999

Berggren R. 39th IDSA Conference 2001


Cause of Death by CD4 count

0

5

10

15

20

25

30

35

40

ESLD PCP Sepsis Malig Pneum

> 200< 200

P<.0001 P=.025

Berggren R. 39th IDSA Conference 2001


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


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


HAART and Mortality in HCV

• SMART Study– “Interruption of antiretroviral therapy is

particularly unsafe in persons with hepatitis virus coinfection. Although HCV- and/or HBV-coinfected 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


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


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


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


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 10-

12,000• GI vs. interventional radiology


Histologic StagingNo Fibrosis Portal Fibrosis Few septa

Stage 0 Stage 1 Stage 2

Numerous septa

Stage 3Cirrhosis

Stage 4


Progression of Fibrosis on Biopsy

No FibrosisNo Fibrosis

Stage 1: Fibrous Stage 1: Fibrous expansion of expansion of some portal areassome portal areas

Stage 3: Stage 3: Fibrous Fibrous expansion of expansion of most portal most portal areas areas with occasional with occasional portal to portal portal to portal bridgingbridging

Stage 4: Fibrous Stage 4: Fibrous expansion of expansion of portal areas with portal areas with marked bridging marked bridging (portal to portal (portal to portal and portal to and portal to central)central)

Stage 5,6: Cirrhosis, Stage 5,6: Cirrhosis, probable or definedprobable or defined

Cirrhotic liver: Cirrhotic liver: Gross anatomy Gross anatomy of cadaverof cadaver

Courtesy of Gregory Everson, MD.Courtesy of Gregory Everson, MD.


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


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


Polling Question

• When patients have chronic hepatitis, they should be advised to limit acetaminophen use to:– 1. none at all– 2. less than 500 mg per day– 3. less than 1000 mg per day– 4. less than 2000 mg per day– 5. less than 4000 mg per day


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


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


Alcohol Use in HCV

• More rapid fibrosis progression • Higher viral loads

• 2 schools of thought– No use acceptable– Minimal or special occasion use accepted


Baseline Screenings

Ophthalmologic exam in patients with HTN/DM

Alcohol and Depression screen

Consider anti-depressant prophylaxis


Polling Question

• The standard therapy for treatment of hepatitis C in HIV is:– 1. Herbal medications– 2. Interferon-alpha plus ritonavir– 3. Pegylated-interferon-alpha plus ribavirin– 4. Lamivudine plus entacavir– 5. Tenofovir plus emtricitabine


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


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 website- www.unos.org.

• Scores range from 6-40


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


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


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


Treatment for Hepatitis CCandidates for Treatment

Baseline Histology Initial Therapy Maintenance Therapy

Mild Individualize No

Moderate Yes No

Severe Yes No

Cirrhosis Yes/Individualize No

Decompensated No No


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 2-3 months to sort out toxicities


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


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


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

How long to treat?


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.


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.


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


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


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


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 co-infected patients should be evaluated for treatment.


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


Contact Info

• [email protected]

• Office: 504-903-7301• Pager: 504-363-1692• Cell: 504-491-1219

• Delta AETC: www.deltaaetc.org– 504-903-0788

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