Welcome to I-TECH HIV/AIDS Clinical Seminar Series

HIV and Viral Hepatitis (B & C)

H. Nina Kim, MD MSc

University of Washington

July 9, 2009

36 yo man to establish care HIV infection: Risk factor: unprotected heterosexual

sex. Dx 2004 with CD4 155, HIV RNA 222,000. No hx OIs. Started Combivir & Efavirenz 9/2004 Switched to Atripla in Jan 2007

Chronic hepatitis B Started on adefovir Jan 2007 Normal alpha-fetoprotein, abdominal ultrasound

March 2007 PMH otherwise notable for:

BRBPR – negative EGD/colonoscopy; attributed to hemorrhoids

Hypertriglyciridemia

Additional Hx

Medications Truvada Efavirenz Omeprazole Gemfibrozil

Soc HxWorks as cleaner in Chinese restaurant. Born in Mexico;

immigrated to US 15 yrs ago. Lives with several coworkers in hotel. Smokes 2 cigs per day. Used cocaine 1 mon ago. Rare EtOH.

PEx & LabsT 36.3 C, 117/66, HR 84, RR 20 Wt 68.5 kgWell-appearing young Latino in NAD. Exam normal; no stigmata of cirrhosis; no palpable hepatosplenomegaly.

Hep B surface Ag positive, HB surface Ab negative, HBV core Ab+, HAV Ab+, HBV Ab negative.

CD4 375/28%, HIV RNA <30 copies/mL.

HBV PCR 240,000 IU/mL – no prior values available. ALT 42, AST 30, alk phos 91. Normal total bilirubin & albumin.

Questions Does this patient need treatment for

chronic hepatitis B? How would you risk stratify this patient? If tx, what agent(s) would you use?

What is natural hx in this HIV-HBV coinfected patient? Special considerations esp re HAART

Does this patient need screening for HCC?

Chronic Hepatitis B:Epidemiology

Definition: HBsAg+ for >6 months US – Low endemic

Most infections occur in adolescents, young adults Sexual transmission > percutaneous

Asia – High endemic Perinatal transmission predominates Genotypes B, C

Africa – Intermediate to High endemic Childhood Vertical transmission less important role (possibly b/c

lower prevalence of HBeAg+ mothers)

Chronic HBV: Worldwide prevalence

www.cdc.gov

www.hepwebstudy.com

Chronic Hepatitis B:Stage the infection

Phases of Chronic HBV Infection

ImmuneTolerance

Immune Clearance/

HBeAg-Positive

Nonreplicative(Inactive Carrier)

Reactivation/ HBeAg-Negative

HBV DNA, IU/mL

105 - 1010 104 - 1010 < 104 103 - 108

HBeAg HBeAg+ HBeAg+ HBeAg- HBeAg-

ALT NormalHigh or

fluctuatingNormal High or fluctuating

Other --Active

inflammation on liver biopsy

HBsAg may become

undetectable

Active inflammation on liver biopsy

Candidates for therapy?

No Yes No Yes

Chronic Hepatitis B & HIV:Epidemiology & Natural Hx Prevalence 6-17% depending on population Consequences of coinfection:

Higher risk of developing chronic hepatitis B when exposed (estimated 5X greater c/w HIV-unininfected)

Higher HBV viremia higher risk of reactivation & transmission

Higher rates of disease progression w/ adverse outcomes, i.e. cirrhosis

Poorer response to standard therapies? Increased risk of HAART-related hepatoxicity

Colin JF, et al. Hepatology. 1999;29:1306-1310. Puoti M, et al. AIDS Rev. 2002;4:27-35. Hadler SC, et al. J Infect Dis. 1991;163:454-459.

≥ 100,00010,000-99,999

HBV DNA Associated With Increased Risk of HCC & CirrhosisREVEAL: Long-term follow-up of untreated HBsAg+

individuals in Taiwan

Baseline HBV DNA (copies/mL)

Pat

ien

ts (

%)

Cumulative Incidence of HCC at Year 13 Follow-up[1] (N = 3653)

50

40

30

20

10

01.3 1.4 3.6

12.214.9

Cumulative Incidence of Cirrhosis at Year 13 Follow-up[2] (N = 3582)

4.5 5.99.8

23.5

36.2

< 300 300-999

1000-9999

< 300 300-9999

10,000-99,999

100,000-999,999

≥ 1 million

1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

Risk of Liver-related Mortality among MSM in MACS Cohort

0

2

4

6

8

10

12

14

16

Liv

er

mort

ali

ty p

er

10

00

pers

on

-years

HIV-negative &HBsAg+

HIV-infected &HBsAg-

HIV+ & HBsAg+

0.81.7

14.2

Thio, et. al. Lancet 2002; 360: 1921-26.

Treatment End-points for HIV-uninfected chronic Hep B

HBeAg seroconversion to anti-Hbe (if eAg+) Spontaneous in HIV-negative pt: 8-12% per yr Treatment-associated rate: 15-27%

HBV DNA suppression: ideally, complete (prior threshold goal <20,000 IU/mL)

ALT normalization HBsAg loss & seroconversion

These pts need to be monitored after tx discontinued: q6 mon ALT, annual HBV DNA. 30% over 10 years can reactivate viral replication.

So what about HIV-infected?

Treatment of HBV in HIV+ Patient Interferon (standard or pegylated)

Pros: HBsAb loss, short duration, no drug resistance Cons: SC, freq adverse effects, HBeAg seroconversion rate lower than in

HIV-negative population (11.5% vs. 28%) Lamivudine

Use in ESLD, pregnant women High rate resistance (~20%/yr approaches 100% x 5 yr if only anti-

HBV drug) Adefovir

Use in ESLD Drug resistance: delayed, less common than 3TC

Entecavir Potent Drug resistance rare in nucleoside-naïve pt (<1% in 4 yrs), higher if

treatment-experienced (14% at year 2) Telbivudine

Drug resistance: intermediate (~22% at year 2). Category B pregnancy

Tenofovir Potent with high genetic barrier for HBV resistance

Antiviral agents active against HBV

Lamivudine (3TC) or Emtricitabine (FTC)

Adefovir (ADF)

Entecavir (ETV)

Telbivudine (LDT)

Tenofovir (TDF)

… & HIV

Matthews, AIDS 2006. 20:863-870.

Lamivudine (3TC) Resistance in HIV-HBV infected patients on 3TC monotherapy

Treatment of HBV in HIV+ Patient

Combination Therapy Not yet the paradigm the way it is for HIV

infection Dual nucleos/tide analogues: more widely

used in Cirrhotic patients HIV-coinfected patients s/p OLT after HBV infection

Combination Peg-IFN & lamivudine – results disappointing No additional efficacy c/w Peg-IFN alone

Asian males >40 years Asian females >50 years All cirrhotic hepatitis B carriers (stage 3+

fibrosis) Family history of HCC Africans over age 20 Other risks – severity of liver disease as

measured by current & hx inflammation, esp +ongoing HBV viremia, ?coinfection HCV, alcohol

HCC Screening for HBV+ Pts

AASLD Practice Guidelines 2005, Hepatology 42(5): 1208.

Cutoff = 20 ng/ml

Alpha-fetoprotein: Imperfect screening tool for HCC

Sensitivity of AFP >20 is 60%

PPV = 41% Still see false

positives with this cutoff

CONTEST: Most Interesting Dermatology

Case Submit a dermatology case by Friday, July 24 using the case referral form Instructions will be sent in a follow-up

email Dr Roy Colven will be the judge and

announce the winner during his session on July 30

The winner will receive a 2 GB I-TECH thumb drive!

42 yo woman with remote hx IVDU HIV Hx:

Dx 1996, nadir CD4 120 Has been undetectable on Kaletra + Combivir x

several years, most recent CD4 250 (25%) Tested positive for HCV Ab Hx of alcohol & heroin dependence Hx depression with psychotic features PEx: T 37 BP 104/80 HR 86 RR 12

Well-appearing woman, alert & conversant No stigmata of advanced liver disease (No spider

telangiectasia, palmar erythema, scleral icterus, abd distension, no appreciable HSM

Lab Data ALT 35-45, AST 25-35 Normal alk phos, total bilirubin, serum

albumin HCV RNA 2.8 million IU/mL HCV genotype 1a Hepatitis A & B immune CBC: WBC 3.5, Hgb 11.0, Hct 35% with

MCV 110, platelets 160K.

Chronic Hep C & HIVEpidemiology 1/4 to 1/3 of HIV-infected pts in US &

Europe are coinfected with chronic hepatitis C Much higher prevalence (75%) in high-risk

groups with hx blood exposure: IVDU & hemophiliacs

HCV one of the major causes of morbidity & mortality in HIV-infected pts More rapid disease progression Higher risk of hepatotoxicity from HAART

Rockstroh, J Infect Dis. 2005; 192:992-1002.Pol, Clin Infect Dis. 2008; 47: 94-101.

Factors to ConsiderTo Treat or not Treat? HIV-related

CD4 count Antiretroviral therapy

Liver-related HCV genotype Liver enzymes? Histology

Other Neuropsychiatric history Substance dependence & Alcohol consumption

Normal ALTLess Predictive of Benign Histology in HIV-HCV Coinfected patients

5

2032

37

0

20

40

60

80

100

HCVmonoinfection

(N=117)

HIV-HCVCoinfection

(N=89)

Normal ALTElevated ALT

Gonzalez, et. al. J Acquir Immune Defic Syndr. 2006; 41(5): 582-9.

Percentage of patients with grade 3-4 necroinflammation

Fleischer, R. Clin Infect Dis. 2004; 38: e79-80.

HCV Treatment & Risk of Mitochondrial Toxicity

US FDA Adverse Event Reporting 2002

31 patients had 58 events c/w MT: Pancreatitis Lactic acidosis Elevated LFTs Hepatic steatosis Elevated CK Neuropathy

Ribavirin +

ddI

ddI + d4T

d4T

ABC

3TC

AZT

0.01 0.1 1.0 10 100

12.4

Odds Ratio (95%CI)

8.0

3.3

1.1

0.2

0.06

Alvarez, D. J Viral Hepat. 2006; 13(10):683-9.

Anemia & HCV TreatmentRole of AZT

AZT use associated with higher incidence of anemia in 1st 12 wks

Not associated with lower rates of EVR or higher rates of tx discontinuation

0

10

20

30

40

50

60

RBVreduction

EPO use

No AZTAZT

Current Standard Therapies for HIV-HCV coinfected pts

Peg-IFN + RBV more effective than standard IFN + RBV combination or peg-IFN alone

Genotype 1, 2, 3 or 4 Peg-IFN + RBV 1000 mg/day if wt <75 kg or 1200

mg/day if wt >75 kg → 48 weeks

Goal of treatment is sustained virologic response (SVR) defined as No detectable serum HCV RNA 24 weeks after the end

of treatment Tested using sensitive HCV RNA assay with lower limit of

detection of 50 IU/mL

Definitions of Virologic Response on HCV Treatment

Rapid Virologic Response (RVR)

HCV RNA undetectable by Week 4

Early Virologic Response (EVR)

≥ 2 log10 decline in HCV RNA by Week 12

Partial Virologic Response

≥ 2 log10 decline in HCV RNA by Week 12, but HCV RNA detectable at Week 24

Null ResponseHCV RNA decline < 2 log10 IU/mL by Week 12

NonresponseFailure to achieve HCV RNA undetectability at any time point during therapy

Percentage of HIV-HCV patients achieving treatment response

01020304050607080

APRICOT(n=289)

RIBAVIC(n=205)

ACTG5071

(n=66)

PRESCO(n=389)

ETR (ITT)SVR (ITT)

Clinical Trials of HIV-HCV Coinfected

APRICOT(n=289)

RIBAVIC(n=205)

ACTG 5071(n=66)

PRESCO(n=389)

Type of pegIFN alfa 2a 2b 2a 2a

Ribavirin dose 800 mg/d 800 mg/d 600 -> 1000 mg

1000-2000 mg

IDU (% patients) 62% 81% 80% 89.5%

Cirrhosis (% patients) 15% 18% 11% 8.7%

HCV genotype 1 or 4 67% 69% 77% 61%

Median CD4 count (cells/mm3)

520 525 492 546

On ART 84% 82% 85% 74%

Early Tx Cessation (%)

25% 36% 12% 28%

Pegylated InterferonSide Effects

Reality of Treating HIV-HCV Coinfected Pts: Few eligible

Eligible23%

Ineligible55%

HCV RNA neg22%

Fleming, et. al. Clin Infect Dis 2003; 36:99-101.

23%

21%

23%

12%

13%

8%

Non-adherence tovisitsActive psychiatricdiseaseSubstance use

Decompensatedliver diseaseAdvanced HIV

Medicalcomorbidities

Questions?

Welcome to I-TECH HIV/AIDS Clinical Seminar Series

Next session: July 30, 2009Dr. Roy Colven

HIV Dermatology: Virtual Office Hours

Welcome to I-TECH HIV/AIDS Clinical Seminar Series

Next session: July 30, 2009Listserv:

itechdistlearning@u.washington.eduEmail: DLinfo@u.washington.edu