hepatitis b & hepatitis c in hiv dr k.bujji babu, md consultant hiv physician dr.bujjibabu hiv...

Hepatitis B & Hepatitis C in HIV

Dr K.Bujji Babu,MD

Consultant HIV Physician

Dr.Bujjibabu HIV Clinic.

HIVHIV Hepatitis BHepatitis B 40 million worldwide 1 million in the US RNA retrovirus Integrates in genome 1y target CD4 cells Reverse Transcriptase Nucleoside Analogues Mutations=Resistance

400 million worldwide 1.25 million in the US DNA hepadna virus Integrates into

genome 1y target hepatocytes Reverse Transcriptase Nucleoside Analogues Mutations=Resistance

HIV HBV Co-infectionHIV HBV Co-infection

About 10% of HIV+ patients are HBSAg+ (Rustgi VK, Ann Int Med 1984)

HIV+ pts 3-6x more likely to develop chronic HBV than HIV- (Bodsworth JID 1991)

HIV/HBV is associated with more cirrhosis than HBV alone (Colin JF Hepatology 1999 )

HBeAg and HBV DNA higher levels in HIV+ but AST/ALT lower(Perillo Ann Intern Med 1986)

Much lower rate of spontaneous HbeAg seroconversion (Krogsgaard Hepatology 1987)

HBV DNA found in HBcAb+ only patients (HBSAb and HBsAg negative) (Hofer Eur J Clin Microbiol 1998)

HIV HBV CoHIV HBV Co--infectioninfection

2 Studies found accelerated histologic progression of HBV in HIV+ (Colin Hepatology 1999 and Schechter AIDS 1989)

One study found RR of HIV progression to be 3.6 with HBV, 2 others did not (Scharschmidt Ann Int Med 1992, Eskild AIDS 1992)

Lamivudine active in > 80% of HIV+ and Neg patients (Benhamou Ann Int Med 1996)

HIV HBV CoHIV HBV Co--infectioninfection

HBV & HIV – Rx Guide lines HBV DNA > 105 copies/ml ALT consistently >2-fold above N bioptic detection of liver fibrosis

Healthy carriers don’t require treatment

HBV & HIV – Rx Guide lines Lamivudine and Tenofovir are

primarily indicated for HIV treatment, the status of HIV infection must be considered (e.g. necessity for treatment, prior therapies, resistance).

An individual decision must be reached.

HIV & HBV – Rx guide lines Adefovir can be given as mono Lamivudine or Tenofovir –no monotherapy On HAART - lamivudine (possibly plus

tenofovir) as a component of HAART Resistance with Lam, Tenofovir can be used

as an alternative component of HAART. Treatment to continue till seroconversion or

until there is loss of efficacy (renewed increase of transaminases and viral load)

Lamivudine in Pts Co- Lamivudine in Pts Co- infected with HBV and HIV infected with HBV and HIV

122 co-infected patients treated with lamivudine and antiretroviral therapy in CAESAR study

Safety data comparable across treatment arms

French study of 40 HIV/HBV co-infected patients (Benhamou, et al., Ann. Int. Med., Nov. 1996)

Inhib ition of HBV Polym erases Contain ing Inhib ition of HBV Polym erases Contain ing Lam ivudineLam ivudine --Resistant M utationsResistant M utations

Resistance is defined as a 5-fold increase of K i

Lam ivudine

Adefovir

Enzyme K i (M ) Fold Increase

K i (M ) Fold Increase

W ild type

0 .25 1 0 .10 1

V173L 0.31 1.2 0 .15 1.5

L180M 0.64 2.6 0 .23 2.3

M 204I 2.0 8 0 .13 1.3

M 204V 4.9 19.6 0 .22 2.2

L180M + M 204I

3 .8 15.2 0 .18 1.8

L180M + M 204V

6.3 25.2 0 .08 0.8

Adefovir OverviewAdefovir Overview

Nucleotide analogue that inhibits HBV polymerase via chain termination

Potent anti-HBV activity in early clinical studies

In vitro and in vivo activity against:

wild-type HBVlamivudine- and famciclovir-resistant HBV

N

N N

N

NH2

OP

O

(-) O

Adefovir (PMEA)

(-) O

-5

-4

-3

-2

-1

0

Weeks of adefovir dipivoxil

HB

V D

NA

(lo

g 10

copi

es/m

L)

35 35 35 33 33 33 33 31 31 31 31 31 31 29No. patients

BL 2 4 8 12 16 20 24 28 32 36 40 44 48

HBV DNA Response to ADVHBV DNA Response to ADVMean changes from baseline (8.64±0.08 log10 copies/mL) in serum HBV DNA measured by PCR during ADV

All time points were significantly

lower compared to baseline

p<0.0001

- 4.01±0.17 log10 copies/mL

Tenofovir Disoproxil Tenofovir Disoproxil FumarateFumarate

N

NN

N

NH2

OP

OO

O

O

O

O

O

O

O

TenofovirTenofovir Study 907Study 907AntiAnti--HBV Activity (n=12)HBV Activity (n=12)

Baseline HBV DNA (log10 c/mL) 8.7

Change from baseline to week 24 (log10 c/mL)

Mean -4.6

Median -4.4

Range -2.6 to -6.5

DAPDDAPDDioxolane purine nucleoside analogue

DAPD is deaminated by adenosine deaminase, yielding DAPD is deaminated by adenosine deaminase, yielding dioxolanedioxolane guanosine (DXG); the 5´guanosine (DXG); the 5´--triphosphate is active against triphosphate is active against HIV reverse transcriptase.HIV reverse transcriptase.

1-? -D-2,6-diaminopurinedioxolane

DAPD

dioxolanedioxolane guanosineguanosine

DXGDXG

NH2NHO

O

ON

NNH

O

N

NN

N

NH2

NH2

OHO

O

Monotherapy vs. Combination Monotherapy vs. Combination

Therapy for HBV (I)Therapy for HBV (I) Increased initial cost of combination therapy offset by

greater clinician and patient acceptance of treatment due to:

- greater efficacy, more frequent durable responses

- finite-length treatment regimens

Combination treatments need a virologic rationale from Phase II studies - clinical efficacy and safety still need to be established in large controlled Phase III trials

Combination treatments currently being investigated: Interferons plus lamivudine (Schering, Roche and GlaxoSmithKline)

Lamivudine plus adefovir (GlaxoSmithKline and Gilead)

LdT plus lamivudine (Novirio)

ConclusionsConclusions

HBV infection has worse outcomes in HIV Lamivudine resistance is becoming

increasinly common Newer drugs that have activity against LAM

resistant HBV are coming soon Treating HBV in HIV patients is getting more

challenging daily

Prevention Vaccine less effective due to

immunosuppression - 30 % (2.5 %) Vaccination repeated - double dose

in four steps (months 0,1,6 and12) Post Exposure Prophylaxis as in

normal individuals

Worldwide Prevalence of Hepatitis C

<1

1-2.49

2.5-4.99

5-10

>10

No data

HCV Prevalence

HIV and HCV 30 % of HIV pts can have HCV infection Less likely to clear HCV in co-infected Higher HCV RNA viral load Rapid progression of liver disease -

CD4 <100; 10 yrs vs 20 yrs for Cirrhosis

In Haemophiliacs – higher mortality in co-infected

HCV and HIV

More rapid deterioration of HIV disease CD4 count may not rise much

blunted immune response - HAART

HCV co infection & HAART Drug induced heaptotoxicity more in

co infected – protease inhibitors & ATT 88% co infected pts tolerated HAART

well without hepatotoxicity Antiretrovirals safe in Chronic hepatitis

C Stop Rx – if symptomatic or Liver

enzymes > 5 x normal

HIV & HCV Screen by ELISA – Confirm by RNA

PCR If CD4 count < 100 – Anti HCV may

be low or undetectable

HCV RNA should be done if suspeected

HIV – HCV : Management Avoid Alcohol Vaccinate against HAV & HBV Look for Chronic Liver disease SGPT, HCV RNA – Limited usefulness Liver Biopsy for disease activity

Liver biopsy safe in HIV infected persons

HIV HCV - Treatment HCV to be treated before HIV Peg Interferons with Ribavarin ideal Limited data on its safety in co

infected Significant side effects for Peg IFN

and Ribavarin reported Drug interactions – Ribavarin vs HIV

drugs

CD4 count & HAART If > 350 , IFN and HAART 200 – 350, individual case < 200 IFN relative contra indication might

deteriorate Didanosine contraindicated - Pancreatitis,

mitochondrial toxicity,liver decompensation Zidovudine avoid - additive toxicities

anemia and leukopenia Stavudine - due to mitochondrial toxicity

Guide lines for therapy-HIV HCV Review HIV – CD4 counts HCV RNA, SGPT, Liver Biopsy Exclude co morbid conditionsDuring therapy Blood counts, SGPT, HCV RNA – Adjust HCV RNA at 24 wks – If detected – stop Birth control during & 6 months after

Rx

HCV anti bodiesHCV anti bodies

negativenegativePositivePositive

HCV RNAHCV RNA negativenegative

negativenegative

SGPT, GenotypeSGPT, Genotype elevatedelevated

normalnormal Peg IFNPeg IFN

Liver BxLiver Bx

negativenegative

Positive Positive