Hepatitis-C and HIV

Hepatitis-C and HIV

Michael T. Wong, MD

Assistant Professor of Medicine, Harvard Medical School

Division of Infectious Diseases,

Beth Israel Deaconess Medical Center

Michael T. Wong, MD

Assistant Professor of Medicine, Harvard Medical School

Division of Infectious Diseases,

Beth Israel Deaconess Medical Center

Modes of Transmission HCVHCV

Primarily through blood and Primarily through blood and blood products, IDUblood products, IDU

Historical data now supports Historical data now supports sexual risk of ~10-12% over sexual risk of ~10-12% over lifetime in discordant couple lifetime in discordant couple studiesstudies

Perinatal transmission ~7% but Perinatal transmission ~7% but increases to 28% in HIV increases to 28% in HIV coinfected motherscoinfected mothers

Association with intranasal Association with intranasal recreational agents like cocaine.recreational agents like cocaine.

HIVHIV Sexually through body fluids Sexually through body fluids

(semen, vaginal secretions, (semen, vaginal secretions, blood)blood)

Blood (percutaneous Blood (percutaneous exposures, IDU, blood exposures, IDU, blood products)products)

Perinatally (risk decreased to Perinatally (risk decreased to almost 0 with perinatal almost 0 with perinatal prophylaxis and elective C-prophylaxis and elective C-sections in right settings, sections in right settings, restriction on breast feedingrestriction on breast feeding

HCVHCV Infect primarily Infect primarily

hepatocytes without hepatocytes without becoming integrated becoming integrated into the host genome, into the host genome, but more recently but more recently found in T-found in T-lymphocytes which lymphocytes which represent a secondary represent a secondary reservoirreservoir

HIV-HIV- Infect primarily CD4 Infect primarily CD4

bearing T-lymphocytes bearing T-lymphocytes via secondary binding via secondary binding site, CCR5 or CXCR4site, CCR5 or CXCR4

Also found in variety Also found in variety of other cells including of other cells including neural dendritic cells, neural dendritic cells, GI epithelium, gonadal GI epithelium, gonadal tissuestissues

Genotype 1: most common in the US and Genotype 1: most common in the US and Western Europe (up to 75% of all infections in Western Europe (up to 75% of all infections in US); generally associated with IDU as well as US); generally associated with IDU as well as contaminated blood products; most difficult to contaminated blood products; most difficult to treat and resistant to therapy.treat and resistant to therapy.

Genotype 2 and 3: more responsive to therapyGenotype 2 and 3: more responsive to therapy Genotype 3: associated with insulin resistance Genotype 3: associated with insulin resistance

and steatosis (fatty liver disease).and steatosis (fatty liver disease).

Extrahepatic ManifestationsConditionCondition Relative FrequencyRelative Frequency

Mixed CryoglobulinemiaMixed Cryoglobulinemia 36-45%36-45%11

Porphyria Cutanea TardaPorphyria Cutanea Tarda 62-82%62-82%22

Renal Failure (MPGN, Renal Failure (MPGN, membranous GN, GN membranous GN, GN associated with mixed associated with mixed cryoglobulinemia)cryoglobulinemia)

Uncertain; suggestion of Uncertain; suggestion of up to 27%up to 27%33

Cognitive DysfunctionCognitive Dysfunction 9-38%9-38%44

1. Ferri et al. Blood 1993;81:1132. 2. DeCastro et al. Hepatology 1993;17:551. 3. Johnson et al. N Engl J Med 1993;328:465. 4. Hilsabeck et al. J Int Neuropsychol Soc. 2003;9:847.

Other conditions reported in HCV include: hyper/hypothyroidism, idiopathic pulmonary fibrosis; ITP, non Hodgkins lymphoma,

Psychosocial characterizations VA populationVA population11: :

580 patients referred for treatment for HCV.580 patients referred for treatment for HCV.Mean age: 51Mean age: 51Gender: 99% maleGender: 99% male406 (70%) had psychosocial contraindications to therapy406 (70%) had psychosocial contraindications to therapy

• 1) active alcohol abuse (124, 21%)1) active alcohol abuse (124, 21%)• 2) active non-alcohol substance abuse (21, 3.6%)2) active non-alcohol substance abuse (21, 3.6%)• 3) active untreated clinical depression (93, 16%)3) active untreated clinical depression (93, 16%)

54 (10%) had medical contraindications54 (10%) had medical contraindications• 1) end-stage liver disease (34, 5.9%)1) end-stage liver disease (34, 5.9%)• 2) poorly or uncontrolled diabetes (20, 3.4%)2) poorly or uncontrolled diabetes (20, 3.4%)

VA PopulationVA Population22::33 individuals treated; 68% had active mental health issues33 individuals treated; 68% had active mental health issues

13 or 19 developed psychiatric exacerbations on therapy13 or 19 developed psychiatric exacerbations on therapyThose with history of SA 3 times more likely to discontinue therapy (20 vs 7 individuals)Those with history of SA 3 times more likely to discontinue therapy (20 vs 7 individuals)

1. Rowan et al. J Clin Gastroenterol. 2004;38:530. 2. Ho et al. Am J Gastroenterol, 2001: 3.

Activated, Activated, HIV- cells HIV- cells t1/2 = 1.5 dt1/2 = 1.5 d

Productive Productive HIV+ cells, HIV+ cells, t1/2=1/2-1 dt1/2=1/2-1 d

Free HIV Free HIV t1/2= 30 t1/2= 30 minmin

Macrophage Macrophage t1/2= 14 dt1/2= 14 d

Latent Memory Latent Memory CD4+ HIV+ cell, CD4+ HIV+ cell, T1/2>>>6 moT1/2>>>6 mo

Latent, CD4+ Latent, CD4+ HIV+ cell, HIV+ cell, t1/2= 8.5 dt1/2= 8.5 d

Long-lived CD4+ Long-lived CD4+ HIV+ cells, HIV+ cells, t1/2= 6 mot1/2= 6 mo

93-99%93-99%

1%1%

1-7%1-7%

In situ HIV-associated CD3+CD4+ syncytia, CXCR4 variantIn situ HIV-associated CD3+CD4+ syncytia, CXCR4 variant

Splenic tissue from HIV+ patient, p24+, CD3+CD4+ by immunofluorescent Splenic tissue from HIV+ patient, p24+, CD3+CD4+ by immunofluorescent staining indicating in situ syncytia. Wong, MT, unpublishedstaining indicating in situ syncytia. Wong, MT, unpublished

HIV natural history Acute infection- extraordinarily high HIV viral load, Acute infection- extraordinarily high HIV viral load,

no antibodies, fever, adenopathy, thrush, nonpruritic no antibodies, fever, adenopathy, thrush, nonpruritic rashrash

Viral control- “viral set point” averages ~50,000 Viral control- “viral set point” averages ~50,000 copies/mL and results in a loss of total CD4 count by copies/mL and results in a loss of total CD4 count by 60 cells/year60 cells/year Viral generation time ~24 hoursViral generation time ~24 hours T cell generation time 5-7 daysT cell generation time 5-7 days

Asymptomatic period ~8-12 yearsAsymptomatic period ~8-12 years Death from HIV ~12-15 years after primary infectionDeath from HIV ~12-15 years after primary infection

HIV and HCV, US

Est 800,000 – 1,000,000 persons HIV+ Est 800,000 – 1,000,000 persons HIV+ Est 4,000,000 persons HCV+Est 4,000,000 persons HCV+

Of those HIV+, 30-35% are coinfected with Of those HIV+, 30-35% are coinfected with HCVHCVIDU >90% coinfection ratesIDU >90% coinfection ratesHemophilia >90% coinfection ratesHemophilia >90% coinfection ratesMSM ~15% coinfection ratesMSM ~15% coinfection rates

Of those HCV+, 8-12% are coinfected with Of those HCV+, 8-12% are coinfected with HIVHIV

Over 90% of HAART Regimens PI Based100

80

60

40

20

0

35

30

25

20

15

10

5

0

1994 1995 1996 1997 1998 1999

HOPS: Mortality and Frequency HOPS: Mortality and Frequency of HAART Useof HAART Use

Dea

ths

per

100

per

son

-yea

rs

Deaths

Use of HAART

HA

AR

T, %

patien

t-days

PalellaPalella. N Engl J Med. N Engl J Med 1998;338:853. Update: Palella. Personal Communication, 1999. 1998;338:853. Update: Palella. Personal Communication, 1999.

Causes of Death in HIV-HCV Co-infection240 HIV/HCV co-infected patients in France who 240 HIV/HCV co-infected patients in France who

died in 2000 died in 2000At death:At death:

38% had CD4 count >200 cells/mm38% had CD4 count >200 cells/mm3 3

37% had a viral load <500 c/mL37% had a viral load <500 c/mL

AIDS 28%Non AIDS-related cancer

6%

End-stage liver disease 33%

Other 11%Suicide 4%

Drug overdose 4%

Cardiovascular disease 8%

Bacterial infections 6%

Dominique S et al. 42nd ICAAC; San Diego, 2002: Abstract #1719.

Impact of HIV Coinfection on the Long-Term Outcome of HCV Cirrhosis

VariableVariable Hazards Risk, Hazards Risk, Death overall Death overall (P)(P)

Hazards Risk, Hazards Risk, Cirrhotic Death Cirrhotic Death (P)(P)

HIVHIV 2.7 (0.04)2.7 (0.04) 3.8 (0.2)3.8 (0.2)

ETOH useETOH use 1.2 (NS)1.2 (NS) 1.7 (NS)1.7 (NS)

Age > 40Age > 40 2.2 (0.01)2.2 (0.01) 2.6 (0.001)2.6 (0.001)

AntiHCV AntiHCV therapytherapy

0.6 (0.01)0.6 (0.01) 0.4 (<0.001)0.4 (<0.001)

DiMartino, V, et al. 8th CROI, Chicago, 2001, #567

Determinants of HCV Clearance in coinfection

Variable Adjusted Odds Ratio (95% CI)

P value

HIV- 4.79 (1.63-14.08)

0.005

Age <40 1.23 (1.04-1.47)

0.017

HBSAg- 3.20 (0.98-10.42)

0.054

207 HIV+HCV+ and 121 HIV-HCV+ hemophiliacs, enrolled prospectively 1989-90

Daar, et al. #35

Determinants of HCV Clearance in coinfection

Factor Variable change P value

Q 100 cell increase in CD4

35% decrease in HCV VL

0.02

Q log10 increase in HIV VL

72% increase in HCV VL

0.008

Q 10log10 increase in HCV VL

15% increase in ALT

0.001

ACTG 5071 Study Design

IFN -2a 6 MIU tiw x12 WK then 3 MIU TIW + RBV 600 1 gm/day

PEG IFN -2a 180 g QW + RBV 600 mg 1 gm/day

133 subjects randomized

BaselineBaselineBaselineBaseline

66

67

0 24

41% ETVR

12% ETVR

48

27% SVR

Virologic Virologic response at response at

week 72 week 72 (SVR)(SVR)

Virologic Virologic response at response at

week 72 week 72 (SVR)(SVR)

12% SVR

72

Weeks

10/67 responders (15%)

29/66 responders (44%)

Primary endpoint:Primary endpoint:Virologic response at week 24 Virologic response at week 24

Biopsy for NR: HR continue Biopsy for NR: HR continue

Primary endpoint:Primary endpoint:Virologic response at week 24 Virologic response at week 24

Biopsy for NR: HR continue Biopsy for NR: HR continue

Chung, NEJM 2004

Interferon Interferon PegIFNPegIFN

Overall Response (SVR)Overall Response (SVR) 15%15% 44%44%

Genotype 1Genotype 1 7%7% 33%33%

Non Type 1Non Type 1 40%40% 82%82%

Bx Results (non responders) Bx Results (non responders) 40%40% 26%26%

VR+BRVR+BR 37%37% 53%53%

Absolute CD4Absolute CD4 -215-215 -158-158

CD4 %CD4 % +2.5+2.5 +3.5+3.5

SVR in ACTG 5071 by Genotype

0

10

20

30

40

50

60

70

80

Genotype 1N = 103

Genotype 2/3N = 30

IFN/RBV

PEG/RBV

Chung, NEJM 2004

Predictors of SVR in 5071

VariableVariable Odds Ratio (95% CI)Odds Ratio (95% CI)

PEG/RBVPEG/RBV 4.76 (1.49 – 15.2)4.76 (1.49 – 15.2)

Genotype non-1 Genotype non-1 15.8 (4.94 – 50.5)15.8 (4.94 – 50.5)

Previous IDU Previous IDU 0.48 (0.27 – 0.83)0.48 (0.27 – 0.83)

Base HIV VL >50 Base HIV VL >50 3.55 (1.19 – 10.6)3.55 (1.19 – 10.6)

Chung, NEJM 2004

APRICOT

868 patients with HIV/HCV enrolled at 95 868 patients with HIV/HCV enrolled at 95 centers in 19 countriescenters in 19 countries

Randomized to one of three arms for 48 weeks:Randomized to one of three arms for 48 weeks:IFN alfa-2a (3 MIU TIW) + RBV 800 mgIFN alfa-2a (3 MIU TIW) + RBV 800 mgPEG-IFN alfa 2a 180 PEG-IFN alfa 2a 180 g QW + placebog QW + placeboPEG-IFN alfa 2a 180 PEG-IFN alfa 2a 180 g QW + RBV 800 mgg QW + RBV 800 mg

5 –7 % had CD4 <2005 –7 % had CD4 <200 25% (PEG/RBV) to 39% (IFN/RBV) 25% (PEG/RBV) to 39% (IFN/RBV)

discontinuation rate and 20% dose reduction ratediscontinuation rate and 20% dose reduction rateTorriani, NEJM 2004

SVR in Genotype 1 by HCV VL

0

10

20

30

40

50

60

70

HCV VL< 800,000 IU/ml HCV VL > 800,000 IU/ml

IFN/RBV

PEG-IFN

PEG/RBV

Torriani, NEJM 2004

APRICOT: SVR in Cirrhosis

0

5

10

15

20

25

30

35

40

Cirrhotic

IFN/RBV

PEG/Pl

PEG/RBV

All Patients

3 deaths in cirrhotics: two decompensation, one suicide Sasadeusz, #372 , AASLD 2004

Prediction of SVR with Weeks 4, 12 or 24 ERV in APRICOT

EVR (%) at EVR (%) at weeksweeks

PatientsPatients 44 1212 2424 SVR SVR wk 72wk 72

PPV (%) PPV (%) wks wks

4;4;1212;24;24

NPV (%) NPV (%) wks wks

4;12;244;12;24

All All (289)(289)

15151 1

(52(52))

204 204 (71)(71)

216 216 (75)(75)

116 116 (40%)(40%)

66, 66, 5656, 53, 53 88, 88, 9898,99,99

Geno 1 Geno 1 (176)(176)

71 71 (40(40))

110 110 (63)(63)

120 120 (68)(68)

51 51 (29%)(29%)

58; 58; 4545; 43; 43 90; 90; 9898; ; 100100

Geno Geno 2,3 (95)2,3 (95)

76 76 (80(80))

84 84 (88)(88)

85 85 (89)(89)

59 59 (62%)(62%)

74; 74; 7070; 69; 69 84; 84; 100100; ; 100100

Positive predictive value = probability of SVR after an EVR Rodriguez-Torres, ICAAC 2004, H1751

Predictors of SVR for PEG-IFN/RBV Arm in APRICOT

VariableVariable Odds RatioOdds Ratio

Genotype non-1 Genotype non-1 3.373.37

ALT quotient (I unit incr)ALT quotient (I unit incr) 1.171.17

Age (per 10 year decr)Age (per 10 year decr) 1.281.28

No cirrhosisNo cirrhosis 1.961.96

HCV VL <800,000 IU/mlHCV VL <800,000 IU/ml 3.563.56

Cooper, Bangkok IAC 2004

*Baseline CD4 count did not predict SVR

Histological Improvement with PEG/RBV in APRICOT

0

10

20

30

40

50

60

70

SVR No SVR

Improved

No Change

Worsened

Improvement = 2 or more decrease in HAI score Lissen, #174 AASLD 2004

Adverse events in APRICOTAdverse event PEG-IFN/Placebo PEG-IFN + ribavirin Number Patients 286 288

D/C for any reason 31% 25% Serious Adverse events 21% 17%Dose reduce - anemia 8% 17%Dose reduce - WBC 30% 28%Influenza like symptoms Headache 38% 39% Fatigue 41% 44% Myalgias 33% 36% Fever 43% 44%

GI symptoms Diarrhea 26% 28% Nausea 27% 30%

Psychiatric symptoms Depression 20% 26% Insomnia 21% 26% Asthenia 22% 28%

Torriani, NEJM 2004

APRICOT: Quality of Life Improves in SVR on PEG-IFN with RBV

Dieterich ICAAC 2004

APRICOT Summary

PEG-IFN + RBV was the most effective PEG-IFN + RBV was the most effective regimen for clearance of HCVregimen for clearance of HCV

Relapse rate was lower than 5071:Relapse rate was lower than 5071: Genotype 1: ETR 38% and SVR 29%Genotype 1: ETR 38% and SVR 29% Genotype 2/3: ETR 64% and SVR 62%Genotype 2/3: ETR 64% and SVR 62%

APRICOT had more Caucasian patients than APRICOT had more Caucasian patients than 5071 – in HCV alone, African-Americans 5071 – in HCV alone, African-Americans have a lower response ratehave a lower response rate

Torriani, NEJM 2004

Interaction between Ribavirin and NRTIs FDA Adverse Event Reporting SystemFDA Adverse Event Reporting System 85 cases of ribavirin/NRTI events; 31 cases 85 cases of ribavirin/NRTI events; 31 cases

consistent with mitochondrial toxicityconsistent with mitochondrial toxicity ddI OR 12.4 (3.8, 40.8)ddI OR 12.4 (3.8, 40.8) d4T OR 3.3 (1.3, 8.5)d4T OR 3.3 (1.3, 8.5) AZT OR 0.057 ( 0.007, 0.448)AZT OR 0.057 ( 0.007, 0.448) 5/31 died from lactic acidosis, all on ddI5/31 died from lactic acidosis, all on ddI Don’t combine ddI and ribavirinDon’t combine ddI and ribavirin

Fleisher, 10th CROI, #763

Effect of AZT on Anemia 107 subjects with HIV/HCV on IFN 3 mu TIW with 107 subjects with HIV/HCV on IFN 3 mu TIW with

RBV 800 mg/day or IFN + placebo for first 16 weeks, RBV 800 mg/day or IFN + placebo for first 16 weeks, then RBV added if HCV VL detectablethen RBV added if HCV VL detectable

Hgb decreased –2.52 g/dl on IFN/RBV compared to –Hgb decreased –2.52 g/dl on IFN/RBV compared to –1.02 g/dl on IFN/Placebo1.02 g/dl on IFN/Placebo

On IFN/RBV, those taking AZT had –3.64 g/dl decrease On IFN/RBV, those taking AZT had –3.64 g/dl decrease compared to no AZT –2.08compared to no AZT –2.08Nadir Hgb in AZT group 10.1 g/dl compared to Nadir Hgb in AZT group 10.1 g/dl compared to

13.0 with no AZT13.0 with no AZT 60% of subjects on AZT had anemia related dose 60% of subjects on AZT had anemia related dose

reduction of RBV compared to 16% of those not on AZT reduction of RBV compared to 16% of those not on AZT

Bräu, Hepatotolgy, 2004; 39:989

Drug-Drug Interactions: NRTI and HCV TherapyRibavirin - inhibits the phosphorylation of AZT, d4T and Ribavirin - inhibits the phosphorylation of AZT, d4T and

ddC in vitroddC in vitroRibavirin - enhances the anti-HIV activity of didanosine Ribavirin - enhances the anti-HIV activity of didanosine

(ddI) by increasing intracellular conversion to its active (ddI) by increasing intracellular conversion to its active metabolite and may also increase its toxicitymetabolite and may also increase its toxicity

ddI/d4T and IFN increase mitochondrial toxicityddI/d4T and IFN increase mitochondrial toxicity77% of 47 patients lost weight and 65% had elevated 77% of 47 patients lost weight and 65% had elevated

lactate levels on d4T or ddI with IFN/RBVlactate levels on d4T or ddI with IFN/RBV11

16% of 416 patients with ddI and IFN developed 16% of 416 patients with ddI and IFN developed MT over 48 weeksMT over 48 weeks22

Competition among AZT, d4T, and ribavirin in vitro for Competition among AZT, d4T, and ribavirin in vitro for thymidine kinase phosphorylation is not clinically thymidine kinase phosphorylation is not clinically importantimportant

1Gonzalez-Benayas et al. 42nd ICAAC; San Diego, 2002: Abs #H1727.2Hor ICAAC 2002 Abs H1735.

Incidence of Elevated ALT/AST with HAART: The TARGET Cohort

NNRTIs NRTIs Pls

NV

P

EF

V

ZD

V

d4

T

Co

mb

ivir

3T

C

dd

l

AB

C

NF

V

SQ

V

RT

V

IDV

AP

V

5

4

3

2

1

0

Ra

te (

pe

r 1

00

pe

rso

n-y

ea

rs)

Imperiale et al. 4th International Workshop on Adverse Events and Lipodystrophy in HIV; 2002: Abstract 89.

Risk of ALT/AST >5 x ULN among 2198 patients who received antiretroviral

therapy between 1997 and 2001

Incidence and Relative Risk of Grade 3-4 Hepato-toxicity* Associated With Antiretroviral Regimens

ART RegimenART Regimen

NRTINRTI

PIsPIs

RTV (single PI)RTV (single PI)

RTV + SQVRTV + SQV

SQVSQV

IDVIDV

NFVNFV

TotalTotal

No. of Subjects

87

211

22

28

17

117

51

298

Cases

5

26

6

9

1

8

3

31

Person-Time(100 Person-Month)

246

795

96

79

98

520

153

1041

Incidence (Cases/100

Person-Months)(95% CI)

246

795

96

79

98

520

153

1041

Relative Risk (95% CI)

1.0

2.2 (0.9-5.4)

4.8 (1.6-14.1)

5.6 (2.1-15.3)

1.0 (0.1-8.2)

1.2 (0.4-3.5)

1.0 (0.3)-4.1)

NA

*>5 x ULN AST or ALT levels; > 10 x ULN AST or ALT

Sulkowski. JAMA 2000;283(1):74.

Hepatotoxicity associated with NNRTI

8.2 (3.6-15.6)897EFV

16.7 (11.8-22.6)34203NVP

Incidence (95% CI)Cases (Grade 4)

N*

Sulkowski, M. et al. 8th CROI, Chicago, 2001, #618

* 49% NVP recipients HCV+; 45% EFV recipients HCV+. In multivariate regression analysis, Grade 4 hepatotoxicity was determined only by CD4 increase of >50 cells/uL from baseline.

Impact of PI Containing regimens on HCVBenhamou Y et al, Hepatology 2001;34:283-7

PI PI ContainingContaining

Non PI Non PI based based

RegimensRegimens

P valueP value

Fibrosis ScoreFibrosis Score 1.25+/-0.111.25+/-0.11 1.53+/-0.091.53+/-0.09 0.020.02

Inflammation Inflammation ScoreScore

1.69+/-0.171.69+/-0.17 2.10+/-0.112.10+/-0.11 0.030.03

Multivariate factors associated with HCV progression: absence of PI based therapy; CD4 count <200 cells/mL; alcohol consumption >5g/d; age >20 at time of infection.

SummaryLiver disease has emerged as a major cause of morbidity and Liver disease has emerged as a major cause of morbidity and

mortality in HIV positive patientsmortality in HIV positive patientsPreservation of liver function is important in the co-infected Preservation of liver function is important in the co-infected

populationpopulationMust balance HIV therapy with liver healthMust balance HIV therapy with liver healthTherapies for HCV are not easy, come with significant side Therapies for HCV are not easy, come with significant side

effects and may interact with HIV therapieseffects and may interact with HIV therapiesNewer HCV regimens including serine protease inhibitors Newer HCV regimens including serine protease inhibitors

that act directly upon HCV are in phase 2 and 3 trials nowthat act directly upon HCV are in phase 2 and 3 trials nowSince the initiation of NAT for HIV and HCV RNA in blood Since the initiation of NAT for HIV and HCV RNA in blood

donations, the nation’s blood supply has become significantly donations, the nation’s blood supply has become significantly safersafer