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Hepatitis and HIV Catherine Creticos, M.D. August, 2007 Case study 1

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Hepatitis and hiv l.jpg

Hepatitis and HIV

Catherine Creticos, M.D.

August, 2007


Case study 1 l.jpg
Case study 1

  • D. M. is a 38 y.o. man who has recently immigrated from India to join his wife who works as a nurse in the U.S. As part of the immigration process, he was tested for HIV and found to be positive. He has a history of multiple dental surgeries in India, but otherwise no medical problems. He denies a history of any sexual partners except his wife, who is HIV negative. Upon initial evaluation in the U.S. liver enzymes are minimally elevated. Further studies reveal HAV IgG+, HBsAg+, HBsAb-, HBcAb+(IgG), HBeAg+, HBeAb-, HCVAb-


Hepatitis b virus infection l.jpg
Hepatitis B Virus Infection

  • >300 million chronically infected worldwide

  • Established cause of chronic hepatitis and cirrhosis

  • Human carcinogen—cause of up to 80% of hepatocellular carcinomas


Hepatitis b clinical features l.jpg
Hepatitis B Clinical Features

  • Incubation period 60-150 days (average 90 days)

  • Nonspecific prodrome of malaise, fever, headache, myalgia

  • Illness not specific for hepatitis B

  • At least 50% of infections asymptomatic


Hepatitis b complications l.jpg
Hepatitis B Complications

  • Fulminant hepatitis

  • Hospitalization

  • Cirrhosis

  • Hepatocellular carcinoma

  • Death


Chronic hepatitis b virus infection l.jpg
Chronic Hepatitis B Virus Infection

  • Chronic viremia

  • Responsible for most mortality

  • Overall risk 10%

  • Higher risk with early infection


High viral load predicts poor outcomes l.jpg
High Viral Load Predicts Poor Outcomes

  • Large, long-term, prospective cohort studies have linked high viral load with poor outcomes

    • Haimen City Cohort Chen G, et al. Am J Gastroenterol. 2006;101:1797-1803.

    • Fox Chase Cancer Center Cohort Study Evans AA, et al. AASLD 2004. Abstract 144.

    • R.E.V.E.A.L Study GroupChen CJ, et al. JAMA. 2006;295:65-73.Iloeje UH, et al. Gastroenterology. 2006;130:678-686.


Haimen city cohort viral load and mortality from liver disease l.jpg
Haimen City Cohort: Viral Load and Mortality From Liver Disease

  • 10-year prospective cohort study in Haimen City

  • Permanent cohort of 83,794 subjects established 1992-1993

  • 2354 subjects included in HBV mortality analysis

    • Serum HBV DNA tested on baseline samples

    • Mortality information from death certificate records

    • 448 deaths (231 HCC, 85 CLD, and 132 nonliver deaths)

CLD, chronic liver disease; HCC, hepatocellular carcinoma.

Chen G, et al. Am J Gastroenterol. 2006;101:1797-1803.


Haimen city increased rr of hcc and cld mortality with high viral load l.jpg
Haimen City: Increased RR of HCC and CLD Mortality With High Viral Load

Baseline HBV DNA (copies/mL)

High (≥ 105)

Low (≥ 1. 6 x 103 - < 105)

1.2 (0.6-2.3)

Nonliver

(n = 132)

1.0 (0.5-1.8)

15.2* (2.1-109.8)

CLD

(n = 85)

Cause of Death

1.5 (0.2-12.1)

11.2* (3.6-35.0)

HCC

(n = 231)

1.7 (0.5-5.7)

20

0

5

10

15

Relative Risk† (95% CI)

*P trend < .001†Reference HBV DNA: < 1.6 x 103 copies/mL, adjusted for age and sex

Chen G, et al. Am J Gastroenterol. 2006;101:1797-1803.


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Fox Chase Center Cohort: Association Between Viral Load and HCC

  • 3754 HBV-infected Asian American adults in Philadelphia

  • Nested case-control study

    • 27 case subjects diagnosed with HCC

      • Median age: 54 years (range: 42-74)

    • Case entry < 1-17 years (median: 3) prior to HCC diagnosis

    • 51 control subjects*

      • Median age: 56 years (range: 44-77)

    • HBV DNA quantified with real-time PCR

*Randomly selected from non-HCC subjects and matched for age, sex, and year of study entry but not race

Evans AA, et al. AASLD 2004. Abstract 144.


Fox chase high hbv dna associated with increased risk of hcc l.jpg
Fox Chase: High HBV DNA Associated With Increased Risk of HCC

  • Relative Risk of HCC According to Baseline Viral Load

  • (n = 51 controls; n = 27 cases)

High HBV DNA

(≥ 105 copies/mL)

9.8 (2.3-42.7)

Low HBV DNA

(104 - < 105 copies/mL)

2.1 (0.4-10.0)

Undetectable

(< 104 copies/mL)

Reference

0

5

10

15

Relative Risk* (95% CI) of HCC

*Conditional on the matching variables

Evans AA, et al. AASLD 2004. Abstract 144.


R isk e valuation of v iral load e levation a ssociated l iver disease cancer study l.jpg
R HCCisk Evaluation of Viral Load Elevation & Associated Liver Disease/Cancer Study

  • REVEAL: prospective, multicenter, observational cohort study

7 Taiwanese townships;

individuals aged 30-65 years eligible

(N = 89,293)

1991-1992: recruitment

HCC-free individuals enrolled

(N = 23,820)

Insufficient serum for tests or HBsAg(-)

HBsAg(+) with adequatebaseline HBV DNA sample

(N = 3851)

HCV seropositive ordiagnosed with cirrhosis or died within 6 months of entry

HCV seropositive

HCC

analysis

(n = 3653)

Cirrhosis

analysis

(n = 3582)

HCC follow-up: 41,779 PYs Cirrhosis follow-up: 40,038PYs

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


Reveal high hbv dna associated with increased hcc incidence l.jpg
REVEAL: High HBV DNA Associated With Increased HCC Incidence HCC

Relationship Between Baseline HBV DNA and HCC Incidence:All Participants (N = 3653)

50

40

30

Cumulative Incidence of HCC

at Year 13 Follow-up (%)

20

14.89

12.17

10

3.57

1.37

1.30

0

1000-

9999

300-

999

10,000-

99,999

≥ 100,000

< 300

HBV DNA at Baseline (copies/mL)

Chen CJ, et al.JAMA. 2006;295:65-73.


Reveal high hbv dna associated with increased incidence of cirrhosis l.jpg
REVEAL: High HBV DNA Associated With Increased Incidence of Cirrhosis

Relationship Between Baseline HBV DNA and Cirrhosis Incidence:

All Participants (N = 3582)

50

40

36.2

30

23.5

Cumulative Incidence of Cirrhosis

at Year 13 Follow-up (%)

20

9.8

10

5.9

4.5

0

10,000-

99,999

300-

9999

100,000-

999,999

≥ 1,000,000

< 300

HBV DNA at Baseline (copies/mL)

Iloeje UH, et al. Gastroenterology. 2006;130:678-686.


Hbv viral load and disease progression summary l.jpg
HBV viral load and disease progression - summary Cirrhosis

  • The higher the viral load, the greater the risk for development of cirrhosis, its complications, and HCC

  • Disease can progress even when HBV DNA is < 104 copies/mL (~ 2000 IU/mL)

  • Continued suppression of HBV DNA decreases fibrosis and delays disease progression


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Goals of Hepatitis B Therapy Cirrhosis

  • Primary goal: suppress HBV DNA to the lowest possible level to achieve

    • Prevention of liver disease progression to cirrhosis

    • Prevention of liver failure and HCC

    • Prevention of liver disease–related transplantation or death

  • HBV DNA suppression leads to

    • Histologic improvement

    • ALT normalization

    • HBeAg loss and seroconversion

    • HBsAg loss and seroconversion


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Goals of Therapy: Cirrhosis2 Distinct Patient Populations

  • HBeAg positive (wild type)

    • HBeAg loss  seroconversion

    • Durable suppression of HBV DNA to lowest possible levels

    • Therapy discontinued after seroconversion; durability of response ~ 80%

  • HBeAg negative (precore and core promoter mutants)

    • HBeAg seroconversion not an endpoint

    • Durable suppression of HBV DNA to lowest possible levels

    • Relapse common after stopping oral therapy; therapy usually administered long term


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Reversal of Fibrosis With Long-term CirrhosisNucleos(t)ide Analogue Therapy

  • Paired biopsies from before, after 3 years of lamivudine(N = 63)

    • HAI necroinflammatory scores

      • 56% improved by ≥ 2 points

      • 33% had no change

      • 11% had worsening (YMDD mutations blunted the response)

    • Fibrosis

      • 63% (12/19) had improvement in bridging fibrosis by ≥ 1

      • 73% (8/11) had improvement in cirrhosis (score 4 → ≤ 3)

      • Only 2% (1/52) had progression to cirrhosis and 9% (3/34) to bridging fibrosis—all with YMDD mutations

Dienstag J, et al. Gastroenterology. 2003;124:105-117.


Reversal of fibrosis with long term nucleos t ide analogue therapy19 l.jpg
Reversal of Fibrosis With Long-term CirrhosisNucleos(t)ide Analogue Therapy

  • 47 HBeAg-negative patients treated with up to 2 years of adefovir

  • Fibrosis by rank assessment at Week 96

    • Mean reduction with continued adefovir 0.63 ± 1.07 (P = .031 compared with adefovir → placebo group)

Hadziyannis SJ, et al. N Engl J Med. 2005;352:2673-2681.


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Delayed Disease Progression With Continued Suppression: Cirrhotics

  • 651 cirrhosis patients with evidence of viral replication

Placebo (n = 215)

Lamivudine (n = 436)

P = .001

25

21

20

15

Patients With Disease Progression at Follow-up

9

10

  • Child-Pugh score P = .02; HCC P = .047*

  • Benefit reduced with YMDD emergence

5

0

*5 cases of HCC in Year 1 excluded, P = .052

Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.


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Delayed Disease Progression With Continued Suppression: Noncirrhotics

  • 142 noncirrhotic patients on continuous lamivudine for a median of 89.9 months vs 124 untreated controls

Placebo

Lamivudine

P = .005

14

12

10

8

Percentage of Patients With Cirrhosis/HCC

6

4

2

0

Yuen MF, et al. AASLD 2005. Abstract 985.


Conclusions l.jpg
Conclusions Noncirrhotics

  • Prolonged viral suppression with nucleos(t)ide analogues

    • Reduces necroinflammation

    • Reverses fibrosis and cirrhosis

    • Decreases cirrhotic complications and HCC in both cirrhotic and precirrhotic patients


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HBV DNA as a Marker of Efficacy During Treatment of HBV Noncirrhotics

  • Literature analysis of 26 prospective studies

    • Investigation of the relationship between treatment-induced changes in HBV DNA, histology, other disease activity markers

  • Results

    • Statistically significant and consistent correlations between HBV DNA, histology, biochemical and serologic responses

      • HBV DNA had broader dynamic range than histology

  • Conclusion

    • Treatment-induced reduction in HBV DNA can be used to assess efficacy

    • Treatment goal should be profound and durable suppression of HBV DNA

Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319.


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Correlation Between HBV DNA Levels and Markers of Liver Disease (cont’d)

  • Necroinflammation correlated with

    • HBV DNA levels in untreated patients (r = 0.78; P = .001)

    • HBV DNA levels at the end of treatment (r = 0.71; P = .003)

  • HBeAg seroconversion correlate with change in median HBV DNA from baseline to end of treatment (r = 0.72, P < .0002)

  • Normalized ALT post treatment correlated with HBV DNA level (r = 0.62, P = .0004)

Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319.


Entecavir superior to lamivudine in hbeag positive patients l.jpg
Entecavir Superior to Lamivudine in HBeAg-Positive Patients Disease (cont’d)

Entecavir (n = 354)

Lamivudine (n = 355)

HBV DNA < 300 copies/mL Through Week 96*

HBeAg Seroconversion Through Week 96†

Histologic Improvement Through Week 48

100

100

100

P < .0001

P = .009

80

80

80

80

72

62

60

60

60

P = NS

Patients (%)

39

40

40

40

31

26

20

20

20

(n = 354)

(n = 355)

(n = 354)

(n = 355)

(n = 314)

(n = 314)

0

0

0

*Cumulative confirmed data: 2 data points or last observation on therapy.

†Cumulative confirmed data through last observation and 6 months off treatment.

Gish RG, et al. Hepatology. 2005;42:267A.


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Long-term Entecavir in HBeAg-Negative Patients Disease (cont’d)

Entecavir

Lamivudine

Histologic Improvement Through Week 48

HBV DNA

< 300 copies/mL Through Week 96*

P < .0001

100

100

94

P = .01

77

80

80

70

61

60

60

Patients (%)

40

40

20

20

(n = 287)

(n = 313)

(n = 296)

(n = 325)

0

0

*Cumulative confirmed data: 2 data points or last observation on therapy.

Shouval D, et al. EASL 2006. Abstract 45. Lai C, et al. N Engl J Med. 2006;354:1011-1020.


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Clinical Efficacy 2-Year Results: Disease (cont’d)Telbivudine vs Lamivudine

*P ≤ .05 vs lamivudine.

Lai C, et al. AASLD 2006. Abstract 91.


Week 52 histologic outcomes telbivudine vs lamivudine l.jpg
Week 52 Histologic Outcomes: Disease (cont’d)Telbivudine vs Lamivudine

HBeAg Positive Patients

HBeAg Negative Patients

100

7

8

12

15

Missing Week 52

23

25

80

19

biopsy

26

Histologic Response (%)

60

No improvement

40

69

69

68

60

Improvement

20

0

LdT

LdT

LAM

LAM

Lai C, et al. AASLD 2006. Abstract 91.


Peginterferon alfa 2a in hbeag positive chronic hepatitis b patients l.jpg
Peginterferon alfa-2a in HBeAg-Positive Chronic Hepatitis B Patients

HBV DNA Levels 1 Year Post treatment According to Type of Initial Response

100

HBV DNA 1 year post treatment (copies/mL)

21

29

80

7

60

29

33

> 100,000

96

Patients (%)

10,001-100,000

40

21

401-10,000

20

39

≤ 400

21

0

Early, Sustained

HBeAg

Seroconversion

Late HBeAg

Seroconversion

No HBeAg

Seroconversion

(n=61)

(n=15)

(n=88)

Lau GK, et al. EASL 2006. Abstract 50.


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Histologic Improvement With Peginterferon Therapy Patients

HBeAg-Negative Patients

HBeAg-Positive Patients

100

80

59

58

PegIFN

52

60

51

49

48

Histologic Improvement (%)

PegIFN + LAM

40

LAM

20

0

Lau GK, Piratvisuth T, Luo KX, et al. N Engl J Med. 2005. 30;352:2682-2695.

Marcellin P, Lau GK, Bonino F, et al. N Engl J Med. 2004. 16;351:1206-1217.


Hbv dna and hbeag seroconversion at year 1 in hbeag patients l.jpg
HBV DNA and HBeAg Seroconversion at Year 1 in HBeAg(+) Patients

Data from individual studies, not direct comparisons

(different populations, baseline values, HBV DNA assays)

PegIFN

LAM

ADV

ETV

LdT

30

27

23

21

HBeAg

Seroconversion, %

20

18

12

10

0

0

Log10 Decrease in HBV DNA

-3.6

-4.0

-5.8

-6.5

-6.9

-10

Lau et al. N Engl J Med. 2005;352:2682-2695. Dienstag et al. N Engl J Med. 1999;341:1256-1263. Marcellin et al. EASL 2005. Abstract 73. Lai et al. AASLD 2005. Abstract 72404. Chang et al. AASLD 2004. Abstract 70. Entecavir package insert. Telbivudine package insert.


Emtricitabine impact on hbv in hbv hiv coinfection l.jpg
Emtricitabine impact on HBV in HBV/HIV coinfection Patients

  • Data analyzed from HIV/HBV coinfected individuals enrolled in three Gilead studies designed to evaluate the safety and efficacy of FTC as part of HAART in treatment-naïve patients

  • Anti-HIV and anti-HBV effects of FTC in these individuals evaluated


Emtricitabine effective against hbv l.jpg
Emtricitabine effective against HBV Patients

  • 39 patients from 3 studies

  • Baseline median HBV viral load >500,000 copies/mL

  • Week 24 HBV viral load undetectable in 45%; 59% at week 48

  • HIV viral load undetectable at week 24 in 97%, 94% at week 48

  • In a separate study, undetectable HBV viral load was achieved in 59% of monoinfected individuals at 48 weeks.

  • 12% incidence of drug-resistant HBV at week 48 in coinfected individuals with detectable HBV viral load at baseline

Snow A, Harris J, Borroto-Esoda K, et al. CROI 2004; Poster 836


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Tenofovir active against HBV in coinfected individuals Patients

  • Tenofovir has potent activity against HBV in vitro and in retrospectively analyzed HIV/HBV-coinfected patients

  • Study to assess long-term HBV dynamics and influence of baseline factors on HBV load in HIV/HBV-coinfected patients beginning tenofovir-based HAART

Lacombe K, Gozlan J, Boelle PY, et al. AIDS. 2005;19:907-915


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Summary of Study Design Patients

  • Subgroup of patients enrolled in French multicenter prospective HIV-HBV Cohort Study used in analysis

  • Child-Pugh score determined in cirrhotic patients at beginning and end of follow-up

  • HBV DNA and biochemical data measured at least once during first month and then at least once every 3 months thereafter


Baseline characteristics l.jpg
Baseline Characteristics Patients

  • N = 28

  • Median duration HIV infection, 11.1 years (range, 0.01-17.7 years)

  • Median duration HBV infection, 7.0 years (range, 0.01-16.9 years)

  • Median HIV-1 RNA, 3.81 log10 copies/mL (range, 1.4-5.7 log10 copies/mL)

  • Median HBV DNA, 7.75 log10 copies/mL (range, 3-10 log10 copies/mL)


Main findings l.jpg
Main Findings Patients

  • HBV DNA declined from baseline by mean of 4.6 log10 copies/mL with tenofovir treatment (P < .001)

    • HBV DNA undetectable (< 200 copies/mL) in 21 (87.5%) patients

    • Median time until undetectable, 272.5 days (95% confidence interval [CI], 203.5-416.0)

  • 4 of 24 (16.7%) HBeAg-positive patients at baseline lost HBeAg and seroconverted to hepatitis B antibodies

  • No incidence of grade 3/4 adverse events


Main findings38 l.jpg
Main Findings Patients

  • Tenofovir-based HAART also had significant impact on HIV-1 RNA, ALT

    • HIV-1 RNA declined from baseline by mean of 1.4 log10 copies/mL (P < .0001)

    • Undetectable HIV-1 RNA (< 50 copies/mL) increased from 22% of patients at baseline to 75%

    • Mean ALT declined from 125 to 50 IU/mL (P < .05)


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Key Conclusions Patients

  • Tenofovir demonstrates potent activity against HBV in HIV/HBV-coinfected patients and shows marked impact on liver function by decreasing ALT activity

    • Significant decline in HIV-1 RNA also observed

    • Tenofovir well tolerated

  • Long-term HBV dynamics not affected by concomitant receipt of lamivudine, HBV genotype, or HIV-related immunosuppression


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Treatment of HBV with TDF or ADV Patients

  • Nonrandomized, open label study of TDF vs. ADV in 85 HIV-HBV co-infected patients

    • ADV (n=29), TDF (n=56)

    • Tx-naive, except for past or current 3TC as part of ARV regimen.

  • TDF superior regarding antiviral and biochemical responses

    • More rapid HBV DNA decline and a greater decline at 12 mos. (p<0.0001)

    • Greater decreases in transaminases

    • After adjustment of HBeAg status, HBV-DNA at baseline and level of ALT at baseline, TDF associated with a higher rate of patients achieving undetectable HBV-DNA levels

1.00

P=0.04

0.75

Proportion with <200 copies/mL

0.50

TDF

.025

ADV

0.00

0

1

0

2

0

3

0

4

0

Time to HBV-DNA undetectability (months)

Lacombe Burman W, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Abst. 945.


Conclusions41 l.jpg
Conclusions Patients

  • HBV DNA suppression with anti-HBV therapy improves patient outcomes

  • Continued benefits are observed with long-term HBV therapy

    • Resistance diminishes the benefits of treatment

  • More potent viral suppression can lead to greater patient outcomes

    • HBeAg seroconversion

    • ALT normalization

    • Long-term virologic response

    • Lower risk of resistance


Hbv resistance l.jpg
HBV Resistance Patients

  • HBV resistance can be delayed

    • By using highly potent antivirals

    • By improving adherence

    • By using combination therapies

  • When resistance occurs

    • Consider add-on therapy rather than switching to second monotherapy

    • Consider using the most potent available antiviral combination


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2006 NIH Workshop on the Management of CHB: PatientsWho Should Receive Treatment?

HBsAg Positive

HBeAg

Decompensated cirrhosis

Inactive carrier/mild chronic hepatitis

Neg

Pos

HBV DNA < 104 IU/mL; ALT normal 3-6 months

Grey zone

HBV DNA > 104 IU/mL; elevated ALT 3-6 months

Consider antiviral therapy/ refer for OLT

Consider Liver biopsy

Consider antiviral therapy

Monitor every 3-6 months


Interferon therapy l.jpg
Interferon Therapy Patients

  • Pros

    • Finite duration of therapy

    • Durable response

    • No resistance or cross resistance

  • Cons

    • Route of administration—injection

    • Frequent side effects

    • Cost


Ideal clinical situation for ifn therapy l.jpg
Ideal Clinical Situation for IFN Therapy Patients

  • High ALT (> 5 x ULN) and low HBV DNA level (< 200,000 IU/mL)

  • Younger patient

  • Black

  • Well-compensated cirrhosis

  • No contraindications to use of interferon

  • ? Genotype A or B

  • ?HIV/HBV with high CD4, low HIV-RNA


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Lamivudine Patients

  • Pros

    • Oral

    • Negligible side effects

    • Excellent safety profile

    • Low cost

  • Cons

    • High rate of resistance and cross-resistance with other nucleoside analogues

    • Long/indefinite duration of therapy

    • Cannot be used as monotherapy in HIV/HBV


Ideal clinical situation for lamivudine use l.jpg
Ideal Clinical Situation for PatientsLamivudine Use

  • Short duration of therapy

    • Prevention of disease flares/reactivation during chemotherapy

    • Protracted or severe acute hepatitis

  • Safety a concern

    • During pregnancy

  • Cost a concern

    • HBeAg-negative CHB in developing countries


Lamivudine in haart regimen l.jpg
Lamivudine in HAART Regimen Patients

  • Lamivudine used in HAART regimen for coinfected individual may result in the development of HBV resistance mutations

  • If HAART interrupted or changed, anticipate flare in HBV/hepatitis if lamivudine also stopped


Adefovir l.jpg
Adefovir Patients

  • Pros

    • Route of administration: oral

    • Low rate of resistance

    • Effective against lamivudine resistant virus

    • Can be used as monotherapy in HIV/HBV without inducing HIV resistance mutations

  • Cons

    • Slow response and high rate of primary nonresponse

    • ? Renal toxicity with long-term use

    • Long/indefinite duration of therapy


Ideal clinical situation for adefovir use l.jpg
Ideal Clinical Situation for PatientsAdefovir Use

  • HBeAg-positive and HBeAg-negative chronic hepatitis B with low HBV DNA

  • Management of lamivudine-resistant chronic hepatitis B

  • HIV/HBV coinfected individual not requiring HAART


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Entecavir Patients

  • Pros

    • Route of administration: oral

    • Potent with low rate of resistance

    • Effective against LAM-R

  • Cons

    • Long-term safety unknown

    • Long/indefinite duration of therapy

    • Cannot be used in HIV/HBV coinfected patient not on HAART – will select for M184V mutation


Ideal clinical situation for entecavir use l.jpg
Ideal Clinical Situation for PatientsEntecavir Use

  • HBeAg-positive or HBeAg-negative chronic hepatitis B with high viral load

  • Management of lamivudine resistance

  • Can be used in HIV/HBV coinfection in patients who are on HAART if preferable to other HBV agents


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FTC and TDF for HIV/HBV Coinfected Individuals Patients

  • Evidence supports benefit of this combination for coinfected individuals requiring both HIV and HBV treatment

  • Should be used in combination with a fully HIV suppressive regimen

  • If HAART regimen interrupted or altered, anticipate potential HBV flare if FTC and/or TDF withdrawn without continued HBV suppression


Case study 1 cont l.jpg
Case Study 1 – cont. Patients

  • Additional laboratories:

    • CD4 372

    • HIV RNA 86,000

    • HBV DNA >500,000

  • Treatment options:

    • Treat HBV, not HIV

      • Adefovir

      • Telbivudine

      • Interferon

    • Treat both HBV and HIV

    • Tenofovir and epivir or emtricitabine in a HAART regimen

    • Monitor both HBV and HIV off treatment


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Case Study 2 Patients

  • C. T. is a 53 y.o. man with a history of paranoid schizophrenia and alcohol and cocaine use. He continues to actively use both substances, but not IV cocaine. He has been HIV and HCV positive for the last 10 years; CD4 nadir at time of diagnosis was 125. He has been extremely adherent to HAART over the last 10 years, including a difficult indinavir-containing regimen, maintaining an undetectable HIV RNA for the last 9 years, and CD4 above 600 for most of that time. He has had 2 liver biopsies for staging of liver disease (3 and 1 year ago), that have both show stage 1 fibrosis. His transaminases fluctuate in the 80-100 range. He is anxious to treat his hepatitis C, but although he is extremely adherent to his HAART regimen, refuses to take any psychiatric medications.


Hepatitis c l.jpg
Hepatitis C Patients

  • Identified in 1989

  • Now recognized as the primary cause of non-A/non-B hepatitis

  • Most common blood borne infection in the US

    • 3.9 million people infected

    • 36,000 new cases annually

    • 10,000 deaths annually

  • Causes 40% of chronic liver disease in the US

  • Leading indication for liver transplantation - 10,000 per year


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Screening for HCV disease Patients

  • EVERYONE who is HIV positive should be screened for HCV - similar risk factors

  • Children born to women with suspected chronic HCV infection at the time of the delivery should be screened for HCV infection (risk approximately 5%)

  • History of acute hepatitis - HAV, HBV, and HCV

  • Injection drug users


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Serologic Tests for HCV Patients

  • Anti-HCV by EIA-3

    • May be negative in immunocompromised patients or acute HCV infection

  • HCV RNA by PCR

  • Recombinant Immunoblot Assay (RIBA)

  • Quantitative PCR and branched DNA (bDNA)


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Acute HCV Infection Patients

  • Asymptomatic - 60-70%

  • Jaundice - 20-30%

  • Non-specific symptoms - 20-30%

    • Anorexia, malaise, or abdominal pain

  • Time from exposure to symptoms - 6-7 weeks

  • Time from exposure to seroconversion 8-9 weeks

  • Anti-HCV can be detected in 80% of patients within 15 weeks after exposure

    • >90% within 5 months

    • >97% within 6 months

    • Rarely is seroconversion delayed >9 months


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anti-HCV Patients

Symptoms +/-

HCV RNA

Titer

ALT

Normal

6

1

2

3

4

0

1

2

3

4

5

Years

Months

Time after Exposure

Serologic Pattern of Acute HCV Infection

with Recovery


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Chronic HCV Infection Patients

  • HCV RNA detectable in the blood for > 6 months

  • 60-85% of acutely infected will become chronic

  • Most do not have symptoms

  • Some may experience: fatigue, mild RUQ discomfort or tenderness, nausea, poor appetite, muscle and joint pains


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Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection

anti-HCV

Symptoms +/-

HCV RNA

Titer

ALT

Normal

6

1

2

3

4

0

1

2

3

4

5

Years

Months

Time after Exposure


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Factors Influencing the Progression of HCV Chronic Infection

  • Older age at time of infection

  • Male gender

  • Immunocompromised state

  • Concurrent infection with HBV

  • Alcohol intake

    • Men - 30 g/day (2 beers, 2 glasses of wine, 2 mixed drinks)

    • Women - 20 g/day

  • Other - iron overload, nonalcoholic fatty liver disease, schistosomal co-infection, hepatotoxic medications, environmental contaminants


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Prognosis of Untreated HCV Chronic InfectionVariable Course and Outcome

  • No symptoms - 50-80%

    • Liver biopsy with some chronic hepatitis changes

    • Good prognosis

  • Severe hepatitis - 20-50%

    • HCV RNA detectable

    • Elevated liver enzymes

    • Within 10-20 years, 15% will develop cirrhosis and ESLD

    • 1-4% will develop hepatocellular carcinoma


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Epidemiology and Natural History of HIV/HCV Co-infection Chronic Infection

  • Prevalence - 33% of all HIV infected persons have HCV

    • Injection drug users - 60 - 90%

    • Persons with hemophilia - 85% (blood products prior to 1985)

    • Homosexual men - 4 - 8%


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Natural History of HCV disease in HIV-infected persons Chronic Infection

  • HIV infection - significant co-factor for HCV-related liver disease and mortality

  • HCV-related fibrosis is accelerated in persons with HIV-infection

  • Impact of HCV disease will increase as HIV-related mortality declines due to the use of HAART and OI prophylaxis


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Effect of HCV on HIV Chronic Infection

  • HCV may hasten progression to AIDS or death

  • May impair immune reconstitution following initiation of HAART

  • More frequent vertical transmission

  • Increased risk of hepatotoxicity from HAART


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Effect of HIV on HCV Chronic Infection

  • May have false negative anti-HCV EIA results

  • Vertical transmission of HCV in increased

  • May increase sexual transmission of HCV

  • Higher HCV viremia

  • Associated with higher HIV RNA levels and lower CD4 counts

  • Increases rate of fibrosis

  • Increased rate of HCV-related liver disease (cirrhosis, ESLD, HCC)


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In the Co-Infected Patient Chronic Infection

  • Higher risk of toxicity associated with IFN therapy with patients on HAART

  • Early treatment is key to successful management

  • HCV must be evaluated and treated before the development of ESLD


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Goals of HCV Therapy Chronic Infection

  • Eliminate HCV RNA

  • Delay progression of fibrosis

  • Prevent liver decompensation, HCC, and death

  • Improve tolerance and effectiveness of HAART

    • Permit aggressive ART

    • Potentially enhance immune reconstitution


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HAART reduces liver fibrosis progression in HIV/HCV coinfected individuals

  • Liver biopsies performed on 296 coinfected patients who had not received therapy for HCV

  • Data analyzed from 213 patients on whom date of HCV infection could be ascertained

  • Logistic regression analysis done to assess the association between time on HAART and fibrosis progression index (ratio of fibrosis stage to years of HCV infection)

  • Results: HAART reduces the fibrosis progression rate and the development of bridging fibrosis and cirrhosis in HIV-HCV coinfected patients

S Resino, J Berenguer, P Miralles et al., CROI 2007, Abstract 935


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In the Co-Infected Patient coinfected individuals

  • Higher risk of toxicity associated with IFN therapy with patients on HAART

  • Early treatment is key to successful management

  • HCV must be evaluated and treated before the development of ESLD


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HCV/HIV Co-infection: coinfected individualsWho should be treated?

  • All patients with HIV and HCV should be considered for treatment

  • Patients with well controlled HIV disease

    • HIV RNA undetectable and CD4 count > 200 cells/mm3

  • Patients with advanced liver disease by biopsy


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HCV Treatment Options coinfected individuals

  • Interferon alfa monotherapy

    • Interferon alfa-2b (Intron A)

    • Interferon alfa-2a (Roferon-A)

    • Interferon alfacon-1 (Infergen)

  • Pegylated interferon monotherapy

    • Peginterferon alfa-2b (PEG-Intron)

    • Peginterferon alfa-2a (PEGASYS)

  • Pegylated interferon combination therapy

    • Peginterferon alfa-2b plus ribavirin

    • Peginterferon alfa-2a plus ribavirin


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HIV/HCV Coinfection Trials: coinfected individualsPEG IFN and RBV

ACTG, AIDS Clinical Trials Group; APRICOT, AIDS PEGASYS® Ribavirin

International CO-Infection Trial.

Chung et al. N Engl J Med. 2004;351:451-459.

Perronne et al. 11th CROI. February 8-11, 2004; San Francisco, Calif. Abstract 117LB.

Torriani et al. N Engl J Med. 2004;351:438-450.


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ACTG 5071: Overall Results coinfected individuals

(N=133)

*

**

SVR: HCV<60 IU/mL 24 weeks after end of therapy (EOT).

*P=.0001 versus IFN 2a + RBV. **P<.03 versus IFN 2a + RBV.

Chung R et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 110.


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ACTG 5071: PEG coinfected individualsα-2a + RBV Arm by Genotype

*

*

* P=.0007 vs Genotype 1.

Chung R et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 110.


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ACTG 5071: Summary coinfected individuals

  • Predictors of sustained virologic response included PEG α-2a + RBV treatment, HCV genotype non-1, no previous IDU, and detectable HIV-1 RNA at entry

  • PEG-IFN α-2a + RBV was more effective treatment than standard IFN + RBV

  • Even in virologic nonresponders, 36% had a histological response

IDU = injection drug use.

Chung R et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 110.


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End of treatment coinfected individuals

End of follow-up

APRICOT: Virologic Response*End of Treatment Versus End of Follow-up (Genotype 1)

% Response

PEG-IFN α-2a(40 kDa) + Placebo

PEG-IFN α-2a(40 kDa) + RBV

IFN α-2a + RBV

*Defined as <50 IU/mL HCV RNA.

Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.


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End of treatment coinfected individuals

End of follow-up

% Response

IFN α-2a + RBV

PEG-IFN α-2a(40 kDa) + Placebo

PEG-IFN α-2a(40 kDa) + RBV

APRICOT: Virologic Response*End of Treatment Versus End of Follow-up (Genotypes 2 and 3)

*Defined as <50 IU/mL HCV RNA.

Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.


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APRICOT: Median Change in CD4+ Counts From Baseline coinfected individuals *

g

g

Median Change From Baseline

in CD4+ Count (cells/L)

BL

Time (Weeks)

* Patients receiving 48 weeks of treatment.

Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.


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APRICOT: Change in HIV RNA From Baseline – All Patients Treated*

g

g

Change in Log10 HIV RNA

BL

Time (Weeks)

* Patients receiving 48 weeks of treatment.

Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.


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APRICOT: Summary Treated*

  • SVR was significantly higher for PEG-IFN α-2a (40 kDa) + RBV compared with conventional combination therapy

    • Overall: 40% versus 12%; P <.0001

    • Genotype 1: 29% versus 7%

    • Genotype 2/3: 62% versus 20%

  • Adverse event profile of PEG-IFN α-2a (40kDa) + RBV is generally similar to IFN + RBV therapy

  • Only 15% to 16% of patients discontinued for adverse events or laboratory abnormalities

Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.


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French ANRS RIBAVIC Study Treated*

  • Randomized, multicenter, open-label study in HIV-HCV coinfected patients with CD4>200 and stable HIV RNA for 48 weeks on:

    • PEG-IFN α-2b 1.5 g/kg/wk + RBV (n=205), or

    • Standard IFN-2b 3 MIU tiw + RBV 800 mg QD (n=207)

  • Primary efficacy end point was SVR (undetectable HCV RNA) at week 72

Perronne C et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 117LB.


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RIBAVIC: SVR at Week 72 Treated*

P=.031

Perronne C et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 117LB.


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(n=245) Treated*

RIBAVIC: Response Rates – Patients Who Did Not Discontinue Treatment

Perronne C et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 117LB.


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HIV/HCV Infection Trials: Treated*SVR (combined genotypes)

  • RIBAVIC

    • PEG IFN-alfa-2b and RBV: SVR = 26%

  • ACTG 5071

    • PEG IFN alfa 2-a/RBV: SVR = 27%

  • APRICOT

    • PEG IFN alfa-2a/RBV: SVR = 40%

Chung et al. N Engl J Med. 2004;351:451-459.

Perronne et al. 11th CROI. February 8-11, 2004; San Francisco, Calif. Abstract 117LB.

Torriani et al. N Engl J Med. 2004;351:438-450.


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Contraindications to Peginterferon/Ribavirin Treated*

  • Hypersensitivity to peginterferon or ribavirin

  • Pregnancy

  • Hemoglobinopathies

  • Active OI

  • Decompensated liver disease

  • Autoimmune disease


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Interferon Treated*

Fatigue (70%)

Flu-like symptoms - self limited after initial doses

Bone marrow suppression

Depression, anxiety, insomnia, and irritability

Alopecia

Weight loss

Potential exacerbation of autoimmune conditions

Thyroid dysfunction (4%)

Ribavirin

Teratogenicity

Hemolytic anemia

Dose-dependent and completely reversible

Average 2-3 grams hemoglobin over the first four weeks of therapy

Nausea - take with food

Adverse Effects of Combination Therapy


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Managing Side Effects Treated*

  • Evening injections

  • Increase fluid intake

  • Aerobic exercise

  • Prophylactic acetaminophen or ibuprofen

  • Support groups

  • Psychiatric medications

  • Erythropoetin and G-CSF


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International, US, and Canadian Guidelines Treated*

  • Test ALL HIV-infected patients for HCV antibodies

  • To treat HCV consider

    • Liver biopsy score

    • CD4+ cell count

    • HIV RNA viral load

    • Substance abuse

    • History of depression

    • Active Opportunistic Infection

    • Treatment of choice is PEG IFN/RBV


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AASLD Practice Guidelines Treated*

  • HCV RNA testing for:

    • confirmation of HCV infection in HIV-infected persons who are positive for anti-HCV

    • those who are negative and have evidence of unexplained liver disease

  • HCV treatment for the HIV/HCV coinfected person

    • in whom the likelihood of serious liver disease and a treatment response are judged to outweigh the risk of morbidity from the adverse effects of therapy

  • Initial treatment of HCV in most HIV-infected persons is PEG IFN alfa/RBV for 48 weeks


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AASLD Practice Guidelines Treated*(cont)

  • Monitor coinfected patients on HCV treatment closely

  • Use RBV with caution in persons with limited myeloid reserves and in those taking AZT and D4T

  • Patients receiving ddI should be switched to an equivalent ART before beginning therapy with RBV if possible

  • HIV-infected patients with decompensated liver disease may be candidates for OLT

AZT, zidovudine; OLT, orthotopic liver transplantation.

Strader et al. Hepatology. 2004;39:1147-1171.


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International Guidelines Treated*

ALT, alanine aminotrasferase.

Soriano et al. J Viral Hepat. 2004;11:2-17.


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New International Guidelines for Management of HIV/HCV Coinfection

  • 25-40% of coinfected patients with persistently normal ALT may have fibrosis and thus should be considered for HCV treatment regardless of ALT

  • Non-invasive methods for assessing liver fibrosis accurately predict fibrosis in most cases, so that liver biopsy is not necessary for considering HCV treatment


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New International Guidelines – cont. Coinfection

  • RVR at week 4 predicts SVR in coinfected individuals as it does in monoinfected

  • Coinfected patients on treatment who do not achieve EVR by week 12 or who still have detectable HCV RNA at week 24 should stop treatment early


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Guidelines – cont. Coinfection

  • Weight-based RBV superior to fixed dose

  • 48 weeks PEG IFN + RBV for all HCV genotypes; 24 weeks may be adequate for HCV 2 or 3

  • Slow responders may benefit from 60-72 week courses of therapy


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Guidelines – cont. Coinfection

  • Coinfected non-responders and relapsers must be evaluated on and individual basis and considered for retreatment or interferon maintenance monotherapy to slow liver disease

  • HAART may benefit patients with ESLD


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Acute HCV in HIV-infected Individuals – International Guidelines

  • Outbreaks in Europe among MSM – presumably sexually transmitted

  • HIV infected individuals less likely to clear acute hepatitis C

  • Early treatment especially indicated in patients with HIV

  • Treatment should be initiated after 12 weeks to allow for possible spontaneous clearance, then initiated with PEG IFN and weight-based RBV for 24 weeks


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Case Study 2 Guidelines

  • C.T. is a candidate for Peg IFN and RBV therapy, but active substance use and psychiatric issues may complicate treatment

  • Lack of progression in liver fibrosis on 2 consecutive biopsies reassuring

  • Non-invasive studies to monitor fibrosis may be helpful


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