Fatal and Non-fatal Hepatic Failure in HIV-infected versus HIV-uninfected

Persons Enrolled in Kaiser Permanente California (KP), a Large Managed Care Organization

William J. Towner1, Lanfang Xu2, Michael J. Silverberg3, Wendy A. Leyden3, Chun R. Chao2, Beth Tang2, Daniel Klein4, Leo Hurley3,

Charles P. Quesenberry, Jr.3, , Michael A. Horberg3.

1 Kaiser Permanente Southern California, Los Angeles, CA, USA2 Kaiser Permanente Southern California, Pasadena, CA, USA

3 Kaiser Permanente Northern California, Oakland, CA, USA4 Kaiser Permanente Nothern California, Hayward, CA, USA

Towner et al. Abstract # TUAB0102

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4 Hepatic toxicity is commonly described in HIV infected persons.

– Possible mechanisms: chronic viral hepatitis, alcohol or other drug abuse, opportunistic infections, antiretroviral therapy, or other liver diseases

– Toxicity commonly defined as elevated transaminases which may not accurately prognosticate subsequent hepatic failure

4 Less data exists on fulminate hepatic failure (HF), either fatal or nonfatal, when comparing HIV+ persons to HIV- persons.

Background

Castellares et al. J Viral Hepat. 2008 Mar;15(3):165-72. Pol et al. Clin Infect Dis. 2004 Mar 1;38 Suppl 2:S65-72.

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Study Objectives

4 Assess whether HIV status is independently associated with increased risk of hepatic failure or hepatic related death

– Assess difference in risk by recent CD4 levels

– Assess difference in risk by use of antiretroviral therapy

4 Determine if other factors contribute to hepatic failure or hepatic related death

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Methods

4 Setting

– Kaiser Permanente (KP), large integrated healthcare system in California, USA

4 Design

– Cohort study, 1996 - 2007

4 Study population

– Adult HIV+ and HIV- matched 1:10 by age, sex, year, medical center, index year

4 Data sources

– KP HIV registries, clinical databases, state/national death files

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Analysis

4 Fatal HF: primary or secondary liver related cause of death, or deaths preceded by a recent diagnosis of hepatic failure

4 Nonfatal HF: hepatic failure, hepatic encephalopathy, or bleeding esophageal varicies OR 2/3 lab elevations: ammonia (≥ ULN), INR (≥ 1.2, not on warfarin) & AST/ALT (≥ 5x ULN).

4 Followed until hepatic failure (fatal or nonfatal), death, lost KP membership, or end of study period

4 Cox regression modeling

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HIV+ HIV-

N 20,277 202,313

Mean years follow-up 4 5

Mean age, years 40 40

Men, % 90 90

Race/ethnicity, % WhiteBlackHispanicAsian/Pacific IslanderOther

(% unknown)

51172041

(9)

277

1581

(44)

Study Population

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Study Population (2)

  HIV+ HIV-

N 20,277 202,313

History of Alcohol/drug abuse, % 19 8

Hepatitis C, % 8 1

Hepatitis B, % 4 1

Diabetes, % 2 3

Lipid Lowering Drug Use, % 4 4

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HIV+

N 20,277

HIV exposure risk, %Men who have sex with menInjection drug useHeterosexualOther

(% unknown)

556

122

(25)

Mean baseline CD4, cells/μl 389

Mean baseline log10 HIV-1 RNA, cp/ml 4.7

ART prior to baseline, % 33

Study Population (3)

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HIV+ HIV-Adjusted Hazard Ratio (95% CI)‡n rate† n

rate†

Fatal HF 159 186 126 12 6.70 (5.2 - 8.8)*

Nonfatal HF 455 540 443 44 5.60 (4.8 - 6.5)*

Male HF# 428 564 429 47 5.40 (4.6 - 6.2)*

Female HF# 38 445 28 28 8.40 (4.7 - 14.8)*

1996-2001 HF# 218 695 110 30 10.5 (8.1 - 13.6)*

2002-2007 HF# 75 453 107 50 3.60 (2.6 - 5.1)*† Cases per 100,000 person-years; ‡ Reference = HIV-; adjusted for age, sex, race, smoking, alcohol/drug abuse, hepatitis B/C, hypertension, diabetes, lipid lowering medications* p < 0.001 HIV+ vs. HIV- # Combined fatal and nonfatal HF

Fatal and Nonfatal HFHIV+ vs. HIV-

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Hazard Ratio (95% CI)

Fatal HF Nonfatal HF

HIV- (reference) 1 1

ART+, CD4 > 500 2.2** (1.2 - 4.0) 2.8* (2.1 - 3.7)

ART-, CD4 > 500 1.7** (0.4 - 6.9) 3.3* (1.9 - 5.8)

ART+, CD4 201 – 499 3.8** (2.6 - 5.8) 5.0* (4.1 - 6.2)

ART-, CD4 201 – 499 5.4** (2.5 - 11.6) 5.6* (3.8 - 8.4)

ART+, CD4 < 200 21.9* (15.5 - 30.9) 14.3* (11.5 - 17.8)

ART-, CD4 < 200 51.6* (30.7 - 86.9) 30.8* (21.3 - 44.4)

p value ART+ vs. ART-

Fatal and Nonfatal HFRecent CD4

Hazard Ratios adjusted for age, sex, race, smoking, alcohol/drug abuse, hepatitis B/C, hypertension, diabetes, lipid lowering medications Hazard ratio

*p < 0.001 **p < 0.05

0.33 0.51

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Hazard Ratio (95% CI)

Fatal HF Nonfatal HF

NNRTI based regimen 1.6 (0.9 – 2.9) 1.2 (0.8 - 1.6)

PI based regimen (reference) 1 1

Fatal and Nonfatal HFMedication Class

p = Not Significant for both Fatal and Nonfatal HF

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n Rate†

< 1 year 147 535

1 – 2.9 years 57 512

3 – 3.9 years 15 366

4 – 4.9 years 13 381

≥ 5 years 51 462

Fatal and Nonfatal HFDuration ART Use (unadjusted incidence rates)†

†Cases per 100,000 person-yearsIncludes data through 31DEC2008

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Adjusted HR 95% CI p

Antiretroviral therapy use 0.9 (0.7 – 1.2) 0.515

Recent CD4 ≤ 200 vs. > 200 2.5 (2.0 – 2.3) < 0.001

Nadir CD4 ≤ 200 vs. > 200 1.5 (1.2 – 2.0) 0.003

HIV RNA ≥ 500 vs. < 500 1.7 (1.4 – 2.1) < 0.001

Ever alcohol or drug abuse 1.6 (1.3 – 2.0) < 0.001

Ever hepatitis B or C 5.3 (4.3 – 6.4) < 0.001

Diabetes 1.9 (1.4 – 2.5) < 0.001

Fatal and Nonfatal HFAdjusted Hazard Ratios for Selected Risk Factors in HIV+

(All combined data for Fatal + Nonfatal)†

†Includes data through 31DEC2008.

Factors not associated with elevated risk: sex, race/ethnicity, hypertension, obesity, and lipid lowering drug use.

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4 Hepatic Failure:– Association with recent CD4 suggests hepatic

failure risk is at least partially immune related

– Earlier treatment with antiretrovirals may reduce risk by preventing CD4 decline

4 Antiretrovirals: – Antiretrovirals did not increase hepatic failure or

hepatic related death rate

– No antiretroviral class or duration effect was noted

Discussion

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4 Strengths– HIV+ and HIV- from same health system– Large and population-based– Comprehensive HIV registries– Adjustment for hepatic failure risk factors

4 Limitations– Imperfect measurement of risk factors– No information on pathologic diagnosis for hepatic

failure/death– Newer HIV medication classes (integrase inhibitors,

CCR5 antagonists) not studied

Strengths and Limitations

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4 Hepatic Failure:– Adjusted risk for both hepatic failure and death

increased in HIV+ vs. HIV– persons – No significant gender differences were noted– Risk lower in the more recent ART era– Increase risks In HIV+ include:

• low CD4 cell count (recent and nadir), • high HIV RNA, • alcohol/drug abuse, • hepatitis B/C co-infection • diabetes

– Antiretroviral therapy not associated with risk

Conclusions

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4 Kaiser Permanente Southern California

Lanfang Xu, Chun Chao, Beth Tang, Hai Linh Kerrigan, Wansu Chen

4 Kaiser Permanente Northern California

Wendy Leyden, Michael Silverberg, Michael Horberg, Leo Hurley, Charles Quesenberry, Jr., Amanda Charbonneau, Daniel Klein

4 Funding sources:Pfizer

4 Kaiser Permanente patients and providers

Acknowledgements