1. 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. Towner 1, Lanfang Xu 2, Michael J. Silverberg 3, Wendy A. Leyden 3, Chun R. Chao 2, Beth Tang 2, Daniel Klein 4, Leo Hurley 3, Charles P. Quesenberry, Jr. 3,, Michael A. Horberg 3. 1 Kaiser Permanente Southern California, Los Angeles, CA, USA 2 Kaiser Permanente Southern California, Pasadena, CA, USA 3 Kaiser Permanente Northern California, Oakland, CA, USA 4 Kaiser Permanente Nothern California, Hayward, CA, USA Towner et al. Abstract # TUAB0102

2. 2  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  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.

3. 3 Study Objectives  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  Determine if other factors contribute to hepatic failure or hepatic related death

4. 4 Methods  Setting –Kaiser Permanente (KP), large integrated healthcare system in California, USA  Design –Cohort study, 1996 - 2007  Study population –Adult HIV+ and HIV- matched 1:10 by age, sex, year, medical center, index year  Data sources –KP HIV registries, clinical databases, state/national death files

5. 5 Analysis  Fatal HF: primary or secondary liver related cause of death, or deaths preceded by a recent diagnosis of hepatic failure  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).  Followed until hepatic failure (fatal or nonfatal), death, lost KP membership, or end of study period  Cox regression modeling

6. 6 HIV+HIV- N20,277202,313 Mean years follow-up45 Mean age, years40 Men, %90 Race/ethnicity, % White Black Hispanic Asian/Pacific Islander Other (% unknown) 51 17 20 4 1 (9) 27 7 15 8 1 (44) Study Population

7. 7 Study Population (2) HIV+HIV- N20,277202,313 History of Alcohol/drug abuse, %198 Hepatitis C, %81 Hepatitis B, %41 Diabetes, %23 Lipid Lowering Drug Use, %44

8. 8 HIV+ N20,277 HIV exposure risk, % Men who have sex with men Injection drug use Heterosexual Other (% unknown) 55 6 12 2 (25) Mean baseline CD4, cells/μl389 Mean baseline log 10 HIV-1 RNA, cp/ml4.7 ART prior to baseline, %33 Study Population (3)

9. 9 HIV+HIV- Adjusted Hazard Ratio (95% CI) ‡ nrate † n Fatal HF159186126126.70(5.2 - 8.8)* Nonfatal HF455540443445.60(4.8 - 6.5)* Male HF # 428564429475.40(4.6 - 6.2)* Female HF # 3844528 8.40(4.7 - 14.8)* 1996-2001 HF # 2186951103010.5(8.1 - 13.6)* 2002-2007 HF # 75453107503.60(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 HF HIV+ vs. HIV-

10. 10 Hazard Ratio (95% CI) Fatal HFNonfatal HF HIV- (reference)11 ART+, CD4 > 5002.2** (1.2 - 4.0)2.8* (2.1 - 3.7) ART-, CD4 > 5001.7** (0.4 - 6.9)3.3* (1.9 - 5.8) ART+, CD4 201 – 4993.8** (2.6 - 5.8)5.0* (4.1 - 6.2) ART-, CD4 201 – 4995.4** (2.5 - 11.6)5.6* (3.8 - 8.4) ART+, CD4 < 20021.9* (15.5 - 30.9)14.3* (11.5 - 17.8) ART-, CD4 < 20051.6* (30.7 - 86.9)30.8* (21.3 - 44.4) p value ART+ vs. ART- Fatal and Nonfatal HF Recent 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 0.330.51

11. 11 Hazard Ratio (95% CI) Fatal HFNonfatal HF NNRTI based regimen1.6 (0.9 – 2.9)1.2 (0.8 - 1.6) PI based regimen (reference) 11 Fatal and Nonfatal HF Medication Class p = Not Significant for both Fatal and Nonfatal HF

12. 12 nRate † < 1 year147535 1 – 2.9 years57512 3 – 3.9 years15366 4 – 4.9 years13381 ≥ 5 years51462 Fatal and Nonfatal HF Duration ART Use (unadjusted incidence rates) † †Cases per 100,000 person-years Includes data through 31DEC2008

13. 13 Adjusted HR 95% CIp Antiretroviral therapy use0.9(0.7 – 1.2)0.515 Recent CD4 ≤ 200 vs. > 2002.5(2.0 – 2.3)< 0.001 Nadir CD4 ≤ 200 vs. > 2001.5(1.2 – 2.0)0.003 HIV RNA ≥ 500 vs. < 5001.7(1.4 – 2.1)< 0.001 Ever alcohol or drug abuse1.6(1.3 – 2.0)< 0.001 Ever hepatitis B or C5.3(4.3 – 6.4)< 0.001 Diabetes1.9(1.4 – 2.5)< 0.001 Fatal and Nonfatal HF Adjusted 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.

14. 14  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  Antiretrovirals: –Antiretrovirals did not increase hepatic failure or hepatic related death rate –No antiretroviral class or duration effect was noted Discussion

15. 15  Strengths –HIV+ and HIV- from same health system –Large and population-based –Comprehensive HIV registries –Adjustment for hepatic failure risk factors  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

16. 16  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

17. 17  Kaiser Permanente Southern California Lanfang Xu, Chun Chao, Beth Tang, Hai Linh Kerrigan, Wansu Chen  Kaiser Permanente Northern California Wendy Leyden, Michael Silverberg, Michael Horberg, Leo Hurley, Charles Quesenberry, Jr., Amanda Charbonneau, Daniel Klein  Funding sources: Pfizer  Kaiser Permanente patients and providers Acknowledgements