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Complications, Adverse Events and comorbidities

Pablo Tebas, MD. Complications, Adverse Events and comorbidities. Most relevant studies. ACTG 5202/5224s STARTMRK Metabolic Study STEAL (abacavir and inflammatory markers) EUROSIDA and risk of CKD HOPS and risk of fractures Vitamin D studies Cancer studies Hepatitis.

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Complications, Adverse Events and comorbidities

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  1. Pablo Tebas, MD Complications, Adverse Events and comorbidities

  2. Most relevant studies • ACTG 5202/5224s • STARTMRK Metabolic Study • STEAL (abacavir and inflammatory markers) • EUROSIDA and risk of CKD • HOPS and risk of fractures • Vitamin D studies • Cancer studies • Hepatitis

  3. A5224s design: Metabolic substudy of A5202 A5224s

  4. A5224s design: Metabolic substudy of A5202 A5224s

  5. A5224s design: Metabolic substudy of A5202 A5224s

  6. LIPIDSA5202: ATV/r vs. EFVMedian Changes in Fasting Lipids and Creatinine Clearance Median Change in Fasting Lipids (Week 48, mg/dL) • In low HIV RNA stratum, in comparison between ABC/3TC vs. TDF/FTC: significantly greater increase in TC, LDL, HDL with both EFV and ATV/r; greater increase in TG with ATV/r Change in Calculated Creatinine Clearance, (mL/min) Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

  7. BONESMean (95% CI) percent change in lumbar spine BMD (ITT) * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.63) A5224s

  8. BONESMean (95% CI) percent change in hip BMD (ITT) * * A5224s * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.69)

  9. Bone fractures • A5224s (n=269) • 5.6% had ≥ 1 fracture (all traumatic) • No statistically significant differences between NRTI components or NNRTI/PI components in fracture rate (Fisher’s exact) or time to first fracture (log-rank test) • A5202 (n=1857) • 4.3% fracture rate (12.7% of those atraumatic) • No statistically significant differences between NRTI components or NNRTI/PI components in fracture rate (Fisher’s exact), incidence or time to first fracture (log-rank test) A5224s

  10. FATProportion of subjects with ≥ 10% and ≥ 20% limb fat loss (ITT, primary endpoint) • No statistically significant differences between NRTI components and NNRTI/PI components (Fisher’s exact test) A5224s

  11. FATMean (95% CI) absolute change in limb fat (ITT) * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.67) A5224s

  12. FATMean (95% CI) absolute change in trunk fat(ITT) * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.66) A5224s

  13. Conclusions • Bone • All regimens appeared to produce an initial bone loss with subsequent stabilization or even improvement after week 48 • TDF/FTC led to greater BMD loss in hip and lumbar spine than ABC/3TC • ATV/r led to greater BMD loss in lumbar spine (but not hip) than EFV • Fractures were similarly distributed among study arms • Fat • Regimens containing TDF/FTC or ABC/3TC increased limb fat and trunk fat and were not significantly different • ATV/r led to greater gain in limb fat and trunk fat than EFV • Lipoatrophy, even the mild protocol-defined form, occurred in 16% (95% CI 12-22 %) of the participants and was not significantly different between TDF/FTC and ABC/3TC or between EFV and ATV/r A5224s

  14. STARTMRK Metabolic Study: RAL vs EFV ‡ ‡ • Randomized, double-blind study comparing RAL vs EFV, both with TDF/FTC • Week 96 lipids (all pts, n=563) • EFV increased TC, HDL-C, LDL-C, TG, and glucose sig more than EFV • No sig difference in total/HDL chol ratio • Dexa substudy (n=111) • Overall, limb fat increased over time • By week 96, 3/37 pts on RAL, 2/38 on EFV had >20% loss of limb fat ‡ p <0.001 * P =0.025 ‡ ‡ * Mean Percent (%) Change (SE) in Appendicular Fat Over Time 18.1 18.2 17.7 17.0 Number of Contributing Patients • Raltegravir Group 55 40 37 • Efavirenz Group 56 46 38 DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 720.

  15. The abacavir wars… Quebec nested case control 125 MIs 1084 Control Mild association VA cohort 19424 patients 278 MIs No association with ABC Bedimo et al. MOAB202 Durand et al. TUPEB175

  16. Primary Results: Similar virologic results Increased risk of CV events in ABC/3TC group (8 ABC/3TC vs 1 TDF/FTC, p=0.48) not explained by lipid changes No difference in renal outcomes Loss of bone density in TDF/FTC vs gain in ABC/3TC group Inflammatory Marker Substudy 14 biomarkers (inflammatory/renal, thrombotic, endothelial function) measured at weeks 0, 12, 24, and 48 Primary analysis (change from week 0-12): No significant association between use of ABC/3TC and change in markers Alternative explanation for ABC/3TC association with CVD needed STEAL: Switch to ABC/3TC or TDF/FTC HIV + Suppressed on 2 NRTI + PI or NNRTI (N=357) T DF/FTC FDC n=179 ABC/3TC FDC n=178 Martin A, et al. Clin Infect Dis. 2009 Nov 15;49(10):1591-601; Emery S, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 718.

  17. EuroSIDA Study:Risk for Chronic Kidney Disease • Analysis of patients with ≥3 creatinine measurements + body weight, 2004 • 6,842 patients with 21,482 person-years of follow-up • Definition of CKD (eGRF by Cockcroft-Gault) • If baseline eGFR ≥60 mL/min/1.73 m2, fall to <60 • If baseline eGFR <60 mL/min/1.73 m2, fall by 25% • 225 (3.3%) progressed to CKD Cumulative Exposure to ARVs and Risk of CKD • Risk factors for CKD on TDF: age, HTN, HCV, lower eGFR, lower CD4+ count Kirk O, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 107LB.

  18. Increased Fracture Rate in HIV Outpatient Study Patients (HOPS) Gender-adjusted rates of fracture among adults aged 25-54 years • Comparison of HOPS cohort (n=8456) vs National Hospital Discharge Survey and National Hospital Ambulatory Care Medical Survey • Adjusted for age and gender • Fractures: 276 during median 4.8 yrs follow-up • Risk factors for fractures • Age >47 • Nadir CD4+ count <200 • HCV co-infection • Diabetes • Substance use • Conclusion: Fracture rates are higher in HIV infected population and rate is increasing with age HOPS* P = 0.01 NHAMCS-OPD P = 0.32 * Indirectly standarized using rtes from NHAMCS-OPD data Dao C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 128.

  19. High Prevalence of Vitamin D Deficiency in HIV Infection Vitamin D Deficiency is Not Influenced By ART • Retrospective seasonal analysis of Vitamin D deficiency within Swiss cohort • Started ARV in: Fall (n=108); Spring (n=103) • 75% men; age = 37; White = 87%; CD4+ 227; BMI = 22.9 • ARVs: TDF – 17%; NNRTIs – 43%; PI -56% • Conclusions • Vitamin D deficiency is common, but seasonal • Blacks are at increased risk • NNRTI use a risk factor Deficiency <30 nmol/L Target ≥75 nmol/L Mueller N, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 752.

  20. Cancer Incidence in AIDS patients • Study of cancer risk in AIDS patients from 1980-2006 (n=372,364) • Predominantly male (79%), non-hispanic black (42%), MSM (42%) • Median age of 36 years at the onset of AIDS • Cancer risk in years 3 - 5 after AIDS onset increased for AIDS but also Non-AIDS defining cancers Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  21. HIV infection and Lung Cancer 26 cases per 10,000 pt-yrs • VA-Cohort (3,707 HIV-positive patients) • Predominantly male (98%), white (43%) • Median age of 47 years • Lung cancer risk factors • smoking and drug abuse more often among HIV+ • Similar rates of COPD 15 cases per 10,000 pt-yrs Sigel K, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 30.

  22. Effect of non-SVR on Risk of New ADCand Non–Liver-Related Death 0 1 10 • Crude • Adjusted 0 1 10 100 Berenguer, J. et al. Hepatology 2009;50:407-413; Berenguer, J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 167.

  23. IL-28B Genotypes and SVR Rates • Recent studies demonstrate polymorphisms near interleukin 28 B (IL28B) gen predict sustained virological response (SVR) to treatment with Peg-IFN + RBV in HCV-monoinfected pts harboring genotype 1 • Study assessing potential role of theIL-28B treatment induced clearance of rs12979860 polymorphism in acute and chronic hepatitis C in HIV-positive patients HIV(+)/acute hepatitis C HIV(+)/chronic hepatitis C HIV(-)/HCV(+) 100 100 100 P=n.s. P=0.039 P=0.008 75 75 75 %SVR %SVR %SVR 50 50 50 25 25 25 0 0 0 C/C C/T T/T C/C C/T T/T C/C C/T T/T IL28B genotype IL28B genotype IL28B genotype Rauch A. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 162; Natterman J, et al. ibid., Abst. 164; Rallon N, et al. ibid. , Abst. 165LB.

  24. Predictors of SVR in HIV/HCV Co-Infection Rs12979860 and SVR Predictors of SVR P = 0.684 11.9 HCV-RNA<500,000 IU/ml P <0.001 8.0 HCV Genotype 3 P <0.001 3.7 Rs12979860CC Genotype P=0.002 3.5 Liver Fibrosis Stage F0-F2 P=0.009 Rauch A. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 162; Natterman J, et al. ibid., Abst. 164; Rallon N, et al. ibid. , Abst. 165LB.

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