Pablo Tebas, MD 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 A5224s A5224s A5224s TC LDL HDL TG 29 13 8 24 ABC/3TC ATV/r 40 Lipids (Week 21 48, mg/dL) 12 Median Change in Fasting 15 <0.001 0.002 <0.001 0.26 ATV/r 10 2 5 14 EFV 22 10 8 13 <0.001 0.002 <0.001 0.26 EFV P-value TDF/FTC P-value 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) Week 48 Week 96 ATV/r 3.1 6.1 EFV 4.3 7.8 P-value 0.17 0.33 ATV/r -0.9 -2.6 EFV 4.1 4.9 0.001 <0.001 ABC/3TC TDF/FTC P-value Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB. * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.63) A5224s * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.69) A5224s 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) % with ≥ 1 fractures Incidence per 100 pt-year TDF/FTC +EFV (n=464) TDF/FTC +ATV/r (n=465) ABC/3TC +EFV (n=465) ABC/3TC +ATV/r (n=463) Total (n=1857) 4.5% 4.5% 4.7% 3.4% 4.3% 1.8 1.8 1.9 1.4 1.7 A5224s % Limb fat loss from 0 to 96 weeks ≥ 10% Primary ≥ 20% Post hoc TDF/FTC +EFV (n=56) TDF/FTC +ATV/r (n=45) ABC/3TC +EFV (n=53) ABC/3TC +ATV/r (n=49) Total (n=203) 14.3% 15.6% 18.9% 16.3% (7.5%,28.8%) 16.3% (6.4%,25.3%) (7.0%,28.6%) (9.4%, 31.6%) 8.9% 0% 3.8% (11.8%, 22.0%) 6.1% 4.9% No statistically significant differences between NRTI components and NNRTI/PI components (Fisher’s exact test) A5224s * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.67) A5224s * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.66) A5224s 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 Randomized, double-blind study comparing RAL vs EFV, both with TDF/FTC Week 96 lipids (all pts, n=563) ‡ ‡ ‡ p <0.001 * P =0.025 ‡ 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 DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 720. Raltegravir Group 55 Efavirenz Group 56 ‡ * Mean Percent (%) Change (SE) in Appendicular Fat Over Time 18.1 18.2 17.7 Number of Contributing Patients 40 46 17.0 37 38 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 HIV + Suppressed on 2 NRTI + PI or NNRTI (N=357) T DF/FTC FDC n=179 ABC/3TC FDC n=178 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 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. 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 Univariable Multivariables IRR/year 95% CI P-value IRR/year 95% CI P-value Tenofovir 1.32 1.21-1.41 <0.0001 1.16 1.06-1.25 <0.0001 Indinavir 1.18 1.13-1.24 <0.0001 1.12 1.06-1.18 <0.0001 Atazanavir 1.48 1.35-1.62 <0.0001 1.21 1.09-1.34 0.0003 Lopinavir/r 1.15 1.07-1.23 <0.0001 1.08 1.01-1.16 0.030 • 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. Comparison of HOPS cohort (n=8456) vs National Hospital Discharge Survey and National Hospital Ambulatory Care Medical Survey Adjusted for age and gender Gender-adjusted rates of fracture among adults aged 25-54 years HOPS* P = 0.01 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 * Indirectly standarized using rtes from NHAMCS-OPD data Dao C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 128. NHAMCS-OPD P = 0.32 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 Mueller N, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 752. Fall (n=108) Spring (n=103) 14% 42% Insufficiency 62% 53% Target Level 24% 5% 14% 47% Insufficiency 63% 48% Target Level 23% 5% 18% 52% Insufficiency 59% 38% Target Level 23% 10% Baseline before cART Vitamin D Deficiency 12 Months after cART Start Vitamin D Deficiency 18 Months after cART Start Vitamin D Deficiency Deficiency Target <30 nmol/L ≥75 nmol/L Cancer type 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. No cases SIR 95% CI Kaposi sarcoma 3136 5321 5137 - 5511 Non-Hodgkin lymphoma 3345 32 31 - 33 Cervical cancer 101 5.6 5.5 - 6.8 AIDS-defining cancers Non-AIDS-defining cancers Anal cancer 219 27 24 - 31 Liver cancer 86 3.7 3.0 - 4.6 Lung cancer 531 3.0 2.8 - 3.3 Hodgkin lymphoma 184 9.1 7.7 - 11 All non-AIDS related cancers 2155 1.7 1.5 - 1.8 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 Sigel K, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 30. 26 cases per 10,000 pt-yrs 15 cases per 10,000 pt-yrs Factors Associated with Liver Related Events by Cox Regression Analysis Effect of non-SVR on Risk of New ADC and Non-Liver Related Death by Cox Regression Analysis Factor Adjusted HR (95% CI) P Non-SVR vs SVR 8.92 (1.20-66.11) .032 F3-F4 vs F0-F2 4.96 (2.27-10.85) Geno 1-4 vs 2-3 1.35 (0.63-2.88) .443 HCV RNA <500K IU/mL 0.73 (0.33-1.62) .444 CDC category C vs A/B 0.95 (0.49-1.87) .327 Nadir CD4 cells 0.99 (0.99-1.00) 0 1 10 New ADC .000 .319 Non-liverrelated death New ADC and nonliverrelated death 0 1 100 Liver-related events include: liver-related death, lever decomposition, hepatocellular carcinoma , and transplantation Berenguer, J. et al. Hepatology 2009;50:407-413; Berenguer, J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 167. 10 HR (95% CI) P 3.60 (1.14-9.21) .008 3.24 (1.08-9.74) .06 3.50 (1.22-10.0) .019 2.60 (1.63-6.68) .135 3.30 (1.63-6.68) .001 2.86 (1.24-6.55) .013 Crude Adjusted 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 100 P=n.s. 100 P=0.039 P=0.008 75 %SVR 75 %SVR HIV(-)/HCV(+) 100 50 75 %SVR 50 50 25 25 25 0 0 0 C/C C/T T/T IL28B genotype C/C C/T T/T 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. C/C C/T T/T IL28B genotype 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 Rs12979860 CC Genotype Liver Fibrosis Stage F0-F2 P <0.001 3.7 P=0.002 3.5 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.