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

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 Median Change in Fasting Lipids (Week 48, mg/dL) Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 59LB. Change in Calculated Creatinine Clearance, (mL/min) TCLDLHDLTG ABC/3TC ATV/r EFV P-value< < TDF/FTC ATV/r EFV P-value< < Week 48Week 96 ABC/3TC ATV/r EFV P-value TDF/FTC ATV/r EFV P-value0.001<0.001

A5224s * -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 (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) 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) % with ≥ 1 fractures 4.5% 4.7%3.4%4.3% Incidence per 100 pt-year A5224s

 No statistically significant differences between NRTI components and NNRTI/PI components (Fisher’s exact test) % Limb fat loss from 0 to 96 weeks 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) ≥ 10% Primary 14.3% (6.4%,25.3%) 15.6% (7.0%,28.6%) 18.9% (9.4%, 31.6%) 16.3% (7.5%,28.8%) 16.3% (11.8%, 22.0%) ≥ 20% Post hoc 8.9%0%3.8%6.1%4.9% 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)

 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 %) 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)  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, Abst ‡ p <0.001 * P =0.025 ‡‡ ‡ ‡ *  Raltegravir Group  Efavirenz Group Number of Contributing Patients Mean Percent (%) Change (SE) in Appendicular Fat Over Time

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

 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 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 Nov 15;49(10): ; Emery S, et al. 17th CROI; San Francisco, CA; February 16-19, 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 m 2, fall to <60  If baseline eGFR <60 mL/min/1.73 m 2, fall by 25%  225 (3.3%) progressed to CKD Risk factors for CKD on TDF: age, HTN, HCV, lower eGFR, lower CD4+ count Cumulative Exposure to ARVs and Risk of CKD Kirk O, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 107LB. UnivariableMultivariables IRR/year95% CIP-valueIRR/year95% CIP-value Tenofovir < < Indinavir < < Atazanavir < Lopinavir/r <

 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 * Indirectly standarized using rtes from NHAMCS-OPD data Dao C, et al. 17th CROI; San Francisco, CA; February 16-19, Abst Gender-adjusted rates of fracture among adults aged years HOPS* P = 0.01 NHAMCS-OPD P = 0.32

 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 Vitamin D Deficiency is Not Influenced By ART Mueller N, et al. 17th CROI; San Francisco, CA; February 16-19, Abst Baseline before cART Fall (n=108) Spring (n=103) Vitamin D Deficiency14%42% Insufficiency62%53% Target Level24% 5% 12 Months after cART Start Vitamin D Deficiency14%47% Insufficiency63%48% Target Level23% 5% 18 Months after cART Start Vitamin D Deficiency18%52% Insufficiency59%38% Target Level23%10% Deficiency <30 nmol/L Target ≥75 nmol/L

 Study of cancer risk in AIDS patients from (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 after AIDS onset increased for AIDS but also Non-AIDS defining cancers Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27. Cancer typeNo casesSIR95% CI AIDS-defining cancers Kaposi sarcoma Non-Hodgkin lymphoma Cervical cancer Non-AIDS-defining cancers Anal cancer Liver cancer Lung cancer Hodgkin lymphoma All non-AIDS related cancers

 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, Abst cases per 10,000 pt-yrs 15 cases per 10,000 pt-yrs

Berenguer, J. et al. Hepatology 2009;50: ; Berenguer, J, et al. 17th CROI; San Francisco, CA; February 16-19, Abst Factors Associated with Liver Related Events by Cox Regression Analysis Factor Adjusted HR (95% CI) P Non-SVR vs SVR 8.92 ( ).032 F3-F4 vs F0-F ( ).000 Geno 1-4 vs ( ).443 HCV RNA <500K IU/mL 0.73 ( ).444 CDC category C vs A/B 0.95 ( ).327 Nadir CD4 cells 0.99 ( ).319 Liver-related events include: liver-related death, lever decomposition, hepatocellular carcinoma, and transplantation Effect of non-SVR on Risk of New ADC and Non-Liver Related Death by Cox Regression Analysis HR (95% CI)P New ADC 3.60 ( ) 3.24 ( ) Non-liver- related death 3.50 ( ) 2.60 ( ) New ADC and non- liver- related death 3.30 ( ) 2.86 ( )  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 rs polymorphism in acute and chronic hepatitis C in HIV-positive patients C/CC/TT/T IL28B genotype P=0.008 %SVR HIV(-)/HCV(+) P=0.039 IL28B genotype HIV(+)/chronic hepatitis C C/CC/TT/T %SVR P=n.s. IL28B genotype HIV(+)/acute hepatitis C C/CC/TT/T %SVR Rauch A. 17th CROI; San Francisco, CA; February 16-19, Abst. 162; Natterman J, et al. ibid., Abst. 164; Rallon N, et al. ibid., Abst. 165LB.

Rs and SVRPredictors of SVR Rauch A. 17th CROI; San Francisco, CA; February 16-19, Abst. 162; Natterman J, et al. ibid., Abst. 164; Rallon N, et al. ibid., Abst. 165LB. P = P=0.009 P=0.002 P < HCV-RNA <500,000 IU/ml HCV Genotype 3 Rs CC Genotype Liver Fibrosis Stage F0-F2