BHIVA Best of CROI Feedback Meetings London Birmingham North West England Cardiff Gateshead Edinburgh BHIVA Best of CROI Feedback Meetings 2010
COMPLICATIONS OF HIV DISEASE AND TREATMENT
Overview Cardiovascular Lipodystrophy Renal Bone Neurocognitive impairment
DAD study: Impact of Triglycerides on risk of MI Relative risk was small and clinically insignificant Use of drugs unlikely to have any impact on the outcome Finding similar to general population Worm S, DAD study group, Abs: 127
Smoking cessation decreases MI risk: DAD Study
Cardiovascular disease Summary Elevated triglycerides associated with small increase in risk of MI but not clinically significant (DAD: Abs 127) Smoking cessation associated with decreased risk of MI but not mortality (DAD: Abs 124) HIV associated with increased atherosclerosis compared to HIV negative controls. HAART improves this but does not return to health. ( Abs: 125,126) See also session 33: Progression of atherosclerosis: role of inflammation and T cell activation (Abs 707-710)
EUROSIDA: Cumulative exposure to ARVs and risk of CKD - Multivariate analysis IRR/year 95% CI P-value Tenofovir 1.16 1.06-1.25 <0.0001 Indinavir 1.12 1.06-1.18 <0.0001 Atazanavir 1.21 1.09-1.34 0.0003 Lopinavir/r 1.08 1.09-1.16 0.003 Adjusted for: baseline egfr, AIDS, age, current CD4, HIV RNA, any cardiovascular event, nephrotoxic drugs, diabetes, hypertension, HCV, gender, non-aids malignancy No other ARVs or regimens associated with CKD Overall incidence of CKD: 1.1 (0.9-1.2)/ 100 PYFU CKD: egfr progression to <60 or 25% decrease if egfr <60 at baseline CROI Abs 107Lb
Change in Calculated Creatinine Clearance, (ml/min) A5202: Overall: As-Treated ATV/r vs. EFV Median Change in Creatinine Clearance Wk 48, p=0.17 Wk 96, p=0.33 Week 48 Week 96 Wk 48, p=0.001 Wk 96, p<0.001 p-values: ATV/r vs. EFV ATV/r ATV/r EFV EFV ABC/3TC TDF/FTC N= 377 330 338 287 394 352 360 327 CROI 2010 Abs 59 Lb
Fractional Excretion of Phosphate (%) 10 20 30 40 50 Plasma Phosphate (mg/dl) 2 3 4 5 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Plasma Phosphate (mmol/l) Abs 737 Plasma Phosphate Distribution by Proteinuria Classification Tubular or glomerula r pathology Number of patients Mean uacr (mg/m mol) [NR: < 3.5 mg/mm ol] Mean upcr (mg/m mol) [NR: < 30 mg/mm ol] Mean uacr/ upcr ratio (%) Tubular 3 20 144 14 Possible tubular Glomerul ar 3 40 116 34 12 163 207 79 Normal Normal Trivial Tubular Glomerular Proteinuria Classification Fractional Excretion of Phosphate by Proteinuria Classification Trivial Tubular Glomerular Proteinuria Classification 8 patients had a renal biopsy; all biopsy results correlated with our definitions of proteinuria Conclusions High upcr, low uacr, low plasma phosphate and high fractional excretion of phosphate are useful in identifying patients with tubular proteinuria In patients with heavy proteinuria measuring both upcr and uacr assists in diagnosing type of renal disease and identifies those in whom a renal biopsy may be useful
Mean Change Estimated GFR (ml/min; Cockcroft-Gault) Actual GFR (ml/min; Iohexol) Abs 58Lb: Renal Study of GS-9350 Without ARVs in Healthy Volunteers GS-9350 Alters Estimated GFR Not Actual GFR 30 20 10 0 Placebo GS-9350 150 mg 200 150 100-10 -20-30 Dosing 0 7 14 Day Study of GS-9350 (no ARVs) in healthy volunteers Administered GS-9350 or placebo for 7 days Measured serum creatinine and iohexol clearance concurrently GS-9350 is associated with lower estimated GFR Onset in days, reversible in days GS-9350 has no effect on actual GFR 50 0 BL GS-9350 Day 7 Day 14 BL Placebo n=12 n=12 Day 7 Day 14
Renal Summary Exposure to Indinavir, Tenofovir and Atazanavir associated with increased risk of CKD (EUROSIDA) Abs 107 Lb Atazanavir/r +FTC/TDF associated with decreased egfr (Abs 59Lb) Gilead enhancer (GS 9350) associated with decreased egfr but no change in true GFR.Abs 58Lb Measurement of up/c and ualb/c helpful in differentiation between tubular and glomerular disease (Abs 737)
% 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% 15.6% 18.9% 16.3% (7.5%,28.8%) 16.3% (6.4%,25.3%) (7.0%,28.6%) (9.4%, 31.6%) (11.8%, 22.0%) 20% Post hoc 8.9% 0% 3.8% 6.1% 4.9% No statistically significant differences between NRTI components and NNRTI/PI components (Fisher s exact test) CROI 2010 Abs 106Lb A5224s
* * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.82) A5224s
* * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.95) A5224s
Lipodystrophy ACTG 5224S main findings: 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 CROI 20210: Abs 106Lb
* * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.63) CROI 2010: Abs 106Lb) 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) TDF/FTC+ EFV (n=464) TDF/FTC+ ATV/r (n=465) ABC/3TC+E FV (n=465) ABC/3TC+A TV/r (n=463) Total (n=1857) % with 1 fractures 4.5% 4.5% 4.7% 3.4% 4.3% Incidence per 100 pt-year 1.8 1.8 1.9 1.4 1.7 A5224s
HOPS: prospective cohort study in 10 clinics in 8 cities in USA : Started in 1993 Over 5800 patients followed from 2000 to 2008 246 (4%) had fracture Median age 45 years 76% were male Age over 47, Nadir CD4, diabetes and Hep-C predicted fracture Crude rates of fractures (95% CI) amng HOPS patients 200 175 150 125 100 75 50 No data on BMD Increase fracture could be due to increased awareness or patients living longer 25 0 2000 2002 2004 2006 2008 Dao C et al, abs:128
Fragility fracture common in HIV patients VACS: prospective observational study From 1997 to 2009 (ICD9) Restricted to male Median age 54 Over 119,000 and 34% were HIV positive Older age, CVA, alcohol use, Black ethnicity and cachexia were predictable factors
Bone Summary HIV infection associated with increased fracture rate (HOPS, Abs: 128) Fractures more common in male with older age group (VACS, Abs:129) Fracture rates not increased in younger HIV +ve woman (Abs: 130 WIHS) No difference in incidence of fractures between FTC/TDF and ABC/3TC and between ATV/r and EFV, though significant difference in BMD between NRTI backbone (ACTG 5224S, Abs 106Lb)
Neurology
CHARTER study: Correlates of CSF viral load N: 1221, 31% not on ART, 78% with CSF and plasma VL, crossectional analysis Higher plasma viral load strongest correlate of higher CSF VL both on and off ART Off ART: high CSF viral load associated with older age, lower CD4 count and lower nadir CD4 count. On ART: detectable CSF VL associated with poor adherence, lower CPE score of ART, CD4 count <200 and non-white ethnicity Higher CSF viral load alone not associated with worse NP performance CSF VL greater than plasma viral load (13%) was associated with worse NP performance. On ART with plasma VL <50, only 4% had detectable CSF VL and not correlated with clinical outcome Letendre S, abs:172
Higher CD-4 nadir associated better cognitive performance: to consider starting early treatment: CHARTER Study Ellis R, abs:429
Neurology issues: Summary CHARTER study Compared to CD4 nadir <50, higher nadir CD-4 is associated with reduced risk of HAND: CD4 nadir >350, OR: 0.62 (0.45-0.84) (Abs: 429) Plasma viral suppression correlates with CSF viral suppression. With ART detectable CSF viral load associated with poor adherence, worse CPE and white ethnicity: cross-sectional study (n=1221) (Abs: 172) Similar findings: Stable ART and good CNS penetration associated with better NP performance (Abs:432 and 433)
CPE revised ranks and CSF detectable viral load Revised CPE table, 2010 CSF viral load as such was not predictive But CSF viral load above or equal to plasma VL had worse NP performance Letendre S, abs:172
BHIVA Best of CROI Feedback Meetings London Birmingham North West England Cardiff Gateshead Edinburgh BHIVA Best of CROI Feedback Meetings 2010