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The Double-Edged Sword: Long-Term Complications of ART and HIV

The Double-Edged Sword: Long-Term Complications of ART and HIV. Kidney conundrums: HIV and renal disease Mohamed G. Atta, MD, MPH Johns Hopkins Baltimore, MD, USA. Objectives. Review implications of kidney disease in HIV infected individuals

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The Double-Edged Sword: Long-Term Complications of ART and HIV

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  1. The Double-Edged Sword: Long-Term Complications of ART and HIV Kidney conundrums: HIV and renal disease Mohamed G. Atta, MD, MPH Johns Hopkins Baltimore, MD, USA

  2. Objectives • Review implications of kidney disease in HIV infected individuals • Discuss pros and cons of deferred vs. early HAART in this population: Renal perspectives

  3. Multivariate Hazard Ratios for primary outcome in HOPE Adapted from the HOPE study: N Engl J Med 2000, 342: 145-153

  4. All-cause and cardiovascular mortality according to eGFR and categorical albuminuria 105,872 from 14 studies 1, 128,310 from 7 studies Chronic Kidney Disease Prognosis Consortium, Lancet, May 18, 2010

  5. Kidney Function and the Risk of Cardiovascular Events in HIV-1 Infected Patients • Nested, matched, case-control study • 315 HIV-infected patients (63 cases who had cardiovascular events and 252 controls). • eGFR (CKD-EPI formula/MDRD), and proteinuria were the primary exposures of interest George et. al AIDS, January 2010

  6. Kidney Function and the Risk of Cardiovascular Events in HIV-1 Infected Patients • eGFR of <60: unadjusted OR 15·9 for cardiovascular event (p<0·001). • Adjusted OR (eGFR 10 ml/min ): 1.2 (95% CI 1·1–1·4) for cardiovascular event • Prevalence of proteinuria: 51% in cases vs. 25% in control, p<0·001). • Proteinuria: unadjusted OR 3·6 (95% CI 1·9–7·0) and adjusted OR 2·2 (95% CI 1·1–4·8). George et. al AIDS, January 2010

  7. Relationship between eGFR and cardiovascular event status HIV-1 infected patients Mean eGFR was 68·4 in cases vs. 103·2 ml/min, in control p<0·001 George et. al AIDS, January 2010

  8. VA study of 17,264 patients • 1194 with eGFR < 60 (MDRD) • GFR by MDRD • Urine albumin by dipstick • Outcome: • 1) Incident CVD, defined as coronary, cerebrovascular, or peripheral arterial disease, and • 2) Incident heart failure

  9. Incident event rates stratified by eGFR and Dipstick Proteinuria  eGFR =  Event rates  Events with  albuminuria Choi et al, Circulation, January 2010

  10. Microalbuminuria Is Associated With All-Cause Mortality in women 1547 HIV-infected women (WIHS) No albuminuria Unconfirmed albuminuria Confirmed microalbuminuria Confirmed proteinuria Wyatt et al. JAIDS 2010

  11. Deferred treatment Early treatment

  12. HIVAN: Pathogenesis • Direct role of HIV-1 in the development of HIVAN • Transgenic mouse models • Detection of HIV-1 RNA and DNA in renal epithelial cells • Reports of clinical and pathological reversal of HIVAN w/ HAART

  13. HIVAN:“Classic” clinical characteristics • Exclusive disease of Africans • Proteinuria (often nephrotic range) • Atta et al. Am J Med, 2005 • Detectable viremia or detectable Proviral DNA • Estrella et al. Clin Infect Dis 2006 • Izzedine et al. NDT (July, 2010) • Normal size echogenic kidneys on ultrasound • Atta et al. J Ultrasound Med, 2004 • Progressive renal failure (weeks to months)

  14. Genome-wide admixture analysis and chromosome 22 gene localization (Kopp Nature Genetics 2008)

  15. Frequencies of the candidate genotypes for the MYH9 SNPs (Kopp et al. Nature Genetics 2008)

  16. HIVAN Prevention and Treatment 100 Presumed HIV-Associated Nephropathy Incidence Stratified by AIDS Status and Antiretroviral Use 75 45 No Antiretroviral Therapy 40 Nucleoside Reverse Transcriptase Inhibitor Therapy 35 50 30 Highly Active Antiretroviral Therapy 25 Cases per 1000 person-years 20 25 ARV Treatment (n=26) 15 10 No ARV (n=10) 5 P = (0.025) 0 0 0 3000 0 1000 2000 Time (days) Hopkins Nephrology HIV CohortARV Treatment of HIVAN: Dialysis-free Survival (%) 26.3 14.4 6.8 5 2.6 No AIDS AIDS Lucas GM, et al. AIDS. 2004;20:18(3):541-546. Atta et al., Nephrol Dial Transpl, 2006

  17. Recommendations for Initiating ART in the US August, 2008

  18. Risks of early HAART:Renal perspective

  19. Diabetes in Multicenter AIDS Cohort Study DM incidence 4x more in HIV-+ individuals on HAART PIs associated w/ 3-fold increase risk in DM • Impaired glucose-sensing by β-cells • Glut-4 transporter inhibition • Increased insulin resistance • HCV co-infection? Brown et.al. Arch Intern Med 165, 2005. Brown et al Arch Intern Med. 2005, Koster et.al. Diabetes 52, 2003. Murata et.al. J Bio Chem 275, 2000. Justman et.al. JAIDS 32, 2003. Visnegarwala et.al. J Infection 50,2005.

  20. Hypertension in MACS 5578 men 1984-2003 HAART exposure >2 yrs associated w/ systolic HTN Seaberg et al. AIDS 19, 2005.

  21. Crystalluria and stone formation A: Kopp, J. Ann Intern Med 1997; B: courtesy of Perazella M, Yale University. • Indinavir • Atazanavir Indinavir crystals Atazanivir crystals Couzigou et al. CID 2007

  22. Tenofovir renal toxicity Acute renal failure Fanconi syndrome Nephrogenic diabetes insipidus . . . Chronic kidney disease? Atta et al. Seminars in Nephrology, 6, 2008 Izzedine et.al. AJKD 45, 2005. Winston, et.al. HIV Med 7, 2006.

  23. Model of organic anion transporters in kidney proximal tubule Russel et al. Annu. Rev. Physiol. 2002. 64:563–94

  24. Blood Urine Courtesy of Gilbert Deray Pierre et Marie Curie University, Paris, France

  25. Chronic kidney disease and antiretroviral drug use in HIV-positive patients 3.3% over a median follow-up of 3.7 Mocroft et al. AIDS 2010, EuroSIDA Study Group

  26. Incidence of CKD and increasing exposure to antiretrovirals Mocroft et al. AIDS 2010, EuroSIDA Study Group

  27. Hazard of CKD incidence • Tenofovir 1.16 1.06-1.25 • Indinavir 1.12 1.06-1.18 • Atazanavir 1.21 1.09-1.34 • Lopinavir/r 1.08 1.01-1.16 Mocroft et al. AIDS 2010, EuroSIDA Study Group

  28. Age and Kidney Function on Tenofovir 1031 HIV clinic patients on tenofovir 2002-2009 300 11th International Workshop on Clinical Pharmacology of HIV Therapy,Sorrento, Italy, 2010

  29. Suggested Recommendations • No evidence of benefit from the renal standpoint for early HIV treatment. • In treated or untreated HIV, • Screen all patients with GFR/urine protein/albumin • For high risk patients, monitor kidney disease regularly • For those with (non HIVAN) kidney disease, new studies are needed to determine benefits

  30. Acknowledgements • Derek M. Fine, USA • Gregory M. Lucas, USA • Michelle Estrella, USA • Joel Gallant, USA • Richard Moore, USA • Hassane Izzedine, France • Gilbert Deray, France • Elizabeth George, India

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