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  Discuss pros and cons of deferred vs. early HAART in this population: Renal perspectives

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

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

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

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

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

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

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

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

Early treatmentDeferred treatment

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

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)

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

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

HIVAN Prevention and Treatment Dialysis-free Survival (%) (n=26) No ARV P = (0.025) ARV Treatment (n=10) Time (days) Hopkins Nephrology HIV Cohort ARV Treatment of HIVAN: Cases per 1000 person-years No Antiretroviral Therapy Nucleoside Reverse Transcriptase Inhibitor Therapy Highly Active Antiretroviral Therapy Presumed HIV-Associated Nephropathy Incidence Stratified by AIDS Status and Antiretroviral Use 0 Lucas GM, et al. AIDS. 2004;20:18(3): No AIDS Atta et al., Nephrol Dial Transpl, 2006 AIDS

Recommendations for Initiating ART in the US Symptomatic HIV diseaseAsymptomatic CD4<350 CD4>350 Rapid decline in CD4 count High risk of CVD Active hepatitis B or C coinfection HIVAN August, 2008

Risks of early HAART: Renal perspective

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

Hypertension in MACS Seaberg et al. AIDS 19, men HAART exposure >2 yrs associated w/ systolic HTN

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

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, Winston, et.al. HIV Med 7, 2006.

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

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

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

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

Hazard of CKD incidence Tenofovir Indinavir Atazanavir Lopinavir/r

Age and Kidney Function on Tenofovir 1031 HIV clinic patients on tenofovir th International Workshop on Clinical Pharmacology of HIV Therapy,Sorrento, Italy, 2010

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

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