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
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Objectives
 Review implications of kidney
disease in HIV infected individuals
 Discuss pros and cons of deferred
vs. early HAART in this population:
Renal perspectives
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Multivariate Hazard Ratios for primary outcome in
HOPE
Microalbuminuria
1.59
CAD
1.51
Diabetes
1.42
Cr.>1.4mg/dl
1.4
1.2
Male
1.03
Age
0.79
Ramipril
0
1
Hazard Ratio
Adapted from the HOPE study: N Engl J Med 2000, 342: 145-153
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2
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
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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
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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
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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
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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
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Incident event rates stratified by eGFR and Dipstick
Proteinuria
 eGFR =  Event rates
 Events with  albuminuria
Choi et al, Circulation, January 2010
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Microalbuminuria Is Associated With AllCause Mortality in women
1547 HIV-infected women (WIHS)
No albuminuria
Unconfirmed albuminuria
Confirmed microalbuminuria
Confirmed proteinuria
Wyatt et al. JAIDS 2010
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Deferred treatment
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Early 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
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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)
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Genome-wide admixture analysis and chromosome 22 gene
localization (Kopp Nature Genetics 2008)
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Frequencies of the candidate genotypes for the
MYH9 SNPs (Kopp et al. Nature Genetics 2008)
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HIVAN Prevention and Treatment
45
No Antiretroviral
Therapy
Cases per 1000 person-years
40
Nucleoside Reverse
Transcriptase
Inhibitor Therapy
35
30
Highly Active
Antiretroviral
Therapy
25
20
26.3
15
Hopkins Nephrology HIV Cohort
ARV Treatment of HIVAN:
75
50
25
ARV
Treatment
14.4
10
5
0
100
Dialysis-free Survival (%)
Presumed HIV-Associated
Nephropathy Incidence Stratified by
AIDS Status and Antiretroviral Use
2.6
No AIDS
5
6.8
0
AIDS
Lucas GM, et al. AIDS. 2004;20:18(3):541-546.
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0
0
No
(n=10)
ARV
(n=26)
P = (0.025)
1000
2000
Time
(days)
Atta et al., Nephrol Dial Transpl, 2006
3000
Recommendations for Initiating ART in the US
Symptomatic HIV disease
Asymptomatic
• CD4<350
• CD4>350
• Rapid decline in CD4 count
• High risk of CVD
• Active hepatitis B or C coinfection
• HIVAN
August, 2008
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Risks of early HAART:
Renal perspective
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 glucosesensing 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.
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Hypertension in MACS
5578 men 1984-2003
HAART exposure >2 yrs associated w/ systolic HTN
Seaberg et al. AIDS 19, 2005.
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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
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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.
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Model of organic anion transporters in kidney
proximal tubule
Russel et al. Annu. Rev. Physiol. 2002. 64:563–94
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Blood
Urine
Courtesy of Gilbert Deray
Pierre et Marie Curie University, Paris, France
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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
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Incidence of CKD and increasing exposure to
antiretrovirals
Mocroft et al. AIDS 2010, EuroSIDA Study Group
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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
Age and
Kidney 500
Function on1000
Tenofovir 1500
0
1031 HIV clinic patients on tenofovir 2002-2009
150
days on tenofovir
Age 30-45
100
110
120
130
140
Age<30
Age>45
0
300
500
1000
1500
2000
2500
days on tenofovir
11th International Workshop on Clinical Pharmacology of HIV Therapy,Sorrento, Italy, 2010
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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
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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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