Transcript Dr. M Harris` Lecture on HIV/AIDS

HIV and the Kidney
Marianne Harris, MD, CCFP
Clinical Assistant Professor, Dept. of Family Practice
Associate Member, Division of AIDS, Dept. of Medicine
Faculty of Medicine, UBC
Depletion of circulating CD4+ T Cells results in
progressive immune deficiency
Targets for HIV Inhibition
Non-Nucleoside
Reverse Transcriptase
Inhibitors
(NNRTIs)
Protease
Inhibitors
Entry
Inhibitors
Nucleoside Reverse
Transcriptase Inhibitors
(NRTIs)
Maturation
Inhibitors
Integrase
Inhibitors
HIV Prophylaxis
• HAART to HIV-negative individuals
• Pre-exposure prophylaxis (PrEP)
• Post-exposure prophylaxis (PEP)
Four Prevention Opportunities
Cohen et al, JCI, 2008
Cohen IAS 2008
UNEXPOSED
EXPOSED
(precoital/coital)
Behavioral,
Structural
Vaccines
ART PrEP
EXPOSED
INFECTED
(postcoital)
Microbicides
Vaccines
ART PEP
HOURS
72h
Treatment Of HIV
Reduced Infectivity
Circumcision
Condoms
YEARS
From M Cohen, MD, at New York, NY: April 5, 2011, IAS–USA.
YEARS
Treatment as Prevention (TasP)
• Giving highly active antiretroviral therapy
(HAART) to HIV+ individuals
• Reduces amount of HIV (viral load) in plasma
and other body fluids, rendering that person
less infectious and therefore less likely to
transmit HIV to others
• Mother to child
• Injection drug use (IDU)
• Sexual transmission
Adults and children estimated to be living
with HIV2013
Eastern Europe &
Central Asia
North America and Western and Central Europe
2.3 million
1.1 million
[980 000– 1.3 million]
[2.0 million – 3.0 million]
Middle East & North Africa
Caribbean
250 000
[230 000 – 280 000]
Latin America
1.6 million
[1.4 million – 2.1 million]
230 000
[160 000 – 330 000]
Asia and the Pacific
4.8 million
Sub-Saharan Africa
[4.1 million – 5.5 million]
24.7 million
[23.5 million – 26.1 million]
Total: 35.0 million [33.2 million – 37.2 million]
http://www.unaids.org.
HIV in Canada
• 71,300 Canadians living with HIV in 2011
• 47% men who have sex with men
• 33% heterosexual
• 17% people who inject drugs
• 23% women
• 9% aboriginal (vs. 4% of Canadian population)
HIV and AIDS in Canada: Surveillance Report to Dec. 31, 2012
Public Health Agency of Canada. www.phac-aspc.gc.ca
Number of new HIV positive test
reports in Canada, by year
Public Health Agency of Canada. www.phac-aspc.gc.ca
Age group distribution of positive HIV test
reports in Canada, 1985-2012
Public Health Agency of Canada. www.phac-aspc.gc.ca
Mother-to-Child Transmission
HIV+ Birth
1
1
Rate (per 100,000 population) of
positive HIV test reports: 2012
Canada: 5.9 per 100,000 population
HIV and AIDS in Canada: Surveillance Report to Dec. 31, 2012
Public Health Agency of Canada. www.phac-aspc.gc.ca
HIV Diagnoses by Region and Year
Public Health Agency of Canada
Hogg et al, HIV Medicine, 14, 581-2, 2013
New HIV Diagnoses in BC 1996-2012
238
29
2012
Updated from Montaner et al, Lancet, 2010
BC: All Cause
Mortality (#)
All Cause Mortality in BC
400
350
300
Frequency
250
200
HAART
TasP
150
100
50
0
1996
1997
1998
1999
2000
2001
2002
2003
2004
Years
2005
2006
2007
2008
2009
2010
2011
Montaner et al, PLOS One, Feb 12th 2014
Figure 2. Mid-point life expectancy estimates at age 20 years in three calendar periods, overall and
by sociodemographic characteristics, 2000–2007.
Samji H, Cescon A, Hogg RS, Modur SP, Althoff KN, et al. (2013) Closing the Gap: Increases in Life Expectancy among Treated
HIV-Positive Individuals in the United States and Canada. PLoS ONE 8(12): e81355. doi:10.1371/journal.pone.0081355
http://127.0.0.1:8081/plosone/article?id=info:doi/10.1371/journal.pone.0081355
The Cascade of Care over time in BC
Modified from Nosyk et al, Lancet ID, Oct 2013
www.unaids.org
www.cfenet.ubc.ca
Benefits of antiretroviral therapy (ART)
• Treatment as prevention is a secondary benefit
• Prevent progression of HIV disease to AIDS
– preserve/restore immune function
• Prevent morbidity and mortality due to “nonAIDS” disorders, associated with current and/or
nadir CD4
–
–
–
–
Cardiovascular disease
Liver, kidney, and bone disease
Neurocognitive disorders
Cancers
ART side effects
CVD
Bone
Kidney
Neurocognitive
Chronic inflammation
Chronic Kidney Disease
(CKD) in HIV
• CKD is becoming more common in HIV, and in the
general population
• Related to aging and other risk factors
• People with HIV develop CKD at a younger age, and
are more likely to have rapid progression and
complications
• People with one or more risk factors for CKD are
more likely to develop kidney injury from drugs
(nephrotoxicity)
CKD Stages
Stage
eGFR (mL/min/1.73m2)
Description
I
Kidney damage with
normal or increased GFR
>90
II
Kidney damage with mild
decrease in GFR
60-89
III
Moderate decrease in GFR
30-59
IV
Severe decrease in GFR
15-29
V
Kidney failure
<15 or dialysis
CKD definition: eGFR <60 that persists for >3 months, OR
evidence of kidney damage (eGFR may be normal)
Kidney damage = pathologic abnormalities or markers of damage,
e.g. urine test results or imaging
K/DOQI Clinical practice guidelines for CKD
Am J Kidney Dis 2002.
Chronic Kidney Disease (CKD) in HIV
• Unrelated to HIV
– Diabetes
– High blood pressure
– Hepatitis B/C
– Nephrotoxic medications e.g. NSAIDS
• Related to HIV
– Direct
– Indirect e.g. antiretrovirals
In situ hybridization for HIV-1 mRNA in kidney biopsies.
Wyatt C M , and Klotman P E CJASN 2007;2:S20-S24
©2007 by American Society of Nephrology
HIV-associated nephropathy (HIVAN)
– Direct infection of kidney cells with HIV
– Rapidly progressive kidney failure and death
– Advanced, untreated HIV (high viral load, low CD4)
– Genetic disposition in blacks of west African or
Haitian descent
– Severe proteinuria (nephrotic syndrome)
1.Holden BM, et al. Saudi J Kidney Dis Transplant. 2002;13(3):344-52.
2.Wyatt CM, et al. Clin J Am Soc Nephrol 2007;2:S20.
3.Atta MG, et al. Nephrol Dial Transplant 2006;21:2809-13.
HIVAN: Collapsing glomerulosclerosis
Normal
HIVAN
Glomerular disease
• Normally most protein
is filtered out of urine,
and the little that gets
through is reabsorbed
by the tubules
• If glomerular basement
membrane is damaged,
++ protein in urine
• Diabetic nephropathy
HIV drugs and the kidney
Some HIV drugs are cleared by the
kidney
• Need dose adjustment
if kidney function is
impaired (glomerular
filtration rate ↓)
• Zidovudine (AZT)
• Didanosine (ddI)
• Tenofovir
Kidney stones
• Drugs that are insoluble in
urine precipitate as crystals in
the kidney tubules
• Can form stones which cause
obstruction anywhere in the
urinary tract
• Acute pain, blood in urine
• Risk increased with
dehydration, reduced GFR
• Indinavir (Crixivan®)
• Atazanavir (Reyataz®)
Proximal tubule is susceptible to injury e.g. from drugs, heavy metals
Kidney tubule electronic microscopy
HIV- control
Benign recurrent hematuria
mtDNA/nDNA ratio: 19.1
HIV+ on tenofovir/ddI
Acute tubular necrosis
mtDNA/nDNA ratio: 4.4
Cote, Magil, Harris et al., Antiviral Therapy 2006.
This Is Your Kidney On Drugs
Fanconi Syndrome
Glucose
Phosphate
Amino Acids
Bicarbonate
Sodium
X
X
Phosphate
X
Hypophosphatemia, acidosis, glycosuria, aminoaciduria, hypokalemia = FANCONI SYNDROME
Tubular damage
• Lose water – dilute urine (diabetes insipidus) →
dehydration
• Sugar in urine despite normal blood sugar
(normoglycemic glucosuria)
• Inability to secrete H+ ions and reabsorb HCO3 →
acid builds up in blood (metabolic acidosis)
• Phosphate wasting in urine → low blood phosphate
• Inability to reabsorb K+ ions → low blood potassium
• Amino acids and protein in urine (lower levels than
with glomerular damage)
Presentation of tenofovir
nephrotoxicity
• Fanconi syndrome - acute
• Chronic tubular dysfunction
– Chronic phosphate wasting → hypophosphatemia
→ decreased bone density (osteopenia,
osteoporosis)
Effects of ARV drugs on the kidney
• Tenofovir (Viread®, Truvada®,etc.)
– can cause acute or chronic losses e.g. of
phosphate
– could lead to bone disease after many years
• Atazanavir (Reyataz ®) + others
– Concentrated in the urine and can cause kidney
stones
• Overall, ARV therapy ↓ kidney disease in HIV
Summary
• HIV testing is now recommended for all sexually
active adults – “risk groups” no longer apply
• No cure yet, but can be considered a chronic
manageable disease
• HIV affects all organs, both directly and indirectly
– via chronic inflammation and medication side
effects
• New HIV infections are decreasing where
antiretroviral therapy is widely available –
Treatment as Prevention
www.cfenet.ubc.ca
www.ias2015.org