Transcript Managment of Long Term Complications of HIV Antiretrovial

1
Current HIV Treatment Issues
in the US:
Managing Long-Term
Non-AIDS Co-Morbidities
Ann Khalsa, MD, MSEd, AAHIVS
Centro de Salud Familiar La Fe CARE Center
Texas-Oklahoma AIDS Education
and Training Center
El Paso, Texas, USA
2
Outline
• Non-AIDS comorbidities and premature aging
• Comorbidities:
– Cardiovascular disease
– Liver disease
– Renal disease
– Osteoporosis
• Prevention / treatment of premature aging
Increased Rates of
Non-AIDS Comorbidities
Being seen in TREATED HIV+ patients
•
•
•
•
•
•
•
Cardiovascular disease
Cancer (non-AIDS)
Osteoporosis
Liver disease
Renal disease
Neurocognitive disorders
Metabolic disorders: diabetes, dyslipidemias
The same as in OLDER HIV+ patients
3
Comorbidities & Premature Aging
Even After Adjusting for Age, HAART Exposure & Traditional Risk Factors
Normal
Aging
Life
Style
HAART
Toxicity
Persistent
Immune
Dysfunction
Adapted from Deeks, RWCA Clinical Update 2009
4
Rising Number of Adults Aged ≥50 Living
With HIV in the US
• In 2005, persons aged ≥50 accounted for
– 15% of new HIV/AIDS diagnoses
– 24% of persons living with HIV/AIDS
• Increased from 17% in 2001
– 29% of persons living with AIDS
– 35% of all deaths of persons with AIDS
• Projections indicate that by 2015, older adults will constitute
50% of persons living with HIV/AIDS
• This increase has resulted in part from:
– The availability of effective ART and
– From newly diagnosed infections in older adults
CDC. HIV/AIDS Surveillance Report, 2005. Vol 17. Rev ed, 2007.
5
Elevated Inflammatory Markers in Treated
HIV-Infected Patients
Even after adjusting for demographics and CV risk factors
Participants 45-76years of age
Neuhaus J, et al. CROI 2009 Abstract O-140.
6
7
Immune Dysfunction:
Lower CD4 Count and Non-AIDS Complications
Is Lower Current CD4 Cell Count Significantly
Associated With Increased Risk?
Study
Non-AIDS
malignancies
Renal
disease/death
CVD
events/death
Liver disease/
death
FIRST
Yes
Yes
Trend, NS
No
D:A:D
Yes
Yes
Trend, NS
Yes
CASCADE
Yes
NA
Yes
Yes
Trend, NS
Trend, NS
Trend, NS
Yes
SMART
Phillips A, et al. 15th CROI; 2008; Boston. Abstract 8.
Low CD4 On-Therapy Predicts
Risk of AIDS & Non-AIDS Events (D:A:D)
Relative Risk
100
HIV/AIDS
10 -
Cancer
Heart
Liver
1.0
<50
50–99 100–199 200–349 350–499 >500
CD4+ Cells/mm3
Weber R, et al. CROI 2005, #595. Weber R, et al Arch Int Med 2006; 166:1632-1641.
Philips AN. AIDS 2008; 22:2409-2418. Baker JV, et al AIDS 2008; 22:841-848.
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Outline
• Non-AIDS comorbidities and premature aging
• Comorbidities:
– Cardiovascular disease
– Liver disease
– Renal disease
– Osteoporosis
• Prevention / treatment of premature aging
Increased Risk of Cardiac Events
With Increasing Years of PI Exposure
Incidence per 1000 Person-Yr
D:A:D Study Group:  Risk independent of other risk factors
109876543210-
 Protease Inh.s
NNRTs
N =23,437
Median follow-up
= 4.5yrs
MI’s = 345
0
<1
1-2
2-3
3-4
4-5
5-6
>6
47
7821
Exposure (Years)
Protease Inhibitors
No.of events
33
No. of person-years
21,623
Nonnucleoside ReverseTranscriptase Inhibitors
No.of events
136
No. of person-years
42,013
21
8410
33
10,947
57
23,616
64
13,742
57
10,734
33
7576
59
15,266
42
13,476
47
10,204
37
6739
24
6172
---
---
Total
345
94,469
345
94,469
Friis-Moller N et al. NEJM 2007;326:1723-1735.
10
Inconsistent Results: From major studies on CVD risk in
HIV-infected and HAART-treated patients
Study
Event
36,766
R
1,207
CHD
HOPS8
1807
P
84 CV
events
SMART9
5472
p
Kaiser3
4408
Medi-Cal4
Study
VA1
N
ARV
Effect
Traditional risk factors
HAART or PI
No
Not evaluated
Specific ARVs
No
Age >40 y, diabetes,
HTN
63
CHD
Intermittent
HAART
No – stopping
therapy led to
complication
Age
R
86 MI
PIs
Risk of HIV+ vs.
HIVNo risk on PI
Not evaluated
28,513
R
NA
ART
Risk with ART in
18–33 year olds
Not evaluated
DAD2
23,490
P
345 MI
cART and PI
Yes
Smoking, age, gender,
HTN, DM
French5
34,976
R
49 MI
PI
Yes
Age
Johns
Hopkins6
2671
Case
control
43
CHD
HIV+ vs. HIV-
Yes
Age, HTN, DM
Frankfurt7
4993
R
29 MI
HAART
Yes
Age >40
1. Bozzette SA, New Eng J Med. 2003;348:702–10
2. Friis-Møller N, 13th CROI, Denver 2006, #144
3. Klein D,13th CROI, Denver 2006, #737
4. Currier JS, JAIDS. 2003;33:506–12
5. Mary-Krause M, AIDS. 2003;21:2479–86
6. Moore RD, 10th CROI, Boston 2003, #132
7. Rickerts V, Eur J Med Res. 2000;5:329–33
8. Lichtenstein K, 13th CROI, Denver 2006, #735
9. El-Sadr W, et al. 13th CROI, Denver 2006, #106LB
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Factors Affecting Risk for CVD in
Patients With HIV
Genetic
Influences
Dyslipidemia
Diabetes
Body Fat
Redistribution
CVD
HIV
Infection
Adapted from Grinspoon S et al. N Engl J Med. 2005;352:348.
Antiretroviral
Therapy
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Possible Non-Cholesterol Causes of CVD Risk
With Protease Inhibitor Therapy in HIV
•
•
•
•
•
•
•
•
Endothelial dysfunction
Increased endothelial permeability
Insulin resistance
Accelerated lipid accumulation in vessel wall
Inflammation
Impaired response to vascular injury
Increased oxidative stress
Lipoatrophy / reduced adiponectin
M/ Dube, AAHIVM-AHA CVD Conference Chicago June 2007
FRAM 2 cIMT Study: HIV Infection is
an Independent Risk for Atherosclerosis
• Cross-sectional study
• Evidence of pre-clinical atherosclerosis
Internal cIMT (mm)
HIV+
(n=433)
Controls
(n=5479)
P value
1.17
1.06
<.0001
• After adjusting for demographics and
CVD risk factors, HIV infection has more
atherosclerosis than controls
– Difference 0.15 mm (P =.0001)
• HIV infection similar to
traditional CV risk factors
Multivariable Analysis of
Associated Factors
Estimated
Effect of
Difference in
Internal cIMT (mm)a
HIV infection
0.15
Current smoker
Past smoker
0.17
0.09
Age (per 10 yr)
0.16
Maleb
0.13
Diabetes
0.12
Systolic BP
0.05
aP
<.001 for all values.
gender interaction (women > men).
bSignificant
“Independent association of HIV infection with atherosclerosis should be taken into account when
counseling HIV-infected patients with regard to their CVD risk factors.”
Grunfeld C, et al. 16th CROI; 2009; Montreal. Abstract #146.
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Framingham CVD Risk Score
• To estimate 10-year Risk of Developing
Myocardial Infarction or Coronary Death
• For adults  aged 20 years who do not have
heart disease or diabetes
• Score based on the factors listed below
• Age
• Gender
•  Total Cholesterol
•  HDL Cholesterol
• Smoker
•  Systolic Blood Pressure
• On medication to treat high BP
National Heart, Lung, and Blood Institute. http://hp2010.nhlbihin.net/atpIII/calculator.asp?usertype=prof#moreinfo
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Framingham Risk Score:
Underestimates CVD Risk in HIV+ Patients
Observed and Predicted MI Rates According to ART Exposure
(D:A:D Study)
Rates per 1000 Person-Years
8
7
Observed rates
Best estimate of predicted rates
6
5
4
3
2
1
0
None
<1
1-2
2-3
3-4
Duration of ART Exposure (Years)
Law MG et al. HIV Med. 2006;7:218-230.
>4
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Outline
• Non-AIDS comorbidities and premature aging
• Comorbidities:
– Cardiovascular disease
– Liver disease
– Renal disease
– Osteoporosis
• Prevention / treatment of premature aging
18
HIV/HBV Coinfection
Increases the Risk of ESLD
• Multicenter AIDS Cohort Study
• HIV/HBV coinfection
– 19-fold-higher risk of liver
death than HBV monoinfection
– Risk of liver-related mortality
increased with
• Alcohol consumption
• Low nadir CD4+ cell counts
• Antiretroviral therapy
Thio CL, et al. Lancet. 2002;360:1921-1926.
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Rate per 1000 Person-Years
– 4967 HBsAg-negative MSM
• HIV: 47% (n=2346)
– 326 HBsAg-positive
• HIV: 65% (n=213)
Liver Mortality by HIV and HBV Status
14.2
15
* P <.001
10
5
0.0
0.8
1.7
0
No HIV or HBV Only HIV Only
HBV
HIV/HBV
*P value is for HIV/HBV vs HBV only and HIV only.
DHHS Recommendations For Treatment of
HBV/HIV Coinfected Patients
Infection(s)
Treatment Recommendations
HIV and not HBV
TDF/FTC or TDF + 3TC considered first choice NRTI backbones
Caveat: Use of 3TC, FTC, or TDF as the only active anti-HBV agent should
be avoided because of the risk of HBV resistance
HIV and HBV
TDF/FTC or TDF + 3TC considered first-choice NRTI backbones
(activity against both viruses) OR
ETC (entecavir) with 1 NRTI above
Caveat: Use of 3TC, FTC, or TDF as the only active anti-HBV agent should
be avoided because of the risk of HBV resistance
HBV and not HIV
Peg-IFN-α (does not lead to development of drug-resistant HIV or
HBV mutants) or ADV (with risk of HIV mutants)
Avoid FTC, 3TC, TDF and ETC w/o full HAART regimen to prevent
rapid development of drug-resistant HIV mutations
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. November 3, 2008.
http://AIDSinfor.nih.gov.
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Hepatitis C Infection in HIV+
Increased Morbidity & Mortality
• HIV worsens HCV disease:
–
–
–
–
–
–
Persistent HCV viremia without viral clearance
 End-stage-liver-disease (fibrosis & cirrhosis)
 Hepatocellular carcinoma
Accelerated fibrosis: ~20 vs 30 yrs
Higher inflammatory grade (vs HCV alone)
More extra-hepatic manifestations
• HCV worsens HIV disease:
–  Liver toxicity from HIV ARV medications
– Accelerates HIV disease progression
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Hepatitis C Morbidity & Mortality
Hospitalizations & Death in HAART Era
• New England Medical Center in Boston, Mass.
• HIV-related deaths:
– ESLD:
1991
1996
1998-99
13.9%
11.5%
50 %
58 %
93.8%
– HCV+:
Soriano V, et al. J Antimicrob Chemother. 2006;57:815
DHHS Recommendations For Treatment of
HCV/HIV Coinfected Patients
• Evaluate all coinfected patients for HCV therapy
• Treat of HCV according to standard guidelines
– At CD4 < 200 consider deferring HCV treatment until some immune
reconstitution achieved with HAART (to improve HCV response)
– At higher CD4 consider deferring HAART until after HCV treatment due
to pill burden, drug toxicities and drug interactions
– Try to treat HCV medication side effects rather than dose reduce in
order to maximize HCV response rates
• Use concurrent ARV therapy with caution
– Monitor ARVs for potential hepatotoxicity
– Avoid AZT with ribavirin due to increased anemia
1DHHS.
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. November 3, 2008.
http://AIDSinfor.nih.gov. 2Soriano V, et al. AIDS. 2007. 21(9):1073-1089.
22
HCV Associated with
Blunted CD4 Gains During HAART
Grueb G et al. Lancet 2000; 356(9244):1800-5.
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Outline
• Non-AIDS comorbidities and premature aging
• Comorbidities:
– Cardiovascular disease
– Liver disease
– Renal disease
– Osteoporosis
• Prevention / treatment of premature aging
Epidemiology of CKD in US
≥20 Years of Age
GFR <15*
Stage 5
0.4%
Stage 4
GFR 15-29*
Stage 3
GFR 30-59*
5.4%
Stage 2
25
16.8% of Americans have CKD
• White, non-hispanic 16.1%
• Black, non-hispanic
19.9%
• Mexican-American
18.7%
GFR 60-89*
5.4%
Stage 1
GFR >90*
5.7%
*GFR measurement in mL/min/1.73 m2; MMWR, 2007;56:161-165.; NHANES 1999-2004
Risk Factors Contributing to Development
of Kidney Disease
Modifiable risk factors
Non-modifiable risk factors
•
•
•
•
• Age
• Trauma or accident
• Family history of kidney
disease
• Presence of other diseases
– HIV/AIDS, hepatitis C,
lupus, sickle cell anemia,
cancer, and congestive
heart failure
Diabetes mellitus
High blood pressure
Overuse of painkillers
Allergic reactions to
medications (eg, antibiotics)
• Drug abuse
• Kidney stones
• Inflammation (eg,
glomerulonephritis)
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Proportion with CKD
(in full cohort)
Johns Hopkins HIV Clinical Cohort:
CKD in HIV-Infected Patients by Race (1990-2004)
0.25
Black
White
0.20
HR 1.9, 95% CI (1.2-2.8)
P =.002, log rank test
0.15
0.10
0.05
0.00
0
12
24
36
48
Months
Number at risk
White
924
819
696
565
464
African American
3261
2949
2464
2031
1629
Lucas G et al. 15th CROI; 2008; Boston. Abstract 972.
28
Swiss HIV Cohort : TDF Associated With Increased Risk
for Proximal Renal Tubulopathy (PRT)
•
Cross-sectional analysis of Swiss HIV Cohort Study (N = 1202)
•
PRT = pathological status of ≥ 3 of the following 4 measures: fractional
excretion (FE) of phosphate or uric acid, protein/creatinine ratio in urine,
euglycemic glucosuria
•
Incidence of PRT highest in patients receiving TDF plus a PI (vs no TDF,
no PI): OR: 7.1 (95% CI: 2.5-19.8; P < .001)
TDF+, PI+ (n = 426)
TDF+, PI- (n = 320)
TDF-, PI- (n = 221)
2%
5%
12%
11%
17%
9%
18%
PRT
50%
FE (phos) > 20%
FE (phos) > 10%
and hypophosphatemic
Normal function
20%
97 (80-118)
20%
58%
78%
103 (88-124)
cGFR median (IQR)
Fux C, et al. CROI 2009. Abstract 743. Graphics reproduced with permission.
107 (88-127)
Johns Hopkins HIV Clinical Cohort:
TDF Renal Safety
Kaplan-Meier Plot of GFR Decline
>25% and >50% From Baseline Value
Multivariate Associations With
25% GFR Decline
Probability of GFR Decline
1.00
Hazard
Ratio
95% CI
TDF vs NRTI use
1.04
0.68, 1.59
Black race
1.52
0.85, 2.72
Hypertension
1.56
1.00, 2.45
PI (ritonavirboosted)
2.14
1.37, 3.34
Age >45 years
2.31
1.44, 3.69
CD4 <200
(baseline)
2.66
1.65, 4.29
TDF (n=201)
NRTI (n=231)
0.75
0.50
GFR Decline >25%
0.25
GFR Decline >50%
0.00
0
100 200 300 400 500 600 700 800
Time (Days)
Gallant JE and Moore RD. AIDS. 2009;23(15):1971-1975.
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Outline
• Non-AIDS comorbidities and premature aging
• Comorbidities:
– Cardiovascular disease
– Liver disease
– Renal disease
– Osteoporosis
• Prevention / treatment of premature aging
31
BMD Decreases With Age
Change in Bone Volume (%)
Relative influence on peak bone mass (men):
•40% to 83% genetic
•27% to 60% environmental
0.5% to 1.0% reduction in
bone volume/year
Peak
1.2
1.0
0.8
Men
0.6
0.4
Women
0.2
0
0
10
20
30
40
Age (Yrs)
Orwoll ES, et al. Endocr Rev. 1995;16:87-116.
50
60
70
80
Many Potential Contributors to Decreased
BMD in HIV-infected Patients
•Decreased bone acquisition
•Fat deposition in marrow
•Decreased Physical Activity
•Decreased muscle mass
•Decreased fat mass
•Malnutrition
•HIV infection
•Liver disease
•Premature menopause
•Hypogonadism
•Smoking
Decreased Bone
Mineral Density
•Nucleoside analogs/
mitochondrial dysfunction
•Protease inhibitors
• Other medications (e.g.
corticosteroids,
anticonvulsants)
• Alcohol use
Glesby M et al. CID supplement September 2003.
•Family history
•Female sex
•Increasing age
32
Meta-Analysis of BMD Changes
in HIV+ Patients
HIV+ Patients
% reduced BMD
Publication
• Reduced BMD:
– Prevalence
– Risk
67%
6.4x
• Osteoporosis:
– Prevalence
– Risk
15%
6.4x
HIV+
HIV–
Amiel et al 2004
82.5
35.8
Brown et al 2004
63
32
Bruera et al 2003
64.8
13
Dolan et al 2004
63
35
Huang et al 2002
66.6
11
Knobel et al 2001
87.5
30
68
34
59.3
7.8
Tebas et al 2000
40
29
Teichman et al 2003
76
4
77.4
56
Loiseau-Peres et al 2002
Madeddu et al 2004
Yin et al 2005
Brown TT & Qaqish RB. AIDS. 2006;20:2165-2174.
33
34
Fracture Prevalence is Associated with
HIV Infection: Boston Data Base
1996-2008: N = 8,525 HIV-positive / 2,208,792 HIV-negative
7
6
5
4
3
2
1
0
HIV+
HIV-
P=0.0002
(overall comparison)
Men
Fracture Prevalence/100 Persons
Fracture Prevalence/100 Persons
Women
7
6
5
4
3
2
1
0
HIV+
P=0.0001
(overall comparison)
30-39
30-39 40-49 50-59 60-69 70-79
Age (years)
a
Clinical care data registry from the Partners HealthCare System:
Brigham Women’s Hospital and Massachusetts General Hospital.
Triant, VA et al. JCEM. 2008;93:3499-504.
HIV-
40-49
50-59
Age (years)
60-69
70-79
Vitamin D Deficiency Associated With
Race, Low CD4+ Nadir, and EFV Use
• Cross-sectional study conducted in London cohort in 2008
– Levels of vitamin D, 25(OH)D, measured in consecutive adult pts
– 35% had severe vitamin D deficiency; only 9% had optimal levels
Risk Factors
(Independently Associated with
severe vitamin D deficiency)
All Pts
(N = 1077)
Pts on HAART
(n = 845)
OR
(95% CI)
P Value
OR
(95% CI)
P Value
Black race
3.4 (2.5-4.7)
< .001
2.6 (1.8-3.7)
< .001
Winter season
2.2 (1.6-2.9)
< .001
2.1 (1.6-2.9)
< .001
1.40 (1.03-1.80)
.03
1.4 (1.0-1.9)
< .05
1.7 (1.2-2.3)
< .01
 EFV
1.9 (1.3-2.7)
< .001
 PIs
0.9 (0.6-1.3)
NS
CD4+ cell count nadir < 200
cells/mm3
Current HAART
Welz T, et al. IAS 2009. Abstract TUPEB186.
35
36
Vitamin D Levels and the Effects of
Supplementation in HIV+ Patients
25(OH)D3 levels
1,25(OH)2D3 levels
175
a
300
a
a
125
a
100
75
50
N=20
1,25(OH)2D3 (pmol/L)
25(OH)D3 (nmol/L)
150
250
b
200
150
100
50
25
aP
aP
<.05 vs baseline.
bP
<.05 vs baseline.
<.05 vs 24 weeks.
0
0
0
12
24
Week
48
Van den Bout-van den Beukel CJP et al. HIV Medicine. 2008;9:771-779.
0
12
24
Week
48
37
Bisphosphonates Improve BMD in HIV
Patients with Osteopenia/Osteoporosis
Change in BMD from Baseline (%)
● Percent change in lumbar BMD, N=31 HIV+ patients on HAART
● Treatment: alendronate 70mg weekly + Calcium + Vitamin D
P=.007
P=.02
P<.05 vs Baseline
Mondy K et al. J Acquir Immune Defic Syndr 2005;38:426–431.
P<.05 vs Baseline
38
Outline
• Non-AIDS comorbidities and premature aging
• Comorbidities:
– Cardiovascular disease
– Liver disease
– Renal disease
– Osteoporosis
• Prevention / treatment of premature aging
Prevention / Treatment of
Accelerated “Aging”
• Earlier HIV diagnosis and HAART treatment
• Treat co-infections ( additional inflammation)
– Hepatitis C, STDs, etc.
• Consider PI-based HAART regimens
• Consider addition of anti-inflammatory therapy
– Aspirin & statins
• Consider immune-based therapies
– CCR5 inhibitors
– HAART intensification
– Interleukins, growth hormone
39
Failure to Achieve Normal CD4 Levels
Based on Low CD4 Nadir
~40% failure of CD4 normalization in patients with CD4 nadir <200
~40%
Kelley CF, et al. Clin Infect Dis 2009; 48: 787-794.
40
Low CD4 Nadir at Treatment Initiation:
Reduced Life Expectancy
CD4 Nadir at Start of HAART
Life Expectancy,
years (from age 20)
<100
100-200
>200
32
42
50
10-30 years less life expectancy in modern HAART era
1) ART-Cohort Collaboration. Lancet 2008;372:293-299. 2) Lohse N, et al. Ann Int Med 2007;146:87-95.
3) Lewden C, et al. JAIDS 2007;46:72-77.
41
Need for Earlier Diagnosis:
Pervasive Low CD4 at Start of HAART
2003-2005, 42 countries, 176 sites, n=33,008.
Egger M, et al. CROI 2007. Abstract 62.
42
43
Overall Conclusions
• Virologic suppression and immune restoration remain the
most important goals of HIV disease management
• With increasing longevity of HIV-infected patients, focus is
shifting toward whole health patient care
– Management of age-related comorbidities is critical in order to
optimize long-term outcomes
• Comprehensive initial laboratory assessment and patient
workup ensure that the patient receives the best care
44
New Paradigm of HIV Treatment
Untreated HIV:
 Inflammatory
bio-markers
= associated
with disease
progression,
Chronic
worse with low Inflammation
CD4 nadirs at
start of HAART
HIV Treatment:
CVD
CKD
Osteoporosis
Antiretroviral Diabetes
Sequelae Dyslipidemia
Lipodystrophy