Transcript Diapositiva 1

Terapia ARV: non solo effetti desiderati
Nicola Boffa
Malattie Infettive
Salerno
2nd Infectivology today Paestum 17-19 Maggio 2006
Benefit
Improved
survival
Decreased
symptoms
Improved
QOL
Decreased
OIs
Risk
Short- and
long-term
toxicities
Toxicity Is a Major Reason for HAART
Regimen Discontinuation
ICONA Study Group
Median Follow-up
45 weeks
8%
Total
n=862
28%
Discontinuations
n=312 (36%)
58%
14%
D’Arminio MA et al. AIDS. 2000;14(5):499-507.
Toxicity
Failure
Non-adherence
Other
Categorizing ART Toxicities
• Immediately life-threatening
– Potentially fatal
• Acute or short-term
– Occur within first few months of beginning therapy
– Can affect antiretroviral adherence
• Chronic or long-term
– Can occur at any time
– Anticipate in patients on long-term therapy
Immediately Life-Threatening Toxicities
•
•
•
•
•
Abacavir hypersensitivity
Pancreatitis
Lactic acidosis
Hepatitis
Stevens-Johnson syndrome
Hypersensitivity Reaction to ABC
• Occurs in approximately >5% of patients
– Most common symptoms: fever, rash,
gastrointestinal (GI), malaise/fatigue
• Occurs within 6 weeks of initiation of ABC, low risk
thereafter
– Sooner and more severe on rechallenge
– Never rechallenge if hypersensitivity is
suspected
• May be less common in African-American
population
• Genetic susceptibility to ABC hypersensitivity
carried on the 57.1 ancestral haplotype
(HLA-B*5701, -DR7, and -DQ3)
Martin AM, et al. Proc Nat Acad Sci. 2004;101:4180-5.
Pancreatitis
• Strongly associated with ddI, also d4T, ddC
• Perhaps due to mitochondrial toxicity of pancreatic
acinar cells, pathogenesis currently unclear
• Reported incidence for ddI 4.4% (~.3% fatal)
• Treatment consists of drug withdrawal and
supportive care
• Hydroxyurea led to a 4-fold greater risk of
pancreatitis in combination with ddI and/or d4T
Moore RD. AIDS. 2001;15(5):617-620.
Mitochondrial Toxicity and NRTIs
• Associated with NRTI use
• NRTIs inhibit mitochondrial DNA (mtDNA)
polymerase γ
• “d-drugs” (d4T, ddI) most frequently implicated
• Least likely with abacavir, tenofovir, 3TC, FTC
• Can be life-threatening
Walker UA. HIV Ther. 2003;8(2):32-5.
Effect of NRTIs on mtDNA Content
in Liver and Muscle Cells
HepG2 liver cells
Skeletal muscle cells
Relative mtDNA content (%)
120
Abacavir
100
80
ZDV
d4T
60
40
ddI
ddC
20
0
0
0.1
1
10
100
NRTI concentration (μmol/l)
1000
140
Relative mtDNA content (%)
3TC
Tenofovir
140
Abacavir
120
Tenofovir
3TC
ZDV
100
80
60
d4T
40
ddI
ddC
20
0
0
0.1
1
10
100
1000
NRTI concentration (μmol/l)
Birkus G, et al. Antimicrob Agents Chemother, 2002; 46:716-723.
Lactic Acid Production
Tenofovir DF vs 3TC, AZT
Muscle*
30 µmol
Liver*
300 µmol
291
300
Control (%)
250
207
200
150
141
138
116
108
101
119 121
100
97
96
83
50
Tenofovir
3TC
AZT
Tenofovir
3TC
*Human skeletal muscle cells (SkMC) and liver cells (HepG2) tested in vitro.
AZT
Hyperlactataemia / Lactic acidosis
Symptomatic: 10/1000 py
Prognosis good if recognised
Unwell: abdo. pain, nausea, fatigue
No acidosis or multi-organ failure
LFTs mildly abnormal > d4T/DDI use
Symptoms
Blood 2.5
lactate
3.0
3.5
Subclinical, 8-18%
Benign, stable over time
LFTs normal, no acidosis
NRTI-link poor
John M. Curr Opin Infect Dis. 2002;15:23-29.
4.0
4.5
5.0
5.5
mmol/l
Lactic acidosis
1.3-3.9/1000 py
Rapidly progressive
Acidosis, shock, multiorgan failure
Risks – F, overweight,
pregnancy, d4T/ddI,
HCV/HBV, liver dx.
Mortality >50%
Severe hepatic injury with Nevirapine
• Fever, skin rash and hepatitis occurring relatively
early after the initiation of NVP (within the first six
weeks).
• Severe events were frequently associated with a
progressive rash.
• Higher risk in women and individuals with high CD4
cell counts at the time of starting.
– Women at higher risk at lower CD4 counts than men
(>250 cells/mm3 compared with > 400 cells/mm3).
Imperiale et al. Antiviral Therapy 2002;7:L57.
Study 934: Adverse Events Leading
to Study Drug Discontinuation through Week 48
FTC/TDF/EFV
CBV/EFV
Safety population
(n=257)
(n=254)
No. w/any adverse event
10 (4%)
23 (9%)**
Anemia
0
14 (5%)
Nausea
1 (<1%)
4 (2%)
Fatigue
0
3 (1%)
Vomiting
0
2 (<1%)
2 (<1%)
0
0
2 (1%)
Adverse event*
Dermatitis-(NNRTI)
**p=0.008
Neutropenia
*Occurring in more than 1 patient in either arm; patients may have >1 event
Arribas JR, et al. 18th International Conference on Antiviral Research,
Barcelona, Spain, 2005, Presentation # LB-01.
CNS Effects
Clinical presentation
Wide range of symptoms1-3
Headache, dizziness, vivid dreams, sleep and mood alteration (depression),
and rarely psychosis
Time frame
Occurs early and often, subsides with continued therapy1
Incidence with EFV
Range: 26% to 58%2
2-7% discontinuation rate of EFV due to CNS effects2,3
Occasionally associated with other ARVs (eg, AZT insomnia)
1Zaccarelli
M, et al. 9th CROI, Seattle, 2002. Abstract 720-T.
2Staszewski S, et al. N Engl J Med. 1999;341:1865-1873.
3Dona C, et al. Med Clin (Barc). 2000;115:337-338.
Increased Rate of EFV
Discontinuation in African Americans
• 283 previously treatment-naive patients at Johns Hopkins HIV
clinic
• VL < 400 on EFV less likely in African Americans (AA) than nonHispanic whites (NHW) (P = .01)
– 59% for AA vs 72% for NHW at Month 6
– 66% vs 82% for NHW at Year 1
• Probability of D/C EFV by Year 1: 32% for AA vs 16% for NHW (P =
.002)
• Viral suppression and treatment discontinuation on boosted PIs not
different in AA vs NHW
– Probability of D/C by Year 1: 41% in AA vs 36% in NHW (P =
.84)
• Confirmation required in larger study population
Moore R, et al. Abstract 619. 12TH CROI
Long-Term Complications
Associated with ART
Peripheral nervous system
Neuropathy, myopathy
Metabolic
Glucose disorders
Insulin resistance
Impaired glucose tolerance
Hyperglycemia/diabetes
Lipid elevations
 HDL,  triglycerides
 cholesterol
Hyperlactatemia
Lactic acidosis
Cardiovascular?
Cardiac disease
Morphologic
Fat accumulation
Abdominal obesity
Buffalo hump
Lipomatosis
Breast enlargement
Gynecomastia
Fat loss
Extremities
Face
Buttocks
Fat redistribution
Study 903: Percent of Patients with
Peripheral Neuritis/Neuropathy
Patients with selected toxicities (%)
TDF+3TC+EFV
d4T+3TC+EFV
12
10*
10*
10
8
6**
6
4
3*
3*
2**
2
0
48
96
144
Weeks
*p<0.001; **p=0.013
Gallant JE, XV Int AIDS Conf, Bangkok, July 2004, #4538.
Metabolic Complications in treated HIV
positive patients
Lipid
Dysregulation
abnormalities of glucose
metabolism
Changes in
body fat
• One syndrome or several?
• Multifactorial etiology
Genetic Polymorphisms and Metabolic
Complications
• Individual susceptibility is the missing factor in ARV efficacy and
tolerability
• Polymorphisms also affected pretreatment lipid levels in these
studies
Polymorphism
Association
Resistin gene
• Predicted metabolic toxicity with greater relative
risk in homozygotes compared with
heterozygotes[1]
Lipid-metabolizing enzyme
• Treatment-related changes in TG, TC, and HDLcholesterol[2]
MDR-1 gene (affects Pglycoprotein concentration)
• Treatment-related fat accumulation and HDL-C[3,4]
Apolipoproteins
• Treatment-related changes in TG and TC[5]
1. Ranade K, et al. CROI 2006. Abstract 763. 2. Arnedo M, et al. CROI 2006. Abstract 764.
3. DeLuca A, et al. CROI 2006. Abstract 766. 4. Cossarizza A, et al. CROI 2006. Abstract 767.
5. Gometz E, et al. CROI 2006. Abstract 768.
Prevalence of Metabolic Syndrome in MACS
Cohort

HIV-positive men HAART recipients more likely to have metabolic syndrome
than HIV-negative men
– Low HDL, elevated TGs, elevated glucose more likely in HIV+
– Increased waist circumference less likely in HIV+
Estimated Odds Ratio
for HIV+ vs HIV- Pts
(95% CI)
P Value
Metabolic syndrome
1.50 (1.14-1.98)
.004
• Elevated fasting triglycerides
2.81 (2.25-3.52)
< .001
• Elevated fasting glucose
1.81 (1.38-2.38)
< .001
• Increased waist circumference
0.38 (0.28-0.53)
< .001
• Low HDL cholesterol
3.15 (2.53-3.92)
< .001
• High blood pressure
1.04 (0.84-1.29)
.715
Palella F, et al. IAS 2005. Abstract TuPe2.2B18.
Study 903: Mean (95% CI) Change
in Fasting Triglycerides
TDF+3TC+EFV
d4T+3TC+EFV
Change from baseline (mg/dl)
160
134
140
103
120
90
100
80
60
Wk 48, 96, 144, p<0.001
40
8
20
5
1
0
-20
0
24
48
72
96
120
144
183
182
177
179
175
170
170
162
Weeks
TDF+3TC+EFV 234
d4T+3TC+EFV 250
200
211
184
194
Gallant JE, XV Int AIDS Conf, Bangkok, July 2004, #4538.
Dyslipidemia: Stavudine vs
Abacavir
• ABCDE study
– ABC vs d4T, each with 3TC + efavirenz as initial
therapy
Mean Change From Baseline at Week 48
d4T Arm
ABC Arm
Total cholesterol (mg/dL)
+47.6
+43.7
HDL cholesterol (mg/dL)
+10.5
+31.2
Triglycerides (mg/dL)
+71.2
+43.6
Podzamczer D, et al. 11th CROI, San Francisco, 2004. Abstract 716.
Impact of Lipids on Relationship Between
PIs & Diabetes in D:A:D
• Longer PI use associated with ↑
onset of diabetes
– 5-6% ↑ in diabetes per yr
of PI use
• TGs also associated with
diabetes
– 7.07 RR per 2-fold ↑ in TGs
• PI-diabetes association lost when
adjusted for TGs
Lipid adjustment
none
TC
HDL-C
TGs
0.0
1
1.1
1.2
Risk of Diabetes With PI Use
(adjusted for lipid levels)
Sabin C, et al. IAS 2005. Abstract TuPe2.2B28.
% Change Relative to Placebo
Lack of effect of atazanavir on insulin
sensitivity
50
Insulinstimulated
glucose
disposal rate
per unit of
insulin
(mg/kg*min per
U/mL)
Glycogen
storage
rate
(mg/kg*min)
•
30
P = NS
+ 4%
10
-10
-30
•
< 1%
P = NS
- 24%
P = .008
-50
LPV/RTV (n = 20)
ATV (n = 20)
Noor M, et al. #702 12TH CROI
•
- 34%
P = .006
Placebo-controlled, crossover study in
healthy volunteers
– ATV vs LPV/RTV vs placebo
Hyperinsulinemic euglycemic clamp
at day 6
Atazanavir:
– Did not affect insulin sensitivity
– No effect on insulin-mediated
glucose disposal rates
– No effect on mean glycolic
storage rate
– Did not significantly increase
fasting triglycerides
– Data show a favorable clinical
metabolic profile
Disordini metabolici in corso di HAART:
opzioni terapeutiche
Stop del farmaco potenzialmente tossico
- quale ?
- Irreversibilità ?
(Studi di switch e discontinuation in corso, necessità
di adeguato controllo e durata)
Trattare la complicanza metabolica
- “lipid lowering therapy”
- “insulin sensitizing strategies”
- “growth hormone
Dyslipidemia: Switching Options
550
500
450
400
350
300
250
200
Mean change, -105 mg/dL
(P < .001)
Mean Cholesterol
(mg/dL)
Mean Triglycerides
(mg/dL)
• Switch from d4T to ABC
– No significant or substantial changes in lipids[1,2]
• Switch from d4T to TDF
– Rapid improvements in lipid levels, within 4 weeks3,4]
– RECOVER study
Baseline 24 weeks
1. Carr A, et al. JAMA. 2002;288:207-215.
2. Moyle G, et al. J Acquir Immune Defic Syndr. 2003;33:22-28.
3. Moreno S, et al. ICAAC 2003. Abstract H-855b.
4. Domingo et al. 9 th EACS. Abstract F8/5.
290
280
270
260
250
240
230
220 Mean change, -18 mg/dL
(P = .036)
210
200
Baseline 24 weeks
Impact of Switching From d4T on Lipids and
Limb Fat
TGs
TC
LDL HDL
0
-1
-16
-20
-40
-38
-60
-80
-72
Madruga JVR, et al. IAS 2005. Abstract TuPe2.2b12.
Mean Total Limb Fat (kg)
Mean Change in Fasting
Lipids at Week 48 (mg/dL)
• 96-week open-label extension phase of 903 study
– Data from subgroup of pts given d4T for 144 weeks
who switched to open-label TDF for 48 weeks
5.02
5.0
(n = 74)
4.8
P < .001
4.6
4.60
(n = 74)
4.4
4.2
d4T
TDF
0
Wk 96
Wk 144
Wk 48
post-switch
RAVE: Median Change in Metabolic
Outcomes to Week 48
TDF
ABC
0
0
-0.01
0
0
0
Change (mmol/l)
-0.05
-0.10
-0.1
-0.1
-0.15
-0.17
-0.20
-0.2
-0.25
-0.30
-0.3
-0.35
p=0.27
Lactate
p=0.016
p=0.16
p=0.043
Total cholesterol HDL cholesterol LDL cholesterol
p=0.031
Triglycerides
All data LOCF
All individuals included. Lipid lowering therapy commenced during study for TDF n=1,
at 273 days, ABC n=8, at median 91.5 days. Includes fasting and non-fasting samples.
Observations are similar when only fasting samples are included.
*p-values by Mann-Whitney U test
Moyle et al. 12th CROI, Boston, 2005, #44LB.
ACTG 5188: Additive Effect of Fish Oil and
Fenofibrate on Triglycerides
8 weeks
HIV-positive patients
Stable HAART for 4 weeks
HIV ≤ 10,000 copies/mL
TG > 400 mg/dL (4.52 mmol/L)
LDL ≤ 160 mg/dL (4.14 mmol/L)
Fish oil capsules
3 g BID with meals
n = 47
If TG
> 200 mg/dL
(2.26 mmol/L)
Fenofibrate
160 mg QD
n = 48
Fish oil capsules
3 g BID with meals
+
Fenofibrate
160 mg QD
• 75/87 failed initial treatment and were treated with combination
therapy
• 17/75 (22.7%) responded to combination therapy
– 65% mean decrease in serum TG at Week 18
– No difference in response based on initial treatment
– No significant effect of fish oil on LPV concentration
Gerber J, et al. CROI 2006. Abstract 146.
Dyslipidemia: Lipid-Lowering Therapy vs PI
to NNRTI Switch
Mean Total Cholesterol
(mg/dL)
EFV
NVP
Pravastatin
Bezafibrate
300
-10%
250
-27%
200
-38%
150
-46%
100
50
0
3
Calza L, et al. AIDS. 2005;19:1051-1058. TuFo0105
6
Months
9
12
Prevalenza della variazione della distribuzione
dei grassi (MACS Cohort)
Prevalenza di lipodistrofia
in 868 MACS pazienti
Variazione distribuzione
periferica o centrale grassi
(33% HIV neg vs. 66% HIV
positive)
Moderata o severa wasting
periferica (grasso/braccia)
e adiposità centrale
Adattato da: Kingsley et al. 2001
Rischio di lipodistrofia con d4T vs ZDV
in studi di coorte (n= 8,885)
28%
Bernasconi et al. SHCS (n = 1,355)*
Boufassa et al. (n = 595)
Galli et al. (n = 188)*
Saint Marc et al. (n = 139)*
Carr et al. (n = 220)*
Gervasoni et al. (n = 306)
Wolf et al. (n = 93)*
Mauss et al. (n = 221)*
HOPS (n = 1,077)*
Mallal et al. (n = 277)*
Carmena et al. (n = 232)*
Galli et al. LipoICONA (n = 704)*
Chêne et al. APROCO (n = 321)
Mallolas et al. (n = 506)*
Galli et al. LIMS (n = 2258)*
Schwenk et al. (n = 278)*
Bogner et al. (n = 115)*
57%
16%
53%
52%
11%
53%
34%
49%
44%
10%
62%
17%
33%
32%
34%
10%
NB: % referita a
prevalenza LD
*analisi multivariata
0
Aumento rischio con
ZDV
1
Aumento rischio con d4T
10
White AJ. Sex Trans Inf 2001; 77(3): 158-173
% Patients with Selected Toxicities
GS 903
TDF+3TC+EFV
d4T+3TC+EFV
30
28 *
25
20*
20
15
10*
10
5
0
6*
4*
3*
Week 48
Week 96
Week 144
†Peripheral
neuritis/neuropathy, lipodystrophy (investigator defined), lactic acidosis
*p value < 0.001
Totale
TDF+3TC+EFV
d4T+3TC+EFV
10 *
12
10 *
10
8
†
6
6
4
†
3*
3*
2
2
0
% Patients with Selected Toxicities
% Patients with Selected Toxicities
Preliminary Data on File, Gilead Sciences, Inc.
*p < 0.001
†p = 0.013
Preliminary Data on File, Gilead Sciences, Inc.
Week 96
19 *
18
16
14
12 *
12
10
8
6
4
*
3
4
2
0
Week 48
TDF+3TC+EFV
d4T+3TC+EFV
20
Week 144
1
Week 48
*
1
Week 96
Week 144
†Investigator-defined
*p value < 0.001
Neuropatia
Preliminary Data on File, Gilead Sciences, Inc.
Lipodistrofia
GS 903 Study: Mean (95% CI) Total Limb Fat
at Week 144
12
10
9
8
7
6
5
4
3
2
1
0
8.6*
7.9*
5.0
48
TDF+3TC+EFV
d4T+3TC+EFV
4.5
96
Weeks
128
134
144
115
117
Gallant et al. Abstract TuPeB4538. International AIDS Conference 2004
* P < .001
TDF+3TC+EFV
d4T+3TC+EFV
Lower Incidence of Lipodystrophy With
ABC/3TC vs d4T/ddI
• FIRST study: randomized, prospective trial
– ABC/3TC vs d4T/ddI backbones
– Subgroup enrolled in metabolic substudy
• Increases in body cell mass and fat through Month 12 in both arms
• Between Months 12 and 32, reductions in total and regional fat in
d4T/ddI arm but not in ABC/3TC arm
Rate of Change From Week 0-32*
d4T/ddI
ABC/3TC
Total body fat (kg/month)
-0.08
0.08
Hip circumference (cm/month)
-0.18
0.10
Mid-arm skinfold fat area (cm2/month)
-0.21
0.05
Waist skinfold fat area (cm2/month)
-0.62
0.62
* All P < .05
Shlay et al. Abstract ThOrB1360 International AIDS Conference 2004
RAVE Study:
Switch Thymidine Analogue to ABC or TDF
Moyle G, et al. Abstract 44LB. 12th CROI
1200
Change in fat mass
(g) by DEXA, Wk 48
• Suppressed patients
with
self-defined lipoatrophy
on thymidine analogue
NRTI
• 105 pts randomized to
replace TA with:
– tenofovir, or
– abacavir
• Total limb fat increased
to similar extent in both
arms over 48 weeks
TDF
ABC
1000
1061 1046
791
800
522
600
400
393
316
200
0
Limb
Trunk
Total Fat
Within-group change in limb fat from baseline:
TDF P = .01, ABC P = .001
• Suppressed patients receiving a
thymidine analogue NRTI
• 101 pts randomized to
– replace TA with abacavir, or
– switch regimen to LPV/RTV +
NVP, or
– delay switch for 24 weeks
• Significant increases in limb fat
from baseline in both arms (P =
.02)
• No significant differences between
arms
Murphy R, et al. Abstract 45LB. 12th CROI
% Change in SC thigh fat
ACTG 5110:
Switch to ABC or to NRTI-Sparing Regimen
10
5
0
ABC LPV/RTV + NVP
(n = 53)
(n = 48)
Week 24 After Switch
Low-dose growth hormone maintenance therapy
• 4 mg/day r-hGH for 12 weeks previously shown to
reduce trunk fat, VAT, TC, and non-HDL-C
• 1 mg/day or 2 mg/day maintenance therapy studied for
up to 60 weeks
• Significant reductions in trunk fat, TC, and non-HDL-C
maintained (60 weeks vs baseline)
– No significant differences between 1 mg/day and 2
mg/day doses except arthralgia (5.7% vs 12.5%,
respectively)
• No change in limb fat
• No effect on insulin resistance
Kotler DP, et al. #80 12th CROI
Treatment Interventions for Lipoatrophy:
Previous Studies
Intervention
Outcome
d4T or ZDV switch to
ABC or TDF[1-6]
•
Small but significant increases in peripheral
fat
•
May take 5-10 years to return to normal
Uridine (36 g TID)[7]
•
Pravastatin (40 mg QD)[8]
•
Increase in total limb fat and subcutaneous
fat
Rosiglitazone (4 trials)[9-
•
12]
~ 1 kg increase in limb fat over 12 weeks)
Limb fat remained unchanged (3 trials) or
increased (1 trial)
1. Carr A, et al. JAMA. 2002;288:207-215. 2. Martin A, et al. AIDS. 2004;18:1029-1036.
3. McComsey G, et al. Clin Infect Dis. 2004;38:263-270. 4. Moyle G, et al. CROI 2005. Abstract 44LB.
5. Milinkovic A, et al. CROI 2005. Abstract 857. 6. Murphy R, et al. CROI 2005. Abstract 45LB.
7. Sutinen J , et al 7th Lipo Workshop. Abstract. 8. Mallon P, et al. AIDS. In press.
9. Sutinen J, et al. Antiviral Ther. 2003;8:199-207. 10. Carr A, et al. Lancet. 2004;363:429-438.
11. Hadigen C, et al. Ann Intern Med. 2004;140:786-794. 12. Cavalcanti R, et al. CROI 2005. Abstract 854.
Treatment Interventions for Lipoatrophy:
New Studies
Intervention
Outcome
Pioglitazone[1]
•
Increase of limb fat of 0.3 kg over placebo (P =
.051)
•
Thigh circumference and tricep skin fold increase
•
No benefit in patients taking d4T
Metformin[2,3]
•
No benefit on fat distribution or dyslipidemia in 2
studies
•
Trend toward decrease in appendicular fat
Rosiglitazone[3]
•
Increased lower extremity fat (P = .034)
Rosiglitazone + metformin[3]
•
No benefit
Testosterone[4]
•
•
Decrease in subcutaneous fat
No effect on visceral fat
1. Slama L, et al. CROI 2006. Abstract 151LB. 2. Kohli R, et al. CROI 2006. Abstract 148.
3. Mulligan K, et al. CROI 2006. Abstract 147. 4. Shikuma C, et al. CROI 2006. Abstract 149.
D:A:D—Prolonged Antiretroviral Exposure
and Myocardial Infarction
Incidence of MI Per 1000 PY
10
All subjects
8
6
4
2
0
None
Events 14
PYFU 10103
<1
1-2
2-3
3-4
4-5
Exposure to HAART (Yrs)
5-6
>6
16
6324
22
8165
39
9073
41
6751
El-Sadr W, et al. Abstract 42.
34
10846
56
13060
55
12254
HAART and the Risk of Myocardial Infarction:
Updated Data From D:A:D
•
•
•
•
•
•
Exposure to elements of HAART
– NNRTI: 6.3 years (3.8-8.3)
– PI: 3.0 (0.5-5.4)
– NNRTI: 0.9 (0-3.2)
Peak RR of MI in 2001; falling since
Adjustment for lipids largely
explains decline in MI
PI exposure associated with similar
increased risk as HAART exposure
NNRTI exposure not associated
with increased risk of MI
Adjustment for NRTI exposure did
not change risk
Suggests that increased risk
previously reported with HAART
largely driven by PIs
El-Sadr W, et al. CROI 2006. Abstract 144.
RR of MI by ART Exposure
1.8
1.6
1.4
RR of MI
•
1.2
1.0
0.8
ART
PI*
NNRTI†
0.6
0.4
0.2
0
*Adjusted for NNRTI exposure.
†Adjusted for PI exposure.
Management of HIV-associated
Metabolic Syndrome
• Stop smoking
• Treat hypertension
• Encourage appropriate diet and exercise
Specific Interventions for Metabolic
Abnormalities
• Change antiretroviral therapy to regimens
less likely to cause metabolic problems
• Lipid-lowering drugs
• Treatment of insulin resistance
Renal Events in Patients Receiving Tenofovir
•
•
•
Many observational series and case reports highlighting renal toxicity in some
patients taking TDF, particularly in patients with other factors for renal disease
More such reports presented at this meeting
Complications data from large clinical trials generally reassuring re. safety of
TDF
Measures of Renal Function
Δ CrCl, mL/min*
Δ GFR,
mL/min/1.73M2†
TDF + 3TC + EFV
+2
-2
d4T + 3TC + EFV
+7
+9
TDF + FTC + EFV
-1
< -1
ZDV/3TC + EFV
+6
< -1
GS903 (Week 144 data)[1]
GS934 (48-week data)[2]
*CrCl calculated by Cockcroft-Gault formula
†GFR calculated by Modification of Diet in Renal Disease formula
1. Gallant JE, et al. JAMA. 2004;292:191-201.
2. Gallant J, et al. N Engl J Med 2006;354:251-260.
Tenofovir and Renal Events in CDC Cohort
• Longitudinal study of CDC Adult/Adolescent Spectrum of HIV
Disease Cohort (N = 11,362)
– Inclusion: GFR ≥ 90 mL/min by MDRD calculation
– Renal insufficiency, if present, determined by calculated GFR
and ranked as mild (GFR 60-89 mL/min), moderate (GFR
30-59 mL/min), or severe (GFR < 30 mL/min)
– Persons taking TDF more likely to have renal insufficiency than
those not taking TDF (odds ratio, 1.6; 95% CI, 1.5-1.8)
• In separate multivariate analyses, TDF associated with mild
or moderate impairment, not severe
– Caveat: Observational cohort, not randomized study
• TDF recipients might have had more advanced/progressive
disease or more exposure to nephrotoxins than those on
other NRTIs
Heffelfinger J, et al. CROI 2006. Abstract 779.
Mechanisms of liver toxicity
 Mythocondrial toxicity and lactic acidosis
(NRTIs)
 Lypodistrophy with liver steatosis (PIs and
NRTIs)
 Hypersensitivity reactions (NNRTIs)
 Immune-reconstitution (HAART)
Liver enzyme elevation (LEE)-free survival in 409 HIV-1-infected patients
who initiated HAART. LEE= transaminases >5 times normal values
M den Brinker et al, AIDS 2000
HAART and Liver Enzyme Elevations
• Meta-analysis of 20 publications of HIV-infected patients ± HCV
coinfection
• Grade 2 or higher liver elevations noted
% LEE in HCV-Coinfected Patients by Drug Class
Patients With LEE,%
P = .025
40
P = .004
32.00
P = .009
30
18.44
20
15.96
14.67
13.62
10
5.26
0
NNRTI
PI
Mixed
BPI
Drug Class
Benhamou Y, et al. CROI 2006. Abstract 88.
NRTI
Overall
Summary
• Antiretroviral therapy is lifelong treatment
• We must select regimens with:
– Good tolerability from the start to ensure adherence
– Adequate long-term safety profiles to preserve
patients’ quality of life
• NRTIs vary in type and degree of toxicities
– We are still learning about the more long-term effects
of mitochondrial-related toxicities
• New ARVs have helped minimize the tradeoff
between efficacy and toxicity