Terapia ARV: non solo effetti desiderati

1
Terapia ARV non solo effetti desiderati 

• Nicola Boffa
• Malattie Infettive
• Salerno

2nd Infectivology today Paestum 17-19 Maggio 2006
2
BenefitImproved survivalDecreased
symptomsImproved QOLDecreased
OIsRiskShort- and long-termtoxicities
3
Toxicity Is a Major Reason for HAART Regimen
Discontinuation
ICONA Study Group Median Follow-up45 weeks Total
n862 Discontinuations n312 (36)
8
28
58
14
DArminio MA et al. AIDS. 200014(5)499-507.
4
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

5
Immediately Life-Threatening Toxicities

• Abacavir hypersensitivity
• Pancreatitis
• Lactic acidosis
• Hepatitis
• Stevens-Johnson syndrome

6
Hypersensitivity Reaction to ABC

• Occurs in approximately gt5 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 hypersensitivitycar
  ried on the 57.1 ancestral haplotype(HLA-B5701,
  -DR7, and -DQ3)

Martin AM, et al. Proc Nat Acad Sci.
20041014180-5.
7
Genetic Susceptibilityfor Abacavir HSR
Martin AM, et al. Proc Nat Acad Sci.
20041014180-5.
8
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. 200115(5)617-620.
9
Mitochondrial Toxicity and NRTIs

• Associated with NRTI use
• NRTIs inhibit mitochondrial DNA (mtDNA)
  polymerase ?
• d-drugs (d4T, ddI) most frequently implicated
• Least likely with abacavir, tenofovir, 3TC, FTC
• Can be life-threatening

Walker UA. HIV Ther. 20038(2)32-5.
10
Effect of NRTIs on mtDNA Content in Liver and
Muscle Cells
HepG2 liver cells
Skeletal muscle cells
3TC
140
140
Abacavir
Tenofovir
120
120
Tenofovir
Abacavir
100
100
3TC
ZDV
80
80
Relative mtDNA content ()
Relative mtDNA content ()
ZDV
d4T
60
60
d4T
40
40
ddI
ddI
ddC
ddC
20
20
0
0
0
0.1
1
10
1000
100
0
0.1
1
10
1000
100
NRTI concentration (µmol/l)
NRTI concentration (µmol/l)
Birkus G, et al. Antimicrob Agents Chemother,
2002 46716-723.
11
Lactic Acid ProductionTenofovir DF vs 3TC, AZT
Muscle
Liver
30 µmol
300 µmol
300
291
250
207
200
Control ()
150
141
138
121
119
116
108
101
100
97
96
83
50
Tenofovir
3TC
AZT
Tenofovir
3TC
AZT
Human skeletal muscle cells (SkMC) and liver
cells (HepG2) tested in vitro.
12
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 gt d4T/DDI use
Symptoms
2.5 3.0 3.5 4.0 4.5 5.0 5.5 mmol/l
Blood lactate

• Lactic acidosis
• 1.3-3.9/1000 py
• Rapidly progressive
• Acidosis, shock, multi-organ failure
• Risks F, overweight, pregnancy, d4T/ddI,
  HCV/HBV, liver dx.
• Mortality gt50

Subclinical, 8-18 Benign, stable over time LFTs
normal, no acidosis NRTI-link poor
John M. Curr Opin Infect Dis. 20021523-29.
13
Add Rash Photo
Carr A, et al. Lancet. 20003561423-1430.
14
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
  (gt250 cells/mm3 compared with gt 400 cells/mm3).
• Imperiale et al. Antiviral Therapy
  20027L57.

15
Study 934 Adverse Events Leading to Study Drug
Discontinuation through Week 48
Safety population FTC/TDF/EFV(n257) CBV/EFV(n254)
No. w/any adverse event 10 (4) 23 (9)
Adverse event Adverse event Adverse event
Anemia 0 14 (5)
Nausea 1 (lt1) 4 (2)
Fatigue 0 3 (1)
Vomiting 0 2 (lt1)
Dermatitis-(NNRTI) 2 (lt1) 0
Neutropenia 0 2 (1)
p0.008
Occurring in more than 1 patient in either arm
patients may have gt1 event
Arribas JR, et al. 18th International Conference
on Antiviral Research, Barcelona, Spain, 2005,
Presentation LB-01.
16
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 582 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. 19993411865-1873. 3Dona C, et al. Med Clin
(Barc). 2000115337-338.
17
Increased Rate of EFV Discontinuation in African
Americans

• 283 previously treatment-naive patients at Johns
  Hopkins HIV clinic
• VL lt 400 on EFV less likely in African Americans
  (AA) than non-Hispanic 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
18
Long-Term Complications Associated with ART
Peripheral nervous system Neuropathy,
myopathy Metabolic Glucose disorders Insulin
resistance Impaired glucose tolerance Hyperglycemi
a/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
19
Study 903 Percent of Patients with Peripheral
Neuritis/Neuropathy
TDF3TCEFV
d4T3TCEFV
12
10
10
10
8
6
Patients with selected toxicities ()
6
4
3
3
2
2
0
48
96
144
Weeks
plt0.001 p0.013
Gallant JE, XV Int AIDS Conf, Bangkok, July 2004,
4538.
20
Metabolic Complications in treated HIV positive
patients
Dysregulation of glucose metabolism
Lipid abnormalities
Changes in body fat

• One syndrome or several?
• Multifactorial etiology

21
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 heterozygotes1
Lipid-metabolizing enzyme Treatment-related changes in TG, TC, and HDL-cholesterol2
MDR-1 gene (affects P-glycoprotein concentration) Treatment-related fat accumulation and HDL-C3,4
Apolipoproteins Treatment-related changes in TG and TC5
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.
22
MACS Study Effects of HIV and Treatment on
Cholesterol
Cholesterol (mg/dL)
Riddler SA, et al. JAMA. 20032892978-2982.
23
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) lt .001
Elevated fasting glucose 1.81 (1.38-2.38) lt .001
Increased waist circumference 0.38 (0.28-0.53) lt .001
Low HDL cholesterol 3.15 (2.53-3.92) lt .001
High blood pressure 1.04 (0.84-1.29) .715
Palella F, et al. IAS 2005. Abstract TuPe2.2B18.
24
Study 903 Mean (95 CI) Change in Fasting
Triglycerides
TDF3TCEFV
d4T3TCEFV
160
134
140
120
103
90
100
80
Change from baseline (mg/dl)
60
Wk 48, 96, 144, plt0.001
40
8
5
20
1
0
-20
0
24
48
72
96
120
144
Weeks
234
200
184
183
177
175
170
TDF3TCEFV
d4T3TCEFV
250
211
194
182
179
170
162
Gallant JE, XV Int AIDS Conf, Bangkok, July 2004,
4538.
25
GS934 Effect of NRTIs on Lipids
Pozniak A, et al. IAS 2005. Abstract WeOa0202.
26
Dyslipidemia Stavudine vs Abacavir

• ABCDE study
• ABC vs d4T, each with 3TC efavirenz as initial
  therapy

Mean Change From Baseline at Week 48 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.
27
Impact of Lipids on Relationship Between PIs
Diabetes in DAD

• 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

Sabin C, et al. IAS 2005. Abstract TuPe2.2B28.
28
Lack of effect of atazanavir on insulin
sensitivity

• 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

Noor M, et al. 702 12TH CROI
29
Disordini metabolici in corso di HAARTopzioni
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
30
Dyslipidemia Switching Options

• Switch from d4T to ABC
• No significant or substantial changes in
  lipids1,2
• Switch from d4T to TDF
• Rapid improvements in lipid levels, within 4
  weeks3,4
• RECOVER study

Mean Triglycerides (mg/dL)
Mean Cholesterol (mg/dL)
Mean change, -105 mg/dL (P lt .001)
Mean change, -18 mg/dL(P .036)
Baseline
24 weeks
Baseline
24 weeks
1. Carr A, et al. JAMA. 2002288207-215. 2.
Moyle G, et al. J Acquir Immune Defic Syndr.
20033322-28. 3. Moreno S, et al. ICAAC 2003.
Abstract H-855b. 4. Domingo et al. 9 th EACS.
Abstract F8/5.
31
Impact of Switching From d4T on Lipids and Limb
Fat

• 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

Madruga JVR, et al. IAS 2005. Abstract TuPe2.2b12.
32
RAVE Median Change in Metabolic Outcomes to Week
48
TDF
ABC
0
0
0
0
0
-0.01
-0.05
-0.10
-0.1
-0.1
-0.15
Change (mmol/l)
-0.17
-0.20
-0.2
-0.25
-0.30
-0.3
p0.27
p0.016
p0.16
p0.043
p0.031
-0.35
Lactate
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
All data LOCF All individuals included. Lipid
lowering therapy commenced during study for TDF
n1, at 273 days, ABC n8, 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.
33
Treatment of Hypertriglyceridemia With Fish Oil
(Omega-3 polyunsaturated fatty acids)

• Randomized, controlled trial of high-dose fish
  oil vs paraffin oil
• N 122 patients with hypertriglyceridemia gt 2
  g/L on HAART
• Mean b/l TG, 4.5 g/L
• Significant efficacy at Week 8
• 10 pts with TG gt 10 g/L given open-label fish
  oil 44 ? in TG after 8 weeks

Week-8 Outcome (ITT) Fish Oil(n 58) Paraffin Oil Control (n 62) P Value
Mean change in TG, -25.5 2.0 .0033
Normalized TG, 22.4 6.5 .126
TG decreased gt 20, 58.6 33.9 .007
Dr Truchis P, et al. Abstract 39. 12th CROI
34
ACTG 5188 Additive Effect of Fish Oil and
Fenofibrate on Triglycerides
8 weeks
Fish oil capsules 3 g BID with meals n 47
If TG gt 200 mg/dL (2.26 mmol/L)

• Fish oil capsules
• 3 g BID with meals
• Fenofibrate
• 160 mg QD

HIV-positive patients Stable HAART for 4
weeks HIV 10,000 copies/mL TG gt 400 mg/dL (4.52
mmol/L) LDL 160 mg/dL (4.14 mmol/L)
Fenofibrate 160 mg QD n 48

• 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.
35
Dyslipidemia Lipid-Lowering Therapy vs PI to
NNRTI Switch
Pravastatin Bezafibrate
EFV NVP
300
-10
250
-27
200
Mean Total Cholesterol (mg/dL)
-38
150
-46
100
50
12
9
6
3
0
Months
Calza L, et al. AIDS. 2005191051-1058. TuFo0105
36
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
37
Rischio di lipodistrofia con d4T vs ZDV in studi
di coorte (n 8,885)
38
GS 903
Totale
Lipodistrofia
Neuropatia
39
GS 903 Study Mean (95 CI) Total Limb Fat at
Week 144
12
10
9
8.6
P lt .001
7.9
8
7
6
Kilograms
5.0
5
4.5
4
3
2
1
0
48
96
144
Weeks
TDF3TCEFV 128 115
d4T3TCEFV 134 117
Gallant et al. Abstract TuPeB4538. International
AIDS Conference 2004
40
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 lt .05
Shlay et al. Abstract ThOrB1360 International
AIDS Conference 2004 .
41
RAVE Study Switch Thymidine Analogue to ABC or
TDF

• 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

1200
TDF
1061
1046
ABC
1000
791
800
Change in fat mass (g) by DEXA, Wk 48
522
600
393
316
400
200
0
Limb
Trunk
Total Fat
Within-group change in limb fat from baseline
TDF P .01, ABC P .001
Moyle G, et al. Abstract 44LB. 12th CROI
42
ACTG A5125S Switch to NRTI-Sparing Regimen

• Rollover study for suppressed patients receiving
  IDV 2 NRTIs NFV or EFV in ACTG 388
• 62 pts randomized
• EFV LPV/r, or
• EFV 2 NRTIs (78 ZDV/3TC, 20 d4T/3TC, 2
  other)
• Increase in peripheral fat with NRTI-sparing
  regimen at Week 48 decrease with NRTI-containing
  regimen
• No significant differences in truncal fat,
  glucose metabolism, HOMA-IR, BMD

EFV NRTIs
EFV LPV/r
1250
P .002
1000
P .085
750
P .07
500
P .05
250
0
Fat change (g)
-250
-500
Baseline 6 kg
-750
P .007
-1000
-1250
0
48
Final
Time (Weeks)
Between arms Within arm
Tebas P, et al. Abstract 40 12th CROI.
43
ACTG 5110 Switch to ABC or to NRTI-Sparing
Regimen

• 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

10
Change in SC thigh fat
5
0
LPV/RTV NVP(n 53)
ABC(n 48)
Week 24 After Switch
Murphy R, et al. Abstract 45LB. 12th CROI
44
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
45
Treatment Interventions for Lipoatrophy Previous
Studies
Intervention Outcome
d4T or ZDV switch to ABC or TDF1-6 Small but significant increases in peripheral fat May take 5-10 years to return to normal
Uridine (36 g TID)7 1 kg increase in limb fat over 12 weeks)
Pravastatin (40 mg QD)8 Increase in total limb fat and subcutaneous fat
Rosiglitazone (4 trials)9-12 Limb fat remained unchanged (3 trials) or increased (1 trial)
1. Carr A, et al. JAMA. 2002288207-215. 2.
Martin A, et al. AIDS. 2004181029-1036. 3.
McComsey G, et al. Clin Infect Dis.
200438263-270. 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. 20038199-207. 10. Carr A, et al. Lancet.
2004363429-438. 11. Hadigen C, et al. Ann
Intern Med. 2004140786-794. 12. Cavalcanti R,
et al. CROI 2005. Abstract 854.
46
Treatment Interventions for Lipoatrophy New
Studies
Intervention Outcome
Pioglitazone1 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
Metformin2,3 No benefit on fat distribution or dyslipidemia in 2 studies Trend toward decrease in appendicular fat
Rosiglitazone3 Increased lower extremity fat (P .034)
Rosiglitazone metformin3 No benefit
Testosterone4 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.
47
DADProlonged Antiretroviral Exposure and
Myocardial Infarction
10
All subjects
8
6
Incidence of MI Per 1000 PY
4
2
0
None
lt 1
1-2
2-3
3-4
4-5
5-6
gt 6
Exposure to HAART (Yrs)
Events
14
16
22
34
56
55
39
41
PYFU
10103
6324
8165
10846
13060
12254
9073
6751
El-Sadr W, et al. Abstract 42.
48
DADProlonged Antiretroviral Exposure and
Myocardial Infarction

• Updated analysis shows continuing increase in
  risk with longer duration1
• Increased risk partially but not completely
  explained by dyslipidemia
• However, trend for decreasing MI incidence from
  2000-2003 after adjusting for ? smoking, ?
  lipid-lowering therapy2

Adjusted RR, 1.17 (95 Cl, 1.081.26)
HAART per addl year
Age per 5 yrs older
Male sex
Previous CVD
Smoking
Family history
1
0
10
Relative rate of MI (95 Cl) Multivariate model
adjusted for family history, BMI, HIV risk,
cohort, year and race
1. El-Sadr W, et al. Abstract 42. 2. Sabin C, et
al. Abstract 866.
49
HAART and the Risk of Myocardial Infarction
Updated Data From DAD
RR of MI by ART Exposure

• 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

1.8
1.6
1.4
1.2
1.0
RR of MI
0.8
ART
PI
NNRTI
0.6
0.4
0.2
0
Adjusted for NNRTI exposure. Adjusted for PI
exposure.
El-Sadr W, et al. CROI 2006. Abstract 144.
50
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

51
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 Measures of Renal Function Measures of Renal Function
GS903 (Week 144 data)1 ? CrCl, mL/min ? GFR, mL/min/1.73M2
TDF 3TC EFV 2 -2
d4T 3TC EFV 7 9
GS934 (48-week data)2
TDF FTC EFV -1 lt -1
ZDV/3TC EFV 6 lt -1
CrCl calculated by Cockcroft-Gault formula GFR
calculated by Modification of Diet in Renal
Disease formula
1. Gallant JE, et al. JAMA. 2004292191-201. 2.
Gallant J, et al. N Engl J Med 2006354251-260.
52
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 lt 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.
53
Mechanisms of liver toxicity

• Mythocondrial toxicity and lactic acidosis
  (NRTIs)
• Lypodistrophy with liver steatosis (PIs and
  NRTIs)
• Hypersensitivity reactions (NNRTIs)
• Immune-reconstitution (HAART)

54
Liver enzyme elevation (LEE)-free survival in 409
HIV-1-infected patients who initiated HAART. LEE
transaminases gt5 times normal values
M den Brinker et al, AIDS 2000
55
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
P .025
40
P .004
32.00
P .009
30
Patients With LEE,
18.44
20
15.96
14.67
13.62
10
5.26
0
NRTI
NNRTI
PI
Mixed
BPI
Overall
Drug Class
Benhamou Y, et al. CROI 2006. Abstract 88.
56
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

57
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