Making antiretroviral therapy forever

1
Making antiretroviral therapy forever

• Andrew Carr
• St Vincents Hospital
• Sydney, Australia

2
Case presentation

• Newly diagnosed, asymptomatic, 48-year old HIV
  man
• CD4 225 cells/mm3
• Hepatitis B / C antibody-negative ALT normal
• Previous history of severe depression
• Keen to start therapy
• Starts AZT-3TC-NVP
• Week 6 fatigue / nausea / anorexia no rash /
  mucositis / fever no signs of acute or
  chronic hepatic decompensation no
  anaemia ALT 150 (4 x ULN) bilirubin
  normal

3
Question 1 - hepatitis

• The most likely cause is
• 1. immune reconstitution
• 2. hypersensitivity
• 3. drug hepatitis
• 4. lactic acidosis
• 5. re-activated hepatitis B or C

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Antiretroviral toxicity
Hepatotoxicity
Cause Lactic acidemia ARVs ddI,
d4T other NRTIs Risks NRTI
durn ribavirin pregnancy obesity
female
5
Antiretroviral toxicity
Hepatotoxicity
Cause Lactic Hyper acidemia sensitivity ARVs
ddI, d4T NVP other NRTIs Risks NRTI durn ?
CD4 ribavirin pregnancy obesity
female
6
Antiretroviral toxicity
Hepatotoxicity
Cause Lactic Hyper Isolated acidemia sensitivit
y hepatitis ARVs ddI, d4T NVP RTV, NVP other
NRTIs Risks NRTI durn ? CD4 HCV
RNA ribavirin ? ALT pregnancy
obesity female
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Antiretroviral toxicity
Hepatotoxicity
Cause Lactic Hyper Isolated Immune acidemia sens
itivity hepatitis reactivation ARVs ddI,
d4T NVP RTV, NVP Any other NRTIs Risks NRTI
durn ? CD4 HCV RNA CD4lt100 ribavirin ? ALT
HBV, HCV pregnancy MAC bacteremia obesi
ty CMV viraemia female recent TB
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Antiretroviral toxicity
Hepatotoxicity
Cause Lactic Hyper Isolated Immune HBV
flare acidemia sensitivity hepatitis reactivation
reactivation ARVs ddI, d4T NVP RTV,
NVP Any stopping other NRTIs 3TC, FTC,
TDF Risks NRTI durn ? CD4 HCV RNA CD4lt100 HBV
DNA ribavirin ? ALT HBV, HCV pre-therapy preg
nancy MAC bacteremia obesity CMV
viraemia female recent TB
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Antiretroviral toxicity
Hepatotoxicity
Cause Lactic Hyper Isolated Immune HBV
acidemia sensitivity hepatitis reactivation
flare Clinical onset late early early
/late early early fever no common occasional yes
yes rash no common no no no
jaundice no occasional occasional common common
dyspnoea yes no no no no failure occasional ?1
?1 common common Laboratory ALT gt
10x no common common common common lactate gt
2 yes no no no no Therapy cease NRTIs cease
ARV cease cease all restart therapy ARVs
treat OI HBV treat HCV therapy or HBV
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Antiretroviral toxicity
Hepatotoxicity
Nevirapine hepatitis

• ALT gt 10 x ULN 5-10
• clinical hepatitis 2-3
• fulminant hepatitis rare
• rash in 50 of those with hepatitis
  (?hypersensitivity)
• risk factors for increase in ALT to gt 5 x
  ULN women CD4 gt 250 11 CD4 lt
  250 1 men CD4 gt 400
  6 CD4 lt 400 2 HBV/HCV ALT
  normal 4 ALT 2.5-5 x ULN 6

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Question 1 - hepatitis

• The most likely cause is
• 1. immune reconstitution baseline CD4 gt200
• 2. hypersensitivity no rash, fever, mucositis
• 3. drug hepatitis
• 4. lactic acidosis early high ALT ? lactate
• 5. re-activated hepatitis B or C occult HBV/HCV
  rare
• Key points - Not all drug hepatitis is clinically
  significant or requires drug cessation. Probably
  cease if
• 1. Clinical sustained nausea or weight
  loss grade 3-4 rash / fever /
  mucositis signs of liver failure (eg.
  encephalopathy)
• 2. Biochemistry elevated bilirubin ALT gt
  10x ULN

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Case presentation

• Switched to d4T-3TC-rLPV
• Nausea and fatigue resolved by week 12
• Continues with RNA lt50 for 18 months CD4 550
• Routine assessments
• 1. total cholesterol 7.2 mmol/l (280mg/dl)
  (baseline cholesterol unknown)
• worried about CVD ( family history)
• 2. marked lipoatrophy, some abdominal fat
  accumulation
• Questions
• 1. Will I get a heart attack? Can I prevent
  this?
• 2. Can you reverse my lipoatrophy?

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Question 2 Cardiovascular risk

• The patient should
• 1. switch rLPV to another boosted PI or EFV
• 2. switch d4T to other NRTI
• 3. stop all ART
• 4. start a statin
• 5. intervene based on full cardiovascular risk
  profile

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Antiretroviral toxicity
Myocardial infarction DAD study
Risk factors

• Relative risk 1.17 per year of ART 1.16 per
  year of PI therapy 0.94 per year of NNRTI
  therapy
• Traditional risk factors remain important (may
  predominate) age male sex smoking
  (50) prior CVD positive family
  history of premature IHD
• Lipid levels (high cholesterol / triglycerides,
  low HDL-C) all affect risk and partly explain PI
  risk

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Antiretroviral toxicity
MI prevention - ART switching
d4T switch to TDF (in presence of PI)
da Silva B et al, 7th Lipo workshop 2005
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Antiretroviral toxicity
MI prevention - ART switching
PI effects

• boosted PI to another boosted PI or EFV no
  data

Shafran et al, HIV Med 2005 Noor et al, 7th Lipo
workshop 2005 Malan et al, 13th CROI, 2006
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Antiretroviral toxicity
MI prevention - ART discontinuation
SMART
N
Events
Relative Risk (95 CI)
Total 114
1.5
CVD, liver, renal death 31
1.4
Non-fatal CVD 63
1.5
Non-fatal liver 14
1.4
gt
Non-fatal renal 7
2.5
Favors VS ?
0.1
1
10
El-Sadr, Neaton et al, 13th CROI 2006
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Antiretroviral toxicity
MI prevention
PI switching vs lipid-lowering therapy
Carr et al, AIDS 2001 Moyle et al, AIDS 2001
Miller et al, AIDS 2002 Mooser et al, AIDS 2002
Aberg et al, AIDS Res Hum Retrovirus 2005 Calza
et al, AIDS 2005
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Antiretroviral toxicity
MI prevention
Predicting MIs with Framingham equation
Observed
Predicted
MI per 1000 years
Law et al, HIV Med 2006
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Antiretroviral toxicity
MI prevention
Framingham equation

• Diabetics should be managed as if they have
  already had an MI

http//hin.nhlbi.nih.gov/atpiii/calculator.asp
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Antiretroviral toxicity
MI prevention
Framingham equation
http//hin.nhlbi.nih.gov/atpiii/calculator.asp
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Antiretroviral toxicity
MI prevention
Framingham equation
http//hin.nhlbi.nih.gov/atpiii/calculator.asp
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Question 2 Cardiovascular risk

• The patient should
• 1. switch rLPV to another boosted PI or EFV
• 2. switch d4T to other NRTI
• 3. stop all ART
• 4. start a statin
• 5. intervene based on full cardiovascular risk
  profile
• Key points
• 1. high total cholesterol is generally important
  only if other CV risk factors are present,
  particularly in women
• 2. if estimated risk is high, consider all risk
  factors
• 3. lipid-lowering therapy or PI switching may
  help but will not be the single most useful
  intervention for many patients with other risks,
  particular smokers

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Question 3 Lipoatrophy

• The patient should
• 1. switch rLPV to another PI or EFV
• 2. switch d4T to tenofovir
• 3. switch d4T to abacavir
• 4. stop all ART
• 5. start a lipoatrophy-specific drug
• 6. arrange for facial polylactic acid injections

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Antiretroviral toxicity
Lipoatrophy
d4T/AZT switch to ABC or TDF
BUT... return to normal 3 to 5kg 5-10
years?
Change from baseline (kg)
week

• PI switching not found to improve lipoatrophy

Carr et al, AIDS 2001 Carr et al, JAMA 2002
Martin et al, AIDS 2004 Moyle et al, CROI 2005
McComsey et al, Clin Infect Dis 2004 Milinkovic
et al, CROI 2005 Murphy et al, CROI 2005
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Antiretroviral toxicity
Lipoatrophy
Facial fillers - Polylactic acid

• Expensive requires plastic surgeon
• Wont stop progression of lipoatrophy unless
  cause(s) removed

Median change
skin thickness (mm)
week
Valantin et al, AIDS 2003
Photos courtesy P. Reiss
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Antiretroviral toxicity
Lipoatrophy investigational drugs
Sutinen et al, 7th Lipo workshop 2005 Mallon et
al, AIDS 2006 Slama et al, 13th CROI 2006
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Antiretroviral toxicity
Lipoatrophy investigational drugs
Sutinen et al, 7th Lipo workshop 2005 Mallon et
al, AIDS 2006 Slama et al, 13th CROI 2006
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Antiretroviral toxicity
Lipoatrophy investigational drugs
Sutinen et al, 7th Lipo workshop 2005 Mallon et
al, AIDS 2006 Slama et al, 13th CROI 2006
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Question 3 Lipoatrophy

• The patient should
• 1. switch rLPV to another PI or EFV no positive
  data
• 2. switch d4T to tenofovir
• 3. switch d4T to abacavir
• 4. stop all ART increased risk of death
• 5. start lipoatrophy-specific drug limited data
• 6. facial polylactic acid injections lipoatrophy
  will progress
• Key points
• 1. Lipoatrophy progressive over first 3 years of
  d4T / AZT
• 2. tNRTIs have a greater lipoatrophic effect
  than PIs
• 2. ART should not be stopped
• 3. ABC or TDF are reasonable choices for
  switching

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Question 4 Which new FDC pill?

• The patient is about to switch to ABC-3TC-EFV
  when he hears of new once-daily fixed-dose
  combination pills (TDF-FTC and ABC-3TC)
• What should he do?
• 1. nothing
• 2. switch d4T-3TC to ABC-3TC
• 3. switch d4T-3TC to TDF-FTC
• 4. doesnt matter

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Antiretroviral toxicity
Abacavir
Effects of HLA-B5701 testing

• Hypersensitivity 8 to 1
• Cessation for any reason 16 to 3

Rauch et al, Clin Infect Dis 2006
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Antiretroviral toxicity
Tenofovir
Nephrotoxicity

• Risk factors in cohort studies
• patient low GFR, low CD4 count, HT, anaemia, DM,
  IDU
• drugs TDF, RTV boosting (AZV/LPV/TPV)

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Antiretroviral toxicity
Tenofovir
Osteopenia

• Greater ? bone turnover markers with TDF
• bone ALP
• osteocalcin
• telopeptides
• Fractures
• d4T (4)
• TDF (1)

week
Staszewski et al, JAMA 2004
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Question 4 Which new FDC pill?

• The patient is about to switch to ABC-3TC-EFV
  when he hears of new once-daily fixed-dose
  combination pills (TDF-FTC and ABC-3TC)
• What should he do?
• 1. nothing
• 2. switch d4T-3TC to ABC-3TC if
  HLAB5701-negative
• 3. switch d4T-3TC to TDF-FTC if at low risk of
  TDF nephrotoxicity (and satisfactory BMD?)
• 4. doesnt matter
• Follow-up assessments
• 1. lipid profile every 12 months
• 2. DEXA in 12 months (soft-tissue and bone)
• 3. eGFR
• 4. FTC - ??

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Case presentation

• Switched d4T-3TC-rLPV to TDF-FTC-EFV
• Severe, acute CNS effects - loses job
• CNS effects resolve gets job back
• Subsequent HLA-B5701 negative on molecular
  typing
• Lipid levels
• total cholesterol - 280 to 200 mg/dl (7.2 to 5.1
  mmol/l)
• HDL cholesterol - no change (44 mg/dl 1.1
  mmol/l)
• estimated 10-year MI risk falls from 9 to 5...
• Lipoatrophy likely to slowly improve but wont
  normalize
• Continues with RNA lt50 and normal CD4 count

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Key points

• Toxicity remains an obstacle to long-term,
  successful ART
• Switching ART incurs risks, sometimes unknown
• New drugs to treat toxicity is probably not an
  ideal strategy for lifelong therapy
• Sometimes we over-react to toxicity, real and
  perceived

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Key points
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For further details, please visit www.intmedpress
.com/lipodystrophy

• Abstract categories
• Adipocyte biology Clinical management of ADRs
• Cardiovascular disease Hepatotoxicity
• Mitochondrial disorders Lipid metabolism
• Body composition Insulin resistance
• Plenary lectures
• Karine Clement Adipose tissue interactions
• Matthias Egger Review of HIV cardiovascular
  studies
• Marion Peters Predictors of hepatotoxicity
• Kitt Petersen Mitochondria and insulin
  resistance
• Jorge Plutzsky New drugs for metabolic
  disorders
• Winfried Sieffert Pharmacogenomics and the
  metabolic syndrome

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Antiretroviral toxicity
Myocardial infarction DAD study
Risk of MI by antiretroviral duration and type
Friis-Møller et al, 13th CROI 2006
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Antiretroviral toxicity
Myocardial infarction DAD study
Risk of MI traditional risk factors
Adjusted relative rate of myocardial infarction
(95 CI) Uni- and multivariable Poisson model
El-Sadr et al, 12th CROI 2005
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Antiretroviral toxicity
Myocardial infarction DAD study
Risk of MI by lipid levels
Relative rate of myocardial infarction (95
CI) Poisson regression models also adjusted for
gender, age, cohort, HIV exposure group,
ethnicity, BMI, family history, previous
cardiovascular event, smoking status and calendar
year.
El-Sadr et al, 12th CROI 2005