Making antiretroviral therapy forever
Andrew Carr St Vincent’s Hospital Sydney, Australia
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
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
Antiretroviral toxicity
Hepatotoxicity
Cause ARVs Risks Lactic acidemia ddI, d4T other NRTIs NRTI durn ribavirin pregnancy obesity female
Antiretroviral toxicity
Hepatotoxicity
Cause ARVs Risks Lactic acidemia Hyper sensitivity
ddI, d4T NVP other NRTIs NRTI durn ribavirin pregnancy obesity female CD4
Antiretroviral toxicity
Hepatotoxicity
Cause ARVs Risks Lactic acidemia Hyper sensitivity Isolated hepatitis RTV, NVP HCV RNA+ ALT
ddI, d4T NVP other NRTIs NRTI durn ribavirin pregnancy obesity female CD4
Antiretroviral toxicity
Hepatotoxicity
Cause ARVs Risks Lactic acidemia Hyper sensitivity Isolated hepatitis RTV, NVP Immune reactivation Any
ddI, d4T NVP other NRTIs NRTI durn ribavirin pregnancy obesity female CD4
HCV RNA+ CD4<100 ALT HBV+, HCV+ MAC bacteremia CMV viraemia recent TB
Antiretroviral toxicity
Hepatotoxicity
Cause ARVs Risks Lactic acidemia Hyper sensitivity Isolated hepatitis RTV, NVP Immune reactivation Any HBV flare reactivation stopping 3TC, FTC, TDF
ddI, d4T NVP other NRTIs NRTI durn ribavirin pregnancy obesity female CD4
HCV RNA+ CD4<100 HBV DNA+ ALT HBV+, HCV+ pre-therapy MAC bacteremia CMV viraemia recent TB
Antiretroviral toxicity
Hepatotoxicity
Cause Clinical onset fever rash jaundice dyspnoea failure Laboratory ALT > 10x lactate > 2 Therapy Lactic acidemia Hyper sensitivity Isolated hepatitis Immune reactivation HBV flare
late no no no yes occasional
no yes cease NRTIs
early common common occasional no ?1%
common no cease ARV therapy
early/late occasional no occasional no ?1%
common no cease ARVs + treat HCV or HBV
early yes no common no common
common no cease all treat OI
early yes no common no common
common no restart HBV therapy
Antiretroviral toxicity
Hepatotoxicity
Nevirapine hepatitis
• ALT > 10 x ULN • clinical hepatitis 5-10% 2-3%
• fulminant hepatitis rare • rash in 50% of those with hepatitis (?hypersensitivity) • risk factors for increase in ALT to > 5 x ULN women CD4 > 250 11% CD4 < 250 1% men CD4 > 400 6% CD4 < 400 2% HBV/HCV+ ALT normal 4% ALT 2.5-5 x ULN 6%
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
baseline CD4 >200 no rash, fever, mucositis
early; high ALT; ? lactate 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 > 10x ULN
Case presentation
• • • • Switched to d4T-3TC-rLPV Nausea and fatigue resolved by week 12 Continues with RNA <50 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?
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
Antiretroviral toxicity
Myocardial infarction – D:A:D 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
Antiretroviral toxicity
MI prevention - ART switching
d4T switch to TDF (in presence of PI)
TC 0 -0.5
mmol/L
-0.41
TG
HDL-C
0 -0.02
LDL-C
0 0
p=NS
p=NS
p=NS p=NS
p=0.009 -0.67 -1 p=0.004
Wk 12 (n=37)
-1.34
-1.5 -2
p=0.023
-2.09
Wk 24 (n=23)
-2.5
p=0.033 da Silva B et al, 7th Lipo workshop 2005
Antiretroviral toxicity
MI prevention - ART switching
PI effects
• boosted PI to another boosted PI or EFV – no data Parameter 10-14 days 48 weeks Patient Cholesterol Triglycerides group Total HDL HIVHIV+ +12% -10% +10% +30% +25% +30% Insulin sensitivity no change or ↓ unknown
Shafran et al, HIV Med 2005; Noor et al, 7th Lipo workshop 2005; Malan et al, 13th CROI, 2006
Antiretroviral toxicity
MI prevention - ART discontinuation
SMART
Events Total CVD, liver, renal death Non-fatal CVD Non-fatal liver Non-fatal renal
0.1
N 114 31 63 14 7 ►
Relative Risk (95% CI) 1.5 1.4 1.5 1.4 2.5
1 10 Favors VS ►
>
Favors DC
El-Sadr, Neaton et al, 13th CROI 2006
Antiretroviral toxicity
MI prevention
PI switching vs lipid-lowering therapy
PI switch Cholesterol HDL cholesterol Triglycerides -10 to -30% 0 to +3% -10 to -25% Statin -11 to -45% 0 to +6% 0 to -25% Fibrate 0 to -5% 0 to +17% -20 to -45%
Insulin sensitivity
Variable
No change
No change
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
Antiretroviral toxicity
MI prevention
Predicting MIs with Framingham equation
8 7
MI per 1000 years
6 5 4 3 2 1 0
Observed
Predicted
0
<1
1-2
2-3
3-4
4+
Duration of HAART (years)
Law et al, HIV Med 2006
Antiretroviral toxicity
MI prevention
Framingham equation
Risk score results: Age Gender 50 male
Total Cholesterol (mg/dl)
HDL Cholesterol (mg/dl) Smoker Systolic Blood Pressure (mmHg) On medication for HBP Risk Score*
280 (7.2 mmol/l)
44 No 125 No (1.1 mmol/l)
9%
• Diabetics should be managed as if they have already had an MI
http://hin.nhlbi.nih.gov/atpiii/calculator.asp
Antiretroviral toxicity
MI prevention
Framingham equation
Risk score results: Age: Gender: 50 male
30
male
50 male
50 male
50 male
50 male
50 male
50 male
Total Cholesterol (mg/dl)
HDL Cholesterol (mg/dl) Smoker: Systolic Blood Pressure (mmHg)
280
44 No 125
280
44 No 125
230
44 No 125
200
44 No 125
280
280
44 No
280
44
280
44
35
No 125
Yes
125
Yes 150
No
150
No
On medication for HBP:
No
No
No
No
No
No
Risk Score
9%
1%
6%
5%
11%
11%
22%
27%
http://hin.nhlbi.nih.gov/atpiii/calculator.asp
Antiretroviral toxicity
MI prevention
Framingham equation
Risk score results: Age: Gender: 50
30
280
44 No 125
50
50
50
50
50
50
Total Cholesterol (mg/dl)
HDL Cholesterol (mg/dl) Smoker: Systolic Blood Pressure (mmHg)
280
44 No 125
230
44 No 125
200
44 No 125
280
280
44 No
280
44
280
44
35
No 125
Yes
125
Yes 150
No
150
No
On medication for HBP:
No
No
No
No
No
No
Risk Score (if male) Risk Score (if female)
9% 2%
1% <1%
6% 1%
5% 1%
11% 3%
11% 3%
22% 8%
27% 12%
http://hin.nhlbi.nih.gov/atpiii/calculator.asp
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
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
Antiretroviral toxicity
Lipoatrophy
d4T/AZT switch to ABC or TDF
Change from baseline (kg)
1.4 1.2 1 0.8 0.6 0.4 0.2 0 0 24 48 week 72 108
BUT... return to normal = +3 to 5kg = 5-10 years?
MITOX - ABC RAVE - ABC RAVE - TDF TARHEEL tNRTI to rLPV d4T4030 - TDF
• 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
Antiretroviral toxicity
Lipoatrophy
Facial fillers - Polylactic acid
• Expensive; requires plastic surgeon
• Won’t stop progression of lipoatrophy unless cause(s) removed
10
Median change skin thickness (mm)
8 6 4 2 0 6 24
Photos courtesy P. Reiss
48 week
72 96 Valantin et al, AIDS 2003
Antiretroviral toxicity
Lipoatrophy – investigational drugs
Uridine Duration 12 weeks Sample size 9 per arm Δ Limb fat (kg) 0.7kg Mechanism unknown Efficacy on AZT / d4T yes no AZT / d4T unknown Cost US$300/month
Sutinen et al, 7th Lipo workshop 2005; Mallon et al, AIDS 2006; Slama et al, 13th CROI 2006
Antiretroviral toxicity
Lipoatrophy – investigational drugs
Uridine Duration 12 weeks Sample size 9 per arm Δ Limb fat (kg) 0.7kg Mechanism unknown Efficacy on AZT / d4T yes no AZT / d4T unknown Cost US$300/month Pravastatin 12 weeks 16 per arm 0.5kg unknown unknown yes cheap
Sutinen et al, 7th Lipo workshop 2005; Mallon et al, AIDS 2006; Slama et al, 13th CROI 2006
Antiretroviral toxicity
Lipoatrophy – investigational drugs
Uridine Duration 12 weeks Sample size 9 per arm Δ Limb fat (kg) 0.7kg Mechanism unknown Efficacy on AZT / d4T yes no AZT / d4T unknown Cost US$300/month Pravastatin 12 weeks 16 per arm 0.5kg unknown unknown yes cheap Pioglitazone 48 weeks 65 per arm 0.33kg PPAR-g no yes US$70/month
Sutinen et al, 7th Lipo workshop 2005; Mallon et al, AIDS 2006; Slama et al, 13th CROI 2006
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 lipoatrophy-specific drug 6. facial polylactic acid injections no positive data
increased risk of death limited data 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
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. doesn’t matter
Antiretroviral toxicity
Abacavir
Effects of HLA-B*5701 testing
• Hypersensitivity • Cessation for any reason
8% to 1% 16% to 3%
Rauch et al, Clin Infect Dis 2006
Antiretroviral toxicity
Tenofovir Nephrotoxicity
Cohorts
(n=9) Follow-up
ARV-naïve trials
Gilead 934 Gilead 903 12 months 24 months 36 months
Change (relative to control) CrCl (ml/min; C-G equation) eGFR (ml/min/1.73m2; MDRD) GFR grade 2 (60-89) GFR grade 3-4 (<60)
-6% -10% ? (1-4%)
0 -12% ? 0
-4% -10% ≈5% 0
• Risk factors in cohort studies – patient low GFR, low CD4 count, HT, anaemia, DM, IDU – drugs TDF, RTV boosting (AZV/LPV/TPV)
Antiretroviral toxicity
Tenofovir
Osteopenia
0 -1 -2 -3 -4 -5 0 24 48 week 72 96 TDF d4T
• Greater bone turnover markers with TDF – bone ALP – osteocalcin – telopeptides • Fractures – d4T (4%) – TDF (1%)
Staszewski et al, JAMA 2004
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 HLAB*5701-negative 3. switch d4T-3TC to TDF-FTC if at low risk of TDF nephrotoxicity (and satisfactory BMD?) 4. doesn’t matter • Follow-up assessments 1. lipid profile every 12 months 2. DEXA in 12 months (soft-tissue and bone) 3. eGFR 4. FTC - ??
Case presentation
• • • • • Switched d4T-3TC-rLPV to TDF-FTC-EFV Severe, acute CNS effects - loses job CNS effects resolve – gets job back Subsequent HLA-B*5701 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 won’t normalize • Continues with RNA <50 and normal CD4 count
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
Key points