Transcript Toxicity

ARV overview and
toxicity
Dr Francois Venter
Reproductive Health Research Unit
University of the Witwatersrand
HAART experience
Current HAART experience
< 9 years
Future safety and efficacy
Non-nuke
2 Nukes
d4T
3TC
Failure –
VL>5000
AZT
Efavirenz/
nevirapine
Protease
ddI
Kaletra
Guidelines….Americans 19962000
► All
symptomatic patients (CD4/VL not an
issue)
► For chronic infection:
- CD4<500 or
- viral load>10 000 – 20 000
So when to start? Critical
questions…
► Can
HIV be eradicated with HAART?
► Better virological outcomes with earlier
treatment?
► Better immunological responses with earlier
treatment?
► Lower drug toxicity with earlier treatment?
► Are there better clinical outcomes?
So when to start? Critical
questions…
► Can
HIV be eradicated with HAART?
NO
► Better virological outcomes with earlier
treatment?
► Better immunological responses with
earlier treatment?
► Lower drug toxicity with earlier
treatment?
► Are there better clinical outcomes?
So when to start? Critical
questions…
► Can
HIV be eradicated with HAART? NO
► Better virological outcomes with
earlier treatment?
► Better immunological responses with
earlier treatment?
► Lower drug toxicity with earlier
treatment?
► Are there better clinical outcomes?
So, to get maximum viral
suppression…
► Viral
load not an issue
► CD4<200 not ideal, but not bad
► CD4<50 definitely less effective
► CD4 200-350 and above 350 – get
equivalent responses
So when to start? Critical
questions…
► Can
HIV be eradicated with HAART? NO
► Better virological outcomes with
earlier treatment? NO
► Better immunological responses with
earlier treatment?
► Lower drug toxicity with earlier
treatment?
► Are there better clinical outcomes?
So when to start? Critical
questions…
► Can
HIV be eradicated with HAART? NO
► Better virological outcomes with earlier
treatment? NO
► Better immunological responses
with earlier treatment?
► Lower drug toxicity with earlier
treatment?
► Are there better clinical outcomes?
Immunological
outcomes…
► Need
quantitative and
qualitative outcome
► CD4 is rough but
robust marker
► The lower the CD4, the less recovery occurs
Immunology cont…
► AIDS
2001; 15;983 ICONA trial:
► CD4 rise 280 if started >350,
► CD4 rise 281 if CD4 201-350, and
► CD4 rise 186 if<200
► Almost no difference in VL undetectable
Immunology cont…
► Ann
Intern Med 2000;133:401 – 17%
patients only had virological response
Immunology cont…
► But:
even with no CD4 response - significant
benefit (Lancet 1999;353:863 – 20.1% vs
55% OI rate if no HAART)
Immunology cont…
► Ideal:
initiate before critical CD4 reached
So when to start? Critical
questions…
► Can
HIV be eradicated with HAART? NO
► Better virological outcomes with earlier
treatment? NO
► Better immunological responses
with earlier treatment? YES
► Lower drug toxicity with earlier
treatment?
► Are there better clinical outcomes?
So when to start? Critical
questions…
► Can
HIV be eradicated with HAART? NO
► Better virological outcomes with earlier
treatment? NO
► Better immunological responses with
earlier treatment? YES
► Lower drug toxicity with earlier
treatment?
► Are there better clinical outcomes?
Drug toxicity…
► In
general – the lower the
CD4, the higher the incidence
of short-term toxicity
► BUT – the long-term toxicity is
the most worrying:
lipodystrophy a major reason
for change in guidelines; lactic
acidosis emerging as problem
► Delay=more short term
toxicity, but delays onset of
long term toxicity
So when to start? Critical
questions…
► Can
HIV be eradicated with HAART? NO
► Better virological outcomes with earlier
treatment? NO
► Better immunological responses with
earlier treatment? YES
► Lower drug toxicity with earlier
treatment? Short term YES, long
term NO
► Are there better clinical outcomes?
So when to start? Critical
questions…
►
►
►
►
Can HIV be eradicated with HAART? NO
Better virological outcomes with earlier treatment? NO
Better immunological responses with earlier treatment? YES
Lower drug toxicity with earlier treatment? YES and NO
►Are
there better clinical
outcomes with earlier
treatment?
BUT…..
► All
retrospective data
► Some discordance from the data
► Blacks and women under-represented
► ?role age, women
► What happens at 3,5, 10 years?
► None of it from Africa
► Does starting later increase risk of TB?
When all think alike, no one is thinking - Lippman
Side effects
Dr Francois Venter
Reproductive Health Research Unit
Johannesburg Hospital
► 1st
350 patients: 1st 10 weeks
► 44% significant side effects
► Dizziness, confusion, rash, bad dreams,
peripheral neuropathy, anaemia
► 10 stopped! Rash, peripheral neuropathy,
dizziness
► IRIS is a problem - ?side effects…
Teratogenicity
► “Safe”
vs “unknown”
► C vs B:
► For SA: nevirapine vs efavirenz – we’ll find
out fast
► Do NOT confuse teratogenicity with
maternal toxicity (lactic acidosis)
Non Nucleoside RTI’s
► Nevirapine
and Efavirenz
- Rash
►Common
- up to 20%
►Stevens Johnson Syndrome
-
Liver Toxicity : up to 20% of pts on NVP, 2x
higher in females, can be fatal. LFTs must be
done
- Rash
- Neuropsychiatric
GIT
► All
manner
► Pancreatitis – all the d’s
MARROW SUPPRESSION
► All



NRTI’s
Most common with AZT
Effect of uncontrolled HIV
Other causes e.g. infections, nutritional,
autoimmune, drugs and infiltrations
Investigations: Full Blood count & smear
Reticulocyte count, coombs
Vitamin B12, Red cell folate, Iron studies
Bone marrow aspirate, trephine and TB culture
NEUROPATHY
 Predominantly axonal degeneration
 EMG
 Exclude
►Drugs
(INH, Metronidazole, Dapsone)
►Alcohol, Diabetes, Hypothyroidism
►B12 deficiency
 Treatment :
1. Stop drugs; 2. Rx underlying
pathology; 3. Avoid trauma; 4. Analgesia
►
Lactic Acidosis
► d4T,
all the others
► Clinical
Symptoms and Signs
Loss weight
Nausea, Vomiting
Abdominal discomfort
Extreme Fatigue
Hyperventilation
Liver failure and Pancreatitis
MYOPATHY
 ?
 Mostly AZT
 Proximal myopathy
Protease Inhibitors
► Lipodystrophy
 Fat redistribution
 Raised triglycerides and cholesterol
 Elevated blood sugar
► General
symptoms are moderately severe
and relatively common
► Nephrolithiasis (Indinavir >30%)
Common side effects and
HAART…
► Diabetes
► Hypertension
► Raised
cholesterol, decreased HDL, raised
LDL
► Endothelial dysfunction
► Lipodystrophy, with increased intraabdominal fat
Prescription pad
Dr WDF Venter, Physician
27 Eton Road, Parktown, 2193
(011) 717 2810
7 October 2005
Re: Mr John Smit
Discovery Super-duper Vitality Xtra member 100234
Please provide:
1)
Trizovir 1 BD
2)
Atenolol 100 mg/d
3)
Aspirin 150mg/d
4)
Perindopril 4 mg/d
5)
Pravastatin 1/d
6)
Metformin 850mg/d
7)
Glicazide 80mg BD
8)
Bezalip 1 BD
9)
Prozac 20mg/d
10) Viagra 25mg PRN
Regards
WDF Venter
FCP (SA), DTM&H
Abdominal MRI Scans
SAT
Control Subject
Increased VAT
SAT
What Are the Treatment Options?
►
►
►
Lifestyle changes
►
Hypoglycemic agents

Exercise

Thiazolidinediones

Diet

Metformin
Lipid-lowering agents

Fibric acid derivatives

Statins
Drugs

Growth hormone

Anabolic steroids

Dietary supplements
►
Surgical interventions

Surgical
removal/liposuction

Facial implants

Fat transfer techniques
“The drugs are toxic. The disease is toxicer.” –
Dr Francesca Conradie
The END…
Drug interactions
WHAT IS THE PATIENT TAKING ?
► Prescription
?
► Non-prescription ?
- OTC drugs antacids, analgesics, H2-antagonists
- Alternative medicines eg St John’s Wort
- Illicit drugs
ANTI-INFECTIVES
-
Antiretrovirals: AZT & d4T, ddI & IDV, ddC & 3TC.
- Antibiotics: Clarithromycin & PIs & NNRTIs,
Ciprofloxacin and ddI
Rifampicin & Pis and NNRTIs also
ddI, AZT
- Antifungals: Fluconazole & AZT,
Ketoconazole/Itraconazole & PIs and NNRTIs
also ddI
ANTICONVULSANTS
- carbamazepine, phenytoin, phenobarbitone
AVOID ALL PI’s and NNRTIs
- Valproate
AVOID AZT AND RTV
COLDS AND ALLERGY AGENTS
Eg Preparations containing astemizol,
loratidine, promethazine and terfenadine.
AVOID WHEN ON Pis and NNRTIS
GASTROINTESTINAL AGENTS
- Antacids, H2-antagonists, proton pump
inhibitors
Must be given 1-2 hours after ddI, IDV
CARDIOVASCULAR AGENTS
- Lipitor/Zocor: AVOID Pis or change to
Pravastatin
- Ca antagonists: AVOID Pis
- Warfarin: AVOID Pis and NNRTIs
HYPOGLYCAEMICS
- Sulphonylureas
- Metformin
AVOID RITONAVIR
HOMEOPATHIC
•St John’s Wort
•Garlic Pills
•Grapefruit juice