arv overview and toxicity dr francois venter reproductive health research unit university of the...

ARV overview and ARV overview and toxicitytoxicity

Dr Francois VenterDr Francois Venter

Reproductive Health Research Reproductive Health Research UnitUnit

University of the WitwatersrandUniversity of the Witwatersrand

HAART experienceHAART experience

Current HAART experience

Future safety and efficacy

< 9 years

ddI

d4T

AZT

3TC

2 Nukes Non-nuke

Efavirenz/ nevirapine

Protease

Kaletra

Failure – VL>5000

Guidelines….Americans Guidelines….Americans 1996-20001996-2000

►All symptomatic patients (CD4/VL not All symptomatic patients (CD4/VL not an issue)an issue)

►For chronic infection:For chronic infection:

- CD4<500 or- CD4<500 or

- viral load>10 000 – 20 000 - viral load>10 000 – 20 000

So when to start? Critical So when to start? Critical questions…questions…

►Can HIV be eradicated with HAART?Can HIV be eradicated with HAART?►Better virological outcomes with earlier Better virological outcomes with earlier

treatment?treatment?►Better immunological responses with Better immunological responses with

earlier treatment?earlier treatment?►Lower drug toxicity with earlier Lower drug toxicity with earlier

treatment?treatment?►Are there better clinical outcomes?Are there better clinical outcomes?

So when to start? Critical So when to start? Critical questions…questions…

►Can HIV be eradicated with HAART? Can HIV be eradicated with HAART? NONO

►Better virological outcomes with earlier Better virological outcomes with earlier treatment?treatment?

►Better immunological responses with Better immunological responses with earlier treatment?earlier treatment?

►Lower drug toxicity with earlier treatment?Lower drug toxicity with earlier treatment?►Are there better clinical outcomes?Are there better clinical outcomes?

So when to start? Critical So when to start? Critical questions…questions…

►Can HIV be eradicated with HAART? NOCan HIV be eradicated with HAART? NO►Better virological outcomes with Better virological outcomes with

earlier treatment?earlier treatment?►Better immunological responses with Better immunological responses with

earlier treatment?earlier treatment?►Lower drug toxicity with earlier Lower drug toxicity with earlier

treatment?treatment?►Are there better clinical outcomes?Are there better clinical outcomes?

So, to get maximum viral So, to get maximum viral suppression…suppression…

►Viral load not an issueViral load not an issue►CD4<200 not ideal, but not badCD4<200 not ideal, but not bad►CD4<50 definitely less effectiveCD4<50 definitely less effective►CD4 200-350 and above 350 – get CD4 200-350 and above 350 – get

equivalent responsesequivalent responses

So when to start? Critical So when to start? Critical questions…questions…

►Can HIV be eradicated with HAART? NOCan HIV be eradicated with HAART? NO►Better virological outcomes with Better virological outcomes with

earlier treatment? NOearlier treatment? NO►Better immunological responses with Better immunological responses with

earlier treatment?earlier treatment?►Lower drug toxicity with earlier Lower drug toxicity with earlier

treatment?treatment?►Are there better clinical outcomes?Are there better clinical outcomes?

So when to start? Critical So when to start? Critical questions…questions…

►Can HIV be eradicated with HAART? NOCan HIV be eradicated with HAART? NO►Better virological outcomes with earlier Better virological outcomes with earlier

treatment? NOtreatment? NO►Better immunological responses Better immunological responses

with earlier treatment?with earlier treatment?►Lower drug toxicity with earlier Lower drug toxicity with earlier

treatment?treatment?►Are there better clinical outcomes?Are there better clinical outcomes?

Immunological Immunological outcomes…outcomes…

►Need quantitative and Need quantitative and qualitative outcome qualitative outcome

►CD4 is rough but CD4 is rough but robust markerrobust marker

►The lower the CD4, the less recovery The lower the CD4, the less recovery occursoccurs

Immunology cont…Immunology cont…

►AIDS 2001; 15;983 ICONA trial: AIDS 2001; 15;983 ICONA trial: ►CD4 rise 280 if started >350, CD4 rise 280 if started >350, ►CD4 rise 281 if CD4 201-350, and CD4 rise 281 if CD4 201-350, and ►CD4 rise 186 if<200 CD4 rise 186 if<200 ►Almost no difference in VL Almost no difference in VL

undetectableundetectable

Immunology cont…Immunology cont…

►Ann Intern Med 2000;133:401 – 17% Ann Intern Med 2000;133:401 – 17% patients only had virological responsepatients only had virological response

Immunology cont…Immunology cont…

►But: even with no CD4 response - But: even with no CD4 response - significant benefit (Lancet significant benefit (Lancet 1999;353:863 – 20.1% vs 55% OI rate 1999;353:863 – 20.1% vs 55% OI rate if no HAART)if no HAART)

Immunology cont…Immunology cont…

► Ideal: initiate before critical CD4 Ideal: initiate before critical CD4 reachedreached

So when to start? Critical So when to start? Critical questions…questions…

►Can HIV be eradicated with HAART? NOCan HIV be eradicated with HAART? NO►Better virological outcomes with earlier Better virological outcomes with earlier

treatment? NOtreatment? NO►Better immunological responses Better immunological responses

with earlier treatment? YESwith earlier treatment? YES►Lower drug toxicity with earlier Lower drug toxicity with earlier

treatment?treatment?►Are there better clinical outcomes?Are there better clinical outcomes?

So when to start? Critical So when to start? Critical questions…questions…

►Can HIV be eradicated with HAART? Can HIV be eradicated with HAART? NONO

►Better virological outcomes with Better virological outcomes with earlier treatment? NOearlier treatment? NO

►Better immunological responses with Better immunological responses with earlier treatment? YESearlier treatment? YES

►Lower drug toxicity with earlier Lower drug toxicity with earlier treatment?treatment?

►Are there better clinical outcomes?Are there better clinical outcomes?

Drug toxicity…Drug toxicity…

► In general – the lower the In general – the lower the CD4, the higher the incidence CD4, the higher the incidence of short-term toxicityof short-term toxicity

► BUT – the long-term toxicity BUT – the long-term toxicity is the most worrying: is the most worrying: lipodystrophy a major reason lipodystrophy a major reason for change in guidelines; for change in guidelines; lactic acidosis emerging as lactic acidosis emerging as problemproblem

►Delay=more short term Delay=more short term toxicity, but delays onset of toxicity, but delays onset of long term toxicitylong term toxicity

So when to start? Critical So when to start? Critical questions…questions…

►Can HIV be eradicated with HAART? NOCan HIV be eradicated with HAART? NO►Better virological outcomes with earlier Better virological outcomes with earlier

treatment? NOtreatment? NO►Better immunological responses with Better immunological responses with

earlier treatment? YESearlier treatment? YES►Lower drug toxicity with earlier Lower drug toxicity with earlier

treatment? Short term YES, long treatment? Short term YES, long term NOterm NO

►Are there better clinical outcomes?Are there better clinical outcomes?

So when to start? Critical So when to start? Critical questions…questions…

► Can HIV be eradicated with HAART? NOCan HIV be eradicated with HAART? NO► Better virological outcomes with earlier treatment? NOBetter virological outcomes with earlier treatment? NO► Better immunological responses with earlier treatment? Better immunological responses with earlier treatment?

YESYES► Lower drug toxicity with earlier treatment? YES and NOLower drug toxicity with earlier treatment? YES and NO

►Are there better clinical Are there better clinical outcomes with earlier outcomes with earlier

treatment?treatment?

BUT…..BUT…..

►All retrospective dataAll retrospective data►Some discordance from the dataSome discordance from the data►Blacks and women under-representedBlacks and women under-represented►?role age, women?role age, women►What happens at 3,5, 10 years?What happens at 3,5, 10 years?►None of it from AfricaNone of it from Africa►Does starting later increase risk of TB?Does starting later increase risk of TB?

When all think alike, no one is thinking - Lippman

Side effectsSide effects

Dr Francois VenterDr Francois Venter

Reproductive Health Research Reproductive Health Research UnitUnit

Johannesburg HospitalJohannesburg Hospital

►11stst 350 patients: 1 350 patients: 1stst 10 weeks 10 weeks►44% significant side effects44% significant side effects►Dizziness, confusion, rash, bad Dizziness, confusion, rash, bad

dreams, peripheral neuropathy, dreams, peripheral neuropathy, anaemiaanaemia

►10 stopped! Rash, peripheral 10 stopped! Rash, peripheral neuropathy, dizzinessneuropathy, dizziness

► IRIS is a problem - ?side effects…IRIS is a problem - ?side effects…

TeratogenicityTeratogenicity

►““Safe” vs “unknown”Safe” vs “unknown”►C vs B: C vs B: ►For SA: nevirapine vs efavirenz – we’ll For SA: nevirapine vs efavirenz – we’ll

find out fastfind out fast►Do NOT confuse teratogenicity with Do NOT confuse teratogenicity with

maternal toxicity (lactic acidosis)maternal toxicity (lactic acidosis)

Non Nucleoside RTI’sNon Nucleoside RTI’s

►Nevirapine and EfavirenzNevirapine and Efavirenz- Rash- Rash

►Common - up to 20%Common - up to 20%►Stevens Johnson SyndromeStevens Johnson Syndrome

- Liver Toxicity : Liver Toxicity : up to 20% of pts on up to 20% of pts on NVP, 2x higher in females, can be fatal. NVP, 2x higher in females, can be fatal. LFTs must be doneLFTs must be done

- RashRash- NeuropsychiatricNeuropsychiatric

GITGIT

►All mannerAll manner►Pancreatitis – all the d’sPancreatitis – all the d’s

MARROW SUPPRESSIONMARROW SUPPRESSION► All NRTI’sAll NRTI’s

Most common with AZTMost common with AZT Effect of uncontrolled HIVEffect of uncontrolled HIV Other causes e.g. infections, nutritional, Other causes e.g. infections, nutritional,

autoimmune, drugs and infiltrationsautoimmune, drugs and infiltrations

Investigations:Investigations: Full Blood count & smearFull Blood count & smear

Reticulocyte count, coombsReticulocyte count, coombs

Vitamin B12, Red cell folate, Iron studiesVitamin B12, Red cell folate, Iron studies

Bone marrow aspirate, trephine and TBBone marrow aspirate, trephine and TB cultureculture

NEUROPATHYNEUROPATHY

Predominantly axonal Predominantly axonal degenerationdegeneration

EMGEMG ExcludeExclude

►Drugs (INH, Metronidazole, Dapsone)Drugs (INH, Metronidazole, Dapsone)►Alcohol, Diabetes, HypothyroidismAlcohol, Diabetes, Hypothyroidism►B12 deficiencyB12 deficiency

TreatmentTreatment : : 1. Stop drugs; 2. Rx 1. Stop drugs; 2. Rx underlying pathology; 3. Avoid trauma; 4. underlying pathology; 3. Avoid trauma; 4. AnalgesiaAnalgesia

►

Lactic AcidosisLactic Acidosis

► d4T, all the othersd4T, all the others

► Clinical Symptoms and SignsClinical Symptoms and Signs

Loss weightLoss weight

Nausea, VomitingNausea, Vomiting

Abdominal discomfortAbdominal discomfort

Extreme FatigueExtreme Fatigue

HyperventilationHyperventilation

Liver failure and PancreatitisLiver failure and Pancreatitis

MYOPATHYMYOPATHY

?? Mostly AZTMostly AZT Proximal myopathyProximal myopathy

Protease InhibitorsProtease Inhibitors

►LipodystrophyLipodystrophy Fat redistributionFat redistribution Raised triglycerides and cholesterolRaised triglycerides and cholesterol Elevated blood sugarElevated blood sugar

►General symptoms are moderately General symptoms are moderately severe and relatively commonsevere and relatively common

►Nephrolithiasis (Indinavir >30%)Nephrolithiasis (Indinavir >30%)

Common side effects and Common side effects and HAART…HAART…

►DiabetesDiabetes►HypertensionHypertension►Raised cholesterol, decreased HDL, Raised cholesterol, decreased HDL,

raised LDLraised LDL►Endothelial dysfunctionEndothelial dysfunction►Lipodystrophy, with increased intra-Lipodystrophy, with increased intra-

abdominal fatabdominal 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

Regards

WDF Venter

FCP (SA), DTM&H

6)      Metformin 850mg/d

7)      Glicazide 80mg BD

8)      Bezalip 1 BD

9)      Prozac 20mg/d

10)    Viagra 25mg PRN

Abdominal MRI Scans

Control Subject Increased VATSAT

SAT

What Are the Treatment What Are the Treatment Options?Options?

► Lifestyle changesLifestyle changes ExerciseExercise

DietDiet

► Lipid-lowering agentsLipid-lowering agents Fibric acid derivatives Fibric acid derivatives

StatinsStatins

► DrugsDrugs Growth hormoneGrowth hormone

Anabolic steroids Anabolic steroids

Dietary supplementsDietary supplements

► HypoglycemicHypoglycemic agentsagents Thiazolidinediones Thiazolidinediones

MetforminMetformin

► Surgical interventionsSurgical interventions Surgical Surgical

removal/liposuctionremoval/liposuction

Facial implantsFacial implants

Fat transfer Fat transfer techniquestechniques

“The drugs are toxic. The disease is toxicer.” – Dr Francesca Conradie

The END…

Drug interactionsDrug interactions

WHAT IS THE PATIENT WHAT IS THE PATIENT TAKING ?TAKING ?

►Prescription ?Prescription ?►Non-prescription ?Non-prescription ?

- - OTC drugs antacids, analgesics, H2-OTC drugs antacids, analgesics, H2-antagonistsantagonists

- Alternative medicines eg St John’s Wort- Alternative medicines eg St John’s Wort

- Illicit drugs- Illicit drugs

ANTI-INFECTIVESANTI-INFECTIVES

- - Antiretrovirals: AZT & d4T, ddI & IDV, ddC & Antiretrovirals: AZT & d4T, ddI & IDV, ddC & 3TC.3TC.

- Antibiotics: Clarithromycin & PIs & NNRTIs, - Antibiotics: Clarithromycin & PIs & NNRTIs, Ciprofloxacin and ddI Ciprofloxacin and ddI

Rifampicin & Pis and NNRTIs also Rifampicin & Pis and NNRTIs also ddI, AZT ddI, AZT

- Antifungals: Fluconazole & AZT, - Antifungals: Fluconazole & AZT, Ketoconazole/Itraconazole & PIs and NNRTIsKetoconazole/Itraconazole & PIs and NNRTIs

also ddIalso ddI

ANTICONVULSANTSANTICONVULSANTS

- carbamazepine, phenytoin, - carbamazepine, phenytoin, phenobarbitonephenobarbitone

AVOID ALL PI’s and NNRTIsAVOID ALL PI’s and NNRTIs

- Valproate- Valproate

AVOID AZT AND RTVAVOID AZT AND RTV

COLDS AND ALLERGY AGENTSCOLDS AND ALLERGY AGENTS

Eg Preparations containing astemizol, Eg Preparations containing astemizol, loratidine, promethazine and loratidine, promethazine and terfenadine.terfenadine.

AVOID WHEN ON Pis and NNRTISAVOID WHEN ON Pis and NNRTIS

GASTROINTESTINAL AGENTSGASTROINTESTINAL AGENTS

- Antacids, H2-antagonists, proton pump - Antacids, H2-antagonists, proton pump inhibitorsinhibitors

Must be given 1-2 hours after ddI, IDVMust be given 1-2 hours after ddI, IDV

CARDIOVASCULAR AGENTSCARDIOVASCULAR AGENTS

- Lipitor/Zocor: AVOID Pis or change to - Lipitor/Zocor: AVOID Pis or change to PravastatinPravastatin

- Ca antagonists: AVOID Pis- Ca antagonists: AVOID Pis

- Warfarin: AVOID Pis and NNRTIs- Warfarin: AVOID Pis and NNRTIs

HYPOGLYCAEMICSHYPOGLYCAEMICS

- Sulphonylureas- Sulphonylureas

- Metformin- Metformin

AVOID RITONAVIRAVOID RITONAVIR

HOMEOPATHICHOMEOPATHIC

•St John’s Wort

•Garlic Pills

•Grapefruit juice