Anti Retro Viral Agents

8/3/2019 Anti Retro Viral Agents

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Antiretroviral Agents and their

Characteristics

Joshua Kimani


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Anti-Retroviral Agents available in Kenya

NRTI NNRTI PI

Zidovudine Nevirapine Saquinavir

Didanosine Efavirenz Indinavir

Zalcitabine Delavirdine Ritonavir Stavudine Nelfinavir

Lamivudine Lopinavir/Ritonavir

Abacavir Amprenavir

(Combivir)

(Trizivir) NtRTITenofovir


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Nucleoside Analogue Reverse Transcriptase

Inhibitors (NRTIs)

First antiretroviral drugs introduced.

Are dideoxynucleoside analogues which are phosphorylated

into the active triphosphate form.

The triphosphate metabolite competitively inhibits the reversetranscriptase by acting as an alternative substrate for theenzyme.

Once the metabolite is incorporated into the developing DNAstrand , chain termination ensues.


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Zidovudine (AZT, ZDV, Retrovir)

Dose:

300mg BD

Dose

adjustment

required in

severerenal

dysfunction

Paediatric:

180mg/m2 QID

Pharmacokinetics:

Bioavailability

64%

Plasma t1/2=1hr

Intracelluler

t1/2=4hr

CSF:Plasma

ratio=0.6

Clinical use:

Synergistic with most

antiretroviralsexceptstavudine

Potential benefitin AIDS

dementia complex and HIV-

associated thrombocytopaenia.

Effectiveinpreventionof

perinatal transmission and PEP.

Use aspartofHAART.


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Zidovudine(AZT, ZDV, Retrovir)

Adverse Effects:

Macrocytic

anaemia

Neutropaenia

Myopathy

Nausea

Fatigue

Headaches

Rarely liver

necrosis

Interactions:

Use withcaution

withother

myelosuppressive

Agents

(Ganciclovir,TMP-

SMX)

Dosesof

clarithromycin

should betaken

onehourapart.

Dietary:

Can be administered withor

aftermealstoreducenausea


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Didanosine(ddI,Videx, Videx-EC)

Dose:

>60 kg 200mg BD

< 60kg 125mg BD

Entericcoatedformulation available

>60kg 400mg OD

< 60kg 250mg OD

Doseshould be

decreased with

impaired renal function

Paediatric:

120mg/m2 BD

Pharmacokinetics:

Bioavailability 21%

to 43%

Food decreasesabsorption

Plasma t1/2 = 1.3-1.5

hr

Intracellulert1/2= 8-

40 hr

Clinical use:

Use aspartof

HAARTtherapy


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Didanosine (ddI,Videx, Videx EC)

Adverseeffects:

Pancreatitis

Peripheral

neuropathy

Diarrhoea

Nausea

Vomiting

Hepatitis

Lactic acidosis

Interactions:

Oral Ganciclovirincreases levelsofddI.

Antacid inprep.

Reduces absorptionof

Ketoconazole

Itraconazole

Dapsone

Rifampicin

Ciprofloxacin

Take 2 hrbeforeor4 hrafterddI

TakePIs at leastone

hourapart

Dietary:

Take 30 mins beforefood or2 hours after

meals.

Takethetwotablets

togethertoprotect drug

from stomach acid.Tabletsto bechewed

ordispersed in 30ml of

water.

Avoid acidic drinks

atsametime as ddI.


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Zalcitabine (ddC, Hivid)

Dose:

0.75mg TDS

Dose adjustmentin

patients withimpaired

renal function

Pharmacokinetics:

Bioavailability 88%

Plasma t1/2= 1-2hr

Clinical use:

Initially approved to

be used incombination

with AZT

No advantageover

existing NRTIs


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Zalcitabine (ddC, Hivid)

Adverseeffects:

Rash

Peripheral

neuropathy

Apthous ulceration

Gastrointestinal upset

Renal toxicity

Pancreatitis

Interactions:

Avoid drugscausing

pancreatitis (e.g. IV

Pentamidine)or

peripheral

neuropathy(e.g.

stavudine and

isoniazid)

Dietary:

Cantaketablets

before, withorafter

food.

Avoid aluminium

and magnesium

anatacids.


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Stavudine(D4t, Zerit)

Dose:> 60kg 40mg BD

< 60kg 30mg BD

ZeritXR

> 60kg 100mg OD

< 60kg 75mg OD

Dose adjustment

required inrenal

dysfunction

Canhalfdoseif

peripheral neuropathydevelops.

Paediatric:

< 30kg 1mg/kg BD

> 30kg 30mg BD

> 60kg 40mg BD

Pharmacokinetics:Bioavailability 80%

Plasma t1/2= 1-1.6 hr

Intracellulart1/2= 3 hr

Clinical use:Synergistic with ddI

and 3TC

Contraindicated use

with AZT.

Avoid use with

Zalcitabine

ddI & d4Tshould beavoided inpregnant

women


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Stavudine (D4t, Zerit)

Adverseeffects:

Peripheral

neuropathy

(doserelated)

Pancreatitis

Elevated liver

enzymes

Lactic acidosis

Drug Interactions:

Avoid drugscausing

peripheral neuropathy

e.g. ddC,isoniazid,

dapsone.

Should not be used in

combination with

zidovudine

Dietary:

Can betaken before,

withoraftermeals


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Lamivudine(3TC, Epivir)

Dose:

150mg BD

Dosage adjustmentis

required inpatients

withrenal impairment

Paediatric:

3mths-16 yrs

4mg/kg BD

Pharmacokinetics:

Bioavailability:80%

Plasma t1/2= 5-7 hr

Clinical use:

Synergistic with

ZDV, D4t, ddI, ABC;

possibly antagonistic

with ddC

Approved forchronic

activehepatitis Btherapy


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Lamivudine ( 3TC, Epivir)

Adverseeffects:

Minimal toxicity

Nausea

Vomiting

Diarrhoea

Abdominalpain

Malaise

Drug Interactions:

Nospecific drug

interactions

Dietary:

Can betaken before,

withorafterfood


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Abacavir (ABC, Ziagen)

Dose:

300mg BD

Paediatric:

3mths-16 years

8mg/kg BD

Pharmacokinetics:

Phosphorylatd by

cellularenzymesto

active metabolite

carbovirtriphospahte

Bioavailabilty:83%

Plasma t1/2= 2 hr

Clinical use:

Use aspartof

HAARTregime.


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Abacavir (ABC, Ziagen)

Adverseeffects:

Hypersensitivity

reactions

Drug should be

stopped and not

restarted ifreactionis

severe.

Nausea

Headaches

Drug Interactions:

Nospecific drug

Interactions

SideeffectsofNVP

may makeit difficultto

differentiate between

abacavirhypersensitivity and

NNRTI rash.

Dietary:

Can betaken before,

withorafterfood.


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Non Nucleoside Reverse Transcriptase Inhibitors

(NNRTIs)

NNRTIs inhibit HIV replication at the same stage as the NRTIsbut are entirely unrelated chemically and in the mode ofaction

NNRTIs non-competitively bind to the active site of reversetranscriptase and are not incorporated into the developingviral DNA.

NNRTI are active in their native state and do not requirephosphorylation


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Nevirapine (NVP, Viramune)

Dose:

200mg OD fortwo

weeks and then

increased to 200mg

twice daily.

This allowsfor

inductionof

metabolising hepatic

enzymes and resultsin

lowerincidenceofrash

Paediatric:

2mths-8yr

4mg/kg OD then

7mg/kg BD

>8yr4mg/kg OD then

BD

Pharmacokinetics:

Bioavailabilty 80%

Plasma t1/2= 20 hr

Clinical use:

Efficacious as a

single doseto mother

and infantfor

preventionofperinatal

transmission.

Use aspart HAART

therapy.


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Nevirapine (NVP,Viramune)

Adverseeffects:

Rashin16% of

patients ( Stephen-

Johnsonsyndrome and

toxicepidermal

necrosis)

Hepatoxicity(serious,even life

threatening hepatic

necrosis)

Nausea

Drug Interactions:

Potential fordrug-

drug interactions:

Substrate and inducer

ofCYP 3A4

Saquanavir, OCs,

terfenadine, astemizoleand cisapride are

contraindicated

Dietary:

Can betaken before,

withorafterfood


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Stocrin;


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Efavirenz (EFV, Stocrin, Sustiva)

Dose:

600mg OD at

bedtime

Paediatric:

10-14kg 200mg OD

15-19kg 250mg OD20-24kg 300mg OD

25-31.5kg 350mg OD

32.5-39kg 400mg OD

>40kg 600mg OD

Pharmacokinetics:

Long terminal t1/2=

40-55 hrs aftermultiple

dosing.

Clinical use:

Potent NNRTI with

virologicresponse

similartoPI when

combined with 2

NRTI.

Contraindicated inpregnancy


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Efavirenz (EFV,Stocrin, Sustiva)

Adverseeffects:

CNSeffectsin>

50% ofpatients

Hallucinations

Dizziness

Vivid dreams

Confusion

Depression

Psychosis

Rash

ElevationofLFTs

Interactions:

Contraindicated with:

Astemizole

Cisapride

Ocs

Midazolam

Ergot derivatives

Dietary:

Taking efavirenz

withfood increasesconcentrations and

may increasethe

frequency ofadverse

effects.

Taking on anempty

stomach at bedtime

improvestolerability


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Protease Inhibitors (PIs)

Inhibit HIV protease, a virus specific enzyme, thus preventing

the cleavage of viral polyproteins in the final stages of viral

protein processing, preventing virus assembly and resulting in a

defective, non-infectious viral particle.

They not only prevent replication in newly infected cells but

are also effective in chronically infected cells.


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Saquinavir [INV, Invirase(HGC) or FTV,

Fortovase(SGC)]

Dose:

INV: 600mg TDS

FTV:1200MG TDS

Pharmacokinetics:

INVpoorly absorbed

afteroral doses.

Bioavailability 4%

FTV hasimproved

bioavailability with

levels 3 to 4 times

higher.

Ifboth used in

boosted PI regimes

withritonavir,

increased

bioavailability

Clinical use:

Use aspartof

HAARTtherapy

preferably in boosted

PI regimes.


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Saquinavir[INV, Invirase(HGC) or FTV,

Fortavase(SGC)]

Adverseeffects:

Diarrhoea

Abdominal

discomfort

Nausea

Hyperlipidemia

Fatredistribution

Interactions:

Antacids and ddI-

administer2 hrs beforeor1hrafter

Contraindicated

Astemizole

Terfenadine

Rifampicin

Rifabutin

Dietary:

Should be

administered within 2hrs aftera meal

Absorptionis

enhanced inpresence

offood.


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Indinavir (IDV, Crixivan)

Dose:

800mg TDS

With RTV

IDV RTV

800mg BD 100mgBD

Paediatric:

4-17 yrs

500mg/m2 TDS

Phamacokinetics:

Bioavailability 60-

65%(empty stomach)

Protein binding 50%

Clinical use:

Use aspartof

HAARTtherapy


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Indinavir (IDV, Crixivan)

Adverseeffects:

Renal stones

Renal impairment

Nephroliathiasis

Dry skin

Nausea

Headache

Nail malformations

FatredistributionHyperlipidaemia

Hyperglycaemia

Interactions:

Antacids and ddI-

administer2 hrs before

or1hrafter

Contraindicated

Astemizole

Terfenadine

Rifampicin

Rifabutin

Dietary:

Presenceoffatin

stomachprevents

absorption

Takeonempty

stomach1hrbeforeor

2 hrafterfood.

With RTV ,take with

normal meals

Must drink1.5 litres

ofwaterperday.


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Ritonavir (RTV, Norvir)

Dose:

600mg BD

Doseescalationover

initial few days

recommended.

Paediatric:

Initiate with 250mg/m2

BD to maximunof

400mg/m2 BD

Pharmacokinetics:

Bioavailability 15%

PoorCSFpenetration

Clinical Use:

Now more

commonly used atlowerdoses as a

Pharmacokinetic

boostertoco-

administered PI.


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Ritonavir (RTV, Norvir)

Adverseeffects:

Nausea

Vomiting

Diarrhoea

Perioral orperipheral

paraesthesia

Tasteperversion

Hypertriglyceridemia

Livertoxicities

ADRs are dose

related

Interactions:

Antacids and ddI-


or1hrafter

Contraindicated

Astemizole

Terfenadine

Rifampicin

Rifabutin

Dietary:

Administered with

food


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Nelfinavir (NFV, Viracept)

Dose:

750mg TDSor

1250mg BD

Paediatric:

2-13 yrs

20-30mg/kg TDS

Pharmacokinetics:

Bioavailability10-

98%

Plasma t1/2= 3.5-5 hr

Plasmaprotein

bound >98%

Clinical use:

Use aspartof

HAARTtherapy


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Nelfinavir (NFV, Viracept)

Adverseeffects:

Diarrhoea (25-40%)

Nausea

Bloating

Rash

Hyperlipidaemia

Fatredistribution

Interactions:

Antacids and ddI-

administer2 hrs beforeor1hrafter

Contraindicated

Astemizole

Terfenadine

Rifampicin

Rifabutin

Dietary:

Take withfood

May crushtablets

and dispersein waterif

swallowing is a

problem.


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Lopinavir 133mg & Ritonavir 33mg (

LPV/r, Kaletra)

Dose:

Fixed dose

combination

3 Capsules BD

Paediatric:

6mths-12 yrs

10-12mg/kg LPV to

2.5-3 mg/kg RTV BD

Pharmacokinetics:

RTV & LPV-

inhibitionofLPVmetabolism via CYP-

3A4

LPV AUCincreased

by 100 fold

Clinical use:

Use aspartof

HAART boosted PIregime.


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Lopinavir 133mg & Ritonavir 33mg (

LPV/r, Kaletra)

Adverseeffects:

Diarrhoea

Nausea

Headache

Pancreatitis

Hyperlipidaemia

Fatredistribution

Interactions:

Antacids and ddI-


or1hrafter

Contraindicated

Astemizole

Terfenadine

Rifampicin

Rifabutin

Metronidazole/Tinida

zole withLiquid

Dietary:

Take withorafter

food


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Thank you.

Asante sana.

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Anti Retro Viral Agents