Treatment of HIV

DR Sara Woods

GUIDE Registrar

St James’s Hospital

Number of people living with HIV/AIDS

Total 33.6 Million

Adults 32.4 Million

Women 14.8 Million

Children < 15 years 1.2 Million

AIDS Deaths in 1999

Total 2.6 Million

Adults 2.1 Million

Women 1.1 Million

Children < 15 years 470,000

HIV Infection in Ireland

0

100

200

300

400

Year of Diagnosis

Num

ber o

f Cas

es

AIDS cases HIV cases

Goal of Antiretroviral Therapy

To the length/quality of life by

• Reducing the Viral Load (VL)

• Preventing infection of new cells

• Preventing further damage to the immune system ( CD4)

AIM:VL<50 copies/ml and CD4>>200

BHIVA GuidelinesWhen to start therapy?

• VL >30,000 & CD4 350-500

• CD4 <350

• Symptomatic

Starting Tx early

• Drug toxicities

• Drug resistance/limit future drug options

Delayed Treatment

• Limit capacity for immune restoration

Antiretroviral Agents (HAART)Divided into 4 groups

• Nucleoside reverse transcriptase inhibitors (NRTIs)

• Protease Inhibitors (PIs)

• Non- nucleoside reverse transcriptase inhibitors (NNRTIs)

• Fusion Inhibitors

Life Cycle of HIV

BINDING

UNCOATING

REVERSETRANSCRIPTION

INTEGRATION

TRANSCRIPTION

TRANSLATIONASSEMBLY

PROTEASE

genomicRNA

double strandedDNA genomic

RNA

viral proteinscellmembrane

cell nucleus

proviralRNA

viralmRNA

Inhibited by:ZDV, ddI, ddC, 3TC, d4TAbacavir, Nevirapine , Delavirdine, Efavirenz

Inhibited by:Saquinavir, Ritonavir,Indinavir, Nelfinavir,

Amprenavir,Lopinavir,

Antiretroviral TherapyNucleoside Analogue

(NRTI)

Non Nucleoside

(NNRTI)

Protease Inhibitors

(PI)

Zidovudine(AZT) Nevirapine (NVP) Rtonavir (RTV)

Stavudine (d4T) Efavirenz (EFV) Indinavir (IND)

Didanosine (ddI) Delaviridine Nelfinavir (NFV)

Lamivudine (3TC) Amprenavir (AMP)

Zalcitabine (ddC) Saquinavir (SQV)

Abacavir (ABC) Lopinavir/Rtn (Kal)

Tenofovir (NtRTI)

Tipranavir (Tip)

Atazanavir (Ataz)

NRTIs• 1st drugs licensed

• Backbone of HAART

• Similar in structure to nuclesides present in HIV RNA

• During viral replication – become incorporated into the genome, competing with cellular nucleosides

• Bring about chain termination & incomplete replication

Zidovudine (AZT)• Dose: 300mg -1000mg

daily• Metabolism – hepatic and

renal• Reduces risk of vertical

transmission of HIV• Good CNS penetration

Side Effects• Bone Marrow Suppression• Nausea• Headache• Insomnia• Myalgia

Lamivudine (3TC)• Dose 150mg BD

• 90% renal excretion

• Hepatitis B

Side Effects

• Pancreatitis

• Abnormal LFTs

• Peripheral neuropathy

• Headache

Emtricitabine (FTC)• Dose 200mg OD• Take with/without food.• CrCl <50ml/min – dose

adjustment• Hepatitis BSide Effects• Headaches, diarrhoea,

nausea CK – muscle pain &

weakness Tg, blood sugar,

WCC & RBC• Disturbance of liver,

kidney & pancreas

Tenofovir (TEN)• Dose 245mg OD

• Take with food

• Hepatitis B

Side Effects

• Hypophosphatemia

• Diarrhoea, nausea, vomiting

• Pancreatitis

• Renal failure, acute renal failure, proximal tubulopathy

Protease InhibitorsAct on the HIV Protease Enzyme – prevent

production of essential proteins.Benefits:• Dramatic decline in clinical progression of HIV

disease/related deaths followed PI introduction in 1996

Drawback:• Pill Burden• Long term metabolic complications

Cholesterol/Lipodystrophy Syndrome/Diabetes• Food/fluid restrictions• DRUG INTERACTIONS

Ritonavir (RTN)• Dose Escalation 600mg

bd• 50% discontinuation rate

Side Effects• N/V/D• Perioral/Peripheral

Neuropathy• Malaise• Fever

AtazanavirAzapeptide PISuperior lipid profile to other PIsDose: 400mg ODOr 300mg OD Ataz/100mg OD RitonavirBoosted if coprescribed with Ten or EFV or previous PI exposureWith food

Side effectsDiarrhoea, nausea, vomiting (taken with RTN)

Tipranavir• Novel nonpeptidic PI

• Active against HIV 1 strains which demonstrate resistance to other PIs

• Dose: 500mg Bd Tip/200mg Bd Ritonavir

Side Effects

• Diarrhoea, nausea, vomiting (taken with RTN)

Atazanavir• Azapeptide PI• Superior lipid profile to other

PIs• Dose: 400mg ODOr 300mg OD Ataz/100mg OD

Ritonavir• Boosted if coprescribed with Ten

or EFV or previous PI exposure• With food

Side effects• Diarrhoea, nausea, vomiting

(taken with RTN)

Drug Interactions - PIs• PIs metabolised by CYP 450 isoenzyme system• Coadministration of enzyme inducers may levels

of PIs – risk of resistance (eg Rifampicin)• Coadministration of enzyme inhibitors may

levels of Pis – risk of toxicity• PIs inhibit CYP3A4 – levels of other drugs

RTN>>IND=NFV=AMP>>SQV(eg/Pethidine/Antiepileptics)

• Some PIs induce isoenzymes levels of other drugs (eg Methadone/O.C.)

NNRTIs• Act on reverse transcriptase enzyme –

preventing HIV RNA from being processed

• Simplier to take than PIs/no food restrictions

• Resistance develops quickly – interclass resistance

• ?delayed toxicities

Nevirapine (NVP)• Dose: 200mg OD x 14/7,

then 200mg BD

• Metabolised by and inducer of CYP 450

Side Effects

• Rash

• Fever

• Nausea

• Hepatotoxicity

Efavirenz (EFV)• Dose 600mg OD• Induces and inhibits

CYP 450• Teratogen

Side Effects• Dizziness/Headache• Insomnia• Increased Dreaming• Irritability• Decreased

Concentration

Drug Interactions NNRTIs

• NNRTIs metabolised by CYP 450 isoenzyme system

• Coadministration of enzyme inducers may levels of NNRTIs - risk of resistance

• Coadministration of enzyme inhibitors may levels of NNRTIs – risk of toxicity

• NNRTIs induce isoenzymes levels of other drugs

Patient Monitoring

• Baseline – VL/CD4/FBC/LFTs

• 1 Month – VL/CD4/FBC/LFTs

• Then every 3 Months – VL/CD4/FBC/LFTs

Virologic Failure• VL > 50copies/ml on 2 occasions more than

one month apartReasons• ? Patient Adherence(<95%)/Intolerance• ? Pharmacological Issues• ? Poor Pharmacokinetics

Perform Resistance Test and change therapy accordingly

HIV ResistanceReduced Susceptibility of Virus to ART

• Virus replicates in the presence of drugs – can result in development of mutations

• Results in changes in structure/function of protease & RT enzymes –less susceptible to drugs

HIV Resistance Testing• Two types -both require VL > 1000copies/ml

Phenotypic Assay:• Measures ability of a HIV isolate from patient to

grow in presence of specific drugs• Time consuming & expensive

Genotypic Assay:• RT/Protease genes from patients virus sequenced

to determine mutations within these genes• Insensitive to presence of minor variants

Genital Wart TherapiesClearance

RateRecurrence

Rate

Podophyllin 38-79% 21-65%

Surgical Excision 89-93% 19-22%

Electrodesiccation 94% 25%

CO2 Laser 72-97% 6-49%

Cryotherapy 70-96% 25-39%

Interferons 36-53% 21-25%

Beutner K, Am J Med, 1997.

Patient Applied Therapies

* No longer recommended

Clearancerate

Recurrencerate

Imiquimod 40-77% 13%

Podophyllotoxin 68-88% 16-34%

5-FU* 68-97% 0-8%

Beutner K, Am J Med, 1997.

Trichomonas vaginalis

• Treatment – • Rx; Metronidazole 2g

stat dose • Rx; Metronidazole

400mg bd x 5/7• Contraindicated in

first trimester• Treat Partner

Bacterial Vaginosis

• Treatment –

Metronidazole 400mg BD x 5d

• Avoid alcohol as possibilty of a disulfiram-like reaction

0

20

40

60

80

100

120lactobacilli

Gardnerella

anaerobes

normal

increasing pH

increasing symptoms

BV

Treatment of chlamydia

• Azithromycin 1g po stat.• Doxycycline 100mg bd x 7/7

• In pregnancy / breastfeeding: Erythromycin 500mg bd x 14/7

• Contact tracing concordance rate 65% of F contacts [80% if epididymitis], 53% M contacts

• Test of cure

NSU• Treatment –Azithromycin 1g stat doseorDoxycycline 100mgs BD x 7d

Alternative regimens Erythromycin 500mgs QDS x 7 days or 250mgs QDS x 14d  orOlfloxacin 300mgs BD x 7d

Gonorrhoea• IM Ceftriaxone 250mg stat

• Screening for other STD

• Contact tracing

• Pregnancy / Breastfeeding - Ceftriaxone 250mg im stat.

• Contact tracing

concordance rates: 78% F contacts, 86% M

• Test of cure

Herpes simplex genitalis

• HSV-1 and 2• Symptomatic primary infection in adult life, as likely to be

HSV-1 as HSV-2

• Antivirals Valcyclovir 500mg bd x 5/7- acute attack Valcyclovir 500mg od x 1 year –suppression Acyclovir 200mg five times day - pregnancy

• Saline baths/Analgesia/Local anaesthetic/Counselling

• May require admission and suprapubic catheterisation

• Treatment of syphillis Benzathine penicillin 2.4MU once/week

x 3 weeks

If allergic - doxycycline 200mg od x 14d

or erythromycin 500mg QDS x 14d