treatment of hiv
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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