Transcript HIV treatment

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
AIDS cases
HIV cases
400
300
200
100
0
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
Number of Cases
HIV Infection in Ireland
Year of Diagnosis
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 Guidelines
When 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
Inhibited by:
Saquinavir, Ritonavir,
Indinavir, Nelfinavir,
Amprenavir,Lopinavir,
BINDING
PROTEASE
viral proteins
TRANSLATION
UNCOATING
genomic
RNA
double stranded
DNA
viral
mRNA
genomic
RNA
INTEGRATION
REVERSE
TRANSCRIPTION
Inhibited by:
ZDV, ddI, ddC, 3TC, d4T
Abacavir, Nevirapine ,
Delavirdine, Efavirenz
TRANSCRIPTION
cell nucleus
cell
membrane
ASSEMBLY
proviral
RNA
Antiretroviral Therapy
Nucleoside
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)
Lamivudine (3TC)
• Dose: 300mg -1000mg
daily
• Metabolism – hepatic
and renal
• Reduces risk of vertical
transmission of HIV
• Good CNS penetration
• Dose 150mg BD
• 90% renal excretion
• Hepatitis B
Side Effects
• Bone Marrow
Suppression
• Nausea
• Headache
• Insomnia
• Myalgia
Side Effects
• Pancreatitis
• Abnormal LFTs
• Peripheral neuropathy
• Headache
Emtricitabine (FTC) Tenofovir (TEN)
• Dose 200mg OD
• Take with/without food.
• CrCl <50ml/min – dose
adjustment
• Hepatitis B
Side Effects
• Headaches, diarrhoea,
nausea
•  CK – muscle pain &
weakness
•  Tg,  blood sugar, 
WCC & RBC
• Disturbance of liver,
kidney & pancreas
• Dose 245mg OD
• Take with food
• Hepatitis B
Side Effects
• Hypophosphatemia
• Diarrhoea, nausea,
vomiting
• Pancreatitis
• Renal failure, acute
renal failure, proximal
tubulopathy
Protease Inhibitors
Act 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
Atazanavir
Azapeptide PI
Superior lipid profile to other
PIs
Dose: 400mg OD
Or 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)
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 OD
Or 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)
Efavirenz (EFV)
• Dose: 200mg OD x 14/7,
then 200mg BD
• Metabolised by and
inducer of CYP 450
• Dose 600mg OD
• Induces and inhibits
CYP 450
• Teratogen
Side Effects
• Rash
• Fever
• Nausea
• Hepatotoxicity
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 apart
Reasons
• ? Patient Adherence(<95%)/Intolerance
• ? Pharmacological Issues
• ? Poor Pharmacokinetics
Perform Resistance Test and change therapy
accordingly
HIV Resistance
Reduced 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 Therapies
Clearance
Rate
Recurrence
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
Clearance Recurrence
rate
rate
Imiquimod
40-77%
Podophyllotoxin 68-88%
5-FU*
68-97%
13%
16-34%
0-8%
* No longer recommended
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 –
120
100
Metronidazole 400mg
BD x 5d
80
BV
lactobacilli
Gardnerella
anaerobes
60
40
20
• Avoid alcohol as
possibilty of a disulfiramlike reaction
normal
0
increasing pH
increasing symptoms
Treatment of chlamydia
• Azithromycin 1g po stat.
• Doxycycline 100mg bd x 7/7
• In pregnancy / breastfeeding:
500mg bd x 14/7
Erythromycin
• Contact tracing
concordance rate 65% of F contacts [80% if epididymitis],
53% M contacts
• Test of cure
NSU
• Treatment –
Azithromycin 1g stat dose
or
Doxycycline 100mgs BD x 7d
Alternative regimens
Erythromycin 500mgs QDS x 7 days or 250mgs QDS x 14d
or
Olfloxacin 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