1. hiv treatment
DESCRIPTION
Teach/learn about the infectionMultidisciplinary teamBaseline assessmentRelationship buildingPreventative measuresOI prophylaxisAnti-retro viral drugsTRANSCRIPT
HIV TREATMENT
Class IC2
Course Haemato-lymphoid and Tropical Medicine
Code HLTM
Title Dr.
Lecturer Eoghan de Barra
Date 2014
RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn
HIV TREATMENT
Class IC2
Course Haemato-lymphoid and Tropical Medicine
Code HLTM
Title Dr.
Lecturer Eoghan de Barra
Date 2014
RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn
HIV Treatment
Class IC2
Course Tropical Medicine
Code TM
Title Professor
Lecturer Samuel McConkey
Date 2014
RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn
1985
1992
1983
“As of last week, there were 1,641 victims of AIDS, including 644 deaths, since it was first identified as a disease in the U.S. two years ago. Each month an average of 165 new cases is reported.”
SUMMARY
• Teach/learn about the infection• Multidisciplinary team• Baseline assessment• Relationship building• Preventative measures• OI prophylaxis• Anti-retro viral drugs
HIV TREATMENT
• Preventative measures– Population– Individual– Mother to Child (PMTCT)
• Opportunistic Infections – Treatment– Prophylaxis
• Anti retroviral drugs
PATIENT LEARNING
• Learning about biology, • CD4 count
• Viral Load
• About prognosis• Risks: spreading infection
– Acquiring another HIV virus
• Safe sex• Which medications are important
AT BASELINE
• Co-morbidities – history, physical, Ix– Drug use, cocaine, heroin, alcohol– Depression – Personality disorders
• Renal, liver, haematology status, CXR• Lipids, glucose
• Baseline status of disease : – CD4 count, Viral Load– Resistance assay/genotype
AT BASELINE
• CMV IgG• Toxoplasma IgG• Hepatitis B & C
• G6PD• [HLA-B5701]?
• Sexually transmitted infections– RPR, chlamydia, GC
• Sexual health- smear tests, contraception
• Social support network • Cardiovascular risk factors – smokes
PREVENTIVE MEASURES / GENERAL HEALTH
• Tell sexual partners• Condoms• Treat STIs• Fertility planning
• Stop smoking• Weight and exercise management• Nutrition
OI PROPHYLAXIS
• Septrin 960 mgs daily if CD4 < 200
–PCP–[needed if Toxo if IgG positive]
• Azithromycin 1250 mgs weekly if CD4 < 50
–Can stop when >100 for 3 months
• Isoniazid 300 mg od x 9 months if Mantoux +
–TST > 5mm = positive in HIV patient
VACCINATIONS
• HBV, HAV
• Pneumovax– Every 5 years
• Influenza– annual
• Typhoid
• Polio• VZV?
• Future– HPV?
Mortality and Frequency of Use of Combination Antiretroviral Therapy According to Calendar Quarter, from January 1994 through June 1997
Palella F et al. 1998
Life Cycle of HIV
BINDING
UNCOATING
REVERSETRANSCRIPTION
INTEGRATION
TRANSCRIPTION
TRANSLATIONASSEMBLY
PROTEASE
genomicRNA
double strandedDNA genomic
RNA
viral proteins cellmembrane
cell nucleus
proviral RNA
viralmRNA
Reversetranscriptase
Binding, fusionand entry Viral protease
Viral integrase
Viral regulatoryproteins
ANTIRETROVIRAL CLASSES
• Reverse transcriptase inhibitors: – Nucleoside analogues (NAs)– Nucleotide analogues (NtIs)– Non-nucleoside analogues (NNRTIs)
• Protease inhibitors (PIs)
• Fusion inhibitors• Integrase inhibitors
NRTIsZidovudineLamivudineDidanosineAbacavirStavudine
NtRTIsTenofovir
Protease InhibitorsRitonavirSaquinavirAtazanavirDarunavirLopinavir/Ritonavir
NNRTIsNevirapineEtravirineEfavirenz
Current Licensed Antiretrovirals
Integrase InhibitorsRaltegravirDolutegravirEvitegravir
Fusion inhibitors
Enfuvirtide
CCR5 antagonists
CD4 or T cell count <300-350
Time
Viral load >30-40,000
TreatmentWhen to start treatment ?When to start treatment ?
WHEN TO START THERAPY?
• Symptomatic • CD4 count low (<200 106/L)
• Asymptomatic• Case by case• CD4 count <350 x 106/L• Viral load >100,000 copies/ml
• Pregnancy
• Wait until the patient is ready – Adherence
• Use three or four effective drugs– Usually of at least 2 different classes
• Start together• Stop together
• Don’t add one new drug to a failing regimen
Principles of when to start therapyPrinciples of when to start therapy
• No active psychiatric co-morbidity• Good relationship with providers• Stable life
• Fewer times per day• Fewer tablets
• Less adverse effects• Strong beliefs about benefit of medication
Predictors of adherencePredictors of adherence
• Clear simple instructions
• Tools: pill box, beeper, alarm, phone,
• Treatment supporter
• ‘Emergency’ supplies• Anticipate difficult times: travel, evenings
– Link to regular daily activities
• Anticipate mild side effects - explain
AdherenceAdherence
WHAT IS TREATMENT SUCCESS ??
Increase in CD4 cell count or T-cells
Reduction in viral load‘undetectable’<50copies per ml
HAART CHOICES
+ NNRTI OR PI
NRTI
NRTI
Tenofovir & Emtricitabine Efavirenz
Tenofovir & Emtricitabine Atazanavir(Ritonavir)
ONE PILL, ONCE A DAY
• Tenofovir / emtricitabine / efavirenz– ?compliance ? Pregnancy?
• Newer agents now too.
Use Ritonavir low -dose for the PK Use Ritonavir low -dose for the PK effecteffect
Green line - levels of lopinavir or saquinavir taken aloneYellow line- levels when taking drug with ritonavir
Green line - levels of indinavir, nelfinavir or amprenavir when taken aloneYellow line- levels when taking drug with ritonavir
Booster Ritonavir treatment Booster Ritonavir treatment
Risk of treatment discontinuation
The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. NEJM 2006
PRINCIPLE TOXICITIES OF ARVS
• Tenofovir– Renal dysfunction
• Efavirenz– CNS toxicity– Rash– LFT abnormalities– Teratogenic?
• Combivir– (zidovudine/Lamivudine)– Anaemia
• Abacavir– Hypersensitivity – HLA B5701
• Emtricitabine– Hyperpigmentation
• Atazanavir– Hyperbilirubinaemia– Dyslipidaemia– Cardiovascular risk?
• Serious Adverse Effects of this class– Lipodistrophy– Lactic acidosis– Hepatic steatosis– Peripheral neuropathy
• Zidovudine - anaemia• Abacavir - hypersensitivity
NRTIS
NNRTI
• Efavirenz, Sustiva®–600mg at night
• Nevirapine, Viramune®–200mg bid
• Serious Adverse Effects of this class– Skin rash … Steven-Johnson Syndrome– Severe hepatitis – Efavirenz – CNS side effects
PROTEASE INHIBITORS
• Lopinavir/r, Kaletra®– 300/100 bid
• Atazanavir +r, Reyataz®– BMS 300/100 od
• Serious Adverse Effects of this class– GI upset- N, V, D,
– Metabolic syndrome– Fat redistribution– Hypercholesterolaemia
Crixi-belly
• Weight• Overall clinical response to therapy• Signs/symptoms of potential drug toxicities• Adherence
• Debate over the need for monitoring in RLS
–Cost effectiveness
MonitoringMonitoring
• For adverse effects
– HbG– LFTs– Renal function– Lipids, cholesterol
• Efficacy
– Plasma RNA Viral Load (aim for < 50 copies/ml)– CD4+ T lymphocyte count rise
Monitoring treatment: Safety Monitoring treatment: Safety bloodsbloods
IMMUNE RECONSITUTION SYNDROME
• In the weeks - months after starting ART
–CD4 counts rise, immune reactivation
–Can mimic a new infection
• Hepatitis flare- HBV• Lymphadenitis - MAC, Mtb• fever
TREATMENT FAILURE
• 1st or 2nd regimen– Viral load > 200 copies per ml
• Subsequent regimens– Rising viral load– Declining CD4 count– Disease progression
• Virological / Immunological / Clinical
POSSIBLE CAUSES OF TREATMENT FAILURE
• Poor adherence• Pharmacologic factors• Host factors• Limited potency of drug of regimen• Drug resistance
CONSEQUENCES OF ONGOING VIRAL REPLICATION DURING HAART
• Accumulation of drug resistance mutations• Development of cross-resistance within multiple drug
classes• Greater difficulty in re-establishing virologic control with
future regimens• Eventual decline in CD4 counts leading to disease
progression
Periodicallyinadequatedrug levels
Mutant selectedwith reducedsusceptibility
Rebound withhighly resistantvirus
Inadequate Drug Levels Ultimately Result in Resistance and Viral Rebound
CONSEQUENCES OF MONOTHERAPY
Rapid emergence of resistance due to
Error prone RT enzyme activity
Rapid viral turnover
Time
ViralLoadLog CopiesPer ml
Lamivudine monotherapy
M184V variant
Wild type
PMTCT
• PMTCT is an encompassing term addressing the methods employed to prevent:
– HIV infection to women of childbearing age
– Unintended pregnancies
– Transmission of HIV from a mother to an infant
– Transmission of HIV from a mother to her children and family
• Pregnant women with indications for ARV should be prioritized
– 3TC, AZT, Kaletra is the preferred regimen here
– AZT, 3TC, NVP in RLS
• Avoid EFV, especially in first term
• All women (regardless of lack of other indications should start ARVs at week 14 or as soon as they present if presenting later)
PERIPARTUM
• AZT at onset of labour
• Treatment of baby post partum
• Different in RLS
–Single dose NVP often done – not good for mother
BREAST FEEDING
• When alternatives are easily available
–No breastfeeding
• In many resourse limited settings
–EXCLUSIVE breastfeeding for 6 months
–Breastfeeding infants should receive prophylaxis for the duration of breastfeeding• NVP can be used
POST EXPOSURE PROPHYLAXIS (PEP)PRE EXPOSURE PROPHYLAXIS (PREP)
• Post needle stick or sexual exposure• ARVs within 72 hours• Need baseline testing and close follow up
• HIV cure? CBS 2011• https://www.youtube.com/watch?v=_eJHMQQljpM
• HIV baby cured• https://www.youtube.com/watch?v=jGDhqZTndwc
• https://www.youtube.com/watch?v=IW7OMMyz9J8• Vaccine..
ARV IN DEVELOPING WORLD
• In 2000 WHO announced the “3 by 5 initiative”– Aimed for Universal access– Standardization and simplification of antiretroviral regimens– Evidence based regimens
• By the end of 2005 approximately 1.3 million people were receiving WHO-recommended first-line regimens at that time compared with 400,000 in 2003
• The most recent estimates indicate that about 4 million people in resource-poor nations are being treated with HAART
•
Estimated total annual resources available for AIDS, 1996-2005
292
1623
8297*
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
1996199719981999200020012002200320042005
US
$ m
illi
on
Signing of Declaration
of Commitment on HIV/AIDS
ARV MANAGEMENT IN DEVELOPING WORLD
• Western model impossible:– Specialist physician management– Advanced laboratory monitoring
• Developing world– Public health approach is more applicable
• Simplified decision making processes based on SSSS
• When to– Start– Substitute for toxicity– Switch for failure– Stop for end-of-life care
TB AND HIV
• Co-epidemic (70% of new TB dx in South Africa are HIV +)
• Detection and treatment
• Drug interactions– Rifampicin – inducer– Pyrazinamide – hepatotoxic– Isoniazide – hepatotoxic
TB AND HIV
• Best ARV = tenofovir / emtricitabine / efavirenz• Monitor
– Monthly clinical review (at least)• Nausea / RUQ pain?
• LFTs
• IRIS– Immun Reconstitution Inflammatory Syndrome
TB AND HIV
• When to start?• Always TB first• Interval to Anti Retro Virals…
– Immediate…within 2 weeks.
SUMMARY
• Advances• Combination therapy controls disease
– Monitor side effects & efficacy
• Adherence• Access