1. HIV Treatment

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Teach/learn about the infectionMultidisciplinary teamBaseline assessmentRelationship buildingPreventative measuresOI prophylaxisAnti-retro viral drugs

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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.”
1996
2001
1996
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
REVERSE
TRANSCRIPTION
INTEGRATION
TRANSCRIPTION
TRANSLATION
ASSEMBLY
PROTEASE
genomic
RNA
double stranded
DNA genomic
RNA
viral proteins
cell
membrane
cell nucleus
proviral
RNA
viral
mRNA
Reverse
transcriptase
Binding, fusion
and entry
Viral protease
Viral integrase
Viral regulatory
proteins
ANTIRETROVIRAL CLASSES
• Reverse transcriptase inhibitors:
– Nucleoside analogues (NAs)
– Nucleotide analogues (NtIs)
– Non-nucleoside analogues (NNRTIs)

• Protease inhibitors (PIs)

• Fusion inhibitors
• Integrase inhibitors
NRTIs
Zidovudine
Lamivudine
Didanosine
Abacavir
Stavudine
NtRTIs
Tenofovir
Protease Inhibitors
Ritonavir
Saquinavir
Atazanavir
Darunavir
Lopinavir/Ritonavir
NNRTIs
Nevirapine
Etravirine
Efavirenz
Current Licensed Antiretrovirals
Integrase Inhibitors
Raltegravir
Dolutegravir
Evitegravir

Fusion inhibitors
Enfuvirtide
CCR5 antagonists
CD4 or T cell count <300-350
Time
Viral load >30-40,000
Treatment When to start treatment ?
WHEN TO START THERAPY?
• Symptomatic
• CD4 count low (<200 10
6
/L)

• Asymptomatic
• Case by case
• CD4 count <350 x 10
6
/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 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 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
Adherence
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 effect

Green line - levels of lopinavir or saquinavir taken alone
Yellow line- levels when taking drug with ritonavir
Green line - levels of indinavir, nelfinavir or amprenavir when taken alone
Yellow line- levels when taking drug with ritonavir
Booster Ritonavir treatment
ALTERNATIVES
• Tenofovir / Lamivudine / Nevirapine
• Stavudine / Lamivudine / Nevirapine
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

Monitoring
• 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
bloods
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
• 1
st
or 2
nd
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
Periodically
inadequate
drug levels
Mutant selected
with reduced
susceptibility
Rebound with
highly resistant
virus
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
Viral
Load
Log
Copies
Per 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..

A global view of HIV infection
38.6 million people [33.4 - 46.0 million] living with HIV, 2005
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
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
U
S
$

m
i
l
l
i
o
n

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.
TOPSY
• https://www.youtube.com/watch?v=-og6PiO0i6k


SUMMARY
• Advances
• Combination therapy controls disease
– Monitor side effects & efficacy

• Adherence
• Access

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