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 Coliste Roga na Minle in irinn
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 Coliste Roga na Minle in irinn
HIV Treatment

Class IC2
Course Tropical Medicine
Code TM
Title Professor
Lecturer Samuel McConkey
Date 2014
RCSI Royal College of Surgeons in Ireland Coliste Roga na Minle in irinn
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

Dont 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
Immediatewithin 2 weeks.
TOPSY
https://www.youtube.com/watch?v=-og6PiO0i6k


SUMMARY
Advances
Combination therapy controls disease
Monitor side effects & efficacy

Adherence
Access