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RCSI Royal College of Surgeons in Ireland Coliste Roga na Minle in irinn

irinn

HIV
HIV Treatment
TREATMENT
Class
Class
Course
Course
Code
Code
Title
Title
Lecturer
Lecturer
Date
Date

IC2
IC2
TropicalHaemato-lymphoid
Medicine
and Tropical Medicine
TM
HLTM
Professor
Dr.
SamuelEoghan
McConkey
de Barra
2015 2014

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.

1985

1996

1996
2001

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

Typhoi
d

Pneumovax

Polio
VZV?

Every 5 years

Influenza
annual

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, fusion
and entry

BINDING

Viral protease
PROTEASE

viral proteins

TRANSLATION
UNCOATING
genomic
RNA

REVERSE
TRANSCRIPTION

Reverse
transcriptase

double stranded
DNA

viral
mRNA

genomic
RNA

INTEGRATIO
N

TRANSCRIPTION
cell nucleus

Viral integrase

cell
membrane
ASSEMBLY

proviral
RNA

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

Current Licensed Antiretrovirals


NRTIs
Zidovudine

NtRTIs
Tenofovir

Lamivudine
Didanosine
Abacavir
Stavudine
NNRTIs
Nevirapine
Etravirine
Efavirenz

Protease Inhibitors
Ritonavir
Saquinavir
Atazanavir
Darunavir
Lopinavir/Ritonavir

Integrase Inhibitors
Raltegravir
Dolutegravir
Evitegravir
Fusion inhibitors
Enfuvirtide
CCR5 antagonists

When to start treatment ?

CD4 or T cell count <300-350

Viral load >30-40,000

Time

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

Principles of when to start therapy


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

Predictors of adherence
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

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

WHAT IS TREATMENT
SUCCESS ??

Increase in CD4 cell count or T-cells


Reduction in viral load
undetectable
<50copies per ml

HAART CHOICES

NRTI

NNRTI
OR

NRTI
Tenofovir & Emtricitabine
Tenofovir & Emtricitabine

Efavirenz
Atazanavir
(Ritonavir)

PI

ONE PILL, ONCE A DAY

Tenofovir / emtricitabine / efavirenz

?compliance ?
Pregnancy?

Newer agents now too.

Booster Ritonavir treatment


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

ALTERNATIVES
Tenofovir / Lamivudine / Nevirapine
Stavudine / Lamivudine / Nevirapine

Risk of treatment discontinuation

viral

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?

NRTIS
Serious Adverse Effects of this class
Lipodistrophy
Lactic acidosis
Hepatic steatosis
Peripheral neuropathy

Zidovudine - anaemia
Abacavir - hypersensitivity

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

Monitoring

Weight
Overall clinical response to therapy
Signs/symptoms of potential drug toxicities
Adherence

Debate over the need for monitoring in RLS

Cost effectiveness

Monitoring treatment: Safety


bloods
For adverse effects

HbG
LFTs
Renal function
Lipids, cholesterol

Efficacy

Plasma RNA Viral Load (aim for < 50 copies/ml)


CD4+ T lymphocyte count rise

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

Inadequate Drug Levels Ultimately Result


in Resistance and Viral Rebound

Periodically
inadequate
drug levels

Mutant selected
with reduced
susceptibility

Rebound with
highly resistant
virus

CONSEQUENCES OF MONOTHERAPY
Rapid emergence of resistance due to
Error prone RT enzyme activity
Rapid viral turnover

Lamivudine monotherapy
Viral
Load
Log
Copies
Per ml

M184V
variant
Wild type
Time

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

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
Signing of
Declaration
of
Commitment
on
HIV/AIDS

9000
8000
7000
US$ million

6000

8297*

5000
4000
3000
2000
1000

1623
292

0
1996199719981999200020012002200320042005

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