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

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

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

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..

A global view of HIV infection38.6 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

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.

TOPSY

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

SUMMARY

• Advances• Combination therapy controls disease

– Monitor side effects & efficacy

• Adherence• Access