INTRODUCTION TO ANTI

RETROVIRAL THERAPY
 PLOS Medicine 2014,11 e1001718

September 2011
MODE OF ACTION OF ARV’s

• ARV’s work at different stages of the HIV replication

cycle in the host cell
• They interfere with the essential enzymatic steps in
the cycle thus preventing the development of new
infectious HIV particles
• As a result, further destruction of CD4 cells is
prevented
• Current ARV drugs prevent viral replication; they do
not kill the virus, therefore there is no cure (yet) for
HIV infection
KEY VIRAL ENZYMES ARE
TARGETS FOR ANTIRETROVIRALS
• Reverse Transcriptase converts viral single-
stranded RNA into a single strand
deoxyribonucleic acid (DNA)
• Integrase enables integration of the HIV DNA
into the host’s DNA:
• Protease enzyme splits macro-proteins into
smaller viral proteins which are then
incorporated into the new viral particles
– Currently the most widely used protease
inhibitor used in Zimbabwe is
Lopinavir/ritonavir (Aluvia®)
 LIFE CYCLE TARGETED BY ANTI-HIV
DRUGS

September 2011
 Classes of ARVs

The major drug classes:

1. Reverse Transcriptase Inhibitors

- Nucleoside Reverse Transcriptase Inhibitors
(NRTIs):
Zidovudine (AZT/ZDV), Lamivudine (3TC), Abacavir
(ABC), Tenofovir (TDF), Didanosine (ddI)
- Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs): Efavirenz (EFV), Nevirapine (NVP)
 Classes of ARVs

2.Protease Inhibitors (PIs)

• Lopinavir/ritonavir (LPV/R), Atazanavir (ATV)

3. Integrase Inhibitors
• Raltegravir (RAL), Elvitegravir, Dolutegravir

4. Entry Inhibitors
• Fusion Inhibitors (FIs): Enfuvirtide
• Chemokine Receptor Antagonists (CRAs):
Maraviroc
Pill Burden – 1st line

$15
8
Pill Burden – 2nd line

$39
9
 Pill Burden – 3rd line

PLUS $172
10
When to Start?

www.newlandsclinic.org.zw Zimbabwe
What to start with?

www.newlandsclinic.org.zw 12 Zimbabwe
 NATIONAL GUIDELINES – 1ST LINE
THERAPY FOR ADULTS &
ADOLESCENTS
TARGET POPULATION 2013 ART GUIDELINES

ADULTS & ADOLESCENTS

HIV+ PREGNANT WOMEN

TDF + 3TC/FTC + EFV
HIV/TB
CO-INFECTION

HIV/HBV
CO-INFECTION
PREFERRED 1ST LINE REGIMEN:
TDF + 3TC (or FTC) + EFV
• Simplicity: regimen is very effective, well tolerated and available as
a single, once-daily FDC and therefore easy to prescribe and easy to
take for patients – facilitates adherence
• Harmonizes regimens across range of populations (Adults, Pregnant
Women (1st trimester), Children >3 years, TB and Hepatitis B)
• Simplifies drug procurement and supply chain by reducing number
of preferred regimens (phasing out d4T)
• Safety in pregnancy
• Efficacy against HBV
• EFV is preferred NNRTI for people with HIV and TB (pharmacological
compatibility with TB drugs) and HIV and HBV coinfection (less risk of
hepatic toxicity)
• Affordability (cost declined significantly since 2010)
DOSING OF NEVIRAPINE

• During the first two weeks of treatment, the

elimination rate of nevirapine increases (induction
of its own metabolism)
• Therefore, the dose has to be increased after two
weeks
• Starting dose for adults is 200 mg q 24 h for
2 weeks, subsequently the dose is increased to 200
mg q 12 h
• Administering a full dose of nevirapine from the
beginning leads to more severe and frequent
adverse events
DOSING OF EFAVIRENZ

• Adult dose 400 mg daily, preferably given at

bedtime
• No data exist for use in children less than 3 years
or less than 13 kg of body weight
• Use adult dose if body weight >25 kg
• Adverse effects: A sense of altered mental state,
described as "spacey," "high," or "confused," is
common. It usually resolves within the first month of
treatment. Other significant adverse effects are
rash, dizziness, nausea, headache, fatigue,
insomnia, and vomiting
OVERVIEW OF ‘NEW’ ARVS

• NRTIs: None!
• NNRTIs: Etravirine, Rilpivirine
• PIs: Darunavir, Tipranavir
• IIs: Raltegravir, Dolutegravir, Elvitegravir
• Entry Inhibitors
- Fusion Inhibitors: Enfuvirtide
- Chemokine receptor Antagonists: Maraviroc
 ETRAVARINE (ETR, INTELENCE)

• A new NNRTI that is able to adapt its binding

orientation and overcome common NNRTI
resistance associated mutations (RAMs) such as
K103N. High genetic barrier to resistance
• It shows activity in people who have developed
resistance to EFV or NVP
• 1st NNRTI to be registered since 1998
• Dosage: Adults 200mg BD
• Registered for use in children 6 -18 years (>16kg)
 DARUNAVIR (DRV, PREZISTA)

• Non-peptide PI which binds rapidly to protease at a

unique site and disassociates slowly → two-fold
higher binding strength vs other PIs
• Potent even against PI resistant strains
• Fewer lipid abnormalities than LPV/r
• Cannot be used with Rifampicin, hepatic
impairment
• Dosage:
- Adults: 600mg BD boosted with 100mg RTV
- Children: Approved for > 3 years
RALTEGRAVIR (RAL, ISENTRESS)

• 1st integrase inhibitor approved by FDA in 2007 – a

new class!
• Demonstrated efficacy in 1st line & salvage therapy
• Good safety & tolerability
• Low barrier to resistance, must be used with at
least 2 active ARV agents
• Dosage:
- Adults: 400mg BD
- Children: Approved for use in infants & children
 DOLUTEGRAVIR

• Intergrase inhibitor
• Higher barrier to resistance
• OD regimen
• 50mg od
THE GOALS OF ANTIRETROVIRAL
THERAPY
 Effective combination therapy inhibits viral
replication in all compartments (brain, breast
milk, semen, vaginal secretions) and
prevents emergence of resistance
 Latent virus remains "wild-type" and therefore
efficacy of combination therapy is sustained
 The immune system remains intact or
improves and HIV associated morbidity and
mortality decrease
WHICH OTHER FACTORS INFLUENCE
THE DECISION TO START ARV‘S?

www.newlandsclinic.org.zw Zimbabwe
ASSESSING AND SUPPORTING
PATIENTS‘ READINESS TO START ARV‘s
• Screen for decision making and adherence barriers
• Patient related factors:
– Depression
– Cognitive problems
– Low health literacy
– Social support and disclosure
– Harmful alcohol or drug use
• System related factors:
– Health insurance and drug supply
– Continuity of drug supply
ASSESSING ADHERENCE
BARRIERS
• Depression:
– “In the past month, have you often been bothered by feeling
down, depressed or hopeless?”
– “In the past month, have you often been bothered by little
interest or pleasure doing things?”
– „Is this something for which you would like to seek help?“
• Cognitive problems:
– “Do you feel you have problems to concentrate in your daily
life?”
– „Do you feel slowed in your thinking?“
– „Do you feel that you are having problems with your memory?“
– „Did family, friends mention to you that you might have
problems with memory or concentration?“
ASSESSING ADHERENCE
BARRIERS
• Harmful alcohol or drug use
– „Have you thought about cutting down?“
– „Have you been annoyed when people talk to
you about your drinking?“
– „Have you ever felt guilty about your drinking?“
– „Do you ever have a drink first thing in the
morning?“
• If patients present in a very late stage (i.e. <50
CD4), initiation of ARV‘s should not be delayed,
support patient and assess barriers later
ASSESS THE STAGE OF THE PATIENTS
READINESS FOR ARV‘s
• „I would like to talk about HIV medication – wait – what do
you think about it?“
• Precontemplation
– I don‘t need any drugs
– I feel good, I am strong
– I don't want to think about it
• Contemplation
– I am weighing things up and feel torn about what to do
• Preparation
– I'm ready, I want to start, I think the drugs will allow me to
live a normal life
SUPPORT PROGRESS BETWEEN
STAGES
• Precontemplation: „I don‘t need it“
– Show respect for patient‘s attitude
– Ask about fears, patient‘s experience with
friends, family members
– Try to understand health and therapy beliefs
– Establish trust and confidence
– Provide individualized short information
– Schedule the next appointment
SUPPORT PROGRESS BETWEEN
STAGES
• Contemplation: „I don‘t know, I am ambivalent“
– Show respect for patient‘s attitude
– Allow ambivalence
– Support to weigh pro‘s and con‘s together
with patient
– Assess information needs and support
information seeking (leaflets, support groups)
– Schedule the next appointment
 SUPPORT PROGRESS BETWEEN
STAGES
• Preparation: „I am ready, I want to start“
– Give support, reinforce decision
– Educate about adherence, resistance, adverse
effects
– Discuss integration into daily life: „When is the best
time of the day for you to take the pills?“
– Ask: „What benefits do you expect from ARV‘s?“
– Ask: „What fears do you have about ARV‘s? “
– Ask: „Do you think you can manage taking ARV‘s
regularly once you have started?“
– Use visual analog scale
I will not manage 0 10 I‘m sure I will manage