1 Introduction to ARV Therapy HAIVN Harvard Medical School AIDS Initiative in Vietnam

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Introduction to ARV Therapy

HAIVNHarvard Medical School AIDS

Initiative in Vietnam

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Learning Objectives

By the end of this session, participants should be able to:

Identify the main classes of ARV drugs available in Vietnam and explain their mechanisms of action

Explain the criteria for starting ART Identify the first line ARV regimens

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ARV Drug Classes

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Drug Classes of Antiretrovirals

1. Nucleoside Reverse Transcriptase Inhibitors

(NRTI)

2. Non-nucleoside Reverse Transcriptase

Inhibitors (NNRTI)

3. Protease Inhibitors (PI)

4. Fusion/Entry Inhibitors

5. Integrase Inhibitors

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ARV Drugs Currently Available in the World and Vietnam

Nucleoside/Nucleotide RTI

AZT / Zidovudine

d4T / Stavudine

3TC / Lamivudine

ddI / didanosine

ABC / Abacavir

TDF / Tenofovir

FTC /Emtricitabine

Non-nucleoside RTI

NVP /Nevirapine

DLV / Delavirdine

EFV / Efavirenz

ETR / Etravirine

Protease inhibitors

SQV / Saquinavir

RTV / Ritonavir

IDV / Indinavir

NFV / Nelfinavir

APV / Amprenavir

LPVr / Lopinavir + ritonavir

ATV / Atazanavir

Fos-Amprenavir

DRV / Darunavir

TPV / Tipranavir

Integrase inhibitors

RAL / Raltegravir

Fusion/Entry inhibitors

MVC / Mariviroc

ENF / Enfuvirtide

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Combination Pills Availablein Vietnam

AZT + 3TC = LAMZIDIVIR, Combivir

D4T + 3TC + NVP = D4T - FDC, NEVITRIO 30, Triamune, GPOvir

AZT + 3TC + NVP = AZT - FDC, LAMZITRIO

AZT + 3TC + ABC = ABATRIO, Trizivir

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Review of HIV Lifecycle

HIV is an RNA “retrovirus” Virus containing RNA infects the cell Viral enzymes transcribe RNA to DNA

(reverse transcription) Viral DNA is integrated into the host

cell DNA Cell and viral mechanisms produce

viral proteins and viral RNA New virus is produced

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HIV Lifecycle and ARV

ReverseTranscriptaseInhibitors(NRTI + NNRTI)

Fusion/EntryInhibitors

IntegrationInhibitors

ProteaseInhibitors(PI)

Source: wires.wiley.com-2010Source: wires.wiley.com-2010

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Nucleoside Reverse Transcriptase Inhibitors (NRTI)

Reverse transcriptase (RT) builds DNA from viral RNA by using human nucleotides

NRTI drugs, when present, will be inserted into the growing DNA chain

DNA chain containing NRTIs cannot accept new nucleotides

This blocks DNA chain production so HIV cannot produce new virus to infect new cells

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Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

NNRTIs attach directly to the reverse transcriptase enzyme.

Enzyme with NNRTI attached cannot function normally

Production of viral DNA from RNA is blocked

Virus is unable to convert RNA into DNA, therefore unable to infect the cell and produce new virus

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Site of Action of RTIs

ReverseTranscriptaseInhibitors(NRTI + NNRTI)


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Mechanism of Action of NRTIs and NNRTIs

Source: Nature 2001Source: Nature, 2001

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Protease Inhibitors (PI)

Infected cell produces large viral proteins (polyproteins)

Protease enzyme cleaves polyproteins into enzymes and structural proteins required to make new virus

PIs attach to and block protease enzyme

The virus particles produced are defective and inactive and are unable to infect new cells

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Site of Action on Protease Inhibitors

ProteaseInhibitors(PI)


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ARV Therapy

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Goals of ARV Therapy

Inhibit HIV replication• As low as possible (undetectable)• For as long as possible

Allow recovery of the immune system Prevent opportunistic infection Improve survival, health and quality

of life

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Key Principle of ARV “Triple Therapy” (1)

A 3 drug regimen should be chosen for treatment based on the National ARV guidelines

Treatment with 1 or 2 drugs should not be started for standard treatment of HIV disease

Guidelines for Diagnosis and Treatment of HIV/AIDS, MOH 2009

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Key Principle of ARV “Triple Therapy” (2)

“Highly Active Antiretroviral Therapy” is 3-drug ARV therapy with

2 NRTI + NNRTI

or

2 NRTI + PI

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Treatment of HIV Infection With 1 or 2 Drugs

Viral Load

Limit of detection

Time

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Treatment of HIV Infection with 3 ARVs “Triple Therapy”

Viral Load

Limit of detection

Time

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Patients Progressing to AIDS, by Type of ARV Therapy

%

Month

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When to Start ART?

ARV therapy is never an emergency Patients with high CD4 are not at risk

for OIs and can delay ARV treatment Decide when to start ARV based on:

Risks Benefits

• Allergy• Side Effects• Adherence• Costs

• Improve immune function • Improve quality of life• Decrease risk for OIs

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When to Start ARV in Vietnam

Patients with: CD4 ≤ 350 cells/mm³ irrespective of

clinical stage Clinical stage 3 or 4 irrespective of CD4

cell count

Modification and Supplement to the Guidelines for Diagnosis and Treatment of HIV/AIDS, MOH November 2011

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Which Antiretroviral Drugs Should You Use?

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First Line ARV Regimens in Vietnam (1)

2 NRTI + 1 NNRTI

Stavudine (D4T) is no longer recommended as a first line ARV

Lamivudine (3TC)Tenofovir (TDF)Zidovudine (AZT)

Efavirenz (EFV)Nevirapine (NVP)


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3TCEFVor

NVP+


+TDFor

AZT

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Priority Regimens Alternative Regimens

TDF/3TC/EFVTDF/3TC/NVP

AZT/3TC/EFVAZT/3TC/NVP


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How to Choose a First Line Regimen

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Prioritized Regimens:TDF/3TC/EFVTDF/3TC/NVP

TDF/3TC are the preferred NRTIs• Well tolerated by patients• Once-daily dosing• Treats hepatitis B in patients with HIV-

hepatitis B co-infection

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First Line Regimen NNRTI:NVP vs. EFV

Use EFV Use NVP

•LFTs > 2.5x normal•HBV or HCV co-infection•Patient on Rifampin•Men, CD4 > 400•Female, CD4 > 250

•Pregnancy, 1st trimester•Depression or other mental illness

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Use for patients who cannot take TDF Suitable choice for patients with:• Renal failure• Pregnancy

Alternative Regimens:AZT/3TC/EFVAZT/3TC/NVP

Do not use AZT in patients with severe anemia (Hgb < 8 g/l)

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Alternative First Line Regimens: AZT + 3TC + TDF

For patients who cannot use NVP or EFV However, research shows less efficacy

than regimens that contain 2 NRTI + (1 NNRTI or 1 PI)• Lower rates of virological suppression• Higher chance for developing resistance to

NRTI Recommended only when no other

ARV regimens are available

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Small Group Activity: Mini Case Scenarios

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Key Points

NRTI, NNRTI, PI are 3 ARV classes used in Vietnam

Only prescribe triple therapy ARV regimens – they are most effective

Two priority first ARV regimens in Vietnam:• TDF + 3TC + EFV• TDF + 3TC + NVP

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Thank You!

Questions?

Documents

1 Introduction to ARV Therapy HAIVN Harvard Medical School AIDS Initiative in Vietnam