Dr.

Amit M Shah

ANTIRETROVIRAL
DRUGS
INTRODUCTION
• Acquired Immunodeficiency syndrome (AIDS)
• Human Immunodeficiency Virus (HIV)
• Retrovirus
• Two major forms:
 HIV-1, the most prevalent worldwide, and
 HIV-2, the most common in western Africa
 NRTIs Raltegravir Protease
Enfuvertide
NNRTIs Inhibitors
Maraviroc NTRTIs
ANTIRETROVIRAL DRUGS
• Nucleoside Reverse Transcriptase Inhibitors
(NRTIs): Zidovudine, Stavudine, Lamivudine,
Abacavir
• Non Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs): Efavirenz, Nevirapine, Delaviridine
• Nucleotide Reverse Transcriptase Inhibitors
(NTRTIs): Tenofovir
• Protease Inhibitors (PIs): Saquinavir, Indinavir,
Nelfinavir, Fosamprenavir, Ritonavir, Lopinavir
• Entry/Fusion Inhibitors: Enfuvirtide, Maraviroc
• Integrase Inhibitor: Raltegravir
 NRTIs
Zidovudine (ZDV), Stavudine (d4T), Lamivudine (3TC),
Abacavir (ABC), Emtricitabine (FTC), Didanosine (ddI)
• Incorporate themselves into the DNA of the virus
(competing with natural nucleotides) ⇒
Stopping the building process of transcription
from RNA to DNA ⇒ Incomplete DNA ⇒ No new
virus
• Block the HIV replication, block the infection of
new cells
• No effect on already infected cells

• Adverse effects: Lactic acidosis, severe

hepatomegaly, hepatic steatosis
 • Pharmacokinetics:
Oral Renal
Drug Distribution Metabolism T1/2
BA Excretion
All tissues, CSF,
Zidovudine 60-65 Hepatic 15% 1-3
PB 35%
Good, CSF,
Stavudine 85-90 Minor 40% 1.2
Negligible PB
Lamivudine 85-90 CSF 20%, PB 35% Minor 72% 5-7
Abacavir 83 CSF 33%, PB 50% Liver, AD <5% 1.5
Zalcitabine >80 CSF 20%, PB <4% Minor 60% 2
Emtricitabine 93 <4% PB Liver 13% 86% 10
Purine metabolic
Didanosine 42 CSF 20%, <5% PB 18% 1.5
pathway
ZIDOUVIDINE (AZT, ZDV)
• First antiviral drug used against HIV
• Thymidine analogue that is effective against HIV-
1, HIV-2, and HTLV I and II
• Approved for the treatment of HIV infection in
adults and children in combination with one or
more other antiretroviral agents
• Approved for the post-exposure prophylaxis
• Alone or in combination for the prevention of
prenatal and perinatal transmission to the baby
by HIV-infected pregnant women
• Adverse Effects:
 Headache, nausea, vomiting, anorexia
 Fatigue, confusion, insomnia, malaise
 Hepatitis
 Myopathy, myositis
 Bone marrow toxicity, anaemia, neutropenia, and
other haematological abnormalities
STAVUDINE (D4T)
• Thymidine nucleoside analogue
• Active against HIV-1 and HIV-2
• It is approved for the therapy of HIV infection as
part of a multidrug regimen and is also used for
Postexposure prophylaxis
• Adverse effects: Headache, diarrhoea, skin rash,
nausea, vomiting, insomnia, anorexia, myalgia,
peripheral neuropathy. Lactic acidosis occurs
more frequently with Stavudine than with other
NRTIs.
LAMIVUDINE (3TC)
• Cytosine nucleoside analogue
• Active against HIV-1, HIV-2, and hepatitis B
virus.
• It is approved as part of a multidrug regimen for
the therapy of HIV infection in adults and
children and has been used for HIV postexposure
prophylaxis.
• Best-tolerated NRTI

• Adverse Effects: Headache, malaise, fatigue,

insomnia
ABACAVIR (ABC)
• Guanosine nucleoside analogue
• Indicated as part of a multidrug regimen for the
therapy of HIV-1 infection in adults and children
• Post exposure HIV infection prophylaxis.
• Adverse Effects:
 Anorexia, nausea, vomiting, malaise, headache, and
insomnia
 Hypersensitivity reaction (5%): Fever and rash to
fatal anaphylactic shock
DIDANOSINE (DDI)
• Adenosine analogue
• Active against HIV-1, HIV-2, and HTLV-I
• Approved as part of a multidrug regimen for the
therapy of HIV infection and is also used as Post
exposure HIV prophylaxis.

• Adverse Effects: Diarrhea, abdominal pain,

nausea, vomiting, anorexia and dose-related
peripheral neuropathy, pancreatitis,
hyperuricemia, bone marrow suppression,
retinal depigmentation, and optical neuritis
NNRTIs
• Efavirenz, Nevirapine, Delaviridine, Etravirine
• Mechanism of Action:
 They act by stopping HIV production by binding
directly onto Reverse Transcriptase (non-
competitively) and preventing the conversion of RNA
to DNA.
 Do not require activation through phosphorylation
• Adverse effects:
 Skin rashes including Steven-Johnson syndrome
 Elevation of liver enzymes
• Pharmacokinetics:
PARAMETER NEVIRAPINE EFAVIRENZ ETRAVIRINE
Oral BA 90-93 50 NR
Effect of meals on AUC 17-28% 33-102%
Plasma t1/2 25-30 hr 40-55 hr 41 hr
PPB 60% 99% 99.9%
Metabolism CYP3A4 > CYP2B6 > CYP3A4, 2C9,
CYP2B6 CYP3A4 2C19, UGT
Renal excretion <3% <3% 1%%
Autoinduction Yes Yes NR
of metabolism
Inhibition of CYP3A No Yes No
EFAVIRENZ (EFV)
• Approved for the therapy of HIV infection of
adults and children and for Post-exposure
prophylaxis
• Only NNRTI approved for once-daily dosing
• Adverse effects:
 Rash, elevated liver enzymes and serum cholesterol
 CNS Effects: dizziness, headache, insomnia,
drowsiness, euphoria, agitation, impaired cognition,
nightmares, vivid dreams, and hallucinations
• Teratogenic in primate studies
NEVIRAPINE (NVP)
• Approved for the treatment of HIV infection in
adults and children as part of a combination
therapy
• Mild to moderate rash, fever, nausea, fatigue,
headache, and elevated liver enzymes
• Fatal hepatic toxicity (i.e., hepatitis, hepatic
necrosis, and hepatic failure) and skin reactions
(i.e., Stevens-Johnson syndrome, toxic epidermal
necrolysis, and hypersensitivity reactions)
• First 12 weeks of treatment, patients must be
closely monitored
NTRTIs - TENOFOVIR (TFV)
• Active form Tenofovir diphosphate
competitively inhibits HIV reverse transcriptase
enzyme ⇒ termination of chain elongation after
getting incorporate into viral DNA
• Pharmacokinetics:
 Oral bioavailability: 25% (fasting), 40% (after meals)
 Distribution: PB is negligible (2-5%)
 Plasma T1/2: 17 Hrs
 Excretion: Urine, 70-80% FD
• Adverse effects: Nausea, vomiting, diarrhea,
osteomalacia
PROTEASE INHIBITORS (PIs)
Saquinavir, Indinavir, Nelfinavir, Amprenavir,
Fosamprenavir, Ritonavir, Lopinavir, Atazanavir
• Inhibitors of the viral protease ⇒ Prevent the
correct cleavage of viral proteins
• Ritonavir is used in low doses to increase blood
levels of other protease inhibitors and to extend
their dosing interval (potent inhibitor of CYP3A4)
• Nelfinavir has low incidence of serious ADR⇒
Most commonly used protease inhibitor
• Adverse effects: Diarrhea, nausea, abdominal
discomfort; Hyperglycemia, fat redistribution,
hyperlipidemia; Bleeding episodes in hemophilics
• Pharmacokinetics:
Drug Oral BA Distribution Metabolism Excretion T1/2
Saquinavir-H 4 PB 97% CYP3A4, FPM Feces 85%, 8
Urine 3%
Saquinavir-S 13 Wide, CSF nil, CYP3A4, FPM Feces 85%, 11
PB 97% Urine 3%
Ritonavir 75 PB 98% CYP3A4 Fecea 98%, 3-5
Urine 1%
Lopinavir variable PB 98% CYP3A4 Mainly Feces, 5-6
Urine 2%
Nelfinavir Variable PB 98% CYP3A4 Mainly Feces, 4-5
Urine 2%
Indinavir 65 CSF 76%, CYP3A4 Feces, 1.8
PB 60% Urine 10%
Amprenavir 63 PB 90% CYP3A4 Feces 75%, 7-11
Urine 15%
Atazanavir >70 CSF 3%, CYP3A4 Feces, 7
PB 86% Urine 7%
ENFUVIRTIDE
• Entry/Fusion inhibitors
• Binds to gp41 subunit of viral envelop
glycoprotein
• Prevents the entry of HIV-1 into CD4+ cells by
interfering with fusion
• Oral bioavailability: Poor, Hence give S/C
• Adverse effects: Local reaction (nodule) at
injection site, skin rash, eosinophilia, pneumonia
like manifestation
 WHEN TO START
Target population WHO ART guideline
HIV+ asymptomatic CD4 ≤350 cells/mm3

WHO clinical stage 1 or 2 if CD4 ≤350 cells/mm3

HIV+ symptomatic
WHO clinical stage 3 or 4 irrespective of CD4 cell
count
CD4 ≤350 cells/mm3 irrespective of clinical
HIV+ pregnant symptoms
women WHO clinical stage 3 or 4 irrespective of CD4 cell
count
HIV + TB Presence of active TB disease, irrespective of CD4
coinfection cell count
HIV + HBV Individuals require treatment for their HBV
coinfection infection, irrespective of CD4 cell count
 WHAT TO START
Target population WHO ART guideline
TDF + 3TC + EFV or NVP or
First Line
AZT + 3TC + NVP or EFV
AZT + 3TC + LPV/r or ATV/r
Second Line
TDF + 3TC + LPV/r or ATV/r
HIV+ pregnant women TDF + 3TC (or FTC) + EFV
HIV + TB PIs are not recommended during TB
coinfection treatment with Rifampicin
HIV + HBV Contain TDF and FTC or 3TC
coinfection TDF + 3TC (or FTC) + EFV

• PEP Regimens: 3TC + AZT or TDF