Antiretroviral drugs

1. Antiviral drugs
Antiretroviral drugs
S. Parasuraman, M.Pharm., Ph.D.,
Associate Professor
Faculty of Pharmacy
AIMST University, Malaysia

2. Antiretroviral drugs - Learning Outcomes
• At the end of this session, the student would be able
to:
– classify drugs used for the management of retrovirus
infection. (CLO1)
– describe the mechanism of action, pharmacological
actions, pharmacokinetic features, therapeutic uses,
adverse effects, interaction and contraindications of anti-
retrovirus drugs. (CLO1)

3. Retrovirus
• A retrovirus is a type of RNA
virus that inserts a copy of
its genome into the DNA of a
host cell that it invades, thus
changing the genome of that
cell.
• These are drugs active
against human
immunodeficiency virus
(HIV) which is a retrovirus.

4. HIV-1 vs HIV-2
HIV-1 HIV-2
This strain is found worldwide
and is more common.
This strain is found
predominantly in West Africa.
This strain is more likely to
progress and worsen.
This strain is less likely to
progress and many of those
infected remain lifelong non-
progressors.
Average level of immune
system activation are higher.
Average level of immune
system activation are lower.
During progression, HIV-1 has
lower CD4 counts than HIV-2.
During progression, CD4 counts
are higher in this strain.
Plasma viral loads are higher. Plasma viral loads are lower.
Ref: https://www.stdcheck.com/blog/the-differences-between-hiv-1-and-hiv-2/ [Last assessed on 20/03/2020]

5. Antiretroviral drugs
• The clinical efficacy of antiretrovirus drugs is monitored
primarily by plasma HIV-RNA assays and CD4 lymphocyte
count carried out at regular intervals.
• The two established targets for anti-HIV attack are
– HIV reverse transcriptase: Which transcripts HIV-RNA into proviral
DNA.
– HIV protease: Which cleaves the large virus directed polyprotein into
functional viral proteins.
– Other targets: Chemokine coreceptor (CCR5) on host cells, HIV-
integrase ( Viral enzyme which integrates the proviral DNA into host
DNA)

6. Antiretroviral drugs
• Nucleoside reverse transcriptase inhibitors (NRTIs):
Zidovudine (AZT), Didanosine, Stavudine, Lamivudine,
Abacavir, Emtricitabine, Tenofovir (Nt RTI)
• Nonnucleoside reverse transcriptase inhibitors
(NNRTIs): Nevirapine, Efavirenz, Delavirdine
• Protease inhibitors: Ritonavir, Atazanavir, Indinavir,
Nelfinavir, Saquinavir, Amprenavir, Lopinavir
• Entry (Fusion) inhibitor: Enfuvirtide
• CCR5 receptor inhibitor: Maraviroc
• Integrase inhibitor: Raltegravir

7. Antiretroviral drugs (NRTIs) - Zidovudine
• Zidovudine is a thymidine analogue and first anti-
retrovirus (ARV).
• MOA: Zidovudine phosphorylated in the host cell -
zidovudine triphosphate selectively inhibits viral
reverse transcriptase in preference to cellular DNA
polymerase.
• Resistance: when AZT was used alone, >50% patients
became nonresponsive to AZT within 1–2 years
therapy due to growth of resistant mutants.

8. Antiretroviral drugs (NRTIs) - Zidovudine
• Pharmacokinetics:
– Oral absorption of AZT is rapid, but bioavailability is ~65%.
– Cleared by hepatic glucuronidation (t½ 1 hr)
– Excreted in urine
– Plasma protein binding is 30% and CSF level is ~50% of that
– in plasma.
– It crosses placenta and is found in milk.

9. Antiretroviral drugs (NRTIs) - Zidovudine
• Adverse effects:
– Toxicity is mainly due to partial inhibition of cellular
mitochondrial DNA polymerase γ which has higher affinity
for zidovudine triphosphate than chromosomal DNA
polymerase.
– Anaemia and neutropenia are the most important and
dose-related adverse effects
– Nausea, anorexia, abdominal pain, headache, insomnia
and myalgia.
– Myopathy, pigmentation of nails, lactic acidosis,
hepatomegaly, convulsions and encephalopathy are
infrequent.

10. Antiretroviral drugs (NRTIs) - Zidovudine
• Use:
– HIV treatment: Zidovudine is used in HIV infected patients
only in combination with at least 2 other ARV drugs. Highly
Active Antiretroviral Therapy (HAART) is used to prevent
the likelihood of HIV resistance.
– HIV prevention: AZT, along with two other ARV drugs is the
standard choice for post-exposure prophylaxis of HIV, as
well as for mother to offspring transmission.

11. Antiretroviral drugs (NRTIs)
Drug Type Action
Didanosine Purine nucleoside
analogue
• Inhibits HIV reverse transcriptase
• Terminates proviral DNA
Stavudine Thymidine
analogue
• Acts in the same way as AZT
Lamivudine Deoxycytidine
analogue
• Inhibits HIV reverse transcriptase
• Inhibits HBV-DNA polymerase
Abacavir Guanosine
analogue
• Reduce plasma HIV-RNA count
• Rapid rise in CD4 cell count
Tenofovir It is nucleotide (not
nucleoside)
analogue
• Relatively newer/ clinically used anti-HIV
drugs
• It is also active against HBV.
• Tenofovir is first line 3 drug regimen as
an alternative when either zidovudine or
nevirapine/efavirenz cannot be used due
to toxicity/ contraindication

12. Antiretroviral drugs (NRTIs) - Tenofovir
• MOA:
– Tenofovir is a nucleotide analog reverse-transcriptase
inhibitor (NtRTI). It inhibits HBV-DNA polymerase and
HIV-reverse transcriptase. Tenofovir preventing the
formation of the 5′ to 3′ phosphodiester linkage
essential for DNA chain elongation thereby causes
premature termination of DNA transcription, preventing
viral replication.
• Use:
– Tenofovir is nonselective and inhibit viruses belonging to
different classes and cover both DNA and RNA viruses
– Active against hepatitis B virus (HBV) [DNA virus]
– Active against retroviruses (anti-HIV drugs)

13. Antiretroviral drugs (NNRTIs) - Tenofovir
• Nevirapine (NVP) and Efavirenz (EFV):
– Nevirapine and Efavirenz, directly inhibit HIV reverse
transcriptase without the need for intracellular
phosphorylation.
– They are more potent than Zidovudine on HIV-1, but do
not inhibit HIV-2.
– NVP is well absorbed orally (t½ of ~ 30 hours)
– EFV is well absorbed orally (t½ of ~ 48 hours)

14. Antiretroviral drugs
(Retroviral protease inhibitors)
• Protease inhibitors (PIs) are a class of antiviral drugs that are
widely used to treat HIV/AIDS and hepatitis C
• Antiretroviral HIV-1 protease inhibitors — class stem –navir
• Ritonavir, Atazanavir, Indinavir, Nelfinavir,
Saquinavir, Amprenavir, Lopinavir:
– An aspartic protease enzyme encoded by HIV is involved in
the production of structural proteins and enzymes
(including reverse transcriptase and integrase) of the virus.

15. Antiretroviral drugs
(Retroviral protease inhibitors)
Drug
Atazanavir • Administered with light meal which improves
absorption (t½ is 6–8 hours).
• Dyslipidaemia and other metabolic complications are
minimal with ATV, but jaundice occurs in some
patients without liver damage due to inhibition of
hepatic glucuronyl transferase
Indinavir • It is to be taken on empty stomach; g.i. intolerance is
common; excess fluids must be consumed to avoid
nephrolithiasis.
• Hyperbilirubinaemia occurs
Nelfinavir • It is to be taken with meals, since food increases
absorption

16. Antiretroviral drugs
(Retroviral protease inhibitors)
• ADR
– The most prominent adverse effects of Pis are
gastrointestinal intolerance, asthenia, headache, dizziness,
limb and facial tingling, numbness and rashes.
– Of particular concern are lipodystrophy (abdominal
obesity, buffalo hump with wasting of limbs and face),
dyslipidaemia (raised triglycerides and cholesterol) which
may necessitate hypolipidaemic drugs, and insulin
resistance.

17. Antiretroviral drugs
(Entry [fusion] inhibitor)
• Enfuvirtide
– Enfuvirtide is a synthetic peptide acts
by binding to HIV-1 envelope
transmembrane glycoprotein (gp41)
which is involved in fusion of viral and
cellular membranes.
– It is not active against HIV-2.
– No cross resistance with other classes
of ARV drugs occurs.
– The injections are painful and cause
local nodules/cysts.
Ref: https://aidsinfo.nih.gov/images/glossaryimages/Fusion-Inhibitor2-600.jpg [Last assessed on 20/03/2020]

18. Antiretroviral drugs
(CCR5 receptor inhibitor)
• Maraviroc
– The globular glycoprotein
gp120 of the HIV envelope
anchors to the CD4 site of
host cell by binding to a cell
membrane receptor, which
mostly is the CCR5
chemokine receptor (most
HIV are CCR5-tropic).
Ref: https://aidsinfo.nih.gov/images/glossaryimages/CCR5-Antagonist2-800.jpg [Last assessed on 20/03/2020]

19. Antiretroviral drugs
(Integrase inhibitor)
• Raltegravir
– Raltegravir is an
orally active drug
that blocks this
step by inhibiting
the integrase
enzyme. It is
active against
both HIV-1 and
HIV-2.
Ref: https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/380/integrase-strand-transfer-inhibitor/ [Last assessed on 20/03/2020]

20. HIV Treatment principles and Guidelines
• The treatment of HIV infection and its complications is
complex, prolonged, needs expertise, strong motivation and
commitment of the patient, resources and is expensive.
• Antiretroviral therapy (ART) is only 25 years old, and is still
evolving.
• Initially, anti-HIV drugs were used singly one after the other as
each failed in a patient due to emergence of resistance.
• Understanding the biology of HIV infection: ‘highly active
antiretroviral therapy’ (HAART) with combination of 3 or
more drugs.

21. HIV Treatment principles and Guidelines
• Initiating antiretroviral therapy
• Therapeutic regimens (HAART)
• Prophylaxis of HIV infection
– Post-exposure prophylaxis (PEP)
– Prophylaxis after sexual exposure
– Perinatal HIV prophylaxis (First line regimen for pregnant
women: Zidovudine + Lamivudine + Nevirapine)

23. HIV prevention