Antiretroviral agents

1. Antiretroviral Agents
Dr Shivaprakash G
23/01/2024

3. HIV-2
• Transmission as HIV-1
• Western Africa
• Less pathogenic
• Slow disease progression
• Long asymptomatic stage
• Slow decline in CD4 count
• Low vertical transmission
• Lower viral loads
• Dolutegravir (DTG) is now recommended as the preferred
drug for all lines of treatment of HIV infection, it is
expected that patients with HIV- 2 infection will benefit
• NNRTI ineffective

4. Classification(Anti-Retrovirus)
(a) Nucleoside reverse transcriptase inhibitors (NRTIs):
Zidovudine (AZT), Didanosine, Stavudine,
Lamivudine, Abacavir, Emtricitabine,
Tenofovir (Nt RTI)
(b) Nonnucleoside reverse transcriptase inhibitor (NNRTIs):
Nevirapine, Efavirenz, Delavirdine
(c) Protease inhibitors: Ritonavir, Atazanavir, Indinavir,
Nelfinavir, Saquinavir, Amprenavir, Lopinavir
(d) Entry (Fusion) inhibitor: Enfuvirtide
(e) CCR5 receptor inhibitor: Maraviroc
(f) Integrase inhibitor: Raltegravir, Dolutegravir

5. CCR5 receptor inhibitor-Maraviroc
• Glycoprotein gp120 + CD4 site + CCR5 chemokine [host
cell membrane co-receptor].
• No effect on HIV strains that are CXCR4 receptor tropic.
• Active orally and cyp3A4 substrate but itself is not inhibitor
or inducer.
• Hypotension, hypersensitivity and hepatotoxicity

6. Fusion inhibitor
• Enfuvirtide
• Syn. peptide + HIV-1 gp41 Fusion entry blocked.
• It is not active against HIV-2.
• Administered s.c. twice daily, it is used as add on drug and
failed earlier regimens
• Injections are painful and cause local nodules/cysts.
• Cost and inconvenience are prohibitive

7. Competitive inhibitors
• NRTI-PK Zidovudine Thymidine analogue
• Forms active Zidovudine triphosphate intracellularly.

8. • The oral absorption of AZT is rapid, but
bioavailability is ~65%.
• Cleared by hepatic glucuronidation (t½ 1 hr);
• Excreted in urine.
• It crosses placenta and is found in milk.

9. Zidovudine(AZT)
• ADE: Anaemia and neutropenia are common
• Headache, nausea, vomiting, anorexia, insomnia,
fatigue.
• Myopathy, pigmentation of nails, lactic acidosis,
hepatomegaly, convulsions and encephalopathy rare
• DI:
• Paracetamol increases AZT toxicity, by competing for
glucuronidation.
• Azole antifungals also inhibit AZT metabolism.
• Nephrotoxic, myelosuppressive drugs & probenecid
enhance toxicity.
• Stavudine and zidovudine exhibit mutual antagonism by
competing for the same activation pathway

10. Uses
• ARV regimen for failed first line Dolutegravir
regimen. Is a component of alternative regimen.
• AZT+two other ARV drugs is the standard choice
for PEP of HIV in children <10y and <30kg, for
mother to offspring transmission.
• Effective on HIV-1 and HIV-2

11. Stavudine (d4T-thymidine analogue)
• AZT antagonises the effect of stavudine.
• Peripheral neuropathy combined with didanosine.
• ADE: Peripheral neuropathy, lipodystrophy, lactic
acidosis & pancreatitis are the Sae

12. Tenofovir
• NACO includes tenofovir in its first line 3 drug regimen
• Nucleotide analogue.
• Good tolerability profile.
• Tenofovir least as effective and less toxic as other first line
regimens.
• Preferred 1st line WHO regimen for adults and adolescents for
HIV-1,HIV-2 and HBV. Renal toxicity is to be watched.
• No cyp interactions and eliminated unchanged in urine.Fatty
food increase absorption, T1/2=17hr, metabolism not
determined,F=25%

13. Lamivudine (deoxycytidine analogue=3TC)
• Inhibits HIV1,HIV2 reverse transcriptase & HBV DNA
polymerase.
• F high=87% and t½ longer (6–8 hours). It is mainly excreted
unchanged in urine
• Synergizes with NRTIs and component of all first line triple drug
NACO regimens
• It is also a first line drug for chronic hepatitis B.
• Side effects —
• Headache, fatigue, rashes nausea, anorexia, abdominal pain.
• Pancreatitis and neuropathy are rare.

14. Abacavir
• Guanosine nucleoside analogue
• Oral F is 80% and t½ is 1–1.5 hour.
• AE: Hypersensitivity reactions such as rashes, fever,
abdominal pain, bowel upset, flu-like respiratory &
constitutional symptoms.
• Avoided in patients with cardiovascular risk factor.
• Preferred 1st line WHO regimen for children.

15. NNRTI M/A
• Non-competitive, Nucleoside unrelated compounds directly
inhibit HIV reverse transcriptase.
• Virus strain specific, act on HIV-1, but do not inhibit HIV-2.
• Cross resistance between NVP and EFV is common, but not
with NRTIs/PIs.
• Patient failing any NNRTI regimen should not be treated
with another NNRTI

17. Nevirapine
• NVP oral F90%; metabolized, by CYP3A4, t½ of ~ 30 hours.
 EFV F ~ 50%, t½ 48 hours, completely metabolized, mainly
by CYP2B6 and a smaller fraction by CYP3A4.
• Both are enzyme inducers, and cause autoinduction of their
own metabolism hence dose doubled after 2 wk. EFV
inhibits CYP3A4 as well.
• NVP used in infant ARV prophylaxis
• Patient on NVP if develops TB on rifampin, NVP should be
replaced by EFV.

18. Nevirapine
• Rashes are the commonest, nausea and headache.
• NVP is potentially hepatotoxic. Replaced by EFV
which has low hepatotoxicity.
EFZ
• Headache, rashes, dizziness, insomnia and a variety
of neuropsychiatric symptoms.
• Use: Alternative to first line Dolutegravir
ART(TLD)

19. Integrase inhibitors

20. Integrase inhibitor-Dolutegravir
• Active against both HIV-1 and HIV-2.
• Dose of dolutegravir doubled when given with enzyme inducers like
rifampin and efavirenz.
• Glucuronide conjugated, T1/2=12hr
• Cationic medication (Ca2+, Mg2+ salts) should be avoided or
staggered with dolutegravir.
• Good tolerability profile with rashes and hypersensitivity as the
infrequent adverse effects-hepatotoxicity.
• 1st line regimen for treatment-naïve HIV patients

21. Raltegravir
• HIV-integrase nicks host chromosomal DNA and integrates
the proviral DNA and reseals it.
• Raltegravir orally active inhibit integrase enzyme.
• Active against both HIV-1 and HIV-2.
• Absorbed orally, metabolized in liver by glucuronide
conjugation,T1/2=12hr.
• Rifampicin induce its metabolism, Ca, Mg, Fe to be avoided
• Side effects; headache, dizziness, myopathy

22. PI- Atazanavir (ATV), Indinavir(IDV), Nelfinavir (NFV),
Saquinavir (SQV),Ritonavir (RTV) and Lopinavir
• Aspartic protease enzyme encoded by HIV.
• It acts at a late step in HIV replication, effective in
both newly as well as chronically infected cells
• HIV-infected cells produce immature noninfectious viral
progeny—hence prevent further infection.
• Plasma t½ ranges from 2–8 hours.
• All are metabolized by CYP3A4, except NFV which is
mainly a substrate of CYP2C19.
• All PIs (especially ritonavir and lopinavir) are potent
inhibitors of CYP3A4, while some induce

23. • Large tablet load are to be taken daily, some on
empty stomach, but others with meals.
• One of the strategies adopted to reduce the dose is to
combine them with a low and subtherapeutic dose
(100 mg) of ritonavir.
• ‘Boosted PI regimen’ permits reduction in the
number/ frequency of tablets to be taken each day.
• Lopinavir is marketed in combination with ritonavir.
• Nelfinavir(CYP2C19) not combined with ritonavir

24. • Use: Current recommendations are to use a PI in
combination with either two NRTIs or one NRTI +
one NNRTI.
• First line regimen with Abacavir, Lamivudine for
children <6yr and <20Kg*[T and D cannot be given]
• Acts on HIV-2 as well*
• Used as an alternative ART TL+Dalutegravir
regimen.*
• Used in Tb co-infection- along with TL

25. AE
• Gastrointestinal intolerance, asthenia, headache,
dizziness, limb and facial tingling, numbness and
rashes.
• Lipodystrophy (abdominal obesity, buffalo hump
with wasting of limbs and face), dyslipidaemia
(raised triglycerides and cholesterol), diabetes may
be exacerbated.
• Indinavir crystallizes in urine and increases risk of
urinary calculi.

27. First line Drugs for all >10y and >30kg
• Tenofovir (TDF 300 mg) + Lamivudine
(3TC 300 mg) + DOLUTEGRAVIR (DTG
50 mg) regimen (TLD) as FDC in a single
pill once a day (at a fixed time every day as
per patient’s convenience)

31. Prophylaxis of HIV Infection

34. Perinatal HIV prophylaxis
• Placenta, or during delivery, or by breastfeeding.
• The highest risk (>2/3rd) of transmission is during
the birth process
• As per current recommendation, all HIV positive
women, who are not on ART, should be put on the
standard 3 drug ART.
• This should be continued through delivery and into
the postnatal period, and has been shown to prevent
vertical transmission of HIV to the neonate, as well
as benefit mother’s own health.

36. Ibalizumab
• Monoclonal antibody that binds to CD4 receptors on
the surface of CD4-positive cells.
• Approved in March 2018 for the management of
treatment-resistant HIV 5. In October 2022, the FDA
approved the administration of Trogarzo by
intravenous push, allowing for a faster drug
administration.
• Highly treatment-experienced adults with multidrug-
resistant HIV-1 infection failing their current
antiretroviral regimen

37. • T1/2= 3 to 3.5 days.
• AEs
• Immune reconstitution inflammatory syndrome has
been reported in one patient treated in combination
with other antiretrovirals