3. • HIV virus : Single stranded RNA retrovirus
• Other virus : RNA transcripted from DNA
• Retrovirus : DNA transcripted from RNA by the enzyme Reverse
transcriptase
• AIDS
• 2 types for viruses : HIV 1 (worldwide)
HIV 2 (western Africa & India)
• HIV infection : cell mediated immunity collapses – CD4+ T-cell decline
• So, massive opportunistic infection and malignancies - death
5. Genes of HIV virus
• gag- codes for core proteins (RT, integrase and protease enzymes)
• pol – Same as gag
• env- codes for envelope proteins (gp120 and gp41)
Co-receptors
• CCR5 & CXCR
8. Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
Mechanism of Action :
• All drugs require intra-cytoplasmic activation via phosphorylation by cellular
enzymes to tri-phosphate form
• Inhibit reverse transcriptase
• Incorporate into viral DNA and cause chain termination
Resistance :
• Mutation in reverse transcriptase - Monotherapy
9. • NRTIs backbone of an HIV treatment
• Preferred as First line drugs because of
Favourable pharmacokinetic profile, especially long intracellular half life
High oral bioavailability and administration without regard to food
Availability as fixed dose combinations (FDC) with convenient once or
twice daily dosage schedule and
Low risk for drug-drug interactions
10. • Thymidine analogue
• Oral absorption is rapid ; bioavilability 65%
• Metabolize by hepatic glucuronidation
• t1/2 : 1 hour
• Excreted unchanged in urine
Zidovudine (AZT)
11. Adverse effects :
• Anaemia & Neutropenia (MC)
• Nausea , anorexia, abdominal pain, headache, insomnia , myalgia
• Myopathy , Pigmentation of nails
• Convulsion,hepatomegaly, encephalopathy – infrequent
• Reason: inhibition of cellular mitochondrial DNA polymerase γ
Use :
• Palliative treatment of HIV-1 and HIV-2 with other 2 ARV drugs
• As Post exposure prophylaxis
• For mother to offspring transmission
12. • Thymidine analogue
Adverse effects :
• Peripheral neuropathy (Main)
• Lactic acidosis more frequent
• Pancreatitis & joint pain
Interaction :
• Neuropathic drugs (Didanosine, Zalcitabine & Isoniazid) –avoided
One of the optional component of first line regimen used by NACO
Stavudine (d4T)
13. • Cytosine analogue
• Oral bioavailability is very high – 85-90%
• t1/2 : 5-7 hrs
• Well tolerated & lower toxicity – high priority in use
• Dose adjustment is needed in patient with renal insufficiency
• Lamivudine + Zalcitabine – inactivate each other
Dose : 150 mg BD orally
S/E:headache, fatigue, rashes nausea, anorexia,
abdominal pain
Lamivudine (3TC)
14. • Adenosine analogue
Adverse effects:
• Peripheral neuropathy ,Rarely pancreatitis
Use
• Declined due to higher toxicity than other NRTIs
Didanosine (ddl)
15. Non-nucleoside reverse transcriptase enzyme
inhibitors (NNRTIs)
Mechanism of Action :
• Do not require activation through phosphorylation
• Bind directly to the catalytic site of viral reverse transcriptase
• Cause enzyme inactivation and
• Inhibition of viral DNA synthesis
Resistance :
• Mutation in reverse transcriptase
• Cross resistance – in between NNRTIs
No activity against HIV-2
17. Use :
• HIV infected Adults and Children as multidrug therapy
• Prevention of mother to newborn transmission
18. • 50% bioavailability
• Metabolised mainly by CYP2B6; lesser by CYP3A4
Adverse effects :
• Headache, insomnia, dizziness, rashes
• Neuropsychiatric symptoms
Dose : 600 mg OD on empty stomach
Efavirenz (EFV)
19. • Use in HIV-1 infection in adults
• Use decline : 3 times daily dosing schedule
• Side effects : Skin rash, pruritus, elevate hepatic enzyme
• Teratogenic in rats
• Avoided in pregnancy
Delavirdine
New NNRTIs
20. • US-FDA approved in May-2011
• Shown in vitro activity against HIV resistant strains
• Evaluated as an alternative to efavirenz
• High genetic barrier to drug resistance
• Effective against HIV strains resistant to conventional NNRTIs
• Lack of antagonism with other ARV drugs
• Fewer adverse reactions
Rilpivirine
21. Nucleotide Reverse Transcriptase Inhibitors
(NtRTIs)
• Analogue of adenosine-5’-monophosphate
• Available as tenofovir disoproxil fumarate – prodrug
• Hydrolysed in liver → tenofovir → tenofovir diphosphate
• Action is same as NRTIs (except triphosphate form)
• Bioavilability 25% ; ↑ed after meal 40%
• t1/2 : 17 hrs
Tenofovir
23. Protease Inhibitors (PIs)
Mechanism of Action :
• Competitively inhibit the viral protease enzyme
• Prevent cleavage of gag-pol poly proteins;
Necessary for virion production
• Result in production of immature , non-infectious virions
• Effect on late step of viral cycle- effective in both newly as well as
chronically infected cells
• This isoform of protease is not present in the host – better option
25. • Current recommendation – use of PI in combination with either two NRTIs
or one NRTIs + one NNRTIs
• Avoided as 1st line regimen
• Most guideline reserve them for failure cases
• Problem : large tablet load
• “Boosted PI regimen”
• Combine with low & subtherapeutic dose of Ritonavir (100 mg)
• Ritonavir reduce first pass metabolism – increase bioavailability
Slowing systemic metabolism – decrease clearance
26. • PIs inhibit as well as induce specific CYP isoenzymes
• So, drug interactions are common
• Lopinavir is marketed only in combination with Ritonavir
• Nelfinavir is not to be combine with Ritonavir – mainly metabolise by
CYP2C19 ; not inhibited
27. • Oral bioavailability 65% ; food decrease it
• Characteristic S/E : Nephrolithiasis
Urolithiasis
Renal insufficiency
• Other : Hyperbilirubinaemia
Alopecia
Paronychia
Anaemia
Dose : 800 mg BD with 100 mg Ritonavir
Water intake is
recommended
Indinavir
28. • Most commonly used PI
• Relatively low toxicity profile
• Food increase bioavalability
• Only PI – cannot be boosted with Ritonavir (Not metabolise by CYP3A4)
• But, clinical efficacy somewhat lower than other
Nelfinavir
29. • Not well tolerated
• Food increase bioavalability
• Potent CYP3A4 enzyme inhibitor
• Always used as pharmacokinetic booster with other PIs
Side effects :
• Peripheral paraesthesias
• Elevated triglyceride and hepatic transamianses
Dose : 100 mg to boost other PIs
Ritonavir
30. • Only PI fixed dose combination
• Available as a 4:1 ratio
• Lopinavir (400mg BD) : Ritonavir (100 mg BD) with food
• If coadministered with Efavirenz or Nevirapine – Dose increase
Lopinavir + Ritonavir
32. Chemokine Receptor Inhibitors
(1) CCR5 receptor inhibitors
• FDA approved in August 2007
• Approved for use in treatment-experienced patients
• Investigations in treatment-naïve patients have demonstrated it to be
similar to efavirenz
• Hepatotoxicity, muscular/joint pain
Maraviroc
33. Fusion Inhibitors
• Approved by US FDA for treatment-experienced patients who failed other
antiretroviral therapy
• Synthetic peptide ; structurally similar to a section of gp41
• Blocks the conformational changes in gp41 and hence blocks an entry of
virus in the host cell
• Targets both CCR5 and CXCR4
Enfuvirtide
34. • Assessed as a part of multi-drug antiretroviral regimen
• Greater decline in viral RNA load when combined with darunavir/ritonavir,
tipranavir, tenofovir and zidovudine
• Hence, it is important as add on therapy
Side effects : local reaction due to subcutaneous administration
Bacterial pneumonia
• Reserve drug for patients when all treatment fails
• Resistance develops within a few weeks due to mutation of gp41
35. Integrase Inhibitors
Mechanism of action :
• Inhibit the viral enzyme integrase
• Preventing the insertion of HIV genetic material into chromosomes of the
host cells
• Halting the viral replication process
36. • Significant antiviral activity against HIV resistant to protease inhibitors,
NRTIs and NNRTIs
• Approved in October 2007
• As effective as efavirenz in reducing viral RNA count at 48 and 96 weeks
Raltegravir
37. • Integrase inhibitor; Superior to Raltegravir
• FDA approved in August 2013
• Absorption increase by food
• Metabolised by UDP-glucuronyltransferase
• Distribute in CSF, male & female genital tract tissue
Main S/E : Hypersensitivity reaction
Lipodystrophy
• Recommend for adults & children >12 yrs ; weighing at least 40 kgs
Dolutegravir
38. HIV Vaccine
• None of the vaccines tested so far has been successful
• Main problems : diversity of the virus, an ability of the virus to elude the
immune system and lack of animal models
• STEP study :
• Tested the efficacy of recombinant Ad5 HIV-1 vaccine (viral vector carrying
HIV-1 gag, pol and env antigens)
• But lack of efficacy and an increased HIV-1 acquisition in some subjects lead
to premature termination of the trial
