Pharmacology: Chemotherapy, Anti HIV Drugs

1. Dr.Ankita Bist
Assistant professor
Dept. of pharmacology

2. gp120
gp41
Gag, pol, env genes

3.  Established targets for anti-HIV drugs:
1. Chemokine coreceptor (CCR5) on host cells : provide
anchorage for the surface proteins of the virus.
2. Fusion of viral envelope with plasma membrane of CD4
cells: through which HIV- RNA enters the cell.
3. HIV reverse transcriptase: Which transcripts HIV-
RNA into proviral DNA.
4. HIV-integrase: Viral enzyme which integrates the
proviral DNA into host DNA.
5. HIV protease: Which cleaves the large virus directed
polyprotein into functional viral proteins.

4. 1
2
3
4
5

6. • Nucleoside analogs (NRTI) act as competitive inhibitors or
chain terminators at the substrate binding site of RT.
• The first anti-HIV drug approved was the NRTI known as
AZT or Zidovudine (1987).

7. • Thymidine analogue (azido- thymidine, AZT), the
prototype NRTI
• Phosphorylation in the host cell—zidovudine
triphosphate selectively inhibits viral reverse
transcriptase in preference to cellular DNA polymerase
Single-stranded viral RNA
Virus directed reverse transcriptase
(inhibited by zidovudine triphosphate)
Double-stranded proviral DNA
•Resistance : point mutations

8.  Pharmacokinetics:
• The oral absorption is rapid, bioavailability is ~65%
• It is quickly cleared by hepatic glucuronidation (t1⁄2 =1 hr);
15–20% of the unchanged drug along with the metabolite is
excreted in urine.
• CSF level is ~50% of that in plasma
• It crosses placenta and is found in milk.
• AZT also reduces neurological manifestations of AIDS and
new Kaposi’s lesions do not appear while on treatment with
this.

9.  Adverse effects:
• Anaemia, neutropenia.
• Nausea, anorexia, abdominal pain, headache,
insomnia and myalgia are common at the start of
therapy, diminish later.
• Myopathy, pigmentation of nails, lactic acidosis,
hepatomegaly, convulsions and encephalopathy -infrequent

10. • Inhibits HIV reverse transcriptase as well as HBV DNA
polymerase
• Oral bioavailability is high and plasma t1⁄2 longer (6–8
hours).
• Synergizes with most other NRTIs for HIV & is an
essential component of all first line triple drug NACO
regimens.
• Side effects are few—fatigue, rashes, abdominal pain
• Pancreatitis and neuropathy are rare
• Hematological toxicity does not occur

11. • A guanosine nucleoside analogue.
• Indicated for the therapy of HIV-1 infection in adults and
children.
 Adverse effects:
• Anorexia, nausea, vomiting, malaise, headache, and
insomnia.
• A potentially fatal hypersensitivity reaction (approx 5% of
patients).

12. • Is the only nucleotide analogue, relatively newer.
• It is also active against HBV
• Due to good tolerability profile, it is now included in first
line regimens.
• Renal toxicity is to be watched.

13. • Nucleoside unrelated compounds which directly inhibit HIV
reverse transcriptase
• No need for intracellular phosphorylation.
• Bind at the allosteric non-bonding site of RT, causing a
conformational change of the active site.
• More potent than AZT on HIV-1, but do not inhibit HIV-2.
• Resistance : point mutations
• General ADR’s: Rashes including Stevens Johnson syndrome,
elevated liver enzymes.

14. • Either NVP or EFV is included in the first line triple drug
regimen used by NACO.
• Cross- resistance between NVP and EFV is common.
• Enzyme inducers and Inhibitors

15.  NEVIRAPINE
• Rashes are the commonest, followed by nausea and
headache. Occasionally severe skin reaction. Potentially
hepatotoxic.
 EFAVIRENZ
• Side effects are headache, rashes, dizziness, insomnia
and a variety of neuropsychiatric symptoms.
• Because of its longer plasma t1⁄2, occasional missed doses
of EFV are less damaging.
• Teratogenic on animals.

16. • Acts at a late step in HIV replication.
• Bind to the active site of protease molecule, interfere with
its cleaving function.
• More effective viral inhibitors than AZT.
• Effective in both newly as well as chronically infected cells.
• Nelfinavir, lopinavir and ritonavir induce their own metabolism,
• Ritonavir used in booster dose.
• Also metabolism of PIs is induced by rifampicin and other
enzyme inducers rendering them ineffective.

17. • Most prominent adverse effects of PIs are gastrointestinal
intolerance, asthenia, headache, dizziness, limb and facial
tingling, numbness and rashes.
• Lipodystrophy, dyslipidaemia and insulin resistance are of
particular concern.
• Diabetes may be exacerbated.
• Indinavir crystallizes in urine and increases risk of urinary
calculi.

18.  Ritonavir (RTV)
• Drug interactions.
• More commonly employed as a booster drug in a low dose.
• Nausea, diarrhoea, paresthesias, fatigue and lipid
abnormalities are prominent.

19. • Binds to HIV 1 envelope transmembrane glycoprotein (gp41)
involved in fusion of viral and cellular membranes
entry of virus into host cell is blocked
• Not active against HIV 2
 Pharmacokinetics:
• Administered s.c twice daily
• Used as add on drug in earlier regimens
 Adverse reactions:
• Local nodule/ cyst at injection site, rash, pneumonia like sym.

20. • Targets the host cell chemokine -CCR5 receptor and blocks it
attachment and entry of virus is inhibited
• Used in highly treatment experienced patients
 Adverse reactions:
• Impaired immune surveillance
• Increased risk of infection/malignancy
• Hepatotoxicity
• Skin rashes

21. • HIV Integrase nicks the host chromosomal DNA and
integrates the proviral DNA with it
• Active against both HIV 1 and 2 and causes improved
CD4 cell count
 Uses:
• As a component of drug regimen along with other
drugs in treatment experienced patients
• Adverse effect: myopathy

22. • Greater the suppression of viral replication, lesser is the
chance of emergence of drug resistant virus.
• Monotherapy is contraindicated.
• HAART: highly active antiretroviral therapy with a
combination of 3 or more drugs is indicated.
• The current NACO guidelines (2017) on when to start
ART: All persons diagnosed with HIV infection should
be initiated on ART regardless of the CD4 count or
WHO Clinical Staging or age group or population sub-
groups.
• Proper counselling.

23. • Regimen should have 2 NRTI+ 1NNRTI and treatment is
life long.
• Efavirenz is indicated for patient with hepatic dysfunction and
concurrently taking rifampicin. It is contraindicated in
pregnancy.
• PI containing regimen: 2NRTI+PI or NRTI+NNRTI +PI (low
dose ritonavir boosted PIs are used)
• Development of drug toxicity: no dose reduction
 Either entire regimen should be interrupted
 Or the offending drug should be changed

25. An ART regimen is considered to have failed when:
• Plasma HIV-RNA count is not rendered undectable
(<50 copies/μl) with in 6 months therapy.
• Repeated detection of virus in plasma after initial
supression to undectable levels despite continuation of
drug regimen.
• Clinical deterioration,fall in CD4 cell count, serious
opportunistic infection while continuing drug therapy.

26. • Drugs with known overlapping viral resistance should not be
used.
1. Indinavir should not be substituted for nelfinavir or
saquinavir
2. Efavirenz should not be replaced by nevirapine
• Viral resistance testing is recommended for selecting the
salvage regimen.
• A boosted PI is nearly always included.

27. NRTI component
Standard regimen
1.Lopinavir
2.Atazanavir
1. Tenofovir + Abacavir
2. Didanosine + Abacavir
3. Tenofovir + Zidovudine
4. Tenofovir + Lamivudine
3.Saquinavir
4.Indinavir
5.Nelfinavir
Special circumstances
1. Didanosine + Zidovudine
2. Didanosine + Lamividine
PI component
..

28.  Third-line regimens should include new drugs with
minimal risk of cross-resistance to previously used
regimens such as Integrase inhibitors and second-
generation NNRTIs and PIs.
 Accordingly, such a regimen is Raltegravir (400 mg) +
Darunavir (600 mg) + Ritonavir (100 mg); one tablet
each twice daily.

29. Zidovudine + stavudine Pharmacodynamic
antagonism; inhibits
phosphorylation of
Stavudine
Stavudine + didanosine Increased toxicity
(neuropathy, lactic
acidosis )
Lamivudine + didanosine Clinically not additive

30. For adults and adolescents
Preferred 2 NRTI Tenofovir 300mg daily ±
Emtricitabine 200mg daily ±
Preferred PI Lopinavir/r (400+ 100mg) or
Atazanavir/r (300+ 100mg) daily
Alternative 3rd drug Darunavir/r or Raltegravir or
Efavirenz
For children ≤ 10 yrs
Preferred 2 NRTI Zidovudine + lamivudine
Preferred PI Lopinavir/r
Alternative 3rd drug Atazanavir/r or Darunavir/r or
Raltegravir or Efavirenz

31. Drug regimen
Tenofovir 300mg daily ± Emtricitabine 200mg daily
Key risk groups
Homosexual men
Sex workers
Injection drug users
Transgender
Uninfected partner of a heterosexual serodiscordant couples

32. • Vertical transmission: Highest rate of transmission (2/3rd)
through placenta, during delivery or breast feeding.
• All HIV positive pregnant women including those presenting
in labour and breast feeding should be initiated on a triple
drug ART and continue lifelong ART.
• Nevirapine prophylaxis to HIV exposed infant: minimum 6
weeks and extended to 12 weeks, if the duration of ART in
pregnant mother falls less than 4 weeks before delivery.
• Drugs safe in pregnancy: Zidovudine, Lamivudine,
Nevirapine, Nelfinavir, Saquinavir

33. • ART should be initiated as soon as possible in all HIV/TB-
co-infected patients with active TB.
• If an NNRTI-based regimen is used, EFV would be the
preferred drug.
• Except for SQV/r, PIs are not recommended during TB
treatment with Rifampicin, even then Rifampicin
should be substituted with Rifabutin.