This document discusses various classes of antiviral drugs, including those that target herpes viruses, influenza virus, hepatitis viruses, and HIV. It provides details on the mechanism of action, pharmacokinetics, uses, and adverse effects of representative drugs in each class, such as acyclovir for herpes, amantadine/rimantadine for influenza, lamivudine/adefovir for hepatitis B, ribavirin/interferon for hepatitis C, and zidovudine as the prototype nucleoside reverse transcriptase inhibitor for HIV. The goal of antiviral treatment is to inhibit virus-specific replication events while minimizing effects on host cell processes.

1. Antiviral drugs
PRIYANKA NAMDEO
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACOLOGY

2. Virus-Introduction
• Viruses are obligate intracellular
parasites
• Their replication depends primarily
on synthetic processes of the host
cell
• Effective antiviral agents inhibit
virus-specific replicative events or
preferentially inhibit virus-directed
rather than host cell-directed
nucleic acid or protein synthesis

3. Viral replication and sites of antiviral
drug action

4. Classification of Antiviral Drugs
CLASSES DRUGS
1. Anti-Herpes virus Idoxuridine, Trifluridine
Acyclovir, Valacyclovir,
Famciclovir
Ganciclovir, Valganciclovir
Cidofovir
Foscarnet
Fomivirsen
2. Anti-influenza virus Amantadine, Rimantadine
Oseltamivir, Zanamivir
3. Anti-Hepatitis
virus/Nonselective antiviral
drugs
a. Primarily for Hepatitis B Lamivudine, Adefovir dipivoxil,
Tenofovir
b. Primarily for Hepatitis C Ribavirin, Interferon α

5. CLASSES DRUGS
4. Anti-retrovirus
a. Nucleoside reverse
transcriptase inhibitors (NRTIs)
Zidovudine (AZT), Didanosine,
Stavudine
Lamivudine, Abacavir,
Emtricitabine
Tenofovir (Nt RTI)
b. Nonnucleoside reverse
transcriptase inhibitors (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

6. 1. Anti-Herpes Virus
Acyclovir
 Mechanism of action:
Acyclovir
Herpes virus specific thymidine kinase
Acyclovir monophosphate
Cellular kinases
Acyclovir triphosphate Inhibits herpes virus DNA
polymerase competitively
Gets incorporated in viral DNA and stops lengthening of
DNA strand; the terminated DNA inhibits DNA-
polymerase irreversibly

7. Acyclovir
 Pharmacokinetics:
• About 20% of an oral dose of acyclovir
is absorbed
• Less plasma protein bound
• Primarily excreted unchanged in
urine both by glomerular filtration
and tubular secretion
• It accumulates in patients with renal failure
• Its plasma half life is 2-3 hours

8. Acyclovir
 Uses:
• Genital Herpes simplex
Primary disease
Recurrent disease
• Mucocutaneous H. simplex•
• H. simplex encephalitis
(type-1 virus)
• H. simplex keratitis
• Herpes zoster
• Chickenpox
 Adverse effects:
• Topical: stinging and burning
sensation after each
application
Oral: Headache, nausea,
malaise and some CNS
effects
• Intravenous: Rashes,
sweating, emesis, and fall in
BP(in few)
• Dose dependent decrease in
GFR (in renal failure)

9. Valacyclovir
• An ester prodrug of acyclovir
• Improved oral bioavailability due to active transport by
peptide transporters in the intestine
• Drug of choice in herpes zoster
• High-dose can cause gastrointestinal problems and
thrombotic thrombocytopenia purpura in patients with AIDS
• An ester prodrug of penciclovir
• Used as an alternative to acyclovir for genital or orolabial
herpes and herpes zoster
• Side effects are headache, nausea, loose motions, itching,
rashes and mental confusion

10. Ganciclovir
• An analogue of acyclovir
• Active against all herpes viruses- H. simplex, H. zoster,
EBV and CMV
• Its active metabolite attains higher concentration inside
CMV cells (plasma t1/2 >24 hrs)
 Adverse effects:
• Systemic toxicity is high ( bone marrow toxicity, rash,
fever, vomiting, neuropsychiatric disturbances)
• Note: Used only for prophylaxis and treatment of severe
CMV infections in immunocompromised patients

11. Cidofovir
 Mechanism of action:
 It inhibits viral DNA synthesis. Its phosphorylation is not
dependent on viral enzymes (viral phosphokinase) and is
converted to the active diphosphate by cellular enzymes.
 Cidofovir diphosphate does not preferentially accumulate
in virus infected cells, but remains intracellularly for long
periods to inhibit viral DNA polymerase
 Pharmacokinetics:
• Available in intravenous, intravitreal (injection into the
eye's vitreous humor between the lens and the retina),
and topical administration

12. Cidofovir
 Uses:
• CMV-induced retinitis in patients with AIDS
 Adverse effects:
• Dose related kidney damage
• Neutropenia, metabolic acidosis, uveitis and ocular
hypotony also occur
• Note: Probenecid must be coadministered with cidofovir to
reduce the risk of nephrotoxicity, but probenecid itself
causes rash, headache, fever, and nausea
 Contraindications:
• Patients with preexisting renal impairment
• Patients taking concurrent nephrotoxic drugs, including
NSAIDS

13. Foscarnet
• It is not a purine or pyrimidine analog;
phosphonoformate pyrophosphate derivative and does
not require activation by viral (or human) kinases
• CMV retinitis in immunocompromised hosts
• Acyclovir-resistant HSV and herpes zoster infections
 Mechanism of action:
 It reversibly inhibits viral DNA and RNA polymerases,
thereby interfering with viral DNA and RNA synthesis

14. Foscarnet
 Pharmacokinetics:
• Poorly absorbed orally; intravenously
• Must also be given frequently to avoid
relapse when plasma levels fall
• It is dispersed throughout the body;
>10% enters the bone matrix
• Excreted into the urine
 Adverse effects:
• Nephrotoxicity, anemia, nausea, and fever
• Hypocalcemia and hypomagnesemia
• Hypokalemia, hypo- and hyperphosphatemia
• Seizures and arrhythmias

15. 2. Anti-influenza virus
Amantadine
• Its antiviral activity is strain specific = inhibits replication of
influenza A virus but not influenza B
 Mechanism of action:
 It acts at uncoating as well as viral assembly in viral
replication
 Blocks the viral membrane matrix protein, M2, which
functions as a channel for hydrogen ion
 This channel is required for the fusion of the viral
membrane with the cell membrane that ultimately forms
the endosome (during internalization of the virus by
endocytosis)

16. Amantadine
 Pharmacokinetics:
• Well absorbed orally and excreted
unchanged in urine over 2-3 days
 Adverse effects:
• Nausea, anorexia, insomnia, dizziness, nightmares, lack
of mental concentration
• Hallucinations (rarely)
• Ankle edema (local vasoconstriction)

17. Amantadine
 Uses:
• Prophylaxis of influenza A2 during an epidemic or
seasonal influenza (~ 2 months)
• Treatment of influenzal (A2) illness
 Reduction in fever, congestion, cough and quicker
recovery
 Parkinsonism
 Contraindications:
• Epilepsy and other CNS disease; gastric ulcer,
pregnancy

18. Rimantadine
• Methyl derivative of amantadine
• More potent, longer acting (t½ 30 hours) and better
tolerated
• Side effects is lower
• Oral bioavailability is higher and it is largely metabolized
by hydroxylation followed by glucuronide conjugation
• Metabolites are excreted in urine

19. Oseltamivir
• Influenza A (amantadine sensitive as well as resistant),
H5N1 (bird flu), nH1N1 (swine flu) strains and influenza
B
• An ester prodrug; rapidly and nearly completely
hydrolysed during absorption in intestine and by liver to
the active form oseltamivir carboxylate ( an oral
bioavailability of ~ 80%)
• Active metabolite is excreted unchanged by the kidney
• t½ of 6–10 hours

20. Oseltamivir
 Mechanism of action:
 Neuraminidase enzyme
Release of progeny virions from the infected cell
Spread of the virus in the body
 Uses:
• Prophylaxis and treatment of influenza A, swine flu, bird
flu and influenza B
Oseltamivir

21. Oseltamivir
 Side effects:
• Nausea and abdominal pain
(gastric irritation)
• Headache, weakness, sadness,
diarrhoea, cough, and insomnia
• Skin reactions
• Influenza A (including amantadine-resistant, nH1N1,
H5N1 strains) and influenza B virus neuraminidase
inhibitor
• Low oral bioavailability; t½ of 2–5 hours
 Containdication: Asthmatics ( bronchospasms)

22. 3. Anti-Hepatitis Virus/ Nonselective
Antiviral Drugs
• Hepatitis A, B, C, D, and E viruses replicate in and
destruct hepatocytes
• Hepatitis B and C are the most common causes of
chronic hepatitis, cirrhosis, and hepatocellular carcinoma
• Hepatitis B virus (HBV) is a DNA virus, can integrate into
host chromosomal DNA to establish permanent infection
• Hepatitis C virus (HCV) is a RNA virus

23. Lamivudine
• An inhibitor of both hepatitis B virus (HBV) DNA
polymerase and human immunodeficiency virus (HIV)
reverse transcriptase
• First line drug for chronic hepatitis B
• Chronic treatment decreased plasma HBV DNA
levels, improved biochemical markers, and reduced
hepatic inflammation
 Mechanism of action:
 It must be phosphorylated by host cellular enzymes to
the triphosphate (active) form
 This compound competitively inhibits HBV DNA
polymerase at concentrations that have negligible effects
on host DNA polymerase

24. Adefovir dipivoxil
 Mechanism of action:
 It is phosphorylated to adefovir diphosphate
incorporated into viral DNA termination of
further DNA synthesis prevents viral replication
 Both decreased viral load and improved liver function
• Indicated in chronic hepatitis B, also in lamivudine-
resistant cases and in concurrent HIV infection
• Its plasma t½ is 7 hours; intracellular t½ of the
diphosphate is upto 18 hours

25. Adefovir dipivoxil
 Adverse effects:
• Sore throat, headache, weakness, abdominal pain
and flu syndrome
• Nephrotoxicity ( higher doses and in those with
preexisting renal insufficiency )
• Lactic acidosis ( patients receiving anti-HIV drugs )

26. Ribavirin
• Broad-spectrum antiviral activity
• Influenza A and B, respiratory syncytial virus (in children
only) and many other DNA and double stranded RNA
viruses
• Oral ribavirin is commonly used in chronic hepatitis C
 Mechanism of action:
• Its mono- and triphosphate derivatives generated
intracellularly inhibit GTP and viral RNA
synthesis

27. Ribavirin
• Oral bioavailability ~50%
• Partly metabolized and eliminated
• Accumulates in the body on daily dosing
and persists months after discontinuation
• Long term t½ is > 10 days
 Adverse effects:
• Anaemia, bone marrow depression
hemolysis; CNS and GI disturbances
• Teratogenic
• Aerosol can cause bronchospasm and
irritation of mucosae

28. Interferon
• Cytokines produced by host cells in response to viral
infections and other inducers
• Three types of human IFNs (α, β and γ) are known to
have antiviral activity
 Mechanism of action:
 Induction of host cell enzymes that inhibit viral RNA
translation degradation of viral mRNA and
tRNA
 Interferon receptors are JAK-STAT tyrosine protein
kinase receptors which on activation phosphorylate
cellular proteins
 These then migrate to the nucleus and induce
transcription of ‘interferon-induced- proteins’ which exert
antiviral effects

29. Interferon
 Uses:
• Chronic hepatitis B
• Chronic hepatitis C
• AIDS-related Kaposi’s sarcoma
• Condyloma acuminata
• H. simplex, H. zoster and CMV

30. Interferon
 Pharmacokinetics:
• Not active orally; administered intralesionally,
subcutaneously, or intravenously
• High cellular uptake and metabolism by the liver and
kidney; less plasma level
• Negligible renal elimination occurs

31. Interferon
 Adverse effects:
• Flu-like symptoms: fatigue, aches and pains, malaise,
fever, dizziness, anorexia, nausea, taste and visual
disturbances develop few hours after each injection, but
become milder later
• Neurotoxicity: numbness, neuropathy, altered behaviour,
mental depression, tremor, sleepiness, rarely
convulsions
• Myelosuppression: dose dependent neutropenia,
thrombocytopenia
• Thyroid dysfunction (hypo as well as hyper)
• Hypotension, transient arrhythmias, alopecia and liver
dysfunction.

32. Interferon
 Drug interaction:
• It interferes with hepatic drug metabolism
• Toxic accumulations of theophylline
• It may also potentiate the myelosuppression caused by
other bone marrow depressing agents ( zidovudine )

33. ANTI-RETROVIRUS DRUGS
• Aim of anti-HIV therapy is to cause maximal suppression
of viral replication for the maximal period of time that is
possible
• ARV drugs are always used in combination of at least 3
drugs and regimens have to be changed over time due
to development of resistance
• Life long therapy is required

34. ANTI-RETROVIRUS DRUGS
Established targets for anti-HIV attack:
(1)Chemokine coreceptor (CCR5) on host cells which
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

36. Nucleoside reverse transcriptase inhibitors
(NRTIs)
 Zidovudine:
• is a thymidine analogue (azido- thymidine, AZT), the
prototype NRTI
• after 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

37. ZIDOVUDINE
 Pharmacokinetics:
• The oral absorption of AZT is rapid, but 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
• Plasma protein binding is 30% and CSF level is
~50% of that in plasma
• It crosses placenta and is found in milk

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

39. ZIDOVUDINE
 Interactions:
• Paracetamol increases AZT toxicity, probably by
competing for glucuronidation
• Azole antifungals also inhibit AZT metabolism
• Other nephrotoxic and myelosuppressive drugs and
probenecid enhance toxicity
• Stavudine and zidovudine exhibit mutual antagonism
by competing for the same activation pathway

40. ZIDOVUDINE
 Uses:
• Zidovudine is used in HIV infected patients only in
combination with at least 2 other ARV drugs
• It is one of the two optional NRTIs used by NACO for
its first line triple drug ARV regimen
• AZT also reduces neurological manifestations of AIDS
and new Kaposi’s lesions do not appear
• 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

41. DIDANOSINE
• Is a purine nucleoside analogue
which after intracellular conversion
to didanosine triphosphate
competes with ATP for
incorporation into viral DNA,
inhibits HIV reverse transcriptase
and terminates proviral DNA
• Antiretroviral activity of didanosine
is equivalent to AZT
• Use has declined due to higher
toxicity than other NRTIs

42. STAVUDINE
• A thymidine analogue
• By utilizing the same thymidine kinase for activation,
AZT antagonises the effect of stavudine and the two
should not be used together
• Should also not be combined with didanosine,
because both cause peripheral neuropathy
• Frequent peripheral neuropathy, lipodystrophy, lactic
acidosis, and rarely pancreatitis are the serious
adverse effects which have restricted its use

43. LAMIVUDINE
• Deoxycytidine analogue, is phosphorylated
intracellularly and inhibits HIV reverse transcriptase
as well as HBV DNA polymerase
• Its incorporation into DNA results in chain termination
• Most human DNA polymerases are not affected and
systemic toxicity of 3TC is low
• Oral bioavailability of 3TC is high and plasma t1⁄2
longer (6–8 hours)

44. LAMIVUDINE
• Used in combination with other anti-HIV drugs, and
appears to be as effective as AZT
• Synergises with most other NRTIs for HIV, and is an
essential component of all first line triple drug NACO
regimens for AIDS
• Side effects are few—fatigue, rashes , abdominal pain
• Pancreatitis and neuropathy are rare
• Hematological toxicity does not occur

45. ABACAVIR
• Guanosine analogue , potent , acts
after intracellular conversion to
carbovir triphosphate
• Hypersensitivity reactions such as
rashes, fever, abdominal pain, bowel,
upset, flu-like respiratory and
constitutional symptoms
• Lypodystrophy is least likely
• Avoidance of alcohol is advised

46. TENOFOVIR
• Is the only nucleotide analogue
,relatively newer
• Due to good tolerability profile, it is
included in first line regimens
• Tenofovir containing regimens have been
found at least as effective and less toxic
as other first line regimens
• NACO includes tenofovir in its first line 3
drug regimen as an alternative when
either zidovudine or nevirapine/efavirenz
cannot be used due to
toxicity/contraindication

47. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
 Nevirapine (NVP) and Efavirenz (EFV)
• are nucleoside unrelated compounds which directly
inhibit HIV reverse transcriptase without the need for
intracellular phosphorylation
• are more potent than AZT on HIV-1, but do not inhibit
HIV-2
• they should always be combined with 2 other effective
drugs
• Cross- resistance between NVP and EFV is common

48. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
 Nevirapine (NVP) and Efavirenz (EFV)
• enzyme inducers, and cause autoinduction of their own
metabolism
• Nevirapine is started at a lower dose (200 mg/day);
the dose is doubled after 2 weeks when its blood
levels go down
• Rifampin induces NVP metabolism and makes it
ineffective, but has little effect on EFV levels
• Either NVP or EFV is included in the first line triple
drug regimen used by NACO

49. NEVIRAPINE
• Rashes are the commonest adverse
effect, followed by nausea and
headache
• Occasionally skin reactions are
severe
• NVP is potentially hepatotoxic

50. EFAVIRENZ
• Side effects are headache,
rashes, dizziness, insomnia
and a variety of
neuropsychiatric symptoms
• Contraindicated in
pregnancy and in women
likely to get pregnant, since it
is teratogenic
• Because of its longer plasma
t1⁄2, occasional missed doses
of EFV are less damaging

51. Retroviral protease inhibitors (PIs)
• Acts at a late step in HIV replication, i.e. maturation of
the new virus particles when the RNA genome acquires
the core proteins and enzymes
• Bind to the active site of protease molecule, interfere
with its cleaving function, and are more effective viral
inhibitors than AZT
• Because they act at a late step of viral cycle, they are
effective in both newly as well as chronically infected
cells

52. Retroviral protease inhibitors (PIs)
• Nelfinavir, lopinavir and ritonavir induce their own meta-
bolism
• metabolism of PIs is induced by rifampin and other
enzyme inducers rendering them ineffective
• patient acceptability and compliance are often low
• most prominent adverse effects of PIs are
gastrointestinal intolerance, asthenia, headache,
dizziness, limb and facial tingling, numbness and rashes

53. Retroviral protease inhibitors (PIs)
• lipodystrophy ,
dyslipidaemia and insulin
resistance are of
particular concern
• Diabetes may be
exacerbated
• Indinavir crystalises in
urine and increases risk
of urinary calculi

54. Retroviral protease inhibitors (PIs)
 Atazanavir (ATV)
• is administered with light meal which improves
absorption, while acid suppressant drugs decrease its
absorption
• Bioavailability and efficacy of ATV is improved by
combining with RTV
• Dyslipidaemia and other metabolic complications are
minimal with ATV
• jaundice occurs in some patients without liver damage
due to inhibition of hepatic glucuronyl transferase

55. Retroviral protease inhibitors (PIs)
 Indinavir (IDV)
• Is to be taken on empty stomach
• g.i. intolerance is common
• excess fluids must be consumed to avoid
nephrolithiasis
• Hyperbilirubinaemia occurs
• less frequently used now
 Nelfinavir (NFV)
• Is to be taken with meals
• Often produces diarrhoea and flatulence; lower clinical
efficacy than other PIs

56. Retroviral protease inhibitors (PIs)
 Ritonavir (RTV)
• Is potent
• Drug interactions, nausea, diarrhoea, paresthesias,
fatigue and lipid abnormalities are prominent
• more commonly employed in a low dose
 Saquinavir (SQV)
• Two types of formulations (hard gel and soft gel
capsules) have been produced
• tablet load is large and side effects are frequent;
photosensitivity can occur

57. Retroviral protease inhibitors (PIs)
 Lopinavir:
• Available only in combination with RTV to improve
bioavailability, though it is itself a CYP3A4 inhibitor
• Diarrhoea, abdo- minal pain, nausea and
dyslipidaemias are more common
• Dose needs to be increased by 1/3rd if either NVP or
EFV is used concurrently

58. Entry (fusion) Inhibitor-Enfuvirtide
• HIV derived synthetic peptide
• 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

59. CCR5 receptor inhibitor-Maraviroc
• Targets the host cell chemokine -CCR5 receptor and blocks
it
attachment and entry of virus is inhibited
• Has no effect on CXCR4 receptor tropic HIV strains
• Adverse reactions:
 impaired immune surveillance
 Increased risk of infection/malignancy

60. Integrase inhibitor-Raltegravir
• Inhibits the viral enzyme integrase
• 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 initial triple drug regimen along with
2NRTIs
• Adverse effect: myopathy

61. HIV treatment principles and guidelines
• Monotherapy is contraindicated
• HAART: highly active antiretroviral therapy with a
combination of 3 or more drugs is indicated
• Greater the supression of viral replication, lesser is the
chance of emergence of drug resistant virus

62. Initiating antiretroviral therapy
• The US Department of Health and Human Services
guidelines (2010) recommend instituting ART to:
1. All symptomatic HIV disease patients.
2. Asymptomatic patients when the CD4 cell count falls to
350/μl or less.
3. All HIV patients coinfected with HBV/HCV requiring
treatment
4. All pregnant HIV positive women.
5. All patients with HIV-nephropathy.

63. Initiating antiretroviral therapy contd..
• In addition to above, the current NACO guidelines give priority
in treatment to:
1. All HIV-positive persons in WHO-clinical stage 3 and 4
2. All persons who tested HIV positive 6–8 years ago
3. Patients with history of pulmonary TB and/ or Herpes zoster
4. HIV infected partners of AIDS patients.
5. All HIV positive children < 15 years of age

64. First line antiretroviral therapy
Preferred regimen
1. Lamivudine + Zidovudine + Nevirapine
Alternative regimens
1.Lamivudine + Zidovudine + Efavirenz
2.Lamivudine + Stavudine + Efavirenz
3. Lamivudine + Stavudine + Nevirapine
Other options
1.Lamivudine + Tenofovir + Nevirapine
2. Lamivudine + Tenofovir + Efavirenz
3.Lamivudine + Zidovudine + Tenofovir
Recommended by National AIDS control Organization

65. First line therapy
• All regimen should have 2 NRTI+ 1NNRTI and
treatment is life long
• Efavirenz is indicated for patient with hepatic
dysfunction and concurrently taking rifampin. 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

66. First line therapy contd…
• Institution of HAART with latent or partially treated
opportunistic infection causes immune reconstitution
syndrome
• Safe drugs in pregnancy :
 Zidovudine
 Lamivudine
 Nevirapine
 Nelfinavir
 Saquinavir

67. Changing a failing regimen
• 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

68. Second line regimen
• 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

69. List of second line regimens (NACO)
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

70. Antiretroviral combination to be avoided
1.Zidovudine + stavudine Pharmacodynamic antagonism
Stavudine + didanosine Increased toxicity ( neuropathy, lactic
acidosis )
Lamivudine + didanosine Clinically not additive

71. Prophylaxis of HIV infection
1.Post- exposure prophylaxis:
Drugs used Comments
A .Basic (2 drug) regimen for
low risk
Both for 4 weeks
Zidovudine ( 300mg) + twice daily
Lamivudine ( 150 mg) Twice daily
B. Expanded ( 3 drugs)
regimen for high risk
Both for 4 weeks
Zidovudine (300 mg )+
lamivudine ( 150 mg )
Twice daily
Indinavir( 800 mg)
(or another PI)
Thrice daily

72. Post exposure prophylaxis(PEP)
•Aim is to supress local viral replication prior to
dissemination to abort infection
•PEP should be started within 1-2 hours of exposure
a) Basic regimen:
 Asymptomatic HIV +ve source with low HIV-RNA titre
and high CD4 cell count
 Exposure is through mucous membrane, superficial
scratch or solid needle
b) Expanded regimen:
 symptomatic HIV +ve source with high HIV-RNA titre or
low CD4 cell count
 Exposure is through large area contact of longer duration
with mucus membrane or large bore hollow needle,
deep puncture.

73. Prophylaxis of HIV infection
2. Prophylaxis after sexual intercourse: the same method as
for needle stick
3. Perinatal HIV prophylaxis:
• Vertical transmission: Highest rate of transmission (2/3rd)
through placenta ,during delivery or breast feeding
• HIV positive mother (not on ART) : should take 3 drug
ART, continue through delivery and into postnatal period.
• First line NACO regimen for pregnant women:
Zidovudine + Lamivudine + Nevirapine
• Nevirapine : higher risk of hepatotoxicity in women with
CD4 cell count > 250 cells /μl
• Efavirenz is teratogenic particularly in 1st trimester

74. Perinatal HIV prophylaxis
• For HIV +ve women not on ART :
1. Zidovudine (300 mg BD) started at 2nd trimester and
continued through delivery to postnatal period with
treatment of neonate for 6 month reduce the
transmission by 2/3rd
2. AZT started during labour and then to infant is
substantially protective

75. Thank you !!!