The document discusses anti-viral drugs used to treat various viral infections such as HIV, hepatitis, herpes and influenza. It describes the classification, mechanism of action, dosing and side effects of various nucleoside analogues, protease inhibitors and other drugs. The summary of treatment of HIV includes the goals of combination antiretroviral therapy to suppress viral replication and prevent drug resistance in order to prolong life and improve quality of life for patients.

1. Anti viral agents and treatment of
HIV infection
1

2. Outline
• Anti herpes , antiinfluenza, anti hepatitis drugs
• Introduction of retrovirus
• Life cycle of the virus, Pathophysiology
• Treatment modalities
• Drug therapy in pregnancy
• Post exposure prophylaxis
2

3. Classification
1.Anti-Herpes virus
Idoxuridine, Trifluridine, Acyclovir, Valacyclovir, Famciclovir,
Ganciclovir, Valganciclovir, Cidofovir, Foscarnet, Fomivirsen
2. Anti-Influenza virus
Amantadine, Rimantadine, Oseltamivir, Zanamivir
3. Anti-Hepatitisvirus/Nonselectiveantiviral drugs
Primarily for hepatitis B: Lamivudine, Adefovir dipivoxil,
Tenofovir
Primarily for hepatitis C: Ribavirin, Interferon a
3

4. 4

5. Herpes
■ The areas most commonly affected in men are:
■ Anus
■ Inside of the thighs
■ Scrotum
■ Penis
■ In women the most affected areas are:
■ Anus
■ Cervix
■ Inside of the thighs
■ Lips
■ Vagina
5

7. Anti herpes agents
■ Idoxuridine It is thymidine analogue.
■ It was the first pyrimidine antimetabolite to be used
as antiviral drug.
■ It competes with thymidine, gets incorporated in DNA
so that faulty DNA is formed which breaks down
easily.
■ Low virus selectivity, higher local toxicity and rapid
development of viral resistance
■ Use of idoxuridine is restricted to superficial dendritic
keratitis

8. Acyclovir

9. • ACYCLOVIR
• Deoxyguanosine analogue – acyclovir triphosphate
is the active component
• Inhibits DNA polymerase irreversibly
• HSV 1>HSV 2> VZV>EBV
• 20% bio-availability, t1/2= 2-3 hrs.
• Genital herpes simplex,muco-cutaneous
HS,encephalitis,herpes Zoster,chicken –pox
• A/E: stinging,rashes,headache,nausea
9

10. • VALACYCLOVIR:
• Prodrug of acyclovir
• DOC for herpes Zoster- 1g TDS 7days
• FAMCICLOVIR
• Prodrug of penciclovir
• DNA polymerase inhibitor
• Rx-genital ,orolabial herpes,herpes zoster & HBV
• 250mg tds for 5 days and 250mg BD for one year
• a/e - headache , nausea , rashes , mental confusion
10

11. • GANCICLOVIR:
• Similar MOA as acyclovir
• Uses- CMV infections
• Sytemic toxicity with Bone-marrow suppression is the major limitation
. Rash , fever.
• 5mg/kg daily for 1-3wks &5mg/kg once daily
• CIDOFOVIR:
• Cytidine analogue, monophosphate
• Uses- HSV,CMV,ADENO viruses
• Also in acyclovir resistance
• Renal damage ,neutropenia , uveitis
11

12. • FOSCARNET:
• Straight chain phophonate
• Inhibits VIRAL DNA polymerase and REVERSE
TRANSCRIPTASE.
• A/E – Renal diabetes and ARF
• Use - CMV retinitis , herpes simplex 2 in AIDS patients
• FOMIVERSIN:
• Antisense oligo-nucleotide
• Binds with mRNA of CMV and inhibits transcription
12

13. 13

14. Anti influenza
• AMANTIDINE:
• Tricyclic amine that inhibits replication of Influenza
A virus
• Resistance caused by mutation of M2 protien
• Uses – PROPHYLAXIS of Influenza A2
• Treatment- five day treatment with 100 mg
• RIMANTIDINE: Methy derivative of amantidine
• Cross resistance exists between the two drugs.
14

15. adverse effects - nausea, anorexia,
insomnia, dizziness, nightmares, lack of
mental concentration, rarely hallucinations
15

16. • OSELTAMIVIR:
• Sialic acid analogue, prodrug
• Active form – oseltamavir carboxylate
• MOA – Inhibits neurominidase of virus preventing
virion release
• Oral bioavailability - 80
• Uses-Influenza A,H1N1,H5N1, Influenza B
• Dose : 75 mg BD for 5 days , 75mg OD
• Nausea and abdominal pain due to gastric irritation
(reduced by taking the drug with food), headache,
weakness, sadness, diarrhoea, cough and insomnia
16

17. • Peramivir

18. • ZANAMIVIR: similar to oseltamivir
• Route- inhalation
• Contra-indicated in asthma
Dose: 10 mg through breath actuated
inhaler, BD × 5 days for treatment, and OD
for prophylaxis.
RELENZA 5 mg/actuation powder inhaler.
18

19. Anti hepatitis

20. Entecavir
• Guanosine nucleoside analogue
• 1st line option for treating chronic hepatitis B.
• Inhibits HBV- DNA polymerase after activation by
intracellular phosphorylation.
• Food decreases bioavailability; it should be taken in
empty stomach.
• t1⁄2 of 128-148 hours.
• side effects are mild dyspepsia, nausea, diarrhoea, fatigue,
and disturbed sleep

21. Anti hepatitis virus drugs
• ADEFOVIR DIPIVOXIL:AMP analogue
• Esterases release the active drug
• Causes termination of viral DNA chain.
• Uses- chronic hepatitis B[Including Lamivudine
resistance]
• 10mg/kg/day
• A/E: flu-like syndrome,nephrotoxicity, and lactic
acidosis
21

22. • TENOFOVIR: monophosphate nucleotide
• Disoproxyl-ester prodrug
MOA - diphosphorylated by cellular kinases into
tenofovir diphosphate which preferentially inhibits
HBV- DNA polymerase
• Inhibits DNA poly & Reverse-transcriptase- 300MG OD
• nausea, flatulence, abdominal discomfort, loose motions
and headache, renal toxicity
22

23. Telbivudine
• Anti-HBV drug is a thymidine nucleoside analogue.
• Telbivudine is absorbed orally and its bioavailability is
not affected by food.
• Faster and more complete suppression of HBV-DNA
titre
• Side effects are abdominal pain, diarrhoea, cough,
headache, dizziness and myalgia
23

24. 24

25. • RIBAVIRIN: purine nucleoside analogue
• Inhibits GTP and viral RNA synthesis
• Uses- Influenza A & B , acute & chronic hepatitis C
• RSV virus bronchiolitis- NEBULISESD
• 200mg QID , 400mg TDS
• Teratogenic potential
• Anaemia, bone marrow depression, haemolysis, CNS
and g.i. symptoms
25

26. • INTERFERON α:
• Supression of viral protein synthesis- inhibition of
translation
• Ch .hepB (Interferon α & β) , peg IFNα2B
• Kaposi sarcoma, condyloma acuminata, H Simplex,
H. zoster & CMV
26

27. MOA - bind to specific cell surface receptors and affect
viral replication at multiple steps, viz. viral penetration,
synthesis of viral mRNA, assembly of viral particles and
their release
JAK-STAT tyrosine protein kinase receptors which on
activation phosphorylate cellular proteins.
They migrate to the nucleus and induce transcription of
27

28. Chronic hepatitis B: IFNa2A 2.5-5 MU/m2 or IFNa2B
5-10 MU given 3 times per week for 4–6 months
pegIFNs 180 mg s.c. once weekly for 24-48 week
Chronic hepatitis C: IFNa2B 3MU 3 times weekly for
6–12 months
28

29. Flu-like symptoms,
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.
29

30. Newer drugs
1.NS5B polymerase inhibitor: Sofosbuvir.
2. NS3 protease inhibitor: Simeprevir.
3. NS5A inhibitor: Daclatasvir, Ledipasvir, Velpatasvir.
30

31. Sofusbuvir
converted into its triphosphate nucleotide within the
hepatocytes and inhibits the HCV nonstructural protein
5B (NS5B)
used in combination, either with one of the NS5A
inhibitors or with simeprevir, or with ribavirin ±
PegINFa.
abdominal pain, fatigue, agitation, joint pain and
anaemia.
31

32. Simiprevir
HCV protease NS3 inhibitor which blocks the cleavage
of HCV polyprotein complex
functional viral RNA is not formed and viral replication
is halted.
nausea, headache, dyspnoea, fatigue, rashes and
photosensitivity
32

33. DACLATASVIR
Blocks HCV-RNA replication as well as assembly of
progeny virions.
•OTHER DRUGS
Ledipasvir
Velpatasvir
33

34. • Thank you
34

35. • RIBAVIRIN: purine nucleoside analogue
• Inhibits GTP and viral RNA synthesis
• Uses- Influenza A & B , acute & chronic hepatitis C
• RSV virus bronchiolitis
• Teratogenic potential
• combined with injected peginterferon for 6–12
months
• Dose: 200 mg QID; 400 mg TDS for body weight >
75 kg (children 15 mg/kg/day).
• A/E - Haemolytic anaemia, bone marrow depression,
CNS and g.i. symptoms.
35

36. Introduction
• Acquired immunodeficiency syndrome (AIDS) was first
characterised in 1980s and was attributed to Human
Immunodeficiency virus (HIV) which is a single
stranded RNA Retrovirus.
• Belongs to the sub family Lentivirinae.
• Two viruses are associated with AIDS : HIV-1 & HIV-
2
36

37. • India is estimated to have around 1.16 lakhs annual
new HIV infections among adults and around 14,500
new HIV infections among children in 2011
• The estimated number of PLHIV in India maintains a
steady declining trend from 23.2 lakhs in 2006 to 21
lakhs in 2011.
• The four high prevalence states of South India
(Andhra Pradesh, Karnataka, Maharashtra, and Tamil
Nadu )
37

38. The Human Retroviruses
• In other viruses RNA is transcribed from DNA .
• Retroviruses have a unique replication cycle whereby
their genetic information is encoded by RNA rather
than DNA.
• Retroviruses contain an RNA-dependent DNA
polymerase (a reverse transcriptase) that directs the
synthesis of a DNA form of the viral genome after
infection of a host cell.
38

39. 39

40. 40

41. 41

42. 42

43. 43

44. Transmission
• Homosexual and heterosexual contact : HIV has been
demonstrated in seminal fluid within infected mononuclear
cells.
• Blood and blood products :HIV can be transmitted to
individuals who receive HIV-tainted blood transfusions,
blood products, or transplanted tissue.
• Parenteral transmission of HIV during injection drug use
does not require IV puncture; SC ("skin popping") or IM
("muscling") injections can transmit HIV as well.
• By infected mothers to infants : either intrapartum,
perinatally, or via breast milk.
44

45. • Virus seeks susceptible target : CD4+ T cells dispersed in the
mucosa.
• This spatial dispersion of targets provides a significant obstacle
to the establishment of infection.
• Both "partially" resting CD4+ T cells and activated CD4+ T
cells serve as early amplifiers of infection.
• Virus is disseminated to the draining lymph nodes and to other
lymphoid compartments .
• Once virus replication reaches this threshold : infection is
firmly established and the process is irreversible.
45

46. Pathophysiology
46

47. 47

48. 48

49. HISTORY OF ANTIRETROVIRAL
THERAPY
• The first effective antiretroviral agent, zidovudine, was
synthesized by Horwitz in 1964 as a false nucleoside with
disappointing anticancer activity.
• The drug was shown by Osterag in 1972 to inhibit the in vitro
replication of a murine type D retrovirus .
• Mitsuya and Broder, working in Bethesda in 1985, reported that
this drug had potent in vitro anti-HIV activity .
• By 1987 this drug was approved and marketed for the control of
HIV infection based on the results of a small but definitive
randomized clinical trial .
49

50. • Selective nonnucleoside reverse transcriptase inhibitors (NNRTIs) were
identified by screening procedures using purified viral enzyme.
• The clinical development of these drugs was hindered by the rapid emergence of
drug resistance.
• However, three drugs in this category were approved by 1998 .
• Highly selective antagonists of the HIV protease were reported as early as 1987.
• Phase I trials of the first of these drugs, saquinavir, began in 1989, approved for
prescription use in 1995.
• Two additional protease inhibitors, ritonavir and indinavir, were approved
within the next 4 months.
• Although many steps in the virus life cycle are potential points for antiviral
intervention, only three are targeted by available agents: virus-cell fusion,
reverse transcription, and proteolytic processing .
50

51. Treatment modalities
• The advent of HAART has been dated to the 11th International
Conference on AIDS in Vancouver, British Columbia, July 7–16,
1996.
• During that Conference, viral dynamics data was presented : HIV
infection produced 10 billion virions/day.
• The conference was followed by sequential publications in The
New England Journal of Medicine by Hammer and colleagues
and Gulick illustrating the substantial benefit of indinavir-based
HAART.
• This concept was quickly incorporated into clinical practice and
rapidly showed impressive benefit with a 60% to 80% decline in
rates of AIDS, death, and hospitalization.
51

52. PRINCIPLES OF HIV CHEMOTHERAPY
• Current treatment assumes that all aspects of disease
derive from the direct toxic effects of HIV on host
cells, mainly CD4+ T-lymphocytes.
• This viewpoint is based on studies demonstrating the
importance of high plasma HIV RNA concentration
and low CD4+ lymphocyte count as predictors of
disease progression and mortality.
• The goal of therapy is to suppress virus replication as
much as possible for as long as possible.
52

53. • More recent natural history studies : Low risk of
short-term disease progression when the CD4 cell
count is greater than 350 cells/mm3 or plasma HIV
RNA concentrations are less than 50,000 copies/ml.
• The toxic risks of long-term combination
chemotherapy, the need for nearly perfect adherence
to prescribed regimens, the inconvenience of some
regimens, and the high cost of lifelong treatment point
to a risk-benefit ratio that favors treating only patients
with low CD4 counts and/or very high viral load .
53

54. • Drug resistance : serious problem.
• Infected individual will harbor viruses with single-amino-acid
mutations : resistance to antiretroviral drug.
• Treatment with only a single antiretroviral drug : provokes the
emergence of drug-resistant virus .
• A combination of active agents therefore is required to prevent drug
resistance.
• Intentional drug holidays (structured treatment interruptions) : increase
the risk of drug resistance.
• This reflects the ability of the virus to persist indefinitely in the face of
effective therapy.
• The current standard of care : three drugs simultaneously for the entire
duration of treatment .
54

55. Goals of ART
Clinical: prolongation of life and improvement of its quality.
• Immunological: quantitative and qualitative immunological
reconstitution, in order to prevent the onset of opportunistic
infections
• Virological: maximum possible reduction of the viral load
for the longest possible time, in order
to halt the progression of disease, prevent and delay the
development of drug resistance.
• Epidemiological: prevention of onward HIV transmission.
55

56. Drugs used to treat HIV infection
1. Nucleoside Reverse Transcriptase Inhibitors
(NRTIs) : Zidovudine, Stavudine, Lamivudine,
Abacavir, Zalcitabine, Emtricitabine, Didanosine
2. Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs) : Efavirenz, Nevirapine, Delavirdine,
Etravirine
3. Nucleotide Reverse Transcriptase Inhibitors
(NtRTIs) : Tenofovir
56

57. 4. Protease Inhibitors (PIs) : Saquinavir, Indinavir,
Nelfinavir, Amprenavir, Fosamprenavir, Ritonavir,
Lopinavir, Atazanavir, Tipranavir, Darunavir
5. Entry/Fusion Inhibitors : Enfuvirtide
6. CCR5 Inhibitors : Maraviroc
7. Integrase Inhibitors : Raltegravir
8. Newer Antiretroviral drugs in Pipeline :
Elvitegravir, Bevirimat, Elvucitabine, Vicriviroc
57

58. 58

59. Nucleosides & Nucleotides : General
considerations
DNA & RNA : Nucleic acids
Nucleic acids are polymers
of nucleotides
Nucleotide = nitrogenous
base+ pentose sugar+
phosphate
Nucleoside = Nucleotide-
phosphate
59

60. Introduction
• The HIV-encoded, RNA-dependent DNA polymerase :
reverse transcriptase : converts viral RNA into proviral
DNA that is then incorporated into a host cell chromosome.
• Available inhibitors of this enzyme are either
nucleoside/nucleotide analogs or nonnucleoside inhibitors.
• Nucleoside and nucleotide reverse transcriptase inhibitors
prevent infection of susceptible cells but have no impact on
cells that already harbor HIV.
• Must enter cells and undergo phosphorylation to generate
synthetic substrates for the enzyme.
60

61. ZIDOVUIDINE
• Deoxythymidine analog with potent broad specrum activity
against HIV 1 & HIV2
• MOA: ZDV
↓thymidine kinase
ZDV-MP
↓ thymidylate kinase
ZDV-DP
↓ NDP kinase
ZDV-TP
↓
terminates elongation of proviral DNA
• Dose : 300 mg BD
61

62. • Active in lymphoblastic and monocytic cell lines
• Less active in chronically infected cells.
• Resistance to zidovudine is associated with mutations
at reverse transcriptase codons 41, 44, 67, 210, 215,
and 219
• These mutations : thymidine analog mutations
(TAMs) able to confer cross-resistance to other
thymidine analogs such as stavudine.
62

63. Absorption, Distribution, and
Elimination
• peak plasma concentrations - 1 hour.
• The elimination half-life of the parent compound -
about 1 hoUR
• intracellular triphosphate - 3 to 4 hours.
• systemic bioavailability to about 64%
63

64. • The drug can be administered regardless of food
intake.
• Parent drug crosses the blood-brain barrier relatively
well.
• Zidovudine also is detectable in breast milk, semen,
and fetal tissue.
64

65. UNTOWARD EFFECTS
• Bone marrow suppression (Anemia & neutropenia)
• GIT- nausea, vomiting, abdominal pain,
hepatomegaly, lactic acidosis.
• Neurotoxicity – peripheral neuropathy, seizures
• CNS- encephalopathy, anxiety, depression
• Chronic administration : nail hyperpigmentation.
• Skeletal muscle myopathy can occur and is associated
with depletion of mitochondrial DNA.
65

66. Interactions:
• Caution with drug undergoing hepatic glucuronidation
(PCT, azole anti-fungal inhibit metabolism)
• Its combination with lamivudine increases blood level by
inhibition of metabolism.
• Stavudine - mutual antagonism
• Rifampine increases the clearance of this drug
• probenecid, fluconazole, atovaquone, and valproic acid may
increase plasma concentrations of zidovudine probably
through inhibition of glucuronosyl transferase .
66

67. Stavudine
• Synthetic thymidine analog reverse transcriptase inhibitor
against HIV1 & HIV2
• Used in multi drug regimen: Stavudine+Lamivudine
• Post exposure prophylaxis
• Adult dose 30-40 mg BD
• Stavudine and zidovudine are antagonistic in vitro, and
thymidine kinase has a higher affinity for zidovudine than
for stavudine.
67

68. Absorption, Distribution, and Elimination.
• Peak plasma concentrations : 1 hour.
• The drug undergoes active tubular secretion, and renal
elimination accounts for about 40% of parent drug.
• Plasma protein binding is less than 5%.
• The drug penetrates well into the CSF.
• Stavudine also readily crosses the human placenta.
68

69. Untoward Effects.
• peripheral neuropathy.
• Lactic acidosis and hepatic steatosis : more common
when stavudine and didanosine are combined.
• Acute pancreatitis : more common when stavudine is
combined with didanosine.
• HIV lipodystrophy syndrome, especially lipoatrophy.
69

70. Lamivudine
• Cytosine nucleoside analog reverse transcriptase inhibitor against HIV 1
& HIV2 ,HBV
• MOA: converted to lamivudine 5 triphosphate , efficient in resting cells
also.
• Used as part of multidrug regimen and post exposure prophylaxis.
• Combined with ZDV : enhanses CD4+ counts
• Best tolerated NRTI : Low affinity for DNA Polymerase
• Oral bioavailability >80%
• Adult dose : 150 mg BD
• Also used in HBV infection
70

71. • Adverse effects : least toxic drug
• Neutropenia
• Nausea, headache, fatigue
• Increased risk of pancreatitis in children
• Lamivudine and Zalcitabine inactivate each other.
• Cotrimoxazole inhibits its renal elimination.
71

72. Abacavir
• Guanosine nucleoside analogue, indicated for HIV-I infection.
• Combination : ZDV+lamivudine+Abacavir
• Adult dose : 300mg BD , bioavailability >80%, 50%bound
• Adverse effects :
• Fatal Hypersensitivity reactions within 6 weeks of therapy: fever,
abdominal pain, maculopapular rash (2-9%)
• Avoid rechallange
72

73. Tenofovir
73
• Adenosine 5'-monophosphate lacking a complete
ribose ring, and it is the only nucleotide analog
• oral bioavailability of 25%
• t1/2 ranges from 14 to 17 hours
• Untoward Effects: well tolerated , rare episodes of
acute renal failure & fanconi syndrome
• Dose – 300mg
• Multi drug regimen
• Also used to treat hep B .

74. Zalcitabine
• Cytidine nucleoside analogue.- ORPHAN drug
• Active against HIV-I, HIV-II, HBV.
• ZDV+ Protease Inhibitor
• Advanced HIV infection
• Suitable for patients resistant to ZDV.
• Adult dose : 0.75mg TDS
74

75. • Adverse effects :
• Peripheral neuropathy (50% incidence)
• Stomatitis, esophageal ulceration
• Oedema of lower limbs
• Use is C/I in pancreatitis, hepatitis, alcohol consumption
• Not to be used with Didanosine, lamivudine: inhibit its
phosphorylation
• No more in production
75

76. Emtricitabine – cytidine analog
• Used in combination with protease inhibitor/ NRTI
• Combination used : Emtricitabine + Tenofovir + Efavirenz
• Longer half life : once daily dosing
• Adult dose : 200mg OD
• Oral bioavailability : 93%
• Best tolerated and least toxic
• Not to be used in patients co infected with HBV
• Prolonged use : hyperpigmentation, pancreatitis, hepatitis
76

77. Didanosine
• Adenosine nucleoside analog
• Activity against HIV-I, HIV-II, HTLV-I.
• Used in multi drug regimen and for post exposure prophylaxis
• Adult dose : 250 mg BD, 30 mins before or 2 hrs after meal, acid
labile,
• Does not cause myleosuppression
• Prominent S/E - Pancreatitis, peripheral neuropathy,
hyperuricemia, diarrhoea, optical neuritis
• Zalcitabine+didanosine : increase risk of pancreatitis
77

78. Drug Interactions and Precautions.
• Buffering agents included in didanosine formulations :
Interfere with the bioavailability of coadministered drugs
• The ciprofloxacin AUC is decreased by up to 98% when
given with didanosine
• Oral ganciclovir can increase plasma didanosine
concentrations twofold : didanosine toxicity.
• Allopurinol ,Tenofovir increases the didanosine AUC by
44% to 60%
• Not given along with ethambutol, vincristine , isoniazid
78

79. Non nucleoside reverse
transcriptase inhibitors
• Do not require
activation through
phosphorylation
• Bind directly to the
catalytic site of viral
reverse transcriptase
• Inhibit viral DNA
synthesis
• Cross resistance
noticed in between
NNRTIs.
79

80. • Bind to a hydrophobic pocket in the p66 subunit of the HIV-1
reverse transcriptase.
• These compounds induce a conformational change in the three-
dimensional structure of the enzyme that greatly reduces its
activity : noncompetitive inhibitors .
• Do not require intracellular phosphorylation to attain activity.
• Active against HIV-1 but not HIV-2 or other retroviruses .
• No activity against host cell DNA polymerases.
• The two most commonly used agents in this category, Efavirenz
and Nevirapine, are quite potent and transiently decrease plasma
HIV RNA concentrations .
80

81. • All three approved NNRTIs are eliminated from the
body by hepatic metabolism.
• Nevirapine and Delavirdine : substrates for the
CYP3A4 isoform
• Efavirenz : substrate for CYP2B6 and CYP3A4.
• Efavirenz and nevirapine are moderately potent
inducers of hepatic drug-metabolizing enzymes
including CYP3A4, whereas delavirdine is a CYP3A4
inhibitor.
81

82. Nevirapine
• Single 200 mg oral dose : effective in preventing vertical
transmission of HIV : excreted in breast milk
• Thereafter , single 2mg/kg oral dose to neonate within 3
days after birth.
• Moderate inducer of CYP3A4 : increases its own clearance
• Decreases plasma levels of Indinavir, Lopinavir, azole group
of anti fungal agents, oral contraceptives, methaodne
• Nevirapine levels may decrease in presence of Rifampicin.
82

83. • Cross resistance- Cross-resistance extends to
efavirenz and delavirdine
• Any patient who fails treatment with this NNRTI
should not be treated with those drugs
• Side effects :Rash, prupritis, steven johnson syndrome
, Hepatitis within first 6 weeks of initiation of therapy
83

84. Efavirenz
• Used in HIV-I infection, post exposure prophylaxis
• Adult dose : 600 mg OD, CYP inducer
• Peak plasma conc – 5hrs, 99%bound , t1/2- 55 hrs
• Adverse effects : Dizziness, nightmares, insomnia, euphoria,
frank psychosis, rashes
• Teratogenic- avoided in pregnancy
• Has produced best long term treatment responses till date.
84

85. • Drug interactions : Inducer of CYP3A4 , inhibitor of
CYP2C9, CYP2C19
• Also a self inducer
• Cisapride, midazolam, triazolam not to be used concurrently
• Increases the plasma concentration of nelfinavir, ritonavir
• Decreases the plasma concentration of saquinavir
• Can be safely combined with Rifampin
85

86. • Etravirine :
unique in its ability to inhibit reverse transcriptase that
is resistant to other available NNRTIs
• favorable long-term suppression of viremia and
elevation of CD4+ lymphocyte counts .
• Peak conc- 2.5 to 4 hrs, t1/2 -42hrs .
86

87. • Rash , toxic epidermic necrolysis , Steven-Johnson
syndrome,
• Elevation of liver enzymes
• Drug interactions due to induction or inhibition of
cytochrome P450
• May increase or decrease levels of Protease Inhibitors
: CYP450 effect
87

88. Protease inhibitors
• Competitively inhibit the viral aspartyl protease
• Prevent the proteolytic cleavage of HIV gag and pol
precursor polypeptides
88

89. • Substrates for the P-glycoprotein drug transporter (P-
gp), which is an efflux pump encoded by the mdr1
gene.
• P-gp in capillary endothelial cells of the blood-brain
barrier limits the penetration of HIV protease
inhibitors into the brain.
• Most HIV protease inhibitors penetrate less well into
semen than do nucleoside reverse transcriptase
inhibitors and NNRTIs.
89

90. • An important toxicity : metabolic drug interactions.
• Inhibit CYP3A4 at clinically achieved concentrations :
Ritonavir the most potent.
• Ritonavir, Nelfinavir, and Amprenavir : inducers of hepatic
enzymes including CYP3A4 and glucuronosyl S-transferase.
• Concentrations of all approved HIV protease inhibitors may be
reduced in the presence of other CYP inducers.
• Nausea, vomiting, and diarrhea are also common, although
symptoms generally resolve within 4 weeks of starting
treatment.
90

91. 91

92. Fusion / entry inhibitor : Enfuvirtide
• Binds to gp41 subunit of viral envelope glycoprotein:
prevents entry of HIV I into CD4+ cells
• Dose : 90mg BD subcutaneously
• Used for advanced HIV-I infection
• Adverse effects : local reaction at injection site, skin
rash, eosinophilia
92

93. 93

94. Chemokine receptor-5 antagonist
• Maraviroc : binds to CCR5 receptor : prevents entry
of virus into host cell
• Prevents interaction of viral gp120 with CCR5 co
receptor
• Used in resistant patients (R5 HIV/ CCR5 tropic HIV
infection)
• Adverse effect : hepatotoxicity, muscular, joint pain,
94

95. MOA of maraviroc
95

96. Dosage
• When used with enzyme inducers :
dose is 600mg BD
• When used with enzyme inhibitors :
dose is 150 mg BD
• With other Anti retroviral drugs :
300 mg BD orally
96

97. Integrase inhibitors : Raltegravir
• Inhibits viral enzyme integrase : prevents insertion of HIV
genetic material into the chromosome of host cell
• Used only in case of resistant patients
• Dose to be doubled when combined with enzyme inducer
• Antacids and iron bind to integrase : dosing to be separated
by 2 hrs
• Dose : 400mg BD
• Adverse effects : nausea, diarrhoea, fever, myopathy
97

98. 98

99. • The Clinical goals of ART are:
• To improve quality of life,
• To reduce HIV-related morbidity and mortality,
• To provide maximal and durable suppression of viral
load and,
• To restore and/or preserve immune function
99

100. 100

101. 101

102. 102

103. 103

104. 104

105. • Currently, the national programme provides the
following drugs/ combinations for first-line
regimens
(i) Zidovudine (300 mg) + Lamivudine (150 mg)
(ii) Tenofovir (300mg) + Lamivudine (150 mg)
(iii) Zidovudine (300 mg) + Lamivudine (150 mg) +
Nevirapine (200 mg)
(iv) Efavirenz (600 mg)
(v) Nevirapine (200 mg)
105

106. • Principles for selecting the first-line regimen
1. Choose 3TC (Lamivudine) in all regimens
2. Choose one NRTI to combine with 3TC (AZT or
TDF)
3. Choose one NNRTI (NVP or EFV)
106

107. 107

108. 108

109. 109

110. FAILING REGIMEN
• <10 fold fall in viral load by 4 wks.
• Failure to suppress viral load to undetectable level in
6 months.
• Clinical deterioration, fall in CD4 count, serious
opportunistic infections.
CHANGING THE REGIMEN
• Should be changed to new drugs entirely.
• Drugs with known overlapping viral resistance to be
avoided.
110

111. Causes of Virologic Failure
Patient characteristics
• higher pretreatment or baseline HIV RNA level
• lower pretreatment or nadir CD4 T-cell count
• comorbidities (e.g., active substance abuse,
depression)
• presence of drug-resistant virus, either transmitted or
acquired
• prior treatment failure
• incomplete medication adherence and missed clinic
appointments
111

112. 112

113. 113

114. • Currently, single dose Nevirapine (Sd NVP) is being
given as prophylaxis to ANCs at the onset of labour
pains/delivery and Syp NVP to the baby soon after
birth
• IST line NACO regimen-
zidovudine+lamivudine+nevirapine
• ARV Prophylaxis is started as early as 14 weeks of
gestation and continued during the entire breast-
feeding period of at-least 12 months.
114

115. PPTCT
• WHO new guidelines (June 2013) 1 recommend two
options:
• 1. Providing lifelong ART to all the pregnant and
breastfeeding women living with HIV regardless of
CD4 count or clinical stage OR
• 2. Providing ART (ARV drugs) for pregnant and
breastfeeding women with HIV during the motherto-
child transmission risk period and then continuing
life-long ART
115

116. 116

117. PEP
• Post-exposure prophylaxis should be offered, and
initiated as early as possible, an ideally within 72
hours.
• Exposures that may warrant post-exposure
prophylaxis include: parenteral or mucous membrane
exposure (sexual exposure and splashes to the eye,
nose or oral cavity); and
• the following bodily fluids may pose a risk of HIV
infection: blood, blood-stained saliva, breast-milk,
genital secretions and cerebrospinal, amniotic, rectal,
peritoneal, synovial, pericardial or pleural fluids.
117

118. • Exposures that does not require post-exposure
prophylaxis include:
• when the exposed individual is already HIV positive;
• when the source is established to be HIV negative;
and
• exposure to bodily fluids that does not pose a
significant risk: tears, non-blood-stained saliva, urine
and swe
118

119. 119