Medical Undergraduate Lecture slides on Pharmacotherapy of HIV-AIDS. These slides include life cycle of HIV. Classification of available drugs based on target site. Individual Drugs with Mechanism of action, PK, AE and drug interactions. Treatment principles and guidelines for HIV-AIDS based on NACO(National Aids Control Organisation, India) Guidelines.

1. Antiretroviral Drugs
Dr. Mayur A. Chaudhari
Assistant Professor
Department of Pharmacology
Government Medical College, Surat

2. Objectives
 Life cycle of HIV
 NRTIs and NNRTIs
 Protease Inhibitors
 Fusion Inhibitors
 CCR5 inhibitor
 Integrase inhibitor
 HIV Treatment Principles and Guidelines

3. History : HIV
 Was reported to be a new and unique disease to CDC
in 1981 with no name
 Cases were diagnosed as Kaposi’s sarcoma,
Pneumocystis Jiroveci Pneumonia with low immunity
 Common in Homosexuals, IV drug Users,
Hemophiliacs
 In 1983 virus was named as Human
Immunodeficiency Virus.

4. History: Drug Development
 1985 – Research on anti-viral medication begins
 1987 – First drug Zidovudine produced (NRTI)
 Early life extending properties except only
temporarily worked as patients became immune
 Mid-1990s – Protease Inhibitors and NNRTIs

5. History: Drug Development
 1995 – first protease inhibitor Sequinavir FDA
approved
 Low Bioavailability led to the development of a
second protease inhibitor Ritonvir
 1996 first NNRTI, Nevirapine approved by FDA
 March 2003 – First Fusion Inhibitor Enfuvirtide
approved by FDA

6. HIV
 Retrovirus
 Cell Has RNA as a genetic material
 HIV-1, the most prevalent worldwide, and
 HIV-2, the most common in western Africa

7. Life cycle of HIV

8. Classification
 Nucleoside reverse transcriptase inhibitors (NRTIs)
Purine Analogue
1)Adenosine analogue – Didanosine, Tenofovir
2) Guanine analogue – Abacavir
Pyrimidine analogue
1) Thymidine analogue – Zidovudine, Stavudine
2) Cytosine analogue – Lamivudine, Emtricitabine

9. Classification
 Nonnucleoside reverse transcriptase inhibitors
(NNRTIs) – Nevirapine, Efavirenz, Delavirdine
 Protease inhibitors – Ritonavir, Atazanavir, Indinavir,
Nelfinavir, Saquinavir, Lopinavir
 Fusion Inhibitor – Enfuvitride
 CCR5 Inhibitor – Maraviroc
 Integrase inhibitor - Raltegravir

10. NRTIs
 Competitively inhibit HIV1 and HIV2
 Activated by triple phosphorylation in cytoplasm
 Incorporates into growing viral DNA to cause
termination
 Inhibit mitochondrial DNA polymerase gamma
 Lactic Acidosis, Hepatic steatosis
 Elevated hepatic transaminase

11. Zidovudine/Azidothymidine (AZT)
 Selective inhibition of viral reverse transcriptase
 Gets incorporated into growing viral DNA and
terminates chain formation
 Zidovudine prevents infection of new cells
 No effect on already infected host cell
 Resistance occur by altered reverse transcriptase
enzyme

12. AZT:Pharmacokinetics
 Rapid oral absorption, 65% Bioavailability
 T1/2 only 1hour
 Crosses placenta and secreted in milk

13. AZT: Adverse Effects
 Anaemia and neutropenia - dose related
 Nausea, anorexia, abdominal pain, headache
 insomnia and myalgia
 Myopathy, lactic acidosis, hepatomegaly
 convulsions and encephalopathy

14. AZT: Drug Interaction
 Paracetamol increases AZT toxicity
 Azoles increase AE due to AZT
 Other nephrotoxic and myelosuppresive drugs
increase toxicity
 Probenecid also increases toxicity
 Stavudine and Zidovudine inhibit each other

15. AZT : Uses
Progressive increase in CD4 counts
Improved immunity and lessen opportunistic
infection
Sense of well being and weight gain
Reduces neurological manifestation of AIDS
Slow the progression of HIV to AIDS
Reduces mortality
nonresponsive state After few months to years
Used for post exposure prophylaxis

16. Stavudine (d4T)
 Same as Zidovudine
 Comparable efficacy to Zidovudine
 Peripheral Neuropathy
 Pancreatitis
 Lipodystrophy

17. Didanosine
 Compete with ATP for incorporation in Viral DNA
 Activity similar to Zidovudine
 Acid Labile, t1/2 only 90 minutes
 Do not cause myelosuppresion
 Pancreatitis and Neuropathy dose related
 Nausea, Abdominal pain and Diarrhoea – Side effects

18. Lamivudine (3TC)
 Inhibits HIV reverse transcriptase and HBV DNA
polymerase
 Human DNA Polymerase not affected
 Resistance due to altered enzyme
 High Oral Bioavailability
 Plasma t1/2 – 8 hours, Intracellular t1/2 – 12 hours
 Excreted unchanged in urine

19. 3TC: Adverse Effects
 Headache, fatigue, nausea
 Anorexia, abdominal pain. Pancreatitis and
 Neuropathy are rare.
 Hematological toxicity does not occur

20. Tenofovir
 Requires only double phosphorylation
 Competitive inhibitor of reverse transcriptase
 Bioavailability increased with fatty food
 T1/2 12-15 hours – once a day
 Eliminated by glomerular filtration and tubular
secretion

21. Tenofovir: AE and Uses
 Nausea, Vomiting, Flatulence and Diarrhoea
 Headache, asthenia and Osteomalacia
 Precaution should be taken in patients of reduced
renal function

22. Abacavir
 More effective than other NRTI
 2-3 concomitant mutation required to develop
resistance
 Good oral absorption with t1/2 of 1.5 hours
 Hypersensitivity reaction
 Should be avoided in cardiac disease

23. Non-Nucleoside Reverse
Transcriptase Inhibitors
 Active drugs- Do not require phosphorylation
 Directly combine with HIV1 Reverse transcriptase and
DNA Polymerase
 Binds at different site than NRTIs
 Substrate for CYP3A4.
 Nevirapine Inducer
 Delavirdine Inhibitor
 Efavirenz – Inducer and Inhibitor

24. Nevirapine
 Potent against HIV1 but no activity against HIV2
 Resistance develop easily and rapidly if used alone
 Cross resistance is very common
 Well absorbed, Crosses placenta and secreted in milk
 Metabolized by CYP3A4 and CYP2B6, Induces own
metabolism
 AE – rashes, Hepatitis, Nausea, Fever, Fatigue, Headache
 Rarely SJ syndrome

25. Drug Interactions
 Reduces concentration of Protease inhibitors
 Reduces the concentration of methadone
 Contraception failure
 Should be started with small dose and increased
gradually to prevent rashes

26. Clinical Uses
 HIV And Aids
 Single Intrapartum dose of 200mg to mother f/b
 2mg/kg orally single dose to newborn to prevent
transmission

27. Efavirenz
 Oral absorption 50% and peak effect in 3-5 hours
 T1/2 is 40-50 hours, highly Plasma Protein bound
 Metabolized by CYP3A4 and CYP2B6.
 CNS side effects in 50% individuals – Dizziness,
Insomnia, Headache
 Confusion, Agitation, Delusion and Nightmares
 Skin rashes
 Nausea, Vomiting, Diarrhoea and Elevated liver
enzymes
 Teratogenic – Neural Tube defects

28. Entry/Fusion Inhibitor
(Enfuvirtide)
 Synthetic polypeptide active against HIV1 not 2.
 Inhibit HIV mediated membrane fusion – prevent
virus entry into host cells
 Only Antiretroviral used by parenteral route (SC)
 t1/2 is 4 hours.
 At Injection site – Pain, erythema and induration.
Nodule or cyst (80%)
 Lymphadenopathy and pneumonia
 Used in resistant cases

29. CCR5 Inhibitor - Maraviroc
 Blocks CCR5 receptor and prevent entry into host cell
 Oral absorption is rapid but variable
 Achieves high concentration in Cervicovaginal
secretions
 Chances of resistance are less
 Reserve when other fails

30. Maraviroc – Adverse Effects
 Cough, URTI, Diarrhoea, Muscle and Joint pain, Sleep
disturbances
 Increase in hepatic transaminase
 Reduced immunity – Chances of Lymphoma
 Substrate for CYP3A4 – Concentration reduced with
phenytoin, Carbamazepine and Rifampin, Efavirenz.

31. Protease Inhibitors
 Ritonavir
 Atazanavir
 Indinavir
 Nelfinavir
 Saquinavir
 Amprenavir
 Lopinavir

32. Protease Inhibitors

33. Mechanism of Action

34. Resistance
 Development of resistance delayed
 Requires 4-5 mutations
 Cross resistance
 Combined with other class of drugs

35. Pharmacokinetics
 Variable Bioavailability by oral route
 Metabolized by CYP3A4 except Nelfinavir (CYP2C19)
 T1/2 2-10 hours

36. Adverse Effects
 Nausea, Vomiting and Diarrhoea – Common
 Headache, Dizziness, Tingling and numbness of face
and limbs
 Redistribution of body fat- Central obesity, buffalo
hump, Peripheral and facial wasting, Breast
enlargement
 ↑ triglycerides, LDL levels
 Glucose intolerance and insulin resistance

37. Interactions
 Ritonavir is most potent inhibitor of CPY3A4
 In presence of inducer concentration of PI reduced
 Low Dose Ritonavir (100-200mg) is used in
combination with other PIs
 To inhibit first pass metabolism and systemic
metabolism
 Better oral Bioavailability and longer elimination half
life.

38. Atazanavir
 Active against HIV1 and HIV2
 Rapid oral absorption with peak in 2 hours
 T1/2 7 hours and 90% PPB
 Unconjugated hyperbilirubineamia and ↑ bilirubin
 No effect on Blood glucose and insulin sensitivity
 Given in combination with ritonavir

39. Indinavir
 10 time more sensitive for HIV1
 Rapid oral absorption with peak in 60 mins, 60% PPB
 Metabolized by CYP3A4 in liver, Short Half life
 Causes crystalluria – Renal Colic and Nephrolithiasis
 Hyperbilirubineamia, Lipodystrophy syndrome, fat
accumulation
 Hyperglycemia, Insulin resistance
 Hair loss, Dry skin, Dry and cracked lips

40. Nelfinavir
 Slower absorption, ↑ with fatty food
 Metabolized through CYP2C19, CYP3A4 and CYP2D6
 Activity of metabolite is 40%
 Induces own metabolism
 AE – Diarrhoea, Glucose intolerance, ↑ cholesterol
and TG

41. Ritonavir
 More active on HIV1
 ↑ absorption with meal
 AE- Nausea, Diarrhoea, Paresthesias, fatigue and
lipid abnormality
 Used for Boosting other PI in Sub therapeutic doses

42. Saquinavir
 Active on HIV1 and HIV2
 Hard gel capsule with ritonavir
 Soft gel capsule – 3 times Bioavailability
 Pill load is higher
 AE – Nausea, Vomiting, Diarrhoea and abdominal
discomfort

43. Lopinavir
 More activity on HIV1
 Extensive first pass metabolism, always used with
ritonavir
 Dose needs to be increased if used with NVP or EFV
 AE – Nausea, Vomiting and Diarrhoea
 ↑ Cholesterol and ↑ TGs

44. Integrase inhibitor: Raltegravir

45. Raltegravir
 Well absorbed
 Rifampicin reduces concentration
 Used in multidrug resistant patients
 Resistance not reported yet
 AE headache, Dizziness, Nausea, Diarrhoea
 Not yet available in India

46. Antiretroviral Drugs: Some
facts
 Most drugs affect Host cells – Unacceptable toxicity
 Most Drugs inhibit viral replication
 Replication starts again when drug is discontinued.
 Good host immunity is essential
 Failure of therapy in immunocompromised pts and
drug resistant variants
 Current drugs do not affect dormant virus

47. Drug Treatment
• Pneumocystis Jiroveci
• Mycobacterium avium complex
• Cytomegalovirus retinitis
• Fungal infections
• Protozoal infections
Opportunistic
Infections
• Kaposi’s Sarcoma
• Cervical
carcinoma
• Lymphoma
Malignancy
To prevent viral replication, prevent depletion of CD4
cells
Treat opportunistic infections and malignancies

48. Problems of Treatment
 Cost of Drugs
 High Toxicity
 Resistance
 Adherence to multidrug therapy
 Pill Load
 Complex Drug interactions

49. Decision to start therapy
 Individualized
 CD4 cell count
 Plasma HIV1 RNA concentration
 Symptomatology

50. Decision to Start Therapy
Clinical
Symptoms
CD4 Count/
µl
Plasma HIV
RNA/ml
Treatment
Status
Asymptomatic > 350 cells < 100000 Defer
treatment
Asymptomatic 200-350 Any Value Treatment
Asymptomatic < 200 Any Value Treatment
AIDS defining
illness
Any Value Any Value Treatment

51. Selection of Drugs
 Combination drugs are selected based on potency,
Susceptibility, Safety, Interactions, tolerability,
convenience and Patient compliance
 Life long treatment
 Preferred regimen – 2NRTI+1NNRTI/1PI and 3NRTI
 Three drug from 2 groups
 Addition of 4th drug do not add benefit- can be used
in resistant cases
 3 Drugs from 3 different groups reserved for resistant
cases

52. Highly Active AntiRetroviral Therapy
 Level of HIV RNA may be undetectable by HAART
 Success depend on life long treatment
 Combinations are used for
1) To increase antiviral activity
2) Reduced dose of individual drug
3) Reduced risk of toxicity
4) Reduced risk of resistance

53. Common Regimens
2NRTI+1 NNRTI 2NRTI+1PI 3NRTI
Lamivudine+Zidovudine+
Efavirens
Lamivudine+Zidovudine+Lop
inavir/Ritonavir
Zidovodine+
Lamivudine
+Abacavir
Lamivudine+Stavudine+Ef
avirenz
Lamivudine+Zidovudine+Indi
navir
Lamivudine+Abacavir+Efa
virenz
Lamivudine+Abacavir+Lopin
avir/Ritonavir
Lamivudine+Zidovudine+
Nevirapine
Lamivudine+Abacavir+Nelfin
avir
Lamivudine+Stavudine+N
evirapine
Lamivudine+Stavudine+Riton
avir
Lamivudine+Abacavir+Ne
virapine

54. Change in Regimen
 Avoid known resistant drugs, Cross resistance should
be considered
 Change whole regimen, should contain which were
not used previously for pt.
 Regimen can be changed if fall in CD4 count or
increase in viral load
 If condition of patient deteriorates
 If patient develops serious opportunistic infection

55. Combinations to be avoided
Combination Reason for
avoiding
Zidovudine+Stavudine
Zalcitabine+Lamivudine
Mutual Antagonism
Abacavir+Tenofovir+Lamivudine High rate of poor
response
Zalcitabine+Didanosine+Stavudine
Atazanavir+Indinavir
Peripheral
neuropathy
Hyperbilirubinemia

56. Post exposure Prophylaxis
 Persons involved in patient care when exposed to
infectious material
 Exposures are categorized depending on source
 All exposure do not need prophylaxis
1. Contamination on intact skin
2. Brief period on mucus membrane
3. If source is HIV Negative

57. Post exposure Prophylaxis
Category Low Risk Source High Risk Source
Criteria • HIV +ve but
asymptomatic, Low
HIV-RNA titer, High
CD4 Count
• Minor exposure
• Symptomatic, High
HIV-RNA titer, Low
CD4 Count
• Major exposure
Regimen Zidovudine
300mg+Lamivudine
150mg BD for 1 month
Zidovudine 300mg +
Lamivudine 150mg BD
+ Indinavir 800mg TDS
for 1 month

58. Perinatal Prophylaxis
 Transmission can occur through placenta, During
delivery and through milk
 Avoid breastfeeding if mother is HIV+
 Treat mother with standard 3 drug regimen from 2
groups or Zidovudine after 1st trimester till delivery
 Put neonate on 6 weeks prophylaxis
 Nevirapine Crosses placenta and secreted in milk

59. Drugs in Pregnancy
Class Preferred Drug Alternate Drug
NRTI Zidovudine,
Lamivudine
Didanosine, Stavudine,
Emtricitabine, Abacavir
NNRTI Nevirapine -
PI Nelfinavir,
Saquinavir
Lopinavir+ Ritonavir,
Indinavir, Ritonavir

60. Summary
Life cycle of HIV
NRTI, NNRTI, PI, Integrase Inhibitor, Fusion
Inhibitors
HAART
Post exposure prophylaxis
Mother to Child Transmission