This presentation deals with important pathophysiological steps involved with HIV infection, the various classes of drugs used in treatment of this condition, along with WHO-guidelines for treatment regimen(depending on various ages & conditions). Newer drugs have also been mentioned and emphasized upon.

1. AUTHOR DETAILS:
VISHNU.R.NAIR,
PHARM.D 5TH YEAR,
NATIONAL COLLEGE OF PHARMACY(NCP).

2. WELCOME TO THE SUMMARIZED
CONCEPTUALIZATION OF ANTI-RETROVIRAL
DRUGS!! HAPPY READING!!

3.  HOW DOES HIV AFFECT THE BODY?
 ANTI-RETROVIRAL DRUGS CLASSIFICATION
 REVERSE TRANSCRIPTASE INHIBITORS
 NON-NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE
INHIBITORS
 PROTEASE INHIBITORS
 ENTRY INHIBITORS
 INTEGRASE INHIBITORS
 IBALIZUMAB
 ANTI-RETROVIRAL THERAPY GUIDELINES
 CONCLUSION

4. HOW DOES HIV AFFECT THE
BODY?

5. HIV virus  initiates FUSION of its viral Gp-41 with
CCRS(C-C Chemokine receptor type-5)/ CXCR4 receptors(C-
X-C chemokine receptor type-4), found on human cells 
virus enters CD4 T-cell  viral RNA gets converted into
viral DNA via the enzyme “REVERSE TRANSCRIPTASE”
 viral DNA integrates with human DNA, using enzyme
“INTEGRASE”  PROVIRUS is formed  pro-viral DNA
replicates  undergoes transcription to form RNA  RNA
forms proteins(via translocation)
Initially, proteins are inactive  thus they make use of
enzyme “PROTEASE” for activation  finally complete virus
is generated  breaks out of host CD4 T-cell, killing it 
virus moves on to infect other cells.

6. CCRS:
- Protein, found on the surface of WBCs
- Involved in immune system
- Acts as receptor for chemokines
• CXCR4:
“Important mediator of cell migration in both leukocytes &
tumor cells”.

7. ANTI-RETROVIRAL DRUGS
CLASSIFICATION

8. A. REVERSE TRANSCRIPTASE INHIBITORS(RTI):
1. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS:
- Zidovudine
- Stavudine
- Lamivudine
- Zalcitabine
- Emtricitabine
- Abacavir
2. NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS:
- Tenofovir.

9. 3. NNRTIs:
- Efavirenz
- Etravirine
- Nevirapine
- Delavirdine
- Rilpivirine

10. B. PROTEASE INHIBITORS(PI):
- Saquinavir
- Ritonavir
- Indinavir
- Nelfinavir
- Amprenavir
- Fosamprenavir
- Lopinavir
- Darunavir
- Tipranavir

11. C. ENTRY INHIBITORS:
- Enfuvirtide
- Maraviroc.
D. INTEGRASE INHIBITORS:
- Raltegravir
- Elvitegravir
- Dolutegravir.
E. MONOCLONAL ANTIBODIES: Ibalizumab

12. REVERSE TRANSCRIPTASE
INHIBITORS:

13.  HIV(retrovirus)  uses REVERSE TRANSCRIPTASE enzyme (RNA-dependant
DNA polymerase)  forms its DNA from RNA.
 Drugs may inhibit RT, either:
a. Competitively
b. Non-competitively
• Competitive inhibitors of RT  known as NUCLEOSIDE/NUCLEOTIDE
REVERSE TRANSCRIPTASE INHIBITORS
• Non-competitive inhibitors of RT  known as NON-
NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS.

14. A. GENERAL PROPERTIES:
- Prodrugs  activated by HOST CELL KINASES  form TRIPHOSPHATES 
act in 2 ways:
1. Competitively inhibit RT
2. Incorporate into DNA chain  cause CHAIN TERMINATION
- Drug resistance develops rapidly  NEVER EVER USE IT ALONE!!!

15. B. ZIDOVUDINE:
- Frequently used drug
- Special indications include:
1. Prophylaxis of needle-stick injury patients
2. Prevention of vertical transmission of HIV(from mother to fetus)
- DRUG INTERACTIONS:
1. Drug + Ganciclovir  high risk of thrombocytopenia  AVOID CO-USAGE!!
2. Drug + Rifampicin  high clearance of former  reduced drug activity.
- CONTRAINDICATED in patients, with Hb< 8 g/dL!!!

16. - ADRs include:
1. Bone marrow suppression  leads to megaloblastic anemia, neutropenia,
thrombocytopenia
2. Myopathy
3. With chronic drug usage  the following may occur:
a. Lipodystrophy syndrome(condition, in which body is unable to produce fat)
b. Nail hyperpigmentation(Grayish-blue discoloration, dose-dependant)
c. Lipoatrophy(localized loss of fat tissue)

17. C. DIDANOSINE:
- Drug , if taken with food  reduced BA!!
- ADRs include:
1. Dose-limiting pancreatitis (high chances)
2. Hyperuricemia
3. Optic neuritis
4. Painful sensory peripheral neuropathy
5. Diarrhea(high chances, more common compared to others)
6. Neutropenia(NOT ANEMIA!)
7. Fulminant hepatic failure
8. Electrolyte abnormalities.

18. D. STAVUDINE:
- ADRs include:
1. Dose-limiting peripheral neuropathy
2. Drug  causes mitochondrial toxicity  high risk of lactic acidosis(max. risk!!)
3. Pancreatitis
4. Lipodystrophy syndrome(maximum, compared to other NRTIs & PIs)

19. E. LAMIVUDINE & EMTRICITABINE:
- Carry the reputation of being the BEST-TOLERATED NRTIs!!!
- NOT ASSOCIATED with peripheral neuropathy/pancreatitis!
- Carry additional property of being effective against HBV!
- Emtricitabine  one-day alternative to lamuivudine!!

20. F. ZALCITABINE:
- EVERYTHING IS WRONG ABOUT THIS DRUG!!
- Reasons include:
1. Oral ulceration propensity
2. Stomatitis
3. LEAST-EFFECTIVE NRTI!!
4. Peripheral neuropathy
5. Pancreatitis!

21. G. ABACAVIR:
- High risk of MI!
- May cause SEVERE HYPERSENSITIVITY REACTIONS in patients with HLA-
B* 5701 ALLELE  thus, check for this allele in patients, before starting
abacavir treatment!

22. H. IMPORTANT CATCHPOINTS ABOUT
NRTIs(NUCLEOSIDE):
- Excreted via kidney  require dosage adjustment in renal failure
- Abacavir  excreted via hepatic route(metabolized by alcohol dehydrogenase)
- Drugs  inhibit mammalian mitochondrial DNA polymerase  leads to the
following:
a. Lactic acidosis High risk in patients, with obesity & existing liver dysfunction!
b. Hepatomegaly
c. Steatosis

23. ADVERSE EFFECT DRUG LIKELY ASSOCIATED
PANCREATITIS DIDANOSINE
PERIPHERAL NEUROPATHY STAVUDINE
LIPODYSTROPHY SYNDROME STAVUDINE
LACTIC ACIDOSIS STAVUDINE
DIARRHEA DIDANOSINE
ANEMIA ZIDOVUDINE

24. ADVERSE EFFECT DRUG ASSOCIATED
BONE MARROW SUPPRESSION ZIDOVUDINE
ORAL ULCERATION ZALCITABINE
STOMATITIS ZALCITABINE
MYOPATHY ZIDOVUDINE
NAIL HYPERPIGMENTATION ZIDOVUDINE
LIPODYSTROPHY SYNDROME ZIDOVUDINE, STAVUDINE
HYPERURICEMIA DIDANOSINE

25. ADVERSE EFFECT DRUG ASSOCIATED
HEPATIC DYSFUNCTION DIDANOSINE
NEUTROPENIA DIDANOSINE, ZIDOVUDINE
ELECTROLYTE ABNORMALITIES DIDANOSINE
SENSORY PERIPHERAL NEUROPATHY DIDANOSINE, STAVUDINE, ZALCITABINE
PANCREATITIS STAVUDINE, DIDANOSINE, ZALCITABINE
OPTIC NEURITIS DIDANOSINE
DIARRHEA DIDANOSINE
MI ABACAVIR
DRUG HYPERSENSITIVITY ABACAVIR

26. DRUGS, POSSESSING ACTIVITY AGAINST BOTH HIV & HBV:
Remember the code: “LET”!
L: Lamivudine
E: Emtricitabine
T: Tenofovir

27.  TENOFOVIR  nucleotide  does not require bio-activation by kinases(contrary
to Nucleoside RTIs!)
 Excreted via kidney
 Drug, if taken along with meals  enhances drug oral BA!(Contrary to
Nucleoside RTIs!)
 Well-tolerated
 Active against HBV as well
 ADRs include:
a. Flatulence
b. Renal impairment(Reversible, Fanconi-like syndrome, with hypophosphatemia)

28.  THYMIDINE ANALOG NRTIs & PROTEASE INHIBITORS  cause
“LIPODYSTROPHY SYNDROME”  leads to:
a. Hyperlipidemia
b. Fat redistribution
c. Hypercholesterolemia
d. Glucose intolerance
• If HIV strains are RESISTANT to LAMIVUDINE(due to alteration in MI84V) 
they show HIGHER SENSITIVITY TO OTHER NRTIs!!!!

29. NON-NUCELOSIDE/NUCLEOTIDE
REVERSE TRANSCRIPTASE
INHIBITORS

30. A. GENERAL PROPERTIES:
- Drugs  act at a different site(allosteric site), compared to NRTIs  inhibit
reverse transcriptase
- Selective for HIV-1(No activity against HIV-2!)
- Resistance develops vary rapidly!!
- General ADR: Skin rashes.

31. B. NEVIRAPINE:
- Used in pregnancy to prevent vertical transmission
- Given in following doses(to prevent vertical transmission):
i. Single oral dose of 200 mg to mother(during labor)
ii. Single 2 mg/kg oral dose, to neonate(within 3 days of birth)
- Drug  reduces transmission by 13%(as compared to 21.5% by Zidovudine)
- ADRs:
i. Hepatotoxicity
ii. SJS
iii. TEN

32. C. EFAVIRENZ:
- Neurotoxic in nature!
- ADRs include:
a. Lack of concentration
b. Vivid dreams
c. Delusions
d. Mania.

33. D. ETRAVIRINE:
- Recently approved drug
- 2nd generation NNRTI
- Indicated for 1st generation NNRTI-refractory patients
E. RILPIVIRINE:
- Recently approved 2nd generation NNRTI
- Same properties & indication as that of etravirine.

34.  Do NOT CAUSE LIPODYSTROPHY!!
 NEVIRAPINE & EFAVIRENZ  CYP-450 enzyme inducers
 DELVIRDINE  Enzyme inhibitor
 NNRTIs are classified as:
A. 1st generation NNRTIs:
- Efavirenz
- Nevirapine
- Delavirdine
B. 2nd generation NNRTIs:
- Etravirine
- Rilpivirine.

35. PROTEASE INHIBITORS(PIs)

36. A. GENERAL PROPERTIES:
- Protease enzyme  helps in maturation of infectious virions
- PIs  inhibit protease enzyme  inhibit post-translational modification of viral
proteins
- Drugs  inhibit CYP3A4  inhibit metabolism of many drugs
- Metabolized by liver

37.  Common ADRs include: (Except ATAZANAVIR):
a. Hypercholesterolemia
b. DM
c. Hyperlipidemia
d. Insulin resistance
e. Altered fat distribution.

38. B. INDINAVIR:
- Food + Indinavir  reduced drug BA!
- ADRs include:
i. Asymptomatic hyperbilirubinemia
ii. Crystalluria
iii. Kidney stones
To prevent this,
MAINTAIN GOOD
HYDRATION!!

39. C. RITONAVIR:
- Given(in low doses) with other PIs, to increase their “C” levels
- According to current guidelines  all PIs-containing regimens  SHOULD USE
RITONAVIR BOOSTING IF POSSIBLE
- NELFINAVIR & ATAZANAVIR  can be used safely WITHOUT RITONAVIR
BOOSTING
- NELFINAVIR + RITONAVIR  high risk of “IMMUNE RECONSTITUTION
SYNDROME”  AVOID CO-USAGE!!!
Immune reconstitution syndrome: “Paradoxical worsening of a known condition/
appearance of a new condition, after initiating ART in HIV patients”

40. D. AMPRENAVIR & FOSAMPRENAVIR:
- FOSAMPRENAVIR: Long-acting prodrug of amprenavir
- Drugs + ETHINYL ESTRADIOL  reduced “C” of former
- Amprenavir  associated with SJS!

41. E. TIPRANAVIR:
- Only “NON-PEPTIDIC PI”
- Used in patients refractory to other PIs
- ADRs:
i. Intra-cranial hemorrhage
ii. Hepatotoxicity

42. F. ATAZANAVIR:
- Drug  requires ACIDIC PH to remain in solution  thus, should NOT BE
GIVEN WITH PPIs!
- Tenofovir, Efavirenz + Atazanavir  reduced “C” of latter  thus RITONAVIR
BOOSTING is MANDATORY in this case!!!
- ADRs include:
i. Asymptomatic unconjugated hyperbilirubinemia
ii. Increased PR-interval.
TESAMORELIN:
- Synthetic analogue of GH-releasing factor
- Used to reduce excess abdominal fat in HIV-infected patients with lipodystrophy!

43. ENTRY INHIBITORS

44. A. ENFUVIRTIDE:
- Drug  binds to Gp-41 subunit of HIV-envelope protein  blocks fusion of viral
& host cell membranes  prevents virus entry into host cells
- Given via s.c route
- Ineffective against HIV-2
- ADRs:
i. Injection site reactions
ii. Hypersensitivity
iii. Pneumonia

45. B. MARAVIROC:
- First CCR5 co-receptor antagonist to be approved for use
- Only active against “CCR5-tropic virus”  thus, conduct “co-receptor tropism
assay” before starting maraviroc treatment
- CCR5-tropic virus(mainly HIV-1 virus)  predominates in early stages of
infection
- Given orally

46. INTEGRASE INHIBITORS

47. - Act by inhibiting integrase enzyme
- Cobicistat  inhibits ELVITEGRAVIR metabolism  used to
boost its effect
- Cobicistat  boosts effect of DARUNAVIR & ATAZANAVIR
as well!

48. IBALIZUMAB

49.  In the current scenario  HIV treatment includes 27 medications from 5
different classes
 Despite proven benefits & efficacy of ARV(Anti-retroviral treatment)  there are
rising concerns, pertaining to numerous ADRs & risks of resistance!
 Thus  there is a need for newer HIV-treatment strategies, with high efficacy &
least toxicities
 Ibalizumab is a monoclonal antibody under the trade name “TROGARZO”
 Approved on March 6, 2018 by the US-FDA, for adult patients, infected with
HIV, who are in refractory state.
 Humanized IgG4 MAb , that was granted “breakthrough therapy”.

50.  Benefits of using monoclonal antibodies in a disease like HIV:
a. Improved antiviral effects  enhanced efficacy!
b. Lesser risks of toxicity
c. Improved resistance profile
d. Enhanced synergistic effects (when given with other ARVs!)
e. Ability to restore CD4 T-cell responses.
f. No risks of immunosuppression!!!

51.  Ibalizumab  comes under the class of “CD4-directed post-attachment HIV-1
inhibitor”
• Drug  shows the following actions:
a. Drug  binds to “domain 2” of CD-4+ T-cells  prevents post-attachment steps
(required for entry of HIV-1 viral particles into host cells)
b. Drug  prevents viral transmission, that occurs via “cell-cell fusion”.
• To be precise :
a. Ibalizumab doesn’t prevent viral attachment to CD-4+ T-cells , but surely
prevents viral entry inside the same!
b. Binding specificity of drug  reduces risks of immunosuppression!!

53.  Ibalizumab  administered via i.v infusion/ s.c injection
 According to recent studies  an intramuscular alternative is also being
evaluated (Lin et al., 2017)
 Average half-life of ibalizumab (after s.c injection) is 3-3.5 days  allows “weekly
administration schedule”(Bruno and Jacobson,2010)

54.  Although most studies maintain that ibalizumab is safe  it does have its own
share of ADRs
 Mild-moderate dose-dependent effects include(Khanlou et al.,2004; Norris et
al.,2006):
a. Rash(14-15%)
b. Diarrhea(0-14%)
c. Headache(7-11%)
d. Nausea(4-11%)
e. Depression(4-11%)

55.  Severe laboratory abnormalities  seen in 9-10% of cases during a 48-week
treatment
 No drug-related deaths/ discontinuations occurred in the above mentioned
studies
 Intramuscular administration of drug was also safe, without local side effects at
the injection site.

56.  Mainly indicated for HIV-1 infection in previously-treated adults with multidrug-
resistant infection(failing their current ART regimen)
 Used in combination with other ART drugs
 Initially  give “single loading dose” of 2,000 mg i.v (infused in 0.9% NS, for at
least 30 minutes)
 Begin “maintenance doses” 2 weeks after loading dose
 If no infusion-related adverse reactions occur  subsequent infusions can be
reduced to no less than 15 minutes.
 Maintenance dose: 800 mg i.v every 2 weeks(infused over 15-30 minutes)

57.  Primary resistance to ibalizumab is estimated at around 10%
 Resistance to ibalizumab  results in a highly infectious viral strain  but does
not show resistance to other ARTs(enfuvirtide, maraviroc, etc)
 Reduced susceptibility to ibalizumab occurs if HIV-1 loses a glycan in the “N-
terminus of gp-120  thus drug susceptibility can be restored by placing a glycan
molecule in the variable region of the antibody.

58.  Ibalizumab is a monoclonal antibody with better anti-HIV-1 activity & lesser side
effects
 Induces conformational changes of CD-4 receptors & gp-120  prevents post-
CD4 binding events, without eliciting immunosuppressive responses.
 Also preserves CD-4 T-cell counts
 Since drug has ability to block entry of HIV-1 multi-resistant isolates  it has
been studied in combination with other anti-HIV drugs with favorable results in
experienced patients
 Although definitive indications for ibalizumab are yet to be established 
ibalizumab is surely expected to be a part of a “salvage regimen” for the most
vulnerable category of HIV patients, especially those with extensive drug
resistance!!!

59. ANTI-RETROVIRAL
THERAPY(ART) GUIDELINES

60. A. GENERAL INTRODUCTION:
- HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY(HAART)  recommended,
with the goal of achieving COMPLETE SUPPRESSION of VIRAL
REPLICATION(i.e, viral load<50 copies/mL).
- Mainly based on WHO GUIDELINES for ART(2016).

61. B. WHO GUIDELINES FOR ART(2016):
1. “WHEN TO START” GUIDELINES:
- Initiate ART in all HIV(+) patients, regardless of Stage/ CD4-T cell count
- For patients with TB & HIV  first start treatment of TB  follow-it up by
ART(within 8 weeks!!)

62. 2. “WHAT TO START” GUIDELINES:
- Depends mainly on age
- Drug of choice is classified into :
a. 1st line ART
b. 2nd line ART.

63. I. TREATMENT REGIMEN FOR ADULTS:
1ST LINE ART 2ND LINE ART
- Focus on combo of: (2 NRTI + 1 NNRTI /
Integrase inhibitor)
- Eg: (Tenofovir+ Lamivudine/
Emtricitabine + Efavirenz)
- Focus on combo of : (2 NRTI + Boosted PI)

64. II. TREATMENT REGIMEN FOR ADOLESCENTS:
1ST LINE ART 2ND LINE ART
- Focus on combo of: (2 NRTI + I
NNRTI/ Integrase inhibitor)
- Eg: (Tenofovir+
Lamivudine/Emtricitabine+
Efavirenz) OR (Tenofovir +
Lamivudine/Emtricitabine +
Dolutegravir)
- Focus on combo of (2 NRTI + Boosted
PI)

65. III. TREATMENT REGIMEN FOR CHILDREN:
AGE GROUP 1ST LINE ART 2ND LINE ART
3-10 YEARS - Focus on combo of (2 NRTI + I
NNRTI)
- Eg: (Abacavir + Lamivudine +
Efavirenz)
- Focus on combo of: (2 NRTI +
Boosted PI/ Raltegravir)
< 3 YEARS - Focus on combo of (2 NRTI +
PI/ Integrase inhibitor)
- Eg: (Abacavir + Lamivudine +
Lopinavir + Ritonavir)
- Focus on (2 NRTI + Raltegravir)

66. IV. TREATMENT REGIMEN FOR INFANT PROPHYLAXIS:
“(Zidovudine + Nevirapine) for 6 weeks”.

67. V. TREATMENT REGIMEN FOR POST-EXPOSURE PROPHYLAXIS:
AGE GROUP 1ST LINE ART ALTERNATIVE
REGIMEN
ADULTS & ADOLECENTS - Focus on: (Tenofovir +
Lamivudine + PI)
- Raltegravir/ Dolutegravir/
Efavirenz can be used as
alternative to PI
CHILDREN < 10 YEARS - Focus on: (Zidovudine +
Lamivudine + Lopinavir +
Ritonavir)
- Abacavir  can be used in
place of zidovudine

68. 3. ANTI-RETROVIRAL COMBINATIONS TO BE AVOIDED:
A. ZIDOVUDINE+ STAVUDINE:
- Pharmacodynamic antagonism!
B. ATAZANAVIR + INDINAVIR:
- Additive unconjugated hyperbilirubinemia!
C. DIDANOSINE/STAVUDINE + ZALCITABINE:
- Additive peripheral neuropathy!
D. LAMIVUDINE + STAVUDINE:
- In-vitro antagonism!

69. CONCLUSION

70. 1. Drugs, whose names end with “NAVIR” are “HIV PROTEASE INHIBITORS”
2. All PIs  substrates of hepatic CYP3A4  undergo excessive oxidative
metabolism in liver
3. Most PIs  inhibit CYP3A4  lead to clinically-significant drug interactions
4. Saquinavir is the weakest CYP3A4 inhibitor
5. With respect to ZIDOVUDINE SAFETY PROFILE:
a. Most common & dose-dependent ADRs:
- Anemia
- Neutropenia
b. ADRs, common at start of therapy, but diminish later:
- Nausea - Insomnia
- Anorexia - Myalgia
- Abdominal pain
- Headache

71. c. Infrequent ADRs:
- Myopathy
- Lactic acidosis
- Hepatomegaly
- Steatosis
- Convulsions
- Encephalopathy.
6. Important points about RITONAVIR:
- PI
- Microsomal enzyme inhibitor  interacts with TERFENADINE,MACROLIDES,
RIFAMPICIN, WARFARIN, etc
- Mainly excreted via feces(86%), urine(11%)

72. - ADRs include:
a. GI manifestations
b. Lipodystrophy syndrome
c. Paresthesia
d. Hepatotoxicity
7. Drugs, that cause Bone Marrow Suppression in Patients with HIV-infection:
- Zidovudine - Interferon-alpha
- Dapsone - Foscarnet.
- Cotrimoxazole
- Pyrimethamine
- 5-flucytosine
- Ganciclovir

73. 8. Cytomegalovirus(CMV)  causes “RETINITIS” in AIDS patients  treated by:
a. Intravenous ganciclovir
b. Intravitreal ganciclovir
c. Foscarnet
d. Cidofovir
e. Fomivirsen.
9. Important points about LAMIVUDINE:
- Can be used for BOTH HIV & HBV
- Dose for HIV: 150 mg, BD
- Dose for HBV: 100 mg OD
- NEVER USE IT ALONE(as resistance develops rapidly!!)

74. HIV PATHO & ACTIONS OF VARIOUS DRUGS

75. THANK YOU!!  