1. HIV is a retrovirus that contains RNA and incorporates its genome into host cells, hijacking their functions to replicate and eventually destroy the cells. 2. HIV targets CD4+ T-cells, weakening the immune system. It was first recognized in 1981. 3. HIV infection progresses through stages from asymptomatic to development of opportunistic infections that define AIDS. Common symptoms include fatigue, weight loss, and recurrent infections.

1. Human Immunodeficiency Virus
• HIV is a Retrovirus which means:
– It contains a single-stranded RNA genome
– HIV will incorporate it’s genome into it’s host cell
– hijack the normal functions of the cell to replicate
– This process will eventually lead to cell destruction
• The target for HIV is the CD-4+ Helper T-Cells, which
are the backbone of the immune system.
• First recognized in 1981 June 5th

2. Immunity
Macrophages
Natural killer cells
lymphocytes
T CELLS
CLONE
B CELLS
PROLIFERATE
ANTIGEN DESTRUCTION
(INNATE IMMUNITY)
IgG
IgM
IgA, E, D
SUPPRESOR (CD8)
CYTOTOXIC (CD8)
cellmediated immunity
HELPER(CD4)
Humoral

3. Disease staging system for HIV
According to the WHO
• Stage I- infection asymptomatic and not categorized as
AIDS, expect presence of lymphadenopathy
• Stage II- Minor mucocutaneous infections and recurrent
URTI
• Stage III- Unexplained chronic diarrhea for longer than
1month, weight loss, several bacterial infections,
pulmonary infections
• Stage IV- Toxoplasmosis of the brain, candidiasis of
esophagous, trachea, bronchi, lungs. All of indicate AIDS

4. Symptoms
• The Majority of Symptoms of an HIV infection do not
show up until the disease has already begun to
damage the immune system
• The incubation time for an HIV infection can be
several weeks to several years

5. • General symptoms :
–
–
–
–
–
–
–
–
Lack of energy
Weight loss
Frequent fevers
Sweats
Persistent or frequent fungal infections
Persistent skin rashes
Flakey skin and mouth,
Genital or anal sores from Herpes infections

6. Opportunistic Infections
• HIV infection is usually discovered when a patient is
diagnosed with an unusually severe or persistent
infection
• Opportunistic infections include:
– Bacterial, Fungal, Parasitic, and Viral Infections
• These infections will be more severe because the
person’s immune system suppressed.

7. Retrovirus
gp140
gp 41
integrease
Protease
RT
Core proteins

8. Replication rate 1010/day, 109 CD cells destroyed , half life 1-2h in plasma,
1.5days in infected CD cells, in latently infected cells 12months

9. HIV replication

10. Drug treatment for HIV
• Currently no vaccine, no cure
• Mostly drugs are postponing complications of
acquired immunodeficiency syndrome & AIDS
related complications .

11. Goals of Treatment
•
•
•
•
•
•
•
Improve quality of life
Reduce HIV-related morbidity and mortality
Restore and/or preserve immunologic function
Maximally and durably suppress HIV viral load
Prevent HIV transmission
Inc. CD4 count
Dec. drug resistance
• Inc. 5-8yr of life span
January 2011
11
www.aidsetc.org

12. Anti-HIV drugs
• Nucleoside reverse transcriptase inhibitors
(NRTIs）
• Nucleotide Reverse Transcriptase Inhibitors
(NtRTIs)
• Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
• Protease inhibitor ( PI )
• Fusion inhibitor

13. DRUG THERAPY OF HIV INFECTION
• Entry /Fusion inhibitor
Enfuvirtide
• Nucleoside reverse transcriptase inhibitors (NRTIS)
Zidovidine Stavudine
Lamivudine Abacavir
Zalcitabine Didanosine Emtricitabine
• Non Nucleoside reverse transcriptase inhibitors (NNRTIS)
Efavirenz
Nevirapine Delaviridine
• Necleotide reverse transcriptase inhibitors (NTRTIS)
Tenofovir
• Protease Inhibitors(PIs)
Saquinvir
Indanavir
Nelfinvir
Amprenavir
Ritonavir
Lopinavir
Atazanavir
Fosamprenavir

14. Newer drugs
• CCR 5 chemokine receptor inhibitor: Maraviroc
• Integrase inhibitors : Raltegravir

15. Problems with drug therapy
•
•
•
•
•
Majority drugs have serious adverse effects
More drug interaction
Have to be taken for life long
HIV can’t be eradicated
HIV viruses have high mutation rate, cross
resistance
• Many drugs block the infection of the new cells
rather than treating the already infected cells

16. Nucleoside reverse transcriptase inhibitors (NRTIS)
• 1985 – research on anti-viral medication begins
• 1987 – First drug Zidovudine produced
– First NRTI
– Early life extending properties
General mechanism
• First converted into triphosphate derivatives
by host cell kinase enzymes
• NRTIs are phosphorylated three times after
they enter the cell to become successful
inhibitors

17. General therapeutic uses
• Generally used in combination with other drugs
(PIs) to avoid devp. of resistance (NRTI)
• Multi drug therapy is need to counter act
• Combination synergetic action
• Sequential blockade
• Highly Active Anti Retroviral Therapy(HAART)
NRTIs(2) + PI
Or
NRTIs(1) + NNRTIs(1) + PI(1)
Or
NRTIs(1) + NNRTIs(1) + PI(2)

19. Adverse Effects: NRTIs
• All NRTIs:
– Lactic acidosis and hepatomegaly due to mitochondrial
damage
– Lipodystrophy

20. zidovudine
• Zidovudine first drug.
• Approved by the FDA on March 20, 1987 and is
thymidine analogue (HIV1 &2, T- cell lympho
trophic virus)
• Inhibits RT and causes chain termination
• Used for post exposure prophylaxis
• It reduces the incidence of neonatal HIV infection
(100mg , 5 times a day) to HIV infected mother
after 14weeks of gestation until birth
• New born receive syrup 2mg/kg 6hrly from birth
to six week of age

21. •
•
•
•
•
Clinical uses:↓mortality & opportunistic infections
gain weight
better quality of life
delays signs and symptoms of AIDS
• Adverse effect:
• Toxicity: Bone marrow suppression
– Granulocytopenia and anemia: 45%
– Severe headache, nausea, insomnia, myalgias

22. Lamivudine
• Deoxycytidine analogue
• Inhibits reverse transcriptase and DNA
polymerase in HBV.
• Systemic toxicity is low, and is well tolerated.
• Resistance rapid
• Used in combination with other ARVs
• Chronic hepatitis B(100mgOD), HIV 1 & 2
(150mg/BD)
• Zalcitabine, Lamivudine inactive each other

23. • Other nucleoside analogs: Didanosine, Stavudine,
Zalcitabine
(MOA is same as zidovudine)
• Zalcitabine is no longer used due to its neurotoxic
effects
• Didanosine : Purine analogue, acid liable, dose
depended pancreatitis
• Stavudine : Thymidine analogue (30-40mg BD)
peripheral neuropathy
Lamvidine + zudovidine synergetic action

24. NRTIs
Drug
Oral Bv
Distribution/PB
Half life
Zidovidine
60-65%
All tissues 35-38%
1-3
Stavudine
85-90%
Less PB
1.2
Lamivudine
85-90%
CSF 20% 35%PB
5-7
Abacavir
83%
CSF33%, 50% PB
1.5
Zalcitabine
>80%
CSF 20%,< 4% PB
2
Emtricitabine
93
<4% PB
10
diadanoside
42
CSF 20%,< 5% PB
1.5

25. Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)
Tenofovir
• In the same class of drugs as NRTIs
• These are not required to be phosphorylated after
they enter the cell.
• ADENOSINE analogue
• Pro drug hydrolyzed in liver
• Same mechanism of action as NTRIs
• 300mg once daily after meals
• Used in combination with NRTIs and PI
• Toxicity: rash
• Contraindication :- Used with caution in renal disease
patients (stone formation)

26. Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• Inhibitors of the viral enzyme reverse transcriptase
• The drug binds to the viral enzyme at other than
the active site
• changes the conformation of the active site so
dec. enzyme’s affinity for nucleoside binding.
• This class of drugs works by non-competitive
inhibition

27. Nevirapine
•
•
•
•
•
Binding to RT and direct inhibition at a site
Used in combination.
Main adverse effect is rash (75%).
More potent against HIV-I.
Single dose 200mg can prevents the transmission
of HIV from mother to newborn when
administrate to women at onset of labour.
• Followed by oral dose of 2mg/kg to neonate with
in 3days of delivery.

28. NNRTIs
Drug
Oral BV
Distribution/PB
Half life
Nevirapine
90-95
Wide, CSF 45%
PB 60%
25-30
Efavirenz
50
CSF 1%
PB 99%
40-45
Delavirdine
(only for HIV I)
85
CSF 0.4%
PB 98%
6

29. Protease Inhibitors
• Reduces the number of new of infection in
susceptible cells
• To be effective must be prolonged, profound and
constant.
• Pharmacokinetics important to maintain constant
concentrations within the effective range
• Metabolic adverse effects (DM, hyperglycemia) and
GI (diarrhea, pain vomiting).

30. Protease inhibitor
• Drugs :
• Saquinavir
• Ritonavir
• Indinavir
• Nelfinavir
• Mechanism: inhibit precursor molecules
convert to mature virions during HIV
replication

31. Protease Inhibitors
• These work by competitive inhibition of the viral
enzyme protease
• These drugs irreversibly bind to the active site of
protease preventing it from completing the
maturation of the virion
• Core is produced by proteolytic cleavage of HIV
gag and pol polyprotines. It inhibits maturation
and function of protiens

32. PIs
Drug
BV
Distribution/ PB
Half life
Saquinavir -S
13
Wide, 97% PB
11
ritonavir
75
98% PB
3-5
Lopinavir
Variable
98-99% PB
5-6
Nelfonavir
Variable
98-99% PB
4-5
Indinavir
65
CSF 76% , PB 60%
1.8
Amprenavir
63
90% PB
7-11
Atazanavir
>70
CSF 76% , PB 86%
7

33. Adverse Effects: PIs
• All PIs:
– Hyperlipidemia
– Lipodystrophy
– Hepatotoxicity
– GI intolerance
– Possibility of increased bleeding risk
for hemophiliacs
– Drug-drug interactions
January 2011
33
www.aidsetc.org

34. Fusion Inhibitors
• Newest Class of Drugs
• This drug binds to the glycoprotein gp41 in the
viral envelope inhibiting its fusion with the CD4+
receptor on the host cell and thus preventing the
cell’s infection.
• Usually used as a last line option for most patient
because it is only available as an injection and its
high cost

35. Fusion Inhibitors vs. Other Classes of Drugs

36. Adverse Effects: Fusion
Inhibitor
• ENF
– Injection-site reactions
– Increased risk of bacterial pneumonia
January 2011
36
www.aidsetc.org

37. Popular drug combinations
•
•
•
•
•
•
Indinavir+ Zidovidine+ Lamivudine
Nelfinavir+ Zidovidine+ Diadinosine
Saquinavir+ Zidovidine+ Zalcitabine
Ritonavir + Lopinavir + Stavudine + Lamivudine
Ritonavir+ Indinavir + Stavudine + Diadinosine
Amprenavir + Zidovidine+ Lamivudine

38. Combinations should not be use
• Atazanvir + Indinavir: Inc. unconjugated hyperbilirubinemia
• Didanosine/ Stavudine+ Zalcitabine: peripheral neuropathy
• Lamivudine+ Zalcitabine: In vitro antagonism
• Zidovidine+ Stavudine: Pharmacological antagonism both
compete for phosphorylation