1. School of Pharmacy, University of Nizwa
Treatment of Aids
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture11
March 30, 2013

2. HIV Infection
HIV are lentiviruses, a family of mammalian retroviruses evolved to establish chronic persistent infection with gradual onset of clinical symptoms
Replication is constant following infection, and although some infected cells may harbor nonreplicating but infectious virus for years, there generally is no true period of viral latency following infection
Humans and chimpanzees are the only known hosts for these viruses

3. Drug Used to Treat HIV Infection
Main classes of anti-HIV drug:
Reverse transcriptase inhibitors
nucleoside reverse transcriptase inhibitors
non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Fusion inhibitors
Integrase inhibitors
Chemokine co-receptor inhibitors

4. Drug Used to Treat HIV Infection
Each class of anti-HIV drug has a different mechanism of action and combinations are used in the therapy of HIV/AIDS
Combination treatment is known as highly active antiretroviral therapy (HAART)
A HAART combination would involve two nucleoside reverse transcriptase inhibitors with either a non-nucleoside reverse transcriptase inhibitor or one or two protease inhibitors

5. Drug Used to Treat HIV Infection
Main classes of anti-HIV drug:
Reverse transcriptase inhibitors
nucleoside reverse transcriptase inhibitors
non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Fusion inhibitors
Integrase inhibitors
Chemokine co-receptor inhibitors

6. Nucleoside Reverse Transcriptase Inhibitor (NRTI)
This class includes
zidovudine
abacavir
lamivudine
didanosine
zalcitabine
stavudine

7. NRTI: Zidovudine
Given to the parturient mother and then to the newborn infant it can reduce mother-to-baby transmission by more than 20%
Administered orally twice daily
Bioavailability is 60-80%
Most of the drug is metabolised to the inactive glucuronide in the liver, only 20% of the active form being excreted in the urine

8. Zidovudine: Adverse Effects
Anemia is common with long-term administration
GI disturbances, skin rash, insomnia, fever, headaches, and abnormalities of liver function are some other unwanted effects
Confusion, anxiety, and depression are also reported

9. NRTI: Abacavir
It is proved to be more effective than most other nucleoside reverse transcriptase inhibitors
Well absorbed after oral administration and is metabolised in the liver to inactive compounds
CSF level is 33% of that in the plasma
Unwanted effects include a generalised hypersensitivity reaction (rare but potentially fatal)
Skin rashes and gastrointestinal disorders
Hypersensitivity reaction refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity

10. Drug Used to Treat HIV Infection
Main classes of anti-HIV drug:
Reverse transcriptase inhibitors
nucleoside reverse transcriptase inhibitors
non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Fusion inhibitors
Integrase inhibitors
Chemokine co-receptor inhibitors

11. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
This class includes
Efavirenz
Nevirapine
Delavirdine
Etravirine
NNRTI: Mechanism of Action
NNRTIs stop HIV from replicating within cells by inhibiting the reverse transcriptase protein

12. NNRTI: Efavirenz Given orally, once daily
Plasma half-life is about 50 hours
It is 99% bound to plasma albumin and its CSF concentration is ∼1% of that in the plasma
Inactivated in the liver
The unwanted effects are relatively mild and consist mainly of CNS symptoms
Skin rashes occur in about 25% of patients

13. NNRTI: Nevirapine Nevirapine is given orally
Bioavailability is >90%
CSF level is 45% of that in the plasma
Metabolized in the liver and metabolite is excreted in the urine
Can prevent mother-to-baby transmission of HIV if given to the parturient mother and the neonate
Rash occurs in about 17% of patients
More common adverse effects are headache, fever and lethargy

14. Drug Used to Treat HIV Infection
Main classes of anti-HIV drug:
Reverse transcriptase inhibitors
nucleoside reverse transcriptase inhibitors
non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Fusion inhibitors
Integrase inhibitors
Chemokine co-receptor inhibitors

15. Protease Inhibitors This class includes Saquinavir Nelfinavir
Indinavir
Ritonavir
Amprenavir
Atazanavir
Fosamprenavir

16. Protease Inhibitors
Mechanism of Actions: Protease inhibitors interrupt HIV replication at a later stage in its life cycle by interfering with an enzyme known as HIV protease.
Usually prescribed with other medications to help avoid drug resistance
Adverse Effects: Nausea, diarrhea and other GI problems
Interactions: Disturbances in glucose and lipid metabolism including diabetes, hypertriglyceridemia and hypercholesterolemia may occur

17. Fusion Inhibitors
Enfuvirtide is one of the drugs belongs to this group
Prevent HIV from binding to or entering human immune cells. For HIV to gain entry into the host cell, it must fuse its membrane with that of the host cell. This is accomplished by changes in the conformation of viral transmembrane glycoprotein gp41, which occurs when HIV binds to the host cell surface. Enfuvirtide binds to gp41 preventing the conformational change
Given subcoutenously
Adverse Effects: Most effects are related to injection including pain, erythema, induration and nodules
Erythema is a skin condition characterized by redness or rash
Induration - dermal thickening
nodule refers to a relatively hard, roughly spherical abnormal structure

18. Integrase Inhibitors
Raltegravir is one of the drugs belongs to this group
Integrase inhibitor interferes with the integrase enzyme, which HIV needs to insert its genetic material into human cells

19. Chemokine Co-receptor Inhibitors
Maraviroc is one of the drugs belongs to this group
It is the first drug that targets a human protein rather than components of the HIV virus itself
Maraviroc reduces viral load by preventing HIV from entering uninfected white blood cells. It does this by blocking CCR5, a major route of entry into the cells. CCR5 is a protein found on the surface of some immune cells, and maraviroc blocks the CCR5 co-receptor from accepting HIV 
Side effects may include liver and cardiovascular problems, as well as cough, fever, upper respiratory tract infections, rash and abdominal pain
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene

20. What Does Combination Therapy Usually Consist of?
Most common drug combination given to those beginning treatment consists of two NRTIs combined with either an NNRTI or a "boosted" protease inhibitor. Ritonavir (in small doses) is most commonly used as the booster
An example of a common antiretroviral combination is the two NRTIs zidovudine and lamivudine, combined with the NNRTI efavirenz.

21. Treatment Guidelines
Treatment should focus on achieving the maximum suppression of symptoms for as long as possible. This aggressive approach is known as highly active anti-retroviral therapy (HAART)
The aim of HAART is to reduce the amount of virus in the blood to very low or even non-detectable levels. This is usually accomplished with a combination of three or more drugs
But the treatment guidelines also emphasize the importance of quality of life. Thus the goal of AIDS treatment is to find the strongest possible regimen that is also simple and has the fewest side effects