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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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