AIDS

Aquired immuno deficiency syndrome

1. ACUIRED IMMUNO DEFICIENCY SYNDROME (AIDS)

2. Introduction AIDS stands for ACQUIRED IMMUNO DEFICIENCY SYNDROME . It is a disease caused by the retrovirus HUMAN IMMUNO DEFICIENCY VIRUS (HIV) and characterized by immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations.

3. ETIOLOGY AIDS is caused by HIV, belongs to family of RNA viruses known as retro viruses. These are differ from other RNA viruses , in that they must replicate through a DNA intermediate. Two genetically different but related forms of HIV called HIV-1 and HIV -2. HIV -1 is most common type in USA ,Europe and central Africa . HIV -2 in west A frica and India.

4. STRUCTURE OF HIV Similar to most retro viruses , the HIV-1 virus is spherical and contains cone shaped core surrounded by lipid envelop derived from the host cell membrane. The virus core contains : 1) The major capsid protein P24. 2) Nucleo capsid protein P7/P9. 3) Two copies of genomic RNA. 4) Three viral enzymes; a) Protease b)Reverse transcriptase c) Integrase .

5. STRUCTURE OF HIV P24 is the most readily detected viral antigen and is the target for antibodies that are used for diagnosis of HIV infection. The viral core is surrounded by a matrix protein called P17, which lies underneath the viral envelop . The viral envelop consist of 2 viral glycoprotein gp120 and gp41, which are critical for HIV infection of cells.

6. PATHOGENESIS OF HIV INFECTION OR AIDS HIV can infect many tissues . There are 2 major targets of HIV infection : 1) The immune system. 2) Central nervous system. HIV possesses the enzyme reverse transcriptase and consist of lipid bilayer membrane surrounding the capsid. It’s surface glycoprotein molecule has strong affinity for CD4 receptor protein found in helper –T cells.

7. Conti ….. HIV enters the body and attaches to CD4 receptors and co-receptors such as CCR-5 or CXCR-4 and membrane fusion also occur. After penetrating the host cell , virus sheds its outer coat and release its genetic material and 3 replication enzymes .they are Integrace Reverse transcriptase Protease.

8. Conti …… Using reverse transcriptase enzyme, the viral RNA is converted into DNA. The viral DNA is then integrated into the host genome in the cell nucleus. When it undergoes transcription and translation , enabling the production of new viral protein. New virus particles are then assembled and matures into infectious virions under the influence of protease enzyme.

9. TRANSMISSION OF HIV 1) Unprotected intercourse : HIV can be found in semen and cervical secretions . 2) parenteral transmission : Through contaminated blood exposure, i.e shared drug injection needles . 3) child birth : Through blood , amniotic fluid and vaginal fluid s. 4) contaminated blood and blood product : Receipt of blood products ,organ transplantation 5) breast feeding : breast milk

10. SIGNS AND SYMPTOMS OF AIDS Flu like symptoms Lack of energy Frequent fever and sweat Persistant skin rashes Short term memory loss Difficult or painful swallowing Cough or shortness of breath.

11. DRUG TREATMENT The drug treatment of HIV disease can be classified as : 1)Management of opportunistic infections. 2)Antiretroviral therapy. 3)Symptom control.

12. MANAGEMENT OF OPPORTUNISTIC INFECTIONS Some of the most common AIDS opportunistic infections are : Meningitis Encephalitis Pneumonia and Tuberculosis Chronic diarrhea Kapoisis sarcoma and non hodkin lymphoma.

13. Conti ….. The general principles for management of opportunistic infections include prospective immunologic monitoring ,primary prophylaxis , treatment and secondary prophylaxis. The treatment of many opportunistic complications of HIV includes high dose therapy followed by maintenance or secondary prophylaxis using lower doses. Primary prophylaxis may be offered to those who are deemed to be at high risk of developing a particular opportunistic infection.

14. Example: Pneumonia prophylaxis Aproximately 15-30 % of HIV infected people develop pneumonia caused by opportunistic fungus Pneumocystis carinii . Treatment of pneumonia with agents such as Cotrimoxazole ( Trimethoprim+sulphamethoxazole ) is associated with 60-100% response rate. Example: Meningitis Amphotericin B is effective for treatment of cryptococcal meningitis, because of its lower rate of early death and disease progression. Patients with meningitis should receive amphotericin B in an i.v dose of atleast 0.5 mg/kg/day for min of 2 weeks.

15. ANTIRETROVIRAL THERAPY The goal of antiretroviral therapy of HIV related diseases are : Arrest of replication of HIV invivo . R econstitution of immunologic system damaged by the retrovirus. A combination of of drugs is used in AIDS to improve prognosis known as “HAART” i.e highly active antiretroviral therapy. HAART regimen includes 2 NRTI with either NNTRTI or PIs. Using a HAART regimen supresses HIV replication and plasma HIV RNA levels are greatly reduced and prolongs patients survival.

16. CLASSIFICATION OF ANTIRETROVIRAL THERAPY A) Nucleoside and Nucleotide Reverse Transcriptase inhibitors (NRTIs) Eg : Zidovudine , Stavudine , Lamivudine , Abacavir , Tenofovir . B) Non-nucleoside Reverse transcriptase inhibitors (NNRTIs) : Eg : Nevirapine , Delavirdine , Etravirine . C) Protease inhibitors : Eg : Saquinavir , Indinavir , Ritonavir, Amprenavir , Darunavir D) Entry inhibitors : Eg : Enfuvirtide,maraviroc E) Integrase inhibitors : Eg : Raltegravir

17. 1. NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS(NRTIs) Eg : Zidovudine (AZT), Stavudine,Abacavir,Lamivudine . It is the first drug to be used in the treatment of HIV infection. Mechanism of action : Zidovudine Zidovudine -triphosphate Binds reverse transcriptase(RNA-dependent DNA polymerase) Incorporate into viral DNA Premature chain termination

18. Adverse effects Bone marrow supression , myelosuppression , anaemia ,head ache,anorexia,myalgia,fatigue,insomnia , myopathy and neurotoxicity. Uses AZT is the drug of choice in AIDS and decreases opportunistic infections Weight gain It decreases disease progression During pregnancy.

19. Drug interactions of NRT inhibitors a)Combination with other Myelosuppressants . b)combination with S tavudine decreases the efficacy. c)combination with zalcitabine and didanosine cause overlapping toxicity. d)combination of zalcitabine and lamivudine may antagonise each other. e)alcohol increases plasma level of abacavir . DOSE : Zidovudine :-200 mg bid. Stavudine :-20-40 mg bid Abacavir :-300 mg bid

20. 2. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS(NNRTIs) Eg:Nevirapine , Delavirdine , Etravirine Mechanism of action : similar to NRTIs. But are not converted to Triphosphate derivatives. NNTRTIs are effective only against HIV-1. Adverse effects GI disturbances , allergic reactions such as skin rashes,nausia,headach,sedation,fattigue,diarrhoea , abdominal pain drowsiness.

21. Uses Treatment of HIV-1 infections Used in labour and in new born to prevent transmission of HIV. Drug interactions Nevirapine is a microsomal enzyme inducer. Failure of oral contraceptives. Delavirdine is microsomal enzyme inhibitor.it also increases plasma level of PIs. DOSE : Nevirapine :-200 mg/kg – onset of action.

22. 3. PROTEASE INHIBITORS (PIs) Eg : Saquinavir , Indinavir , Darunavir,Amprenavir . Mechanism of action HIV protease activity is essential for the activation of viral enzyme and HIV replication. And also for the production of mature virion and for viral infectivity. PIs binds to HIV protease and block viral maturation . This makes daughter viral particles immature and noninfectious. Adverse effects : Nausia,vomiting,diarrhoea,increase serum cholesterol and bilirubin, dry skin,renal stones.

23. uses Treatment of HIV infections. Ritonavir inhibits microsomal enzymes- prolongs plasma half life of other PIs –permits the use of lower doses of other PIs. Drug interactions : a) Metabolised by microsomal enzymes.and inhibits these enzymes.so drug interactions are common. b) inreases the level of corticosteroids. c) H2 antagonists and proton pump inhibitors decreases the level of PIs. DOSE :Saquinavir :-120 mg tid . Ritonavir: 600mg bid.

24. 4. ENTRY INHIBITORS Entry of the virus into the host cell can be blocked by: a)Fusion inhibitors b)CCR5 receptor antagonist

25. a) FUSION INHIBITOR(FI) Eg : Enfuvirtide Mechanism of action It binds to the glycoprotien (gp41) subunit of viral envelope on the virus and inhibits the binding of the virus to the host cell membrane- block the entry of the virus into the cell.Thus FIs prevents transmission of HIV. DOSE: 90mg s.c twice daily Adverse effect :local reaction at injection site,skin rash,pneumonia like manifestation

26. b) CCR5 RECEPTOR ANTAGONIST Eg : Maraviroc Mechanism of action : CCR5 is a co-receptor involved in fusion and entry of virus into CD4 cells. Maraviroc binds to CCR5 receptors and blocks the entry of HIV into the cells. Adverse effects: Nausia,vomiting ,abdominal pain,constipation,dizziness,rash,insomnia,postural hypotension,cough . DOSE :300 mg bid.

27. 5. INTEGRASE INHIBITORS Eg : Raltegravir , elvitegravir Mechanism of action : Integrase is a viral enzyme necessory for viral replication in both HIV-1 and HIV-2 viruses. Integrase inhibitors binds to integrase and prevents integration of HIV-DNA into the chromosome of host cells. Adverse effects : Nausia,headach,dizziness,vertigo,abdominal pain,constipation,fatigue,raised creatinine kinase.

28. PREVENSION OF AIDS Know your and your partnerts HIV status by getting tested regularly. Avoid ingectable illegal drugs Avoid sharing drug needles Avoid intoxication from drugs or alcohol Taking medicines during pregnancy.

29. REFERENCES Clinical pharmacy and therapeutics by ROGER WALKER AND CATE WHITTLESEA. Essentials of medical pharmacology by KD TRIPATHI Medical pharmacology by PADMAJA UDAYKUMAR Pharmacological basis of therapeutics by GOODMAN and GILMAN’S . Clinical pharmacy and therapeutics by HERFINDAL GOURLEY HART . Avery’s drug treatment by SPEIGHT HOLFORD.

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