Recent advances in HIV / AIDS.
Toufiq Shaikh
10/31/2009
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Index.
• • • • • • • • • • • • •
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Overview. Epidemiology. HIV structure. Mode of transmission. Pathogenesis. Disease progression. Recent discoveries. Advances in diagnosis. Advances in treatment. Prevention. Palliative care. Conclusion. References
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HIV / AIDS overview.
• AIDS is a collection of about 29 diseases caused by the immunosuppression of the body by HIV infection. • HIV belongs to the lentivirus family alongwith (SIV), (BIV), (FIV), etc. • HIV was co-discovered by Dr.Robert Gallo & Luc Montagnier & thus, AIDS was recognised on 5 June 1981 (WHO).
• There are two main types of HIV viruses:HIV 1 HIV 2
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Epidemiology.
+ 1 300% + 20% + 20% + 100% + 160% + 60%
+ 40% + 30%
+ 20%
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HIV structure.
• HIV is a spherical, retrovirus infecting human CD4+ T cells.
• It has GP 160 envelope and two surface proteins ; GP 120 GP 41 • Enclosed within the virion capsid proteins are the :-Two single stranded RNAs & three core enzymes namely; Reverse transcriptase Integrase Protease
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Modes of transmission.
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Pathogenesis.
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Disease progression.
• It progresses as the following stages:-
1. Stage I: HIV infection is asymptomatic and not categorized as AIDS 2. Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections 3. Stage III: includes unexplained chronic diarrhoea for longer than a month, severe bacterial infections and pulmonary tuberculosis 4. Stage IV: includes toxoplamosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi’s sarcoma; these diseases are indicators of AIDS, AIDS dementia complex. CD4+ T cell count falls to less than 200 / uL of blood.
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Opportunistic infections.
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Malignancies.
• Kaposi’s sarcoma. • Non-hodgkins lymphoma. • Cervical & anal cancer.
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Recent discoveries.
• Integrin alpha 4 beta 7 co-receptor discovered to be associated with HIV infection. • Relationship discovered by Dr. Anthony S. Fauci et.al on Feb 10, 2008 ( NIAID ).
• Principal receptor:CD 4 +
Co-receptors:1. CCR5 2. CXCR4
• Potential for drug development & use,.one drug candidate is Tysabri ( natalizumab ) which was used for MS.
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Diagnosis.
• The window period is the time from infection until a test can detect any change.
• Avg. window period with :1. Antibody test = 22 days to 6 months. 2. Antigen test = 16 days. 3. Nucleic acid tests = 8 to 12 days. • Traditional diagnostic tests:1. ELISA test. 2. Western blot test. • Newer diagnostic tests:1. P24 antigen tests. 2. RT-PCR test. 3. Quantiplex b-DNA test.
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4. NASBA HIV-1 RNA test. 5. AMPLICOR–HIV monitor.
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Traditional Diagnostic tests.
• ELISA test:- It involves detection of antibodies formed against HIV. The presence of HIV is indicated by an enzyme catalyzed colour reaction.
•
Western blot test:- It is similar in process in detection of antibodies formed against HIV proteins but is more accurate.
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Newer diagnostic tests.
• P 24 antigen test:- It involves use of monoclonal antibodies directed towards p 24 HIV proteins. The enzyme-linked to the antibody gives colour change if P 24 is present.
• RT-PCR test / NASBA HIV test / Quantiplex b-DNA test / AMPLICOR HIV test:This are RNA assays. Conversion of RNA to DNA with the help of RT. PCR technique used for amplification. Specific oligonucleotides are used to detect viral DNA. Then the enzyme-linked gives colour change if the viral DNA is present.
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Treatment.
• Conventional drug therapy. • Combination therapy. • Investigational drugs. • Vaccine development. • Herbal medicines.
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Conventional drug therapy.
• Anti-HIV drugs target the HIV replication process. Following are the classes of anti-HIV drugs:1. Entry & fusion inhibitors. 2. NNRTIs.
3. NRTIs.
4. Integrase inhibitors.
5. Protease inhibitors.
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Entry & fusion inhibitors.
• MOA:- This drugs act by preventing the entry of HIV virus into the cells by blocking the formation receptor-glycoprotein complex. 1. Enfuvirtide (Fuzeon). 2. Maraviroc (Selzentry).
• Possible side effects:Severe allergic reactions, paralysis, flu-like illness, bladder irritation, decrease in blood pressure.
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Non-nucleoside reverse transcriptase inhibitors.
• MOA:- This drugs act by blocking reverse transcriptase enzyme directly & prevent HIV replication. 1. Defavirdine (Rescriptor). 2. Efavirenz (Sustiva). 3. Etravirine (TMC-125, Intellence). 4. Nevirapine (Viramune). • Possible side effects:Rash, blisters, joint or muscle pain, anaemia, hallucinations.
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Nucleoside reverse transcriptase inhibitors.
• MOA:- This drugs are nucleoside analogues which block the activity of reverse transcriptase enzyme by mimicking nucleosides. 1. Zidovudine (Retrovir) 4. Lamivudine (Epivir). 2. Didanosine. 5. Stavudine (Zerit). 3. Emtricitabine (Emtriva). 6. Abacavir. 7. Tenofovir disoproxil fumarate (Viread).
• Possible side effects:Allergic reactions, loss of appetite, trouble sleeping, tingling, burning, numbness, abdominal pain.
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Integrase inhibitors.
• MOA:- This drugs work by blocking integrase, an enzyme which HIV needs to insert its viral genetic material into that of the host cell.
1. Raltegavir. (First integrase inhibitor).
• Possible side effects:Diarrhoea, nausea, headache & fever.
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Protease inhibitors.
• MOA:- This drugs work by blocking protease enzyme which breaks down complex proteins into smaller proteins, which form the viral capsid. 1. Nelfinavir. 2. Ritonavir. 3. Indinavir. 4. Tipranavir.
• Possible side effects:Skin rashes, inflammation of the pancreas, onset or worsening of Diabetes, symptoms of kidney stones.
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Combination therapy.
• Combination of drugs is more effective in reducing HIV count. There is reduced risk of development of drug resistance as compared to monotherapy. • HAART:- 2 NRTIs or 2 NNRTIs + 1 Protease inhibitor. 1. Combivir ( Lamivudine + Zidovudine ) 2. Epzicom ( Abacavir + Lamivudine ) 3. Truvada ( Emtricitabine + Tenofovir DF ) 4. Atripla ( Efavirenz + Emtricitabine + Tenofovir DF ) 5. Trizivir ( Abacavir + Lamivudine + Zidovudine )
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Investigational drugs.
Investigational drugs
Entry & fusion inhibitors
AMD 070 PRO 140 TNX 355 Vicriviroc maleate Integrase inhibitors Phase I Phase I Phase II Phase III Genzyme Corporation. Progenics Pharma Inc. Tanox Inc. Schering-Plough Corp.
Phase of clinical trial
Sponsor company / Laboratory
GS 9137
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Phase II
Gilead Sciences Inc.
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Contd…
Investigational drugs
NNRTIs TMC 278 NRTIs Apricitabine Elvucitabine Racivir KP - 1461 Phase II / Phase III Phase II Phase I Phase II Avexa Ltd. Achillion Pharmaceuticals Pharmasset, Inc. Koronis Pharmaceuticals Phase II Tibotec
Phase of clinical trial
Sponsor company / Laboratory
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Contd…
Investigational drugs
Other drugs Bevirimat Ampligen Phase II Phase II Panacos Pharmaceuticals Hemispherx Biopharma Inc.
Phase of clinical trial
Sponsor company / Laboratory
Valproic acid
Microbicides C – 31G PRO - 2000
Phase II
Abbott Laboratories.
Phase III Phase III
Cellegy Pharmaceuticals Inc. Indevus Pharmaceuticals Inc.
UC - 781
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Phase I
Cellegy Pharmaceuticals Inc.
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KP – 1461
Normal replication:HIV RNA RT HIV DNA Normal base pairing, A to T, G to C Normal HIV virus produced after replication.
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Replication with KP – 1461:HIV RNA RT KP - 1461
HIV DNA Mismatched base pairing, A to KP - 1461 Lethal mutation in the HIV genome takes place.
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Vaccine development.
• HIV vaccines are categorized as:1. Preventive HIV vaccine. 2. Therapeutic HIV vaccine.
Vaccine
Preventive vaccine SCBal/M9 Therapeutic vaccine AS02A vaccine LC002 vaccine
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Phase of clinical trial
Phase I
Sponsor company / laboratory
NIAID
Phase I Phase I / Phase II
Glaxosmithkline NIAID
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Herbal medicines.
• Clinical trials are going on at M.A Poddar hospital of an Arjuna based immuno-booster drug, which helps in controlling the fall in CD4+ T cell count.
• Chinese immune tea called “revivo” is known to improve immune functions in HIV + patients.
• The extracts of this tea is developed into i – drops which has a base of honey to increase the absorption of the ingredients.
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Some drugs used for opportunistic infections.
1. Acyclovir
2. Amphotericin B 3. Azithromycin 4. Clarithromycin 5. Dronabinol 6. Doxorubicin
7. Fluconazole
8. Isoniazid 9. Rifampin 10. Ganciclovir 11. Itraconazole 12. Paclitaxel
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Prevention.
• Safe sex by use of condoms.
• Abstaining from risky sexual behaviour.
• Preventing unwanted pregnancies in case of HIV+ mothers. • Use of well sterilized needles & syringes. • Testing of blood / blood products for HIV before transfusion.
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Post exposure prophylaxis.
• It basically means disease prevention after exposure to the HIV virus by administering anti-retroviral drugs within 72 hrs. • Advantages:It is helpful in reducing HIV infection due to:1. Occupational hazards such as in health care workers (needle stick). 2. Unprotected sex. 3. Ingestion of infected breast milk by the neonate, etc.
• It helps in decreasing the likelihood of HIV infection from the exposure.
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Contd…
• PEP involves either 2 drug or 3 drug therapy followed for a 4 weeks course.
• Two drug combinations:Zidovudine + Lamivudine. • Three drug combinations:Trizivir Disadvantages:1. Adherence issues. 2. Problems of resistances. 3. Side effects.
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Palliative care for HIV / AIDS.
• AIDS is now a chronic manageable illness with the help of anti-retroviral therapy. • Palliative care for HIV is supportive, symptom oriented care. It is needed throughout the disease progression.
• It involves following aspects:1. Management of pain, fatigue, etc. 2. Treatment of adverse effects (nausea, vomiting, etc.). 3. Psychosocial support (depression, advance care planning). 4. End of life care.
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• Drug therapy is used for treatment of symptoms of opportunistic infections, malignancies. • Advance care planning:1. Advance directive. 2. Health care proxy.
• Hospices for HIV / AIDS patients:1. Shanti Avedna Ashram, Mumbai, India 2. SHALOM, Churachandpur, Manipur, India. 3. Sarvashubhamkara, Kalimpong District, Darjeeling, India. 4. Karunashraya Hospice, Bangalore, India.
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Myths about HIV / AIDS.
• HIV is same as AIDS.
• HIV is transmitted through mosquitoes. • HIV / AIDS has a cure. • We both have HIV….we don’t need a condom. • AIDS is a disease.
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Conclusion.
HIV / AIDS is a dangerous pandemic, without a cure. Novel drugs such as KP – 1461 can eradicate HIV & cause its extinction. In the near future it will be possible to live a long & healthy life with HIV. The challenge of mutation & recombination of HIV still remains unsolved. Vaccines undergoing clinical trials are promising but, for now, prevention is the best cure for HIV / AIDS.
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References.
Books referred:1. 16th, Principles of internal medicine – Harrison’s, pg no.1088-1100. 2. 20th, Principles & practice of medicine – Davidson’s, pg no. 397-401. 3. 7th, Pathologic basis of disease – Robbins & Cotrans, pg no. 245-258.
Websites referred:1. www.aidsinfo.nih.gov 2. www.clinicaltrials.gov 3. www.medline.com 4. www.thebody.com 5. www.clinicaltrials.ifpma.org
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