HIV and TB coinfection


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Hiv and Tb coinfection- Management strategies and current momentum of clinical trials

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HIV and TB coinfection

  2. 2. INTRODUCTION <ul><li>AIDS (Acquired Immunodeficiency Syndrome) is a retroviral disease </li></ul><ul><li>Caused by the Human Immunodeficiency Virus (HIV) </li></ul><ul><li>Characterised by profound Immunosuppression </li></ul><ul><li>Opportunistic infections </li></ul><ul><li>Secondary neoplasms </li></ul><ul><li>Neurological manifestations </li></ul>
  3. 3. HISTORY OF AIDS <ul><li>AIDS , first reported in 1981 by CDC (Centre of Disease Control),US : </li></ul><ul><li>5 homosexual males displaying unusual infections: </li></ul><ul><li>Fungal pathogen ( Pneumocystis carinii ) which causes pneumonia, kaposis sarcoma (rare skin tumor), deficiency in cellular immune response and decreased no. of T cells carrying CD4 marker. </li></ul><ul><li>In early 1982 , CDC suggested the name AIDS to be given to disorder that results in decrease in CD4+ count </li></ul>
  4. 4. EPIDEMILOGY: GLOBAL CRISIS Over 38,000,000 people around the world are diagnosed with HIV. <ul><li>Top 5 countries: </li></ul><ul><li>South Africa – 5,700,000 </li></ul><ul><li>Nigeria – 2,600,000 </li></ul><ul><li>India – 2,400,000 </li></ul><ul><li>Kenya – 1,900,000 </li></ul><ul><li>Zimbabwe – 1,800,00 </li></ul>This graph shows how much people would be affected with HIV in 2010 . This graph shows the percentage of the causes of HIV.
  5. 5. HIV : WHAT IS IT? <ul><li>Human Immunodeficiency virus </li></ul><ul><li>In 1983 ,Causative agent of AIDS was discovered & characterized by group at Pasteur Ins. Of Paris-Luc Montagnier as a type of retrovirus isolated by lymph node biopsy of AIDS patient </li></ul><ul><li>In 1986 , retrovirus was first named </li></ul><ul><li>HIV </li></ul><ul><li>Scientist believe that HIV is the descendant of the Simian Immunodeficiency Virus (SIV) . SIV is a lent virus that is found in animals like monkeys. </li></ul>
  6. 6. <ul><li>HIV-1 and HIV-2 </li></ul><ul><li>HIV-1 global and HIV-2 discovered in </li></ul><ul><li>West Africa and found principally in </li></ul><ul><li>West Africa </li></ul><ul><li>HIV-2 more virulent , faster </li></ul><ul><li>progression and associated </li></ul><ul><li>with greater morbidity </li></ul>
  7. 7. ROUTES OF SPREAD <ul><li>Sexual Contact – 75% </li></ul><ul><li>Parental Inoculation – intravenous drug abusers and recipients of blood and blood products. </li></ul><ul><li>Passage of virus from Infected mothers to children through the placenta or through breast milk. </li></ul><ul><li>HIGH RISK GROUPS </li></ul><ul><li>Homosexuals/ Bisexuals </li></ul><ul><li>Intravenous drug users </li></ul><ul><li>Infants born to infected mothers </li></ul><ul><li>Blood & Blood component recipients (through Transfusion) </li></ul><ul><li>Hemophiliacs </li></ul>
  9. 9. PHASES OF HIV INFECTION <ul><li>Early, acute </li></ul><ul><li>Middle, chronic </li></ul><ul><li>Final, late </li></ul><ul><li>Group I : Acute Infection </li></ul><ul><li>lasts about 2 weeks </li></ul><ul><li>Fever, aches, and other flu-like symptoms </li></ul><ul><li>High levels of virus in the blood. </li></ul><ul><li>Group II: Asymptomatic Infection </li></ul><ul><li>Group III: Persistent generalised lymphadenopathy </li></ul><ul><li>Lasts for months or even years </li></ul><ul><li>Few symptoms </li></ul><ul><li>The patient's blood contains few viruses, but contains antibodies to the virus </li></ul><ul><li>Group IV: AIDS </li></ul><ul><li>A rapid decline in the number of CD4 + T cells. </li></ul><ul><li>The patients immunity is sufficiently weakened that opportunistic infections </li></ul><ul><li>viruses, e.g., Herpes simplex , Epstein-Barr virus (EBV ) </li></ul><ul><li>bacteria, e.g., Mycobacterium tuberculosis </li></ul><ul><li>fungi, e.g. Candida albicans </li></ul><ul><li>Opportunistic infections become more severe and cancer e.g, lymphoma , Kaposi's sarcoma )may develop. </li></ul>
  10. 10. SEROLOGIC PROFILE OF AIDS PATIENT <ul><li>BIOMARKERS </li></ul><ul><li>Presence of Anti HIV Antibodies </li></ul><ul><li>Decrease in number of CD4+ T cells </li></ul><ul><li>Presence of serum protein p24 by ELISA & RIA </li></ul><ul><li>Absent of delayed hypersensitive reactions </li></ul><ul><li>Occurrence of opportunistic infections </li></ul>
  11. 11. TREATMENT IN AIDS <ul><li>Nucleoside analogs: Reverse transcriptase inhibitors: </li></ul><ul><li>Zidovudine (Retovir,AZT), </li></ul><ul><li>Didanosine (Videx,ddI) </li></ul><ul><li>Lamivudine (Epivir, 3TC) </li></ul><ul><li>Statuvidine (d4t) </li></ul><ul><li>Nonnucleoside analogs: Reverse transcriptase inhibitors: </li></ul><ul><li>Nevirapine </li></ul><ul><li>Protease Inhibitors: </li></ul><ul><li>Indinavir </li></ul><ul><li>Combination therapy- HAART ) (highly active anti retroviral therapy) </li></ul><ul><li>2 nucleoside analog (AZT, ddI) + protease inhibitor (Retrovir) </li></ul><ul><li>Clinical trials vaccine has been found in monkeys but none yet available for human use. </li></ul>Prolongs survival but does not eliminate the virus Inhibits proviral DNA synthesis but does not eliminate the virus. Inhibits action of reverse transcriptase
  12. 12. PULMONARY TUBERCULOSIS <ul><ul><li>Deadly infectious disease caused by </li></ul></ul><ul><ul><li>Mycobacterium tuberculosis </li></ul></ul><ul><ul><li>First isolated in 1882 by a German physician </li></ul></ul><ul><ul><li>named &quot; Robert Koch &quot; who received the </li></ul></ul><ul><ul><li>Nobel Prize for this discovery </li></ul></ul><ul><ul><li>EPIDEMILOGY </li></ul></ul><ul><li>According to the World Health Organization (WHO), nearly 2 billion people—one third of the world's population—have been exposed to the tuberculosis pathogen. </li></ul><ul><li>Annually, 8 million people become ill with tuberculosis, and 2 million people die from the disease worldwide . </li></ul><ul><li>Tuberculosis is the world's greatest infectious killer of women of reproductive age and the leading cause of death among people with HIV/AIDS . </li></ul>
  13. 13. PATHOGENESIS Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to the alveoli Tubercle bacilli multiply in the alveoli A small number of tubercle bacilli enter the bloodstream and spread throughout the body. The bacilli may reach any part of the body, including areas where TB disease is more likely to develop (such as the lungs, kidneys, brain, or bone Macrophages form a hard shell & keeps bacilli under control
  14. 14. SYMPTOMS TB may be pulmonary or extra-pulmonary Pulmonary TB is most common form
  15. 15. DIAGNOSIS OF TB <ul><li>Injection of Protein: found in TB bacteria into the skin of an arm, skin reacts by swelling </li></ul><ul><li>X-ray </li></ul><ul><li>Sputum test </li></ul><ul><li>Bacteria: A culture of TB bacteria </li></ul>M. tuberculosis (stained red ) in sputum Abnormalities often seen in posterior segments of upper l obe
  16. 16. TREATMENT IN TB <ul><li>ethambutol is EMB or E, </li></ul><ul><li>isoniazid is INH or H, </li></ul><ul><li>pyrazinamide is PZA or Z, </li></ul><ul><li>rifampicin is RMP or R, </li></ul><ul><li>combination of antibiotics- Streptomycin is STM or S. </li></ul><ul><li>Surgery </li></ul><ul><li>DRUGS: </li></ul><ul><li>PREVENTIVE MEASURES : </li></ul><ul><li>Vaccine BCG </li></ul><ul><li>Covering of mouth by a mask </li></ul><ul><li>Exercise regularly to keep your immune system healthy </li></ul><ul><li>Get adequate amounts of sleep </li></ul><ul><li>Get tested regularly.. </li></ul><ul><li>Make sure you eat plenty of healthy foods </li></ul><ul><li>A drug called Isoniazid (INH) can be used as a preventative therapy for those who are at high risk of becoming infected with tuberculosis </li></ul>EHZRS
  17. 17. HIV AND TB(Interaction & Co-infection) <ul><li>HIV infection increases the likelihood that new infection with M . tuberculosis (due to immune suppression) will progress rapidly to TB disease. </li></ul><ul><li>Among HIV-infected individuals, lifetime risk of developing active TB is 50%, compared to 5-10% in persons who are not HIV-infected. </li></ul><ul><li>In a person infected with HIV, the presence of other infections, including TB, allows HIV to multiply more quickly. This may result in more rapid progression of HIV infection </li></ul>
  18. 18. DIAGNOSIS OF TB IN HIV AIDS <ul><li>Frequently negative sputum smears </li></ul><ul><li>Atypical radiographic findings </li></ul><ul><li>Resemblance to other opportunistic pulmonary infections like pneumonia </li></ul><ul><li>WHY is it difficult to diagnose TB in HIV infected patient </li></ul>Arrow points to cavity in patient's right upper lobe --typical finding in patient with TB
  19. 19. <ul><li>CT scan and magnetic resonance imaging (MRI) </li></ul><ul><li>Peripheral blood cultures </li></ul><ul><li>Molecular diagnostic techniques based on detection of M. tuberculosis specific DNA or ribosomal RNA sequences by polymerase chain reaction (PCR ) </li></ul>FURTHER DIAGNOSTIC TECHNIQUES IN HIV TB CO-INFECTION
  20. 20. TREATMENT OF HIV & TB <ul><li>HIV infected patients should be treated according to national guidelines and in cooperation with local authorities such as the district medical officer (DMO) and the district TB supervisor. </li></ul><ul><li>Treatment of TB always takes precedence over the treatment of HIV infection </li></ul><ul><li>Aims of treatment </li></ul><ul><ul><li>To cure the patient of TB </li></ul></ul><ul><ul><li>To prevent death from active TB or its late effects </li></ul></ul><ul><ul><li>To prevent TB relapse </li></ul></ul><ul><ul><li>To decrease TB transmission to others </li></ul></ul>
  21. 21. WHO Recommended TB treatment regimen <ul><li>Drug regimens </li></ul><ul><li>Initial phase - first 2-3 months </li></ul><ul><ul><li>During the initial phase, there is rapid killing of TB bacilli </li></ul></ul><ul><ul><li>Three or more drugs are used in combination </li></ul></ul><ul><ul><li>Infectious patients become non-infectious within about 2 weeks and symptoms usually improve </li></ul></ul><ul><ul><li>Continuation phase - additional 4-6 months </li></ul></ul><ul><ul><li>Fewer drugs are necessary (usually 2), but longer time </li></ul></ul><ul><ul><li>These drugs eliminate the remaining bacilli </li></ul></ul><ul><ul><li>Directly Observed Treatment Strategy (DOTS) </li></ul></ul><ul><ul><li>DOTS is a strategy for TB control which aims to detect 70 percent of active TB cases and to successfully treat 85 percent of them </li></ul></ul><ul><ul><li>Monitoring during treatment-- way to ensure patient adherence where a trained supervisor watches the patient swallow the drugs </li></ul></ul>
  22. 22. WHO Recommended TB treatment regimen <ul><li>Some Authorities recommend 7 month continuation phase with daily isoniazid and rifampicin (7HR) for patients with various forms of disease: TB meningitis, spinal TB with neurological signs </li></ul><ul><li>2 HRZE / 6 HE : This is a common regimen - initial phase - 2 months with isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E). continuation phase is 6 HE isoniazid (H) and ethambutol (E) </li></ul><ul><li>4 H 3 R 3 : 4 months-3 times a week- Initial phase is 2 H 3 R 3 Z 3 E 3 The continuation phase is 4 H 3 R 3 </li></ul>
  23. 23. Antiretroviral Therapy for Individuals with Tuberculosis Co infection <ul><li>WHO Recommendations for ARV Therapy </li></ul><ul><ul><li>WHO recommends that people with TB/HIV complete their TB therapy prior to beginning ARV treatment unless there is high risk of HIV disease progression and death during the period of TB treatment. </li></ul></ul><ul><ul><li>In cases where a person needs TB and HIV treatment concurrently, first line treatment options include ZDV/3TC or d4T/3TC+Niverapine </li></ul></ul>ZDV: Zidovidine 3TC: Lamivudine d4t: Stavudine
  24. 24. HIV-TB CO-INFECTION Clinical trials: Where’s the momentum? <ul><li>Which HAART regimen? </li></ul><ul><li>2 NRTIs + 1 PI ? </li></ul><ul><li>2 NRTIs + 1 NNRTI? </li></ul><ul><li>3 NRTIs? </li></ul><ul><li>Nevirapin 400 or 600 mg? </li></ul><ul><li>Nevirapin or efavirenz? </li></ul><ul><li>When to start HAART? </li></ul>
  25. 25. NVP 400/600 STUDY <ul><li>A 48 week, randomized, open-label, 2 arm study to compare the efficacy, safety and tolerability of HAART containing nevirapine 400mg/day vs. nevirapine 600 mg/day in HIV-1 infected patients started at 2-6 weeks after initiating rifampin containing antiTB therapy: NCT 00476853, Thailand . </li></ul><ul><li>CD4 < 200. Proven TB. </li></ul><ul><li>Primary outcome: HIV-1 RNA quantification in plasma at W 48. </li></ul><ul><ul><li>Started in October 2005. </li></ul></ul><ul><ul><li>Target n= 100. </li></ul></ul><ul><ul><li>Date of completion: October 2008. </li></ul></ul>
  26. 26. NVP/EFZ INDIAN STUDY <ul><ul><li>Safety and efficacy of 2 once daily anti retroviral treatment regimens along with anti-TB treatment: NCT 00332306, India . </li></ul></ul><ul><ul><li>CD4 < 250 </li></ul></ul><ul><ul><li>HAART begun at the end of intensive phase of anti-TB Rx (2EHRZ3/4RH3). ddI + 3TC + NVP vs. ddI + 3TC + EFZ . </li></ul></ul><ul><ul><li>Primary outcome: suppression of VL to < 400 copies/ml at the end of 6 months and a VL<400 copies/ml at 24 months of HAART. </li></ul></ul><ul><ul><li>Started in June 2006. </li></ul></ul><ul><ul><li>Target n= 180. </li></ul></ul><ul><ul><li>Date of completion: December 2009. </li></ul></ul>
  27. 27. TB-HAART STUDY <ul><li>An evaluation of the impact of early initiation of HAART on TB treatment outcomes for TB patients coinfected with HIV: ISRCTN77861053, Uganda, Zambia, South Africa and Tanzania . 220 < CD4 < 500 . </li></ul><ul><li>Study hypothesis: early concomitant treatment with TB and HIV medications may improve TB outcomes and improve survival. </li></ul><ul><li>Primary outcome: proportion of subjects reaching the composite endpoint of treatment failure or death at 6 months after the initiation of short-course chemotherapy for TB. </li></ul><ul><li>Combined HAART with anti-TB vs. delay HAART at 6 months. </li></ul><ul><ul><li>Started in March 2007. </li></ul></ul><ul><ul><li>Target n= 1900. Actual enrollment: 33. </li></ul></ul><ul><ul><li>Date of completion: 2011. </li></ul></ul>AZT + 3TC + efavirenz
  28. 28. CONCLUSION However, still some gaps are remaining ???
  29. 29. REFERENCES <ul><ul><li>Kindt T J, Goldsby R A, Osborne B A: Immunology, Pg No. 525-544 </li></ul></ul><ul><li>http// </li></ul><ul><li>http// </li></ul><ul><li> › ... › Clin Microbiol Rev › v.16(3); Jul 2003 </li></ul><ul><li> › ... › TB/HIV </li></ul><ul><li> </li></ul><ul><li> </li></ul><ul><li> </li></ul>
  30. 30. QUESTIONS??