Treating the Dually Infected Patient Tb 10 1
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This document discusses treating patients with both tuberculosis (TB) and HIV/AIDS. It notes that TB and HIV infections often occur together, with Botswana's co-infection rate being 84%. HIV increases the risk and progression of TB by weakening the immune system. Integrating TB and HIV care and treatment is important. All HIV-positive TB patients qualify for antiretroviral therapy (ART), though the timing of starting ART during TB treatment depends on CD4 count. Adherence to TB treatment and use of cotrimoxazole preventive therapy can improve outcomes for co-infected patients.
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Treating the Dually Infected Patient Tb 10 1
- 1. Unit 10: Treating the DuallyUnit 10: Treating the Dually Infected PatientInfected Patient Botswana National Tuberculosis Programme Manual Training for Medical Officers
- 2. Slide 10-2Unit 10: Treating the Dually Infected Patient ObjectivesObjectives At the end of this unit, participants will be able to: • Explain the relationship between TB and HIV • Describe the effects of immune suppression on TB progression • Describe the ways in which TB and HIV care can be integrated • Identify and address challenges to integrating TB and HIV care • Describe the additional treatments for all TB/HIV patients • Manage ART in a patient on TB therapy
- 3. Slide 10-3Unit 10: Treating the Dually Infected Patient • HIV/AIDS is the #1 infectious killer in the world—TB is #2 • Many people have both infections • Botswana TB/HIV co-infection rate is 84%* HIVHIV TBTB HIV & TBHIV & TB *Source: BNTP, 2007. Source: WHO, 2006. A Deadly Infectious DiseaseA Deadly Infectious Disease
- 4. Slide 10-4Unit 10: Treating the Dually Infected Patient The TB/HIV Relationship (1)The TB/HIV Relationship (1) • TB increases HIV progression • Dually infected and untreated persons often have very high HIV viral loads • Immunosuppression progresses more quickly, and survival may be shorter despite successful treatment of TB • Persons who were co-infected have a shorter survival period than persons with HIV who never had TB disease
- 5. Slide 10-5Unit 10: Treating the Dually Infected Patient The TB/HIV Relationship (2)The TB/HIV Relationship (2) • Screen all HIV-infected patients for TB • Conduct a complete history as well as a physical examination • Screen all patients for TB who present in other situations where there is a high burden of HIV, such as medical wards, VCT centres and PMTCT facilities
- 6. Slide 10-6Unit 10: Treating the Dually Infected Patient Immune SuppressionImmune Suppression and TB Progressionand TB Progression • HIV-positive person is more likely to progress to TB disease following infection • HIV-positive person has a greater risk of reactivation • HIV-positive person has a high risk of relapse or reinfection after treatment • HIV-positive person has a 10% annual risk of developing active TB (versus 10% lifetime risk among HIV negative individuals) Source: WHO, 2004
- 7. Slide 10-7Unit 10: Treating the Dually Infected Patient Natural History of TBNatural History of TB New TBNew TB InfectionInfection LatentLatent TB InfectionTB Infection PrimaryPrimary ProgressiveProgressive TB diseaseTB disease (children,(children, rare adults,rare adults, HIV+)HIV+) ~~ 10%10% reactivatereactivate eacheach yearyear ~~ 5%5% reactivatereactivate afterafter 2 years2 years till deathtill death ~~5 %5 % reactivatereactivate InIn 1-2 years1-2 years HIV +HIV + HIV -HIV -
- 8. Slide 10-8Unit 10: Treating the Dually Infected Patient 0 2 4 6 8 10 12 14 16 HIV-positive HIV negative Deathwithin6monthsofTBdiagnosis(%) Mortality from TBMortality from TB Before Era of ARTBefore Era of ART Murray J et al, Am J Respir Crit Care Med, 1999.
- 9. Slide 10-9Unit 10: Treating the Dually Infected Patient Pattern of TB and SurvivalPattern of TB and Survival of Patients with HIV-related TBof Patients with HIV-related TB Whalen C, et al. AIDS, 1997. PTB EPTB Both Days from diagnosis of TB
- 10. Slide 10-10Unit 10: Treating the Dually Infected Patient Screening for HIV in TB PatientsScreening for HIV in TB Patients • Purpose • Identify TB suspects and patients who are also HIV positive • All TB patients with HIV are eligible for ART, it’s just a matter of timing of ART initiation • Method • At every health care encounter with TB patient: • Counsel on HIV prevention strategies • Offer Routine HIV testing if testing not previously done • CD4 count should be obtained on any HIV positive individual
- 11. Slide 10-11Unit 10: Treating the Dually Infected Patient Screening for TB at HIV ClinicsScreening for TB at HIV Clinics • Purpose • Identify HIV-positive persons eligible for IPT • Identify HIV-positive persons who may have active TB • Method • At each health care encounter, ask about: • History of TB and prior treatment for TB • Current IPT or history of IPT • TB signs and symptoms
- 12. Slide 10-12Unit 10: Treating the Dually Infected Patient Early Diagnosis: Better OutcomesEarly Diagnosis: Better Outcomes • Decrease in mortality for treated patients • Decrease in period of transmission to others especially family members who may be HIV infected • Decrease in transmission in the community • Identification of at-risk contacts in a timely manner
- 13. Slide 10-13Unit 10: Treating the Dually Infected Patient TB and HIV Care StrategiesTB and HIV Care Strategies Persons with TB • Rapid diagnosis and initiation of TB treatment • Test all TB patients for HIV • Maximise treatment completion rates • Offer cotrimoxazole preventive therapy to HIV+ in TB system • Assess HIV+ for ART eligibility and refer HIV-positive Persons • Screen for active TB at every health system encounter • Rapid TB diagnosis and initiation of TB treatment • Reduce TB incidence with IPT • Reduce TB incidence with effective ART • Minimise exposures to active TB cases
- 14. Slide 10-14Unit 10: Treating the Dually Infected Patient TB and HIV Treatment StrategiesTB and HIV Treatment Strategies TB Care and Treatment • Individual • Control their disease • Restore health and ADL* • Preserve their position in family and community • Community • Decrease the spread of TB infection • Mitigate against TB stigma from society • Enforce prevention HIV Care and Treatment • Individual • Control their disease • Restore health and ADL* • Preserve their position in family and community • Community • Decrease the spread of HIV infection • Mitigate against HIV stigma from society • Enforce prevention
- 15. Slide 10-15Unit 10: Treating the Dually Infected Patient Challenges to IntegrationChallenges to Integration What do you think are the challenges to integrating the two services? What strategies can you suggest to address these potential challenges?
- 16. Slide 10-16Unit 10: Treating the Dually Infected Patient Treating a Person with HIV and TBTreating a Person with HIV and TB • Common scenario in Botswana • TB case definitions are the same regardless of HIV status • TB treatment is the priority • Clinician should decide the optimal timing for initiation of ART during TB treatment guided by National policy
- 17. Slide 10-17Unit 10: Treating the Dually Infected Patient When to Start ARTWhen to Start ART During TB TherapyDuring TB Therapy • All HIV-infected TB patients qualify for ART • CD4<100 should start ART within one to two weeks after start of ATT • CD4 100 – 200 should start ART within two to four weeks after start of ATT • CD4s>200 may defer ART until end of ATT • HIV-infected patients already on ART who develop TB should begin anti-TB meds immediately • Management of TB patients on ART is complex and patient care needs to be coordinated with IDCC
- 18. Slide 10-18Unit 10: Treating the Dually Infected Patient ART in the BotswanaART in the Botswana National ProgrammeNational Programme Special Order: ABC (Abacavir), TDF (Tenofovir) NRTIs NNRTIs PIs AZT (Zidovudine) 3TC (Lamivudine) d4T (Stavudine) ddI (Didanosine) (AZT+3TC) (Combivir) EFV (Efavirenz) NVP (Nevirapine) LPV/r (Kaletra or Alluvia) RTV (Ritonavir) SQV (Saquinavir)
- 19. Slide 10-19Unit 10: Treating the Dually Infected Patient TB Disease ProgressionTB Disease Progression with HIV Co-infectionwith HIV Co-infection Source: de Jong BC et al, Annu Rev Med, 2004. • TB progresses more rapidly with HIV co-infection • Up to 10% of co-infected individuals develop active tuberculosis each year • 10%–20% lifetime risk among those without HIV infection • ART alone can reduce the risk of progression to active tuberculosis in latently infected individuals by as much as 80%–92% • Patients on or about to start ART should still be offered IPT if they meet the criteria
- 20. Slide 10-20Unit 10: Treating the Dually Infected Patient Years of enrollment Baseline CD4 cell count Use of ART during TB treatment Death within 1 year of start of TB therapy Death or new OI within 1 year of start of TB therapy TBTC 23 ARV 1999-2002 90 80% 4.5% 15.7% CPCRA/ACTG No ARV 1993-1995 85 0% 20% 38.9% HIV Disease Progression onHIV Disease Progression on TB Treatment, ARTTB Treatment, ART Source: Burman et al, CROI, 2003.
- 21. Slide 10-21Unit 10: Treating the Dually Infected Patient • Appropriate treatment of TB • TB treatment regimens are the same for HIV- infected patients as for non-infected patients • Assure adherence with TB treatment (use of directly observed therapy, DOT) • Cotrimoxazole prophylaxis • ART How To ImproveHow To Improve Outcomes of HIV-Related TB?Outcomes of HIV-Related TB?
- 22. Slide 10-22Unit 10: Treating the Dually Infected Patient TB Treatment andTB Treatment and Outcome of HIV-Related TBOutcome of HIV-Related TB • Poor adherence to TB treatment is associated with the following adverse outcomes • Treatment failure: patient suffers morbidity or mortality of TB • Increased risk of TB drug resistance or MDR complicating future treatment of the patient • Continued transmission of TB and development of new cases of active TB • Possible transmission of drug resistant or MDR TB • DOT can lead to improved outcomes by supporting better adherence practices
- 23. Slide 10-23Unit 10: Treating the Dually Infected Patient Cotrimoxazole PreventativeCotrimoxazole Preventative Therapy (CPT) (1)Therapy (CPT) (1) • Reduces the risk of • Pneumocystis jiroveci pneumonia (PCP) • Toxoplasmosis • Bacterial infections • Reduces deaths and hospitalisations • Also effective against: • Pneumococcus, salmonella, nocardia and malaria
- 24. Slide 10-24Unit 10: Treating the Dually Infected Patient CPT (2)CPT (2) • All HIV-positive TB patients should receive CPT regardless of the CD4 count for, at least, the duration of anti-TB treatment • Extend CPT beyond the end of anti-TB treatment if the CD4 cell count is less than 200 cells/mm3 Source: WHO, 2006
- 25. Slide 10-25Unit 10: Treating the Dually Infected Patient Cotrimoxazole DosingCotrimoxazole Dosing AGE (weight) OF CHILD RECOMMENDED DAILY DOSE SUSPENSION (5ML syrup = 200mg/40mg) Child tablet (100mg/20mg) Single strength adult tablet (400mg/80mg) 6 weeks to 6 months (<5kg) 100mg sulfamethoxazole/ 20mg trimethoprim 2.5ml One tablet 6 months – 5 years (5- 15kg) 200mg sulfamethoxazole/ 40mg trimethoprim 5ml Two tablets Half tablet 6 to post- pubertal 400mg sulfamethoxazole/ 80mg trimethoprim 10ml Four tablets One tablet Post-pubertal Adolescents and Adults 800mg sulfamethoxazole/ 160mg trimethoprim Two tablets
- 26. Slide 10-26Unit 10: Treating the Dually Infected Patient • Identification of patients who will benefit from antiretroviral therapy • Drug-drug interactions • Immune reconstitution events • Overlapping ARV and TB medicine side effect • Adherence with multi-drug therapy for two infections • Coordinating care between TB and HIV care providers Issues in UsingIssues in Using ART During TB TherapyART During TB Therapy
- 27. Slide 10-27Unit 10: Treating the Dually Infected Patient Immune Function andImmune Function and Survival During TB TreatmentSurvival During TB Treatment Source: Mansouthi W et al., J Acquir Immune Defic Syndr, 2006. • Survival during TB treatment is associated with level of immune function • ART can substantially reduce mortality among HIV/TB co-infected patients • Initiation of ART within six months of TB diagnosis can improve survival
- 28. Slide 10-28Unit 10: Treating the Dually Infected Patient Who Would Benefit from ARVsWho Would Benefit from ARVs During TB Therapy?During TB Therapy? • HIV is associated with markedly increased mortality during TB treatment • Early deaths (< 30 days after TB diagnosis) often due to TB; later deaths - other complications of HIV • All HIV+ patients with TB are stage 3 (pulmonary) or 4 (extra-pulmonary) and are eligible for ART
- 29. Slide 10-29Unit 10: Treating the Dually Infected Patient Benefits and RisksBenefits and Risks • Benefits: • Strengthen immune system for fighting TB and other infections • Avoid deaths due to OIs and AIDS during TB therapy • Risks • Drug interactions limit ART regimens • Immune reconstitution inflammatory syndrome • Drug toxicity
- 30. Slide 10-30Unit 10: Treating the Dually Infected Patient Treatment of TB for HIV-PositiveTreatment of TB for HIV-Positive PersonsPersons Initial treatment phase should consist of • Isoniazid (H) • Rifampicin (R) • Pyrazinzamide (Z) • Ethambutol (E)
- 31. Slide 10-31Unit 10: Treating the Dually Infected Patient Rifampicin DecreasesRifampicin Decreases Blood Levels of NVP and EFVBlood Levels of NVP and EFV NNRTI Effect of rifampicin Nevirapine ↓ 37-58% Efavirenz ↓ 13-26%
- 32. Slide 10-32Unit 10: Treating the Dually Infected Patient ART and Rifampicin-BasedART and Rifampicin-Based TB TherapyTB Therapy • AZT/3TC/EFV* • Men • Women outside of child bearing years • Children >3 years old • AZT/3TC/NVP* • Women of child bearing age • Children < 3 years old *Note: if Hb < 7.5, substitute AZT with d4T
- 33. Slide 10-33Unit 10: Treating the Dually Infected Patient Rifampicin MarkedlyRifampicin Markedly Decreases Blood Levels of all PIsDecreases Blood Levels of all PIs Protease Inhibitor Rifampicin effect Saquinavir ↓ by 80% Ritonavir ↓ by 35% Indinavir ↓ by 90% Nelfinavir ↓ by 82% Lopinavir/ritonavir ↓ by 75%
- 34. Slide 10-34Unit 10: Treating the Dually Infected Patient Treatment Options: ART DuringTreatment Options: ART During Rifampicin-Based TB TherapyRifampicin-Based TB Therapy Ritonavir boosting of other PIs can achieve adequate blood levels: • Lopinavir/ritonavir, 400mg/400mg BD • = 3 capsules Kaletra + 3 capsules ritonavir BD • =2 tablets Alluvia* + 3 capsules ritonavir BD • Lopinavir/ritonavir, 800mg/200mg BD • =6 capsules Kaletra BD • =4 tablets Alluvia* BD
- 35. Slide 10-35Unit 10: Treating the Dually Infected Patient Case Study: M.L. (1)Case Study: M.L. (1) • 31 year old female with HIV infection diagnosed 5 years ago • She has been non-adherent to ART • She presented with fever and cough of 2-3 weeks duration • Exam: a small (1 cm) submandibular lymph node was found on the right side • Lab: CD4 count 26, Sputum smears x 2 positive for AFB
- 36. Slide 10-36Unit 10: Treating the Dually Infected Patient Case Study: M.L. (2)Case Study: M.L. (2) • M.L. was started on TB medications (EHRZ) plus ART as inpatient • 2 wks after starting medications, she developed increased cervical lymphadenopathy with worsening respiratory symptoms • Repeat CD4 count was 120 • A CXR was done
- 37. Slide 10-37Unit 10: Treating the Dually Infected Patient Courtesy of: © M. Narita, 2006. What do you think is happening? What would you do next? Case Study: M.L. (3)Case Study: M.L. (3)
- 38. Slide 10-38Unit 10: Treating the Dually Infected Patient • HIV medications were discontinued • TB medications were continued • Repeat CXR was done • M.L.’s CD4 decreased to 34 Case Study: M.L. (4)Case Study: M.L. (4) Courtesy of: © M. Narita, 2006.
- 39. Slide 10-39Unit 10: Treating the Dually Infected Patient Case Study: M.L. (5)Case Study: M.L. (5) • ART resumed 3 months into TB treatment • TB was cured • At the end of TB treatment her CD4 was 342
- 40. Slide 10-40Unit 10: Treating the Dually Infected Patient • Improved immune response against MTB leads to new or worsening signs or symptoms despite effective TB treatment • Closely associated with starting ARV (days to weeks), but rarely associated with starting TB therapy • Natural history • Duration - days to months • Waxing and waning is common Immune ReconstitutionImmune Reconstitution Inflammatory Syndrome (IRIS)Inflammatory Syndrome (IRIS)
- 41. Slide 10-41Unit 10: Treating the Dually Infected Patient • Fever • New or worsening lymphadenitis - peripheral or central nodes • New or worsening pulmonary infiltrates, including respiratory failure • New or worsening pleuritis, pericarditis, or ascites • Intracranial tuberculomas, worsening meningitis • Disseminated skin lesions • Epididymitis, hepatosplenomegaly, soft tissue abscesses IRIS Among Patients with HIV/TBIRIS Among Patients with HIV/TB
- 42. Slide 10-42Unit 10: Treating the Dually Infected Patient • Shorter time from the initiation of TB therapy to the initiation of antiretroviral therapy (e.g., within six weeks) • Low initial CD4 count or high viral load at ART initiation • CD4 count rises rapidly on ART • Good immunological and virological response during ART • Extrapulmonary or disseminated disease Source: Colebunders R, et al., Int J Tuberc Lung Dis, 2006. Risk Factors for IRISRisk Factors for IRIS
- 43. Slide 10-43Unit 10: Treating the Dually Infected Patient Managing IRISManaging IRIS • Inform patients about the possibility of an event after starting ART– may feel like the “TB is coming back” • Evaluate for possible TB treatment failure • Drug resistance, non-adherence, malabsorption • Assess for other HIV-related complications, e.g., another opportunistic infection • Management of symptoms, e.g., use non-steroidal anti inflammatory drugs • For severe symptoms may need to use steroids (prednisolone), 1 mg/kg or even stop ART temporarily
- 44. Slide 10-44Unit 10: Treating the Dually Infected Patient Case Study: MikaCase Study: Mika • A 40 year-old male from Gaborone presents with fever for 4 weeks, cough with bloody sputum, sweats and weight loss of 7kg • Chest X-ray shows right lobe infiltrate • Sputum AFB x 1 results “scanty” • His HIV test is positive and CD4 is180 cell/cu mm
- 45. Slide 10-45Unit 10: Treating the Dually Infected Patient Case Study:Case Study: Mika at 2 months ATTMika at 2 months ATT • Mika returns after two months • His fevers, cough, and night sweats have stopped and he has gained 5kg • His TB regimen is changed to the continuous phase (R/H) • He is started on ART X-ray shows improvement Source: I-TECH, Tanzania
- 46. Slide 10-46Unit 10: Treating the Dually Infected Patient Case study: Mika at 4 Months ATTCase study: Mika at 4 Months ATT • Mika comes back for his 2nd ART monitoring visit • He reports fever, cough and night sweats have returned • He has taken his ARTs as prescribed but thinks they are making him more sick and would like to stop them
- 47. Slide 10-47Unit 10: Treating the Dually Infected Patient Case Study: MikaCase Study: Mika Findings at 4 Months ATTFindings at 4 Months ATT • Mika reports excellent adherence and denies nausea, vomiting or diarrhoea • His oxygen saturation is 96% on room air • Heart rate, respiratory rate and other vital signs are normal • Remainder of physical exam is normal • Sputum smear is 1+ for AFB New CXR Source: I-TECH, Tanzania
- 48. Slide 10-48Unit 10: Treating the Dually Infected Patient Case Study: MikaCase Study: Mika 2 Weeks Later2 Weeks Later • He is worse • Sputum culture from last visit shows no growth to date (2 weeks) • Sputum smear is still 1+ AFB • On physical exam is tachypnoeic • Oxygen saturations is 90% on room air • Crackles heard in right lung field X-ray shows worsening Source: I-TECH, Tanzania
- 49. Slide 10-49Unit 10: Treating the Dually Infected Patient Adverse Events DuringAdverse Events During Combined TB+HIV Treatment (1)Combined TB+HIV Treatment (1) Common adverse events include: • Peripheral neuropathy - more common with use of ddI & d4T • Skin rash • TB drugs • Cotrimoxazole • Nevirapine • Other drugs • Hepatitis, due to TB drugs or unknown causes Source: Dean GL, et.al., AIDS, 2002.
- 50. Slide 10-50Unit 10: Treating the Dually Infected Patient Overlapping Side Effects ofOverlapping Side Effects of Anti-TB and ARV DrugsAnti-TB and ARV Drugs Side Effect Possible Causes Antituberculosis Drugs Antiretroviral drugs Skin rash S, Z, R, H nevirapine, efavirenz, abacavir Nausea, vomiting Z, R, H zidovudine, ritonavir, protease inhibitors Hepatitis Z, R, H nevirapine, efavirenz, protease inhibitors Leukopenia, anemia R zidovudine
- 51. Slide 10-51Unit 10: Treating the Dually Infected Patient Adverse Events DuringAdverse Events During Combined TB+HIV Treatment (2)Combined TB+HIV Treatment (2) • Some adverse events related to advanced AIDS, some to other infections or malignancies, and some to their treatment • Few events result in permanent discontinuation of first-line TB drugs, even though therapy may have been temporarily discontinued Do not give up on the first-line TB drugs unless it is clear that one of them is causing a severe side effect! Source: Dean GL, et.al., AIDS, 2002.
- 52. Slide 10-52Unit 10: Treating the Dually Infected Patient Managing Adverse EventsManaging Adverse Events • Do one thing at a time-- makes it easier to decide the cause of an event • Stop medications for severe adverse events • Use sequential re-challenge to decide the cause of an event • Don’t switch from the first-line TB drugs (especially INH and RIF) without evidence of an association with a significant side effect • Remember IRIS as a possible cause of adverse events during treatment
- 53. Slide 10-53Unit 10: Treating the Dually Infected Patient Increasing TB/HIVIncreasing TB/HIV Treatment AdherenceTreatment Adherence • TB treatment uses directly observed therapy (DOT)-- use DOT visits for TB treatment to enhance adherence to antiretroviral therapy • Try to coordinate medication pickups where possible
- 54. Slide 10-54Unit 10: Treating the Dually Infected Patient Preventing Active TBPreventing Active TB Among HIV-Infected PersonsAmong HIV-Infected Persons Four strategies: 1. INH Preventive Treatment 2. Antiretroviral Therapy 3. Infection Control • HIV+ Health Care Workers should avoid TB exposure (medical and TB wards) 1. TB case finding • Early case-detection and effective TB therapy (effective DOTS program)
- 55. Slide 10-55Unit 10: Treating the Dually Infected Patient Key PointsKey Points • Both TB and HIV increase the other’s disease progression • Early Diagnosis of TB has better outcomes for patients, families and community • Standard TB treatment correctly implemented cures TB in TB/HIV • ART for eligible patients greatly improves survival • Different ART regimens are required because of drug interactions with rifampicin
Editor's Notes
- This unit will introduce participants to the synergy of combined HIV and TB infection and treatment options to improve survival of patients with both The first few slides of this Unit will review and emphasise points made in Units 3 and 4 about the interaction of HIV and TB regarding clinical presentation. The rest of the slide set addresses issues on treatment: both technical and organisational Ask the participants if they have any questions about the learning objectives before continuing
- An increasing number of people have both HIV and TB together. HIV/AIDS is the number one infectious cause of death in the world, but many people with HIV/AIDS become ill with TB and die with TB Rates of co-infected persons, 2004: Worldwide: 370 thousand Africa: 300 thousand Mortality rates in Africa, 2004 586 thousand infected with TB 205 thousand co-infected The TB/HIV burden in Botswana is estimated as not all TB patients are tested for HIV; it may even be higher than 80% Our TB case notification rate in Botswana has risen because of HIV Epidemiologic synergy: HIV and TB often occur in the same populations: the same country, same region, and same households. So there is a lot of opportunity for persons with TB to be exposed to HIV, and for persons with HIV to be exposed to TB. HIV infected persons with latent TB infection are much more likely to develop active disease, so that TB transmission increases in the population as well *Source: Botswana National Tuberculosis Programme Manual, 2007. Source: WHO. Global tuberculosis control: surveillance, planning, financing. 2006 [cited 2008 Jan 30]. Table A2.1, p 143. Available from: http://www.who.int/tb/publications/global_report/2006/pdf/annex_2_en.pdf. Discuss the following studies with participants: In an autopsy study of 128 patients done in Francistown in 1997-1998 , 81% were HIV-positive Among HIV-positive patients, 40% had TB, 23 % had bacterial pneumonia 23%, 11% had Pneumocystis carinii pneumonia, and 11% had Kaposi’s Sarcoma. These conditions were the cause of death in 38%, 14%, 11%, and 6%, respectively Of the 40 pulmonary TB cases, 90% also had disseminated extra-pulmonary TB. Chest radiology could not reliably distinguish the pathologies pre-mortem Source: Nsari N. Kombe A, Kenyon T, Hone N, Tappero J, Nyirena S, Binkin N, Lucas S. Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana 1997-1998. The International Journal of Tuberculosis and Lung Disease, 2002 Jan; 6(1):55-63(9).
- TB and HIV interact in both biological and epidemiological ways. These interactions lead to increases in both conditions HIV makes TB worse by reducing the immunologic control of TB infection. HIV reduces cell mediated immunity, which leads to higher rates of development of active disease from TB exposure or infection, and to more severe and atypical forms of TB disease TB has a higher death rate in persons with advanced immunosuppression from HIV, and TB has a higher relapse rate after treatment in HIV-infected persons Immune system activation by TB increases the rate of HIV growth. Activation of CD4 lymphocytes, macrophages, and other immunologic cells, along with the production of immunologic chemicals called cytokines, increase the growth of HIV. This leads to more rapid development of immunosuppression than with HIV alone
- Because of the impact that TB has on increasing the progression of HIV to AIDS, it is essential that patients who are newly diagnosed with HIV be educated about tuberculosis and be screened. Further work up is necessary if a patient has positive clinical findings
- An HIV-positive person who becomes infected with TB has a 10% annual risk of progressing to active TB disease and a 50% lifetime risk for developing tuberculosis. (Compared with a 2-10% lifetime risk of active TB in an HIV negative person) HIV infects white blood cells (WBC), which are a part of the body’s immune system. If a person has a weak immune system, she is: more likely to progress to TB disease immediately following infection at greater risk for progressing to TB disease from latent infection and at higher risk of becoming reinfected Source: World Health Organization. TB/HIV: A Clinical Manual. Second Edition. WHO. 2004.
- Among persons with TB infections and without HIV, there is a 10% lifetime risk of active disease, whereas among HIV-positive persons with TB infection there is about an average 10% risk per year of developing active disease
- This slide shows the effect of HIV infection on the death rate of TB during treatment (6 months) The vertical axis shows the percent of patients who died during the first 6 months of TB diagnosis The horizontal axis divides patients by HIV status Patients with HIV/TB co-infection had a much higher death rate – 14% vs. 0.5% The high death rate suggests that treatment of HIV, in addition to treatment of TB, could improve outcomes of patients with HIV-TB Source: Murray J, Sonnenberg P, Shearer SC, Godfrey-Faussett. Human immunodeficiency virus and the outcome of treatment for new and recurrent pulmonary tuberculosis in African patients. Am J Respir Crit Care Med. 1999 Mar;159(3):733-40. There seems to be a lack of data regarding the impact of ART on morbidity and mortality of TB patients. A study in Malawi showed little difference in short-term mortality in TB patients with or without ART. Most co-infected patients died during the first two months of TB treatment However, most patients in the study were started on ART after the intensive phase, and ART might need to be started early to have an impact on short-term mortality Source: Zachariah R, Fitzgerald M, Massaquo M et al. Does ART reduce case fatality among HIV-positive patients with tuberculosis in Malawi? Int J Tuberc Lung Dis 2007; 11(8):848-53. Data might be scarce for Botswana but ART could reduce mortality significantly, though to what extent it is unknown Other references: Manosuthi W, Chottanapand S, Thongyen S, Chaovavanich A, Sungkanuparph S. Survival Rate and Risk Factors of Mortality Among HIV/Tuberculosis-Coinfected Patients with and without Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2006 Sep;43(1):42-6. Lawn SD; Myer L; Bekker LG; Wood R. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS. 2006; 20(12):1605-12.
- This slide shows that the clinical pattern of TB disease is associated with survival among people with HIV-related TB. HIV-infected persons who have both pulmonary and extra-pulmonary TB have the poorest survival in general, perhaps because they have more severe immunosuppression. Knowledge of the patient’s extent of TB may help prioritise who should be considered for ART Orient participants to this graph The vertical axis shows survival after the diagnosis of HIV-related TB The horizontal axis shows time since that diagnosis, in days Patients with pulmonary-only TB had the best survival, patients with pulmonary + extrapulmonary TB had the worst survival This relationship is probably due to the effect of CD4 count and presence of extrapulmonary TB – the lower the CD4 cell count, the more the chance of extrapulmonary involvement The results of this study suggest that presence of extrapulmonary TB can be one way of targeting patients to receive potent antiretroviral therapy Source: Whalen C, Horsburgh CR Jr, Hom D, Lahart C, Simberkoff M, Ellner J. Site of disease and opportunistic infection predict survival in HIV-associated tuberculosis. AIDS. 1997 Mar 15;11(4):455-60.
- Compare the purpose and methods of TB and HIV screening (HIV screening listed on the next slide)
- Health care encounters include: Mother-to-child (PMTCT) IDCC/ART Clinic Other health unit TB symptoms: cough &gt;2-3 weeks, weight loss, fatigue, night sweats, loss of appetite, haemoptysis, TB contact, chest pain, fever.... Ask the group: If you had 50 patients waiting to be seen and you had 3 questions you could ask each patient, what would they be?
- HIV and TB often occur in the same populations: the same country, same region, and same households. So there is a lot of opportunity for persons with TB to be exposed to HIV, and for persons with HIV to be exposed to TB HIV infected persons with TB are much more likely to develop active disease, so that TB transmission increases in the population as well Therefore, diagnosing TB early among HIV patients is even more important to improving outcomes in all of these ways
- Review the strategies to confront HIV and TB by looking at the tasks directed at HIV-positive persons and the tasks directed at persons with TB
- Ask participants to share their observations about the content of the past two slides Answer: the tasks for addressing TB and those for addressing HIV are very similar and have a lot of overlap *ADL = Activities of Daily Living Note the similarity between the two columns– we need coordination of efforts
- Coordination needed between HIV and TB programs and clinics to: Prevent HIV among TB patients Prevent TB among HIV patients Test patients and contacts for both conditions Coordinate therapy Manage drug interactions Maximise adherence with DOT/treatment supporters Divide participants into small groups of about 4-5 people Ask each group to select a reporter and recorder Distribute flip chart paper to each group Ask the groups to list challenges they see to integrating these two services. For each challenge listed, the groups should try to brainstorm a potential strategy to address these potential challenges Allow participants 5-10 minutes to work as a small group Ask each group to share 2-3 of their responses (challenge and strategy). If groups had trouble coming up with a strategy, ask the rest of the group for other ideas Discuss as a large group for about 5 minutes. Give example that at Marina Hospital, all TB/HIV co-infected patients are seen on Fridays (for ART refills, episodic visits, etc.) so that it becomes a “TB/HIV integration day” Another example of integration is provision of cotrimoxazole preventive therapy to HIV positive patients at clinics where TB services (but not ART) are provided
- Decision on when to start ART after starting TB treatment involves a balance between the pill burden, potential drug interactions, overlapping toxicities and possible immune reconstitution syndrome versus the risk of further progression of immune suppression with its associated increase in mortality and morbidity
- This has been a source of confusion for many It’s controversial and a lot of people have different ways of doing this Current first-line ARVs used in Botswana are AZT + 3TC with either efavirenz or nevirapine (women of childbearing age). If the patient is anaemic with a haemoglobin&lt;7.5, d4T is used instead of AZT In the next 6 months, the first line ART regimen is going to be changed to TDF + FTC instead of combivir. It will be in a fixed dose combination like combivir, but will be taken once daily. FTC has the same mechanism of action as 3TC, and tenofovir (TDF) has fewer side effect and complications & is a nucleotide reverse transcriptase inhibitor Risks of starting ARVs early: Toxicity Pill burden IRIS Drug-drug interaction
- The drugs listed in the slide are from 3 classes: NRTI=nucleoside reverse transcriptase inhibitor TDF & ABC are both NRTIs; NRTIs act by competing with natural occurring deoxynucleotides in building the viral DNA chain and cause chain termination. NNRTI=non-nucleoside reverse transcriptase inhibitor; NNRTIs are non-competitive inhibitors of reverse transcriptase. They do not actually become incorporated into viral DNA chain like NRTIs. PI=protease inhibitor; PIs work by prohibiting HIV from cutting up the protein molecule into viral particles (virions) Alluvia is a tablet form of lopinavir/ritonavir and is now available in the Botswana HIV treatment programme. Patients take 2 tablets BD rather than 3 capsules BD. It does not need to be stored in the refrigerator, therefore it is more appropriate for patients in under-resourced settings. With the impending ART guideline revision, AZT/3TC is going to be replaced with FTC/TDF as the “backbone” of the first line regimen. (with EFV or NVP). FTC has a similar mechanism of action as 3TC.
- Source: de Jong BC, Israelski DM, Corbett EL, Small PM. Clinical Management of Tuberculosis in the Context of HIV Infection. Annu Rev Med . 2004; 55:283-301
- This study illustrates the 75% reduction in death rates (from 20% to about 5%) and reductions in new opportunistic infections when TB therapy is combined with antiretroviral therapy in persons who started with low CD4 cell counts. Details follow. However, this analysis does not provide information regarding the best time to start ART among patients on TB treatment To evaluate the clinical outcomes of using antiretroviral therapy during TB treatment, we compared the outcomes in a study in which patients were encouraged to take potent antiretroviral therapy (TBTC Study 23) to the outcomes of patients enrolled in study of treatment of HIV-related TB taking place before the availability of potent antiretroviral therapy (CPCRA 019 / ACTG 223). Both studies were done in the United States. As this slide shows, the two cohorts had very similar baseline CD4 cell counts at the time of TB diagnosis, but differed in the expected manner in the use of ART – 80% of the patients in the present trial received ART compared to none of the patients in the CPCRA/ACTG study. The differences in clinical outcomes were dramatic – decreases in the risk of death and new opportunistic infections So, among patients with advanced HIV disease, use of potent antiretroviral therapy appears to markedly decrease the risk of death during and shortly after TB treatment Source: Burman W. et al. Use of Antiretroviral Therapy During Treatment of Active Tuberculosis with a Rifabutin-based Regimen. 10th Conference on Retroviruses and Opportunistic Infections (CROI) Abstract No. 136, 2003.
- Outcomes can be improved with appropriate treatment of TB (the purpose of this entire course) as well as by maximizing other factors We will discuss adherence, opportunistic infection prophylaxis and ART in the next several slides State that this was a change in the revised guidelines
- New guidelines state that everybody with HIV and TB should be put on cotrimoxazole, regardless of CD4 count
- Where CD4 cell testing is available, co-trimoxazole prophylaxis is recommended for everyone with a CD4 cell count &lt;350 per mm3, particularly in resource-limited settings where bacterial infections and malaria are prevalent among people living with HIV. Bacterial infections are prevalent in individuals living with HIV in all settings, which supports the use of the 350 cells per mm3 threshold People with WHO clinical stage 3 or 4 HIV disease (including people with pulmonary as well as extrapulmonary TB) should, however, still initiate co-trimoxazole prophylaxis irrespective of the CD4 cell count Source: Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults in resource-limited settings: Recommendations for a public health approach. World Health Organization, 2006.
- Paediatric dosing does not need to be addressed here, it was discussed in previous paediatric unit
- Despite the dramatic benefits of treating HIV during TB treatment, there are a number of factors which make it complicated to use potent antiretroviral therapy during TB treatment
- Highest risk of death during TB treatment is among patients with poor immune function (equivalent to CD4 count &lt;200) Very low rate of death among patients with relatively good immune function (high CD4 values) at the time of TB diagnosis Source: Manosuthi W, Chottanapand S, Thongyen S, Chaovavanich A, Sungkanuparph S. Survival Rate and Risk Factors of Mortality Among HIV/Tuberculosis-Coinfected Patients With and Without Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2006 Sep;43(1):42-46.
- Large international randomized controlled trial of immediate versus delayed antiretroviral therapy among persons with HIV and TB are underway in South Africa and elsewhere, and others are being planned. Until then, the guideline on when HIV/TB patients should start ARVs will be based on limited data and expert opinion All HIV patients with TB are eligible for ART because they are either in stage 3 or stage 4
- A large international randomized controlled trial of immediate versus delayed antiretroviral therapy among persons with HIV and TB is being planned. Until then, the guideline on when HIV/TB patients should start ARVs will be based on limited data and expert opinion
- There is no change in TB treatment in HIV positive individuals, whether on ART or not. The same drug, and the same dose, for the same duration is to be used
- Rifampicin is a strong inducer of the cytochrome p450 cytochrome system and substantially lowers the levels of nevirapine. It lowers the levels of efavirenz less.
- There is no dose escalation of efavirenz recommended. There is some concern that rifampicin lowers level of NVP to below therapeutic levels, but there is successful clinical experience in Spain, and Botswana ART programme recommends that NVP be used.
- The effects of rifampicin on blood levels of protease inhibitors means that protease inhibitors should not be used among people on rifampicin – the blood levels would be so low that the protease inhibitors would be ineffective in suppressing HIV Ritonavir is not used by itself, instead is used in combination with other PIs It’s the combinations that you need to worry about
- This slide lists alternatives to efavirenz-based antiretroviral therapy These would have to be considered for pregnant patients (efavirenz is a teratogen), if there is efavirenz intolerance, or probable resistance to efavirenz (prior failure of efavirenz-based therapy) There is limited experience with these alternatives As mentioned previously, high-dose ritonavir is not well-tolerated by most patients *Alluvia is now available in Botswana – it is a tablet form of Kaletra and does not need to be refrigerated
- Tell participants that this case illustrates how IRIS can present in the setting of HIV-related TB Ask participants what they would do now before moving to next slide
- Ask the participants what her ART regimen was likely to have been
- Ask participants what they think is happening and what they would do next. Answer: Diffuse nodular infiltrates bilaterally with right pleural effusion Source: © M. Narita, 2006
- Source: © M. Narita, 2006
- What ART regimen would M.L. be started on now? Answer: the same regimen – AZT/3TC/NVP Ask the group what the criteria are for M.L. to be considered “cured”
- Immune Reconstitution Inflammatory Syndrome (IRIS) can occur in persons with HIV and a variety of opportunistic infections. For this course, we are discussing ONLY immune reconstitution events related to TB Immune reconstitution events are relatively common among HIV/TB co-infected patients starting ART in resource-limited settings Small cohort studies found that 11-45% of HIV-infected patients with active TB experienced TB IRIS upon ART initiation Source: Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynent L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis. 2006 Sep;10(9):946-53.
- Immune Reconstitution Inflammatory Syndrome is a syndrome of increased immune reaction against an infection that occurs shortly after ART is begun. In sub-Saharan Africa, it is most often an immune response against MTB, which may or may not have been diagnosed before the ART treatment began. This slide focuses on immune reconstitution against TB. In the ARV course and OI course, immune reconstitution against TB and other opportunistic pathogens is discussed. Disseminated skin lesions are not that common in Botswana
- Only small cohort studies have been done to date on TB IRIS on initiation of ART. The risk factors listed on this slide have been suggested by some studies, but not found to be significant in others. Source: Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynent L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis. 2006 Sep; 10(9):946-53
- Before concluding that an event is an immune reconstitution event, it is important to consider other possible explanations – failure of TB treatment or the occurrence of another process (a new opportunistic infection, a tumor, etc.) There are many uncertainties about the optimal management of immune reconstitution events Relatively mild events may be managed with reassurance and encouragement – the event is a sign that the HIV treatment is working Fevers and pain may respond to non-steroidal anti-inflammatory drugs, like Aspirin Severe manifestations – enlarging lymph nodes that compromise ability to move the neck, swallow or breath, an enlarging tuberculoma in the central nervous system, worsening meningitis, respiratory failure – should be treated with corticosteroids. In addition, it may be necessary to stop antiretroviral therapy for a time The duration of steroid therapy has not been studied, but most experts would try to taper the steroids after several weeks, if there has been a good response Remember that not all worsening of patients may be due to IRIS
- Ask a participant to read case study presented on this slide. Ask the group, “What medications do you start this patient on?” Allow the group to discuss treatment options for this and come to consensus about what the treatment regimen would be Once the group has come to consensus, give them the answer. If it is different than what they determined, discuss why this is the appropriate regimen Answer: Start patient on rifampicin, isoniazid, pyrazinamide and ethambutol plus cotrimoxazole
- Ask a participant to read case study, part 2 presented on this slide. Ask the group, “Do you agree with the ARVs that Mika has started? Why or why not? What ARVs would make up his regimen?” Facilitate a discussion for a few minutes Answer: AZT/3TC/EFV
- Ask a participant to read case study, part 3 presented on this slide. Ask the group, “What else would you want from a history and physical?” Answers: Was Mika adherent to all his medications? Does Mika have other symptoms including nausea, vomiting, diarrhoea, which may indicate other infections or malabsorption? Ask the group, “What further tests would you order?” Answers: Blood pressure, heart rate, temperature, respiratory rate and oxygen saturation Additional labs: sputum smear for AFB and bacteria, sputum culture, FBC, liver tests, CD4 count. Viral load if available Ask the group, “What is you’re your differential diagnosis?” Answers: TB IRIS Drug-resistant TB Failure of TB therapy due to poor adherence or malabsorption of medications Bacterial pneumonia PCP Drug toxicity Ask the group, “What will you look for on physical examination?” Answers: Detailed physical examination concentrating on the chest Enlarged lymph nodes Body swelling (edema) Abdominal distention Jaundice (icterus) Neurologic exam
- You get the chest x-ray back and you see that he has right side infiltration Ask the group, “What would you do now?” Answer: Advise him to continue ART and the TB continuation regimen. You reassure him and discuss the importance of taking all of his medications as prescribed. Schedule him to come back in two weeks or sooner if he gets worse
- Ask the group, “What do you think is happening?” Answer: This is TB IRIS. The immune system is reacting to dead mycobacteria in the system. The inflammation is worsening as his immune system reconstitutes itself on ART Ask the group, “How you would manage this patient?” Answer: Admit him to the hospital. Give oxygen. Check blood work, CBC, chemistry panel. Administer steroids at this point to reduce inflammation. (Consider administration of treatment for community-acquired pneumonia, in addition to steroids). If he continues to worsen despite steroid treatment, stop ART until he has clinically improved (resolution of chest x-ray, respiratory distress). Restart ART once clinically stable. Continue TB treatment continuation regimen throughout. If culture turned positive, then you would suspect drug resistance and you would do sensitivity testing.
- Adverse events and treatment interruption (TB and/or HIV) are common Because of the degree of immunodeficiency and the use of multiple medications, it isn’t surprising that adverse events are common among patients being treated for HIV-related TB In one cohort study from London, 34% of patients stopped TB or HIV therapy, at least temporarily The most common adverse events were peripheral neuropathy, skin rash, and hepatitis Source: Dean GL et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS. 2002 Jan 4;16(1):75-83.
- A problem with starting many drugs at the same time is that of knowing which of the drugs is the cause, if a side effect occurs This is particularly a problem in the treatment of HIV-related TB, because both diseases have to be treated with multi-drug therapy and because the drugs used to treat these two diseases can have the same side effects An additional factor is that many patients also need to receive other drugs, most often cotrimoxazole for PCP prophylaxis, and this can cause rash, hepatitis, and anemia/leukopenia
- Emphasize severe and reoccurring side effects; don’t give up on first-line ATT Source: Dean GL et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS. 2002 Jan 4;16(1):75-83.
- If there are severe reactions (such as Stevens Johnsons), then you need to stop everything
- The key is a good relationship between the TB and HIV programs, and an overlap regarding adherence issues. Coordination is essential. Practical planning in most countries however, is lacking.
- The issue of keeping HIV+ health care workers away from TB patients is quite difficult in practice although it is a useful goal. TB is widespread among patients in Botswana, HIV is widespread even among health care workers, and usually health care workers have either not been tested for HIV or have not disclosed their status with their employer
- Summarise the presentation and review the Key Points Ask participants if they have any questions