Diagnosis and management of active HIV-related TB

Diagnosis and management of active HIV-related TB Estimated HIV-MTB Coinfection Prevalence, 2000 Rate per 100 000 <5 5 - 9.9 10 - 99 100 - 999 1000 - 4999 5000 or more No estimate Source: WHO 2002. The MTCT - Plus Initiative 2 Outline • Diagnosis of active TB (disease) • Management of HIV-related TB – Avoiding overlapping side effects of TB and HIV therapy – Avoiding serious drug-drug interactions – Minimizing immune reconstitution events • Coordination of HIV and TB care • Need for adherence The MTCT - Plus Initiative 3 Diagnosis of active TB in HIV-infected patients Case 1 51 year old man enrolled in MTCT-Plus: • Cough with yellow sputum and daily fevers for 3 weeks • Diarrhea for 1 week • Increasing confusion for 3 days • Labs: – WBC 2.4 – Hb 10.8, HCT 32.4 – HIV positive The MTCT - Plus Initiative 5 Clinical and radiographic manifestations of HIV-related TB • How does HIV change the signs, symptoms, and radiographic manifestations of TB? • Is there an association between the stage of HIV and the clinical/radiographic manifestations of TB? • Is it more difficult to diagnose HIV-related TB than non-HIV TB? The MTCT - Plus Initiative 6 The effect of HIV infection on symptoms and signs of TB Symptom/sign Dyspnea Fever Sweats HIV positive (%) HIV negative (%) 97 79 83 81 62 64 83 4 21 15 13 Weight loss Diarrhea Hepatomegaly Splenomegaly 89 23 41 40 Lymphadenopathy 35 Chest 1994;106:1471-6 The MTCT - Plus Initiative 7 Symptom Checklist The MTCT - Plus Initiative 8 Sites of involvement and HIV status Site Pulmonary Extrapulmonary Both HIV positive (%) HIV negative (%) 40 34 26 31 15 19 72 16 12 19 3 3 Pleural Pericardial Lymph node J Trop Med Hygiene 1993;96:1-11 The MTCT - Plus Initiative 9 Extrapulmonary manifestations (%) and the severity of immunosuppression (CD4 cell count) 80 70 % Extra-Pulmonary TB 60 50 40 30 20 10 0 >300 201-300 101-200 CD4 cell count The MTCT - Plus Initiative 0-100 10 Common forms of extrapulmonary TB among HIV-infected persons • Nodal – peripheral nodes - cervical > axillary > inguinal – central nodes - mediastinal > hilar, intraabdominal • Disseminated disease • Serosal - pleural, pericardial > ascites • Central nervous system - meningitis, tuberculoma • Soft tissue abscesses The MTCT - Plus Initiative 11 Sputum smear and HIV status 60 50 Percentage (%) 40 30 20 10 0 Negative 1+ 2+ 3+ Smear Status Tubercle Lung Dis 1993;75:191-4 HIV positive HIV negative The MTCT - Plus Initiative 12 Yield of needle aspiration for diagnosis of HIV-related lymphadenopathy - Zambia Final diagnosis Tuberculosis HIV adenopathy Number (%) 130 (65%) 47 (24%) Sensitivity 79% 66% Kaposi’s sarcoma Lymphoma Other Total 18 (9%) 3 (1%) 3 (1%) 200 29% 56% J Clin Pathol 1993;46:806-9 The MTCT - Plus Initiative 13 The yield of tests to diagnose pleural TB Test Pleural fluid - smear HIV pos. (%) HIV neg. (%) 15 8 culture Pleural biopsy - smear Sputum culture The MTCT - Plus Initiative 91 69 53 78 21 23 Chest 1994;105:1338-41 14 The effect of degree of immunosuppression on chest radiographic features of HIV-related TB The MTCT - Plus Initiative 15 The MTCT - Plus Initiative 16 The MTCT - Plus Initiative 17 The MTCT - Plus Initiative 18 Effect of stage of HIV disease on chest x-ray manifestations of TB Early HIV disease  upper lobe predominance  cavities  pleural disease Advanced HIV disease      lack of cavitation intrathoracic adenopathy lower and middle lobe infiltrates nodular infiltrates pleural and pericardial involvement The MTCT - Plus Initiative 19 Early diagnosis of TB is associated with better outcomes in patients • • • • Mining company in South Africa Culture confirmed TB in men (N= 2236) Outcome: 6 months mortality rate Overall case fatality rate: 3.6% – HIV: OR 15.0 (95% CI: 7.4-30.6) – Self presentation versus active radiologic screening: OR 5.6 (95%CI: 2.6-12.2) – Presence of silicosis: OR 3.0 (95%CI: 1.4-6.3) Churchyard, Int J Tuberc Lung Dis 4:705-712, 2000 The MTCT - Plus Initiative 20 Early diagnosis of TB is associated with better outcomes for families and community • 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 The MTCT - Plus Initiative 21 Fostering early diagnosis of HIV-related TB • Maintain a high index of suspicion – Review history – have close contacts had TB? – Conduct symptom checklist regularly • Know what to expect – remember the effect of CD4 cell count on the clinical and radiographic manifestations of TB • Evaluate suspected cases promptly – Suspected pulmonary TB: sputum for AFB – Suspected extrapulmonary TB: obtain specimens for AFB as appropriate – node aspirate, pleural fluid, etc. The MTCT - Plus Initiative 22 Case 1: continued • Sputum AFB-smear positive • Patient rapidly improved with INH, rifampin, pyrazinamide, and ethambutol – CD4 cell count 18 cells/mm3 – Repeat CBC: WBC 2.1, HCT 26.2% Questions: • When should ARV be started? • What are the complications of using ARV during TB treatment The MTCT - Plus Initiative 23 Treatment of Patients with HIVassociated Tuberculosis Association between HIV serostatus and risk of death during TB treatment Death within 6 months of TB diagnosis (%) 16 14 12 10 8 6 4 2 0 HIV-positive HIV negative Am J Respir Crit Care Med 1999;159:733-40 The MTCT - Plus Initiative 25 How can outcomes of HIV-related TB be improved? • Appropriate treatment of TB • Assure adherence with TB treatment (use of directly observed therapy, DOT) • Use of ART to treat HIV in selected patients The MTCT - Plus Initiative 26 Effect of mode of administration of TB treatment on outcome of HIV-related TB Outcome DOT 41 (85%) 5 (10%) 2 (4%) Self-administered 17 (57%) 11 (37%) 2 (7%) Alive Died from TB Died, not due to TB AIDS 1994;8:1103-8 The MTCT - Plus Initiative 27 Comparison of HIV disease progression with and without potent antiretroviral therapy TBTC 23 CPCRA/ACTG ARV Years of enrollment Baseline CD4 cell count No ARV 1993-1995 85 0 20% 38.9% Burman et al, CROI 2003, Clin Infect Dis 1999-2002 90 80% 4.5% 15.7% Use of HAART during TB treatment Death within 1 year of start of TB therapy Death or new OI within 1 year of start of TB therapy The MTCT - Plus Initiative 28 Issues in using antiretroviral therapy during TB therapy • Identification of patients who will benefit from antiretroviral therapy • Drug-drug interactions • Immune reconstitution events • Overlapping ARV and TB drug side effect • Adherence with multi-drug therapy for 2 infections • Coordinating care between TB and HIV care providers The MTCT - Plus Initiative 29 Association between pattern of TB and survival of patients with HIV-TB AIDS 1997;11:455-50 The MTCT - Plus Initiative 30 Association between CD4% and survival during TB treatment Survival at 6 months after TB diagnosis (%) 90 70 50 < 14% 14-28% >28% Am J Respir Crit Care Med 1999;159:733-40 The MTCT - Plus Initiative 31 Identifying patients who should benefit from ARV 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 • Laboratory (CD4 count < 350) and clinical criteria (extrapulmonary TB) allow identification of patients at increased risk for HIV disease progression during TB treatment The MTCT - Plus Initiative 32 Issues in using antiretroviral therapy during TB therapy • Identifying patients who would benefit from antiretroviral therapy • Drug-drug interactions • Immune reconstitution events • Overlapping drug side effect profiles - HIV and TB drugs • Adherence challenge of multidrug therapy for 2 infections • Coordinating care between TB and HIV care providers The MTCT - Plus Initiative 33 Rifampin has a moderate effect on blood levels of nevirapine and efavirenz NNRTI Nevirapine Effect of rifampin  37-58%  13-26% Efavirenz The MTCT - Plus Initiative 34 Rifampin markedly decreases blood levels of all protease inhibitors PI Saquinavir Ritonavir Rifampin  80%  35% Indinavir Nelfinavir Amprenavir Lopinavir/ritonavir The MTCT - Plus Initiative  90%  82%  81%  75% 35 ART and rifampin-based TB therapy • Recommended regimen: efavirenz plus 2 nucleosides – Use usual efavirenz dose (600 mg) (some experts suggest increasing efavirenz dose to 800 mg/day) • Choice of nucleosides* – Zidovudine (ZDV) + lamivudine (3TC) for most patients – Stavudine + lamivudine for those with anemia, leukopenia, or intolerance to ZDV * Depending on regimen selected at the site The MTCT - Plus Initiative 36 Treatment options: ART during rifampin-based TB therapy • Other options - limited clinical experience – Nevirapine - during pregnancy or if intolerant to efavirenz; consider increasing nevirapine to 300 mg twice-daily – Triple nucleoside- zidovudine + lamivudine + abacavir – Ritonavir (at least 400 mg twice-daily) + saquinavir (400 mg twice-daily) + nucleosides – Ritonavir (600 mg twice-daily) + 2 nucleosides - this dose of ritonavir is not well-tolerated The MTCT - Plus Initiative 37 Case 2 • • • • • 43 yr old man from Ethiopia seen for fevers and cough Sputum: smear-positive for acid-fast bacilli Chest X-ray: Left lower lobe infiltrate HIV-positive, CD4 cell count =12 Patient started on TB treatment (INH, Rifabutin, Pyrazinamide, Ethambutol) • Rapid clinical improvement • Chest X-ray after 2 months of TB treatment is markedly improved The MTCT - Plus Initiative 38 The MTCT - Plus Initiative 39 The MTCT - Plus Initiative 40 Case 2: continued • Started on HIV treatment after 2 months of TB therapy • 7 days later – patient developed fevers, cough and left pleuritic chest pain The MTCT - Plus Initiative 41 The MTCT - Plus Initiative 42 Issues in using antiretroviral therapy during TB therapy • Identifying patients who would benefit from antiretroviral therapy • Drug-drug interactions • Immune reconstitution events • Overlapping drug side effect profiles - HIV and TB drugs • Adherence challenge of multidrug therapy for 2 infections • Coordinating care between TB and HIV care providers The MTCT - Plus Initiative 43 Immune reconstitution events in HIV - related TB • Definition - increase in manifestations of TB at prior sites or new manifestations of disease • Closely associated with starting ARV (days to weeks) • Rarely associated with starting TB therapy • Natural history • duration - days to months • waxing and waning is common The MTCT - Plus Initiative 44 Types of immune reconstitution events among patients with HIV - related TB • Hectic 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 The MTCT - Plus Initiative 45 Recurrent fever and increasing abdominal pain after starting ARV HAART - 6/25 The MTCT - Plus Initiative 46 Psoas abscess causing abdominal pain on CT scan of abdomen The MTCT - Plus Initiative 47 Worsening axillary adenopathy after starting ARV The MTCT - Plus Initiative 48 Frequency of immune reconstitution events among patients starting ARV % with immune reconstitution event 40 35 30 25 20 15 10 5 0 1 2 3 4 Study 5 6 7 49 The MTCT - Plus Initiative Risk Factors for the Development of Immune Reconstitution Events • Low CD4+ cell count • Shorter time from the initiation of TB therapy to the initiation of antiretroviral therapy The MTCT - Plus Initiative 50 Management of suspected immune reconstitution events • Inform patients about the possibility of an event after starting ARV (“You may feel like the TB is coming back”) • Evaluate for possible TB treatment failure • Assess for other HIV-related complications, e.g. another opportunistic infection • Management of symptoms, e.g. use nonsteroidal anti inflammatory drugs • Steroids may be needed for severe symptoms (1mg/kg) The MTCT - Plus Initiative 51 Issues in using antiretroviral therapy during TB therapy • Identification of patients who would benefit from antiretroviral therapy • Drug-drug interactions • Immune reconstitution events • Overlapping ARV and TB drug side effect • Adherence with multi-drug therapy for 2 infections • Coordinating care between TB and HIV care providers The MTCT - Plus Initiative 52 Adverse events during treatment • 54% (99/167) had adverse events • 34% interrupted TB or HIV therapy • Common adverse events – Peripheral neuropathy (21%) - more common with use of stavudine – Skin rash (17%) • • • • TB drugs (16) co-trimoxazole (7) nevirapine (2) other drugs (4) AIDS 2002;16:75-83 – hepatitis (6%) – TB drugs (6), unknown (5) The MTCT - Plus Initiative 53 Overlapping side effect profiles of first-line antituberculosis drugs and antiretroviral drugs Side effect Possible causes Antituberculosis drugs Skin rash PZA, RIF, INH Antiretroviral drugs NVP, EFV, ABC Nausea, vomiting Hepatitis Leukopenia, anemia PZA, RIF, INH PZA, RIF, INH RIF ZDV, RIT, AMP, IDV NVP, PIs, immune reconstitution ZDV NVP (nevirapine), EFV (efavirenz), ABC (abacavir), ZDV (zidovudine), RIT (ritonavir), AMP (amprenavir), IND (indinavir), PI (protease inhibitors) The MTCT - Plus Initiative 54 Adverse events during treatment of HIV-TB Event Any grade 4 AST > 10x ULN ANC < 500 Arthralgias Skin rash Temporary DC Permanent DC Number (%) 55 (33%) 13 (8%) 8 (5%) 2 (1%) 13 (8%) 24 (14%) 2 (1%) The MTCT - Plus Initiative 55 Managing adverse events during treatment of HIV-TB • Do one thing at a time - make 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 immune reconstitution events as a possible cause of adverse events during treatment The MTCT - Plus Initiative 56 Issues in using antiretroviral therapy during TB therapy • Identification of patients who would benefit from antiretroviral therapy • Drug-drug interactions • Immune reconstitution events • Overlapping ARV and TB drug side effect • Adherence with multi-drug therapy • Coordinating care between TB and HIV care providers The MTCT - Plus Initiative 57 Adherence with Treatment for TB and HIV • Establish a close relationship with TB treatment program • Make sure patient is ready for antiretroviral therapy – multiple new medications, chance of overlapping adverse events, more complicated than once-daily TB treatment The MTCT - Plus Initiative 58 Adherence with Treatment for TB and HIV • TB treatment often uses directly observed therapy (DOT) - if possible, use DOT visits for TB treatment to enhance adherence to antiretroviral therapy • Try to coordinate medication pickups where possible The MTCT - Plus Initiative 59 Issues in using antiretroviral therapy during TB therapy • Identification patients who would benefit from antiretroviral therapy • Drug-drug interactions • Immune reconstitution events • Overlapping ARV and TB drug side effect • Adherence with multidrug therapy for 2 infections • Coordinating care between TB and HIV care providers The MTCT - Plus Initiative 60 Collaboration with TB Control Program • • • • • Reporting of TB cases Access to TB medications Access to DOT program (if available) Coordination of care Communication regarding management decisions (medications, lab tests, etc.) • Assist in contact investigation through access to family members The MTCT - Plus Initiative 61 Conclusions: I • Early identification of TB with symptom checklist • Start appropriate anti-TB medications, manage any side effects • Evaluate stage of HIV disease and readiness for ARV, discuss with TB control program if patient co-managed with TB provider • For appropriate patients, start ARV (usually 4-8 weeks after starting TB therapy) continued ….. The MTCT - Plus Initiative 62 Conclusions: 2 • Discuss side effects and possibility of immune reconstitution events with patient and TB program • Early follow-up after starting ARV as per MTCTPlus guidelines to check for side effects and/or immune reconstitution events. • Support adherence • Use of encounters for DOT visits for TB therapy to support adherence with antiretroviral therapy • Assure ongoing communication with TB care provider The MTCT - Plus Initiative 63