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Medical Grandrounds February17, 2010 Ledesma Hall Presenter: Kristine S de Luna Moderator: Dr. Maricel Gler DOUBLE TROUBLE (TB -HIV)

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Presentation on theme: "Medical Grandrounds February17, 2010 Ledesma Hall Presenter: Kristine S de Luna Moderator: Dr. Maricel Gler DOUBLE TROUBLE (TB -HIV)"— Presentation transcript:

1 Medical Grandrounds February17, 2010 Ledesma Hall Presenter: Kristine S de Luna Moderator: Dr. Maricel Gler DOUBLE TROUBLE (TB -HIV)

2 Objectives 1. To present a case of a patient with AIDS who developed disseminated TB. 2. To discuss the pathophysiology of TB in AIDS. 3. To discuss the challenges in the diagnosis of TB in AIDS. 4. To discuss the challenges in the treatment of TB in AIDS, as well as current guidelines in the management.

3 Identifying Data R.A. 51 years old, male Single

4 Chief Complaint Fever and cough

5 History of the Present Illness 1 month PTA cough; fever; weight loss (50%) 3 weeks PTA right upper quadrant abdominal pain nausea; appetite loss 2 weeks PTA GI consult, Impression: pancreatitis, liver abscess CT scan of the abdomen Meds: Cefixime, Metronidazole, pancreatin Infectious Diseases Specialist Referral

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10 PLAIN DELAYEDPORTAL VENOUS ARTERIAL

11 PLAINARTERIAL PORTAL VENOUS DELAYED

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13 Prominent pancreatic head with moderate surrounding fat stranding and prominent lymph nodes. Small pockets of air within the pancreatic head with a suspicious connection to the duodenum. Duodeno-pancreatic fistula has to be ruled out.

14 Mildly enhancing central focus with partially calcified wall in hepatic segment VII. Ovoid focus in hepatic segment II, likely a hemangioma.

15 Upper gastrointestinal series

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18 Normal upper gastrointestinal series

19 History of the Present Illness 5 days PTA Probable disseminated TB and immunocompromised state Few hrs PTA Persistence ADMISSION

20 Review of Systems no rashes no sore throat no difficulty in swallowing no chest pain no dysuria

21 Past Medical History (-) PTB gallbladder stones in 2005 post open cholecystectomy (-) blood transfusion

22 Personal Social History non-smoker Occasional alcoholic beverage drinker goes to the gym 3 times a week for 15 years Denies illicit drug use Admits to have unprotected sex with a male partner for the past 10 years Currently in a sexual relationship with a male

23 Family History (+) pulmonary tuberculosis- mother

24 Physical Examination BP: 100/60 CR: 110, reg RR: 22 T: 38.1 Height: cm Weight: 65.2 kg BMI : 23.9 Pain Scale: 2/10 General Appearance: weak-looking, conscious, not in CP distress Skin: warm, no active dermatoses, (+) pallor HEENT: no nasaoaural discharge, no oral lesions, non-hyperemic posterior pharyngeal walls, tonsils not enlarged, 2 movable, non- tender, non-matted submandibular lymph nodes (approx 1 x 1 cm each) bilateral, midline trachea

25 Physical Examination Lungs: symmetric chest expansion, no retractions, equal vocal and tactile fremiti, resonant, clear breath sounds Heart: AB 5th LICS MCL, no heaves, no thrills, regularly regular rhythm, no murmurs Abdomen: flat, surgical scar RUQ, NABS, direct tenderness RUQ, no rebound tenderness, no masses, non-palpable liver edge, non-palpable spleen Genitourinary: no costovertebral angle tenderness Extremities: (-) edema, (-) cyanosis, pulses full and equal

26 AFB smear and TB PCR AFB smear result: Negative GeneXpert MTb/Rif result: MTB detected, No Rifampicin resistance

27 Initial Impression Pulmonary TB, Smear Negative To consider disseminated tuberculosis To consider immunocompromised state

28 DIFFERENTIAL DIAGNOSIS Source: Irwin, Richard MD & Mark Madison, MD. Diagnosis and Treatment of Cough. New England Journal of Medicine. Vol 343, No. 23 pg 1715 – 1721.

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30 DIFFERENTIAL DIAGNOSIS

31 Course in the Ward Day 1: Admitted to isolation room. Referred to GI. The following were requested: CXR-PA, CBC, ESR, CRP Quantitative, CD4, blood CS at 2 sites, liver function test, amylase, lipase, prothrombin time.isolation room Meds: HRZE 4 tabs daily, pantoprazole 40 mg/IV once daily, vitamin B complex once daily, ocreotide drip x 24 hours, pancreatin 150 mg/tab 3 times a day.

32 AFB smear and TB PCR AFB smear result: Negative GeneXpert MTb/Rif result: MTB detected, No Rifampicin resistance

33 Course in the Ward Day 1: Admitted to isolation room. Referred to GI. The following were requested: CXR-PA, CBC, ESR, CRP Quantitative, CD4, blood CS at 2 sites, liver function test, amylase, lipase, prothrombin time.CXR-PA Meds: HRZE 4 tabs daily, pantoprazole 40 mg/IV once daily, vitamin B complex once daily, ocreotide drip x 24 hours, pancreatin 150 mg/tab 3 times a day.

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36 Infiltrates in the right upper lobe, compatible with pulmonary tuberculosis of undetermined activity.

37 Course in the Ward Day 1: Admitted to isolation room. Referred to GI. The following were requested: CXR-PA, CBC, ESR, CRP Quantitative, CD4, blood CS at 2 sites, liver function test, amylase, lipase, prothrombin time.CBC Meds: HRZE 4 tabs daily, pantoprazole 40 mg/IV once daily, vitamin B complex once daily, ocreotide drip x 24 hours, pancreatin 150 mg/tab 3 times a day.

38 Complete Blood Count Dec 9, 2010 Haemoglobin (nv )12.6 g/dl (l) Hematocrit (nv 41.5 – 50.4)35.9% (l) RBC (nv )4.67 x 10^6/UL WBC (nv )11.16 x 10^3/UL (h) Segmenter (nv 40-70)78% (h) Lymphocyte (nv 22-43)6% (l) Eosinophils (nv 0-4)2% Monocytes (nv 0-7)14% (h) Platelets (nv 150, ,000)198,000/UL MCV (nv 80-96)76.9 um^3 (l) MCHC (nv )35.10 % MCH (nv )27 pg (l) RDW (nv )14.6 %

39 Chemistry Dec 9, 2010Dec 10, 2010 Amylase (nv 13-60) 523 U/L (h)436.5 (h) Lipase (nv ) 711 U/L (h)316 (h) Total protein (nv ) 8 g/dl Albumin (nv ) 3.5 g/dl Globulin 4.5 g/dl A/G ratio (nv 1.1 – 1.6) 0.78 AST (nv 10-50) 36 U/L ALT (nv 10-50) 17 U/L Alkaline phosphatase (nv ) 95 U/L Total Bilirubin (nv 0-1) 0.73 mg/dl Direct Bilirubin (nv 0-0.3) 0.37 mg/dl (h) Indirect Bilirubin (nv ) 0.36 mg/dl CRP-LX mg/l (h) ESR (nv 0-20 mm/hr) 98 (h)

40 Other Laboratory Tests CD4: 74/mm3 (500 to 1500/mm3) Blood CS: negative Prothrombin Time: normal

41 Course in the Ward Day 2: Febrile episodes. No pain. Abdomen: soft, non-tender. Ocreotide 100 mcg SC once a day. Day 3: For HBsAg, VDRL, anti-HCV, anti-HAV IgG, HIV viral load. Soft, low fat diet. May go home.HBsAg, VDRL, anti-HCV, anti-HAV IgG, HIV viral load

42 HBsAg: negative VDRL: negative Anti-HAV IgG:positive Anti-HCV: negative HIV VIRAL LOAD PCR: 780, 000 copies/ml

43 HIV Screening, Agglutination (Dec 13, 2010): reactive to anti-HIV 1 HIV Screening, EIA (Dec 14, 2010): reactive Chemiluminescence Microparticle Immunoassay Test for HIV Ag/Ab, Western Blot (Dec 14, 2010): + HIV Ab, bands present (gp 160, gp 120, p 66, p 51, gp 41, p 31, p 24)

44 Final Diagnosis Disseminated Tuberculosis Acquired Immune Deficiency Syndrome

45 Epidemiology of TB The Philippines is the 9 th among the the 22 high burden countries for TB

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47 HIV Prevalence in the Philippines Department of Health – National Epidemiology Center November 2010

48 Department of Health – National Epidemiology Center November 2010

49 Types of Sexual Transmission Mode of Transmission

50 Dual infection HIV + TB

51 EPIDEMIOLOGY of TB in HIV Of 33.2 million persons infected with Human Immunodeficiency Virus (HIV), one-third are estimated to also be infected with Mycobacterium tuberculosis HIV Infection associated tuberculosis: The Epidemiology and Response. Getahun, et al Stop TB and HIV/AIDS Department WHO Geneva Switzerland May 2010

52 WHO Data – Philippines 2009

53 Late 1980s HIV epidemic increased the number of TB cases in countries with a high prevalence of HIV infection 3-fold increase in the number of TB case notifications over the decade

54 2000 Increases in HIV-related TB cases mirrored the increase in the prevalence of HIV infection but with a 4-7 year delay Nunn et al, Tuberculosis Control in the Era of HIV. Nat Rev Immunol 2005

55 % - Countries on sub-Saharan Africa 10% - Southeast Asia TB accounted for 26% of AIDS-related deaths Getahun, et al. HIV Infection-Associated Tuberculosis-The Epidemiology and Response. Clinical Infectious Disease 2010.

56 Philippine Data 2009 Estimated number of HIV+ TB cases: 256 Number adults with advance HIV infection who are currently receiving Anti-retroviral therapy and who were started on TB treatment: 205 Data Source: DOH-NASPCP Philippine National AIDS Council, Country Report of the Philippines December 2009

57 Susceptibility HIV TB Disease Progression

58 Effects of HIV on TB

59 Increases the risk for activation of latent infection and rate of disease progression 7 to 10% increase per year in HIV-infected adults compared to 5 to 10% lifetime risk for HIV-negative adults Increased disseminated disease and extrapulmonary infection with lower CD4 (60%) HIV is the most powerful factor known to increase the risk of TB

60 Effects of TB on HIV

61 Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area Badri M, et al Int J Tuberc Lung Dse 2001 CONCLUSION: Increases HIV replication The onset of tuberculosis in HIV-infected patients is associated with an increased risk of AIDS and death CONCLUSION: Increases HIV replication The onset of tuberculosis in HIV-infected patients is associated with an increased risk of AIDS and death

62 Pattern of HIV-Related TB HIV infection Progression CD 4 T-lymphocytes decline Immune system less able to prevent growth/spread of M. tuberculosis

63 DIAGNOSIS TB + HIV

64 Past History sexually transmitted infection herpes zoster (shingles) which often leaves a scar recent or recurrent pneumonia severe bacterial infections recent treated TB Symptoms weight loss (> 10 kg or > 20% of original weight) diarrhea (> 1 month) retrosternal pain on swallowing (suggests esophageal candidiasis) burning sensation of feet (peripheral sensory neuropathy) Signs scar of herpes zoster pruritic (itchy) papular skin rash Kaposi sarcoma symmetrical generalized lymphadenopathy oral candidiasis persistent painful genital ulceration aphthous ulceration Clinical features suggestive of HIV co-infection in TB patients

65 Diagnostics Sputum smear microscopy - cornerstone of TB diagnosis since mycobacteria per milliliter to be positive - sensitivity in HIV infection is 43% to 51% Chest X-Ray - no CXR pattern is absolutely typical of PTB with underlying HIV infection - CXR changes in TB/HIV reflect the degree of immunocompromise 1. Mild – cavitation & upper lobe infiltrates 2. Severe- interstitial infiltrates esp in lower zones, no abnormality

66 Diagnostics Sputum Culture - gold standard for diagnosis of TB - HIV individuals require more incubation time than for non-HIV infected individuals - careful feasibility studies are in progress (i.e. liquid culture systems that are more sensitive and rapid) - should be encouraged in patients with (-) sputum for people living with HIV who are being evaluated for AFB smear (-) TB

67 Case Definitions Smear PositiveSmear Negative One sputum smear examination positive for AFB and Laboratory confirmation of HIV Infection or Strong evidence of HIV infection At least 2 sputum specimens negative for AFB and Radiological abnormalities consistent with active TB and laboratory confirmation of HIV infection or strong clinical evidence of HIV and Decision to treat with full course of Anti-TB chemotherapy OR AFB smear negative sputum which is culture positive

68 TREATMENT TB + HIV

69 Recommended Treatment

70 2HRZE/4HR May prolong treatment up to 9 mos (for patients with delayed response) Advanced HIV (CD4 counts < 100/ul) - treated daily Rifampicin plays a key role in treatment: 2-3x higher recurrence rate if not included in continuation phase

71 When to start anti-retroviral treatment? Treating HIV and TB Together

72 Anti-Retroviral Therapy Introduced in 1996 Highly Active Anti-Retroviral Therapy (HAART) - combination of ARV drugs Dramatic reductions in morbidity and mortality in HIV-infected people

73 Promise of ART in TB/HIV High mortality in pts w/ HIV+TB before ART - 20 to 30% in first yr Early deaths due to TB but later mortality due to AIDS & other OIs Highest mortality w/ low CD4 ( 100)

74 Balance on timing of start of ART GI Tolerability High Pill Burden Overlapping toxicities IRIS Risk of death due to HIV/AIDS Progression

75 ART and TB Treatment – Drug Interactions Isoniazid & Nucleoside Reverse Transcriptase Inhibitors - cause peripheral neuropathy Rifampicin – can decrease blood levels of PIs and NNRTIs (MOA: stimulates the activity of cytochrome P450)

76 At present, the challenge is to use available ART in patients being treated with rifampicin- containing TB regimens.

77 Immune Reconstitution Inflammatory Syndrome (IRIS) Occurs as a result of simultaneous administration of ART and anti-TB drugs Occurs in 6% to 36% of patients on HAART Symptoms: high fever, lymphadenopathy, CNS lesions Worsening of CXR findings No diagnostic laboratory tests (must exclude treatment failure)

78 IRIS more frequent w/ low CD4 & those w/ extra- pulmonary TB usually begins within 2 to 3 wks of starting ART more frequent in patients started on ART during first 2 mos of anti-TB Tx

79 IRIS Management Treat symptomatically w/ anti-inflammatory drugs to decrease fever & pain (once other causes excluded) Prednisone 1 mg/kg/day tapered over several wks - severe reactions (airway compromise, enlarging pericardial effusion, etc)

80 World Health Organization (WHO). Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach (2006 revision) Timely access to ART minimizes immune deterioration and improves tuberculosis outcomes

81 When is the optimal time to start ART in patients on TB treatment? 2 Trials: SAPiT (Starting Antiretroviral therapy (ART) in three Points In Tuberculosis therapy) CAMELIA (Survival Benefit Associated With Earlier HAART Initiation in Cambodian HIV- Infected Patients Receiving Tuberculosis Therapy)

82 SAPiT HIV-infected patients diagnosed with TB and CD4+ cell count < 500 cells/mm 3 (N = 642) Early ART ART initiated during intensive or continuation phase of TB therapy (n = 429) Sequential ART ART initiated after TB therapy completed (n = 213) Primary endpoint: all-cause mortality From Larry William Chang, MD, MPH, Johns Hopkins School of Medicine, Cochrane Collaborative Group on HIV/AIDS at UCSF

83 Abdool Karim SS, et al. CROI Abstract 36a Survival Months Post-randomization Intensive phase of TB treatment Post-TB treatment Continuation phase of TB treatment Early ART Sequential ART SAPiT: Increased survival with concurrent HIV and TB treatment

84 Primary Endpoint: Survival at the end of trial CAMELIA Trial

85 Mortality was reduced by 34% when HAART was initiated 2 weeks vs 8 weeks after onset of TB treatment HAART has been extremely successful, as evidenced by >95% of patients with undetected viral load HAART initiation after 2 weeks after onset of TB treatment could potentially save 150,000 to 450,000 annual TB-HIV deaths

86 2010 WHO Guideline Start TB treatment first, followed by ART as soon as possible afterwards (and within the first 8 weeks) Start ART in all HIV infected individuals with active TB irrespective of CD4 count - Strong recommendation, low quality of evidence - Strong recommendation, moderate quality of evidence

87 Approach to Decrease Burden of TB/HIV INTERVENTIONS against TB INTERVENTIONS against HIV Intensified case finding Cure and TB preventive therapy Condom promotion STD treatment or prophylaxis Anti-retroviral therapy

88 CONCLUSION HIV is the most powerful factor known to increase the risk of TB TB increases HIV replication and viral load Treatment of co-infected patients requires anti-TB and antiretroviral drugs to be administered concomitantly

89 THANK YOU.


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