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DOUBLE TROUBLE (TB -HIV)

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

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

6 Axial cut at the level of the pancreatic head: Unenhanced CT scan shows prominence of the pancreatic head with peripancreatic fat stranding.

7 Axial cut at the level of the pancreatic head: Contrast-enhanced CT scan shows prominence of the pancreatic head. No discernable mass seen.

8 There are small locules of air seen within the pancreatic head and uncinate process.

9 There is an appreciable connection between the duodenal bulb and the small locules of air in the pancreatic head. No extravasation of contrast into the peritoneal cavity.

10 PLAIN ARTERIAL PORTAL VENOUS DELAYED
2.2 x 2.2 x 2.0 cm. ovoid mildly enhancing central focus with partially calcified wall in hepatic segment VII. (less than 10HU increase; significant increase if more than 20HU) PORTAL VENOUS DELAYED

11 PLAIN ARTERIAL PORTAL VENOUS DELAYED
A 3.1 x 3.0 cm. ovoid focus is also noted in hepatic segment II. It is isodense during the non-contrast phase. It exhibits peripheral enhancement in the arterial phase with centripetal filling appreciated in the portal and delayed phases of the examination. PORTAL VENOUS DELAYED

12 0.3 cm. punctate calcification in segment VI.

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

16 Showing the stomach and first and second portions of the duodenum
Showing the stomach and first and second portions of the duodenum. No appreciable extravasation of contrast seen from the duodenum.

17 Showing the stomach and first and second portions of the duodenum
Showing the stomach and first and second portions of the duodenum. No extravasation of contrast from the duodenum seen.

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
DISCUSSION: DIFFERENTIALS Estimating the duration of cough is the first step in narrowing the list of possible diagnoses. acute, defined as lasting less than three weeks; subacute, lasting three to eight weeks; and chronic, lasting more than eight weeks. Since the acute cough is a very common symptom, we would like to consider the patient’s other chief complaint. One point that I would like to highlight is the positive family history of asthma because this indicates that the patient has hereditary asthma, however we can rule out asthma because it is considered as subacute cough. The patient could also have silent asthma and this could be manifested only when the patient became immunocompromised. However, we could also rule this out since the patient does not manifest the symptoms (wheezes, rales, crackles) of asthma. Chronic could be ruled out because it is not 8 weeks in duration Source: Irwin, Richard MD & Mark Madison, MD. Diagnosis and Treatment of Cough. New England Journal of Medicine. Vol 343, No. 23 pg 1715 – 1721. 28

29

30 DIFFERENTIAL DIAGNOSIS
DISCUSSION: DIFFERENTIALS Estimating the duration of cough is the first step in narrowing the list of possible diagnoses. acute, defined as lasting less than three weeks; subacute, lasting three to eight weeks; and chronic, lasting more than eight weeks. Since the acute cough is a very common symptom, we would like to consider the patient’s other chief complaint. One point that I would like to highlight is the positive family history of asthma because this indicates that the patient has hereditary asthma, however we can rule out asthma because it is considered as subacute cough. The patient could also have silent asthma and this could be manifested only when the patient became immunocompromised. However, we could also rule this out since the patient does not manifest the symptoms (wheezes, rales, crackles) of asthma. Chronic could be ruled out because it is not 8 weeks in duration 30

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. 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 . 31

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. 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 . 33

34 December 9, 2010

35

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. 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 . 37

38 Complete Blood Count Dec 9, 2010 Haemoglobin (nv 14 -17.5)
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, 2010 Dec 10, 2010 523 U/L (h) 436.5 (h) 711 U/L (h)
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 42.21 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 40

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. 41

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 9th among the the 22 high burden countries for TB

46

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 Types of Sexual 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 1980’s 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 2008 80% - 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. Tb and Hiv coinfection

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 This represents TB treatment only. Isoniazid prohylaxis not included

57 Disease Progression Susceptibility HIV TB
HIV increases susceptibility to TB and TB increases HIV viral load. Co-infection increases disease progression and risk of mortality

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
CONCLUSION: Increases HIV replication The onset of tuberculosis in HIV-infected patients is associated with an increased risk of AIDS and death Badri M, et al Int J Tuberc Lung Dse 2001

62 Pattern of HIV-Related TB
HIV infection Progression CD 4 T-lymphocytes decline CD 4 cells play an important role in the body’s immune system against tubercle bacilli. Thus, the immune system becomes less able to prevent the growth qnd spread of M. Tuberculosis. Immune system less able to prevent growth/spread of M. tuberculosis

63 DIAGNOSIS TB + HIV

64 Clinical features suggestive of HIV co-infection in TB patients
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 If we see these in TB patients, we must highly consider HIV co-infection!!

65 Diagnostics Sputum smear microscopy
- cornerstone of TB diagnosis since 1882 - 105 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 The diagnostics of Tb in HIV is similar with that of non hiv infected pxs

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 One sputum smear examination positive for AFB and
Smear Positive Smear 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 Recommended Treatment
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 Treating HIV and TB Together
When to start anti-retroviral treatment?

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 As with anti TB tx

73 Promise of ART in TB/HIV
High mortality in pts w/ HIV+TB before ART 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 Overlapping toxicities
Risk of death due to HIV/AIDS Progression GI Tolerability High Pill Burden Overlapping toxicities IRIS There are major challenges in giving ART along with TB treatment

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) Rifampicin - stimulates the activity of cytochrome P450 liver enzymes, which metabolizes NNRTIs

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

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) 2 trials which led to the 2010 WHO recommendation on ART

82 SAPiT Early ART ART initiated during intensive or continuation phase of TB therapy (n = 429) HIV-infected patients diagnosed with TB and CD4+ cell count < 500 cells/mm3 (N = 642) 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 SAPiT: Increased survival with concurrent HIV and TB treatment
1.00 Early ART Sequential ART 0.95 0.90 Survival 0.85 56% lower rate of death associated with concurrent ART and TB treatment (early ART) Mortality: HR: 0.44 (95% CI: ; P = .003) The SAPIT trial is a randomized, open-label clinical trial to determine the optimal time to start ART in patients on TB treatment, conducted at the CAPRISA eThekwini TB-HIV research unit in KwaZulu-Natal, South Africa 645 patients were randomly allocated into three treatment groups: Integrated treatment groups: Patients start ART within the first two months of starting TB treatment Patients start ART after completing the two-month intensive phase of TB treatment (i.e. initiation of ART in third or fourth month after TB treatment initiation) Sequential treatment group: Patients start ART after completing their TB treatment (i.e. initiation of ART six-eight months after TB treatment initiation) The mortality rate was 55% lower in the integrated treatment groups, 1 and 2, meaning that deaths can be more than halved by combining ART with TB treatment The dire outcomes of patients undergoing sequential treatment, group 3, prompted the Trail Safety Monitoring Committee to intervene and cancel this arm of the trial 0.80 Intensive phase of TB treatment 0.75 Continuation phase of TB treatment Post-TB treatment 0.70 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Post-randomization Abdool Karim SS, et al. CROI Abstract 36a. 83

84 CAMELIA Trial Primary Endpoint: Survival at the end of trial
Prospective, randomized, open-label, 2-armed trial with no placebo Designed as a superiority trial to answer the question of the best timing for the introduction of HAART in severely immunosuppressed (CD4 count <200) HIV infected adults with newly diagnosed TB in Cambodia Primary Endpoint: Survival at the end of trial

85 CAMELIA Trial 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 ART in all HIV infected individuals with active TB irrespective of CD4 count - Strong recommendation, low quality of evidence Start TB treatment first, followed by ART as soon as possible afterwards (and within the first 8 weeks) - 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 Prevention of HIV should be a priority for TB control TB care and prevention should be priority concerns of HIV/AIDS programs

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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