Medical GrandroundsFebruary17, 2010

Ledesma HallPresenter: Kristine S de Luna

Moderator: Dr. Maricel Gler

DOUBLE TROUBLE(TB -HIV)

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.

Identifying Data

R.A.51 years old, maleSingle

Chief Complaint

Fever and cough

History of the Present Illness1 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

PLAIN

DELAYEDPORTAL VENOUS

ARTERIAL

PLAIN ARTERIAL

PORTAL VENOUS DELAYED

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.

Mildly enhancing central focus with partially calcified wall in hepatic segment VII.

Ovoid focus in hepatic segment II, likely a hemangioma.

Upper gastrointestinal series

Normal upper gastrointestinal series

History of the Present Illness5 days PTA Probable

disseminated TB and

immunocompromised state

Few hrs PTA Persistence ADMISSION

Review of Systemsno rashes no sore throatno difficulty in swallowing no chest painno dysuria

Past Medical History(-) PTBgallbladder stones in 2005 post open cholecystectomy

(-) blood transfusion

Personal Social Historynon-smokerOccasional alcoholic beverage drinkergoes to the gym 3 times a week for 15 years

Denies illicit drug useAdmits to have unprotected sex with a male partner for the past 10 years

Currently in a sexual relationship with a male

 

Family History(+) pulmonary tuberculosis- mother

Physical ExaminationBP: 100/60 CR: 110, reg RR: 22 T: 38.1

Height: 165.1 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

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

AFB smear and TB PCR

AFB smear result: Negative

GeneXpert MTb/Rif result: MTB detected, No Rifampicin resistance

Initial Impression

Pulmonary TB, Smear Negative

To consider disseminated tuberculosis To consider immunocompromised state

DIFFERENTIAL DIAGNOSIS

A cu te< 3 w e e ks

S ub a cu te3 - 8 w ee ks

C h ro n ic> 8 w e e ks

C O U G H

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

DIFFERENTIAL DIAGNOSIS

g a llb ladd er , b i lia ry p a nc rea tic h e pa tic re na l p u lm o na ry

r ig ht up per qu ad ran t p a in

Course in the WardDay 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 .

AFB smear and TB PCR

AFB smear result: Negative

GeneXpert MTb/Rif result: MTB detected, No Rifampicin resistance

Course in the WardDay 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 .

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

Course in the WardDay 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 .

Complete Blood CountDec 9, 2010

Haemoglobin (nv 14 -17.5) 12.6 g/dl (l)Hematocrit (nv 41.5 – 50.4) 35.9% (l)RBC (nv 4.5 -5.9) 4.67 x 10^6/ULWBC (nv 4.4 -11) 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 150,000-450,000) 198,000/ULMCV (nv 80-96) 76.9 um^3 (l)MCHC (nv 33.4 -35.5) 35.10 %MCH (nv 27.5-33.2) 27 pg (l)RDW (nv 11.6-14.6) 14.6 %

ChemistryDec 9, 2010 Dec 10, 2010

Amylase (nv 13-60) 523 U/L (h) 436.5 (h)Lipase (nv 28-100) 711 U/L (h) 316 (h)Total protein (nv 6.4-8.3) 8 g/dlAlbumin (nv 3.5 -5.2) 3.5 g/dlGlobulin 4.5 g/dlA/G ratio (nv 1.1 – 1.6) 0.78AST (nv 10-50) 36 U/LALT (nv 10-50) 17 U/LAlkaline phosphatase (nv 40-130)

95 U/L

Total Bilirubin (nv 0-1) 0.73 mg/dlDirect Bilirubin (nv 0-0.3) 0.37 mg/dl (h)Indirect Bilirubin (nv 0.1 -1) 0.36 mg/dlCRP-LX 42.21 mg/l (h)ESR (nv 0-20 mm/hr) 98 (h)

Other Laboratory Tests

CD4: 74/mm3 (500 to 1500/mm3)

Blood CS: negativeProthrombin Time: normal

Course in the WardDay 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: negativeVDRL: negative Anti-HAV IgG:positiveAnti-HCV: negativeHIV VIRAL LOAD PCR: 780, 000

copies/ml

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)

Final Diagnosis

Disseminated TuberculosisAcquired Immune Deficiency Syndrome

Epidemiology of TB

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

HIV Prevalence in the Philippines Department of Health – National Epidemiology

Center November 2010

Department of Health – National Epidemiology Center

November 2010

Types of Sexual Transmission

Mode of Transmission

HIV + TB

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

WHO Data – Philippines 2009

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

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

200880% - Countries on sub-Saharan Africa

10% - Southeast AsiaTB accounted for 26% of AIDS-related deaths

Getahun, et al. HIV Infection-Associated Tuberculosis-The Epidemiology and Response. Clinical Infectious Disease 2010.

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

Susceptibility

HIV

TB Disease Progression

Effects of HIV on TB

• 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

Effects of TB on HIV

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

Pattern of HIV-Related TBHIV infection

Progression

CD 4 T-lymphocytes decline

Immune system less able to prevent growth/spread of M. tuberculosis

DIAGNOSISTB + HIV

PastHistory

• 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

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 immunocompromise1. Mild – cavitation & upper lobe infiltrates2. Severe- interstitial infiltrates esp in lower zones, no abnormality

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

Case Definitions

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

TREATMENTTB + HIV

Recommended Treatment

Recommended Treatment2HRZE/4HRMay prolong treatment up to 9 mos (for patients with delayed response)Advanced HIV (CD4 counts < 100/ul)

- treated dailyRifampicin plays a key role in

treatment: 2-3x higher recurrence rate if not included in continuation phase

When to start anti-retroviral treatment?

Treating HIV and TB Together

Anti-Retroviral TherapyIntroduced in 1996Highly Active Anti-Retroviral

Therapy (HAART)- combination of ARV drugs

Dramatic reductions in morbidity and mortality in HIV-infected people

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)

Balance on timing of start of ART

GI Tolerability

High Pill Burden

Overlapping toxicities

IRIS

Risk of death due

to HIV/AIDS

Progression

ART and TB Treatment – Drug InteractionsIsoniazid & Nucleoside Reverse

Transcriptase Inhibitors - cause peripheral neuropathy

Rifampicin – can decrease blood levels of PIs and NNRTIs (MOA: stimulates the activity of cytochrome P450)

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

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 findingsNo diagnostic laboratory tests

(must exclude treatment failure)

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

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)

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

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)

SAPiT

HIV-infected patients diagnosed with TB and

CD4+ cell count < 500 cells/mm3

(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

Abdool Karim SS, et al. CROI 2009. Abstract 36a.

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Su

rviv

al

Months Post-randomization

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Intensive

phase of TB

treatment

Post-TB treatmentContinuationphase of TB

treatment

Early ARTSequential ART

SAPiT: Increased survival with concurrent HIV and TB treatment

Primary Endpoint: Survival at the end of trial

CAMELIA Trial

CAMELIA TrialMortality 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

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

Approach to Decrease Burden of TB/HIVINTERVENTIONS against TB

INTERVENTIONS against HIV

Intensified case finding

Cure and TB preventive therapy

Condom promotionSTD treatment or

prophylaxisAnti-retroviral

therapy

CONCLUSION

HIV is the most powerful factor known to increase the risk of TB

TB increases HIV replication and viral loadTreatment of co-infected patients requires

anti-TB and antiretroviral drugs to be administered concomitantly

THANK YOU.