Presentation on theme: "DOUBLE TROUBLE (TB -HIV)"— Presentation transcript:
1 DOUBLE TROUBLE (TB -HIV) Medical GrandroundsFebruary17, 2010Ledesma HallPresenter: Kristine S de LunaModerator: Dr. Maricel Gler
2 Objectives1. 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.
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 VENOUSDELAYED
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 VENOUSDELAYED
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.
19 History of the Present Illness 5 days PTA Probable disseminated TB and immunocompromised state Few hrs PTA PersistenceADMISSION
20 Review of Systems no rashes no sore throat no difficulty in swallowing no chest painno dysuria
21 Past Medical History (-) PTB gallbladder stones in 2005 post open cholecystectomy(-) blood transfusion
22 Personal Social History non-smokerOccasional alcoholic beverage drinkergoes to the gym 3 times a week for 15 yearsDenies illicit drug useAdmits to have unprotected sex with a male partner for the past 10 yearsCurrently in a sexual relationship with a male
23 Family History(+) pulmonary tuberculosis- mother
24 Physical ExaminationBP: 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 ExaminationLungs: symmetric chest expansion, no retractions, equal vocal and tactile fremiti, resonant, clear breath soundsHeart: AB 5th LICS MCL, no heaves, no thrills, regularly regular rhythm, no murmursAbdomen: flat, surgical scar RUQ, NABS, direct tenderness RUQ, no rebound tenderness, no masses, non-palpable liver edge, non-palpable spleenGenitourinary: no costovertebral angle tendernessExtremities: (-) 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 tuberculosisTo consider immunocompromised state
28 DIFFERENTIAL DIAGNOSIS DISCUSSION: DIFFERENTIALSEstimating 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 durationSource: Irwin, Richard MD & Mark Madison, MD. Diagnosis and Treatment of Cough. New England Journal of Medicine. Vol 343, No. 23 pg 1715 – 1721.28
30 DIFFERENTIAL DIAGNOSIS DISCUSSION: DIFFERENTIALSEstimating 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 duration30
31 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 .31
32 AFB smear and TB PCR AFB smear result: Negative GeneXpert MTb/Rif result: MTB detected, No Rifampicin resistance
33 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 .33
36 Infiltrates in the right upper lobe, compatible with pulmonary tuberculosis of undetermined activity.
37 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 .37
40 Other Laboratory Tests CD4: 74/mm3 (500 to 1500/mm3) Blood CS: negative Prothrombin Time: normal40
41 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.41
43 HIV Screening, Agglutination (Dec 13, 2010): reactive to anti-HIV 1 HIV Screening, EIA (Dec 14, 2010): reactiveChemiluminescence 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 TBThe Philippines is the 9th among the the 22 high burden countries for 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 tuberculosisHIV Infection associated tuberculosis: The Epidemiology and Response. Getahun, et al Stop TB and HIV/AIDS Department WHO Geneva Switzerland May 2010
53 Late 1980’sHIV epidemic increased the number of TB cases in countries with a high prevalence of HIV infection3-fold increase in the number of TB case notifications over the decade
54 2000Increases in HIV-related TB cases mirrored the increase in the prevalence of HIV infection but with a 4-7 year delayNunn 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 deathsGetahun, 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: 205Data Source: DOH-NASPCP Philippine National AIDS Council, Country Report of the Philippines December 2009This 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
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 adultsIncreased disseminated disease and extrapulmonary infection with lower CD4 (60%)HIV is the most powerful factor known to increase the risk of TB
61 Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area CONCLUSION:Increases HIV replicationThe onset of tuberculosis in HIV-infected patients is associated with an increased risk of AIDS and deathBadri M, et al Int J Tuberc Lung Dse 2001
62 Pattern of HIV-Related TB HIV infectionProgressionCD 4 T-lymphocytes declineCD 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
64 Clinical features suggestive of HIV co-infection in TB patients PastHistorysexually transmitted infectionherpes zoster (shingles) which often leaves a scarrecent or recurrent pneumoniasevere bacterial infectionsrecent treated TBSymptomsweight 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)Signsscar of herpes zosterpruritic (itchy) papular skin rashKaposi sarcomasymmetrical generalized lymphadenopathyoral candidiasispersistent painful genital ulcerationaphthous ulcerationIf 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 immunocompromise1. Mild – cavitation & upper lobe infiltrates2. Severe- interstitial infiltrates esp in lower zones, no abnormalityThe diagnostics of Tb in HIV is similar with that of non hiv infected pxs
66 DiagnosticsSputum 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 PositiveSmear NegativeOne sputum smear examination positive for AFB andLaboratory confirmation of HIV Infection orStrong evidence of HIV infectionAt least 2 sputum specimens negative for AFB andRadiological abnormalities consistent with active TB and laboratory confirmation of HIV infection or strong clinical evidence of HIV andDecision to treat with full course of Anti-TB chemotherapy ORAFB smear negative sputum which is culture positive
70 Recommended Treatment 2HRZE/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
71 Treating HIV and TB Together When to start anti-retroviral treatment?
72 Anti-Retroviral Therapy Introduced in 1996Highly Active Anti-Retroviral Therapy (HAART)- combination of ARV drugsDramatic reductions in morbidity and mortality in HIV-infected peopleAs with anti TB tx
73 Promise of ART in TB/HIV High mortality in pts w/ HIV+TB before ART to 30% in first yrEarly deaths due to TB but later mortality due to AIDS & other OIsHighest mortality w/ low CD4 ( 100)
74 Balance on timing of start of ART Overlapping toxicities Risk of death due toHIV/AIDS ProgressionGI TolerabilityHigh Pill BurdenOverlapping toxicitiesIRISThere are major challenges in giving ART along with TB treatment
75 ART and TB Treatment – Drug Interactions Isoniazid & Nucleoside Reverse Transcriptase Inhibitors - cause peripheral neuropathyRifampicin – 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 drugsOccurs in 6% to 36% of patients on HAARTSymptoms: high fever, lymphadenopathy, CNS lesionsWorsening of CXR findingsNo 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 ARTmore frequent in patients started on ART during first 2 mos of anti-TB Tx
79 IRIS ManagementTreat 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 SAPiTEarly ARTART 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 ARTART initiated after TB therapy completed(n = 213)Primary endpoint: all-cause mortalityFrom 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 1.00Early ARTSequential ART0.950.90Survival0.8556% 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 Africa645 patients were randomly allocated into three treatment groups:Integrated treatment groups:Patients start ART within the first two months of starting TB treatmentPatients 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 treatmentThe dire outcomes of patients undergoing sequential treatment, group 3, prompted the Trail Safety Monitoring Committee to intervene and cancel this arm of the trial0.80Intensive phase of TB treatment0.75Continuation phase of TB treatmentPost-TB treatment0.70123456789101112131415161718192021222324Months Post-randomizationAbdool 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 placeboDesigned 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 CambodiaPrimary Endpoint: Survival at the end of trial
85 CAMELIA TrialMortality was reduced by 34% when HAART was initiated 2 weeks vs 8 weeks after onset of TB treatmentHAART has been extremely successful, as evidenced by >95% of patients with undetected viral loadHAART initiation after 2 weeks after onset of TB treatment could potentially save 150,000 to 450,000 annual TB-HIV deaths
86 2010 WHO GuidelineStart ART in all HIV infected individuals with active TB irrespective of CD4 count- Strong recommendation, low quality of evidenceStart 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 TBINTERVENTIONS against HIVIntensified case findingCure and TB preventive therapyCondom promotionSTD treatment or prophylaxisAnti-retroviral therapyPrevention of HIV should be a priority for TB controlTB care and prevention should be priority concerns of HIV/AIDS programs
88 CONCLUSIONHIV is the most powerful factor known to increase the risk of TBTB increases HIV replication and viral loadTreatment of co-infected patients requires anti-TB and antiretroviral drugs to be administered concomitantly