Tuberculosis and HIVTuberculosis and HIV

Dr. Stuart Skinner MD, FRCPCDr. Stuart Skinner MD, FRCPC

Assistant Professor, Division of Infectious DiseasesAssistant Professor, Division of Infectious Diseases

University of SaskatchewanUniversity of Saskatchewan

Clinical Director, Saskatchewan HIV Provincial Clinical Director, Saskatchewan HIV Provincial Leadership TeamLeadership Team

ObjectivesObjectives

Review the interactions between HIV and Review the interactions between HIV and Mycobacterium tuberculosisMycobacterium tuberculosis

Discuss the current HIV epidemic in Discuss the current HIV epidemic in SaskatchewanSaskatchewan

Provide an overview of the need for Provide an overview of the need for screening for HIV in TB patients and for screening for HIV in TB patients and for TB in HIV patients in Saskatchewan TB in HIV patients in Saskatchewan

Case – HIV/TB Co-infectionCase – HIV/TB Co-infection

38 y.o. from La Loche, 38 y.o. from La Loche, presented with fever, cough presented with fever, cough and weight loss in Dec ‘10and weight loss in Dec ‘10– History of HTN History of HTN

nephropathy, alcohol usenephropathy, alcohol use– HCV negativeHCV negative

Diagnosed with TB empyemaDiagnosed with TB empyema– Started INH/RMP/EMBStarted INH/RMP/EMB

No drug resistance No drug resistance

HIV test positiveHIV test positive

January 2011January 2011Admitted to hospital for 1 Admitted to hospital for 1 monthmonth– Needed drainage of effusionNeeded drainage of effusion

HIVHIV– CD4 = 42 CD4 = 42 – Viral load > 10,000,000Viral load > 10,000,000– Opportunistic infections:Opportunistic infections:

Extrapulmonary TBExtrapulmonary TB

ThrushThrush

Proximal onychomycosisProximal onychomycosis

Extensive HPVExtensive HPV

Eosinophilic folliculitisEosinophilic folliculitis

March 2011March 2011Adherence was excellent with medicationsAdherence was excellent with medications– CD4 = 141 ; VL = 260CD4 = 141 ; VL = 260

Struggled with alcohol use due to issues of isolation, Struggled with alcohol use due to issues of isolation, stigma, and being overwhelmed with recent eventsstigma, and being overwhelmed with recent events

Increased chest pain and SOB Increased chest pain and SOB – Required additional 40 day hospitalization for chest tube Required additional 40 day hospitalization for chest tube

insertion and drainage likely due to IRISinsertion and drainage likely due to IRIS

Liver enzymes significantly elevatedLiver enzymes significantly elevated– Necessitated the discontinuation of HIV and TB medsNecessitated the discontinuation of HIV and TB meds

Further follow-upFurther follow-up

May 2011May 2011– Liver enzymes improved enough to start TB medsLiver enzymes improved enough to start TB meds– HIV viral load now > 10,000,000HIV viral load now > 10,000,000

August 2011August 2011– Liver enzymes normalizedLiver enzymes normalized– CD = 41 ; VL = 51,000CD = 41 ; VL = 51,000– Antiretrovirals re-startedAntiretrovirals re-started– Still on TB medsStill on TB meds

HIV - GlobalHIV - Global

Estimated 39.5 million people are living with HIV Estimated 39.5 million people are living with HIV – 4.3 million new infections 20064.3 million new infections 2006– 2.9 million deaths in 20062.9 million deaths in 2006– Only 5% of infected individuals received treatment Only 5% of infected individuals received treatment

Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO). UNAIDS/WHO AIDS epidemic Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO). UNAIDS/WHO AIDS epidemic update: December 2006. update: December 2006.

Estimated 12-14 million people are also infected Estimated 12-14 million people are also infected with TBwith TB

1.6% to 5.8% of AIDS cases estimated to have 1.6% to 5.8% of AIDS cases estimated to have TB in CanadaTB in Canada

– Harris et al. HIV Testing among Canadian Tuberculosis Cases from 1997 to 1998. Can J Infect Dis Med Microbiol. 2006 Harris et al. HIV Testing among Canadian Tuberculosis Cases from 1997 to 1998. Can J Infect Dis Med Microbiol. 2006 May;17(3):165-8.May;17(3):165-8.

HIV Cases in SaskatchewanHIV Cases in Saskatchewan

Fig. 1 HIV Cases in Saskatchewan,2000 to 2010

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Saskatchewan Saskatoon Canada

Rates of New HIV Infections

Slide courtesy of Dr. Opondo

Increased Cases in Central and Increased Cases in Central and Northern Saskatchewan (FNIH)Northern Saskatchewan (FNIH)

• Between January and Between January and May 2011 there were May 2011 there were 21 new FNIH cases in 21 new FNIH cases in SaskatchewanSaskatchewan• Age range 17-57 Age range 17-57 • 15 IDU 15 IDU

• 6 reported no risk6 reported no risk

• 19 HCV co-infected19 HCV co-infected

Majority were from 2 Majority were from 2 communitiescommunities• 3 clusters3 clusters

HIV and TB Co-infections in SKHIV and TB Co-infections in SK

Increasing numbers of HIV/TB co-infectionIncreasing numbers of HIV/TB co-infection– Particularly in past 12 monthsParticularly in past 12 months

33rdrd most common opportunistic infection most common opportunistic infection– Extrapulmonary TB commonExtrapulmonary TB common

Lymphadenitis, meningitis, osteomyelitisLymphadenitis, meningitis, osteomyelitis

– Miliary TB Miliary TB – 3 deaths this past year3 deaths this past year

HIV and TuberculosisHIV and Tuberculosis‘The Perfect Storm’‘The Perfect Storm’

‘‘The intersection of these 2 diseases is a The intersection of these 2 diseases is a synergy from hell.’synergy from hell.’

Bartlett J. Tuberculosis and HIV infection: partners in human tragedy. J Infect Dis. 2007 Aug Bartlett J. Tuberculosis and HIV infection: partners in human tragedy. J Infect Dis. 2007 Aug 15;196 Suppl 1:S124-5.15;196 Suppl 1:S124-5.

Both are concentrated in areas of povertyBoth are concentrated in areas of poverty– minimal resources for diagnosis, treatment, and minimal resources for diagnosis, treatment, and

infection controlinfection control

Both diseases progress despite the great Both diseases progress despite the great achievements in treatment that have been madeachievements in treatment that have been made

Each epidemic accelerates the otherEach epidemic accelerates the other

Effect of Tuberculosis on HIVEffect of Tuberculosis on HIV

Globally, the most likely cause of death in HIV Globally, the most likely cause of death in HIV infected individualsinfected individuals

Infection with TB results in immune activationInfection with TB results in immune activation– Higher viral loads, rapid progressionHigher viral loads, rapid progression

TB patients are 200x more likely to have AIDS TB patients are 200x more likely to have AIDS than general populationthan general population

Immune reconstitution inflammatory syndromeImmune reconstitution inflammatory syndrome

Overlapping toxicities and interactions between Overlapping toxicities and interactions between anti-TB and antiretroviral drugs complicate anti-TB and antiretroviral drugs complicate treatmenttreatment

Effect of HIV on TuberculosisEffect of HIV on Tuberculosis

HIV is the most significant risk factor for developing HIV is the most significant risk factor for developing active TB active TB – 10% per year among co-infected patients10% per year among co-infected patients

Increasing global burden of TB related to HIVIncreasing global burden of TB related to HIV– Estimated that 10% to 19% of adult TB cases are attributable to Estimated that 10% to 19% of adult TB cases are attributable to

HIVHIVCorbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: Global trends and interactions with the HIV epidemic. Arch Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: Global trends and interactions with the HIV epidemic. Arch

Intern Med 2003 May;163(9):1009.Intern Med 2003 May;163(9):1009.

TB notification rates in countries in sub-Saharan Africa, TB notification rates in countries in sub-Saharan Africa, with high rates of HIV have increased 5%–10% annually with high rates of HIV have increased 5%–10% annually over the past decadeover the past decade– including in countries with well-established TB control programsincluding in countries with well-established TB control programs

Due to immune senescenceDue to immune senescence

Figure 1. Incidence estimates of all forms of tuberculosis (TB), per 100,000 general population, by year, 1990–2004 [7]. “Africa–low HIV” denotes all sub-Saharan African countries where HIV infection prevalence in the adult (15–49 years of age) population is 4%. “Africa–high HIV” denotes all sub-Saharan ⩽countries where HIV infection prevalence in the adult population is >4%. ”World exc AFR EEUR” denotes the world with the exception of Africa and Eastern Europe.

From The Journal of Infectious Diseases 196(s1):S5–S14.© 2007 by the Infectious Diseases Society of America.For permission to reuse, contact journalpermissions@press.uchicago.edu.

Clinical Effect of HIV on Clinical Effect of HIV on TuberculosisTuberculosis

Alters TST resultsAlters TST results

More likely to have atypical radiographs More likely to have atypical radiographs and disseminated diseaseand disseminated disease– Pleural effusions, lymphadenopathyPleural effusions, lymphadenopathy– More likely to have positive blood culturesMore likely to have positive blood cultures– Normal CXR in 15% with AIDSNormal CXR in 15% with AIDS

Challenges of Treating HIV/TB Challenges of Treating HIV/TB Co-infectionCo-infection

Pill burdenPill burden

HepatotoxicityHepatotoxicity

Other drug toxicityOther drug toxicity

Drug interactionsDrug interactions

StigmaStigma

Immune reconstitution syndromeImmune reconstitution syndrome

HIV and TB ResistanceHIV and TB Resistance

HIV co-infection associated with acquired HIV co-infection associated with acquired rifamycin resistancerifamycin resistance

–Jenny-Avital ER. Acquired rifampin resistance in AIDS-related TB. AIDS Clin Care 2002; 14:72-3.Jenny-Avital ER. Acquired rifampin resistance in AIDS-related TB. AIDS Clin Care 2002; 14:72-3.

HIV can lead to malabsorption of anti-TB drugs HIV can lead to malabsorption of anti-TB drugs

Infections with >1 pathogen, including Infections with >1 pathogen, including M. M. tuberculosis, tuberculosis, are not uncommon in HIV-infected are not uncommon in HIV-infected personspersons– Overlapping drug toxicitiesOverlapping drug toxicities

HIV and MDR-TBHIV and MDR-TB

Outbreaks are occurring due to convergence of the TB Outbreaks are occurring due to convergence of the TB and HIV epidemics and HIV epidemics

– Transmission of MDR-TB and XDR-TB to an enlarging pool of Transmission of MDR-TB and XDR-TB to an enlarging pool of HIV-infected and immunocompromised individualsHIV-infected and immunocompromised individuals

Infections result in severe disease:Infections result in severe disease:

– 72% of HIV infected patients with MDR-TB died in outbreak 72% of HIV infected patients with MDR-TB died in outbreak during treatment, compared with 20% of HIV-uninfected during treatment, compared with 20% of HIV-uninfected

Mannheimer et al. Risk factors and outcome of human immunodeficiency virus-infected patients with Mannheimer et al. Risk factors and outcome of human immunodeficiency virus-infected patients with sporadic MDR TB in New York City. Int J Tuberc Lung Dis 1997; 1:319-25.sporadic MDR TB in New York City. Int J Tuberc Lung Dis 1997; 1:319-25.

– 62% of HIV-infected patients with MDR-TB died during treatment 62% of HIV-infected patients with MDR-TB died during treatment in one outbreak, compared with 26% of HIV-infected patients in one outbreak, compared with 26% of HIV-infected patients with TB but without MDR-TBwith TB but without MDR-TB

Park MM et al. Outcome of MDR-TB patients, 1983-1993: prolonged survival with appropriate therapy. Park MM et al. Outcome of MDR-TB patients, 1983-1993: prolonged survival with appropriate therapy. Am J Respir Crit Care Med 1996; 153:317-24.Am J Respir Crit Care Med 1996; 153:317-24.

HIV and MDR-TB in Industrialized CountriesHIV and MDR-TB in Industrialized Countries

Wells et al. HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis. 2007 Aug 15;196 Suppl 1:S86-107

MDR-TB and HIV OutbreaksMDR-TB and HIV OutbreaksNew York City 1990’sNew York City 1990’s– Closely associated with HIV infection, many cases Closely associated with HIV infection, many cases

were nosocomial, and most were lethal were nosocomial, and most were lethal

RussiaRussia– The MDR-TB epidemic in Tomsk Oblast accompanies The MDR-TB epidemic in Tomsk Oblast accompanies

the most explosive epidemic of HIV infection in the the most explosive epidemic of HIV infection in the worldworld

South AfricaSouth Africa– Outbreak of 53 cases of XDR-TB in KwaZulu Natal, Outbreak of 53 cases of XDR-TB in KwaZulu Natal,

all who underwent testing were found to have HIV all who underwent testing were found to have HIV infection, with median survival after specimen infection, with median survival after specimen collection of 16 dayscollection of 16 days

Why Screen for HIV?Why Screen for HIV?

Benefits of treatment before symptoms Benefits of treatment before symptoms developdevelop

Identify asymptomatic patientsIdentify asymptomatic patients– Implement measures to prevent HIV Implement measures to prevent HIV

transmissiontransmission

Clinical Outcome Improved by Starting Clinical Outcome Improved by Starting Therapy at Higher CD4+ Cell CountTherapy at Higher CD4+ Cell Count

Results suggest a Results suggest a lower risk of disease lower risk of disease progression/death progression/death when starting when starting between 351-500 between 351-500 cells/mmcells/mm33

Cumulative Probability of AIDS/Death by CD4+ Cell Count at HAART Initiation

Years Since Initiation of HAART1 2 3 4 5

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Sterne J, et al. CROI 2006. Abstract 525.

101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3

CAMELIA: ART Initiation at Wk 2 CAMELIA: ART Initiation at Wk 2 vs Wk 8 of TB Therapy in HIV-vs Wk 8 of TB Therapy in HIV-

Coinfected PatientsCoinfected Patients

WHO 2010 guidelines WHO 2010 guidelines recommend torecommend to[1][1]

– Initiate HAART in all HIV-Initiate HAART in all HIV-infected patients with TB, infected patients with TB, regardless of CD4+ cell countregardless of CD4+ cell count

– Initiate TB therapy before Initiate TB therapy before HAART, with HAART added HAART, with HAART added as soon as possibleas soon as possible

CAMELIA: randomized, open-label CAMELIA: randomized, open-label trial of HIV-infected patients with trial of HIV-infected patients with newly-diagnosed AFB-positive TB newly-diagnosed AFB-positive TB and CD4+ cell count ≤ 200 and CD4+ cell count ≤ 200 cells/mmcells/mm3 [2]3 [2]

Compared HAART initiation Compared HAART initiation (d4T + 3TC + EFV) at (d4T + 3TC + EFV) at

– Wk 2 (n = 332) vs Wk 2 (n = 332) vs

– Wk 8 (n = 329) of TB therapy Wk 8 (n = 329) of TB therapy

All patients received standard TB All patients received standard TB therapy for 6 mostherapy for 6 mos

1. WHO. Available at: http://www.who.int/hiv/pub/arv/adult/en. 2. Blanc FX, et al. AIDS 2010. Abstract THLBB106.

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0 50 100 150 200 250Time from TB treatment initiation (weeks)

Early arm Late arm

Log-rank p-value: p=0.0042

Survival Survival probability probability (95% CI)(95% CI)

Early armEarly arm Late armLate arm Log-Log-rank rank pp--valuevalue

Week 50Week 50 86.1 (81.8 – 89.4)86.1 (81.8 – 89.4) 80.7 (76.0 – 80.7 (76.0 – 84.6)84.6)

0.070.07

Week 100Week 100 82.6 (78.0 – 86.4)82.6 (78.0 – 86.4) 73.0 (67.7 – 73.0 (67.7 – 77.6)77.6)

0.0060.006

Week150Week150 82.0 (77.2 – 85.9)82.0 (77.2 – 85.9) 70.2 (64.5 – 70.2 (64.5 – 75.2)75.2)

0.0020.002

Kaplan-Meier survival curves

CAMELIA - ConclusionsCAMELIA - Conclusions

Mortality reduced by 34% when HAART Mortality reduced by 34% when HAART was initiated 2 vs 8 weeks after onset of was initiated 2 vs 8 weeks after onset of TB treatmentTB treatment– Highest benefit in those with CD4 < 50Highest benefit in those with CD4 < 50

Early HAART initiation could potentially Early HAART initiation could potentially save 150,000 of the HIV-TB deathssave 150,000 of the HIV-TB deaths

HIV Testing in SaskatchewanHIV Testing in Saskatchewan

Very high incidence rates in SKVery high incidence rates in SK

Late presentation and advanced disease Late presentation and advanced disease seen in SK indicate a need to increase seen in SK indicate a need to increase HIV testing, particularly among hard-to-HIV testing, particularly among hard-to-reach populationsreach populations

Reasons for Reduced HIV Testing Reasons for Reduced HIV Testing

Stigma of getting the testStigma of getting the test

Fear of community exposureFear of community exposure

PovertyPoverty– Loss of housing, income, childrenLoss of housing, income, children

‘‘Sexual code of silence’Sexual code of silence’– Denial of possibility of sexual transmissionDenial of possibility of sexual transmission

Other health priorities above HIV statusOther health priorities above HIV status

Fear of stigma and discrimination of being HIV positiveFear of stigma and discrimination of being HIV positive

Disclosure to partnersDisclosure to partners

HIV Pre-Test CounselingHIV Pre-Test Counseling

Basic education about HIV/AIDSBasic education about HIV/AIDS

HIV antibody testingHIV antibody testing– ELISA and Western BlotELISA and Western Blot

Benefits of testingBenefits of testing

Right to refuseRight to refuse– Opt-out vs. opt-inOpt-out vs. opt-in– Need only verbal consent Need only verbal consent

Availability of follow-upAvailability of follow-up

Confidentiality and reportingConfidentiality and reporting– Test result from Regina is sent directly to physicians officeTest result from Regina is sent directly to physicians office– HIV is reportableHIV is reportable– No information disclosed unless patient consentsNo information disclosed unless patient consents– Patient will be expected to disclose partner names if positivePatient will be expected to disclose partner names if positive

Post-Test CounselingPost-Test Counseling

Assist in understanding test resultAssist in understanding test result– Review meaning of positive and negative resultReview meaning of positive and negative result– Review transmission and partner notificationReview transmission and partner notification– If positive, effective treatments are availableIf positive, effective treatments are available

Address psychological reactionsAddress psychological reactions

Promote behavioural changesPromote behavioural changes

Assess need for follow-upAssess need for follow-up

HIV Testing in TB PatientsHIV Testing in TB Patients

Only 23% of the 1613 cases of TB in 2004 Only 23% of the 1613 cases of TB in 2004 in Canada were tested for HIVin Canada were tested for HIV

Rates of HIV co-infection for those tested Rates of HIV co-infection for those tested in 2004 was 10%in 2004 was 10%–Overestimate due to selection biasOverestimate due to selection bias

Proportion of TB cases reported in Canada for Proportion of TB cases reported in Canada for

which HIV status was known: 1997-2004which HIV status was known: 1997-2004

Special Report of the Canadian Tuberculosis Committee: Tuberculosis and HIV co-infection in Canada. Can Commun Dis Rep 2007; 33(8); 77-83.

HIV Testing in TB Patients and HIV Testing in TB Patients and ContactsContacts

All patients with TB should undergo HIV All patients with TB should undergo HIV testingtesting

HIV testing of contacts of infectious TB HIV testing of contacts of infectious TB cases should be consideredcases should be considered

Information concerning HIV should be Information concerning HIV should be available to patients for whom testing is available to patients for whom testing is recommendedrecommended

Source: 2007 Canadian Tuberculosis StandardsSource: 2007 Canadian Tuberculosis Standards

TB Screening in HIV Positive TB Screening in HIV Positive PatientsPatients

All newly diagnosed HIV patients are screened on All newly diagnosed HIV patients are screened on history, TST and chest x-rayhistory, TST and chest x-ray– Induration ≥5 mm is considered positiveInduration ≥5 mm is considered positive– False negatives in patients with low CD4 countsFalse negatives in patients with low CD4 counts

Should be repeated when CD4 counts have recoveredShould be repeated when CD4 counts have recovered

Annual TST should be done if patients have Annual TST should be done if patients have ongoing TB exposureongoing TB exposure

Only 20-25% of HIV patients who receive a TST Only 20-25% of HIV patients who receive a TST have it read at 48 hourshave it read at 48 hours– Need new strategies to improve screeningNeed new strategies to improve screening

Unique Aspects of Treatment Unique Aspects of Treatment for HIV/TB Co-infectionsfor HIV/TB Co-infections

Consider LTBI treatment for HIV positive patients Consider LTBI treatment for HIV positive patients who are close contacts with infectious TB who are close contacts with infectious TB regardless of TST resultregardless of TST result

If malabsorption a concern, may need to do ARV If malabsorption a concern, may need to do ARV or TB drug levelsor TB drug levels

Regarding drug interactionsRegarding drug interactionsNNRTI class is recommended due to drug interactions NNRTI class is recommended due to drug interactions with rifampinwith rifampin

If PI regimen is used, rifabutin would be preferred If PI regimen is used, rifabutin would be preferred agent agent

Joint Clinical TB/HIV Initiatives Joint Clinical TB/HIV Initiatives in Saskatchewanin Saskatchewan

Joint HIV/TB remote clinicsJoint HIV/TB remote clinics– La Loche, La RongeLa Loche, La Ronge

Increased communication between Increased communication between servicesservices– Development of TB/HIV co-infection case Development of TB/HIV co-infection case

conferencesconferences– Begin developing management recommendations for Begin developing management recommendations for

co-infectionsco-infections

Increase testingIncrease testing

HIV and TB - ConclusionsHIV and TB - ConclusionsHIV and TB infections epidemics act synergisticallyHIV and TB infections epidemics act synergistically– Higher prevalence and altered clinical courseHigher prevalence and altered clinical course– Management may be altered and is more challenging if co-Management may be altered and is more challenging if co-

infectedinfected– HIV/AIDS increases incidence of TB and MDR-TBHIV/AIDS increases incidence of TB and MDR-TB

HIV epidemic is occurring in SaskatchewanHIV epidemic is occurring in Saskatchewan– Increasing HIV numbers in communities with active TBIncreasing HIV numbers in communities with active TB

PHAC and CDC recommend universal HIV testing for newly PHAC and CDC recommend universal HIV testing for newly diagnosed TB patientsdiagnosed TB patients– More testing is needed to identify asymptomatic patients and More testing is needed to identify asymptomatic patients and

those with limited access to carethose with limited access to care