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Tuberculosis and HIV Dr. Stuart Skinner MD, FRCPC

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1 Tuberculosis and HIV Dr. Stuart Skinner MD, FRCPC
Assistant Professor, Division of Infectious Diseases University of Saskatchewan Clinical Director, Saskatchewan HIV Provincial Leadership Team

2 Objectives Review the interactions between HIV and Mycobacterium tuberculosis Discuss the current HIV epidemic in Saskatchewan Provide an overview of the need for screening for HIV in TB patients and for TB in HIV patients in Saskatchewan

3 Case – HIV/TB Co-infection
38 y.o. from La Loche, presented with fever, cough and weight loss in Dec ‘10 History of HTN nephropathy, alcohol use HCV negative Diagnosed with TB empyema Started INH/RMP/EMB No drug resistance HIV test positive

4 January 2011 Admitted to hospital for 1 month HIV
Needed drainage of effusion HIV CD4 = 42 Viral load > 10,000,000 Opportunistic infections: Extrapulmonary TB Thrush Proximal onychomycosis Extensive HPV Eosinophilic folliculitis

5 March 2011 Adherence was excellent with medications
CD4 = 141 ; VL = 260 Struggled with alcohol use due to issues of isolation, stigma, and being overwhelmed with recent events Increased chest pain and SOB Required additional 40 day hospitalization for chest tube insertion and drainage likely due to IRIS Liver enzymes significantly elevated Necessitated the discontinuation of HIV and TB meds

6 Further follow-up May 2011 August 2011
Liver enzymes improved enough to start TB meds HIV viral load now > 10,000,000 August 2011 Liver enzymes normalized CD = 41 ; VL = 51,000 Antiretrovirals re-started Still on TB meds

7 HIV - Global Estimated 39.5 million people are living with HIV
4.3 million new infections 2006 2.9 million deaths in 2006 Only 5% of infected individuals received treatment Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO). UNAIDS/WHO AIDS epidemic update: December 2006. Estimated million people are also infected with TB 1.6% to 5.8% of AIDS cases estimated to have TB in Canada Harris et al. HIV Testing among Canadian Tuberculosis Cases from 1997 to Can J Infect Dis Med Microbiol May;17(3):165-8. Between 1990 and 2005, the incidence of TB increased at an average rate of 7% per year in those countries where the prevalence of HIV infection among adults is high ( 5%), but the average rate of increase was only 1.3% per year in countries where the prevalence of HIV infection is low (<5%)

8 HIV Cases in Saskatchewan

9 Rates of New HIV Infections
Slide courtesy of Dr. Opondo

10 Increased Cases in Central and Northern Saskatchewan (FNIH)
Between January and May 2011 there were 21 new FNIH cases in Saskatchewan Age range 17-57 15 IDU 6 reported no risk 19 HCV co-infected Majority were from 2 communities 3 clusters

11 HIV and TB Co-infections in SK
Increasing numbers of HIV/TB co-infection Particularly in past 12 months 3rd most common opportunistic infection Extrapulmonary TB common Lymphadenitis, meningitis, osteomyelitis Miliary TB 3 deaths this past year

12 HIV and Tuberculosis ‘The Perfect Storm’
‘The intersection of these 2 diseases is a synergy from hell.’ Bartlett J. Tuberculosis and HIV infection: partners in human tragedy. J Infect Dis Aug 15;196 Suppl 1:S124-5. Both are concentrated in areas of poverty minimal resources for diagnosis, treatment, and infection control Both diseases progress despite the great achievements in treatment that have been made Each epidemic accelerates the other

13 Effect of Tuberculosis on HIV
Globally, the most likely cause of death in HIV infected individuals Infection with TB results in immune activation Higher viral loads, rapid progression TB patients are 200x more likely to have AIDS than general population Immune reconstitution inflammatory syndrome Overlapping toxicities and interactions between anti-TB and antiretroviral drugs complicate treatment

14 Effect of HIV on Tuberculosis
HIV is the most significant risk factor for developing active TB 10% per year among co-infected patients Increasing global burden of TB related to HIV Estimated that 10% to 19% of adult TB cases are attributable to HIV 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. TB notification rates in countries in sub-Saharan Africa, with high rates of HIV have increased 5%–10% annually over the past decade including in countries with well-established TB control programs Due to immune senescence

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

16 Clinical Effect of HIV on Tuberculosis
Alters TST results More likely to have atypical radiographs and disseminated disease Pleural effusions, lymphadenopathy More likely to have positive blood cultures Normal CXR in 15% with AIDS

17 Challenges of Treating HIV/TB Co-infection
Pill burden Hepatotoxicity Other drug toxicity Drug interactions Stigma Immune reconstitution syndrome

18 HIV and TB Resistance HIV co-infection associated with acquired rifamycin resistance 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 Infections with >1 pathogen, including M. tuberculosis, are not uncommon in HIV-infected persons Overlapping drug toxicities

19 HIV and MDR-TB Outbreaks are occurring due to convergence of the TB and HIV epidemics Transmission of MDR-TB and XDR-TB to an enlarging pool of HIV-infected and immunocompromised individuals Infections result in severe disease: 72% of HIV infected patients with MDR-TB died in outbreak during treatment, compared with 20% of HIV-uninfected 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: 62% of HIV-infected patients with MDR-TB died during treatment in one outbreak, compared with 26% of HIV-infected patients with TB but without MDR-TB Park MM et al. Outcome of MDR-TB patients, : prolonged survival with appropriate therapy. Am J Respir Crit Care Med 1996; 153:

20 HIV and MDR-TB in Industrialized Countries
Wells et al. HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis Aug 15;196 Suppl 1:S86-107

21 MDR-TB and HIV Outbreaks
New York City 1990’s Closely associated with HIV infection, many cases were nosocomial, and most were lethal Russia The MDR-TB epidemic in Tomsk Oblast accompanies the most explosive epidemic of HIV infection in the world South Africa Outbreak of 53 cases of XDR-TB in KwaZulu Natal, all who underwent testing were found to have HIV infection, with median survival after specimen collection of 16 days

22 Why Screen for HIV? Benefits of treatment before symptoms develop
Identify asymptomatic patients Implement measures to prevent HIV transmission

23 Probability of AIDS or Death Years Since Initiation of HAART
Clinical Outcome Improved by Starting Therapy at Higher CD4+ Cell Count Results suggest a lower risk of disease progression/death when starting between cells/mm3 Cumulative Probability of AIDS/Death by CD4+ Cell Count at HAART Initiation cells/mm3 cells/mm3 cells/mm3 0.12 0.10 0.08 CI, confidence interval; HR, hazard ratio. One cohort study that helps to inform us on when to start therapy comes from the Antiretroviral Therapy Cohort Collaboration. In this particular 2006 analysis, the hazard ratio of progression to AIDS or death was determined for more than 10,000 antiretroviral-naive patients who started therapy within 3 different CD4+ cell count strata. The 3 CD4+ cell count categories were cells/mm^3, cells/mm^3, and cells/mm^3. The results demonstrated a strong trend in favor of starting therapy with a CD4+ cell count > 350 cells/mm^3. For more information about this study, go online to: Probability of AIDS or Death 0.06 0.04 0.02 0.00 1 2 3 4 5 Years Since Initiation of HAART Sterne J, et al. CROI Abstract 525.

24 CAMELIA: ART Initiation at Wk 2 vs Wk 8 of TB Therapy in HIV-Coinfected Patients
CAMELIA: randomized, open-label trial of HIV-infected patients with newly-diagnosed AFB-positive TB and CD4+ cell count ≤ 200 cells/mm3 [2] Compared HAART initiation (d4T + 3TC + EFV) at Wk 2 (n = 332) vs Wk 8 (n = 329) of TB therapy All patients received standard TB therapy for 6 mos WHO 2010 guidelines recommend to[1] Initiate HAART in all HIV-infected patients with TB, regardless of CD4+ cell count Initiate TB therapy before HAART, with HAART added as soon as possible CAMbodian Early vs. Late Introduction of Antiretrovirals 1. WHO. Available at: 2. Blanc FX, et al. AIDS Abstract THLBB106.

25 Survival probability (95% CI)
Kaplan-Meier survival curves Log-rank p-value: p=0.0042 Significantly higher incidence of IRIS with early vs late HAART 4.03 vs 1.44 per 100 person-mos, respectively (P < .0001) Get multivariate analysis here Survival probability (95% CI) Early arm Late arm Log-rank p-value Week 50 86.1 (81.8 – 89.4) 80.7 (76.0 – 84.6) 0.07 Week 100 82.6 (78.0 – 86.4) 73.0 (67.7 – 77.6) 0.006 Week150 82.0 (77.2 – 85.9) 70.2 (64.5 – 75.2) 0.002 25

26 CAMELIA - Conclusions Mortality reduced by 34% when HAART was initiated 2 vs 8 weeks after onset of TB treatment Highest benefit in those with CD4 < 50 Early HAART initiation could potentially save 150,000 of the HIV-TB deaths

27 HIV Testing in Saskatchewan
Very high incidence rates in SK Late presentation and advanced disease seen in SK indicate a need to increase HIV testing, particularly among hard-to-reach populations

28 Reasons for Reduced HIV Testing
Stigma of getting the test Fear of community exposure Poverty Loss of housing, income, children ‘Sexual code of silence’ Denial of possibility of sexual transmission Other health priorities above HIV status Fear of stigma and discrimination of being HIV positive Disclosure to partners

29 HIV Pre-Test Counseling
Basic education about HIV/AIDS HIV antibody testing ELISA and Western Blot Benefits of testing Right to refuse Opt-out vs. opt-in Need only verbal consent Availability of follow-up Confidentiality and reporting Test result from Regina is sent directly to physicians office HIV is reportable No information disclosed unless patient consents Patient will be expected to disclose partner names if positive

30 Post-Test Counseling Assist in understanding test result
Review meaning of positive and negative result Review transmission and partner notification If positive, effective treatments are available Address psychological reactions Promote behavioural changes Assess need for follow-up

31 HIV Testing in TB Patients
Only 23% of the 1613 cases of TB in 2004 in Canada were tested for HIV Rates of HIV co-infection for those tested in 2004 was 10% Overestimate due to selection bias Retrospective analysis

32 Proportion of TB cases reported in Canada for which 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);

33 HIV Testing in TB Patients and Contacts
All patients with TB should undergo HIV testing HIV testing of contacts of infectious TB cases should be considered Information concerning HIV should be available to patients for whom testing is recommended Source: 2007 Canadian Tuberculosis Standards

34 TB Screening in HIV Positive Patients
All newly diagnosed HIV patients are screened on history, TST and chest x-ray Induration ≥5 mm is considered positive False negatives in patients with low CD4 counts Should be repeated when CD4 counts have recovered Annual TST should be done if patients have ongoing TB exposure Only 20-25% of HIV patients who receive a TST have it read at 48 hours Need new strategies to improve screening

35 Unique Aspects of Treatment for HIV/TB Co-infections
Consider LTBI treatment for HIV positive patients who are close contacts with infectious TB regardless of TST result If malabsorption a concern, may need to do ARV or TB drug levels Regarding drug interactions NNRTI class is recommended due to drug interactions with rifampin If PI regimen is used, rifabutin would be preferred agent

36 Joint Clinical TB/HIV Initiatives in Saskatchewan
Joint HIV/TB remote clinics La Loche, La Ronge Increased communication between services Development of TB/HIV co-infection case conferences Begin developing management recommendations for co-infections Increase testing

37 HIV and TB - Conclusions
HIV and TB infections epidemics act synergistically Higher prevalence and altered clinical course Management may be altered and is more challenging if co-infected HIV/AIDS increases incidence of TB and MDR-TB HIV epidemic is occurring in Saskatchewan Increasing HIV numbers in communities with active TB PHAC and CDC recommend universal HIV testing for newly diagnosed TB patients More testing is needed to identify asymptomatic patients and those with limited access to care

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