1. Tuberculosis in the Setting of HIV Infection
Sample 2
Zelalem Temesgen, M.D.
Tuberculosis Clinical Intensive
Sept 9-11,2013
test

2. Disclosures Unrestricted educational grants
Gilead, Janssen, ViiV, Merck, CDC
Research grants
Gilead, Pfizer, NIH

3. Learning Objectives Describe the epidemiology of TB/HIV co-infection
Describe the impact of HIV on the natural history of TB
Describe current guidelines for the diagnosis and treatment of LTBI in the setting of HIV infection
Explain treatment and management strategies for TB patients with HIV.

4. Epidemiology

5. Tuberculosis: 2011 Global Burden of Disease
12 million prevalent cases (10-13 million)
8.7 million incident cases (8.3-9 million)
125 cases per population
Asia (59%)
Africa (26%)
Eastern Mediterranean Region (7.7%)
Europe (4.3%)
Americas (3%)
1.4 million people died from TB in 2011
1 million deaths among HIV-negative individuals
among people who were HIV-positive.

7. Tuberculosis: High-Burden Countries
Afghanistan
Bangladesh
Brazil
Cambodia
China
DR Congo
Ethiopia
India
Indonesia
Kenya
Mozambique
Myanmar
Nigeria
Pakistan
Philippines
Russian Federation
South Africa
Thailand
Uganda
UR Tanzania
Viet Nam
Zimbabwe

8. United States: Reported TB Cases United States, 1982–2012
2012 Data
9,951 Cases
Rate 3.2/100,000
No. of Cases
Although this figure only shows the reported number of TB cases annually since 1982, the 9,951 cases reported is the lowest number since national reporting began in The rate of 3.2 cases per 100,000 is also the lowest rate marks the 20th consecutive year of declines for both the reported number of TB cases and the rate.
Year
Data are updated as of 2/22/13 and are provisional

9. Reported new tuberculosis cases, by county — United States, 2010–2012DC
From 2010 through 2012, 44.2% of the 3143 counties in the US did not report a new TB case. As mentioned prior, all states and Washington DC reported at least one TB case in 2012.
Reported a new TB case
Did not report a new TB case

10. Rate* of TB Cases by Race/Ethnicity — United States, 2012
2012
Race
Rate
Hispanic
5.2
Asian
19.8
Black
5.7
White
0.8
2012
Race
Rate
Hispanic
5.2
Asian
19.8
Black
5.7
White
0.8
2012
Race
Rate
Hispanic
5.2
Asian
19.8
Black
5.7
White
0.8
7.3 times higher for non-Hispanic blacks
6.6x
7.3x
25.0x
* Per 100,000 population
Data are updated as of 2/22/13 and are provisional.

12. In 2011, among the 39,495 diagnoses of HIV infection among adult and adolescent males in the United States and 6 dependent areas, 42% were black/African American, 30% were white, and 23% were Hispanic/Latino. Approximately 2% each was Asian and males of multiple races, and less than 1% each was American Indian/Alaska Native and Native Hawaiian/other Pacific Islander.
Among the 10,512 diagnoses among adult and adolescent females in 2011, 63% were black/African American, 17% were Hispanic/Latino, and 17% were white. Approximately 1% each was among Asians and females of multiple races, and less than 1% each was among American Indians/Alaska Natives and Native Hawaiians/other Pacific Islanders.
Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data are estimates. Estimated numbers resulted from statistical adjustment that accounted for reporting delays, but not for incomplete reporting.
Hispanics/Latinos can be of any race.

13. In the United States and 6 dependent areas, the estimated rate of diagnoses of HIV infection among adults and adolescents was 19.1 per 100,000 population in The rate of diagnoses of HIV infection for adults and adolescents ranged from zero per 100,000 in American Samoa, Guam, and the Republic of Palau to per 100,000 in the District of Columbia, 39.5 in the U.S. Virgin Islands, 36.6 in Louisiana, and 36.4 in Maryland.
The District of Columbia (i.e., Washington, DC) is a city; please use caution when comparing the HIV diagnosis rate in DC with the rates in states.
Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data are estimates. Estimated numbers resulted from statistical adjustment that accounted for reporting delays, but not for incomplete reporting.

14. TB
HIV/TB
HIV

15. TB and HIV Coinfection
Of the 8.7 million incident cases in 2011, 1.1 million (13%) were among people living with HIV
In Africa, 39% of TB cases were estimated to be coinfected
Africa accounted for 79% of TB cases among people living with HIV worldwide

17. Estimated HIV Coinfection in Persons with HIV Test Results, United States, 1993–2012
In 2012, 82% (8,119 of 9,951) of TB cases had HIV results. Among those with results, 7.7% were co-infected represented by the green line. Among those aged 25 to 44 years, 12.0% were coinfected represented by the blue line.

18. Natural History

19. HIV Immune Deficiency Loss of specific antibody responses
Diminished T cell repertoire
Reduced lymphocyte function - decreased
Delayed hypersensitivity response to recall antigens
Phagocytosis
Chemotaxis
Intracellular killing
Natural killer cell-mediated killing
Loss of specific antibody responses
Increased immune activation
disruption of immunoregulatory cytokine expression and production
Decreased IL-2, γ interferon, and IL-12
Increased IL-1, IL-6, TNFα

20. Natural History of M. tuberculosis infection.
A Koul et al. Nature 469, (2011) doi: /nature09657

21. Tuberculous infection progressed to active disease within 106 days of acquiring the infection in 37 percent (11 of 30) of HIV-infected patients.
Tuberculosis did not develop in any of 28 staff members with exposures, although there were 6 with documented tuberculin conversions and 8 others had positive tuberculin reactions of unknown duration.

22. 7 of 18 (39%) HIV-infected inpatients developed active tuberculosis within 60 days of diagnosis of the index case

23. Natural History of M. tuberculosis infection.
A Koul et al. Nature 469, (2011) doi: /nature09657

24. Forty-nine HIV-seropositive subjects and 62 HIV-seronegative subjects had a positive TST response.
Active tuberculosis developed in eight of the HIV-seropositive subjects (4 percent) and none of the seronegative subjects during the study period (P<0.002).

25. HIV Epidemic State and Estimated Relative Risk of Developing Tuberculosis (TB) in HIVInfected Persons in Comparison with HIV-Uninfected Persons (Incidence Rate Ratio).
HIV Epidemic State and Estimated Relative Risk of Developing Tuberculosis (TB) in HIVInfected Persons in Comparison with HIV-Uninfected Persons (Incidence Rate Ratio)‏
Getahun H et al. Clin Infect Dis. 2010;50:S201-S207

26. Diagnosis of LTBI in HIV-Infected Individuals

27. 294 HIV-infected subjects TST vs. QFT
Am J Respir Crit Care Med Vol 175. pp 737–742, 2007
294 HIV-infected subjects
TST vs. QFT
89.3% concordance between QFT and TST
only 28% subjects with positive test results by either TST or QFT had positive test results by both modalities.

28. 2348 household contacts of sputum smear positive TB cases followed over 24 months
Twenty six contacts diagnosed with definite TB
TST sensitivity 56%
ELISPOT 52%
71% were positive by one or other test
Those negative on either or both tests had the lowest rate of progression

29. 37 studies with 5736 HIV-infected individuals
J Acquir Immune Defic Syndr 2011;56:230–238
37 studies with HIV-infected individuals
Are IGRAs better than TST at predicting which HIV-infected individuals are at highest risk of progression to active TB?
Are IGRAs more sensitive than TST for diagnosis of MTB infection in HIV-infected individuals with advanced immunosuppression?
Insufficient evidence to conclude that either test is superior to the other.

30. Testing for LTBI at the time of HIV diagnosis should be routine regardless of epidemiologic risk factors
Annual testing for LTBI only in those with ongoing exposure
If negative screen for LTBI while CD4 count is low, repeat testing post cART once CD4 is above 200.
Both TST and FDA-approved IGRAs are appropriate for TB screening in HIV-infected individuals
Routine use of both TST and IGRAs to screen for LTBI is not recommended

31. Natural History of M. tuberculosis infection.
A Koul et al. Nature 469, (2011) doi: /nature09657

32. 23,517 culture-positive, pulmonary tuberculosis patients from the California tuberculosis case registry from 1993 to 2007 who completed anti-tuberculosis therapy.
148 (0.63%) had a late recurrence.
Human immunodeficiency virus infection (adjusted hazard ratio, 1.81; p =

33. Rates of tuberculosis recurrence:
The Journal of Infectious Diseases 2010; 201:704–711
Retrospective cohort study of South African gold miners, men with known dates of seroconversion to HIV (from 1991 to 1997) and HIV-negative men were followed up to 2004.
342 HIV-positive and 321 HIV-negative men who had had1 previous episode of tuberculosis,
Rates of tuberculosis recurrence:
HIV-positive 19.7 cases per 100 person-years at risk (95% confidence interval [CI], 16.4–23.7)
7.7 cases per 100 PYAR (95% CI, 6.1–9.8)

34. Diagnosis of Active Tuberculosis in the Setting of HIV

35. TB in the Setting of HIV: Clinical Presentation
In general, similar to that seen in HIV-uninfected patients
However, differential diagnosis broader
HIV itself
Other opportunistic infections
Extrapulmonary
HIV main risk factor
35-80% vs %
Bones and joints, lymph nodes, the pleura, peritoneum, CNS

36. Laboratory Diagnosis of Active TB
Sputum smear
HIV-infected patients are more likely to have smear- negative pulmonary TB
Range 31 – 81%
CXR
Individuals with advanced HIV are likely to have atypical presentations
Lower lobe locations
Less cavities
Consolidation
Intrathoracic LAD
May appear normal

37. Treatment of Tuberculosis

38. Treatment of LTBI Drugs Duration Interval Minimum doses Isoniazid
9 months
Daily
270
Twice weekly* 76
6 months
180
Twice weekly 52
Isoniazid and Rifapentine
3 months
Once weekly 12
Rifampin
4 months
120

39. Studies of the Effect of Human Immunodeficiency Virus (HIV) Coinfection on the Outcome of Tuberculosis Treatment.
Studies of the Effect of Human Immunodeficiency Virus (HIV) Coinfection on the Outcome of Tuberculosis Treatment
Swaminathan S et al. Clin Infect Dis. 2010;50:
© 2010 by the Infectious Diseases Society of America

40. Treatment of TB in HIV-infected individuals is the same as for those who are HIV uninfected
Treatment of TB in HIV-infected individuals should include an initial 4-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol
DOT is recommended for all patients with suspected HIV-related TB
Daily therapy (5–7 days per week) given as DOT is recommended during the intensive phase
Daily (5–7 days per week) or thrice-weekly dosing is recommended during the continuation phase
Once- or twice-weekly dosing during the continuation phase assoc. with treatment failure/relapse with acquired rifamycin resistance

41. TB and HIV coinfection: Treatment Issues
Drug-drug interactions
Overlapping drug toxicities
Pill Burden
Immune-reconstitution inflammatory syndrome (IRIS)
Sequencing with antiretroviral therapy
Highly intermittent Dosing
TB treatment outcome in HIV
ART treatment effect on TB incidence

42. TB/HIV Treatment Issues: Drug Interactions
Rifamycins induce hepatic cytochrome P450 (CYP3A4) enzymes, accelerating metabolism of:
Protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), etc.
Rifampicin >> Rifabutin
For patients receiving PIs or NNRTIs, substitute rifabutin for rifampin, if available
Alternative non-rifamycin regimens less optimal, longer duration of therapy

43. Rifampicin decreases blood levels of NVP and EFV
NNRTIs and Rifampicin
Rifampicin decreases blood levels of NVP and EFV
NNRTI
Effect of Rifampicin
Nevirapine
 37–58%
Efavirenz
 22%
In choosing an NNRTI as part of the ART regimen, efavirenz is favored over nevirapine (see below).
In several cohort studies, standard-dose efavirenz + two NRTIs was well-tolerated and efficacious in achieving complete viral suppression.
Rifampicin has a greater effect on serum nevirapine levels. Despite the interaction with RIF, there is reasonable data that ART with nevirapine can be effective, but there are more concerns for overlap of common side effects (skin rash and hepatitis).
[CDC. Managing drug interactions in the treatment of HIV-related tuberculosis, 2007,

44. Rifampicin decreases blood levels of all PIs
PIs and Rifamycins
Rifampicin decreases blood levels of all PIs
Protease Inhibitor
Effect of Rifampicin
Saquinavir
 by 84%
Ritonavir
 by 35%
Indinavir
 by 89%
Nelfinavir
 by 82%
Amprenavir
 by 81%
Lopinavir/ritonavir
 by 75%
The notable effect of rifampicin on blood levels of most protease inhibitors means that protease inhibitors (whether boosted or not with ritonavir) generally should not be used for patients receiving rifampicin – the blood levels would be so low that the protease inhibitors would be ineffective in suppressing HIV.
[Exception discussed on upcoming slide: Lopinavir/ritonavir (Kaletra) combined with rifampicin resulted in hepatitis in all adult healthy volunteers. Kaletra “super-boosted” with extra ritonavir has had some favorable pharmacokinetic and clinical data among young children.]
[Slide credit: MTCT-plus: Diagnosis and management of TB/HIV (

45. Rifamycins and Intermittent Therapy
Evidence for development of acquired rifamycin resistance with intermittent therapy
Intermittent therapy not recommended during initial phase of TB treatment in patients with HIV infection
No twice-weekly continuation phase with advanced immune suppression
[Review content of slide]
Studies of HIV-associated TB cases have shown an association between intermittent anti-TB treatment (rifapentine once weekly, and rifabutin or rifampicin twice weekly) with the development of acquired rifamycin resistance.
This association was strongest in the groups with severe immunosuppression (CD4 <100).
Patients with advanced HIV and those with significant diarrhea appear to be at risk for lower concentrations of the orally administered first-line anti-TB medications compared to non-HIV TB patients (but some conflicting data). However, the doses remain the same.
Because of the risk of acquired drug resistance, intermittent therapy during the initiation phase of treatment using a rifamycin drug is generally not recommended in HIV-associated TB. For the same reason, twice-weekly (or less) intermittent therapy is not recommended in the continuation phase as well in cases of advanced immunsuppression.

46. Overlapping Side Effects
TB Drug
ARV
Skin rash*
PZA, RIF, INH
Nevirapine
Efavirenz
Abacavir
Nausea,
vomiting
Zidovudine
Ritonavir
Amprenavir
Indinavir
Adverse reactions to both TB and ARV drugs are common among patients with HIV-related TB and there are significant overlaps in the toxicity profiles between the drugs.
To simplify the clinical management, it is often recommended that ARV initiation be deferred until there has been time to identify and manage side effects from the TB treatment – usually 2-8 weeks. [Recommendations for when to start ARVs reviewed in earlier slides.]
Listed on two slides are the major areas of overlapping toxicities:
[Review content of slide]
* May also see rash with cotrimoxazole
Burman et al, Am J Respir Crit Care Med 2001

47. Overlapping Side Effects
TB Drug
ARV
Hepatitis
PZA, RIF, INH
Nevirapine
Protease inhibitors
IRIS (with chronic hepatitis)
Leukopenia,
anemia
RIF
Zidovudine
Overlapping side effects continued:
[Review content of slide]
Burman et al, Am J Respir Crit Care Med 2001

48. TB/HIV: Barriers to Adherence
Dual social stigma
Higher pill burden
Greater number of potential drug side effects
Additional illness (opportunistic infections)
Difficult medical access, drug-supply interruptions
The additive issues that can complicate adherence for patients undergoing treatment for both TB and HIV infections include:
[Review slide content]
[Interactive option: Ask participants for further examples that may be particular to their location or situation.]

50. Immune Reconstitution Inflammatory Syndrome (IRIS)
Clinical worsening in the setting of an adequate response to ART
“Paradoxical” worsening of previously known treated (completed or ongoing) opportunistic pathogen
“Unmasking” of subclinical opportunistic pathogen
Immune reconstitution inflammatory syndrome (IRIS), also known as immune restoration disease, is described as a phenomenon of clinical worsening that may occur in association with an appropriate immune recovery after the initiation of antiretroviral therapy (ART).
An IRIS response may be seen in association with a wide range of infectious agents or with autoimmune disease, but is most commonly seen in relation to tuberculosis.
Two mechanisms may occur with TB-associated IRIS:
A paradoxical worsening of clinical and/or radiographic findings of known active TB after the start of ART.
Or, due to the restoration of the immune response seen on ART, subclinical TB may be “unmasked”, manifesting the clinical signs and symptoms of TB once the immune response is recovered.

51. Incidence of Tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS) in Human Immunodeficiency Virus (HIV)–Tuberculosis Coinfection.
Incidence of Tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS) in Human Immunodeficiency Virus (HIV)–Tuberculosis Coinfection
Swaminathan S et al. Clin Infect Dis. 2010;50:
© 2010 by the Infectious Diseases Society of America

52. Risk factors Timing of onset IRIS Disseminated TB
Shorter delay between onset of TB and ART drugs
Low baseline CD4, higher baseline viral load
Greater CD4 or viral load response to ART
Timing of onset
Usually within first 6 weeks of ART (often 2–3 weeks, but can be months after ART started)
Risk factors for the development of IRIS:
[Review slide content]
Timing of onset of IRIS is typically relatively early in the course of ART, but has been reported as many as several months after ART initiation.
Reported incidence rates for TB-related IRIS are highly variable (8% - 43%).

53. IRIS Clinical presentation: Fever Nodal enlargement
Worsening pulmonary infiltrates (with or without respiratory symptoms)
Local worsening in extrapulmonary sites
While the clinical manifestations of IRIS may present much like the spectrum of TB in general within the HIV-infected population, in some instances the onset may be unusually rapid with an intense inflammatory component.
Common clinical manifestations may include:
[Review slide content]
It has been suggested that the rate and intensity of IRIS presentation is likely related to the underlying mycobacterial load and reflects the rate and intensity of the immune recovery response to ART.
[Interactive option: Ask participants to give examples of IRIS presentation that they may have encountered.]
[Upper photo: IRIS-related enlarged cervical adenopathy]
[Lower photo: IRIS-related development of TB skin abscesses]
[Image credit: Bob Colebunders, MD]

54. IRIS Differential Diagnosis
TB treatment failure
Drug-resistant TB
ART failure
Other opportunistic (or non-opportunistic) infections
Lymphoma, Kaposi’s sarcoma
Hypersensitivity drug reactions
There is no diagnostic test to confirm the presence of IRIS. The diagnosis of IRIS is one of exclusion and can be challenging, particularly in resource limited settings.
To complicate the matter further, the differential diagnosis for IRIS can be broad and includes:
[Review slide content]
Of major concern during the course of TB treatment is the possibility for treatment failure or drug-resistant disease. Re-evaluation of patient adherence and repeat sampling of sputum or extrapulmonary sites would be indicated.
If IRIS appears later in the course of ART, a further consideration would be the possibility of ART failure. Evaluation of CD4 and/or viral load would be helpful here to differentiate failure of ART (falling CD4) vs. IRIS associated with immune recovery (rising CD4).

55. IRIS Management Adherence Drug resistance Continue TB treatment
Continue ART
Exclude TB treatment failure
Adherence
Drug resistance
Exclude additional/new diagnosis
Consider NSAIDS, steroids
Drainage of lesions
If clinical indicators raise the suspicion for IRIS:
[Review slide content]
A significant point is that TB (and ART if status not life-threatening) treatment should continue during the evaluation.
Median symptom duration has been reported to be approximately 57 days, but can be significantly longer in cases of lymphadenopathy (median 195 days).
Cases are usually self-limiting (although rare reports of death due to IRIS).
Symptomatic relief can often be achieved using non-steroidal anti-inflammatory drugs (NSAIDS) if needed, or with the use of corticosteroids in more severe disease presentations.
On some occasions, more direct interventions, ex. aspiration of abscesses, placement of biliary stents, may be indicated.

56. Studies of the Timing of Antiretroviral Therapy (ART) in Human Immunodeficiency Virus (HIV)–Infected Patients with Tuberculosis Undergoing Antituberculosis Therapy.
Studies of the Timing of Antiretroviral Therapy (ART) in Human Immunodeficiency Virus (HIV)–Infected Patients with Tuberculosis Undergoing Antituberculosis Therapy
Swaminathan S et al. Clin Infect Dis. 2010;50:
© 2010 by the Infectious Diseases Society of America

57. When to Start Antiretrovirals
HIV-infected TB patients not yet on ART
CD4
Start ART
<50
Within 2 weeks of TB Rx
>50 and TB severe
Within weeks of TB Rx
>50 but TB not severe
Can defer ART beyond weeks but should start within 8-12 weeks
Although the optimal timing of ART initiation is not known, general recommendations based on the CD4 cell count (reflecting the degree of immunosuppression at the onset of TB treatment) from 2006 WHO consensus guidelines are outlined here.
In patients with HIV-related TB, the priority is to treat TB and ideally ART can be safely postponed.
However, in more severely immunosuppressed patients with HIV-related TB there may be need for the earlier initiation of ART and this may be done with careful oversight within the first 2-4 weeks of starting TB treatment.

58. Antiretroviral Therapy (ART) Significantly Reduces TB Incidence
Decrease in TB incidence after starting ART in resource-limited, high-burden area
The initiation of appropriate antiretroviral therapy (ART) has proven to be a major intervention, reducing the incidence of TB within HIV-infected populations.
As an example: In a community-based ART cohort in South Africa (median baseline CD4 96), the initiation of ART reduced the incidence of TB in the cohort from 23 cases per 100 person-years to 7 cases during the first year of treatment. This decline in the risk for TB was strongly associated with improving immune status.
Lawn SD, et al, Am J Respir Crit Care Med, 2008;177:

59. Tuberculosis/HIV Coinfection: Summary
Substantial global disease burden, individually and as coinfection
Bidirectional impact on natural history
Difficulties in diagnosis and treatment
TB, even in the setting of HIV, is curable
ART has tremendous impact on TB incidence in the population