Rafael Laniado-Laborin MD, MPH, FCCP Universidad Autónoma de Baja California Tuberculosis and HIV/AIDS

Rafael Laniado-Laborin MD, MPH, FCCP

Universidad Autónoma de Baja California

Tuberculosis and HIV/AIDS

Background

The World Health Organization (WHO)

estimates that approximately one third of the

total population of the world harbors tubercle

bacilli in a latent form A new infection occurs every secondA new infection occurs every second

Int J Tuberc Lung Dis 2003; 7:S328

Background

IUTLD-NAR Meeting 2006

The WHO also estimates that each year

more than 9 million new cases of tuberculosis

occur and approximately 2 million persons

die from the disease One case can infect from 10 to 15 One case can infect from 10 to 15

peoplepeople

How frequent is the co-infection?

TB cases in persons with HIV co-infection, USA 1993-2003 (25-44 years old)

29 2926 25

21 20 1917 16 16 16

0

5

10

15

20

25

30

35

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

(%)

CDC Website, Sep 2006CDC Website, Sep 2006

CACA

AZAZ NMNM

TXTXSONSON

CHI COHCOH

TAM

NLNL

BC25.325.3

18.711.711.7

31.1

41.5

21.9

8.38.3

4.74.7 2.22.2

7.57.5

SOURCE: DGE MEXICO / CDC EUA

TB: Border states USA & Mexico

Bacteriology

MTB belongs to the

genus Mycobaterium

Mycobacterium

tuberculosis complex

o M. tuberculosis

o M. bovis

o M. africanum

o M. microti

o M. canetti

Nontuberculous mycobacterium (MOTT) In the US up 30 % of the isolates are NTM

(rate: 1.8 per 100,000 h. The most common NTM are:

o Mycobacterium avium complex (60 %)

o Mycobacterium fortuitum (20 %)

o Mycobacterium kansasii (10 %)

Pathogenesis Tuberculosis is spread from person to person

through the air by droplet nuclei, particles <5 mm in diameter that contain M. tuberculosis complex

Pathogenesis

4 factors determine the risk of infection: o the number of organisms

being expelled into the airo the concentration of

organisms in the air (volume of the space and its ventilation)

o the length of time an exposed person breathes the contaminated air

o the immune status of the

exposed individual

HIV-infected persons and others with impaired cell-mediated immunity are thought to be more likely to become infected with M. tuberculosis after exposure than persons with normal immunity

Also, HIV-infected persons and others with impaired cell-mediated immunity are much more likely to develop disease if they are infected

Pathogenesis

Inhalation and deposition in the lungs of the tubercle bacillus leads to one of four possible outcomes:o immediate clearance of the organism

o chronic or latent infection

o rapidly progressive disease (or primary disease)

o active disease months to years after the infection (reactivation disease)

Pathogenesis

Only 5 to 10 percent of patients with no underlying medical problems who become infected develop active disease in their lifetime

The risk increases markedly in patients with AIDS

Pathogenesis

Once they are inhaled, the bacilli will

reach the distal bronchioles and alveoli

Inside the alveolar macrophages M.

tuberculosis will multiply slowly (once

every 24-32 hours) and kill the cell

Pathogenesis

The infected macrophages produce cytokines that attract other phagocytic cells which eventually form a nodular granulomatous structure called the tubercle

Pathogenesis

If the bacterial replication is not controlled, the tubercle enlarges and the bacilli enter the local draining lymph nodes

The lesion produced by the expansion of the tubercle into the lung parenchyma and lymph node involvement is called the Ghon complex

Primary complex (Gohn’s)

Pathogenesis

Failure by the host to mount an effective CMI response and tissue repair leads to progressive destruction of the lung

If the bacterial growth continues to remain

unchecked, the bacilli may spread

hematogenously to produce disseminated TB

HIV-infected persons, especially those with low CD4+ cell counts, develop tuberculosis disease rapidly after becoming infected with M. tuberculosis

Up to 50 percent of such persons may do so in the first two years after infection with M. tuberculosis

Conversely, an individual who has a prior

latent infection with M. tuberculosis (not

treated) and then acquires HIV infection will

develop tuberculosis disease at an

approximate rate of 5 to 10 percent per year

Voluntary HIV counseling and testing is recommended for all patients with TB and should be considered the standard of care

Am J Respir Crit Care Med 2005; 172:1169Am J Respir Crit Care Med 2005; 172:1169

Physicians who provide primary care to persons with HIV infection or populations at increased risk for HIV infection should maintain a high index of suspicion for TB

Every patient in whom HIV infection has been newly diagnosed should be assessed for the presence of TB or LTBI


The risk depends, however, on the degree of

immunosuppression—the risk of a patient

with AIDS developing tuberculosis is 170

times higher than a non immunosuppressed

person

Reactivation disease

Reactivation TB results when the persistent bacteria in a host suddenly proliferate

While immunosuppression is clearly associated with reactivation TB, it is not clear what host factors specifically maintain the infection in a latent state for many years and what triggers the latent infection to become overt

Reactivation disease

Immunosuppressive conditions associated with reactivation TB include:o HIV infection and AIDSHIV infection and AIDS

o end-stage renal disease

o diabetes mellitus

o malignant lymphoma

o corticosteroid use

o old age

Clinical manifestations

Clinical manifestations

In immunocompetent individuals, 85% of the cases are exclusively pulmonary, and the rest have extrapulmonary manifestations

This distribution is modified in HIV patients: o 38% exclusively pulmonary

o 30% extrapulmonary

o 32% pulmonary + extrapulmonary

Systemic manifestations

Fever (37-80%)

Weight loss

Night sweats

Loss of appetite

Malaise

Pulmonary TB

Cough: is the most common symptom

Sputum, hemoptysis

Pleuritic pain

Dyspnea

Radiographic manifestations

Radiographic findings

PTB is almost associated to radiographic

abnormalities

Patients with HIV and PTB might have a

normal chest x-ray


In patients with HIV infection, the nature of the x-ray findings depends to a certain extent on the degree of immunocompromise produced by the HIV infection

TB that occurs relatively early in the course of HIV infection tends to have the typical x-ray findings of the immunocompetent patient


With more advanced HIV disease the

radiographic findings become more

"atypical": cavitations is uncommon, and

lower lung zone or diffuse infiltrates and

intrathoracic adenopathy are frequent

Disseminated tuberculosis

Disseminated tuberculosis

The term "miliary" is derived from the visual similarity of some disseminated lesions to millet seeds

Grossly, these lesions are 1- to 2-mm yellowish nodules that, histologically, are granulomas

Thus disseminated tuberculosis is sometimes called "miliary" tuberculosis

Disseminated TB

Because of the multisystem involvement in disseminated tuberculosis, the clinical manifestations are protean

The presenting symptoms and signs are generally nonspecific and are dominated by systemic effects, particularly fever, weight loss, night sweats, anorexia, and weakness

Other symptoms depend on the relative severity of disease in the organs involved

Disseminated TB

Laboratory diagnosis

Diagnosis

Microscopy:o this is principally applied to sputum but other

specimens include bronchoalveolar lavage fluid, gastric washings, laryngeal swabs, cerebrospinal fluid, pleural, pericardial and peritoneal effusions, fine needle lymph node aspirates, bone marrow aspirates, and tissue biopsies.

Diagnosis

A wide range of acid-fast smear positivity has been reported (31 to 81 percent), but most studies find a 50 to 60 percent yield

The yield is substantially higher (85 to 100 percent) on sputum culture

Mycobacteria cultures

Diagnosis

In patients infected with HIV, a positive smear for acid-fast bacilli (AFB) is very specific for Mycobacterium tuberculosis (MTB), even in a setting with a high incidence of Mycobacterium avium complex (MAC)

Diagnosis

At San Francisco General Hospital, for example, 248 of 271 (92 percent) expectorated sputum samples which were positive for AFB grew MTB on culture

This value is comparable to that found in HIV-negative patients.

Diagnosis

Urine cultures – Although genitourinary TB rarely occurs in the absence of other sites of extrapulmonary disease, it is frequently involved in disseminated TB, even in the absence of pyuria

In one series, for example, 77% HIV-infected patients with extrapulmonary TB whose urine was sent for culture grew MTB

Diagnosis

Invasive testing should be performed when noninvasive studies yield no immediate answer and the wait for culture results would be detrimental to the patient

Bronchoscopy is a sensitive technique for diagnosing TB

An immediate diagnosis can be made from AFB smears in about one-half of patients, and the sensitivity of cultures approaches 100 percent

Diagnosis

The central nervous system is frequently involved in disseminated TB

Given the number of opportunistic infections affecting the central nervous system in AIDS, there should be a low threshold for collecting CSF

Diagnosis

In a patient with suspected miliary disease and a negative sputum examination, bone marrow biopsy as well as blood cultures should be performed

Blood cultures are positive in 49 percent of patients with disseminated disease and CD4 counts less than 100/mm3

Molecular methods

The application of nucleic acid (DNA and RNA) amplification techniques—the polymerase chain reaction (PCR) and the ligase chain reaction (LCR)—is the subject of intense research activity

As a result, a number of rapid, sensitive, and specific test kits are commercially available

Diagnosis of LTBI

TST is considered as positive if > 5 mm

Contacts of an active TB case

Subjects with a chest x-ray anomalies

(fibrosis) suggestive of old (untreated) TB

Immunosuppression (including HIV)Immunosuppression (including HIV)

Drug induced immunosuppression ( >15

mg/day of prednisone)

Patients with 5 mm or more of induration be considered to have a positive test and should receive, in addition to chest x-rays, a clinical evaluation to rule out TB


IFN- assays

Patient’s T cells release IFN- when exposed to mycobacterial antigens

The genes encoding for two antigenic targets, ESAT6 and CFP10 are absent in the BCG vaccine strain and most environmental mycobacteria

Eur Respir J 2006; 28:1-3Eur Respir J 2006; 28:1-3

IFN- assays

There are two different assay formats:o ELISA detection after blood is incubated in a tube

with ESAT6/CPF10 antigens (Quantiferon-Gold)

o ELISA immunospot technique (T-Spot.TB) Advantage: one blood sample; no repeated

visits as in TST Disadvantage: cost


IFN- assays

These assays are not as sensitive for diagnosing active TB since IFN- responses decline as TB develops


75 individuals with active TB and control group (HS students

with risk of infection)Active TB Immuno

Controls

(specificity)

TST 72% 37% 82%

T-Spot.TB 96% 100% 86%

QF-Gold 77% 75% 92%


Guidelines for using the QF-Gold test

CDC 2005/54(RR15):49-55 FDA approved Diagnosing infection with M. tuberculosis

including both TB disease and LTBI QF-G can be used in all circumstances in

which the TST is used

Guidelines for using the QF-Gold test

CDC 2005/54(RR15):49-55 QF-G can be used in place of (and not in addition to) TST

A positive QF-G result should prompt the same public health and medical interventions as a positive TST result

Treatment

Treatment of HIV related tuberculosis The standard WHO recommended

antituberculosis regimen is a six month course of RIF and INH, PZA, together with ETH (or SM) during the first two months of treatment

Supplementation with daily pyridoxine (vitamin B6) to prevent isoniazid induced neuropathy is now routine

There is little or no difference in relapse rate between HIV infected and uninfected patients when RIF based short course treatment is used

Thus, in the absence of drug resistance, the standard short course just described is recommended

Antituberculous drug interactions A number of interactions between

antituberculosis agents and other drugs have been described

Most interactions are associated with RIF due to its ability to induce cytochrome CYP450 enzymes in the liver which affect the metabolism of many other drugs

Antituberculous drug interactions The current recommendation is to replace

RIF by rifabutin, a much less powerful inducer of cytochrome enzymes, and to start or continue with the antiretroviral drugs

Management recommendations for the use

of ARV + antituberculosis drugs

Frequent communication between TB and HIV care providers

Adjust dose of rifabutin as needed Use rifampin with efavirenz or ritonavir (>400

mg BID)

Am J Respir Crit Care Med 2001; 164:7-12Am J Respir Crit Care Med 2001; 164:7-12

Antituberculous drug interactions Even if rifabutin is substituted for RIF, care

should be exercised in the use of the protease inhibitor saquinavir and the non-nucleoside reverse transcriptase inhibitors as rifabutin decreases their levels, with the risk of selection of drug resistant viruses

It appears usually after two weeks of ARV

treatment

Most of the patients have far advance AIDS

o median CD4+: 35 cells/mm3

o median viral load: 581,694 copies/mL

Immune reconstitution syndrome

Paradoxical reactions (immune reconstitution syndrome) These manifest as fever, enlargement of

affected lymph nodes, and a worsening of the radiological appearance

Paradoxical reactions (immune reconstitution syndrome) These reactions are not indicative of

treatment failure and usually subside spontaneously

Treatment should not be modified but short courses of steroids may be required for severe paradoxical reactions.

When should ART be started? ARVs should be given to those with WHO

Stage IV disease, including individuals with extra-pulmonary TB, regardless of CD4 T-cell count

Int J Tuberc Lung Dis 2005; 9:946Int J Tuberc Lung Dis 2005; 9:946

Those with Stage III conditions, including individuals with pulmonary TB (PTB), should have CD4 T-cell counts taken into consideration; treatment is recommended when counts are <350 cells/mm3

Those with Stage I and II disease should only receive ART for CD41 T-cell counts <200 cells/mm3

When should ART be started?

Int J Tuberc Lung Dis 2005; 9:946Int J Tuberc Lung Dis 2005; 9:946

Treatment of LTBI

Incidence of active TB in PPD positive subjects according to risk

factorRisk factor

TB cases /1000 patient-years

TB infection<1 year 12.9

TB infection 1-7 years 1.6

HIV infection 35-162

IV drug use (HIV negative) 10

x-ray abnormality (old TB) 2-13.6

Weight loss >15% 2.6

Weight loss 10-14% 2.0

It has been used for more than 30 years Evidence is classified as:

o A= preferred treatment

o B= acceptable alternative

o C= offer if A and B are not an option

o I= randomized clinical trial

o II= clinical trail; not randomized

o III= experts opinion

Treatment of LTBI

Targeted testing and treatment for LTBI are strongly recommended at the time the diagnosis of HIV infection is established (AII)


Persons with known or suspected HIV infection who have contact with a patient with infectious pulmonary TB should be offered a full course of treatment for LTBI regardless of the initial result of tuberculin skin testing once active TB has been ruled out (AII)


In view of the very high risk of a co-infected person developing active TB, and the adverse effect of this disease on the immune status and survival of the patient, there is a very good theoretical case for provision of prophylactic treatment for those at risk

Prophylaxis against TB in co-infected persons

Treatment of LTBI

In the initial studies, a 12 month course of isoniazid was found to lower the incidence of tuberculosis in co-infected persons

Subsequently, shorter combination regimens have also been shown to be effective

DrugsDuration (months)

Interval HIV- HIV+

INH 9Daily

Bi-weekly

A(II)

B(II)

A(II)

B(II)

INH 6Daily

Bi-weekly

B(I)

B(II)

C(I)

C(I)

RIF-PZA2

2-3

Daily

Bi-weekly

B(II)

C(II)

A(I)

C(I)

RIF 4 Daily B(II) B(II)

An HIV-infected patient who is severely immunocompromised and whose initial tuberculin skin test result is negative should be retested after the initiation of antiretroviral therapy and immune reconstitution, when CD4 cell counts are greater than 200 cells/l (AII)


BCG VACCINATIO

N

BCG VACCINATIO

N

Results of randomized controlled trials (RCT)

and case control studies (CCS) showed the

protective efficacy against tuberculosis as

uncertain and unpredictable, as protective

efficacy varied from 0 to 80%

Is BCG effective?

BCG: a meta-analysis

Meta-analysis of over 1,200 articles from

international publications

Only 14 prospective trials and 12 case-

control studies met the selection criteria

JAMA 1994; 271:698-702JAMA 1994; 271:698-702

BCG: a meta-analysis

Combining data from the trials the RR for TB

among those vaccinated with BCG was 0.49

(95%CI, 0.34 to 0.70); protective effect 51%

Combining data from the case-control

studies, the OR for BCG vaccination

against TB was 0.50 (95%CI 0.39 to 0.64)

JAMA 1994; 271:698-702JAMA 1994; 271:698-702

Immunization of children at risk of infection with HIV

The available data is not adequate to permit

definitive conclusions about the effectiveness

of BCG vaccine to protect HIV-infected

children or adults against tuberculosis

Bull World Health Org 2003;81:61Bull World Health Org 2003;81:61

BCG vaccination

There is a risk that vaccination with Bacille Calmette-Guérin (BCG), a living attenuated vaccine, will cause infectious complications in HIV positive persons

There is a small increase in the incidence of adverse effects of BCG in the children of HIV infected women, but most such effects are mild

A consensus view currently exists, however,

that BCG should not be given to infants with

active HIV disease and that the vaccine is

contraindicated in older asymptomatic

children who are found to be HIV positive

Adverse events associated with BCG vaccination in children

infected with HIV

Dissemination 0-31%

Lymphadenitis 0-24%


More than 28 cases of disseminated BCG

infection have been reported in HIV-infected

children and adults

Progressive immune suppression can lead

to the reactivation of latent BCG organisms,

causing regional or disseminated disease

Adverse events associated with BCG vaccination in children

infected with HIV


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Rafael Laniado-Laborin MD, MPH, FCCP Universidad Autónoma de Baja California Tuberculosis and HIV/AIDS