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Pathogen:
HIV-infected people are particularly susceptible to infection by Mycobacterial
tuberculosis, and the course of the disease is accelerated. Nosocomial
outbreaks of tuberculosis have occurred in health care settings. One report
(Daley et al.) described 'a tuberculosis outbreak among 18 HIV-infected patients
on an inpatient ward in an Italian hospital. 8/18 patients exposed to a patient
with active tuberculosis developed TB. Another report (Daley et al.) described
an outbreak of tuberculosis among residents of a group housing facility; active
tuberculosis developed within four months in 11/30 (37%) and newly positive skin
tests developed in 4/30 (13%).
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Sites of Infection:
Initially, the alveoli of the lungs. Extrapulmonary tuberculosis is unusual in
non-HIV-infected patients but frequently occurs in HIV-positive people,
especially in those with lower CD4 counts (Jones et al.). While most patients
with AIDS-associated tuberculosis have pulmonary involvement, in at least half of
these cases the disease is not confined to the lungs. The lymphatic system is
frequently involved. Bergenguer et al. report that while tuberculous meningitis
occurs more frequently in HIV-infected people, clinical outcomes are similar to
those in non-HIV-infected people.
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Symptoms:
The classic symptoms of tuberculosis (cough, weight loss, fever, night sweats,
fatigue) are often present but not necessarily indicative of TB in people with
AIDS.
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Diagnosis:
The sensitivity of tuberculin skin tests is reduced in most cases of TB with
severe immune suppression, however, PPD testing should be done. Diagnosis of TB
requires isolation of
M. tuberculosis by culture.
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Treatment:
The CDC has released guidelines for the treatment of TB (Centers for Disease
Control and Prevention, 1994). These guidelines address the growing prevalence of
multi-drug resistant TB (MDR-TB). All HIV-infected Patients with M.
tuberculosis should have drug-susceptibility testing performed on their
first isolate; the results of testing should provide the basis for clinical
therapeutic decisions. Initial treatment of susceptible organisms should include
four drugs; during the first two months the regimen should include isoniazid,
rifampin, pyrazinamide, and ethambutol or streptomycin. If the organisms are
susceptible, they should be continual on therapy with isoniazid and rifampin.
Since data are not available to determine if a six-month regimen is sufficient
for HIV-infected patients, they should be treated for a total of 9 months, and
for at least 6 months after sputum conversion. CDC also recommends that directly
observed therapy (DOT) be considered for all patients.
El-Sadr et al. have reported that the addition of levofloxacin to a four drug
combination of isoniazid, rifampin, pyrazinamide, and ethambutol does not improve
culture responses in HIV+ patients with M. Tuberculosis. CPCRA
019/ACTG 222 enrolled 227 patients from both isoniazid-resistant and sensitive
geographic locations (geographic areas with resistance rates of greater or less
than 10%, respectively). Pulmonary TB was confirmed by culture in 145 patients,
111/174 (64%) patients enrolled from resistant areas and 34/53 (64%) patients
from sensitive areas; patients enrolled in resistant areas were evenly randomized
to receive either the addition of levofloxacin or placebo (87 patients in each
arm). The primary endpoint was negative sputum culture at eight weeks or at
least two negative follow-up sputum cultures with no intervening or subsequent
positive cultures and a completed eight week visit. In the resistant areas,
36/37 in the four drug group and 46/48 patients in the five drug group responded
to treatment. In the sensitive areas, 28/29 patients responded to treatment.
Malabsorption of anti-mycobacterial drugs occurs relatively frequently in AIDS on
et al., Peloquin et al.). To prevent treatment patients with TB (Berning et al.,
Gordon failure, screening for drug malabsorption may be indicated in situations
where patients do not respond to correct therapy given under direct observation.
One recent report (Holt et al.) concluded that three-weekly therapy is equally
effective in both HIV-positive and HIV-negative patients with tuberculosis. 423
patients in Haiti were enrolled in the trial, 176 (42%) of whom were
HIV-positive. Patients received isoniazid rifampin, pyrazinamide, and ethambutol
administered three times a week for two months, followed by isoniazid and
rifampin for four months. Improvement in symptom and sputum conversion occurred
equally frequently in both HIV-positive and HIV-negative patients. Mortality was
more frequent in the HIV-positive subjects (9% vs.1%).
A randomized, placebo-controlled phase I study of aerosolized recombinant gamma
interferon in combination with standard therapy (isoniazid, rifampin, ethambutol,
pyrazinamide, vitamin B6) is underway. Participants will receive aerosolized
gamma interferon (1000 ug qd) for four weeks, with a follow-up in nine months.
Unfavorable response to therapy and treatment-limiting toxicities will be the
major study endpoints.
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Multi-Drug Resistant Tuberculosis:
Several outbreaks of multi-drug resistant tuberculosis (MDR-TB) among
HIV-positive people in hospitals and prisons have been reported. Mortality among
these patients is very high (approximately 80%) and the disease progression is
extremely rapid. Edlin et al. and Fischi et al. studied outbreaks of MDR-TB in
hospitals. They report that nosocomial transmission of MDR-TB bacilli among
HIV-infected patients can occur. They caution that acid-fast-bacilli isolation
procedures must be strictly enforced in hospitals. Additional data (Small et al.
1992) indicate that mult-drug resistance in HIV-infected people can result from
re-infection with resistant strains of M. tuberculosis. This
re-infection can occur during or after therapy for drug-sensitive tuberculosis.
Inadequate treatment is the primary cause of the development of MDR-TB (Mahmoudi
and Iseman, 1993). Multiple levels of resistance are especially likely to accrete
when single drugs am added to a failing regimen. When initiating treatment in
patients with confirmed MDR-TB, both the treatment history and the in
vitro susceptibilities of the patient's strain should be evaluated
(Iseman, 1993). The patient should be hospitalized, and the selected regimen
should include between four and seven drugs. Drugs with potential utility in a
re-treatment regimen include pyrazinamide, ethambutol, streptomycin, ofloxacin,
ciprofloxacin, ethionamide, cycloserine, capreomycin and PAS. In cases where
chemotherapy is unsuccesful, adjunctive treatment with resectional surgery may be
concidered.
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Ongoing Treatment Studies:
A clinical trial (ACTG 238/CPCRA 026) is underway to identify risk factors for
the development of MDR-TB and to evaluate the efficacy of multiple-drug regimens
including levofioxacin. A Phase I trial of aerosolized recombinant human
interferon-gamma with standard mycobacterial chemotherapy is about to begin
enrolling. A Phase II trial (ACTG 270) of pentoxifylline for the treatment of
tuberculosis in being developed.
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Prophylaxis:
The CDC has recommended that HIV-positive patients with latent M.
tuberculosis infection (as detemiined by a tuberculin skin test reaction
greater than 5mm, or prior history of positive skin test not followed by
treatment) receive12 months of preventive isoniazid therapy (CDC,1995).
Isoniazid prophylaxis may also be indicated for some anergic HIV-positive
patients at high-risk for TB (such as those from areas with a high incidence of
TB). Since HIV-positive patients are at risk for peripheral neuropathy, those
receiving isoniazid should also receive pyridoxine.
A retrospective chart review (Moreno et al.) illustrated both the high risk of
re-activation of latent infection and the rapid progression newly acquired
infection in HIV-infected people. The study population included 374 HIV-infected
people in Spain. The risk for active tuberculosis in patients not receiving
isoniazid prophylaxis was 10.4 cases/100 person-years in patients with a positive
PPD; 12.4 cases/100 person-years in anergic patients, and 5.4cases/100
person-years in patients with a negative PPD. Further, Markowitz et al. have
shown that the prevalence of PPD reactivity decreases and the prevalence of
anergy increases as CD4 counts decline in HIV-infected people. The investigators
concluded that since responses to delayed-type-hypersensitivity tests depend on
immune status, such tests should be conducted early in the course of disease.
Because of recent nosocomial outbreaks of MDR-TB and the lack of data on
effective prophylaxis for contacts to MDR-TB cases, BCG vaccination has been
considered. BCG vaccine is used extensively outside the U.S. for the prevention
of TB. It is generally given at birth. A recent meta-analysis (Colditz et al.)
suggested that the average effectiveness may be about 50% (although the efficacy
reported in individual studies ranged from less than 0% to 80% protective
efficacy). However, disseminated disease from BCG vaccine has occurred in
HIV-infected persons, and it is contra-indicated in seropositive adults.
One study (Halsey et al.) has found that isoniazid prophylaxis decreases the
incidence of tuberculosis in HIV-infected asymptomatic patients compared to
rifampin and pyrazinaniide. 784 HIV-infected people in Haiti were randomized to
receive a six-month course of isoniazid or a combination of rifampin and
pyrazinamide. The risk of TB during the fust 10 months after randomization was
3.5% for the rifampin/pyrazinamide group and 0.8% for the isoniazid group
(P =0.01). No significwit differences in the rates of TB were
observed 10 months after treatment had stopped. No TB was detected in either
group during the first three months after randomization. The optimal duration of
prophylaxis has not been determined.
An effective prophylaxis regimen for people exposed to MDR-TB has not been
established. One report (Hom et al.) described the use of ofloxacin 800 mg/day
with pyrazinamide 1500 mg/day in 16 health-care workers exposed to MDR-TB. The
health-care workers were not HIV-infected. 14/16 discontinued prophylaxis before
the completion of six months of therapy because of side effects (arthralgia, GI
distress, and others).
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Ongoing Prophylaxis Studies:
A clinical trial (ACTG 177/CPCRA 004) in 1600 HIV-positive patients with
confirmed latent tuberculosis infection is currently underway. Isoniazid for 12
months is being compared to 2 months of rifampin and pyrazinamide.
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REFERENCES:
Berning SE et al. Malabsorption of anti-tuberculosis medications by a patient
with AIDS. NEJM 327:1817-8,1992.
Berenguer J et al. Tuberculous meningitis in patients infected with the human
immunodefeciency virus. NEJM 326:668-72,1992.
Centers for Disease Control. USPHS/IDSA Guidelines for the Prevention of
Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus.
MMWR 44:1-24,1995.
Centers for Disease Control and, Prevention. Initial therapy for tuberculosis in
the era of multi-drug resistance. Recommendations of the advisory council for the
elimination of tuberculosis. Amer J Resp Crit Care Med 139:1359-1374, 1994.
Colditz GA et al. Efficacy of BCG vaccine in the prevention of tuberculosis.
Meta-analysis of the published literature. JAMA 271:698-702,1994.
Daley CI et al. An outbreak of tuberculosis with accelerated progression among
persons infected with HIV. NEJM 326: 231-5, 1992.
Di-Perri G et al. Nosocomial epidemic of active tuberculosis among HIV-infected
patients. Lancet 2:1502-4,1989.
Edlin BR et al. An outbreak of multi-drug-resistant tuberculosis among
hospitalized patients with the acquired immunodeficiency syndrome. NEJM 326:
1514-21, 1992.
Fischl MA et al. An outbreak of tuberculosis caused by multiple-drug resistant
tubercle bacilli among patients with HIV infection. Ann Int Med 117: 177-83,
1992.
Gordon S et al. Impaired absorption of oral regimen in treatment of disseminated
M. avium complex. 32nd ICAAC, abstract #896,1992.
Halsey NA et al. Twice weekly INH for TB prophylaxis. Abstract #PB0681, X Intl
Conf AIDS, Yokohama, 1994.
Holt E et al. Efficacy of supervised, intermittent, short course therapy of
tuberculosis in HIV infection. Abstract WS-BO94, IX Intl Conf AIDS, 1993.
Horn DL et al. Limited tolerance of ofloxacin and pyrazinamide prophylaxis
against tuberculosis (correspondence). NEJM 330:1241,1994.
Iseman MD. Treatment of multi-drug-resistant tuberculosis. NEJM 329:784-91, 1993.
Jacobs WR et al. Rapid assessment of drug susceptibilities of Mycobacterium
tuberculosis by means of luciferase reporter phages. Science 260:819-22, 1993.
Jones B et al. Relationship of the manifestations of tuberculosis to CD4 cell
counts in patients with human immunodeficiency virus infection. Am Rev Respir
Dis 148:1292-7,1993.
Mahmoudi A and Iseman D. Pitfalls in the care of patients with tuberculosis;
Common errors and their association with the acquisition of drug resistance. JAMA
270: 65.8, 1993.
Markowitz N et al. Tuberculin and anergy testing in HIV-seropositive and
HIV-seronegative persons. Ann Int Med 119:185-93, 1993.
Moreno S et al. Risk for developing tuberculosis among anergic patients infected
with HIV. Ann Int Med 119:194-8, 1993.
Peloquin CA et al. Malabsorption of antimycobacterial medications. NEJM
329:1122-3,1993.
Small PM et al. Exogenous re infection with multi-drug-resistant Mycobacterium
tuberculosis in patients with advanced HIV infection. NEJM 328:1137-44.1993.
OTHER REPORTS:
Banerjee A et al. inhA, a gene encoding a target for isoniazid and ethionamide in
Mycobacterium tuberculosis. Science 263:227-30, 1994.
Barnes PF et al. Tuberculosis in patients with HIV infection. NEJM 324: 1644-50,
1991.
Davidson PT and Le HQ. Drug treatment of tuberculosis - 1992. Drugs 43(5):
651-72, 1992.
Driver CR et al. Transmission of Mycobacterium tuberculosis associated with air
travel. JAMA 272: 1031-1035,1994.
Goble M et al. Treatment of 171 patients with pulmonary tuberculosis resistant
and rifampin. NEJM 328: 527-32,1993.
