Tuberculosis in Patients Infected with Human Immunodeficiency Virus: Perspective on the Past Decade

683

Tuberculosis in Patients Infected with Human Immunodeficiency Virus:Perspective on the Past Decade

Robert W. Shafer and Brian R. Edlin From the Division ofInfectious Diseases and Geographic Medicine,Stanford University Medical Center, Stanford, California; and the

Division ofHIVIAIDS, Centers for Disease Control and Prevention,Atlanta, Georgia

Tuberculosis (TB) is the most common opportunistic infection and the leading cause of death inpersons infected with human immunodeficiency virus (HIV) worldwide. Because HIV is spreadingin regions with the highest rates of Mycobacterium tuberculosis infection, HIV is responsible for anincreasing proportion of the world's cases of TB. However, advances in molecular biology, clinicalpractice, and public health policy during the past 5 years offer reasons for hope. Molecular methodshave provided insights into the epidemiology of M. tuberculosis transmission and the mechanismsof drug resistance. Rapid diagnostic tests have been developed to facilitate the diagnosis of TB.Retrospective and prospective studies have shown that TB in the HIV-infected person is highlytreatable and often preventable. Moreover, directly observed therapy can decrease rates of treatmentfailure, relapse, drug resistance, and secondary spread. For two consecutive years, the incidence ofTB in the United States has declined. Additional resources are needed, however, to achieve similargains in the developing world.

When the first AIDS cases were diagnosed in 1981, onethird of the world's population was estimated to be infectedwith Mycobacterium tuberculosis [1]. Each year active diseasedeveloped in 8-10 million persons, and nearly 3 million persons died of tuberculosis (TB) [1]. As many as 7% of all deathsand 26% of preventable deaths in developing countries werecaused by TB [1, 2]. Nonetheless, before the emergence ofHIV, the vast majority of M. tuberculosis infections were keptin check by the host immune response and remained latent forthe lifetime of the human host [3]. With host and pathogen ina standoff, the elimination ofTB from parts ofthe industrializedworld was considered an achievable goal, and inroads into TBcontrol had been made in many developing nations [1, 2, 4].

However, the worldwide spread of HIV infection has undermined human defenses against M. tuberculosis. HIV infectionis the strongest risk factor for the progression of latent Mtuberculosis infection to active TB [5-7]. The HIV pandemichas stalled the elimination of TB in the United States and hasreversed many of the hard-won gains in TB control in thedeveloping world [8-13]. By mid-1995, nearly 6 million persons worldwide were estimated to be coinfected with M. tuberculosis and HIV [12] (table 1); by the year 2000, an estimated

Received 8 August 1995; revised 17 November 1995.Use of trade names and commercial sources is for identification only and

does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

Reprints: Dr. Brian R. Edlin, Division of HIV/AIDS, Centers for DiseaseControl and Prevention, 1600 Clifton Road, E-45, Atlanta, Georgia 30333.

Correspondence: Dr. Robert W. Shafer, Division of Infectious Diseases,Room S-156, Stanford University Medical Center, Stanford, California 94305.

Clinical Infectious Diseases 1996;22:683-704© 1996 by The University of Chicago. All rights reserved.1058-4838/96/2204-0013$02.00

14% of incident cases of active TB (about 1.4 million) will beattributable to HIV [12].

TB is the most common life-threatening HIV-related infection worldwide and is often the sentinel illness ofHIV infection[11, 14]. An additional threat ofTB lies in its communicabilitythrough the air. During the past decade, much has been learnedabout the interaction of HIV and TB from research in molecular, clinical, and epidemiologic disciplines.

Pathogenesis

M. tuberculosis Infection

M. tuberculosis is acquired by inhalation of infectious airborne particles small enough (,...., 1-5 microns) to reach thealveolar air spaces. The probability of infection depends on theintensity of exposure and probably also on the effectiveness ofinnate host defenses. Alveolar macrophages in some individuals may have a high degree of innate mycobacterial resistance,and in these persons the tubercle bacilli are presumably destroyed before infection is established [3, 15]. In other individuals the inhaled mycobacteria survive phagocytosis, replicate,and spread to regional lymph nodes and throughout the body.Although functional macrophage defects [16, 17] and abnormallung surfactant [18] have been associated with HIV infection,it is not known whether HIV-infected persons are more susceptible than HIV-seronegative persons to acquisition of M. tuberculosis infection following exposure.

Active TB

The cell-mediated immune response to M. tuberculosis ischaracterized by complex interactions between different sub-

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684 Shafer and Edlin

Table 1. Estimated number of adults infected with TB and HIV in mid-1995.

HIV- and TB-infectedHIV-infected TB-infected

Region (thousands) (%) No. (thousands) % of total

Sub-Saharan Africa 8,500 47 4,000 67.0South and Southeast Asia 3,000 46 1,380 23.1

Latin America and Caribbean 1,500+ 29 428+ 7.2North America 750+ 8 60+ 1.0Western Europe 450 10 45 0.8

North Africa and Middle East 100+ 22 22+ 0.4East Asia and Pacific 50+ 43 21+ 0.3Eastern Europe and Central Asia 50+ 16 8+ 0.1Australasia 20 18 4 0.1

All regions 14-15,000 5,968+ 100

NOTE. Data are from [13] and courtesy of the Tuberculosis Programme, World Health Organization, Geneva,Switzerland.

em 1996;22 (April)

sets of lymphocytes and monocyte-macrophage cells [3, 19].After ingesting mycobacteria, macrophages sensitize T lymphocytes by secreting IL-1 and presenting lymphocytes withprocessed mycobacterial antigens. M. tuberculosis-specificprecursor lymphocytes are stimulated to proliferate and secrete1ymphokines. These 1ymphokines in tum recruit circulatingmonocytes and induce their maturation into macrophages withenhanced phagocytic and microbicidal activity. In the ensuinggranulomatous response, tubercle bacilli are killed by repeatedcycles of phagocytosis, cytolysis, and exposure to microbicidalproducts.

However, the immunologic response to M. tuberculosis isfrequently not sterilizing, and surviving but dormant organismsoften cause latent infection. Clinical disease occurs when themycobacterial replication that follows initial infection cannotbe controlled (progressive primary TB) or when latent organisms overcome immunologic control (reactivation TB). In'""5% of immunologically normal adults who become infectedwith M. tuberculosis, progressive primary TB develops within2 years of initial infection. In another 5%, TB reactivates laterin life [5].

CD4+ T lymphocytes are involved in many aspects of theimmune response to M. tuberculosis, including binding to processed antigen, secreting cytokines, and killing mycobacteriainfected cells [3, 19]. HIV-induced CD4+ T-Iymphocytedepletion leads to a defective immunologic response to Mtuberculosis [20-23]. HIV-infected persons with latent M. tuberculosis infection are at high risk of reactivation TB, andthose with recently acquired M tuberculosis are at high riskof progressive primary TB.

Active TB develops at an annual rate of 5%-12% in HIVinfected persons with previous M. tuberculosis infection [2430] (table 2). The risk ofTB is more than 25-30 times higheramong HfV-infected persons than among HIV-seronegativecontrols [24-26]. Among HIV-infected persons, the risk ofTBis several times higher for those whose tuberculin skin tests

are positive rather than negative [24, 28-30], a finding whichsuggests that reactivation of latent M. tuberculosis is the mostcommon mechanism of active TB.

Rapid progression from recent M. tuberculosis infection toactive TB (progressive primary TB) has been demonstratedin HIV-infected persons exposed to M. tuberculosis duringinstitutional outbreaks [31-40]. HIV-infected persons are sovulnerable to progressive primary TB that active disease maydevelop within weeks of exposure to M. tuberculosis. In patients with advanced HIV infection, previous M tuberculosisinfection is not always protective, and exogenous reinfectionwith a different strain of M. tuberculosis may occur [41].

HIV-infected patients with TB are usually less immunocompromised than HIV-infected patients with other AIDS-definingopportunistic infections, and their CD4+ T lymphocyte countsare generally in the range of 150-350/mm3 [42-52]. However,TB also may occur in HIV-infected persons with marked CD4+T lymphocyte depletion as a result of newly acquired M tuberculosis infection.

Infectiousness

Although HIV infection may increase host susceptibility toM. tuberculosis infection and strongly increases the risk ofprogression to active TB, it may decrease the infectiousnessof patients with TB. The presence of acid-fast bacilli (AFB)in a sputum smear and evidence of pulmonary cavitation on achest radiograph are the best indicators of a patient's potentialfor transmitting M tuberculosis [9]. Most studies show thatHIV-infected patients with TB have fewer AFB in their sputumand less frequent pulmonary cavitation than do HIV-seronegative patients with TB [42, 45, 53-59]. Indeed, the frequencyof sputum-smear AFB-positivity and pulmonary cavitation decreases with increasing immunosuppression. In addition, tuberculin skin test reactivity rates among contacts of HIV-infected



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CID 199;22 (April) Tuberculosis and HIV 685

Table 2. Incidence of TB in HIV-seropositive (HIV+) and HIV-seronegative (HIV-) persons in various studies.

21 1 0.3

22 7 7.9

19 6 0.5

15 62 3.0

17 15 5.4

16 0

16 8 2.6

18 11 8.4

29 19 5,4

17 20 12,4

30 24 10,4

Type of study and/or participants (n)

HIV-seropositive persons and HIV -seronegative controls

Intravenous drug users, New York City [24]

HIV +!PPD+ (49)

HIV+/PPD- (166)HIV -!PPD+ (62)HIV -/PPD- (236)

Women of childbearing age, Zaire [25]*

HIV+ (249)

HIV- (310)

Women of childbearing age, Rwanda [26]*HIV + (401)

HIV- (917)

HIV -seropositive persons, categorized according to

tuberculin skin test results

Intravenous drug users, New York City [24]

PPD- (166)PPD+ (49)

Multicenter study, Italy [30]

PPD- (849)

Anergic! (1,649)

PPD+ (197)

Natural history study, Spain [28]

PPD- (87)

Anergic (235)

PPD+ (87)Natural history study, Spain [29]

PPD- (154)

Anergic (112)

PPD+ (84)

Months of follow-up

(median)

22

21

23

23

30

32

24

26

No. of TB cases

71oo

19

1

20

2

Incidence of TB

(0/0 per year)

7.9

0.3

3.1*0.1

2.5*

0.1

NOTE. PPD+ = tuberculin skin test (purified protein derivative)-positive; PPD- = tuberculin skin test-negative.* Tuberculin skin testing was not performed in these studies.t Anergy was determined with use of multiple puncture skin tests.

patients with TB are generally lower than among contacts ofHIV-seronegative patients with TB [60-64].

Impact on the Course of HIV Infection

Findings from several studies suggest that active TB mayaccelerate HIV-induced immunologic deterioration. First, active TB is associated with transient CD4+ T-Iymphocyte depression [65, 66]. Second, TB causes immune stimulation andincreased production of cytokines, such as TNF [3, 67, 68],which increase HIV replication in vitro [69, 70]. Third, HIVinfected patients with TB appear to have a higher risk of opportunistic infections and death than do HIV-infected patients withsimilar CD4+ T cell counts but without TB [71]. Finally, inone study, preventive therapy with isoniazid for HIV-infectedpatients not only reduced the risk ofactive TB but also appearedto delay other opportunistic infections and death [27].

Epidemiology

Resurgence of TB in the Uoited States

Between 1985 and 1992 the number of reported cases of TBin the United States increased by 19% [72]. During this interval

an estimated 52,000 more cases occurred than would have beenexpected had the downward trend of 1981-1984 continued[72, 73]. In 1993 and 1994 the number of reported TB casesdecreased 5% and 4%, respectively, probably reflecting theeffectiveness of recently introduced prevention and controlmeasures [74, 75].

Epidemiologic evidence suggests that HIV has played an important role in the resurgence of TB in the United States. Thelargest increases in incidence of TB occurred in demographicgroups and locations in which the prevalence of HIV was highest[76]. Between 1980 and 1992 the number ofcases ofTB increased> 150% in New York City, and between 1984 and 1990 theincidence of TB increased 400/0-50% in California, Florida, andNew Jersey [77, 78]. Among persons aged 25-44 years, theincidence of TB increased 52%; most of the increase occurredamong blacks and Hispanic persons [9,76,79].

Between 1981 and 1991 at least 11,299 patients with AIDS inthe United States also had TB [80]. Persons with AIDS were 59times more likely to be found to have TB than the rest of thepopulation, and persons with TB were 204 times more likely tobe found to have AIDS than the rest of the population [80].



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686 Shafer and Edlin cm 1996;22 (April)

Table 3. Outbreaks of TB involving HIV-infected (HIV+) persons, 1988-1992.

Type of TB, setting Comments

Drug-susceptible TBHospital HIV unit, Verona, Italy [31]

Housing for HIV+ persons, San Francisco [33]Hospital HIV unit, Puerto Rico [38]

Health clinic, Florida [32]Hospital, Texas [87]

Multidrug-resistant TB (MDR TB)>5 Hospitals in New York City [34-36, 40, 90]

Prison system, New York State (NYS) [91]

Hospital and clinic, Miami [39, 88]Substance-abuse treatment facility, Michigan [89]TB ward, New York City [41]

NOTE. TST = tuberculin skin test.

TB developed in 8 (44%) of 18 exposed HIV+ patients; CD4 cell counts were lower forexposed patients in whom TB developed than for exposed patients in whom it did not (232vs. 562 cells/ul.; P < .01).

TB developed in 11 residents within 4 months of exposure to the index case.HIV+ patients sharing a room with a pulmonary TB patient were more likely to acquire TB

than were other hospitalized HIV+ patients.A case-control study suggested an association with aerosolized pentamidine treatments.Thirty of 158 health care workers had TST conversions after exposure to an HIV-infected

patient with pulmonary TB; the diagnosis of TB was initially obscured by simultaneousinfection with P. carinii and M avium complex.

Of >200 patients with TB, >80% were HIV-infected; mean incubation was 1-3.5 months inthe different hospital outbreaks; multiple failures in infection control contributed totransmission.

Thirty-eight of 39 inmates were HIV+; 29 inmates were infected with a strain resistant toisoniazid, rifampin, streptomycin, ethambutol, ethionamide, rifabutin, and kanamycin; inmateswith MDR TB lived in 23 of the 68 NYS prisons while potentially infectious (12 weretransferred through 20 prisons while ill with MDR TB); TST conversions occurred for ~30%of exposed inmates in one prison, 60 staff members in another prison, and > 50 health careworkers.

Sixty-two HIV-infected patients had MDR TB over a 3-year period.At least 15 and possibly as many as 31 exposed clients and staff members had TST conversions.Four HIV-infected patients hospitalized with drug-susceptible TB were reinfected with an MDR

TB strain and had active TB within 2-9 months of initial hospitalization.

Moreover, in the locations in which the greatest increases in thenumber of cases of TB have occurred, the prevalence of HIVamong TB patients has been high. Studies of patients with TB inNew York City, Miami, and San Francisco have revealed HIVprevalence rates of 30%-50% [45,46, 81-83].

Transmission of M. tuberculosis

The HIV epidemic contributed to the resurgence of TB byincreasing the susceptibility ofHIV-infected individuals to bothprimary and reactivation TB. In addition, transmission of M.tuberculosis has probably increased. Over the past 2 decades,fiscal constraints led to cutbacks in many TB control programs[82, 84]. At the same time, the overlapping social problems ofhomelessness, substance abuse, and poverty have increased inpopulations affected by both TB and HIV and have limited thesuccess of TB control in these groups.

Studies employing restriction fragment length polymorphism(RFLP) analysis have suggested that perhaps one-third ofrecentcases of TB in New York City and San Francisco resultedfrom recently transmitted infections [85, 86]. In addition, TBoutbreaks have occurred as persons with HIV and persons withactive TB have been brought together in health care facilitiesand other institutional settings [31-40, 87-91] (table 3) (figure1). In these outbreaks, HIV-related immunosuppression amplified and accelerated transmission of M. tuberculosis because

exposed HIV-infected patients often had active TB withinweeks and then became additional sources of transmission.During the outbreaks, many health care workers' tuberculinskin test findings converted and in some active TB developed[37-40,87,91-95].

During the 1980s, the homeless and prison populations increased and included large numbers of HIV-infected persons [82,86, 96-98]. TB among HIV-infected homeless persons becamecommon [82, 86, 96, 97], and the number of TB cases increasedsharply in the correctionalsystems of New York, California,NewJersey, and several other states [99-101]. The potential for Mtuberculosis to spread within prisons was demonstrated by anoutbreak in which a single highly drug-resistant organism wasisolated from> 30 HIV-infected inmates who had been incarcerated in more than 20 different prisons [91, 102].

The recent increase in pediatric cases of TB is also evidenceof increased transmission of TB. Between 1985 and 1991, theincidence of TB increased 36% among children 0-4 years old[76]; the largest increase occurred in New York City [103]. Somepediatric cases are due to transmission from HIV-infected adults,and some cases reflect the high risk of progression to active TBfor children coinfected with HIV and M tuberculosis [104-108].

Drug-Resistant TB

Resistance ofM. tuberculosis to drugs is caused by mutationsin genes encoding the targets of anti-TB therapy [109-114].



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Figure 1. Restriction fragmentlength polymorphisms ofM tuberculosis isolates obtained fromHIV-infected patients with multidrug-resistant TB during a hospitaloutbreak (arrows) and from HIVinfected controls with drug-susceptible TB from the same hospital(reprinted with permission from[34]).

These mutations occur with a predictable frequency of one in105-108 organisms [115]. When anti-TB drugs are used incombination, growth of mutant M tuberculosis organisms resistant to any single drug is prevented by the other drugs inthe combination. However, when organisms are exposed toonly one effective drug because of incomplete or erratic antiTB therapy, drug resistance may develop. Once M tuberculosisbecomes resistant to one drug, continued treatment or the addition of a single active drug to the treatment regimen maycause resistance to additional drugs [116]. In cases in whichM tuberculosis becomes resistant to isoniazid and rifampin(i.e., multidrug-resistant TB [MDR TB]), treatment is oftenunsuccessful [117, 118]. Patients with active MDR TB mayremain chronically ill and persistently infectious, and the condition is associated with high mortality.

The prevalence of MDR TB in the United States increasedfrom 0.5% during 1982-1986 to 3.5% during the first 3 monthsof 1991 [119, 120]. The highest rates of prevalence of MDRTB have been reported from New York City, New Jersey, andFlorida [119]. In April 1991, 19% of all patients with TB inNew York City whose M. tuberculosis cultures were positivehad MDR TB [121].

Data regarding institutional outbreaks have demonstrated thehigh rate of disease progression among HIV-infected personswho become infected with M tuberculosis strains that are already multidrug-resistant (i.e., initial drug resistance). However, HIV-related immunosuppression does not appear to increase the likelihood that drug resistance will develop in aperson infected with drug-susceptible M tuberculosis (i.e., acquired drug resistance). At one center in New York City, acquired drug resistance was more common among HIV-seronegative patients with MDR TB, whereas initial drug resistance

was more common among HIV-infected patients with MDRTB [122]. Indeed, RFLP analysis ofMDR TB strains from thatcenter showed that most HIV-infected patients with MDR TBin 1990-1991 were infected with the same M. tuberculosisstrains that had been isolated from HIV-seronegative patientsin previous years [122].

TB and HIV Infection Outside the United States

Even before the AIDS pandemic, the countries of sub-Saharan Africa suffered disproportionately from TB. Approximately 50% of adults in sub-Saharan Africa are estimated tobe infected with M tuberculosis, and the incidence of activeTB may be as high as 200 per 100,000 persons [1, 10, 12]. Insome urban areas 10%-30% of adults are HIV-seropositive[123-125], and 4 million Africans are estimated to be coinfected with HIV and M tuberculosis [11-13] (table 1). Nationwide notification rates and hospital-based studies suggest thatthe incidence of TB has more than doubled since the early1980s in those countries in which the rates of HIV infectionare highest [11, 123-129]. In some African cities, most hospitalbeds are occupied by HIV-infected patients, about one-half ofwhom have TB [14, 125, 126, 130-133].

Historically, the largest number of cases of TB have occurredin Asia, where HIV is spreading rapidly. Already, > 1.3 millionadults in southeast Asia are estimated to be coinfected withHIV and TB (table 1) [13,134-136]. By the year 2000, becauseof the rapid spread of HIV in Thailand, India, and Myanmar(Burma), the number of cases of TB in Asia attributable toHIV may approximate the number of such cases in sub-SaharanAfrica [12].



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688 Shafer and Edlin CID 1996;22 (April)

More than 400,000 adults in Latin America and the Caribbean islands are estimated to be coinfected with HIV and TB(table 1). TB has been noted in 26%-60% of Haitian personswith AIDS [137-139] and 7%-28% of Latin American persons with AIDS [13, 140].

In Spain and Italy, the incidence of TB appears to haveincreased as a result of TB among HIV-infected intravenousdrug users [141]. The occurrence of TB in >30% of personswith AIDS in Spain [141-143] and in 2%-13% of HIV-infected persons in other western European countries has beenreported [48, 49, 141, 144, 145].

Clinical Features

In HIV-infected patients with TB, immunodeficiency is associated with increased dissemination of tuberculosis, increasednumber and severity of symptoms, and rapid progression todeath unless treatment is begun [55]. Fever, weight loss, andother constitutional symptoms almost always occur. Cough,chest pain, and other respiratory symptoms are also commonsince most patients have some degree of pulmonary involvement. Shaking chills, hypotension, and acute respiratory distress may occur in patients with disseminated TB [55, 146148]. Localized signs and symptoms depend on the organsinvolved and coexisting HIV-related complications.

Sites of Disease

Pulmonary TB occurs in 70%-90% of patients with TB,including most of those with extrapulmonary TB [6, 7, 49, 52,149-151]. The frequency of extrapulmonary TB ranges from40%-80% and increases with the severity ofimmunosuppression and the extent of diagnostic evaluation. Disseminated disease and lymphadenitis are the most common forms of extrapulmonary TB [55]. M tuberculosis bacteremia, extremelyunusual in patients without HIV infection, has been noted inup to 20%-40% of HIV-infected patients with TB [152-155].

Cervical, supraclavicular, and axillary lymph nodes are themost common sites of peripheral TB lymphadenitis [21, 48,55, 156-160]. The intrathoracic and intraabdominal lymphnodes, rare sites of TB in patients without HIV infection, arecommonly involved in HIV-infected patients with advancedimmunodeficiency [55, 161]. Tuberculous lymph nodes inHIV-infected patients appear to have an increased tendencyto caseate, which may predispose these patients to abscesses,fistulas, and unusual sites of infection [55, 162, 163]. Tuberculous retroperitoneal lymph nodes may erode into the stomachor pancreas; mediastinal lymph nodes may erode into theesophagus, trachea, or bronchi; and mesenteric lymph nodesmay erode into the lower intestine [55, 164-168].

CNS TB occurs in 5%-10% of HIV-infected patients withTB [50,55, 142, 143, 151, 169, 170]. Most have meningitis,but tuberculomas are also common [171-173]. Urine culturesare positive for most patients with disseminated TB, but local-

ized renal TB is rarely diagnosed [50, 55, 169]. Pleural diseaseand pericardial disease are commonly recognized forms of extrapulmonary TB in HIV-infected African patients [174-177].TB of the skin and soft tissues may result from hematogenousseeding or contiguous organ involvement [55, 146, 162,178-180].

Radiographic Findings

Chest radiographs of HIV-infected patients with TB andadvanced immunosuppression are notable for evidence of nonapical distribution of infiltrates, infrequent cavitation, and anincreased frequency of intrathoracic adenopathy, miliary infiltrates, and pleural effusions [6, 7, 53, 57, 181-183] (figure 2).Apical fibrocavitary infiltrates, the classic finding in adults withreactivation TB, occur predominantly in HIV-infected patientswith TB who are not severely immunodeficient. Localized alveolar infiltrates may be confused with bacterial pneumonia, anddiffuse interstitial infiltrates may mimic Pneumocystis cariniipneumonia. The occurrence ofhilar and/or mediastinal adenopathy, which is noted in about one-third of HIV-infected patientswith TB, suggests the diagnosis of TB because intrathoracicadenopathy does not occur with most other HIV-related pulmonary complications. Miliary infiltrates and pleural effusionsoccur in > 10% of HIV-infected patients with TB and oftendevelop during diagnostic evaluation. A normal chest radiograph does not preclude the diagnosis of pulmonary TB becauseradiographic findings may lag behind the rapid evolution ofactive TB [55, 182, 184].

In patients with intrathoracic adenopathy, CT scans usuallydemonstrate clusters of enlarged lymph nodes, often containinglow-density centers consistent with caseous necrosis [55, 181,185] (figure 3). In patients with disseminated TB, abdominalsonography and CT scans may demonstrate intraabdominallymphadenopathy and focal hepatic and splenic lesions [55,143, 163, 186-188] (figure 3).

Tuberculin Skin Testing and Histopathology

The sensitivity of tuberculin skin testing in HIV-infectedpatients is inversely related to the degree of immunosuppression. Among HIV-infected patients with active TB, tuberculinreactions are ~ 10 mm in 40%-60% of those with otherwiseasymptomatic HIV infection but in only 10%-30% of thosewith symptomatic HIV infection [6, 7, 42, 45, 46, 55, 83, 169,189, 190].

The histopathologic appearance of TB in HIV-infected patients also depends on the degree of host immunity. Biopsyspecimens from patients with early immunodeficiency tend tohave granulomas composed of lymphocytes, epithelioid cells,and giant cells [21, 55, 191, 192], whereas those from moreimmunocompromised patients tend to contain necrosis, polymorphonuclear cells, and macrophages [55, 156, 193, 194](figure 4). This histologic appearance ofTB contrasts with that



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Figure 2. Chest radiographs of patients with TB and HIV infection. A, right-middle-lobe infiltrate and widening of the mediastinum due tosubcarinal, right paratracheal, and hilar lymphadenopathy; B, right-lower-lobe infiltrate and pleural effusion (courtesy of Dr. Bernard Suster,Saint Luke's Roosevelt Medical Center, New York; reprinted with permission from [183]).

of Mycobacterium avium complex, in which granulomas areeither absent or small and nonnecrotizing [195].

Diagnosis

Because the clinical features of HIV-infected patients withTB are often nonspecific, diagnosis can be difficult. Many HIVinfected patients with TB have died or been hospitalized for aprolonged period before TB has been diagnosed [55, 125, 149,196-198]. Decreased tuberculin reactivity, atypical radio-

graphic presentations, and confusion with other HIV-relatedinfections hinder the diagnosis ofTB in HIV-infected patients.However, failure to suspect TB and order the appropriate diagnostic tests is often the most common reason for diagnosticdelays.

TB should be considered when HIV-infected persons haveunexplained fever, cough, pulmonary infiltrates, lymphadenopathy, meningitis, brain abscess, pericarditis, pleural effusions,or intraabdominal, musculoskeletal, or cutaneous abscesses.The probability of active TB is increased among patients who

Figure 3. CT scans of patients with TB and HIV infection. A, chest scan demonstrating multiple enlarged necrotic mediastinal lymph nodes;B, abdominal scan demonstrating a large necrotic periportal lymph node (arrow). (Courtesy of Dr. Bernard Suster, Saint Luke's RooseveltMedical Center, New York; reprinted with permission from [183].)



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690 Shaferand Edlin CID 1996;22 (April)

Figure 4. Histopathologic appearance ofbiopsy specimens of lung (A) and liver (B) from patients with TB and HIV infection. Both specimensdemonstrated focal areas of necrosis and cellular debris without lymphocytes, epithelioid cells, or giant cells, and both specimens containedmany acid-fast bacilli on Fite staining (original magnification: A, X 200; B, X 100). (Courtesy of Dr. Ross Hill, State University of New York,Health Science Center at Brooklyn; reprinted with permission from [183].)

have a history of TB, whose tuberculin skin test is positive, orwho have emigrated from a country or belong to a group inwhich the prevalence of TB is high (e.g., racial and ethnicminorities, homeless persons, intravenous drug users, alcoholics, and correctional facility inmates). In areas where nosocomial outbreaks have occurred, recent hospitalization shouldalso be considered a risk factor for TB.

The chest radiograph may show a classic reactivation pattern(apical fibrocavitary disease or miliary infiltrate), an "atypical"pattern (intrathoracic adenopathy, with or without single ormultilobar infiltrates, or pleural effusion), or evidence of pastinfection (calcified lymph node or lung nodule, or pleural orparenchymal fibrosis). Although the sensitivity of the tuberculin skin test decreases with declining immunity, a positive testfor symptomatic persons with advanced HIV infection suggestsactive TB [68, 199, 200].

AFB are found on microscopic examination of sputum specimens from 40%-67% of HIV-infected patients with TB; Mtuberculosis is recovered from 74%-95% in culture [42, 45,48, 49, 54-56, 59, 143, 169, 196, 201] (table 4). If adequatesputum specimens cannot be obtained, sputum should be induced with nebulized hypertonic saline [202]. Acid-fast staining and culture of gastric washings are also useful, particularlyfor infants and children. Fiberoptic bronchoscopy, with bronchoalveolar lavage and transbronchial biopsy, is indicated forpatients with progressive unexplained pulmonary disease [203206]. During bronchoscopy, specimens from enlarged mediastinal lymph nodes may be obtained by endobronchial needleaspiration.

Lymphatic, eNS, pericardial, pleural, and musculoskeletalTB may be suggested by physical examination findings. Newsigns often develop during diagnostic evaluation and may directfurther tests or indicate new complications. Enlarged, tender,or fluctuant lymph nodes should be aspirated percutaneously.

In some series, as many as 90% of suspicious lymph nodescontainAFB [50,55,143,169, 196,207,208] (table 4). Amongpatients with disseminated TB, biopsies of skin lesions haverevealed AFB or granulomas [146, 179, 180,209].

Blood and urine should be cultured for mycobacteria; however, patients with M tuberculosis bacteremia will requiretreatment before these cultures become positive [152, 153].Although AFB are often seen in the buffy coat smears ofbloodfrom patients with disseminated M avium complex infection

Table 4. Diagnostic yield of clinical specimens from HIV-infectedpatients with TB.

Percent of patients for whomfindings are positive

Specimen Microscopy* Culture

Sputum 40-67 74-95Bronchoscopy

Bronchoalveolar lavage 7-20 52-89Transbronchial biopsy 10-39 42-85

Urine 22 45-77Blood NAt 26-64Lymph nodes 37-90 40-95Bone marrow 18-52 25-67Liver biopsy 78 56-78CSF 0-27 NAt

Pleural specimens

Pleural fluid 3-6 NAt

Pleural biopsy 52-55 NAt

* Acid-fast bacilli seen on smears or granulomas seen on histopathologicspecimens.

t Not available. Blood smears have rarely been examined for HIV-infectedpatients with TB. The yields of cultures of CSF and pleural specimens are notshown because most reports present data regarding only M tuberculosispositive cultures of these specimens.



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[210], there has been only one report of a positive buffy coatsmear of blood from an HIV-infected patient with M. tuberculosis infection [211]. Some studies have reported urine-culturepositivity for most HIV-infected patients with extrapulmonaryTB, and in several cases the diagnosis of TB has been basedon the finding of AFB in smears of concentrated urine [50, 55,143, 169, 212] (table 4). Although CSF and pleural fluid aregenerally abnormal in patients with involvement of these sites,stains for AFB are usually negative.

In the absence of localized findings, biopsy of the bonemarrow and/or liver may be effective in diagnosing disseminated TB [49, 55,213,214] (table 4). Abdominal sonographyor CT scanning should be considered in difficult cases becausethese tests may demonstrate necrotic lymph nodes, which provide a high diagnostic yield when aspirated percutaneously [55,163, 186].

The rapidly progressive nature of TB in HIV-infected patients requires that the diagnosis of suspected TB be pursuedexpeditiously. For patients whose initial evaluation is nondiagnostic, including AFB stains of sputum and other readily obtainable specimens, invasive procedures must be considered.For patients who are at high risk of TB or whose conditionsare deteriorating rapidly, empirical anti-TB therapy should bestarted. Because sputum, urine, and blood cultures will mostlikely be positive for patients with fulminant TB, specimensfor these cultures should be obtained before empirical therapyis begun to provide later confirmation of the diagnosis andto provide an M tuberculosis isolate for drug susceptibilitytesting.

Microbiology

The rapid progression of TB among HIV-infected individuals and the increase in prevalence of drug-resistant TB underscore the importance of rapidly identifying and determiningthe drug susceptibility of M tuberculosis strains. The preferredmethod for examining clinical specimens for AFB is fluorochrome staining, which is more rapid and slightly more sensitive than the Ziehl-Neelsen and Kinyoun stains [215]. Radiometric culture methods using liquid media (e.g., BACTEC[Becton Dickinson, Sparks, MD]) are recommended becausethey detect mycobacterial growth in 1-4 weeks, an average of10 days before colonies can be seen on solid media [215, 216].Solid culture media, however, should be used in conjunctionwith liquid media to detect mixed mycobacterial infections.

Traditional methods for determining the species ofmycobacterial isolates (e.g., on the basis of the growth rate, colonialmorphology, pigmentation, and biochemical profile) are unacceptably slow for identifying M tuberculosis. A nucleic acidhybridization assay (Gen-Probe, San Diego, CA) can identifyM. tuberculosis complex organisms within several hours aftergrowth is detected [217]. Rapid hybridization assays also areavailable to identify M avium, Mycobacterium intracellulare,and several other nontuberculous mycobacteria. Because mixed

mycobacterial infections occur, a positive hybridization assayfor another species, such as M avium, does not exclude thesimultaneous presence of M. tuberculosis [87,218]. Mycobacterium bovis and M bovis BCG belong to the M. tuberculosiscomplex and have been isolated from HIV-infected persons[219- 221]. Differentiating these organisms from M. tuberculosis requires classic biochemical tests.

HPLC, a popular method in some reference laboratories, canreliably identify any Mycobacterium species in <4 hours onthe basis of its mycolic acid profile [217]. HPLC is particularlyuseful in identifying mixed and unusual mycobacterial infections, which are common in HIV-infected patients [222- 225].

Because of the rising incidence of drug resistance, initial M.tuberculosis isolates from all patients should be submitted forantimicrobial susceptibility testing [120, 215]. Radiometricmethods using liquid media can be employed to test susceptibility to isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin and will usually yield results 4- 7 days after the initialdetection of mycobacterial growth [215].

Several gene amplification techniques have been developedthat can detect M tuberculosis nucleic acid directly from clinical specimens within hours. Assays using peR (Roche Amplicor MTB; Roche Diagnostic Systems, Somerville, NJ) ortranscription-mediated amplification (Gen-Probe amplifiedMycobacterium direct test) have been evaluated extensively onclinical samples and are likely to be licensed soon [217, 226232]. In reference laboratories, both techniques are highly specific (>95%) and somewhat more sensitive than staining forAFB [230-235]. The sensitivity of these amplification techniques depends on the volume and means of specimen processing and on clinical circumstances. The usefulness of thesetechniques will be determined by their cost and their successin decreasing the need for invasive procedures and prolongeddiagnostic evaluations.

Treatment

The problems of HIV infection, drug resistance, and nonadherence with therapy have led to the publication ofnew guidelines for treating TB [236, 237]. The Centers for DiseaseControl and Prevention (CDC) and the American ThoracicSociety (ATS) do not currently recommend longer treatmentregimens for HIV-infected patients with TB than for HIVseronegative patients with the disease. Instead, the clinicaland bacteriologic response to treatment of HIV-infected patients with TB should be followed closely, and therapy shouldbe prolonged only for patients with a slow or suboptimalresponse [237].

Effectiveness of Therapy for DIV-Infected Patients

HIV-related immunosuppression does not interfere with theeffectiveness of therapy for TB. Defervescence, sputum conversion, and resolution of chest radiographic abnormalities oc-



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692 Shafer and Edlin em 1996;22 (April)

cur as rapidly in HIV-infected patients as in those withoutHIV infection [55, 58, 169, 197, 238-243]. Most early deathsamong HIV-infected patients with TB result from undiagnosedTB or from nontuberculous HIV-related complications [55,169, 197, 243-245]. Most treatment failures result from drugresistance or poor adherence with therapy, although anecdotalcases of treatment failure attributed to undrained tuberculousabscesses [246-248] or malabsorption of anti-TB medications[249-252] have been reported. Indeed, the rare occurrence ofacquired rifampin resistance among HIV-infected patients withTB may result from malabsorption of isoniazid [252, 253].

HIV-infected patients with TB have a low risk of relapseduring the first year after completing therapy. Of >500 HIVinfected patients who completed 6-9 months of standard antiTB treatment with regimens including at least isoniazid andrifampin and who were monitored for 12- 24 months, fewerthan 5% relapsed, and some of those 5% adhered poorly totherapy [49, 169, 197, 240, 241, 254-256]. However, in theonly completed prospective randomized study of HIV-infectedpatients with TB, 9% of those receiving therapy for 6 monthsrelapsed, compared with only 2% of those receiving treatmentfor 12 months [243]. As HIV-infected patients are living longerbecause of advances in medical treatment, studies are urgentlyneeded to assess the risk of relapse more than I - 2 years afterthe completion of anti-TB therapy. Studies are also needed todetermine the prevalence and clinical significance of malabsorption of anti-TB drugs in HIV-infected patients.

Initial Therapy (for Drug-Susceptible TB)

An initial three-drug regimen is currently recommended foruse only in areas where careful surveillance has documentedthat drug resistance rates are lower than 4% [236]. For use inall other areas, a four-drug regimen consisting of isoniazid,rifampin, pyrazinamide, and either ethambutol or streptomycinis now recommended as initial therapy, to be administeredwhile the results of drug susceptibility tests are pending [236](table 5). Use of four-drug regimens reduces the likelihood thattherapy for patients with drug-resistant M tuberculosis willfail and that organisms will develop resistance to additionaldrugs. In addition, four-drug regimens reduce infectiousnessmore rapidly than do three-drug regimens [236].

Therapy for Suspected or Proven Drug-Resistant TB

All patients with TB should be evaluated for possible drugresistance. Patients should be questioned thoroughly about previous preventive or curative therapy for TB and exposure toknown cases of TB. The possibility of resistance to any drugthe patient has received should be considered, and results ofpast susceptibility testing of isolates from the patient or fromknown contacts should be sought. Emigration from many developing countries could also be considered a risk factor fordrug resistance [257].

Patients with drug-resistant TB should receive supervisedtherapy that is managed in consultation with clinicians whoare experienced at treating such TB [236]. Resistance to eitherisoniazid or rifampin can usually be overcome by the substitution of other first-line drugs (table 5). The duration of therapyis usually determined by the extent of drug resistance, severityof TB, severity of immunodeficiency, and response to therapy.

If resistance to both isoniazid and rifampin is suspected,the initial drug regimen should include isoniazid, rifampin,pyrazinamide, and three drugs to which local MDR TB strainsare susceptible [236] (table 5). HIV-infected patients withMDR TB who are treated initially with at least two (or three)anti-TB drugs to which the causative organism is susceptibleimprove clinically, become noninfectious, and survive longerthan patients treated with fewer effective drugs [194, 258261]. Isoniazid and rifampin should be withdrawn once resistance to these drugs is proved by antimicrobial susceptibilitytesting.

For patients with MDR TB, it is necessary to determinesusceptibilities to the second-line anti-TB drugs and to thequinolones, The optimal drugs for treating MDR TB includethe other first-line anti-TB drugs (ethambutol, streptomycin,and pyrazinamide) and the quinolones (ofloxacin or ciprofloxacin) [117,118]. Administration ofaminosalicylic acid, ethionamide, and cycloserine may need to be initiated in the hospitalto permit observation of toxicity, intolerance, and initial response [118]. Resectional surgery should be considered forpatients with extensive drug resistance, localized disease, andgood cardiopulmonary reserve [262]. Although HIV-infectedpatients with MDR TB show improvement with appropriatetherapy and become noninfectious [194, 258-261], it is notknown whether discontinuing anti-TB treatment exposes suchpatients to a high risk of relapse.

Nonadherence and Directly Observed Therapy

Although generally highly efficacious, therapy for TB requires a prolonged course of multiple medications that oftenhave side effects. Because patients with TB often no longerfeel ill after the first few weeks.of treatment, continuing antiTB therapy may become a low priority for them. Indeed, failureto complete anti-TB therapy is common in many parts of theUnited States [263]. Although persons leading disadvantagedand disorganized lives, such as homeless persons and substanceabusers, are less likely than others to complete therapy, personsof all backgrounds have been nonadherent [264].

Adherence to TB therapy can be improved by "enablers"such as transportation and short waiting times, incentives suchas meals or money, and a trusting relationship between patientand health care worker. The use of formulations with multipledrugs of demonstrated bioavailability, such as Rifater (isoniazid, rifampin, and pyrazinamide; Marion Merrell Dow, KansasCity, MO) and Rifamate (isoniazid and rifampin; Marion Merrell Dow) may enhance adherence and, by preventing discontin-



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Table 5. Treatment regimens for HIV-infected adults with TB.

Clinical circumstances andtreatment considerations

DOT

DOT not considered necessary toensure patient's compliance

Resistance (or intolerance) to INHt

Resistance (or intolerance) to Rift

Possible or confirmed resistance to

both INH and Rif (cases ofMDR TB)t

Initial therapy*

INH, Rif, PZA, and Eth or Stm daily for 2 w and then2-3 X/w for 6 w or

INH, Rif, PZA, and Stm or Eth 3 x/w for 6 moINH, Rif, PZA, and Stm or Eth daily (pending

susceptibility data) and then INH, Rif, and PZA tocomplete 8 w of therapy with these 3 drugs

INH, Rif, PZA, and Eth or Stm, plus additional 2ndline drugs or a quinolone antibiotic, so that patient

receives ~3 drugs to which local MDR TB strainsare likely to be susceptible

Continuation phase of therapy

INH and Rif 2-3 X/w to complete 6 mo of treatment

INH and Rif daily to complete 6 mo of treatment

Rif, Eth, and PZA X 18 mo (and for ~ 12 mo afterculture conversion)

INH, Eth, and PZA X 18 mo (and for ~ 12 mo afterculture conversion)

~3 drugs to which patient's M tuberculosis strain issusceptible; appropriate duration of therapy is notknown

NOTE. Data are from [118, 236, 237]. DOT = directly observed therapy; INH = isoniazid, 5 mg/kg (maximum [max], 300 mg) for daily therapy or 15 mg/kg (max, 900 mg) for intermittent therapy; Rif = rifampin, 10 mg/kg (max, 600 mg) for daily and intermittent therapy; PZA = pyrazinamide, 15-30 mg/kg(max, 2 g) for daily therapy or 50-70 mg/kg (max, 8-9 g/w) for intermittent therapy; Eth = ethambutol, 15-25 mg/kg (max, 2.5 g) for daily therapy or 25-50mg/kg (max, 2.5 g) for intermittent therapy; Stm = streptomycin, 15 mg/kg (max, 1 g) for daily therapy or 25-30 mg/kg (max, 1-1.5 g) for intermittent therapy.

* In areas where surveillance for drug-resistant TB has documented drug resistance rates of <4%, INH, Rif, and PZA alone may be used for initial therapy.t All patients with drug-resistant TB should receive DOT; MDR TB should be treated in consultation with physicians experienced at treating such patients.

uation of anyone of the component drugs, reduce the likelihoodthat drug resistance will develop [265, 266].

However, the best way to ensure adherence is to directlysupervise the administration of therapy. Directly observed therapy (DOT), administered 2 or 3 times per week, has beenhighly successful in a wide variety of settings [236, 267]. Thecosts of supervision are more than offset by savings resultingfrom the decreased risk of treatment failure, relapse, drug resistance, and secondary spread [267-270]. The use of DOT reduced the risk of relapse and drug resistance in Tarrant County,Texas, from 1986 to 1992 [268] (figure 5A). The increased useof DOT in New York City and Baltimore has been responsiblein part for large decreases in the number ofcases ofTB recentlyobserved in those cities [269, 270] (figure 5B). Although theefficacy of intermittent (twice or thrice weekly) DOT has beenestablished primarily among patients without HIV infection,recent data suggest that HIV-infected patients with TB alsorespond well to supervised intermittent therapy [197, 236,240, 243].

Drug Toxicity and Interactions

In some studies, as many as 20% of HIV-infected patientstreated with standard chemotherapy experienced an adversereaction that prompted a change in therapy [47,49, 169]. Mostof these reactions occurred within the first 2 months of treatment and consisted of mild rash or hepatitis, most often attributed to rifampin. However, most studies have found that antiTB medications are well tolerated by HIV-infected patients[48,55,83, 197,240, 243, 254]. Because ofrifampin's impor-

tance in short-course therapy, studies are needed to determinethe optimal management of this drug's toxicity in HIV-infectedpatients with TB.

Rifampin is a potent inducer of the hepatic cytochrome P450enzyme system and thus reduces the activity of several medications commonly used by HIV-infected patients; these includeketoconazole, fluconazole, methadone, oral contraceptives, andseveral experimental antiretroviral compounds such as thenonnucleoside reverse transcriptase inhibitors and protease inhibitors [271, 272]. Although the combination ofanti-TB medications and zidovudine is well tolerated [273, 274], pharmacokinetic data from a study of four patients suggest that rifampinmay increase hepatic clearance of zidovudine and decreasezidovudine plasma levels by 50o~ [275]. The cations in didanosine tablets may reduce the bioavailability of the quinoloneantibiotics [276], and there is one report of decreased rifampinabsorption that was attributed to simultaneous administrationof ketoconazole [277].

Treatment in Developing Countries

In resource-poor developing countries, limited funds haveoften forced administrators of TB control programs to use suboptimal treatment regimens. In most of sub-Saharan Africa,standard therapy has consisted of the use of isoniazid, thiacetazone, and streptomycin for 2 months and then isoniazid andthiacetazone for 10 months. Unfortunately, this regimen failsfor > 10% of fully compliant HIV-seronegative patients withTB [1] and is even less effective for HIV-infected patients [245,278-280]. Furthermore, 10%-20% of HIV-infected patients



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B

198319841985198619871988198919901991199219931994

Year

3,000

1,000

2,000

In 4,000CI)Incao"-ooz

A

Relapse I

1988 1990 1992

Primary resistance I~

Acquired resistance

198619841982

•

1.6 ~1.2 •

~::~0.0 ....a-__I....__--'-__~__..a...__ ___a.____'__

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Figure 5. A, incidence of tuberculosis relapse, initial drug resistance, and acquired drug resistance in Tarrant County, Texas, before andafter a comprehensive, directly observed therapy (DOT) program was instituted in 1986 (adapted from [268]); B, number of TB cases in NewYork City between 1983 and 1994 (dots) and the association of a decline from 1992 to 1994 with an increase in the number of personsreceiving DOT (bars) (adapted from [269]).

receiving thiacetazone experience severe and occasionally fatalcutaneous hypersensitivity reactions [174, 281-283]. For thesereasons, the World Health Organization (WHO) is attemptingto obtain the resources to increase the use of supervised shortcourse chemotherapy with rifampin-including regimens incountries in which the prevalence of HIV and TB is high [14].

Prevention

Preventive Therapy

Preventive therapy with isoniazid decreases the risk ofactiveTB in HIV-infected persons latently infected with M tuberculosis (table 2) [24, 27, 28, 30, 256, 284, 285]. In a controlledtrial in Haiti, for example, the incidence of TB over a 3-yearperiod was >5-fold lower among tuberculin-reactive HIV-infected patients receiving isoniazid for 12 months than amongtuberculin-reactive HIV-infected patients receiving placebo[27]. In a controlled trial in Zambia, a 6-month course ofisoniazid decreased the risk of active TB, although the incidence of TB among isoniazid recipients gradually increasedduring the postprophylaxis period [284].

Because HIV-infected persons with latent M. tuberculosisinfection have an extraordinary risk for reactivation and because preventive therapy can reduce that risk, identifyingindividuals dually infected with M. tuberculosis and HIVis critically important. Tuberculin skin testing is thereforerecommended for all HIV-infected persons [286]. Skin testing and preventive therapy should be available to persons athigh risk for dual infection; these include prison inmates,residents of homeless shelters, and clients of drug treatmentprograms [287].

Patients whose tuberculin skin test is positive require chestradiography and careful assessment to exclude both pulmonaryand extrapulmonary TB, because administration of isoniazidalone to patients with active TB will select for isoniazid-resistant strains. After active TB is excluded, all HIV-infected persons whose tuberculin skin test is positive should receive isoniazid for 12 months unless such treatment is medicallycontraindicated [237]. Because TB may develop in HIV-infected persons following exogenous reinfection [41], preventive therapy after new exposure to an infectious case of TBshould be considered, even for persons who have previouslybeen treated for active TB or have received prophylaxis forlatent TB. HIV-infected persons who have been significantlyexposed to infectious MDR TB should receive preventive therapy with a combination of2 or 3 drugs to which the multidrugresistant organism is susceptible [237, 288].

The sensitivity of tuberculin skin testing for detecting latentM tuberculosis infection is reduced in HIV-infected persons.In several studies, HIV-infected persons have been less likelythan matched HIV-seronegative controls to have positive tuberculin skin tests [97, 289-293] (table 6). To improve the sensitivity of tuberculin skin testing in HIV-infected persons, theCDC and ATS recommend that, in this population, indurationof ~5 mm should be considered positive [237, 294]. Mantouxtuberculin skin testing with 5 tuberculin units of PPD shouldbe done as early as possible in the course of HIV infectionbecause the utility of tuberculin testing declines as immunodeficiency increases [190]. The yield of tuberculin skin testing isincreased slightly if those with negative tests are retested after~7 days [295].

Some experts recommend that HIV-infected persons whosetuberculin tests are negative be tested for skin-test anergy withat least two control antigens-such as mumps, tetanus toxoid,



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em 199;22 (April) Tuberculosis and HIV 695

Table 6. Results of tuberculin skintests (TSTs) for asymptomatic HIV-seropositive (HIV+) persons and HIV-seronegative (HN - ) controls.

Percent of subjects forTST cutoff* (mm) whom TST was positive

Subjects (study location and period), reference HIV+ HIV- HIV+ HIV- P value

Postpartum women (Uganda, 1988-1989) [289] 3 3 48 82 <.01Adult residents (Haiti, 1990-1991) [290] 10 10 52 63 <.01

5 5 65 67 NSInjection drug users (Baltimore, 1990) [291] 5 10 14 25 .02

2 10 20 25 NSHomeless adults (San Francisco, 1990-1992) [97] 5 10 19 37 <.01Intravenous drug users and homosexual men

(pulmonary complications of HIV study group,United States, 1988-1990) [292] 5 10 6 10 .09

*Minimum diameter of induration at skin test site required for test to be considered positive.

or Candida antigens-and that those who do not have a ~3

mm induration to any control antigen (anergic patients) beconsidered for preventive therapy if they belong to a group inwhich the prevalence of M. tuberculosis infection is ~ 10%[28, 29, 285, 296]. However, the scientific basis for anergytesting is tenuous; therefore, regardless of skin-test findings,preventive therapy should be considered for all HIV-infectedpatients with a high likelihood ofM tuberculosis infection [28,29, 285, 286, 296-298].

Although >95% of dually infected individuals live in developing countries, wide-scale TB-preventive therapy in some ofthese locations has not been feasible [299]. For example, thePan American Health Organization recommends preventivetherapy for HIV-infected, tuberculin skin test-positive personsin all areas and for all HIV-infected persons in areas of highTB transmission [300]. However, in sub-Saharan Africa, facilities for diagnosing HIV infection are not routinely available,and TB control programs are designed primarily for treatingactive TB. Because preventive therapy could have a majorimpact on TB control in this region, studies of the operationalaspects of such therapy are being conducted [131, 299,301-304].

BeG Vaccination

BCG, a live attenuated strain ofM bovis, is used throughoutthe developing world for vaccinating newborns against M. tuberculosis. Although BCG vaccine does not prevent M tuberculosis infection, it reduces the risk of active TB, particularlythe serious forms of extrapulmonary TB such as meningitis, ininfants and young children [305]. BCG does not appear toprevent the activation of latent TB induced by HIV-relatedimmunodeficiency [26].

Because BCG is a live vaccine, its safety is a concern inareas where HIV is prevalent. Reported complications includelocal ulcers, regional suppurative adenitis, and disseminatedBCG infection [219]. Such complications occurred in infants

weeks to months after vaccination [306, 307] and in adultsyears after childhood vaccination [308] or within weeks aftervaccination during adulthood [309]. Although complicationsdeveloped in 13% ofvaccinated infants in one institution [310],serious BCG-related complications have not been observed asfrequently in other studies [311-314].

Because most developing countries have no practical meansof diagnosing HIV infection in newborns and because TB transmission to children is common in these countries, the WHOrecommends that all infants in Africa without symptomaticHIV infection continue to receive BCG vaccine [315]. Theputative benefits of BCG among infants without HIV infection,and possibly among HIV-infected infants who are not yet immunocompromised, are thought to outweigh the low risk ofBCG-related complications in HIV-infected infants. However,BCG vaccination is contraindicated in HIV-infected adults[316].

Infection Control

The large number of recent institutional outbreaks and theincrease in number of cases ofMDR TB have led to a reassessment of TB prevention in high-risk environments, and newinfection control guidelines have been published [317]. However, analysis of recent outbreaks demonstrated that transmission resulted from inadequate implementation of previouslyrecommended preventive measures rather than the inadequacyof existing infection control guidelines [36, 73, 298, 318, 319].In some cases, diagnosis of TB was delayed because of insufficient clinical evaluation. In other cases, lapses in infectioncontrol procedures facilitated transmission.

Current guidelines for preventing TB transmission withininstitutions emphasize a hierarchy of three strategies. Mostimportant is to rapidly identify, isolate, and treat persons withTB. The second is to use environmental controls to minimizethe density of infectious droplet nuclei in areas containingpersons with TB. The third is to protect institutional workers



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696 Shafer and Edlin CID 1996; 22 (April)

who have contact with persons with infectious TB. The intensity of control measures necessary in each institution dependson the number of TB patients cared for and indicators of nosocomial transmission, such as tuberculin skin test conversionrates among health-care workers [317].

Guidelines for preventing nosocomial TB transmission arenot specific to HIV-infected persons. However, HIV-infectedpatients often undergo cough-inducing procedures (e.g., sputum induction, bronchoscopy, and the administration of aerosolized pentamidine), and screening for active TB beforecough-inducing procedures is an important part of managingHIV-infected patients. In addition, HIV-infected health careworkers need to be informed of their increased risk of developing active TB should they become infected with M tuberculosis, so that they can follow appropriate preventive measuresand consider voluntary work reassignment [94, 95, 317].

Research and Public Health Priorities

Basic research is yielding many practical tools for controllingTB. Gene amplification techniques have led to rapid tests fordiagnosing TB. The identification of an M tuberculosis insertion sequence (IS6110) has led to a method for fingerprintingM tuberculosis strains [320]. The development of a reportermycobacteriophage has led to a rapid screening test for evaluating anti-TB compounds [321, 322]. Advances in understandingthe targets of anti-TB drug therapy can be applied to the rapidassessment of drug resistance and the rational design of newanti-TB compounds [323, 324]. Progress in identifying thedeterminants of mycobacterial virulence and the correlatesof human immunity should lead to a more effective vaccinethan BeG.

Still, the experience of the past decade demonstrates that ifexisting TB control strategies are aggressively applied theywill be successful in controlling HIV-associated TB. If recentgains made against the resurgence of TB in the United Statesare sustained, the incidence of TB in this country will continueto decline. However, continual strengthening of the publichealth infrastructure will be required for controlling TB.

In developing nations the number of HIV-infected personsis increasing rapidly, and the resurgence of TB will be contained only if new resources and political resolve are infusedinto the effort. TB programs need to be expanded with thefinancial assistance and logistical support of donor agenciesand international health organizations. The annual risk of TBinfection must be reduced by increases in the detection andcure rates associated with infectious pulmonary TB to 70%and 85%, respectively, as proposed by the WHO [2]. The riskof HIV infection must be reduced by education and improvedtreatment of sexually transmitted diseases, which are cofactorsfor HIV transmission. Studies also are needed to determine theefficacy and feasibility of administering preventive therapy topersons coinfected with M tuberculosis and HIV. With thehelp of such resources, resolve, and research, the balance be-

tween host and pathogen, now causing rapid increases in themorbidity and mortality associated with TB, may tip back infavor of TB control.

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Tuberculosis in Patients Infected with Human Immunodeficiency Virus: Perspective on the Past Decade

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Transcript of Tuberculosis in Patients Infected with Human Immunodeficiency Virus: Perspective on the Past Decade