Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 10 - November, 1993
Saundra Johnson and David Gold

Until recently, it was believed that TB would be eradicated by the end of the century. However, widespread homelessness, substance abuse, and high rates of HIV-infection, have enabled TB to reemerge in many American cities. Moreover, new drug-resistant strains of TB have developed which are difficult to treat and often deadly. In New York City, the number of cases of active TB increased 143 percent from 1980 to 1991 and rates of coinfection with HIV and TB are believed to be similar to those seen in Central Africa.[2] While all people are at risk for TB infection, people with HIV are estimated to have over 100-times greater likelihood of developing active disease once infected with TB.[3] In the U.S., between 5 to 10 percent of symptom-free HIV-positive individuals may develop active TB within a year of HIV diagnosis.[4]

TB Infection

TB is transmitted when a person with active TB coughs or sneezes, releasing microscopic particles into the air. These particles, also called droplet nuclei, contain live tubercle bacteria, and may result in infection when inhaled by another person. Once infected by TB, most people, remain healthy and develop only latent infection. People with latent infection are neither sick nor infectious. However, they do have the potential to become sick and infectious with active TB.

Active TB

The immunological factors which allow latent TB infection to develop into active disease are unknown. It is estimated that, once infected with TB, HIV-negative people have a 10 percent life-time risk of developing active TB disease. For people with HIV, the risk is much higher, estimated to be 8 to 10 percent per year after infection.[5] It is believed that some people with HIV will develop active disease from a newly acquired infection due to their inability to mount a sufficient immune response.[6]

TB Transmission

Although TB is spread through the air, infection usually occurs only after prolonged exposure to someone with active TB. According to the National Institute of Allergy and Infectious Diseases, (NIAID), there is a 50 percent chance of infection after being with someone with active TB for eight hours a day over six months or 24 hours a day over two months.[7] However, the exact nature of what is required for TB transmission is still unclear. Documented TB outbreaks have been primarily associated with hospitals, clinics, nursing homes, prisons, shelters for the homeless, and other places where persons who may have TB congregate. One recent report, however, suggested that a flight attendant with active TB may have transmitted TB to co-workers aboard an aircraft.[8] It has been reported by one study that the likelihood of transmission is similar for both drug resistant and drug sensitive TB.[9]

Clinical Symptoms of TB

The most common site of active TB is the lungs. This is called pulmonary TB. However, TB may affect any part of the body (extrapulmonary TB), including the skin, bone marrow, liver, spleen, kidney, bones and even the breast and may occur simultaneously as pulmonary and extrapulmonary disease. General symptoms of disease include fever, night sweats, dramatic weight loss and a feeling of malaise. Symptoms of TB in the lungs include these symptoms, as well as unexplained cough lasting longer than three weeks and bloody sputum. Since the symptoms of TB can mirror the symptoms of a number of other infections, it is important that TB be considered along with Pneumocystis carinii pneumonia (PCP) and other mycobacterial infections such as MAI.

The clinical manifestations of active TB in persons with HIV infection can vary considerably depending on the stage of disease. TB can occur early in HIV disease, when CD4 cell counts average 300 to 400.[10] At this stage of HIV disease, TB is usually localized to the lungs and the sputum is smear positive. As the CD4 count declines the presentation of TB may change, with more extra pulmonary disease, miliary lung involvement, negative sputum smears, and atypical chest x-ray patterns.

In one large study from Rwanda, presented at the Ninth International Conference on AIDS , it was found that HIV positive patients with TB had a greater likelihood of extrapulmonary involvement, disease in the middle and lower lobes of the lung and anergy to PPD skin testing.[11] A study from the Côte d'Ivoire reported that HIV positive patients with extrapulmonary TB had lower CD4 counts than those with pulmonary TB.[12]

TB Diagnosis

The PPD Skin Test

The purified protein derivative (PPD) skin test is the first step in diagnosing TB. PPD is injected under the skin of the forearm. After 48 to 72 hours, the injection site will be indurated (i.e. a red, hard bump) if a person has been infected with TB. This induration is caused by an immune response. Therefore, immunosuppressed persons may have little or no reaction to the test, even if they have been exposed to TB. According to the CDC, an HIV-infected individual with an induration of greater than or equal to 5mm is considered to be infected with TB.[13] However, some researchers believe that even the 5mm cutoff may underestimate the rate of true TB infection and suggest that a 2mm induration be considered a positive skin test in HIV-infected patients.[14] A positive PPD skin test does not mean that the person has active TB, only that the individual has been infected with the bacterium that causes TB. Lack of response to PPD skin test is more frequent when CD4 cells drop below 200.[15]

The Anergy Test

Along with a PPD test, HIV-positive individuals should receive an anergy test to verify immune competence. An anergy test consists of two or three common antigens, usually candida, mumps, or tetanus toxoid, which are injected under the skin. If there is a reaction to the antigens, the person is considered non-anergic and the TB skin test results are considered reliable. If there is no reaction to either the antigens or the PPD, the person is considered anergic. A negative PPD reaction should never be used to exclude the diagnosis of TB infection in persons who are anergic.

Chest X-Rays and Sputum Tests

A person who has a positive skin test or who has symptoms of active TB should have a chest radiograph (x ray) and sputum sample analysis. The sputum will be examined microscopically for the presence of acid fast bacilli (AFB) and cultured for TB. While an AFB smear can determine within minutes if there are mycobacteria in the specimen, it cannot distinguish among different types of mycobacteria, such as Mycobacterium avium intracellulare (MAI) and TB. A TB diagnosis relies on the ability to culture or grow the organism in the laboratory. Therefore, a person with suspected active TB (based on AFB in the sputum or clinical symptoms) might be placed on medication until laboratory confirmation is available. In addition, isolation in a private room will be required until the diagnosis has been confirmed or the person has been shown to be non-infectious (usually determined by the clearance of the AFB from the sputum). Individuals who are PPD positive but show no evidence of active TB, will be placed on preventive medication (prophylaxis) for a period of six to twelve months to prevent active TB from developing. A number of leading TB researchers recommend that chest x-rays be performed on all patients with HIV infection who present with respiratory or constitutional symptoms.[16]

TB Treatment

TB is treated with a combination of several antibiotics for at least six months. When effective therapy is given, symptoms typically improve within four weeks and sputum cultures become negative within three months. This pattern of clinical improvement and sputum conversion is seen in over 90 percent patients who are HIV-positive.

The standard treatment of drug-sensitive TB in HIV-positive people includes the following[17]:

Isoniazid (INH) (300mg/day), Rifampin (450 to 600mg/day), Pyrazinamide (PZA) (20 to 30mg/kg/day for nine months), Ethambutol (15 to 25mg/kg/day), or Streptomycin (15/mg/kg/day).

PZA should be given for the first two months; ethambutol or streptomycin should be given for at least six months beyond culture conversion. INH and rifampin should be continued for at least another seven months. Persons who cannot tolerate INH and rifampin together (or in whom resistance is suspected), should be treated for at least eighteen months with a minimum of three drugs to which the organism is sensitive.[3]

Although most HIV-positive people respond well to standard treatment, there are some reports of continued progression or recurrence of disease, particularly in persons who do not complete the entire course of treatment. Because compliance is so crucial to successful outcome, directly observed therapy (DOT) is recommended for persons who may have difficulty finishing the entire treatment (possibly creating resistant strains in the process). Alternative treatment regimens which require less frequent medication include using INH, rifampin, PZA, and either ethambutol or streptomycin three times weekly from the onset or twice weekly after a two week daily regimen. These regimens should be administered under DOT.

A study of supervised, short course therapy with three times weekly INH, rifampin, ethambutol and PZA showed the regimen to be highly successful.[18] The study, performed in Haiti, included 117 HIV-positive and 310 HIV negative patients with TB. Eighty-two percent of the HIV-positive and 91 percent of the HIV-negative TB patients completed greater than 80 percent of the therapy. However, the death rate among the HIV-positives was higher (9 percent) than in the HIV negatives (1 percent). Proven cures (defined as negative AFB smears, negative cultures, and radiologic resolution of disease) were more common among the HIV-negative patients. Relapses were equally as common in both groups. Among the HIV-positives, those who died had a lower CD4 count (116) than those who survived eighteen months (559). Multiple Drug Resistant TB

TB is considered multi-drug resistant (MDR-TB) if it does not respond to two or more standard anti-TB drugs, usually INH and rifampin. MDR-TB usually occurs when treatment is interrupted thus allowing mutations to occur which confer drug resistance. However, primary infection with MDR-TB can occur as well. In 1991, cases of MDR-TB were reported in at least 36 states, Puerto Rico and the District of Columbia.[19] In one study in New York City, one-third of TB cases were resistant to at least one TB drug and 15 percent resistant to at least two drugs.[20]

MDR-TB has serious public health implications due to the rapid progression to life threatening disease, the efficient transmission to others, and delays in diagnosis. It is estimated that the death rate from MDR-TB can be as high as 40 to 60 percent and possibly greater than 80 percent in individuals coinfected with HIV.[21] One outbreak among 38 patients in a NY hospital revealed an incubation period of 1.5 to six months and a mean survival of only nineteen weeks.[22] Survival was better among those who received at least two drugs to which the organism was susceptible within two weeks of diagnosis. Thus, delays in obtaining drug susceptibility tests make it more difficult to institute proper treatment. One TB susceptibility study in NY hospital found that only six and seven drug regimens conferred greater than 90 percent effectiveness as initial regimens.[23]

A study by Fischl and colleagues reported that HIV-positive persons with MDR-TB were three times more likely to have both pulmonary and extrapulmonary disease than HIV-positive persons with drug sensitive TB.[24] Median survival from time of diagnosis of MDR-TB was 2.1 months compared to 14.6 months for persons with drug sensitive TB. The study also noted delays in prescribing effective TB drugs, suggesting that in areas with a high prevalence of MDR-TB, it may be advisable to begin therapy based on patterns of resistance rather than waiting for drug susceptibility tests to be completed. At least three TB-susceptible drugs should be used. Some of these drugs include the aminoglycosides (amikacin, kanamycin or capreomycin), the quinolones (ciprofloxacin, ofloxacin, sparfloxacin), ethionamide, cycloserine and para-amino sallcylic acid (PAS).

TB Prophylaxis

Prophylaxis with anti-TB drugs can prevent the development of active TB. Therefore, TB screening should be a routine part of HIV clinical management. HIV-positive individuals responding to the PPD test with an induration of greater or equal to 5mm should be considered as having TB infection and offered prophylaxis medication. Standard TB prophylaxis is INH (300mg/day) for twelve months, along with pyridoxine (vitamin B-6). Vitamin B-6 is given in order to prevent peripheral neuropathy, which can be a side effect of INH. INH is considered to be quite effective in preventing TB. One recent study followed 374 HIV positive patients in an area of Spain where TB is widely prevalent.[25] Of the 374 participants, 108 were PPD-positive, 154 were PPD-negative, and 112 were PPD-negative but were anergic. The risk of developing TB was significantly higher in PPD-positive patients (10.4 per 100 patient years) and anergic patients (12.4 per 100 patient years) compared to PPD-negative, non- anergic patients (5.4 per 100 patient years). Active TB developed in only one of 27 PPD-positive individuals who were given INH prophylaxis, compared to 29 of 94 PPD-positive patients who did not receive the drug. A placebo-controlled study released at the Ninth International Conference on AIDS demonstrated that INH can reduce the rate of development of active tuberculosis in HIV-infected people by 50 percent, from 5.3/100 person years to 2.3/100 person-years.[26]

Research examining TB prophylaxis regimens of shorter duration and less frequent dosage appears promising. The New York City Department of Health has proposed a TB prophylaxis regimen of INH at a dose of 900mg twice weekly under supervised conditions. Combination regimens using rifampin and PZA are being studied in an attempt to shorten the time of prophylaxis. A recent study compared these two drugs, twice weekly for two months versus INH daily for six months in 784 HIV-positive, PPD-positive individuals. Both regimes were well-tolerated. However, compliance was higher in the rifampin/ PZA arm (64 percent) than in the INH arm (46 percent).[27] Rifampin should be used when infection with INH resistant bacteria is suspected. Prophylactic treatment of TB infection caused by MDR bacteria is especially difficult.

Usage of unapproved drugs such as ofloxacin and sparfloxacin in combination with PZA and ethambutol is an option but may be poorly tolerated.

TB Prophylaxis in Anergic Patients

Deciding whether to give HIV-positive anergic patients INH prophylaxis can be a difficult question since the probability of developing TB infection is unknown. Several studies show that HIV-infected injecting drug users and persons from areas where TB is endemic (Spain, Latin America, Haiti) who are anergic, develop active tuberculosis at the same rate as those who are PPD-positive.[28] This has led to the practice of offering INH prophylaxis to HIV-positive anergic persons who belong to "high incidence groups," such as prisoners, homeless persons, and injecting drug users. It is unclear whether anergic HIV-positive persons who do not belong to high TB incidence groups, such as gay men, heterosexuals and women, should receive INH. A large federally funded CPCRA trial is comparing a six-month regimen of INH to placebo in a large sample of HIV-positive anergics, in order to answer this question. One concern with using INH as prophylaxis has been the risk of hepatitis, which occurs in a small percentage of those who take the drug, especially over the age of 35. Another concern is the lack of knowledge about the long-term effects of drug interactions between INH and the broad range of drugs that an anergic HIV-positive person may be taking (AZT, ddI, bactrim and fluconazole).

TB Drug Toxicities

Persons with HIV are more likely to suffer adverse reactions to anti-TB drugs and therefore require careful monitoring.[29] INH, rifampin and PZA can cause liver toxicities, hematological toxicities (blood), gastrointestinal (GI) upset, and skin rashes. The risk of INH-induced hepatitis increases after age 35.[30] Rifampin and PZA can cause hepatitis and liver function test elevations, and rifampin can also cause a reddish discoloration of the urine.

Ethambutol can cause problems with vision and thus requires periodic ophthalmologic exams. The aminoglycosides cause kidney dysfunction and hearing loss and also require close clinical monitoring. Anti-TB drugs can also interfere with the absorption or concentration levels of other drugs such as fluconazole, ketaconazole, oral contraceptives and methadone.

TB Vaccine

The Bacille Calmette-Guerin (BCG) vaccine is the only TB vaccine currently available. While not used much in the U.S., BCG is widely used in parts of Africa and Asia where TB is endemic. BCG is not recommended for anyone who is immunocompromised, due to reported incidents of disseminated infection with the Calmette-Guerin bacillus.[31] BCG vaccination should only be given to immune competent children who are at unavoidable risk of exposure to TB and for whom other methods of prevention and control have failed or are not feasible.

TB Transmission in Health care, Prison, and Residential Settings

Since health care and prison workers have been infected with TB on the job, it is important that proper infection controls be in place at all times. Cough-producing procedures such as aerosolized pentamidine (AP) treatments and sputum induction should only be administered in properly ventilated rooms with at least ten air exchanges per hour.[32] Individuals hospitalized with suspicion of TB should be placed in isolation in a negative pressure room with a vent leading outside and the door closed. Hospitals, clinics, and some AIDS service organizations, such as GMHC, have installed high efficiency particulate air (HEPA) filters which remove TB bacteria from recirculating air. Although the use of germicidal ultraviolet lamps is controversial, the CDC still recommends their usage in settings where risk of TB transmission is high.[33] Those attending clinics who have a cough should be asked to use a mask and wait in a better ventilated hall outside the waiting room.

All healthcare and service workers (including prison and social service workers) should have a PPD upon employment and a follow-up PPD annually. This allows tracking of PPD conversion rates. The CDC also recommends PPD testing every six months for persons working in areas with frequent exposure to persons with TB infection or who perform cough inducing procedures, such as AP and bronchoscopy.[34]

Funding for TB Research and Control

The American Lung Association reports that the President's 1994 budget of $128.8 million for TB control was cut by both the Senate and the House in final budget negotiations.[35] ACT UP's TB Working Group reports that an additional $26 million will go to the CDC for TB control among HIV-affected populations.[36] In 1993, the entire TB research program at NIAID was funded at less than $21 million dollars. In 1994, this figure is expected to increase to $27 million.[37] The World Health Organization (WHO) recently reported that a total of only $15 million is being spent on TB treatment and prevention in the entire developing world.38 The agency estimated twelve million deaths from TB could be avoided over the next ten years if aid for TB treatment were increased to $100 million annually.

Conclusion

HIV-positive individuals should receive a PPD test, with an anergy test, at least annually as a part of their routine medical examination. Individuals living or working in areas with high TB rates should be screened for TB every six months. If placed on TB medication, HIV-positive persons should be closely monitored for adverse reactions to the medications. Techniques for faster identification of MDR TB need to be placed on the development fast track. Funding must be allotted for TB screening and treatment in diverse care facilities (substance abuse treatment programs, mobile medical outreach units) in order to reach affected populations. Hospitals and clinics must continue to develop and implement detection and isolation protocols to prevent the spread of TB. Shelters, prisons, and AIDS service providers must employ infection controls to the extent possible (using ultra violet light and HEPA filters where ventilation to the outside is not available). Increased funding for TB screening, treatment and research must be allocated.

1 Barnes P et al. Annals of Internal Medicine. 1993; 119:400-410.

2 Selwyn P. New York State Journal of Medicine. June 1991; 233-235.

3 Ellner J. Oral Presentation. 33rd ICAAC. New Orleans. October 17-20, 1993.

4 Selwyn P, et al. New England Journal of Medicine. 1989; 320:545-550.

5 National Institutes of Health, NIAID. Backgrounder: Tuberculosis. 1992.

6 Daley CL, et al. New England Journal of Medicine. 1992; 326:231-5.

7 National Institutes of Health, NIAID. Backgrounder: Tuberculosis. 1992

8 Driver C, et al. Abstract 1369. 33rd ICAAC. New Orleans. October 17-20, 1993.

9 MTB. Grudert DE American Review of Respiratory Diseases. 1985;132:125.

10 Chaisson RE, Johnson MP. Tuberculosis and HIV infectiion. AIDS Clinical Care. 1991; 3:57-59.

11 Batungwanayo J, et al. Abstract WS-B09-1. Ninth International Conference on AIDS. Berlin. June 6-11, 1993.

12 Ackah A, et al. Abstract WS-B09-2. Ninth International Conference on AIDS. Berlin. June 6-11, 1993.

13 MMWR. 1989. 34:236-250.

14 Graham N et al. JAMA. 1992. 267:369-373.

15 Hopewell PC. Clinical Infectious Diseases 1992; 15:540- 547.

16 Chaisson et al. Journal of Infectuous Diseases. 1989; 159:96-100.

17 MMWR 1990; 39 (suppl RR-17) :1-29.

18 Holt E, et al. Abstract WS-B09-4. Ninth International Conference. on AIDS. Berlin. June 6-11, 1993.

19 National Institutes of Health,NIAID. Backgrounder: Tuberculosis. December 1992.

20 Friedland G. Oral Presentation. 16th ACTG Meeting February 1993 ACTG Meeting.

21 National Institutes of Health, NIAID. Backgrounder: Tuberculosis. December 1992.

22 Edlin BR, et al. Abstract WS-B09-6. Ninth International Conference on AIDS. Berlin. June 6-11, 1993.

23 Rose DN, et al. Abstract WS-B09-5. Ninth International Conference on AIDS. Berlin. June 6-11, 1993.

24 Fischl MA, et al. Annals of Internal Medicine. 1992; 117:184-190.

25 Moreno S, et al. Annals of Internal Medicine. 1993; 119:194-198.

26 Wadhawan D, et al. Abstract PO-B07-1114. Ninth International Conference on AIDS. Berlin. June 6-11, 1993.

27 Coberly J et al. Abstract PO-B07-1158. Ninth International Conference on AIDS. Berlin. June 6-11, 1993

28 Pape, J. The Lancet. 1993; 342:268-272.

29 Chaisson RE and Johnson MP. Tuberculosis and HIV infectiion. AIDS Clinical Care 1991; 3: 57-9.

30 Sherris JC and Plorde. Mycobacteria. Clinical Microbiology 1990; 443-61.

31 MMWR. 1988;37:663-75.

32 MMWR 1990; 39:1-29.

33 Ibid

34 Ibid.

35 Personal Communication. Robyn Henderson, American Lung Association. November 16, 1993.

36 Personal Communication. Iris Long. TB Working Group/ACT UP. November 16, 1993.

37 National Institutes of Health,NIAID. Backgrounder: Tuberculosis. December 1992.

38 "Agency Cites Urgent Need to Fight Increase in TB." The New York Times. November 16, 1993; C8.

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