A 35-year-old female prisoner presented to the infirmary with a complaint of fever and 22-pound weight loss. She denied cough, nausea, emesis, headache, diarrhea, skin rash, or recent change in medication. She stated that she had received treatment for tuberculosis several times over the past ten years, none by directly observed therapy (DOT). She states that she has never completed more than six consecutive months of treatment.
The patient's examination was notable for wasting, thrush, and a purulent cervicitis. Her chest x-ray demonstrated right hilar adenopathy. Laboratory results revealed a hemoglobin of 10.8, WBC of 2,900 with lymphocytopenia, and serum albumin of 2.9. A urinalysis revealed 25 white blood cells, and 10 red blood cells. The patient was placed in the infirmary and treated with ceftriaxone and azithromycin.
Blood and urine cultures were negative. A urine specimen was positive for chlamydia and gonorrhea by ligase chain reaction. A HIV antibody test was strongly reactive, and a CD4 count was 27/mm. Three sputum smears were negative for AFB. On the twelfth day, growth in broth was detected for one out of three specimens. A gene probe for tuberculosis was positive. Because of the patient's history of multiple prior incomplete courses for therapy for TB, she was started on five drugs (INH, rifampin, PZA, ethambutol, and ofloxacin). After seven weeks, the susceptibility report was received demonstrating resistance to both INH and rifampin. Her regimen was changed to include four drugs to which her isolate was susceptible, administered by strict DOT.
Human Immunodeficiency Virus (HIV) increases the risk of reactivating latent Mycobacterium tuberculosis (MTB) and also increases the risk of rapid MTB progression. The presentation of tuberculosis in the HIV-infected patient is variable. Radiographic findings are often atypical in that they may not demonstrate classic upper lobe cavitary lesions. In some series, the most common chest x-ray finding is hilar fullness without infiltrate.
MTB infection may lead to significant morbidity and mortality, yet it is a preventable and treatable disease. Multi-drug resistant tuberculosis (MDR TB) is defined as MTB that is resistant to at least isoniazid and rifampin. MDR TB is often more challenging to treat, and is more likely to be fatal.
The percentage of tuberculosis cases in the United States due to MDR TB increased from 2% to 9% in the 1990s. Resistance is not uniformly distributed, but is more common in large urban areas and coastal or Southern border communities. In Los Angeles, one survey revealed that resistance rates were higher for Hispanics, Asians, and Blacks than for Whites. Southeast Asian countries have a higher prevalence of MDR TB than do African countries. Among immigrants from endemic areas, the risk of MDR TB is greatest during the first few years after immigration and then decreases to a rate similar to that seen in general population. Epidemics of MDR have been described among those with Human Immunodeficiency Virus (HIV) infection as well as those without HIV or AIDS. Epidemics have also been described in nosocomial settings. In a group of 62 patients with MDR TB in Florida, risk factors among those with HIV infection included homosexuality, AIDS, and previous hospitalization on an inpatient HIV ward. The median survival for AIDS patients during this outbreak was 1.5 month vs. 14.8 months for HIV-infected patients without AIDS.
MDR mutants occur as a result of failure to kill random preexisting mutations. A mutant can occur as a consequence of monotherapy, irregular administration, neglect in taking one or more of the prescribed drugs, poor absorption, or insufficient number of active agents in the regimen. Patients who are at increased risk of relapse are those who have cavitation on initial chest radiograph and those who have a positive culture after completing two months of therapy.
TB susceptibility results may not be available for up to two months. Smear negative specimens can take longer to yield a positive culture, therefore delaying susceptibility testing. Obtaining susceptibility results and using them to modify treatment in a timely manner is essential to effective treatment and to limiting the development of further drug resistance.
Usual MTB empiric therapy as recommended by the CDCP, American Thoracic Society (ATS), and the Infectious Diseases Society of America (IDSA) includes isoniazid, rifampin, pyrazinamide, ethambutol. Medication options for those who have MDR TB include streptomycin, amikacin, kanamycin, capreomycin, ofloxacin, ciprofloxacin, ethionamide, aminosalicylic acid, and cycloserine. The CDCP, ATS, and IDSA have compiled guidelines to the "Treatment of Tuberculosis" that appeared in the Morbidity and Mortality Weekly Report on June 20, 2003. This comprehensive guide is designed to help providers managing TB. If a patient needs modification of his treatment regimen due to failure, at least two drugs should be added to a failing regimen until susceptibilities return. Some drugs may require levels be checked and some may require dose-adjustment for renal insufficiency.
Treatment of the HIV- and TB-coinfected patient can be challenging. In a study of HIV-infected individuals infected with tuberculosis in Greater London and Southeast England by G.L. Dean and his colleagues, 54% (99/183) of patients experienced adverse events during HIV and TB therapy. One-third of patients had to interrupt or change therapy. The most common adverse events included peripheral neuropathy (21%), rash (17%), and gastrointestinal upset (10%). These most often occurred in the first two months of therapy. Patients with CD4 counts >100/mm were unlikely to experience AIDS defining illnesses during the course of therapy, so the authors concluded that the initiation of highly active anti-retroviral therapy (HAART) therapy should be deferred until the first two months of TB therapy is completed. An Italian study showed that HAART therapy after TB diagnosis is associated with a decreased risk of death; while older age, CD4+ cell count <25/mm3, and an AIDS-defining illness before TB diagnosis were associated with a higher risk of death.
Drug interactions complicate treatment of patients co-infected with HIV and tuberculosis. Two medications that commonly cause drug interactions are rifampin and ritonavir. The same premise of adherence as a way to decrease the emergence of MDR TB holds true as the key to success for HAART. Adherence to treatments that may include more than 20 pills each day is very challenging and requires close monitoring by experienced providers.
Treatment outcomes vary among patients with MDR-TB. Response depends on the extent of pulmonary involvement, the number of bactericidal drugs used, community resources available, and the patient's ability to comply and tolerate therapy. Reported success rates have varied between 60% and 95% in selected groups.
Prevention is still key to reduce the spread of tuberculosis and is emphasized for the control of MDR-TB. Directly Observed Therapy (DOT) has aided in the effort to ensure compliance of therapy for TB and prevent the emergence of MDR TB. It is also essential to recognize risk factors of prior noncompliance to therapy or being in or from an epidemic area for MDR-TB. The recent treatment guidelines in the June 2003 issue of the MMWR are a valuable resource to be used in the treatment of tuberculosis. Cooperation with public health departments and experts in the management of HIV and TB is essential to the success of treatment of the HIV and MTB- co-infected patient.
Tanvir K. Bell, M.D. is a member of the Speaker's Bureau for Gilead, GlaxoSmithKline, Bristol-Myers Squibb.
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