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Until therapy becomes available to reverse the immunologic abnormalities that predispose HIV-infected patients to opportunistic infections, the standard of care will continue to consist of offering these patients combinations of antiretroviral medications and precise prophylactic compounds to decrease their risk for development of specific life-endangering infections [primary prophylaxis for Pneumocystic carinii pneumonia (PCP), toxoplasmosis, tuberculosis, and disseminated Mycobacterium avium complex (MAC) infection]. In essence, primary prophylaxis is designed to prevent initial infection or morbidity from preexisting but asymptomatic infection. Secondary prophylaxis (which consists of maintenance therapy for patients with PCP, Toxoplasma encephalitis, disseminated MAC infection, invasive cryptococcosis, invasive histoplasmosis, and invasive cytomegalovirus infection) is offered to prevent recurrence or reactivation of an established infection.
Although the goal of prophylaxis is to improve the quality and extend the duration of life, it is important to appreciate the concerns regarding prophylaxis (expense, side effects of the medication, potential for drug-drug interactions, difficulty of maintaining confidentiality, and perhaps modification of the manifestations of disease). Clinicians should limit prophylaxis to those disorders associated with substantial morbidity or mortality, and the consequences of the disease should outweigh those of the prophylactic regimen. Some research has also established that in addition to reducing morbidity and mortality, primary prophylaxis for PCP is cost effective and reduces the socioeconomic burden of illness. I should also stress that the prophylactic programs are not infallible, and breakthrough disease has developed following prophylactic regimens for PCP, toxoplasmosis, tuberculosis, and MAC infection, both in compliant and noncompliant patients.
Historically, the decision regarding when to initiate prophylaxis has been based on the CD4-cell count, as researchers have identified the ranges within which most opportunistic infections are manifested. It needs to be stressed, however, that numerous factors influence the quantitative CD4-cell determination, and the usual upper threshold value for an opportunistic infection can on occasion be exceeded; for example, more than 10% of cases of PCP occur in patients with a CD4-cell count above 200/µL. In addition, drug combinations that contain a protease inhibitor can on occasion elevate the CD4-cell count by 100 to 250 cells per microliter, so that the clinician acquires a false sense of security that the patient is no longer at risk and no longer a candidate for drug prophylaxis. Although this issue is “cloudy,” the current recommendation is that prophylaxis be continued on the basis of the lowest CD4-cell count. In essence, once initiated, primary or secondary prophylaxis for PCP, MAC infection, and toxoplasmosis should be continued for life, regardless of the potential of antiretroviral treatment to elevate the CD4-cell count.
Before primary prophylaxis is initiated, it is essential to exclude active disease. Traditionally, this is accomplished through a combination of medical history, physical examination, laboratory tests, and chest roentgenography. As an example, special blood cultures and chest roentgenography should be performed (to exclude invasive MAC infection and tuberculosis) before a patient receives lifelong prophylaxis for MAC infection. To complement drug prophylaxis, additional preventive measures, namely vaccines, should be administered to HIV-infected patients. The vaccines to be considered are the 23-valent polysaccharide pneumococcal vaccine (to be administered as soon as HIV infection has been diagnosed) and hepatitis B vaccine [to be administered to all susceptible patients who are negative for antibody to hepatitis B core antigen (anti-HBc)]. Pneumococcal immunization has been associated with a transient increase in levels of HIV-1 RNA, but most experts feel that the benefit of pneumococcal immunization outweighs the potential risk.
HIV-infected patients (including pregnant women) should receive prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) as one double-strength tablet per day when the CD4-cell count is below 200/µL or the patient has had oropharyngeal candidiasis (unrelated to antibiotic or steroid therapy). Some experts would recommend TMP-SMX prophylaxis for any patient in whom an opportunistic infection develops regardless of the CD4-cell count. TMP-SMX has the potential to decrease the development of cerebral toxoplasmosis, isosporiosis, salmonellosis, and infections caused by Nocardia species, Listeria species, and Haemophilus influenzae. Unfortunately, however, TMP-SMX can precipitate headache, nausea, vomiting, fever, pruritus, rash, and hematologic and hepatic toxicity, and this medication can produce drug-drug interactions with oral anticoagulants, phenytoin, glipizide, and methotrexate. Myelosuppression can be enhanced when patients receive zidovudine. If a patient experiences an untoward event while taking prophylactic TMP-SMX and it is considered necessary to discontinue the medication, the clinician should (if the reaction was not Stevens-Johnson syndrome or another life-endangering adverse event) rechallenge and desensitize the patient after an interruption of 2 weeks. Some researchers have noted a relationship between an adverse reaction to TMP-SMX and rapid progression of disease.
If TMP-SMX cannot be tolerated, alternative prophylaxis should consist of dapsone (50 mg orally daily) plus pyrimethamine (50 mg orally per week) plus leucovorin (20 mg orally per week) (this regimen also prevents toxoplasmic encephalitis), dapsone (50 mg orally twice daily), or aerosolized pentamidine (300 mg daily administered with a Respirgard II nebulizer). Major adverse reactions attributed to dapsone include rash, nausea, vomiting, fever, bone marrow suppression, and transaminase elevation. The compound is contraindicated for patients with glucose-6-phosphate dehydrogenase deficiency (producing hemolytic anemia, methemoglobinemia), and it interacts with trimethoprim, rifampin, and didanosine. When dapsone is prescribed with didanosine, the absorption of dapsone is decreased, and the absorption of dapsone is impaired by achlorhydria. Pryrimethamine can cause neutropenia and thrombocytopenia.
Aerosolized pentamidine should be administered only to those patients who cannot tolerate the alternative prophylactic agents, as it is a less effective form of prophylaxis, particularly for patients with CD4-cell counts below 100/mm3, does not offer protection against invasive toxoplasmosis, and has been associated with the development of extrapulmonary P. carinii infection. Aerosolized pentamidine has induced cough, bronchospasm, pneumothorax, pancreatitis, hypoglycemia, and nephrotoxicity. Prophylactic failure with aerosolized pentamidine has resulted in atypical PCP (cysts, blebs, pneumothoraces). Before aerosolized pentamidine is offered, it is necessary to perform chest roentgenography to attempt to exclude tuberculosis. It is essential that Centers for Disease Control guidelines be followed to minimize the risk for respiratory transmission of this infectious disease.
Patients who are seropositive for Toxoplasma and who have a CD4-cell count below 100/µL are candidates for primary prophylaxis against Toxoplasma encephalitis. The recommended treatments, similar to those offered to patients to prevent PCP, consist of TMP-SMX or the dapsone-pyrimethamine combination. More research needs to be performed before azithromycin, clarithromycin, or atovaquone can be recommended for prevention of this disease. For pregnant women, if the clinician is planning to use dapsone-pyrimethamine prophylaxis, it is preferable to delay this drug combination until after the pregnancy.
Patients who have been treated and survived Toxoplasma encephalitis should receive lifelong secondary prophylaxis (suppressive treatment) with pyrimethamine plus sulfadiazine plus leucovorin to prevent relapse. If the patient cannot tolerate a sulfonamide, a clindamycin-pyrimethamine combination should be used. This latter combination does not, however, offer protection against PCP. Pyrimethamine is a drug with teratogenic potential; however, after a pregnant patient has been counseled, strong consideration should be given to the administration of the combination treatment because the recurrence rate of encephalitis is very high.
MAC infection prophylaxis protects patients from the disabling symptoms of a disorder that is common in severely immunosuppressed HIV-infected patients. Patients with CD4-cell counts below 50/µL should receive lifelong chemoprophylaxis against disseminated MAC infection. Three FDA-approved prophylactic regimens are currently available—azithromycin (1,200 mg orally every week), clarithromycin (500 mg orally twice a day), and rifabutin (300 mg orally every day). Azithromycin is probably the preferred prophylaxis; it is administered once a week, shares with clarithromycin the ability to prevent respiratory infections, is unsurpassed in efficacy by any other regimen, appears to be safe in pregnancy, and does not appear to have a potential for drug-drug interactions, which is a characteristic of clarithromycin. Clarithromycin has the potential to cause drug interactions with theophylline, carbamazepine, digoxin, ritonavir, cisapride, felodipine, fluconazole, warfarin, ergotamine, terfenadine, astemizole, and buspirone. Concerns with azithromycin treatment, however, include gastrointestinal adverse events, the development of reversible ototoxicity, and the possible emergence of drug-resistant MAC organisms.
Rifabutin is an effective prophylactic agent and is not associated with the development of resistant organisms. Rifabutin has caused rash, myalgias, arthralgia, nausea, headache, uveitis, thrombocytopenia, and hepatitis. A major concern with rifabutin is the potential for drug-drug interactions, such as with fluconazole, phenytoin, metha-done, warfarin, oral contraceptives, dapsone, clarithromycin, phenytoin, saquinavir, indinavir, nelfinavir, ritonavir, zidovudine, beta blockers, and oral hypoglycemics.
Although absence or diminution of delayed hypersensitivity is common in HIV-infected patients with impaired cell-mediated immunity, tuberculin skin testing is the only screening method to detect tuberculosis. All HIV-infected patients who have a positive test result (skin reaction of 5 mm or greater on administration of intermediate-strength purified protein derivative) by the Mantoux method should receive a year of prophylaxis with isoniazid (300 mg daily) and pyridoxine (50 mg daily) unless they have active disease or have a history of treatment or prophylaxis for tuberculosis. In addition, HIV-infected persons who are close contacts of persons who have infectious tuberculosis should receive preventative therapy after active disease has been excluded. If there is concern that the exposure was to a patient with multidrug-resistant disease, prophylaxis should perhaps consist of pyrazinamide plus ofloxacin, but the evidence supporting this recommendation is modest, and the combination has not been well tolerated. HIV-infected patients with negative results on tuberculin skin testing should undergo repeated testing annually if they are at substantial risk for exposure to Mycobacterium tuberculosis.
Retrospective, case-control, and prospective studies have demonstrated the protective value of fluconazole (200 mg daily) against the development of cryptococcosis, a disseminated fungal disorder that is usually manifested when the CD4-cell count is below 50/µL. However, experts recommend that fluconazole not be routinely prescribed to prevent cryptococcosis (primary prophylaxis) because of the relative infrequency of the disease, lack of survival benefit associated with prophylaxis, potential for the development of resistant organisms, costs, and potential for drug-drug interactions (with rifampin, phenytoin, warfarin, sulfonyl urea, cyclosporine, theophylline, and rifabutin).
Patients, including those who are pregnant, who have completed therapy for invasive cryptococcosis are candidates for lifelong treatment with fluconazole (secondary prophylaxis or suppressive therapy); without suppressive therapy, 50% to 60% of patients suffer a relapse, and research studies have established the benefit of fluconazole in preventing relapse. Presumably, some of these relapses result from a persistent focus in the prostate.
Oral ganciclovir is FDA-approved for the prophylaxis of cytomegalovirus retinitis in patients with a CD4-cell count below 50/µL, although the data for efficacy are conflicting, the medication is prohibitively expensive, a cumbersome quantity of pills must be taken each day, and there are concerns regarding safety (the drug causes neutropenia, thrombocytopenia, and anemia) and the potential for drug-drug interaction (zidovudine, antimetabolites, alkylating agents). Initial research suggests that polymerase chain reaction testing may indicate which patients are at risk for development of cytomegalovirus disease, so that clinicians will have an opportunity to prescribe prophylaxis for specific patients. (R.A.G.)
Brosgart CL, et al. A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals. AIDS 1998;12:269–277.
Oral ganciclovir decreased the risk for CMV disease in patients not prescribed didanosine.
Centers for Disease Control. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1997;46:1–46.
A comprehensive guide to reduce opportunistic infections.
Freedberg KA, et al. The cost effectiveness of preventing AIDS-related opportunistic infections. JAMA 1998;279:130–136.
An analysis of the cost effectiveness of prophylaxis against HIV-related opportunistic infections.
Fuller JD, Stanfield LED, Craven DE. Rifabutin prophylaxis and uveitis. N Engl J Med 1994;330:1315–1316.
Rifabutin-induced uveitis.
Selik RM, Karon JM, Ward JW. Effect of the human immunodeficiency virus epidemic on mortality from opportunistic infections in the United States in 1993. J Infect Dis 1997;176:632–636.
Most HIV-associated mortality is caused by opportunistic infections.
Sepkowitz KA. Effect of prophylaxis on the clinical manifestations of AIDS-related opportunistic infections. Clin Infect Dis 1998;26:806–810.
Prophylaxis can affect the clinical presentation of opportunistic infections.
Sepkowitz KA. Effect of HAART on natural history of AIDS-related opportunistic disorders. Lancet 1998;351:228–230.
An unanticipated (undesired) consequence of highly active antiretroviral therapy (HAART) may be exuberant inflammation of infection because of improved immune function.

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