Download Effect of Prophylaxis on the Clinical Manifestations of AIDS

806
AIDS COMMENTARY
Effect of Prophylaxis on the Clinical Manifestations of AIDS-Related
Opportunistic Infections
Kent A. Sepkowitz
From the Department of Medicine, Memorial Sloan-Kettering Cancer
Center, New York, New York
Introduction. The availability of highly active antiretroviral therapy has altered the epidemic
of human immunodeficiency virus infection among individuals with access to medical care. The
Centers for Disease Control and Prevention and other public health authorities have reported
decreases in both morbidity and mortality among HIV-infected patients. As Dr. Sepkowitz documents, however, opportunistic infections continue to occur in spite of antiretroviral therapy and
prophylaxis. ‘‘Breakthrough’’ infections often present atypically, and thus the clinician must be
alert to the changing picture of common infections impacting patients with advanced immunosuppression. Dr. Sepkowitz has reviewed the available literature and suggests a need to continue to
document the atypical presentations of common opportunistic diseases in these patients.
— John P. Phair
Administration of targeted prophylaxis for AIDS-related opportunistic infections has contributed
significantly to the recent decrease in mortality among patients with AIDS in the United States. Most
reported prophylaxis trials have focused on determining (a) the percentage of cases prevented and
(b) the effect of widespread antibiotic use on drug susceptibility. A third phenomenon that is seldom
reported on is the attenuating effect of failed prophylaxis on the clinical presentation of opportunistic
infections (OIs). With the increasingly widespread use of prophylaxis for OIs, more atypical ‘‘breakthrough’’ cases of opportunistic infections will be seen. Reports of clinical changes are reviewed below.
Investigators should routinely report the clinical manifestations of breakthrough cases in all articles
pertaining to prophylaxis for opportunistic infections in patients with AIDS.
In 1996, 68,473 new cases of AIDS were reported to the
Centers for Disease Control and Prevention (CDC), including
29,227 (43%) due to AIDS-indicator conditions [1]. Overall,
the CDC estimates that Ç60,000 AIDS-related opportunistic
illnesses have occurred each year in the United States since
1992. Despite the large number of opportunistic conditions and
the bewildering array of diseases described, most illness is
caused by a relatively small handful of pathogens, including
Pneumocystis carinii, cytomegalovirus, various fungi, and mycobacteria; conditions such as the wasting syndrome and dementia; and neoplastic diseases, including Kaposi’s sarcoma
and lymphoma.
Therefore, in 1995, the United States Public Health Service
(USPHS) and the Infectious Diseases Society of America
(IDSA) issued guidelines for prevention of opportunistic infec-
Received 21 November 1997.
Reprints or correspondence: Dr. Kent A. Sepkowitz, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 288,
New York, New York 10021.
Clinical Infectious Diseases 1998;26:806–10
q 1998 by The University of Chicago. All rights reserved.
1058–4838/98/2604–0002$03.00
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tions (OIs) in persons infected with human immunodeficiency
virus (HIV) [2], which were updated in 1997 [3]. The strongest
recommendations concerned strategies to prevent Pneumocystis
carinii pneumonia (PCP) and infections due to Toxoplasma
gondii, Mycobacterium tuberculosis, M. avium complex
(MAC), Streptococcus pneumoniae, and varicella zoster virus
[3]. Routine prophylaxis for cytomegalovirus, candidal, and
endemic fungal diseases was considered indicated only in unusual circumstances. Secondary prophylaxis was strongly recommended for PCP and infections with T. gondii, MAC, cytomegalovirus, Salmonella species, Cryptococcus neoformans,
and endemic fungi [3].
Despite targeted and effective prophylaxis and despite the
effect of potent antiviral therapies on the type and frequency
of hospital admissions [4 – 6], opportunistic infections continue
to occur. Most reports of trials examining a specific approach
to the prevention of an opportunistic infection (prophylaxis
studies) focus on two outcomes of interest: (1) the quantitative
effect, i.e., how many cases were prevented, and (2) the microbiological effect, i.e., the susceptibility profile of breakthrough
cases. Few, however, have examined the third effect of prophylaxis: the clinical presentation of prophylactic failures, or the
qualitative effect.
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Prophylaxis and AIDS-Related OIs
For the clinician, however, this last effect may be the most
important, because the clinical presentation of an opportunistic infection in a patient receiving targeted prophylaxis may
not resemble the opportunistic infection in a patient not receiving prophylaxis. In addition, potent protase-inhibitorcontaining antiviral regimens also may fundamentally alter
the presentation and natural history of OIs [7], further complicating diagnosis.
I therefore will review reports describing qualitative changes
in the presentation of common opportunistic infections in persons whose targeted prophylaxis fails. I will exclude failures
of secondary therapy, since the diagnostic dilemma facing the
clinician in such a setting is far less acute. Recognition of the
potentially attenuating effects of failed prophylaxis is essential
for clinicians caring for HIV-infected patients in the years
ahead.
Well-Described Atypical Presentations
Pneumocystis carinii Pneumonia
In the absence of prophylaxis, PCP in patients with HIV
infection typically presents as an indolent illness with constitutional as well as respiratory symptoms that may extend 1 month
or longer. Diffuse bilateral interstitial infiltrates, hypoxemia,
and an elevated lactic dehydrogenase level further suggest the
disease. The diagnosis can readily be made by examination of
an induced sputum or bronchoalveolar lavage specimen.
Currently, there are three prophylactic agents commonly
used to prevent PCP among patients with AIDS: aerosol pentamidine, dapsone, and trimethoprim-sulfamethoxazole. Because none of the three is completely effective and because PCP
is a common illness, ‘‘breakthrough’’ cases are encountered
relatively often. In many circumstances, the clinical presentation and approach to diagnosis have been altered by the failed
prophylactic regimen.
Aerosol pentamidine. Numerous reports have described the
atypical features that may be encountered when a patient receiving aerosol pentamidine develops PCP [8]. Features such
as upper-lobe disease (in 38% of aerosol pentamidine recipients
vs. 7% of those not receiving it) [8], pneumothorax [9], lower
yields from bronchoalveolar lavage (BAL) and other respiratory specimens (100% vs. 62%) [8], fever of unknown origin
[10], and (possibly) extrapulmonary pneumocystosis [11] have
been described. Thus, the radiologic appearance of and diagnostic approach to PCP are substantially altered by use of
aerosol pentamidine.
Dapsone. Unlike aerosol pentamidine, the clinical features
of failed dapsone prophylaxis are not well-characterized. A
report comparing PCP developing in patients receiving aerosol
pentamidine vs. those receiving dapsone found similar clinical
presentations, including respiratory complaints and chest radiographic features [12]. In addition, the sensitivity of sputum
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induction and BAL was similar (60% – 70%). Another report
suggested that chest radiographic features may be atypical and
may include lobar as well as nondiffuse bilateral changes [13].
A recent report of cutaneous pneumocystosis documented the
potential for extrapulmonary pneumocystosis in persons whose
dapsone therapy fails [14].
Trimethoprim-sulfamethoxazole. The clinical characteristics of PCP among patients whose trimethoprim-sulfamethoxazole prophylaxis fails have not been described.
Toxoplasmosis
Trimethoprim-sulfamethoxazole is recommended as prophylaxis for both PCP and toxoplasmosis [3], and it decreases rates
of bacterial sinopulmonary disease as well. One report from
France described breakthrough toxoplasmosis in two men receiving trimethoprim-sulfamethoxazole prophylaxis [15]. Both
had low CD4 cell counts and protracted fever. Extensive workup included multiple blood cultures and radiographic examinations, as well as CT scans of the brain. All tests were negative.
Eventually, PCR and blood cultures demonstrated T. gondii.
The diagnosis was verified by a clinical response to targeted
antitoxoplasmosis therapy (clindamycin with pyrimethamine).
Thus, toxoplasmosis in these patients receiving prophylaxis
presented not as a classic brain abscess but rather as a fever
of unknown origin associated with parasitemia.
Mycobacterium avium Complex (MAC)
Three agents are approved for prophylaxis against disseminated MAC infection: rifabutin, clarithromycin, and azithromycin. Even with optimal prophylaxis, however, breakthrough
occurs in 3% – 12% of patients, depending on the regimen used.
In a large series, patients whose rifabutin prophylaxis failed
were found to have reduced fever and fatigue, higher hemoglobin levels, lower alkaline phosphatase levels, and an improved
Karnofsky score, when compared with placebo-control patients
who developed MAC infection [16]. No change between the
groups was seen with regard to signs such as weight loss, night
sweats, abdominal pain, or diarrhea.
In another study that compared rifabutin, azithromycin, and
combination rifabutin/azithromycin, ‘‘typical’’ disseminated
MAC infection was seen in prophylaxis failures, including fever in 70% and anemia and weight loss in Ç50% [17]. Elevation of the alkaline phosphatase level, however, was seen in
only 4% overall, a rate significantly lower than expected. In
addition, while all azithromycin-treated patients with breakthrough MAC infection developed symptoms, symptoms were
seen in only 56% of those receiving combination rifabutin/
azithromycin prophylaxis. This suggests that the most potent
prophylactic regimen (with rifabutin/azithromycin) may have
suppressed symptoms for many, even when the regimen ultimately failed.
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CID 1998;26 (April)
Table 1. Effect of prophylaxis on the clinical presentation of opportunistic infections.
Opportunistic infection
Well-described effect
Pneumocystis carinii
pneumonia
Toxoplasmosis
MAC
Herpes zoster
No described effect
Endemic fungi
Tuberculosis
CMV
Prophylaxis
Aerosol pentamidine
Clinical effect
Azithromycin
Acyclovir
Upper-lobe infiltrates [8], lower yield on BAL [8], pneumothorax [9], fever of
unknown origin [10]
Atypical chest radiograph (?) [13], extrapulmonary disease [14]
Fever of unknown origin [15], extracranial disease [15]
Less fever [16], fatigue [16], lower alkaline phosphatase level [16], higher
Karnofsky score [16]
With rifabutin (combination), fewer symptoms [17]
Extradermatomal, hyperkeratotic verrucous papules [19]
Oral azoles
Isoniazid
Ganciclovir
No distinct differences described
More AFB smear – negative disease (?) [23], less extrapulmonary disease (?) [23]
Less-frequent colitis (?) [24]
Dapsone
Trimethoprim-sulfamethoxazole
Rifabutin
NOTE. AFB Å acid-fast bacilli; BAL Å bronchoalveolar lavage; CMV Å cytomegalovirus; MAC Å Mycobacterium avium complex.
No clinical description of clarithromycin prophylaxis failures
has been reported [18].
Varicella Zoster Virus
Primary or secondary prophylaxis for both herpes simplex
and varicella zoster virus with acyclovir is a relatively common
practice. One report described the clinical appearance of
acyclovir-resistant varicella zoster virus infection in four patients who had received many months of chronic acyclovir
prophylactic therapy [19]. The authors reported culture-proven
acyclovir-resistant varicella zoster virus infection, presenting
as atypical hyperkeratotic verrucous papules in a disseminated
(nondermatomal) distribution.
Atypical Presentations Not Well Described
Deep-Seated Fungal Infections
The oral azoles, including fluconazole and itraconazole, are
widely used in the care of persons infected with HIV. Intermittent doses are often given for oral and/or vaginal thrush. In
addition, odynophagia is often presumed to be due to C. albicans, and an azole is prescribed. This widespread use of oral
azoles has resulted — serendipitously in many instances — in
prophylaxis against various deep-seated fungal infections. Because the protection from these agents is incomplete even when
dosing is sustained, and because the drug often is given only
intermittently, breakthrough of deep-seated fungal infection
may occur.
A recently reported prospective study examined rates of histoplasmosis among patients in Kansas City, Missouri, an area
of endemicity [20]. Investigators found 5 breakthrough cases
in persons receiving azoles (4, fluconazole; 1, ketoconazole)
among 304 patients followed for 2.5 years. No clinical descrip-
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tion of the breakthrough cases was given. Cryptococcosis similarly has occurred among patients receiving fluconazole in various trials. No clinical descriptions have been given, and
investigators have tended to ascribe development of disease
with individual-patient noncompliance [21, 22].
Tuberculosis
Little has been written about the clinical characteristics of
tuberculosis in patients whose isoniazid prophylaxis fails, although the microbiological consequences — namely, the emergence of resistance — have been much discussed. In a recent
report from Nairobi, 48 cases of tuberculosis developed among
684 HIV-infected persons randomized to receive isoniazid or
placebo (25 developed in the isoniazid arm, vs. 23 in the placebo arm) [23].
Patients receiving isoniazid had higher rates of smear-negative, culture-positive disease than did those receiving placebo,
but the trend was not statistically significant (10/25 vs. 5/23;
P Å .29). Rates of extrapulmonary disease were higher in the
placebo group, but this also failed to reach statistical significance (1/25 vs. 5/23; P Å .15). These trends possibly suggest
a more attenuated clinical presentation in those receiving (and
failing to improve with) isoniazid therapy, but they are far too
preliminary to allow firm conclusions to be drawn.
Cytomegalovirus
Oral ganciclovir has been shown to decrease the rates of
cytomegalovirus retinitis in patients with advanced AIDS [24]
by Ç50%. In the largest published report, both breakthrough
retinitis and colitis were seen, although the rate of colitis may
have been lower among those receiving ganciclovir. No additional description of clinical differences was reported [24].
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Conclusion
Routine use of prophylaxis against specific opportunistic infections has had a significant impact on the trends in opportunistic infections [25] as well as upon overall patient mortality
[7]. A series of landmark articles over the past decade have
served to define our current approach regarding when and how
to deliver optimal prophylaxis for opportunistic infections. The
main focus of these reports has been to determine the effectiveness of a given strategy, usually expressed as a reduction in
cases/rates compared to rates among patients receiving placebo.
In addition, because of growing concern that prophylaxis might
contribute to an increase in drug resistance, some prophylaxis
studies, particularly those involving MAC infection, have also
reported on the influence of the study regimen upon the susceptibility profile in breakthrough cases.
The qualitative effect of failed prophylaxis on the clinical
presentation of opportunistic infections is less well characterized. The attenuating effect of failed prophylaxis, however,
wherein a specific disease is only partially prevented, has
changed the clinical presentation of many AIDS-related opportunistic infections. As this review demonstrates, the clinical
presentation of four common opportunistic infections — PCP,
MAC, toxoplasmosis, and varicella-zoster virus — may be altered significantly in persons receiving prophylaxis, while data
are incomplete for other infections, such as deep-seated fungal
infections, tuberculosis, and cytomegalovirus (table 1).
Promising advances in prophylaxis for opportunistic infections [2, 3] and in antiretroviral therapy [26, 27] have combined
to improve greatly the quality and duration of life of persons
infected with HIV [28]. With these advances, however, have
come a new set of challenges for the clinician and the patient
alike [7]. Attention must now be paid to the subtle changes in
the clinical presentation and expected natural history of the
opportunistic conditions brought about by these interventions,
because, despite these improvements, opportunistic infections
will continue to occur. And with each opportunistic infection,
however atypically it may present, will come significant patient
morbidity and mortality.
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