THE OI REPORT: A Critical Review of the Treatment & Prophylaxis of AIDS-Related Opportunistic Infections (OIs)

CANDIDA AND OTHER PATHOGENIC FUNGI
by Theo Smart

INTRODUCTION
Ninety percent of people with AIDS develop at least one fungal infection over the course of the disease, ranging from mucosal candidiasis (thrush) to serious systemic infections, such as cryptococcal meningitis, and 10-20% of the systemic infections prove fatal (Benedict 1994). Both environmental organisms such as Histoplasma and Coccidioides, and endogenous flora such as Candida can be pathogenic in an immunocompromised host. Susceptibility to in these infections in people with late-stage AIDS may stem both from HIV-associated cell-mediated immune deficits and from weakened defenses due to prolonged neutropenia caused by chemotherapy (Brown 1990). The clinical manifestations of fungal infection are varied, so fungal pathogens must be considered as etiologic agents in a range of conditions for which no other cause can be found.

ENDEMIC FUNGAL INFECTIONS
In endemic regions, the incidence of histoplasmosis and coccidioidomycoses in people with AIDS is as high as 20-30% (Dixon 1996). Unfamiliarity with these infections outside of the endemic region may result in delays in diagnosis and treatment. The infections may be contracted within a very short period - two cases of coccidioidomycosis recently were reported in military personnel who spent less than 3 weeks in California (Standaert 1995).

HISTOPLASMOSIS and BLASTOMYCOSIS
Histoplasma capsulatum is an organism endemic to the Ohio and Mississippi River valleys, Puerto Rico, the Caribbean islands, and Central America. It is the most common acute fungal infection in the US - more than 80% of people who live in the endemic regions have a positive skin test to the pathogen (Kirchner 1996). The acute infection results in fever, hypoxia and pulmonary infiltrates, and may resemble bacterial pneumonia. Outbreaks have been associated with exposure to soil contaminated with bat or bird droppings. In one recent episode, 28 employees of a company meeting in Martinique, French West Indies, separated for a day of hiking in a canyon (N=15) or a mountain-climbing trip which involved passing through a tunnel in which bats dwelt (N=13). All 13 tunnel visitors developed acute histoplasmosis within 17 days, and all recovered after two months of itraconazole (De Truchis 1996).

Histoplasmosis occurs in 2 to 5% of people with AIDS (PWAs) and is more common in endemic areas. During outbreaks in places such as Indianapolis and Kansas City, the incidence has been reported to be over 25% (Wheat 1990; Sarosi 1992). This suggests that the AIDS-defining condition may be acutely acquired, and justifies public health recommendations that immunocompromised people avoid chicken coops, bird roosts and caves (Hajjeh 1995; CDC 1995). Histoplasmosis also may result from reactivation of latent infection (Wheat 1990).

In AIDS, histoplasmosis is almost always a disseminated infection (Wheat 1994), usually occurring in people with fewer than 75 cells (Hajjeh 1995), but the fungi can produce a wide variety of clinical conditions. Initial symptoms are nonspecific (fevers, weight loss, and fatigue). There are respiratory complications in half of the cases, which may be particularly severe and life-threatening in smokers and those with emphysema. Pulmonary infections may mimic lung cancer or tuberculosis and are associated with infiltrates and sometimes hilar adenopathy. Even so, many AIDS patients have no evidence of infiltrates of chest radiographs (Conces 1993). Lymphadenopathy occurs in around 20%, and gastrointestinal complaints (bleeding, diarrhea, abdominal pain, obstruction, and hepatosplenomegaly) in 10% of cases (Wheat 1994; Sarosi 1992; Wheat 1990). Ten to twenty percent of Histoplasma cases may involve neurologic complications such as meningitis, focal brain lesions, and encephalitis (Kirchner 1996).

The fungus also can infect the skin, causing ulcers, plaques, or pustules that can be diagnosed by biopsy (Eidbo 1993). Oral lesions develop in up to 50% of patients with disseminated histoplasmosis, and may also occur without dissemination (Swindells 1994). Rare cases of septicemia with shock and multiple organ failure have been documented (Wheat 1990). Progressive optic neuritis and other ocular histoplasma infections have also been observed in people with AIDS (Font 1995; Yau 1996).

Recognition of histoplasmosis on the basis of clinical presentation may be difficult given the broad spectrum of conditions the fungus can cause. One review article by McKinsey and colleagues recommends that in endemic regions, "Clinicians must maintain a high level of suspicion for histoplasmosis in any HIV-infected patient who presents with unexplained fever, particularly if the patient has evidence of hepatosplenomegaly, generalized lymphadenopathy, pancytopenia, abnormal liver function tests, or bilateral pulmonary infiltrates" (McKinsey 1994).

Blood or other specimen (particularly bone marrow) culturing has been the gold standard for diagnosis, but cultures may take weeks to become positive (Saag 1995). Histologic examination of peripheral blood smear or bone marrow aspirate is diagnostic (Drew 1993), but not always sensitive (Medoff 1992). Histologic diagnosis may permit prompt treatment. In one study, histology results took 48 hours by histology, but culture took 18 to 35 days (Zarabi 1992).

Wheat and colleagues developed a rapid radio-immunoassay technique for Histoplasma polysaccharide antigen (HPA). The test has a sensitivity of 97% and can detect antigenemia in serum, urine, bronchoalveolar lavage fluids or cerebrospinal fluid (Wheat 1986; Williams 1994). The test currently is available at several reference laboratories (Kirchner 1996).

Blastomycosis, caused by Blastomyces dermatitidis is much less common than histoplasmosis but the infections are coendemic to the same regions of the US. Blastomyces causes pulmonary and extrapulmonary disease that can involve skin, bone, prostate, and central nervous system (Bradsher 1996). The course of disease is much more progressive in people with HIV than in the uninfected population, and usually occurs in patients with less than 200 CD4 cells (Witzig 1994). Diagnosis is based on cultures from blood or other samples and histology (Pappas 1992). An enzyme immunoassay seems highly sensitive but not entirely specific (Sekhon 1995).

COCCIDIOIDOMYCOSIS
Also known as Valley Fever, coccidioidomycosis is an AIDS-defining illness endemic to the southwestern USA and northern Mexico. The causative organism, Coccidioides immitis is found in the soil and may be inhaled into the respiratory tract (Fish 1990; Ampel 1993). While most cases probably result from the reactivation of latent infections, an increased number of diagnoses occurred in California after the January 1994 Northridge earthquake stirred up dust containing arthoconidia - the infectious stage of the organism (Centers for Disease Control and Prevention 1994). A 1997 report described a church group comprised of 126 teenagers from Washington state who visited northern Mexico to volunteer at an orphanage and build a swimming pool there. 21 teenagers developed acute coccidioidomycosis upon their return home, and providers were unfamiliar with the disease, particularly an associated rash rarely seen in adults but apparently more common in teenagers (Cairns 1997). There may be considerable underreporting of this condition. From 1990 to 1991 there was an 281% increase in the number of cases reported in California, but just one lab was responsible for most of the new cases (Dixon 1996). Climate changes -- long periods of drought, followed by periods of heavy rain and winds - may play a role in the increased number of cases (Galgiani 1993).

In one study from an endemic region, the incidence of coccidioidomycoses in people with HIV was as high as 24.6% after 41 months of follow-up (Ampel 1993). According to CDC researchers, in endemic areas, the rate of disseminated coccidioidomycoses is much higher among injecting drug users with AIDS than gay or bisexual men. Survival averaged less than one year in 63% of the patients with disseminated coccidioidomycoses (Jones 1995).

Like other systemic opportunistic fungal infections, coccidioidomycosis has a variety of clinical presentations, including focal and diffuse pulmonary disease, cutaneous and bone/joint infections, extrathoracic lymph node, liver and neurologic involvement. Diffuse pulmonary infections appear to be the most common and rapidly fatal condition (Fish 1990). Neurologic involvement is ultimately fatal as well (Mischel 1995).

Focal disease caused by the infection may occur in patients with fewer than 200 CD4 cells, but patients with more extensive, life-threatening disease tend to have fewer than 25-50 CD4 cells (Fish 1990; Cone 1990). The disseminated infection may present with fevers, fatigue, weight loss, coughing, and nodular infiltrates may be observed on chest X-rays.

While serology can diagnose coccidioidomycosis, it is often negative in people with AIDS (Antoniskis 1990). Diagnosis is made by histologic biopsy, antigenemia, and blood cultures.

TREATMENT OF ENDEMIC MYCOSES

Three major groups of antifungal compounds are in clinical use: the polyene antibiotics, the azole derivatives, and the allylamines-thiocarbamates. All interact with or inhibit ergesterol, the major sterol in the fungal plasma membrane. [These drugs are thus ineffective against P. carinii, which has cholesterol instead of ergesterol in its membrane.] (Georgopapadakou 1994).

Amphotericin B and nystatin are both polyene antibiotics. The azole antifungals fluconazole, itraconazole, ketoconazole and miconazole inhibit ergesterol synthesis. Trimethoprim, sulfamethoxazole and 5-Fluorocytosine (5-FU) inhibit fungal nucleic acid synthesis. Newer antifungal compounds such as the nikkomycins and echinocandins inhibit cell wall synthesis (Georgopapadakou 1994).

For treatment of systemic fungal infections, intravenous amphotericin B generally is still recommended as induction therapy, at least for serious cases. The dose depends upon the particular fungal infection. A cumulative dose of 500 to 1,000 milligrams is recommended for histoplasmosis and blastomycosis while doses as high as 1,000 to 2,000 milligrams (which have never been evaluated in clinical trials) have been recommended for disseminated coccidioidomycosis (Sarosi 1994). These regimens start with 20 milligrams of amphotericin B daily and escalate as quickly as is safe to 50 mg/day. The more aggressive treatment may reflect the fact that the condition is rapidly progressive and highly lethal. Higher doses of amphotericin B (2,000 to 3,000) are also recommended when there is a fungal infection of the central nervous system, although again, aside from cryptococcal meningitis, no controlled studies demonstrate whether these doses are effective enough to justify the greater toxicity (Sarosi 1994). Cumulative doses higher than 2-3 grams carry with them a risk of fatal injury to the kidneys.

Treatment of Histoplasmosis
Initial treatment for histoplasmosis is amphotericin B for moderate-to-severe cases, and oral itraconazole for mild cases. Itraconazole is the preferred maintenance therapy. Itraconazole blood levels should be monitored to ensure absorption.

Eighty to 90% of patients with histoplasmosis respond within the first week of amphotericin B therapy (Kirchner 1996). Amphotericin B became established as the treatment of choice for induction therapy before any of the new azoles became available. Nevertheless, more recent studies suggest that there is a more rapid response to treatment with amphotericin than with the azoles (Wheat 1994), though amphotericin B may not always be tolerated in the sickest patients.

Oral itraconazole may be an option for cases that are not life-threatening. ACTG 120, a study of open-label oral itraconazole (300 mg twice daily for three days followed by 200 mg twice daily for 12 weeks) in 59 people with mild histoplasmosis found that 85% of patients responded (Wheat 1995). In another study, itraconazole 200 mg twice daily prevented relapse for over two years in 40 out of 42 (95%) patients who initially responded to four to 12 weeks of amphotericin B induction therapy. Lifelong maintenance with itraconazole at this dose is necessary in people with HIV (Wheat 1993).

Fluconazole does not seem as effective as itraconazole. In one study, 50 patients with histoplasmosis were treated with fluconazole (1600 mg loading dose followed by 800 mg daily) for twelve weeks. Patients who improved were treated with 400 mg daily for at least one year. Thirty-seven patients improved on treatment, but 12 relapsed on maintenance therapy, leading the authors to conclude that fluconazole was not as effective as itraconazole for maintenance therapy (Wheat 1994). In another small, uncontrolled trial of 20 patients with histoplasmosis, itraconazole also performed slightly better than fluconazole. There was one complete remission and one improvement in five patients treated with fluconazole 100 mg daily, and two complete response and three failures in those treated with fluconazole 400-800 mg daily. Seven of 12 patients treated with itraconazole 400 mg daily (including two who previously failed fluconazole) had complete remissions, and two others had clinical improvements (Sharkey-Mathis 1993).

Some patients are unable to take itraconazole because of drug interactions, malabsorption, or side effects. A retrospective analysis of 76 patients with AIDS and disseminated histoplasmosis suggested that doses of fluconazole of at least 200 mg daily were a reasonable choice for chronic suppressive therapy of histoplasmosis in patients who cannot take itraconazole (Norris 1994). In light of the relapses reported in the ACTG study, though, anyone with histoplasmosis taking fluconazole maintenance therapy should be closely monitored.

Prophylaxis for histoplasmosis is not generally seen as cost-effective in non-endemic areas (Kirchner 1996). Nightingale and colleagues assessed the incidence of systemic fungal infections in 329 fluconazole-treated patients (followed for 145 patient-years) as compared to that of 337 historical controls (followed for 157 patient-years). Three fluconazole cases developed histoplasmosis versus four historical controls (Nightingale 1992). Mycoses Study Group (MSG) 028 is currently evaluating the use of itraconazole as prophylaxis in endemic areas.

Treatment of Blastomycosis
Aside from a few anecdotes, the literature is silent on the treatment of blastomycosis in HIV-infected persons. In one retrospective study, nine patients who survived for more than one months all were treated with amphotericin B. Most received subsequent lifelong therapy with ketoconazole, and only two died with evidence of active blastomycosis (Pappas 1992). The standard treatment of choice is amphotericin B (one or two grams) followed by maintenance with itraconazole or ketoconazole.

Treatment of Coccidioidomycosis
Coccidioidomycosis is incurable but may be suppressed and sometimes requires intrathecal amphotericin B therapy (injected into the spinal fluid); more recently, fluconazole in higher doses has been given successfully (Spitz 1991, Sarosi 1994, McNeil 1995, Singh 1996).

A retrospective study of 91 patients at Maricopa Medical Center in Phoenix, Arizona, illustrates the inadequacy of current treatment for disseminated coccidioidomycosis. Given the renal toxicity of amphotericin B, doses must gradually be increased until there is a clinical response, or the maximum tolerated dose is reached. In this cohort, doctors administered a test dose of one milligram, and if it was tolerated, a further 20 mg were infused. On subsequent days the dose was increased as rapidly as possible to 50 mg/day, with a goal of administering a cumulative dose of 1.5-2.5 grams as rapidly as renal function allowed. Forty-nine of 59 patients with pulmonary infections in this study used amphotericin B as induction therapy; three used fluconazole, five died shortly after diagnosis and two were untreated. The median survival was 54 days. The authors concluded that "a meaningful analysis to assess the impact of amphotericin B on mortality could not be performed." (Singh 1991).

Most available systemic antifungal drugs have been used to treat coccidioidomycosis in case studies, but no comparative studies have been performed. All published treatment studies enrolled mostly HIV-negative subjects. One open-label study reported a response (elimination of more than 40% of the baseline symptoms) to fluconazole (400 mg per day) in 78.7% (37 of 47) evaluable patients. While only 9 patients were HIV-positive, the authors reported that they responded just as well as the HIV-negatives (Galgiani 1993). In another study of fluconazole (200-400 mg) in 75 patients, seven of whom were HIV positive, 55-86% of the participants had some clinical improvement, based upon the site of infection. 37% of patients experienced a relapse off therapy (Catanzaro 1995). Another study found that fluconazole (200 mg daily increased to 400 mg daily in the absence of response) was effective in 23 of 30 patients (76.7%) with life-threatening coccidioidomycosis who could not take amphotericin B because of intolerance, drug interaction or failure (Robinson 1990).

An open-label study with the new oral triazole antifungal, SCH 39304 (100 to 200 mg daily), was conducted in 54 patients with Coccidioides immitis infections. Only 13% were HIV-infected. Cumulative overall response rates at 4, 8 and 12 months were 7%, 36% and 66% respectively. The drug was generally well tolerated (Hostetler 1994).

ASPERGILLOSIS
Infections with Aspergilla species are increasingly being observed in patients with late-stage AIDS. Although this fungal infection is neither endemic to certain areas nor as common as Candida or Cryptococcus neoformans, its incidence appears to be increasing, especially in patients who have developed neutropenia either from underlying HIV infection, from opportunistic causes, or from myelotoxoic chemotherapy such as ganciclovir or KS or lymphoma treatment. Aspergillosis was among the original CDC-designated AIDS-defining conditions, but it was removed from the list in 1984 because it was then so rare (Jaffe 1984). Back then, many people died of PCP long before they developed the profound immunosuppression and neutropenia which give rise to aspergillosis.

There are hundreds of Aspergilla species, but infection in humans is predominantly by A. fumigatus and A. flavus. The organism is ubiquitous, being found in soil, water, decaying vegetation, spilled food, soft contact lenses and opened medicine bottles (Rosenberg 1996). Nosocomial outbreaks among cancer patients, steroid recipients and organ transplant patients have been reported subsequent to hospital remodeling (Opal 1986). The organism enters the body through the lungs; the fungal hyphae germinate in the alveolae and invade pulmonary tissue and blood vessels, leading to tissue necrosis and dissemination. Aspergilla species can also infect the skin, leading to cutaneous disease. Risk factors for aspergillosis include prolonged neutropenia, steroid use, leukemia and lymphoma, diabetes, pulmonary disease and intravenous drug use, marijuana smoking and antibiotic use (Rosenberg 1996). One case series reported that a history of fluconazole use also preceded aspergillosis (Woitas 1996). In people with HIV it primarily infects those with fewer than 50 CD4 cells.

Aspergillosis in people with AIDS most commonly involves the lungs (48-66%), causing symptoms ranging from fever, cough and chest pain. Patients with focal disease tend to fare better than those with bilateral disseminated disease (Miller 1994). The brain may also be involved in about 24% of cases (Minamoto 1992, Henochowicz 1985, Woods 1990). Other reported sites of infection include heart, liver, spleen, kidneys, pancreas, sinuses and skin.

Diagnosis is by culture and histopathology. Culture positivity alone may reflect environmental contamination; fewer than 10% of patients with positive sputum cultures may have invasive disease, though among neutropenic patients this rises to 23%. A chest X-ray or computerized tomography (CT) scan should be conducted; it will display cavitary or nodular lesions, interstitial infiltrates and other characteristic signs of pulmonary aspergillosis. A bronchoscopy can also be diagnostic (van der Horst 1997). Tissue should be biopsied if invasive aspergillosis is suspected. Serum or bronchoalveolar lavage testing for culture, antibodies or antigen are not useful.

Like many complications of late-stage AIDS, aspergillosis tends to respond better to treatment when it is diagnosed early and treated aggressively. Intravenous amphotericin B (1.0-1.5 mg/kg) is generally used as induction therapy. Based on in vitro synergy, it has been combined in pilot clinical studies with rifampin or flucytosine, without any demonstrable survival benefit (Denning 1990). Liposomal amphotericin B has been used in leukemia patients with aspergillosis, and 13 of 17 (76.5%) responded in one study, even though 11 had failed previous standard amphotericin B, and six had been intolerant (Mills 1994). Based on this and other studies in non-HIV-infected patients (Lopez-Berestein 1989, Weber 1987), thought should be given to comparing standard with liposomal amphotericin B in AIDS patients with aspergillosis.

Itraconazole also has in vitro activity against Aspergilla, but its use for disseminated disease is limited by its unpredictable bioavailability. In one study, 76 patients with invasive aspergillosis were treated with itraconazole (600 mg/day for four days followed by 400 mg/day) for a median of 46 weeks. 36% of patients had a complete or partial response, 4% were stable and 56% failed therapy or withdrew from the study. The failure rate for itraconazole was 44% among the AIDS patients in this study at twelve weeks, and all ultimately failed. (Denning 1994). It should perhaps be reserved for maintenance among patients who have responded to induction with amphotericin B, or for those intolerant of the latter.

Considering the poor prognosis of invasive aspergillosis in AIDS, and its increasing incidence, it would seem like a matter of some urgency for researchers to conduct carefully-controlled studies investigating 1) standard versus liposomal amphotericin B for induction therapy and 2) amphotericin B versus high-dose (or intravenous?) itraconazole for maintenance. Several new antifungals now in advanced pre-clinical or early clinical studies show intriguing activity against Aspergilla species (DuPont 1996).

CANDIDA
Candida is an endogenous yeast which in healthy individuals dwells predominantly in the gastrointestinal tract, and sometimes in the respiratory tract. It can be pathogenic in immunocompromised patients. Though C. albicans is the most prevalent form, a number of other species can cause disease including Candida tropicalis, C. krusei, C. glabrata (also classified as Torulopsis glabrata), and C. parapsilosis. Candida can cause infections of the esophageal, oral, anorectal, and vaginal mucosa, the eyes, skin and nails, as well as life-threatening fungemia (Benedict 1994). Candida infections are particularly common in patients with a long history of antibiotic use; antibacterial agents encourage the overgrowth of fungal Candida species in the gastrointestinal tract (Bodey 1988).

Thrush or oral candidiasis is the most common opportunistic infection in people with HIV (Selik 1987; Dodd 1991). It occurs in approximately one third of people with HIV before progression to AIDS, and over 90% of people with AIDS will develop oral thrush at some time during the course of their illness (McCarthy 1992). Thrush is perceived to be a marker of impaired immune response in people with HIV, since about half of those with the condition develop an AIDS-defining illness within two years.

Candida invades cells of the oral mucosa, forming several types of lesions. The most common are pseudomembranous lesions -- raised creamy white patches which can be easily scraped off to reveal a bleeding red base upon the cheek, the palate or the dorsum of the tongue. Erythematous lesions are spotty red patches without plaques which may be easily overlooked. Hyperplastic lesions are similar to the pseudomembranous lesions, except that the plaque cannot be removed. Painful fissuring and ulceration of the corner of the mouth indicates angular cheilitis (inflamation of the lips) (Brawner 1992).

Esophageal candidiasis
Esophageal candidiasis is an AIDS-defining illness which occurs in around 15% of people with AIDS (Reef 1995), is associated with pain upon swallowing and retrosternal pain. This burdensome condition can make it extremely difficult to eat. One recent report suggests that the incidence of symptomatic oropharyngeal candidiasis, C. albicans carriage and fluconazole resistant Candida may have declined recently (between July 1995 and March 1997) among individuals who recently switched from nucleoside monotherapy or bitherapy to triple therapy including protease inhibitors:

Vaginal candidiasis
Although many women get yeast infections, recurrent vaginal candidiasis is a more persistent problem in women with HIV, in 30-60% of whom it is estimated to occur (Sha 1993, Duerr 1993). One longitudinal study of 66 HIV-positive women found that chronic vaginal thrush occurred before CD4 cells declined, while oral or esophageal Candida tended to occur only after significant reductions (Imam 1990). Researchers from the HIV Epidemiology Research Study Group (HERS), interviewed and obtained vaginal yeast cultures and CD4 counts from 833 HIV positive and 427 HIV negative women. The median age of the participants was 34.9 years. 58% were African American, 25% were white and 16% were Latina. The median CD4 count for the HIV-infected women was 382. Oral, esophageal and vaginal colonization was more common among women with HIV infection. Unlike oral colonization, vaginal colonization was not predicted by CD4 count. Non-albicans species were no more common in those with HIV or with lower CD4+ cell counts. Vaginal colonization was not associated with intravenous drug use, antibiotic use or recent sexual activity when adjusted for age, HIV status and CD4 count. Of 398 participants with vaginal colonization, just 34 (9%) had vaginal candidiasis on exam (Sobel 1996).

In a smaller study conducted by researchers at the Yale School of Nursing, 121 HIV positive women were evaluated for factors associated with presence of Candida vaginitis. The median CD4 count was 330. 43% were taking antibiotics and 37% were currently using illicit intravenous drugs. Fifty-six of 115 women (48.7%) had positive vaginal yeast cultures (C. albicans 76%, T. glabrata 14%). Eighteen subjects (15.6%) had clinical candidal vulvovaginitis and a positive KOH smear (a swab rubbed on the lesion and treated with potassium hydroxide for examination by microscope). Of 27 participants with CD4 counts below 100, seven (26%) had vaginal candidiasis compared to 11 of 128 (9%) with counts greater than 100 (OR=3.7 with 95 percent CI 1.3-10.7). However, no multivariate analysis was performed to adjust for such factors as antibiotic use, intravenous drug use and wasting (Williams 1996).

Candidemia
Candidemia and invasive candidiasis are more common in cancer patients, but can occur in people with AIDS, especially those with an indwelling catheter or those who are receiving parenteral nutrition (Weems 1992). It can disseminate to any organ of the body especially the liver, spleen, or lungs. There may also be skin involvement, which presents as a nodular rash that may hemorrhage.

Diagnosis of Candidiasis
The diagnosis of oral and vaginal candidiasis is based on clinically consistent signs and symptoms and a positive culture or a positive gram, KOH, or calcofluor stain (Reef 1995). Cultures are not by themselves diagnostic, since they may be positive in 60% of healthy, non-smoking gay men (Torssander 1987; Sirjanen 1988). Infections may be distinguished from natural oral flora by higher colony counts (though this is unproven), and by wet mounts or gram stains that can detect the presence of pseudomycelia (Brawner 1992b). Yeast cells may convert to pseudomycelia when C. albicans invades the mucosa (Skeryl 1984), though positive stains for pseudomycelia are less often positive in erythematous lesions than in pseudomembranous lesions. Nevertheless, given the frequency of thrush in people with AIDS, and the rapid response to topical treatment, if it looks like thrush, most physicians treat it as such.

Since Candida is the most common esophageal infection in HIV-positive patients, esophageal symptoms also are usually treated empirically with oral systemic antifungal therapy (Wilcox 1994). However, other pathogens such as CMV, HSV, and bacteria can infect the esophagus in PWAs. Symptoms may be idiopathic or caused by medications (Baehr 1994). Definitive diagnosis of esophageal candidiasis requires endoscopic biopsy and histopathology (Wilcox 1994, Reef 1995). Only 30% of individuals with esophageal candidiasis have positive blood cultures, which may result from transient local infections (Stein 1989).

Treatment of Oral Candidiasis
Oral Candidiasis is usually treated with topical agents such as clotrimazole, nystatin or oral amphotericin B (which is not systemically absorbed), or systemic oral agents such as fluconazole, itraconazole or ketoconazole. The triazole antifungals, fluconazole and itraconazole, appear to be somewhat more effective - and more expensive. It is not clear whether they are more cost-effective. The toxicity and inconvenience of IV amhotericin B make it the treatment of last resort (e.g., for azole-resistant candidiasis).

A trial in 334 patients with oral candidiasis found that the rate of clinical improvement after two weeks of therapy with either fluconazole (100 mg per day) and clotrimazole (10 mg five times daily) was roughly equivalent (98% versus 94%, respectively) (Pons 1993). However, there were significantly fewer relapses on fluconazole for the two weeks of follow-up after treatment (82.3% versus 50% respectively), and fluconazole was significantly better at eradicating Candida from the oral flora. Fluconazole also appears to be more effective than ketoconazole. In a 28-day double-blind study of 37 patients receiving fluconazole (50 mg daily) or ketoconazole (200 mg daily), 100% on fluconazole experienced complete remissions, as compared to 75% of those on ketoconazole (De Wit 1989).

A study conducted by Pons and colleagues at the University of California, San Francisco, demonstrated that an oral suspension of fluconazole was more effective than topical liquid oral nystatin for oral candidiasis. 136 patients with AIDS-related oral thrush were randomized to receive fourteen days of oral suspension fluconazole (100 mg/day) (N=68) or "rinse, retain and swallow" oral nystatin 5 ml per day (N=68). At 14 days, 85% of the fluconazole patients compared with 48% of the nystatin patients achieved clinical resolution (p<0.05) (Pons 1995). It is unclear what the best dose of fluconazole might be, or how long treatment must last. A study by de Wit and colleagues in 51 patients found that one 150 mg dose of fluconazole was almost as effective as seven days of fluconazole at 50 mg per day. At day seven, clinical remission occurred in 21 of 24 (85%) of the single-dose treated patients, and 26 of 27 (96%) of those treated for seven days (De Wit 1993).

Itraconazole (200 mg daily) appeared marginally better than ketoconazole (200 mg daily) in one 28 day study of 93 patients with oral and esophageal candidiasis. There was no difference in the time to clinical improvement, but fewer patients relapsed, and the time to relapse was longer in the itraconazole arm (de Repentigny 1992). In another study comparing the same dose of itraconazole to ketoconazole (200 mg twice a day) in 111 patients with oral or esophageal candidiasis, 93% of the patients in both groups had a clinical response at week four. There was no difference in the relapse rates, with 80% of patients experiencing a further episode within the next three months (Smith 1991).

Some of most promising new data have been on the itraconazole oral solution (cyclodextrin) for the treatment of oral and esophageal candidiasis. Cyclodextrin itraconazole solution is 30 to 60% more bioavailable than the standard itraconazole capsule when it is taken in a fasting state. It also has a topical effect. The solution is not currently available in the United States, although Janssen has filed an application with the FDA.

A Canadian/European study compared fluconazole to the oral itraconazole solution for treatment of oral candidiasis. 244 patients with thrush received the itraconazole solution (100 mg twice daily for seven days or 100 mg daily for fourteen days) or fluconazole (100 mg daily for fourteen days). All three regimens were equivalent, as were the rates of relapse (20 to 22 percent). Side effects were also similar (Frechette 1995). Darouiche and colleagues treated a total of 190 patients (179 evaluable), who had a median CD4 count of 94, with itraconazole solution 200 mg daily for 7 days (IS-7), 14 days (IS-14), or fluconazole 200 mg on day 1, then 100 mg daily for 14 days (F-14).

(Darouiche 1996)

There were no significant differences in lesion clearance, Candida eradication, or four-week relapse rate, though two weeks of therapy tended to be superior to one week. Another study by the same team compared itraconazole oral solution with clotrimazole troches. 83% of the 149 patients were HIV-positive. Participants were randomly assigned to two weeks of itraconazole oral suspension or to 10 mg of clotrimazole troches five times daily (Darouiche 1996).

(Darouiche 1996)

Treatment of Esophageal Candidiasis
Esophageal candidiasis requires systemic treatment. Laine and colleagues compared fluconazole (100 mg daily) to ketoconazole (200 mg daily) in 169 patients with esophageal candidiasis. Treatment continued for two weeks after clinical improvement for a maximum of eight weeks. By study's end, 96% of conazole-treated patients had a complete clinical cure on endoscopy, compared to only 57% of ketoconazole-treated individuals (Laine 1992).

A much larger study of esophageal candidiasis also shows fluconazole superior, this time to itraconazole. The Candida Esophagitis Italian MulticenterStudy Group compared standard itraconazole (100 mg twice daily) and fluconazole (100 mg twice daily), each for two weeks, in 2,213 patients with endoscopy-proven esophageal candidiasis.

(Barbaro 1996)

Fluconazole was clearly more effective in the acute therapy of esophageal candidiasis. By the fourth week of therapy, however, response to the two agents was similar (Barbaro 1996). However, in another trial, the oral suspension of itraconazole, as opposed to standard pill, compared much more favorably with fluconazole. In this trial, 110 patients were randomized to receive itraconazole solution (IS) at 100-200 mg daily or fluconazole (F) at 100-200 mg daily for the treatment of esophageal candidiasis. Treatment lasted for two weeks beyond symptom resolution. Patients were assessed clinically every week and received an endoscopy at the end of treatment (Moskowitz 1996).

(Moskowitz1996)

Treatment of Vaginal Candidiasis
Over-the-counter antifungal treatments are available for vaginal yeast infections, but there are no data from controlled clinical trials in women with HIV to show which antifungal is most effective in treating recurrent vaginal candidiasis in this population. However, one large study has evaluated the use of fluconazole to prevent candidiasis in women (see below). Available agents include both topical and oral (systemic) approaches:

(Sobel 1997)

Treatment of Systemic Candidiasis in HIV-Infected Persions
There have been no controlled studies in PWAs who develop systemic candidiasis, though amphotericin B is generally recommended as first line treatment (Edwards 1992; Sarosi 1994). Fluconazole (400 mg daily) appears as effective and significantly less toxic than amphotericin B (25-50 mg daily; 0.67 mg/kg daily in those with neutropenia) (Anaissie 1996), although disseminated Candida infections are often less responsive to fluconazole. Biological response modifiers may have some potential in treating systemic candidemia. One study in nine neutropenic AIDS patients with Candida and cryptococcal meningitis suggested that G-CSF stimulated the immune system's antifungal response (Vecchiarelli 1995).

Candida Prophylaxis
Various regimens of fluconazole have been shown to prevent oral candidiasis. In several open-label studies, 50 or 100 mg of fluconazole daily prevented the recurrence of Candida (Esposito 1990; Just-Nubling 1991; Stevens 1991). In one study, patients with a median CD4 count of 27 who had experienced at least two prior cases of oral or esophageal candidiasis were treated with 100 mg of fluconazole twice a week. Fourteen of 69 patients had relapses within nine months while on secondary prophylaxis. Seven developed oral candidiasis, five esophageal and two both (Grünewald 1992). After two to four weeks of treatment with fluconazole, Marriot and colleagues randomized 84 patients to receive fluconazole (150 mg weekly) or placebo. In 73 evaluable patients, the median time to relapse was over 168 days in the treatment arm and 37 days for those on placebo (Marriot 1993).

Fluconazole (200 mg daily) also proved more effective than clotrimazole troches (10 mg five times a day) at preventing esophageal candidiasis in ACTG 981. This study, nested into a PCP prophylaxis trial (ACTG 081), evaluated the effect of each antifungal on the development of mucosal and systemic fungal infections. Only three confirmed cases of esophageal candidiasis occurred in 217 patients (1.4%) on fluconazole compared to 17 of 211 patients (8%) on clotrimazole (p=0.004) (Powderly 1995).

Vaginal Candidiasis Prophylaxis
Results of CPCRA 010, a double-blind, placebo-controlled comparison of fluconazole (200 mg weekly) versus placebo in preventing oral, esophageal or vaginal candidiasis in 323 HIV-infected women, were presented at Vancouver. Those with a history of esophageal candidiasis or receiving antifungal therapy were excluded. Median follow-up was 29 months (Schuman 1996, 1997).

(Vazquez 1996)

Candidal events were confirmed by culture and presence of two symptoms or signs. Prophylaxis failure was defined as two episodes of confirmed oral or vaginal candidiasis or a diagnosis of confirmed or probable Candida esophagitis.

Fluconazole reduced the incidence of oral more than it did that of vaginal candidiasis. There was no significant difference in the development of esophageal candidiasis between the two arms of the study -- 11% on fluconazole and 12% on placebo, with too few events (38) to reach statistical significance. Among the 70% of patients reporting a history of mucosal candidiasis at study entry, 54 in the fluconazole group and 69 in the placebo group had at least one candidal event on study (RR=0.51, p=0.0005). Baseline predictors for vaginal candidiasis included positive vaginal yeast culture for C. albicans and two or more episodes of vaginal candidiasis in the year prior to study entry. Baseline predictors of oral thrush included a history of oral thrush, a history of HIV disease progression, and systemic PCP prophylaxis. Fluconazole altered vaginal candidal colonization. Of the 970 vaginal cultures performed in patients randomized to fluconazole, 33% were positive compared to 41% of the 900 cultures obtained from placebo assigned patients. C. albicans was isolated from vaginal cultures in 53% of those in the fluconazole group and 68% of the placebo group. Six patients on fluconazole and seven on placebo developed clinically resistant mucocutaneous candidiasis. Seven of these were oral and only C. albicans was isolated. In vitro resistance was found in five of 83 isolates (6%) from the fluconazole group and in four of 114 isolates (3.5%) from the placebo group (Schuman 1996, 1997), and fluconazole did not appear to increase the rate of azole-resistant Candida albicans, though there was a significant incidence of azole cross-resistance among non-albicans Candida species (Vazquez 1996).

The role of fungal prophylaxis continues to be uncertain. Enthusiasm for using systemic fluconazole to prevent largely mucosal Candida infections which respond well to topical therapy is also tempered by concern about the development of azole-resistant Candida and the cost of lifelong prophylaxis. For example, the New York State AIDS Drug Assistance Program (ADAP) spent $3 million on fluconazole in 1995 -- more than on any other drug -- mainly for prophylaxis. Many clinicians feel that secondary prophylaxis with fluconazole for Candida infections should be reserved for those with frequent or severe recurrences.

Azole-Resistant Candida
Since the organism that causes Candida albicans is a natural part of the intestinal and vaginal flora, and thrush is merely its overgrowth, drugs that keep candidiasis in check may never completely eradicate it. The continued presence of the organism during treatment makes the selection of drug-resistant fungal organisms more likely. In fact, as prophylactic use of the azoles has increased so has the incidence of azole-resistant Candida (Pfaller 1994, Vuffray 1994, He 1994, Sangeorzan 1994, Rex 1995). Fluconazole-resistant Candida accounts for 9-11% of the isolates from HIV-positive patients (Newman 1994, Bailey 1994, Laguna 1994). Therefore, many clinicians do not prescribe systemic antifungal prophylaxis or use it to treat mild cases, for fear of creating yeast strains resistant to treatment. Instead, they opt to treat thrush as it occurs.

It is unclear whether this approach is any better. Initially a team of researchers from Dijon, France reported that prophylaxis with fluconazole selected for resistance in a study of 153 patients. In a more recent study, however, they found just as much resistance in 142 people who had not received fluconazole prophylaxis. Some patients with less susceptible Candida had received treatment for thrush with fluconazole or ketoconazole (Grappin 1995). A Spanish study of 130 episodes of oral candidiasis in 95 people also found that fluconazole resistance was not significantly more common in people recently treated with the drug (Corzo 1995). In one case-controlled study, the incidence of fluconazole resistance was primarily related to duration of prior azole treatment (Maenza 1996).

ACTG 816 enrolled 846 subjects with CD4 counts below 100, who were clinically evaluated every 8 weeks for up to one year for evidence of thrush. Oral cultures were obtained every six months in a subset of 250 patients whose median CD4 count was 23. Twenty percent of those patients reported more than 3 episodes of oral thrush in the previous year. Fluconazole failure, defined as persistent mucosal candidiasis despite 14 days of fluconazole therapy at a dose of at least 200 mg per day, occurred at a rate of 3.9% with 682 person-years of follow-up. Fluconazole failure was more common among those treated with the compound at some time during the previous six months, with an annual incidence of 4.9% after 426 person years of follow-up. All patients experiencing fluconazole failure had Candida isolates which were resistant in vitro. Factors associated with fluconazole failure included more than three episodes of oral thrush in the previous six months, previous history of esophageal candidiasis, recent prior oral thrush, and previous history of opportunistic infection, particularly toxoplasmosis or disseminated Mycobacterium avium complex (MAC) (Fichtenbaum 1996).

Doctors at Cochin Hospital in Paris evaluated the factors leading to fluconazole failure in fourteen patients. While resistance was the most important factor, concurrent use of other medications such as rifabutin and rifampin, which lower the levels of fluconazole in the blood occurred in 43%of these patients. Other cofactors such as tobacco use and poor oral cavity condition were also common. Fluconazole at 400 mg a day was successful in 66% of these cases. Those failing at 400 mg daily did not respond to higher doses (Khanlou 1995). Such patients may have few treatment options. Several studies report that previous therapy with ketoconazole or fluconazole may decrease susceptibility to the entire class of azole antifungal drugs (Rodero 1995, Fong 1995, Valsco-Martinez 1995).

Resistant Candida infection, particularly when associated with esophagitis, is a devastating complication associated with profound inanition and weight loss. If overuse of the systemic azoles predisposes patients to azole resistance, the use of these therapies for Candida should be reserved for esophagitis and oral thrush refractory to local treatment with clotrimazole troches, nystatin or oral amphotericin B. Unfortunately, these precautions may not be enough. Several groups report that azole-resistant Candida strains can be transmitted from patient to patient, raising the specter of an even greater increase in azole-resistance (Boerlin 1995, Sangeorzan 1994, Dupont 1994). More frightening still, though still theoretical, is broad-spectrum resistance to all the currently available antifungals, since in one way or another, they all target ergosterol, the major sterol of the fungal cell wall (Georgopapadakou 1994).

EXPERIMENTAL ANTIFUNGALS
The development of another class of well-tolerated oral antifungals could ultimately reduce the incidence of azole resistance, and provide treatment options for those infected with azole-resistant fungi. Two members of a new class of antifungal drugs, known as echinocandins, have now entered clinical trials. One, L-724,872 is owned by Merck, and the other, LY303366, by Lilly. As opposed to the azole antifungal drugs such as fluconazole or itraconazole which block fungal growth, echinocandins kill the fungi by interrupting the synthesis of ß-1,3 glucan, an integral part of the fungal cell wall (Kurtz 1996). In laboratory and animal studies, these new drugs show activity against azole-resistant Candida and other fungi (Friesen 1996, Pfaller 1996, Flattery 1996, Najvar 1996, Nelson 1996).

Merck's L-724,872 is not absorbed orally and must be given as a once-a-day intravenous infusion, which will limit the drug's use in clinical practice. Lilly's LY303366 is orally bioavailable however, and easily achieved blood levels over the MIC50 for Candida in one dose-ranging study (Lucas 1996). It also has a very long half-life, allowing for once a day dosing. Lilly is currently conducting a dose-ranging study of LY303366 in 160 people with HIV and oral candidiasis.

Many other antifungals also are in development, but it is too early to see whether they will be orally bioavailable. These include pradimicin (Gonzalez 1996), the pradamicin derivative BMS181184 from Bristol-Myers Squibb (Hoban 1996), SP-920704/nikkomycin z, from Shaman Pharmaceuticals, which blocks the synthesis of fungal chitin, used in making the exoskeletal structure of the fungal organism (Li 1996, Flores 1996); and synthetic peptides in development by XOMA Corp. which are reported to act earlier in the fungal life cycle than amphotericin B, but kill the fungus by increasing the permeability of the fungal cell wall (Lim 1996, Horwitz 1996; Appenzeller 1996).

*

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