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Gay Men's Health Crisis
Reports From Berlin: Opportunistic Infections Overview
Gabriel Torres, M.D.
September 1, 1993
GMHC Treatment Issues 1993 Sep 1; 7(8): 1

Opportunistic infections remain the most common cause of morbidity and death in persons with HIV disease. The expanding knowledge base on the management and prevention of opportunistic infections was evident at the Berlin conference; many presentations dealt with refinements in treatment and prophylaxis strategies, rather than epidemiological observations.

Epidemiology Update Dr. M. Flepp from the University Hospital in Zurich reported trends in the incidence of opportunistic infections (OIs) in a Swiss cohort of over 6,000 men and women with HIV who experienced an OI during 1985-91 and who had CD4 counts performed within two months of diagnosis.[1] Persons treated with zidovudine (AZT) developed OIs at lower CD4 cell levels compared with those who did not receive AZT. Since 1986 there has been a dramatic decline in the incidence of PCP, Candida esophagitis, herpes, Kaposi's sarcoma, and dementia, yet there has been an increase in CMV, MAI, and lymphoma.

Extracerebral Toxoplasmosis and Diagnosis Two presentations by French researchers demonstrated that toxoplasmosis can occur outside the brain (extracerebral) in a disseminated form, with parasites found in the eyes, lungs, blood, bone marrow, muscles, bladder, and heart. In one series, only 42 percent of cases had cerebral involvement.[2] Another report examined toxoplasmosis in the lungs.[3] Pulmonary toxoplasmosis presented most commonly when CD4 counts were less than 100 and was associated with fever, cough, shortness of breath, and septic shock in 12.5 percent. Fourteen percent had negative toxoplasma titers. Diagnosis was made by bronchoalveolar lavage (BAL) in most cases; others had parasites detected in the blood or other sites. In the cases with septic shock, serum LDH was elevated over 1,000. In 29 percent, extracerebral toxoplasmosis was the cause of death. Various poster presentations described new methods for diagnosis of toxoplasmosis including PCR, dot blot hybridization, in vitro production of toxoplasma antibodies, CSF culture on THP-1 cells, and direct immunofluoresence using anti-P30 monoclonal antibodies in human embryo lung fibroblasts.

New treatment strategies for toxoplasmosis A small study from Texas showed that tetracycline derivatives (in particular, doxycycline or minocycline) alone or in combination with pyrimethamine were effective in seven patients with toxoplamosis.[4] A larger multicenter study showed that atovaquone at a dose of 750mg four times daily was associated with clinical and radiological responses in patients with toxoplasmosis who were intolerant or failing standard therapy.[5] Response to atovaquone and survival in this study were related to plasma concentrations of the drug.

Toxoplasmosis Prophylaxis Various studies demonstrated that trimethoprim/sulfmethoxazole (T/S) is an effective prophylaxis for toxoplasmosis. In the ALPHA study, a European study which compared two doses of ddI, those receiving T/S developed toxoplasmosis at a significantly lower rate than those receiving aerosolized pentamidine (AP).[6] In this large trial, 68 percent of participants had positive toxoplasma serologies. Only one case of toxoplasmosis occurred in the group receiving T/S compared with 30 cases among those receiving AP. A large Italian study of 528 patients randomized to receive either aerosolized pentamidine or dapsone/pyrimethamine showed that toxoplasmosis developed more frequently in those on AP (24 cases) compared with those on D/P (two cases) after a median follow-up of 335 days.[7] Cryptosporidiosis Several studies were presented which evaluated the use of paromomycin or letrazuril for the treatment of cryptosporidial diarrhea. In one study from France, 24 patients with cryptosporidial diarrhea were treated with two grams of paromomycin for four weeks, followed by one gram per day for maintenance. After a mean follow-up period of seven months, a clinical response was observed in 22, with a mean weight gain of 2.7 kg. All responders had clearance of the parasite from the stool and/or intestinal biopsies. Six patients relapsed under maintenance therapy; four recovered after the dose of paromomycin was increased to two grams per day.[8] In a Canadian study, fifteen patients with cryptosporidiosis were treated with letrazuril in escalating doses of 50 to 100mg orally for up to six weeks.[9] Of fourteen evaluable patients, seven responded. Of the responders, five had a complete response (defined as eradication of the parasite from the stool and symptomatic improvement) and two had partial responses (defined as symptomatic improvement but persistence of the parasite in the stool.) Half of the patients developed a drug-related rash.

In a second Canadian letrazuril study, 4 percent of 24 patients had a complete response and 50 percent had a partial clinical response at a dose of 50 mg per day.[10] Half of patients relapsed 1.6 months after starting letrazuril; thus the investigators conclude that the effect of letrazuril was incomplete and transient.

A presentation made by French researchers described the natural history of cryptosporidiosis in 37 patients.[11] Forty-six percent of the patients had spontaneous resolution of the infection. Fifty-four percent of patients had worsening of disease with chronic diarrhea in 15 percent and death in 14 percent. A relationship of biliary involvement to poor prognosis was noted. Biliary involvement was defined as dilatation or thickening of the bile ducts on abdominal CT scans or sonograms.

Microsporidiosis Microsporidiosis was found in the respiratory tract of several patients studied by the Centers for Disease Control in the United States.[12] The microsporidia Encephalitozoan hellem was cultured in vitro from two patients and in several it was visually detected from sputum or BAL specimens using electron microscopy or fluorescent antibody staining. Other extraintestinal sites of microsporidiosis reported include the eye, the urinary tract, and the gall bladder. Nasal and ocular microsporidiosis can be diagnosed by scraping the conjunctival or nasal mucosa and staining with the Weber chromatrope stain or Gram stain.[13] Mycobacterium-avium complex (MAC) MAC infections received considerable attention at the Berlin conference. A symposium of leading MAC experts highlighted that MAC was rapidly becoming one of the leading infections in persons with advanced HIV disease in the United States, occurring in 15 to 24 percent of patients with AIDS. One presentation noted that laboratory measurements of resistance can be useful in the management of MAC infections. In one study of clarithromycin to treat MAC bacteremia, 90 percent of responders had MAC isolates which were sensitive to the drug at a minimum inhibitory concentration (MIC) of less than 2.0ug/ml compared with MICs greater than 32ug/ml in those who relapsed.

An observational study of 467 patients enrolled in CPCRA trials showed that the incidence of MAC increases as CD4 counts decrease. The development of MAC increased the risk of death by 2.3 times. Use of ethambutol or clarithromycin decreased the risk of death by 30 percent, better than other drugs, which decreased the risk by only 12 percent.[14] Another study looked at the effect of commonly prescribed drug regimens on survival in patients followed in a primary care clinic in New Orleans. The study found that no treatment regimens improved survival.[15] A poster showed that high-dose rifabutin (600mg/day) can be used to treat MAC bacteremia even in patients who break through rifabutin prophylaxis. The regimen of rifabutin, clofazimine, and ethambutol was more effective than ethambutol and clofazimine in this study group.[16] An ongoing Canadian trial compares rifampin, ethambutol, ciprofloxacin, and clofazamine with rifabutin, ethambutol, and clarithromycin given orally for sixteen weeks. Patients in the study have been stratified by prior rifabutin prophylaxis use. Seventy patients have been enrolled yet the study remains blinded.[17] There was little new information on MAC prophylaxis. Various posters showed that clarithromycin at doses of 250 to 1000mg/day was effective in preventing MAC infections in small groups of patients, yet these studies were uncontrolled and had relatively short lengths of follow-up.

In addition to MAC, another atypical mycobacterium, Mycobacterium genavense, has been found to cause disease in persons with AIDS in many European countries, Australia, and the United States. Patients with this infection had very low CD4 counts (an average of fifteen) and presented with massive weight loss, diarrhea, hepatomegaly, and abdominal pain. Two-thirds of the patients died within one year, despite treatment for mycobacteria.[18] Tuberculosis One-third of the population of the world is infected with tuberculosis and 8 million cases of active disease occur every year, accounting for 3 million deaths. Four to five million persons worldwide are co-infected with tuberculosis and HIV, 75 to 80 percent of whom are in Africa. In 1990, three percent of TB cases globally were HIV-related; by the year 2000, ten percent are estimated to be HIV-related.

Tuberculosis infection causes immune activation and can increase the rate of progression to AIDS. Patients with higher CD4 counts can develop TB, which is usually localized to the lungs and commonly smear-positive. As the CD4 count declines the presentation of TB may change, with more disseminated disease, miliary lung involvement, negative sputum smears, atypical chest x ray patterns, and false negative anergy tests. Reinfection has been demonstrated to occur in HIV-infected patients resulting in relapse after adequate treatment.

Several studies of tuberculosis among African patients with HIV infection were presented at the conference. In one large study from Rwanda, 89 percent of patients with tuberculosis were found to be HIV-positive. Features which distinguished HIV-positive patients with TB included more extrapulmonary involvement, disease in the middle and lower lobes of the lung, and anergy to PPD skin testing.[19] In another study from Cote d'Ivoire, HIV-positive patients with extrapulmonary TB were found to have lower CD4 counts than those with pulmonary TB.[20] Another double-blind placebo-controlled study demonstrated that isoniazid can reduce the rate of development of active tuberculosis by 50 percent - from 5.3/100 person-years to 2.3/100 person-years.[21] One study of supervised, intermittent short-course therapy with thrice weekly isoniazid, rifampin, ethambutol and pyrazinamide proved to be highly successful.[22] The study was performed in Haiti and included 117 HIV-positive and 310 HIV-negative patients with tuberculosis. Eighty-two percent of the HIV-positive and 91 percent of the HIV-negative TB patients completed more than 80 percent of the therapy, yet the death rate among the HIV-positives was higher (9 percent) than in the HIV-negatives (1 percent). Proven cures (negative AFB smears and cultures and radiologic resolution of disease) were more common among the HIV-negative patients. Relapses were equally common in both groups. Among the HIV- positives, those who died had a lower CD4 count than those who survived eighteen months.

Several presentations described outbreaks of multi-drug-resistant TB in the United States, mostly in New York City, New Jersey, and Florida. In New York in 1991, 7 percent of newly diagnosed TB cases and 30 percent of previously treated TB patients were resistant to isoniazid and rifampin. One outbreak among 38 patients in a NY hospital revealed a short incubation period of 1.5 to six months and survival of only nineteen weeks.[23] Survival was better among those who received within two weeks at least two drugs to which the organism was susceptible. Another study of susceptibilities of TB isolates in a different NY hospital found that only six and seven drug regimens would confer greater than 90 percent effectiveness as initial regimens.[24] Cytomegalovirus Various studies investigating new treatment strategies for cytomegalovirus retinitis were presented. One compared two dose regimens of foscarnet (90mg/kg twice daily versus 60mg/kg three times daily) for induction therapy among 87 Italian patients with CMV retinitis.[25] Both dosage regimens were equally effective in arresting CMV and side effect profiles were similar. In another comparative study, patients with CMV gastrointestinal disease were randomized to either ganciclovir or foscarnet.[26] Endoscopic and symptomatic improvements were similar in both groups, though the toxicities were different.

A pilot study of SDZ MSL 109, a human monoclonal anti-CMV antibody, given in combination with either ganciclovir or foscarnet for maintenance therapy of CMV retinitis, proved to be safe and well-tolerated.[27] The time to retinitis progression was longer than had been seen in patients who received monotherapy with foscarnet or ganciclovir.

A phase I trial of HPMPC, a new anti-CMV agent being investigated by Gilead Sciences at the National Institutes of Health and in San Francisco, showed that the drug led to renal toxicity at a dose of 5mg/kg twice daily.[28] Urine cultures of two patients who received this dose showed transient clearance of the virus.

Fungal Infections Fungal infections received considerable attention at the conference and some useful clinical information was made available to clinicians to bring back to their patients.

Trials using itraconazole, the new azole marketed as Sporonox, were presented which show it is a useful alternative to the other azoles, such as fluconazole, and may have some advantages. One trial from Rwanda compared itraconazole (200mg per day) with amphotericin B (0.75mg/kg/day) for primary therapy of cryptococcal meningitis.[29] Ninety-two patients with newly diagnosed cryptococcal meningitis were randomized to either regimen for six weeks. Survival at eight weeks was similar with both drugs, yet amphotericin B was more effective in clearing cryptoccoccus from the cerebrospinal fluid. A study of a cyclodextrin solution formulation of itraconazole (100 or 200mg twice daily) showed that it was effective in two-thirds of persons with oral or esophageal candidiasis refractory to treatment with fluconazole, ketoconazole or itraconazole capsules.[30] Dr. Marcus Conant reported at a satellite symposium on fungal diseases that itraconazole is effective for onychomycosis (finger- and toenail infections by dermatophytes) with pulse doses of 100mg twice daily for seven days, one week per month. He also reported success in treating eosinophilic folliculitis, a condition caused by the fungus Pityrosporum ovale, with 200mg twice daily of the drug. Another study evaluated the use of high doses of fluconazole alone or in combination with flucytosine for cryptococcal meningitis.[31] Doses of fluconazole used were 800mg, 1200mg or 1600mg/day with or without flucytosine 150mg/kg/day. Response rates were 71 to 80 percent in the flucytosine-containing regimens compared to 25 to 38 percent in the fluconazole alone groups. Another study from UCLA examined the use of in vitro susceptibility assays to determine whether cryptococcus has developed fluconazole resistance. This assay can be used to determine which patients should receive amphotericin for primary therapy of cryptococcal meningitis. A small study of fluconazole (50mg three times weekly) versus intense monitoring for candidiasis in women showed that 35 percent of those receiving intense monitoring developed candidal infections compared to 6 percent of those receiving fluconazole.[32] Multiple poster presentations also described the rising incidence of fluconazole-resistant candidiasis in advanced HIV-positive patients maintained on long-term fluconazole therapy. Resistant strains of Candida albicans and the emergence of less sensitive Candida strains such as C. krusei, C. tropicalis and C. glabrata were commonly observed.

Another fungal infection which received considerable attention was Aspergillus fumigatus, a fungus found to cause pulmonary disease, sinusitis, external and middle ear disease, and brain and muscle abscesses in patients with AIDS. Predisposing factors for invasive aspergillosis may include neutropenia, previous pulmonary disease (especially PCP), use of antibiotics, marijuana use, and corticosteroids.[33] Pulmonary disease may manifest as thin walled cavities in the upper lobes, nodules, or lower lobe infiltrates. Treatment is with amphotericin B or itraconazole. In one open study of itraconazole (400mg per day), 28 percent had complete responses by the end of the treatment.

Penicillium marneffei is a new fungal infection which has rapidly become one of the major opportunistic infections in southeast Asia, especially in Thailand, China, Hong Kong, and Vietnam. In Thailand alone, 140 cases have been diagnosed thus far. Patients typically present with fever, anemia, weight loss, skin lesions, cough, lymphadenopathy, hepatomegaly, or papules on the palate. The skin rash usually involves the face, ears, upper trunk, and arms and may have a necrotic umbilication. The fungus may be isolated from blood, skin or bone marrow biopsy cultures. Untreated, mortality is 100 percent, whereas 75 percent respond to amphotericin B or itraconazole within two to three weeks.

1 Flepp M, et al. Abstract WS-B01-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

2 May TH, et al. Abstract WS-B13-1. Ninth International AIDS Conference, Berlin. June 6-11, 1993.

3 Rabaud C, et al. Abstract WS-B14-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

4 Blockman KW, et al. Abstract PO-B10-1427. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

5 Torres R, et al. Abstract PO-B10-1453. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

6 Tournerie C, et al. Abstract WS-B13-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

7 Opravil M, et al. Abstract PO-B10-1429. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

8 Bissuel F, et al. Abstract WS-B13-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

9 Harris M, et al. Abstract WS-B13-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

10 Walach C, et al. Abstract PO-B10-1472. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

11 Gerard L, et al. Abstract WS-B13-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

12 Schwartz DA, et al. Abstract WS-B14-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

13 Schwartz DA, et al. Abstract PO-B10-1440. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

14 Church T, et al. Abstract WS-B10-6 Ninth International AIDS Conference. Berlin. June 6-11, 1993.

15 Bucher G, et al. Abstract WS-B10-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

16 Sullam P, et al. Abstract PO-B07-1238. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

17 Shafran SD, et al. Abstract WS-B10-5. Ninth International AIDS Conference. Berlin June 6-11, 1993.

18 Pechere M, et al. Abstract WS-B10-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

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

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

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

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

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

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

25 Carosi G, et al. Abstract WS-B11-3. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

26 Blanshard C, et al. Abstract WS-B11-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

27 Tolpin M, et al. Abstract WS-B11-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

28 Polis M, et al. Abstract WS-B11-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

29 Taelman H, et al. Abstract WS-B12-3. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

30 Cartledge JD, et al. Abstract Ws-B12-2. Ninth International AIDS Conference. Berlin. June 6-11,1993.

31 Milefchik E, et al. Abstract WS-B12-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

32 Fiore TR, et al. Abstract PO-B09-1369. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

33 Tumbarello M, et al. Abstract PO-B09-1382. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

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