TREATMENT ISSUES, Volume 6, Number 9 - October 1992; The Gay Men's Health Crisis Newsletter of Experimental Therapies
Gabriel Torres, M.D.

MYCOBACTERIUM AVIUM COMPLEX

Studies about the epidemiology of Mycobacterium avium complex (MAC)--an AIDS-defining opportunistic infection (OI) that causes fevers, night sweats, and severe diarrhea--have demonstrated that the infection occurs more commonly in patients with advanced HIV disease and low T4 cell counts. In one study MAC occurred in 18% of patients with T4 counts less than 50 and in almost 14% of patients with T4 counts between 50-100. One large study of 1,006 patients showed that MAC infection developed in 21% of patients one year after AIDS was originally diagnosed and in 43% within two years of diagnosis. Of this latter group, 39% with T4 cell counts under 10 developed the infection.[1]

MAC TREATMENT

Several researchers revealed new data concerning the treatment of MAC infection. Dr. Richard Chaisson, of Johns Hopkins University, presented a study comparing three doses of clarithromycin (500 mg, 1000 mg, or 2000 mg twice daily) as a single agent in the treatment of MAC.[2] The majority of the patients with evidence of MAC infection in this study became negative when tested after treatment with clarithromycin. The median time to infection-free blood by using the 2000 mg/twice daily regimen was 27 days compared with 55 days with the 500 mg/twice daily regimen, and 43 days with the 1000 mg/twice daily regimen. Fevers and night sweats improved in 47%-76% of patients. Resistance to clarithromycin was demonstrated in the test tube in blood samples from 22% of patients after 10-12 weeks of treatment. There was no association between the different doses and the development of resistance. The most common side effect of clarithromycin was nausea and vomiting, which occurred more commonly at the higher doses.

In an Abbott-sponsored expanded access program of clarithromycin, the 1000/mg twice daily dose was associated with improved survival. Additionally, three other smaller studies indicate that clarithromycin monotherapy is effective in eradicating MAC from the blood, yet is hampered by the development of resistance. Further studies will test clarithromycin in combination with other agents to prevent such resistance. Another study evaluated ethambutol, rifampin and clofazimine -- each used singly -- and found that only ethambutol reduced the amount of MAC in the body, making it a possible agent for combination regimens.[3]

MAC PROPHYLAXIS

Various studies presented at the conference showed that rifabutin is effective in preventing MAC bacteria infection. One study presented by Dr. William Cameron from Canada compared rifabutin (300 mg/day) to placebo in 556 patients with AIDS and T4 cell counts less than 200. All patients were on antiretroviral therapy and PCP prophylaxis. Mean T4 cell counts were 61 for the rifabutin recipients and 55 for the placebo recipients. Patients were followed for 176 182 days. Twenty-four patients in the rifabutin arm developed MAC compared to 50 in the placebo arm. Survival was similar between both groups. Side effects of rifabutin included urine discoloration and occasional rashes. Fever and fatigue occurred more commonly among the placebo recipients, and rifabutin seemed to prevent declines in performance status.

In another similar study presented in a report by Dr. Fred Gordin from the Veterans Administration Medical Center in Washington, D.C., MAC infection occurred in 9% of patients taking rifabutin, compared to 15% of patients taking placebo.[4] The time for a MAC infection to occur and the length of MAC-free survival were prolonged in patients on rifabutin. However, no difference in survival was noted between the two groups. Side effects of rifabutin in this study included a few cases of neutropenia (lowered neutrophil cell counts) and muscular and joint pain. Rifabutin did not affect liver function tests in either of the two large placebo controlled studies. A final study conducted by the San Francisco Community Consortium showed that clofazimine (50 mg/day) was ineffective in preventing MAC infection. Of 99 patients taking either the drug or a placebo, seven taking clofazimine developed MAC compared to six patients taking a placebo, after a mean follow-up of less than ten months.[5]

PNEUMOCYSTIS CARINII PNEUMONIA (PCP)

Two new treatments for PCP showed encouraging results compared to the standard treatment, which is Bactrim or Septra (TMP/ SMX). Dr. Emil Toma from Canada reported on the combination use of clindamycin/primaquine compared to TMP/SMX in a doubleblind, randomized trial of 56 patients with first episodes of pcp.[6] The dose of clindamycin was 600 mg every six hours intravenously for ten days followed by 450 mg every six hours orally. The dose of primaquine was 15 mg/day. The combination of clindamycin / primaquine was 92% effective compared to TMP/ SMX, which was 90% effective. Survival was similar in the two groups. Toxicity was less frequent and severe with clindamycin/primaquine, and shortness of breath resolved more quickly (within three days).

Another comparative trial was presented by Dr. Walter Hughes from St. Jude's Children's Research Hospital in Memphis, Tennessee.[7] This trial compared 566c80, also called atoraquone, an oral Burroughs Wellcome drug, with TMP/SMX in 322 patients with mild-moderate PCP. In patients with mild PCP, both drugs were similarly effective (63%) in successfully treating PCP. More toxicity (19%) was noted in the TMP/SMX group. But more treatment failures (18% v. 7%) were observed in the 566c80 group. Similar findings were seen in the group of patients with moderate PCP. Survival was slightly better with TMP/SMX (99%) than with 566c80 (93%) within four weeks of completing therapy. People with diarrhea who were taking 566c80 seemed to have shorter survival times. This may be related to poor absorption of 566c80 in patients with diarrhea.

PCP PROPHYLAXIS

Various studies presented in Amsterdam reported new information on the prevention of PCP. Dr. Margaret Schneider from the Netherlands presented a comparative study of aerosolized pentamidine (AP) and TMP/SMX for the primary prevention of PCP in patients with less than 200 T4 cells.[8] AP was given at a dose of 300 mg once monthly and was compared to either double-strength or single-strength TMP/SMX given once daily. Both doses of TMP/SMX were more effective and resulted in no episodes of PCP, compared to 16 episodes in the group taking AP. However, no difference in survival was noted. In another large multicenter European trial, the combination of dapsone (50 mg daily) and pyrimethamine (50 mg weekly) given with folinic acid (25 mg weekly) was compared to AP (300 mg monthly) in patients with less than 200 T4 cells. Barely a year into the trial, which had by then enrolled 362 patients, researchers decided to stop the study because the dapsone/pyrimethamine arm showed a benefit in the prevention of toxoplasmosis. Notably, no differences in the prevention of PCP occurred (ten cases of PCP developed in each arm). However, 19 cases of toxoplasmosis occurred in the dapsone/pyrimethamine arm, compared to 32 in the AP arm. Death rates were similar in both arms. More patients had to discontinue dapsone/pyrimethamine (42) than AP (3) due to side effects, including skin rashes, neutropenia, fever, and anemia. Patients who discontinued dapsone/pyrimethamine ran a high risk of developing toxoplasmosis. Finally, one related report showed that 67% of patients with a history of allergy to TMP/SMX were successfully treated with dapsone.[9]

CYTOMEGALOVIRUS (CMV) AND HIV

CMV received attention at the conference as a potential co-factor in the progression of HIV disease and as a virus causing serious disease, such as retinitis and colitis. In one observational study of 1,002 persons with AIDS or ARC and T4 cell counts under 250 who were treated with AZT and followed for two years, CMV disease developed in 109 (11%) during follow-up.[10] Median survival after a diagnosis of CMV was 173 days. A baseline T4 cell count of less than 100 was associated with the development of CMV. Previous anemia, neutropenia, or herpes infections were also associated with the development of CMV.

Several studies seemed to indicate that the presence of CMV infection was associated with a higher risk of developing AIDS. In one study by Dr. Roger Detels from UCLA, semen specimens were studied in a group of 164 HIV-positive men enrolled in the Multicenter AIDS Cohort Study (MACS).[11] Those who had CMV detected in the semen progressed to AIDS twice as fast as those who did not have CMV; these same participants were more likely to develop Kaposi's sarcoma (KS) or lymphoma. In another study from a group in Houston led by Dr. Sally Stroud, PCR tests were used to detect CMV in a group of 100 HIV-positive men.[12] After 14 months, 47% of the participants who evidenced CMV progressed to AIDS, compared to only 22% of those in whom CMV could not be detected. Mortality was greater among the CMV-positive participants (78%), compared to the CMV-negative participants (15%). This study may suggest that intervention with anti-CMV therapies may influence survival and disease progression.

CMV TREATMENT

Various studies examined ganciclovir and foscarnet as treatments for CMV disease. Dr. Henry Balfour from the University of Minnesota, after a review of several trials, concluded that while both drugs are 75%-80% effective in arresting CMV retinitis, most patients still experience disease progression despite maintenance therapy. Additionally, most patients have less than 30 T4 cells at the time of diagnosis of CMV retinitis. A previous trial, published earlier this year, had shown that foscarnet therapy was associated with a four-month survival advantage over ganciclovir, though both drugs were equally effective in treating CMV retinitis.[13] Dr. Judy Feinberg from Johns Hopkins University commented that though there was a four month survival advantage, patients on foscarnet spent 17% of that additional time receiving foscarnet infusions, which may negatively affect their quality of life.

Dr. Catherine Katlama from France stated that twice-daily infusions of foscarnet are less toxic than three-times-daily infusions and just as effective. She recommended the use of isotonic saline (1000-1500 cc/day for induction, or 500-1000 cc/day for maintenance) to prevent some of the kidney toxicities of foscarnet. Increasing the infusion time also seemed to help prevent the abnormally low levels of calcium caused by the drug. One trial from Germany presented by Dr. Peter Maltes showed that the combination of ganciclovir and foscarnet was effective in the acute treatment of CMV disease.[14] Ten patients received the combination (at the usual doses) for three weeks followed by maintenance therapy with both drugs alternated every other day. One patient developed acute kidney failure during the induction and discontinued treatment. Eight patients had a positive response to the treatment during the induction phase. During the maintenance phase, three patients with CMV retinitis developed disease at a median interval of 42 days.

One experimental therapy presented in a poster was the use of liposomal ganciclovir injected directly into the eye.[15] One patient who had ganciclovir-induced neutropenia received one injection which prevented reactivation of retinitis for at least 20 days.

HERPES SIMPLEX VIRUS (HSV)

Foscarnet is the therapy of choice for acyclovir-resistant HSV, although long-term maintenance therapy with the drug is required. Another promising topical therapy for this condition, presented by Dr. Harold Kessler from Rush Medical College, is with a drug called trifluridine.[16] The drug is usually used to treat herpetic eye infections. In an open label trial, 12 patients were treated with trifluridine applied directly to herpes lesions three times per day for 10-42 days. Eight patients responded and six experienced complete healing of lesions, within 42 days. The drug was administered as a 1% ophthalmic solution applied as a thin film and covered with bacitracin/polymyxin ointment and a non-absorbent dressing. The overall response rate to this therapy was 68%, and no toxic side effects were observed. Five patients developed satellite lesions which required treatment off protocol. However, since the treatment is not systemic, careful observation for additional lesions is advised.

CRYPTOSPORIDIOSIS

New information on cryptosporidiosis was presented in Amsterdam by Dr. Brian Gazzard from London. Diarrhea associated with the disease seems to occur in three patterns, including transient (randomly appearing and disappearing), chronic (continuing indefinitely), and fulminant (occurring suddenly and violently). These three patterns are associated with worsening survival times (60, 24 and 7 weeks, respectively). Stool concentration and small bowel biopsy remain the diagnosing tests available. Abnormal liver function tests in one retrospective series were associated with inflammation of the bile duct, pancreas and gall bladder in patients with cryptosporidiosis.[17] Dr. Gazzard stated that heating water inhibits cryptosporidia, therefore boiling water may be a preventive strategy for patients with T4 cells less than 200.

Aminosidine sulfate was administered in a small trial at a dose of 2000 mg/day to 34 patients with cryptosporidiosis at St. Mary's Hospital in London.[18] Among 18 evaluable patients, nine cleared the disease-causing organisms from their stool. The number of bowel movements in these patients decreased from five per day to approximately two per day. Side effects from the drug included headache in one patient and a rash in another. In a second small series of four patients with cryptosporidiosis, letrazuril was given at a dose of 50 mg/day for 6 weeks.[19] Stool frequency decreased from 11 per day to four per day after six weeks. Cryptosporidia cleared transiently from the stool in two patients, yet all patients relapsed after three months. None was receiving maintenance therapy. Roxithromycin was effective in reducing cryptosporidial diarrhea in four patients treated with a dose of 300 mg/day for two weeks.[20] Three of four patients also cleared the organism from their stool.

Finally, a study of the sandostatin analog, SMS 201-995, found the drug to be useful in decreasing the frequency of bowel movements in ten of 12 patients with cryptosporidial diarrhea who had failed all other therapies.[21] Overall survival for patients with cryptosporidiosis seems to have improved slightly. In one study of 66 patients, median survival was ten months, compared to previous reports which had shown an average survival of six months.[22]

MICROSPORIDIOSIS

Microsporidia received some attention at the conference, since various presentations implicated these organisms as the cause of diarrhea in 32%-50% of pathogen-negative diarrhea.[23] Several studies showed that the T4 counts of patients with microsporidia are usually less than 50. Dr. Douglas Dieterich presented a report of 24 patients treated with albendazole (400 mg twice daily) in an open pilot study. Twenty-two patients had E. bieneusi and two had the "new species," called E. cuniculi and E. hellem. Of 12 evaluable patients, 45% had a reduction in stool frequency, and the microsporidia were not found in small bowel biopsy specimens, after a course of albendazole for one month. Weight increased by an average of 7.5 lbs after a follow-up of almost four months.

PML

Only one study of PML was presented at the conference, by Dr. Carolyn Britton from Columbia University.[24] She used Ara-C (cytosine arabinoside) administered into the spinal cord in 13 patients with confirmed PML. Eight patients stabilized and improved; four stabilized for a period of up to two years, and four patients stabilized for a period of up to six months. Non-responders had larger lesions, major neurological deficits, and brainstem disease. She also described five patients who stabilized on AZT therapy and two who stabilized without AZT. Four additional patients had rapid disease progression despite AZT therapy and had a survival of only four to five months.

TOXOPLASMOSIS

A natural history study described the survival of patients after a diagnosis of toxoplasmosis as being an average of 320 days.[25] No difference in survival was noted between those treated with sulfadiazine/pyrimethamine (260 days) and those treated with clindamycin/pyrimethamine (280 days). Those patients who had to be switched from sulfadiazine/pyrimethamine to clindamycin/pyrimethamine survived an average of 360 days. One large study of Navy and Marine Corps personnel showed that cat ownership was not related to toxoplasmosis infection as measured by seroconversion.[26]

The combination of dapsone (100 mg/day) and pyrimethamine (25 mg/day) was effective in six patients without significant toxicities.[27] The drug 566c80 was proven effective in one study from New York in reducing and stabilizing the size of toxoplasmic brain lesions and in preventing the development of new lesions in 11 of 14 patients treated with the drug at a dose of 750 mg four times daily for six weeks.[28] A final study of azithromycin at doses of 1200 mg/day, found the drug to be ineffective in two patients. However, the combination of 566c80 and pyrimethamine was effective in two of four patients who had failed 566c80 alone.

TOXOPLASMOSIS PROPHYLAXIS

In one French study comparing various maintenance regimens, pyrimethamine/sulfadiazine was superior to either pyrimethamine alone or pyrimethamine/clindamycin in preventing recurrences of disease.[29] Clindamycin was not tolerated because of toxicities (rashes and diarrhea) in over 40% of patients. Primary prophylaxis proved to be effective in various studies with fansidar,[30] dapsone,[31] dapsone/pyrimethamine,[32] trimethoprim/sulfamethoxazole,[33] and high-dose pyrimethamine (50 mg/day).[34] Studies seem to confirm that patients receiving either TMP/SMX or dapsone with or without pyrimethamine for PCP prophylaxis developed toxoplasmosis less frequently than those taking AP maintenance therapy.

CANDIDIASIS

In one Mexican study the risk of progression to AIDS among 64 HIV-positive patients with oral candidiasis and oral hairy leukoplakia was 26% at 12 months, 46% at 18 months, and 68% at 24 months.[35] In another study it was determined that oral candidiasis and oral hairy leukoplakia occur at the same rate after seroconversion.[36] Both of these studies suggest that the presence of these oral lesions should be used as endpoints to indicate disease progression in clinical trials.

An association between candidiasis and cigarette smoking was discovered.[37] In a study of 135 HIV-positive women at Brown University, vaginal candidiasis was observed in 41% of the women with a mean T4 count of 424. Notably, vaginal thrush occurred earlier in HIV disease than oral thrush, which was found in 25% of the women with T4 counts of about 185.[38]

One German study evaluated 69 patients with recurrent candidiasis receiving fluconazole (100 mg twice weekly) for prophylaxis.[39] Twenty-two percent of patients on this regimen relapsed with oral and/or esophageal candidiasis. Resistant strains did not occur, but culture of oral swabs revealed positive results in 60%, indicating that prophylaxis was not effective in eradicating the organism. One patient also developed cryptococcosis.

CRYPTOCOCCOSIS

Dr. Michael Saag reported that the overall incidence of cryptococcal disease in AIDS patients was 7%, with a mortality of 14%. He recommended the use of higher doses of amphotericin (0.7-0.8 mg/kg) for the initial two weeks of therapy followed by either fluconazole or itraconazole. A report from the Community Based Clinical Trial Network's Observational Data Base found a gender difference im the occurrence of the disease. In fact, of the 4,080 participants in the study, cryptococcosis was reported in 9% of men and 20% of women. Cigarette smoking was found to increase the risk of cryptococcal meningitis; 12 of 16 cases of cryptococcal meningitis reported cigarette smoking within 30 days prior to the diagnosis compared to two control groups.[41]

The combination of fluconazole (400 mg/day) and 5-flucytosine cleared the infection from the brain in 72% of patients in one study. New agents that appear promising in the therapy of cryptococcosis include liposomal amphotericin (Ambisome) and amphotericin lipid complex. The latter cleared the fungus in eight of 12 patients after 6 weeks of therapy.[42] The higher dose used (5 mg/kg/day) was most effective. In a small German trial of liposomal amphotericin, 18 of 20 patients were cured or improved with an eradication of the fungus in 65% of those taking the drug.[43]

FOOTNOTES ---------

1. Nightingale S et al. Incidence of MAI complex bacteria in HlV-positive patients. J Infec Dis 165:1082 5,1992.

2. VIII Int'l Conf on AIDS, Abstract # We B 1052, Amsterdam, July, 1992.

3. VIII Int'l Conf on AIDS, Abstract # Po B 3087, Amsterdam, July, 1992.

4. VIII Int'l Conf on AIDS, Abstract # Po B. 3081, Amsterdam, July, 1992.

5. VIII Int'l Conf on AIDS, Abstract # PoB. 3345, Amsterdam, July, 1992.

6. VIII Int'l Conf on AIDS, Abstract # WeB. 1020, Amsterdam, July, 1992.

7. VIII Int'l Conf on AIDS, Abstract # WeB. 1019, Amsterdam, July, 1992.

8. VIII lnt'l Conf on AIDS, Abstract # WeB.1018, Amsterdam, July,1992.

9. VIII Int'l Conf on AIDS, Abstract # PoB. 3301, Amsterdam, July, 1992.

10. VIII Int'l Conf on AIDS, Abstract # PoB. 3834, Amsterdam, July, 1992.

11. VIII Int'l Conf on AIDS, Abstract # PoB. 3325, Amsterdam, July, 1992.

12. VIII Int'l Conf on AIDS, Abstract # PoB. 3354, Amsterdam, July, 1992.

13. Mortality in patients with AIDS treated either with foscarnet or ganciclovir for CMV retinitis, NEMS 326 (4): 213-20,1992.

14. VIII Int'l Conf on AIDS, Abstract # WeB. 1054, Amsterdam, July, 1992.

15. VIII Int'l Conf on AIDS, Abstract # PoB. 3131, Amsterdam, July, 1992.

16. VIII Int'l Conf on AIDS, Abstract # WeB. 1056, Amsterdam, July, 1992.

17. VIII Int'l Conf on AIDS, Abstract # PoB. 3220, Amsterdam, July, 1992.

18. VIII Int'l Conf on AIDS, Abstract # PoB. 3229, Amsterdam, July, 1992.

19. VIII Int'l Conf on AIDS, Abstract # PoB 3257, Amsterdam, July, 1992.

20. VIII Int'l Conf on AIDS, Abstract # PoB 3209, Amsterdam, July, 1992.

21. VIII Int'l Conf on AIDS, Abstract # PoB. 3212, Amsterdam, July, 1992.

22. VIII Int'l Conf on AIDS, Abstract # PoB. 3239, Amsterdam, July, 1992.

23. VIII Int'l Conf on AIDS, Abstract # PoB. 3340, # PoB. 3223, Amsterdam, July, 1992.

24. VIII Int'l Conf on AIDS, Abstract # Th B 1512, Amsterdam, July, 1992.

25. VIII Int'l Conf on AIDS, Abstract # PoB. 3224, Amsterdam, July, 1992.

26. VIII Int'l Conf on AIDS, Abstract # PoB 3275, Amsterdam, July, 1992.

27. VIII Int'l Conf on AIDS, Abstract # PoB. 3277, Amsterdam, July, 1992.

28. VIII Int'l Conf on AIDS, Abstract # PoB. 3185, Amsterdam, July, 1992.

29. VIII Int'l Conf on AIDS, Abstract # PoB 3218, Amsterdam, July, 1992.

30. VIII Int'l Conf on AIDS, Abstract # PoB 3230, Amsterdam, July, 1992.

31. VIII Int'l Conf on AIDS, Abstract # PoB 3244, Amsterdam, July, 1992.

32. VIII Int'l Conf on AIDS, Abstract # WeB 1017, Amsterdam, July, 1992.

33. VIII Int'l Conf on AIDS, Abstract # PoB 3312, Amsterdam, July, 1992.

34. VIII Int'l Conf on AIDS, Abstract # PoB 3198, Amsterdam, July, 1992.

35. VIII Int'l Conf on AIDS, Abstract # ThB. 1577, Amsterdam, July, 1992.

36. VIII Int'l Conf on AIDS, Abstract # PoB. 3369, Amsterdam, July, 1992.

37. VIII Int'l Conf on AIDS, Abstract # PoB. 3362, Amsterdam, July, 1992.

38. VIII Int'l Conf on AIDS, Abstract # PoC 4371 Amsterdam, July, 1992.

39. VIII Int'l Conf on AIDS, Abstract # PoB. 3252, Amsterdam, July, 1992.

40. VIII Int'l Conf on AIDS, Abstract # PoC 4356, Amsterdam, July, 1992.

41. VIII Int'l Conf on AIDS, Abstract # PoB. 3172, Amsterdam, July, 1992.

42. VIII Int'l Conf on AIDS, Abstract # PoB. 3132, Amsterdam, July, 1992.

43. VIII Int'l Conf on AIDS, Abstract # PoB. 3156, Amsterdam, July, 1992.

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