GMHC Treatment Issues; September 1, 1996
Michael Marco

Viral Infections: CMV

--Oral Ganciclovir for CMV Prophylaxis

The CMV symposium was mostly comprised of clinical trial data (follow-up and final analyses) which had been presented at previous AIDS meetings. The two most interesting (and competing) studies presented were Syntex/Roche Study 1654 by Steve Spector, M.D., (abstract Th.B.302) and CPCRA 023 by Carol Brosgart, M.D. (abstract Th.B.301). In a nut shell, Syntex/ Roche 1654 demonstrated that oral ganciclovir was approximately 50% better than placebo in preventing CMV retinitis, and CPCRA 023 found that there was no statistically significant benefit of oral ganciclovir over placebo.

Dr. Brosgart's presentation was much anticipated because she was going to reveal the "reason" why oral ganciclovir "didn't work." After a run-through of the basic study data, Dr. Brosgart revealed the reason: ddI. Patients on the placebo arm who were taking ddI (alone or in combination with other antivirals) had a very low rate of developing CMV: 64 of the patients in the placebo arm were taking ddI and only one developed CMV disease. Conversely, patients in the oral ganciclovir arm who were on ddI had a high probability of developing CMV disease.

Of note, Dr. Spector reported that the Syntex/Roche 1654 team did a post hoc analysis of all patients taking ddI but did not find the same results seen in CPCRA 027. Dr. Brosgart stood by her team's analysis but cautioned that the results should be interpreted carefully and that the supposed negative ddI and oral ganciclovir interaction should be investigated further. Other groups have previously noted that 1) ganciclovir decreases ddI's anti-HIV effect -- possibly by reducing cellular conversion of ddI into its active form within the cell1 -- and 2) sequential co-administration of ddI and ganciclovir reduces blood levels of ganciclovir.2

Dr. Spector's presentation focused on the fascinating (yet depressing) virology data of 619 of the 725 patients from Roche/Syntex 1654. This was one of the first CMV prophylaxis trials with a CMV DNA PCR (viral load) sub-study. (Note: This is cytomegalovirus viral load not HIV viral load.) Out of all patients who were CMV PCR positive at study entry (approximate 45% in both arms), CMV disease developed in 43% of the placebo patients and 26% of the oral ganciclovir patients. Among the CMV PCR-negative patients at study entry, CMV disease developed in 1% of the oral ganciclovir patients and 14% of the placebo recipients, a highly significant difference.

Quantitatively, CMV PCR-positive patients were stratified by their CMV viral load count into three groups, those with: less than 2,500 copies; 2,500-50,000 copies; and 50,000 to 150,000 copies. The patients with CMV counts below 50,000 benefited from oral ganciclovir: 20% of the oral ganciclovir patients developed CMV disease versus 40% of those on placebo. For those with CMV loads more than 50,000, oral ganciclovir's protective effect was no better than placebo. Of note, there were ten patients with over 150,000 copies (all randomized to the oral ganciclovir arm), all of whom went on to develop CMV disease.

Hence, this viral load sub-study tells us three things: 1) a CMV PCR-negative patient can benefit from oral ganciclovir, (although that patient only has a 14% chance of developing CMV if he/she took nothing); 2) if a patient is PCR-positive and has a low viral load (less than 50,000 copies) he or she could get some benefit by using oral ganciclovir; and 3) if a patient has high viral load (over 50,000 copies), oral ganciclovir will not help. It is possible that some other drug will prevent the onset on CMV disease in a patient with high CMV load. In the meantime, perhaps such patients should receive preemptive intravenous therapy, even when there is no retinitis.

--Oral Ganciclovir for Maintenance CMV Therapy

Jay Lalezari, M.D., of San Francisco (filling in for Dorothy Friedberg, M.D.) presented data from Syntex/Roche study 2226, a trial comparing three doses of oral ganciclovir (3, 4.5, or 6 grams) with IV ganciclovir (5 mg/kg daily) for CMV maintenance therapy (abstract Th.B.305). The median time to first progression was 41 days for 3 grams; 50 days for 4.5 grams; 57 days for 6 grams; and 70 days for IV treatment. The difference in time to progression between the low dose arm versus the IV arm was statistically significant.

These are important -- yet disquieting -- results. The 3 grams dose is what is currently recommended to thousands of patients, but it is not as effective as higher oral doses or using IV ganciclovir. Moreover, 3 grams is twelve pills a day and costs at least $15,000 a year. If one is to start taking 6 grams a day, that would be an impractical 24 pills a day costing over $30,000 a year.Hoffmann-La Roche at present is developing a 500 mg capsule to reduce the number of required pills. The price needs reducing, too.

Bacterial Infections: MAC

The MAC symposium also was comprised of clinical trial data which had mostly been presented at previous AIDS meetings. The two most important studies presented, ACTG 196 (clarithromycin versus rifabutin versus a combination of the two for MAC prophylaxis) and the Canadian MAC treatment study CTN 010 (a combination of three drugs versus four) have been detailed in Treatment Issues (October 1995, pages 2-3).

--High Dose Clarithromycin Yields Excess Mortality

Of interest, and eliciting considerable protest by ACT UP, were the results (and their subsequent mishandling) of CPCRA 027 (abstract: LB.B.6025). CPCRA 027 was a MAC treatment study comparing two doses of clarithromycin (500 mg twice a day versus 1000 mg twice a day) in combination with other agents. This study was stopped early because a high mortality rate was observed in the group of patients receiving 1000 mg twice a day. As of February 6, ten of 45 (22%) patients in the 500 mg arm had died versus 17 out of 40 (43%) patients in the 1000 mg arm, a significant difference. No plausible explanation was given for this increase in mortality; to this date these findings still puzzle the principal investigators and statisticians. These findings of increased mortality with high-dose clarithromycin are similar to those observed in two previous MAC treatment trials.3 CPCRA 027 -- a study some believe to have been unethical from its inception -- was, in part, conducted in order to confirm or disprove those earlier findings of higher mortality.

Azithromycin Helps Prevent MAC and boosts PCP Prophylaxis

While the full data set of the azithromycin MAC prophylaxis study (MOPPS study 006-174) was not presented in Vancouver, analysis of its Pneumocystis carinii pneumonia (PCP) sub-study was detailed by Dunne and colleagues (abstract: Tu.B.410). This sub-study analyzed the incidence of PCP among rifabutin recipients versus those receiving azithromycin-containing regimens in this MAC prophylaxis trial of 693 patients with under 100 CD4 cells. With 95% of the patients on PCP prophylaxis (58% on TMP-SMX; 18% on dapsone, 19% on aerosolized pentamidine), 22.7% of those in the rifabutin arm developed PCP compared to 10.9% of those in the azithromycin arms. Thus, it is suspected that azithromycin (a macrolide) not only helps prevent the occurrence of MAC, but also adds to PCP prophylactic medications and reduces one's chance of developing PCP (the study was not designed or powered to evaluate the use of azithromycin as a PCP prophylaxis, though). Similar findings from ACTG 196, a MAC prophylactic study which used clarithromycin (a sister macrolide), will be presented in early 1997 (William Powderly, M.D., personal communication).

AIDS-Related Malignancies: Kaposi's Sarcoma (KS)

--Doxil versus Bleomycin + Vincristine

The results of a trial of Doxil versus the combination of bleomycin plus vincristine (BV) for the treatment of KS were presented in a late-breaking poster (abstract LB.B.6026). Doxil -- a liposomal encapsulated form of adriamycin, a common, yet powerful, cytotoxic chemotherapeutic agent -- was recently granted accelerated approval by the FDA for the treatment of relapse or refractory KS.

Both regimens were administered every three weeks by intravenous infusion, consisting of 15 mg/m2 of bleomycin and 2 mg of vincristine versus 20 mg/m2 of Doxil. Mostly conducted in Europe, this study enrolled 241 patients with 102 evaluable patients in the BV arm and 116 evaluable in the Doxil arm. Seventy percent of the patients had under 50 CD4 cells and no G-CSF was allowed. Of the Doxil patients, seven (5.8%) achieved a complete response and 64 (52.9%) achieved a partial response compared to one (0.8%) complete response and 27 (22.5%) partial responses achieved by the BV patients. The difference was statistically significant. At the end of treatment (when patients stopped drug) the response rates were lower in both arms: the rate of complete response was 3.3% and 35.5% for partial responses on Doxil versus no complete responses and 14.2% partial responses on BV.

While Doxil was found to be efficacious in treating patients' lesions, it was more bone marrow-suppressive with 76.1% of the Doxil patients registering an absolute neutrophil count (ANC) below 1500 compared to 52.5% of the BV patients. Paresthesia (numbness and tingling in the mouth) was more common for the BV patients (14.2% versus 3.3%) and oral candidiasis was found to be more common in the Doxil patients (28.9% versus 17.5%). No survival data were given.

These results are similar to those seen in a study comparing Doxil against ABV.4 Since both studies were conducted in chemotherapy-naive subjects and demonstrated Doxil's superiority, the FDA is likely to grant, Sequus, the makers of Doxil, full approval to market Doxil as first-line therapy.

Fungal Infections

--Oral Candidiasis

New data on itraconazole oral solution (cyclodextrin) for the treatment of oral and esophageal candidiasis were presented in a number of sessions. Cyclodextrin is 30% to 60% more bioavailable than the standard itraconazole capsule when it is taken on an empty stomach. It is not available in the United States at present.

A study presented by Rabih O. Darouiche, M.D., compared the safety and efficacy of two doses of cyclodextrin with fluconazole (200 mg per day) for the treatment of thrush or oral candidiasis (abstract: Mo.B.117). A total of 190 patients (179 evaluable with a median CD4 cell count of 94) were enrolled to receive either itraconazole solution 200 mg daily for seven days or 14 days, or fluconazole 200 mg on day one and then 100 mg daily for 14 days.

There was no statistically significant difference between the three patient arms in terms of clinical response (freedom from lesions), fungal eradication (negative Candida culture) or relapse rates after four weeks' follow-up. Even so, the investigators concluded that itraconazole solution for 14 days was at least as effective (if not a bit better) as fluconazole in suppressing symptoms of oral candidiasis and in achieving a clinical and anti-fungal response.

Dr. Darouiche conducted an identically-designed study comparing the itraconazole solution to clotrimazole troches for the treatment of oral candidiasis. 149 patients (83% HIV-positive) were randomized to receive either the fourteen day dose of itraconazole or clotrimazole troches at 10 mg five times daily for 14 days.

There was no statistically significant difference between the treatment arms in their ability to achieve a clinical response: 77% for itraconazole solution versus 66% for clotrimazole. Itraconazole solution, however, was determined to be more effective in decreasing fungal colony counts and culture positivity: the itraconazole solution had a 66% response rate compared to 47% for clotrimazole.

--Esophageal Candidiasis

Bruce Moskovitz, M.D., presented data on 110 patients enrolled in a multicenter, double-blinded, placebo-controlled study comparing itraconazole solution to fluconazole for the treatment of esophageal candidiasis (abstract: Mo.B.116). Patients who had both endoscopy-proven and culture-positive esophageal candidiasis received either itraconazole solution at 100-200 mg daily or fluconazole at 100-200 mg daily for two weeks beyond symptom resolution (minimum of three and maximum of eight weeks of therapy). Patients were assessed clinically every week and received an endoscopy at the end of treatment.

In the itraconazole arm, 48 of the 53 (91%) patients were symptom-free at the end of treatment as compared to 49 of the 57 (86%) patients in the fluconazole arm. The median time to clinical response was 27 days for the itraconazole arm and 28 days for the fluconazole arm. At the end of treatment, an endoscopy determined cure occurred more often in the itraconazole patients (90%) than in the fluconazole patients (80%). Likewise, 92% of the itraconazole patients as compared to 78% of the fluconazole patients achieved fungal eradication. Relapse -- during the four-week follow-up period -- occurred in 18% of the itraconazole patients and 27% of the fluconazole patients.

All three studies support the efficacy of cyclodextrin/itraconazole oral solution and will probably be used in Jannsen's application to the FDA. If it is priced fairly, cyclodextrin might be a more suitable option over fluconazole given the latter drug's high price, drug interactions and potential to cause resistance.

References

1 Medina DJ et al. Antimicrobial Agents and Chemotherapy. May 1992; 36(5):1127-30.

2 Gaines K et al. Tenth International Conference on AIDS. August 7-12, 1994; 10(1):7 (abstract 0048).

3 Chaisson RE et al. Annals Internal Medicine. December 15, 1994; 121:905-911.

4 Northfelt DW et al. Third Conference on Retroviruses and Opportunistic Infections. Washington DC, January 28-February 1, 1996; page 123 (abstract 379).

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