Coadministration doubles time to disease progression
A trial conducted by the Study of Ocular Complications of AIDS (SOCA) group has found that a combination of the intravenous formulations of ganciclovir and foscarnet is superior to either IV agent alone in preventing the progression of CMV retinitis in patients with advanced HIV disease. SOCA recruited 279 AIDS patients with diagnosed retinitis, all of whom were already receiving treatment with one of the study drugs, and randomized those subjects to one of three therapy arms:
Masked fundoscopic examinations revealed a difference in mean time to disease progression, with patients on combination therapy deriving a significant advantage. (Mean time to progression was 1.3 months with IV foscarnet, 2.0 months with IV ganciclovir, and 4.3 months with the combination.) Investigators found that patients on monotherapy suffered greater loss of visual field than those who received both drugs. Furthermore, patients on combination therapy had a smaller area of retinal involvement (1.19% per month with the two-drug combination, versus 1.40% with ganciclovir alone and 2.47% with foscarnet alone).
However, patients in all three arms of the study experienced similar changes in visual acuity, and combination therapy did not appear to confer a survival benefit. (Mean survival was 8.4 months with foscarnet, 9.0 months with ganciclovir, and 8.6 months with both drugs.) Both drugs are toxic, and the investigators report that most of their patients required treatment with Neupogen® during the trial, to combat the adverse effects of therapy.
Overall, the combination of ganciclovir and foscarnet appears to be associated with better management of CMV retinitis, but the formidable demand that two lengthy daily infusions place on a patient's time, tolerance, and quality of life is an important factor of clinicians and their patients to consider before initiating combination therapy.
In a related development, French researchers report having achieved favorable results with the combination of IV ganciclovir and foscarnet in AIDS patients with neurological complications of CMV infection. This group used 60 mg/kg q8 of foscarnet and 5 mg/kg q12 of ganciclovir for induction, then switched to 90 mg/kg/d of foscarnet and 5 mg/kg/d of ganciclovir for maintenance therapy.
Studies of the Ocular Complications of AIDS Research Group in Collaboration With the AIDS Clinical Trials Group. Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS: The Cytomegalovirus Retreatment Trial. Arch Ophthalmol 1996; 114: 23-33.
Couderc LJ, Honderlick P, Gozlan J, Frachon I, Balloul E, Caubarrere I. Combination ganciclovir and foscarnet in cytomegalovirus (CMV) related neurological diseases in AIDS patients. 3rd Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28-February 1, 1996. Abstract 173.
Mutation of nef gene apparently contributes to continuing health
In the mid-1980s eight Australians received HIV-infected blood products from a single donor. More than a decade later, not one of these recipients has developed the profound immunosuppression that is the hallmark of advanced HIV disease, and the original donor is also healthy. One member of this Sydney cohort did die from complications of systemic lupus erythematosis, but all of the remaining patients have stable CD4 counts above 500 cells/mm3 and no clinical manifestations of HIV infection. Two of the recipients are HIV-negative, and PCR testing of the others reveals that their viral burdens are low.
Genomic studies of isolates from these patients have revealed significant deletions in the nef gene as well as the overlap region between nef and the long terminal repeat region. Although the size of the deletions varied from patient to patient, the locations were conserved. Interestingly enough, some of the deletions affected binding sites for HIV-1 transcription factors. Other long-term non-progressors (LTNPs) -- a term applied to individuals who have no signs of immunosuppression or HIV-related clinical disease after years of documented infection -- have been found to have nef-deficient HIV genomes, although the viral isolates from many other LTNPs are nef-competent. Nonetheless, the investigators assert that there is a "causal relationship" between the abnormal nef regions seen in these patients and their failure to develop HIV disease.
Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DK, et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 1995; 270: 988-91.
Dr. Paul A. Volberding, the editor-in-chief of HIV Newsline, comments:
The investigators involved in this study presented some additional data at the third Conference on Retroviruses and Opportunistic Infections, which convened in Washington, D.C., in late January. Using recombinant nef proteins, they searched for antibodies to HIV-1 in the blood of three groups: patients with rapidly progressive disease, LTNPs, and members of the Sydney cohort. The first two groups were found to have a full complement of antibodies to nef, but all of the members of the Sydney cohort lacked antibodies to a specific epitope of the protein -- a peptide spanning amino acids 162-179. To date, it has not been possible to isolate a full-length nef protein from anyone in the cohort.
These intriguing findings may revive talk of a live attenuated AIDS vaccine that is nef-attenuated. There have been mixed results to date in animals challenged with SIV containing an altered nefgene, but the Australian data suggest that more studies may be warranted. A comprehensive review of current HIV-1 vaccine strategies appeared recently in The New England Journal of Medicine. The authors of that review cite the need for practitioners to understand the issues involved in vaccine development, "because these physicians are at the interface between the public and the scientists involved in vaccine research."
Two trials establish efficacy of clarithromycin-ethambutol combination
At a time in the AIDS epidemic when the talk is mostly of double and triple combination therapies, it is refreshing to learn that in at least one therapeutic area -- the treatment of Mycobacterium avium complex -- less may be more. At the third Conference on Retroviruses and Opportunistic Infections, Dr. Richard Chaisson presented data from a multicenter trial that dispensed either a two- or a three-drug regimen to AIDS patients with MAC. All patients received clarithromycin (500 mg b.i.d.) and ethambutol (15 mg/kg/d); 47 of the 106 participants were randomized to receive clofazimine (100 mg/d) in addition.
Most of the parameters of efficacy and safety used by the investigators supported the use of the two-drug regimen over the triple combination of antimycobacterial drugs. At entry 89% of the study subjects had positive MAC cultures. With treatment, 65% of culture-positive patients treated with clarithromycin plus ethambutol reverted to negative cultures, versus 54% of those treated with all three drugs. Moreover, the patients who did not receive clofazimine reverted more quickly to negative cultures.
Similar percentages of patients in both treatment cohorts experienced symptomatic improvement of fever and night sweats, but a larger percentage of patients in the two-drug arm suffered less severe weight loss (41% vs. 28%). Not surprisingly, a high proportion of patients randomized to triple-drug therapy withdrew from the trial due to adverse events (22% vs. 13%).
Significantly, investigators also noted a survival benefit for patients on the clarithromycin-ethambutol regimen: 38% of those subjects died during the course of the study, versus 61% of subjects treated with the three-drug combination. Investigators speculate that the difference in survival rates may be attributable to higher numbers of colony-forming units at baseline in patients in the three-drug arm.
In any event, Chaisson and coworkers concluded that clofazimine did not appear to improve the efficacy of clarithromycin-etambutol in the treatment of MAC, and the data suggest that the addition of clofazimine to this regimen may actually have a detrimental effect.
In a related study, also presented at the third Conference on Retroviruses, 80 AIDS patients with MAC were randomized to receive clarithromycin (1000 mg b.i.d.) and clofazimine (100 mg/d), with or without ethambutol (800 mg/d). Response to treatment was identical in both cohorts: in each therapeutic arm 69% of patients with positive MAC cultures at baseline reverted to negative cultures. However, there were eight relapses in the two-drug arm of the study and only two in the three-drug arm. All of the patients who relapsed were found to have mycobacterial isolates that were resistant to clarithromycin. This resistance developed within 16 weeks in patients receiving only two drugs, versus 40 weeks in patients receiving all three. From these findings the investigators concluded that the three-drug combination was preferable.
Chaisson RE, Keiser P, Pierce M, Fessel WJ, Ruskin J, Lahart C, Meek K. Controlled trial of clarithromycin/ethambutol with or without clofazimine for Mycobacterium avium complex bacteremia in AIDS. 3rd Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28-February 1, 1996. Abstract LB 17.
Dubé M, Sattler F, Torriani F, See D, et al. Prevention of relapse of MAC bacteremia in AIDS: A randomized study of clarithromycin plus clofazimine, with or without ethambutol. 3rd Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28-February 1, 1996. Abstract 206.
Dr. W. David Hardy, the author of "Recent Advances in Prophylaxis for MAC" (Vol. 1, No. 3, pages 52-57) and a members of the editorial advisory board of HIV Newsline, comments:
While these two trials reach different conclusions about the number of drugs needed to treat AIDS-related MAC, it should be noted that the superior regimen in both trials included clarithromycin and ethambutol. The survival data from the study conducted by Chaisson et al. should lead clinicians to give careful consideration to using a regimen for the treatment of MAC bacteremia that includes clofazimine. This medication, which once appeared useful with clarithromycin or azithromycin, now seems to add very little to these agents, while ethambutol is associated with longer survival. But what these data really tell us is that we are still a long way from an effective treatment for this opportunistic infection. We need a more effective combination of agents -- a regimen that will reduce the 30% relapse rate seen with either combination therapy in these two studies.
New drugs expected to become standard treatment for HIV infection
Acting with unprecedented dispatch, the F.D.A. has approved two more protease inhibitors, bringing the number of approved agents in this class to three. These newest additions to the AIDS armamentarium are ritonavir, which Abbott Laboratories markets as Norvir®, and indinavir, which Merck & Company will sell as Crixivan®. It took the F.D.A. only 72 days to approve Abbott's application to market ritonavir -- a record pace for the agency, which has lately been under considerable Congressional pressure to accelerate its approval process. Swift as this approval was, it was positively laggard compared to the speed with which the F.D.A. acted on Merck's application -- which was approved in a mere 42 days.
The promptness with which the F.D.A. processed both applications is a reflection of the merits of these two antiretroviral agents, not a capitulation to Congressional demands. Both drugs have exhibited remarkable efficacy in early trials, and both have highly favorable safety profiles at the doses used to date (see "Ritonavir prevents disease progression and prolongs life," Vol. 2, No. 1, page 14, and "Potent, sustained antiviral activity of ZDV and 3TC combined with indinavir," same issue, pages 15-16). Experts concur that these new agents, alone or in combination with other antiretroviral drugs, are likely to become standard therapy in HIV-infected patients. Monotherapy with these agents should be avoided, since it is associated with more rapid development of resistance.
The data submitted by Merck in support of its application indicates that indinavir, when given as monotherapy, reduces viral load by 80% to 90% from baseline levels; when given in combination with ZDV and/or other nucleoside analogs, viral activity is suppressed by 90% to 98%. In a separate study, conducted in patients with moderately advanced HIV infection (average CD4 count at entry: 280 cells/mm3), indinavir monotherapy boosted CD4 counts by an average of 100 cells/mm3.
Merck has announced that it will sell indinavir to distributors for 25% to 33% less than Abbott charges for ritonavir and Roche charges for saquinavir (Invirase®). This pricing policy will bring the wholesale cost of daily doses of the combination of indinavir and ZDV down to approximately $14 per day.
Michael S. Saag, author of "The Protease Inhibitors" (Vol. 1, No. 3, pages 42-45) and a member of the editorial advisory board of HIV Newsline, comments:
We now have compelling clinical evidence of the benefits of protease inhibition. The durability of this benefit will be determined through accumulating clinical experience. One thing is already clear, however: patients must be encouraged to comply scrupulously with the daily dosing regimen these drugs require -- to delay the development of drug-resistant viral strains. Experience gained in the early clinical trials of protease inhibitors has taught us that the patients who do best are those who take the highest tolerable dose of drug and take it consistently, to minimize viral replication and thereby reduce the likelihood that resistant strains will develop.
Back to the April 1996 HIV Newsline contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.