These options include two new modes of delivering ganciclovir, which is now available in an oral formulation and in the form of an intraocular implant. Both of these modalities are likely to have a major therapeutic impact. Moreover, both are likely to have a major impact on the quality of life of patients with late-stage HIV disease -- by eliminating the cumbersome, time-consuming daily infusions that intravenous administration necessitates. In the process, these newer therapeutic modalities will eliminate the high risk of infection associated with daily IV infusions through an indwelling catheter.
Data from two large, randomized, comparative trials published in 1995(1, 2) seem to confirm that the oral formulation of ganciclovir (at a dose of 3000 mg three times daily) is as effective as IV ganciclovir (at a dose of 5 mg/kg daily) in delaying progression of CMV retinitis in patients who complete three weeks of IV induction therapy (Figure).
Some doubt remains as to whether these two regimens are truly equivalent, however. When the effects of the two treatment strategies were compared using retinal photographs, the mean time to progression of retinitis was similar: 62 days for IV ganciclovir versus 57 days for oral ganciclovir.(2) But when the median time to disease progression was calculated, the results favored the IV regimen: 49 days versus 29 for the oral formulation. In addition, oral ganciclovir appeared to be somewhat less successful in delaying progression when the assessment of progression was performed by ophthalmologists. This may reflect observer bias, since these ophthalmologists knew the regimen to which patients had been assigned, or it may truly reflect subtle differences in disease progression of the sort that can only be picked up by experienced clinicians.
Oral ganciclovir is poorly absorbed -- with a bioavailability that ranges from 2.5% to 7% -- so it is not unreasonable to expect the oral formulation to be somewhat less effective than the intravenous. And, indeed, the response of patients who entered these studies with unilateral retinitis seems to bear out this expectation: retinitis in the uninvolved eye was more likely to occur in patients receiving oral ganciclovir. However, patients on oral ganciclovir do not require long-term indwelling catheters, and this distinct advantage contributes significantly to their quality of life.
Although oral ganciclovir is not suited for patients with sight-threatening retinitis, it is a useful alternative to IV therapy in selected patients, particularly those whose retinitis is more peripheral. Studies are currently under way to evaluate the effectiveness of higher doses of oral ganciclovir (4500 mg and 6000 mg daily) as maintenance therapy. In either formulation the major side effect of ganciclovir is myelosuppression, especially neutropenia.
The second innovative delivery system for ganciclovir takes the form of an intraocular "bead," a tiny, double-layered plastic membrane, 4 mm in diameter and saturated with ganciclovir. This device is surgically implanted in the pars plana, and it releases a sustained amount of ganciclovir over a period of about 8 months. In several studies the median time to disease progression in treated eyes was about 7 to 8 months, suggesting that CMV retinitis is effectively controlled for as long as the drug is being released.(3,4) Anecdotal evidence suggests that this effect is sustained in patients who receive a new bead implant every 6 to 8 months.
These rates of progression are among the lowest seen with any therapy. Clearly, this mode of treatment is a highly effective way of managing retinitis, with a median time to disease progression that is much superior to that achieved with IV ganciclovir. Although the implanting of these drug-impregnated beads is a straightforward surgical procedure, lasting approximately one hour, early surgical complications, such as endophthalmitis and retinal detachment, do occur in about 10% of patients (see "Advances in the treatment of CMV retinitis," Vol. 1, No. 1, page 8).
The conundrum for clinicians is that ganciclovir implants are a highly effective local therapy for what is, in actuality, a systemic infection -- and while the bead implants are immensely effective in preventing CMV retinitis, their effect is highly localized. Almost half of all patients who receive a bead implant in one eye develop retinitis in the other eye, and fully 30% eventually develop visceral CMV infection. A combination of local and systemic therapy -- through the combination of an intraocular implant and oral ganciclovir -- may lead to considerably more effective control of this common opportunistic infection, and several clinical studies are examining the effectiveness of this approach.
A recent multicenter clinical trial, conducted by Studies of the Ocular Complications of AIDS (SOCA) in collaboration with the AIDS Clinical Trials Group (ACTG), evaluated the efficacy of a maintenance regimen that combined IV ganciclovir and foscarnet in patients who had experienced disease progression with standard monotherapy.(5) Patients were randomized to receive either high doses of monotherapy with one of the two study drugs or a combination of 90 mg/kg of foscarnet and 5 mg/kg of ganciclovir.
The combination regimen significantly improved visual outcome compared with either monotherapy, with treated patients experiencing a doubling of the median time to progression of retinitis (see "Combination of ganciclovir and foscarnet better than monotherapy for retinitis," in this issue). There was no difference in survival among the groups, however. And, not surprisingly, the combination therapy was less well tolerated, and quality of life was deemed poorer in patients who were randomized to that therapy. As a result, it is difficult to draw firm conclusions on the basis of this trial. Physicians and their patients need to weigh the clear clinical benefit of combination therapy -- which is more likely to preserve a patient's vision -- against the greater adverse effects of such therapy. At this point, clinicians may prefer to reserve combination therapy for patients with sight-threatening retinitis.
Cidofovir, also known as HPMPC, is a nucleotide analog of cytidine monophosphate that has demonstrated considerable in vitro activity against cytomegalovirus. One attraction of cidofovir is that it appears to be active against ganciclovir-resistant strains of CMV. Ganciclovir resistance is conferred by mutations in the viral enzyme that mediates monophosphorylation, and because cidofovir requires di- or tri-phosphorylation to become active, ganciclovir-resistant strains usually retain their susceptibility to cidofovir.
Intravenous cidofovir also has the advantage of an extremely long half-life -- which allows for weekly administration, even during induction therapy. Given parenterally, the drug is very effective in delaying disease progression, with a median time to progression, in patients with non-sight-threatening peripheral retinitis, of about 120 days.(6) This is almost twice the time to disease progression seen in all previous trials of IV ganciclovir and foscarnet.
The major drawback of cidofovir -- and the major limitation to its widespread use -- is its toxicity, especially nephrotoxicity. This mainly takes to form of proximal renal tube damage, which first presents a proteinurea and can lead to renal failure. The risk of nephrotoxicity can be reduced by careful hydration, close monitoring, and the co-administration of probenecid on the days of infusion. Unfortunately, probenecid itself is not well tolerated by a substantial number of patients, with fever and skin rashes being particularly common.
Cidofovir has also been assessed as local therapy, and an open-label study of a small number of patients who were given intravitreal injections has reported a mean time to progression, following a single injection of 20 µg of cidofovir, of about 55 days.(7) This finding suggests that monthly injections of cidofovir may be a very feasible method of controlling retinitis, one that is worth further study (see "Intravitreal cidofovir arrests progression of CMV retinitis," Vol. 1, No. 3, pages 49-50).
Two studies of oral ganciclovir for primary prevention of CMV infection have been completed.(8, 9) In the first of these trials, the study population was patients with CD4 counts less than 50 cells/mm3 and patients with a prior, AIDS-defining illness and CD4 counts less than 100 cells/mm3. These patients were randomized to receive either oral ganciclovir (1000 mg three times daily) or placebo. All patients had a baseline ophthalmologic assessment, to rule out the presence of previously undetected retinitis, and all were subsequently screened at bimonthly intervals by experienced ophthalmologists.
This study was halted by its data and safety monitoring board at the time the interim data were analyzed, because those data showed that oral ganciclovir had a significant effect: with the drug, the rates of all CMV infection were reduced from 30% to approximately 16%. CMV retinitis was also significantly less common in treated patients. And although investigators did not find a statistically significant difference in mortality between the two treatment arms, the trend did favor oral ganciclovir.
In contrast to that study, initial reports from a Community Program for Clinical Research in AIDS (CPCRA) trial seemed to find no difference in CMV endpoints for patients assigned to oral ganciclovir and those receiving placebo.(9) However, this study, unlike its predecessor, did not have baseline or interim screening for CMV retinitis but instead relied entirely on clinical manifestations of disease. In addition, when the interim data from the previous trial were announced, placebo-treated patients in the CPCRA study were allowed to cross over to oral ganciclovir.
While these differences confound the analysis of the data obtained by CPCRA investigators and make cross-study comparisons difficult, they do raise questions about the effectiveness of oral ganciclovir, especially given that the duration of prophylaxis in both trials was relatively short.
The conflicting findings of these two trials indicate that the optimal timing of prophylaxis with oral ganciclovir is not yet certain. Trials now in the planning stage should eventually clarify this important issue. Additional issues with oral ganciclovir are its adverse effects with long-term administration, especially myelotoxicity, and its cost, which currently exceeds $15,000 per year.
A Phase I trial of valaciclovir, the valyl ester of acyclovir, indicated that it appears to be safe in patients with advanced HIV infection.(10) Moreover, this trial showed that levels of acyclovir equivalent to those obtained when the drug is given intravenously could be achieved by oral administration. Indeed, such levels often exceed the amount needed to inhibit CMV replication.
Whatever promise this agent might have had as primary prophylaxis against CMV infection was clouded last year when an international Phase III trial (ACTG 204) comparing valaciclovir to oral ganciclovir was stopped in mid-study by its data and safety monitoring board because the interim findings indicated greater mortality in the valaciclovir arm. The cause of this excess has yet to be fully explained.
Analysis of the trial data showed that valaciclovir was effective in preventing CMV retinitis, with a reduction in risk of approximately one third. However, due to the drug's apparent adverse impact on mortality, it is unlikely that this agent will be chosen for long-term administration to HIV-positive patients, at least at the dosages used in the ACTG 204 trial.
Given the expense and the toxicity of the agents currently available for prophylaxis against CMV infection, it is important to target prophylaxis to the patients who are mostly likely to benefit from primary prevention -- thereby reducing the risk of toxic side effects and development of drug-resistant strains in those less likely to benefit from prophylaxis.
The pathogenesis of CMV disease in patients with AIDS is far from clear. The vast majority of HIV-positive individuals have been exposed to CMV; roughly 30% develop overt CMV disease. A high proportion of patients with advanced HIV disease are viremic and/or viruric, yet many of these patients never do develop active cytomegalovirus infection. In the past year several reports have suggested that measurement of CMV DNA, in blood plasma or blood cells, may be predictive of an increased risk of CMV disease, especially retinitis.(12, 13) It might therefore be possible to use this test to identify patients at high risk of developing CMV disease. In that case, regular screening by polymerase chain reaction assays for early evidence of viral replication might be useful as a means of initiating very early intervention, as opposed to true prophylaxis.
In addition, there is some evidence that CMV-specific immune response may be critical in the development of CMV infection. In a small recent study, individuals who developed CMV retinitis had significantly lower CD4 cell proliferation responses to CMV compared to CD4-matched controls. Moreover, certain alleles were associated with a low immune response and the development of CMV retinitis.(14) This is a promising avenue of research, and one that warrants further exploration.
1. Oral Ganciclovir European and Australian Cooperative Study Group. Intravenous versus oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis in patients with AIDS. AIDS 1995; 9: 471-8.
2. Drew WL, Ives D, Lalezari JP, et al. Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. N Engl J Med 1995; 333: 615-20.
3. Martin DF, Parks DJ, Mellow SD, et al. Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant. Arch Ophthalmol 1994; 112: 1531-9.
4. The Chiron Ganciclovir Implant Study Group. A randomized controlled multicenter clinical trial of a sustained-release intraocular ganciclovir implant in AIDS patients with CMV retinitis. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 1995. Abstract I112.
5. 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.
6. Lalezari J, Holland G, Stagg R, et al. A randomized, controlled study of cidofovir (CDV) for relapsing cytomegalovirus retinitis (CMV-R) in patients with AIDS. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 1995. Abstract LB-9.
7. Kirsch LS, Arevalo JF, De Clercq E, et al. Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1995; 119: 466-76.
8. Spector SA, McKinley G, Drew WL, Stempien MJ for the Syntex Ganciclovir Study Group. A randomized double-blind study of the efficacy and safety of oral ganciclovir for the prevention of cytomegalovirus disease in HIV-infected patients. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, 1994. Abstract A/9.
9. Brosgart CL, Craig C, Hillman D, Louis TA, Alston B. A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of CMV retinal and gastrointestinal mucosal disease in HIV-infected individuals with severe immunosuppression. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 1995. Abstract LB-10.
10. Jacobson MA, Gallant J, Wang LH, et al. Phase I trial of valaciclovir, the l-valyl ester of acyclovir, in patients with advanced human immunodeficiency disease. Antimicrob Agents Chemother 1994; 38: 1534-40.
11. Feinberg J, Cooper D, Hurwitz S. Phase III study of valaciclovir (VACV) for cytomegalovirus (CMV) prophylaxis in patients with advanced HIV disease. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 1995. Abstract I 112.
12. Hansen KK, Ricksten A, Hofmann B, Norrild B, Olofsson S, Mathiesen L. Detection of cytomegalovirus DNA in serum correlates with clinical cytomegalovirus retinitis in AIDS. J Infect Dis 1994; 170: 1271-4.
13. Rasmussen L, Morris S, Zipeto D, et al. Quantitation of human cytomegalovirus DNA from peripheral blood cells of human immunodeficiency virus-infected patients could predict cytomegalovirus retinitis. J Infect Dis 1995; 171: 177-82.
14. Schrier RD, Freeman WR, Wiley CA, McCutchan JA. Immune predispositions for cytomegalovirus retinitis in AIDS. J Clin Invest 1995; 1741-46.
William G. Powderly, M.D., is from the Division of Infectious Diseases, AIDS Clinical Trials Unit, Washington University School of Medicine, St. Louis, MO.
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