Is combination antiviral therapy for CMV superior to monotherapy?

Journal of Clinical Virology 35 (2006) 485–488

Is combination antiviral therapy for CMV superior to monotherapy? W. Lawrence Drew ∗ UCSF Mount Zion Medical Center, 1600 Divisadero Street, Box 1629, San Francisco, CA 94115, USA Received 6 June 2005; received in revised form 9 September 2005; accepted 12 September 2005

Abstract Background: Many clinicians are under the impression that the combination of ganciclovir (GCV) and foscarnet is synergistic versus cytomegalovirus (CMV) and/or that combination therapy might prevent the emergence of resistance to one or both antivirals. The combination is frequently used when resistance to either drug is suspected. Objective: To review in vitro and clinical data regarding the activity of ganciclovir plus foscarnet and evidence of synergy between the two drugs. Study design: We reviewed two in vitro studies of synergy between ganciclovir and foscarnet followed by reviewing all clinical studies utilizing series of patients. Results: The combination of ganciclovir and foscarnet was synergistic against three clinical isolates, the Towne strain and one laboratory derived strain moderately resistant to GCV but synergy was not demonstrated against laboratory derived strains highly resistant to GCV or foscarnet. AD169, susceptible to both drugs, was not inhibited synergistically by the combination in one study but was in the second study. In the only carefully controlled in vivo study of combination versus monotherapy for GCV susceptible viremia superiority of the combination was not demonstrated. In treating clinically resistant CMV retinitis, the combination was superior to continued or alternative monotherapy. Conclusion: There is suggestive but inconclusive evidence of in vitro synergy for the combination of GCV and foscarnet versus CMV with very limited data versus GCV resistant virus. The in vivo data for synergy is even less convincing. Additional in vitro and in vivo data is needed, especially to prevent or treat CMV resistance. © 2005 Elsevier B.V. All rights reserved. Keywords: Cytomegalovirus; Foscarnet; Ganciclovir

1. Introduction Combination antiviral therapy has become the standard for certain viruses, e.g., the human immunodeficiency virus (HIV) and hepatitis C. The advantage of combinations may rest in synergy versus the virus and/or suppression of emerging resistance but it is not clear whether the experience with these RNA viruses applies to a DNA virus like cytomegalovirus (CMV). Undeniably, the efficacy of antiCMV monotherapies is suboptimal and emergence of resistance in patients receiving monotherapy is well documented so a combination might be advantageous. Synergistic activity might also allow the use of lower drug dosage, reducing the risk of toxicity. ∗

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In this review, I will summarize studies of the combination of ganciclovir (GCV) and foscarnet (FOS) both in vitro and in vivo. The latter survey will cover attempts to treat CMV viremia and disease in patients with and without possible, or proven, ganciclovir resistant virus.

2. In vitro data Impressive evidence for synergy of GCV plus FOS versus CMV in tissue culture was reported by Manischewitz, from the laboratory of Gerald Quinnan, in 1990 (Manischewitz et al., 1990). They demonstrated remarkable reductions in the ganciclovir IC 50 for strains of CMV as increasing concentrations of foscarnet were added to cultures 1 h post infection (Table 1A). These effects were greater than additive

W.L. Drew / Journal of Clinical Virology 35 (2006) 485–488

486

Table 1 In vitro inhibition of CMV replication by DHPG and PFA alone and in combination Isolate

AD-169 192 209 295 Mean

(A) IC 50 of DHPG (␮M)

(B) IC 50 of PFA (␮M)

With a PFA concentration of:

With a DHPG concentration of:

Alone

30 ␮M

60 ␮M

90 ␮M

Alone

1 ␮M

4 ␮M

11.8 6.3 9.9 8.1 9.0

4.1 3.2 6.4 2.9 4.1

2.1 2.4 3.2 2.3 2.5

1.5 1.6 2.1 1.4 1.6

102.6 163.8 108.5 143.2 133.0

60.8 70.5 81.9 75.4 68.7

49.7 55.6 65.8 43.8 43.8

Table 2 HCMV IC 50 (␮M) combination index (C.I.)a

Towne AD 169 GDG XbaF4 759rD100-1 PAAr PFArD100 PC92

Ganciclovir

Foscarnet

Ganciclovir and foscarnet

4.94 3.09 6.99 83.62 5.49 2.98 2.42

135.66 65.66 34.45 48.65 93.99 285.59 113.52

0.87 1.12 0.84 0.93 1.10 0.92 1.04

a Synergy = C.I. ≤ 0.9, nism = C.I. ≥ 1.2.

additive

effect = C.I.

0.91–1.2,

antago-

and had a fractional inhibitory concentration (FIC) of 0.72 (FIC < 1.0 = synergy). Further, plotting the data as a dose isobologram gave a curve of synergy. Synergy was bidirectional, i.e., the IC 50 of foscarnet decreased similarly when combined with increasing concentrations of ganciclovir (Table 1B). The concentrations of drug were well within the levels found after intravenous administration of recommended doses, e.g., GCV 1–4 ␮M; FOS 30–90 ␮M. Only GCV sensitive viruses were utilized in this study so no conclusions can be reached re synergy of the combination versus GCV resistant virus. A second study of synergistic activity is that of Manion et al. (1996) who used a different method of calculation to obtain a mean combination index (C.I.). In this analysis, synergism is indicated by a C.I. of ≤0.9; zero to additive by a C.I. of 0.91–1.2 and antagonism by C.I. of >1.2. The combination of GCV and FOS was synergistic with Towne but not AD 169 strains and with one laboratory derived mutant, moderately resistant to GCV (Table 2). Additive effects but not synergy was demonstrated against a single CMV strain highly resistant to GCV.

3. Therapy of CMV viremic disease Single case reports have described clinical efficacy of the combination of ganciclovir plus foscarnet for treating CMV viremia and/or disease in patients who were suspected to have GCV susceptible virus (Dieterich et al., 1993). Bacigalupo et al. (1996) used preemptive GCV plus foscarnet to treat 32 allogenic hemopoietic stem cell transplant (HSCT) recipients who developed CMV antigenemia (>4 cells/200,000).

Full dose GCV (10 mg/kg/d) and foscarnet (180 mgm/kg/d) was given for 15 days followed by every other day for 2 weeks (Table 2). Results in 18 patients whose transplants were not T cell depleted were compared to historical HSCT controls, with similar transplant and similar levels of antigenemia, but treated with either ganciclovir (eight patients) or foscarnet (seven patients) as single agents. The end point of the comparison was transplant related mortality (TRM) at 1 year, which was 47% for the monotherapy arm and 13% for the combined arm. In both arms, the mortality was largely due to CMV. The flaws in this study are clear, it is a retrospective analysis using historical controls and the end point was measured months after the primary treatment course was completed. A prospective, randomized trial directly comparing monotherapy (GCV) with combined (GCV plus FOS) for the preemptive treatment of first episodes of CMV viremia was recently reported (Mattes et al., 2004). There were 24 patients in each arm with nearly equal numbers of bone marrow, liver and renal transplants (Table 3). Monotherapy with GCV at a dose of 5 mgm/kg/twice daily was compared with half-dose GCV at 5 mgm/kg once per day plus half dose foscarnet, 90 mg/kg/day. In this study, the end point was more appropriate to assess antiviral efficacy than in the Bacigalupo study cited above. Specifically, the end point was a whole blood quantitative PCR showing <200 genomes/ml by 14 days of treatment. Only 50% of the 24 patients in the combined arm achieved this end point versus 71% in the monotherapy arm (p = 0.012). Among those who reached the primary end point, the median time to a blood sample negative for CMV was 6 days in the GCV arm versus 5.5 days in the combined arm. When all patients were considered, it was 6 days for GCV only versus 11 days for GCV plus foscarnet. The initial viral titers in the two arms were comparable, 104.3 the GCV arm versus 104.0 in the combination arm. The viral decay rate or rate of titer decline did not differ between the two arms. While not assessing the efficacy of combination therapy versus disease, this study does indicate that the antiviral activity of the combination did not surpass that of monotherapy. We performed a very limited assessment of mono versus combined therapy in patients with CMV CNS disease, undergoing serial CSF examinations (Flood et al., 1997). Utilizing the bDNA assay, we compared the rate of decline of CMV signal in patients receiving GCV 10 mg/kg/d versus GCV

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Table 3 Number of patients reaching end points of the study by therapy assignment Therapy allocation

CMV negative by PCR within 14 days of initiation of therapy Time to CMV negative result by PCR, median days Patients stopping or reducing dose because of toxicity within 14 days of initiation therapy Patients developing a second episode of CMV viremia after Successful therapy (within 365 days)

GCV

GCV plus foscarnet

P

17 (71)

12 (50)

0.12

6 0 (0)

11 7 (29)

0.009

6

9

0.53

Adapted from Mattes et al. (2004).

10 mgm/kg/d plus FOS 180 mg/kg/d. Serial samples were obtained prior to treatment and 1–2 weeks post initiation of therapy. The curve of CMV signal decline in the six patients receiving combination therapy could not be distinguished from the curves in the six patients receiving monotherapy. This study would seem to confirm the comparable antiviral activity of the two regimens, in treating CMV disease.

4. Combination therapy for ganciclovir resistant disease The first true study of ganciclovir/foscarnet combination therapy for ganciclovir resistant CMV involved “clinically” resistant CMV retinitis and utilized AIDS patients who had failed one or more courses of either ganciclovir or foscarnet (SOCA, 1996). Unfortunately no phenotypic or genotypic assays for viral resistance were performed so the contribution of ganciclovir resistance to the outcome cannot be known. The comparison randomized patients to three arms: monotherapy with either full dose ganciclovir or foscarnet or combination therapy with half dose of each drug in combination. Approximately 85% of patients in each arm had received ganciclovir, but whether they harbored resistant virus is unknown. Resistance alone, probably did not account for the superiority of the combination (Table 4); the mean number of relapses for the entire group prior to enrollment was 1.8 making it unlikely that a large proportion of all patients in three arms harbored ganciclovir resistant virus after such relatively short exposure to drug. Also, if GCV resistance was the major explanation then patients should have benefited from foscarnet monotherapy but this was not observed. Table 4 Treatment of “clinically” resistant CMV retinitis Time to first progression (months)

Median: masked Median: clinical 95% C.I.

Fos

GCV

Combination

1.3 2.0 1.1–2.0

2.0 3.6 1.3–3.0

4.3 5.4 2.1–6.2

Adapted from SOCA (1996).

As a result of this clinical study switching to combination therapy is a commonly recommended practice whenever patients fail ganciclovir monotherapy. Further support for this practice came from Mylonakis et al. (2002) who treated six solid organ transplant recipients with combined GCV and foscarnet due to documented GCV resistance. These patients had been on prophylactic oral ganciclovir for periods ranging from 3 months to 2 years and developed very high levels of CMV antigenemia which persisted despite ≥3 weeks of full dose intravenous GCV. Blood CMV isolates were obtained from all six and GCV resistance was demonstrated by a hybridization assay. The six patients responded dramatically to combination therapy with all six having negative antigenemia by 4–8 weeks of treatment and a clinical response within 96 h. No recurrences of CMV disease occurred. Although the results of the Mylonakis report are impressive, it is important to remember that we, and others, have reported comparable patients whose GCV resistant disease was successfully treated with foscarnet alone (Jacobson et al., 1991). The results should prompt a prospective randomized and blinded trial of GCV monotherapy versus the GCV/FOS combination if a sufficient number of patients with GCV resistant end organ disease can be identified.

5. Summary Some, but not all, in vitro studies suggest that the combination of GCV and foscarnet may be synergistic versus stock strains and clinical isolates of CMV but, to date, synergy has only been demonstrated with ganciclovir susceptible or weakly resistant isolates. Clearly additional testing in vitro should be performed with isolates resistant to ganciclovir due to UL 97 +/− DNA polymerase mutations. If a sufficiently large group of patients with ganciclovir resistant CMV infection can be identified, a clinical trial of foscarnet alone versus ganciclovir plus foscarnet is highly desireable. At this time, patients undergoing CMV infection post lung transplant are experiencing a high rate of GCV resistance (Limaye et al., 2002). Perhaps they could form the necessary clinical study group. Until then, the rationale for this particular combination will rest on the clinical benefit

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obtained in HIV positive patients with CMV retinitis whose incidence of true ganciclovir resistance is unknown.

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Manion DJ, et al. Susceptibility of human cytomegalovirus to two-drug combinations in vitro. Antiviral Therapy 1996;1:237– 45. Manischewitz JF, et al. Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother 1990;34:373–5. Mattes FM, et al. A randomized, controlled trial comparing ganciclovir to ganciclovir plus foscarnet (each at half dose) for preemptive therapy of cytomegalovirus infection in transplant recipients. J Infect Dis 2004;189:1355–61. Mylonakis E, et al. Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients. Clin Infect Dis 2002;34:1337–41. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Combination foscarnet and ganciclovir therapy versus monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. Arch Ophthalmol 1996;114:23–33.