CMV PCR copy number is also highly responsive to therapy; marked decreases in CMV viral load are seen with effective treatment. Interestingly, cidofovir does not lead to a decrease in viral load, despite clinical response.
For the treatment of CMV retinitis, the combination of IV ganciclovir and foscarnet has been shown to be more effective than treatment with either drug alone, but is also associated with a decreased quality of life because of the additive toxicity and long infusion times. The ganciclovir intraocular implant is superior with respect to rate of recurrence in the affected eye, but unless additional systemic therapy is given (such as oral ganciclovir), retinitis in the opposite eye or extraocular CMV disease is likely to occur. Approximately 12% of patients will develop retinal detachments following insertion of the device.
The use of oral ganciclovir for maintenance therapy (following a two week IV induction phase) can be effective for early retinitis, but is less effective than IV therapy for late retinitis. Because it is less effective, it is not recommended for the treatment of central or sight-threatening retinitis.
Anti-CMV drugs work by inhibiting CMV DNA polymerase. Virus that exhibits low-level ganciclovir resistance has a mutation at UL97. High-level resistance is also associated with a DNA polymerase mutation, which results in cross-resistance to cidofovir.
There have been a number of studies looking at prophylaxis of CMV disease. ACTG 204 compared high-dose valacyclovir with two doses of acyclovir. Although valacyclovir was associated with a reduced incidence of CMV disease, there was also a trend toward increased mortality with that drug. Thus, it is not recommended that chronic high-dose valacyclovir be used to prevent CMV disease.
In the Roche 1654 study which demonstrated that oral gancyclovir is effective in preventing CMV disease, 45% of the cohort had a positive PCR in plasma for CMV at the beginning of the study. Both PCR status and use of oral ganciclovir were associated with the risk of developing CMV disease. Those who were PCR positive had a 3-4 fold increase in the risk of CMV disease versus those who were PCR negative (p Baseline "CMV viral load" correlated well with the risk of CMV disease and with mortality. However, the use of oral ganciclovir was shown to benefit only those with CMV viral loads of 50,000 copies or less. In that group, 40% of placebo recipients developed CMV disease after one year compared to 20% of ganciclovir recipients. In contrast, in those with over 50,000 copies, there was no advantage to prophylaxis.
Thus, it is not clear how CMV PCR, or "CMV viral load," should be used to make prophylaxis decisions, or what the role of CMV prophylaxis is at this point. Using prophylaxis in all patients with CD4 counts less than 70 and no evidence of CMV viremia might provide maximal prevention of CMV disease, but would be enormously expensive. Confining prophylaxis to patients who had some evidence of CMV viremia (positive PCR regardless of viral load) would limit the use of prophylaxis somewhat, but would leave a substantial proportion at risk for CMV disease and would also provide prophylaxis to a subset with high viral loads who would not benefit from treatment. Targeting prevention using regular screening with quantitative CMV PCR and confining prophylaxis to those with viral loads that were positive but less than 50,000 might provide the greatest cost-benefit, but would still be expensive and cumbersome, and would not prevent all cases of CMV disease.
Investigational therapies for CMV disease include lobucavir (Cyclobut G), adefovir, GW 1248, and ganciclovir valine ester, a prodrug of ganciclovir.
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