Recurrence of CMV viraemia and development of anti-CMV drug resistance in patients receiving highly active antiretroviral therapy after CMV retinitis

Patients who have received HAART and have extended survival rates following CMV retinitis (CMVR) have now had prolonged exposure to anti-CMV therapies. This study aims to identify risk factors for recurrence of CMV viraemia in such patients and to investigate the development of ganciclovir resistance associated with the long term receipt of maintenance therapy for CMVR. Patients who received HAART following CMVR were prospectively monitored 1-3 monthly for recurrent CMV viraemia using PCR. CMV load was determined using a quantitative competitive PCR. DNA samples from patients who experienced recurrent CMV viraemia whilst on maintenance ganciclovir therapy for CMVR were sequenced for mutations in the CMV phosphotransferase gene UL97 which confer ganciclovir resistance. Eleven patients were studied. The median time from initial diagnosis of CMVR was 43 months and the median time since staring HAART 39 months. The cohort had received a median of 21 months of anti-CMV therapy. In nine patients who discontinued maintenance therapy after HAART there were no recurrences of either CMV viraemia or CMVR at a median of 25 months of follow-up. CMV viraemia recurred in three patients while on maintenance therapy; the median rebound CMV load was 3.8 x 10 super(4) copies/ml. In patient 1 recurrence of viraemia was associated with hydroxyurea-induced neutropenia. CMV viraemia was cleared following a reduction in the dose of hydroxyurea. Patient 2 experienced recurrent viraemia on two occasions; in both cases viraemia was associated with multiple UL97 mutations and: cleared following HAART intensification. Patient 3 experienced increasing CMV load following failure of HAART. UL97 sequencing at this time showed the C592G mutation and a deletion of codons 590 and 591. Treatment with foscarnet and cidofovir failed to control viraemia. However, at 3 months after stopping ganciclovir the CMV genome had reverted to wild type at the above codons. Reintroduction of oral ganciclovir at this point resulted in control of CMV viraemia but was associated with the reappearance of the resistance mutations in subsequent positive samples. Recurrence of CMV viraemia is a marker of HAART failure and should prompt intensification of therapy. Patients who have received extensive maintenance therapy for CMVR have a high incidence of anti-CMV drug resistance mutations and are at risk of anti-CMV treatment failure. CMV load should be monitored frequently if re-induction therapy is required for re