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Change over Time in Incidence of Ganciclovir Resistance in Patients with Cytomegalovirus Retinitis

  1. Barbara K. Martin1,
  2. Michelle O. Ricks2,
  3. Michael S. Forman3,
  4. Douglas A. Jabs1,2,4,a, and
  5. Cytomegalovirus Retinitis and Viral Resistance Study Groupb
  1. 1Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  2. 2Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
  3. 3Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
  4. 4Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
  1. Correspondence: Dr. Barbara K. Martin, Johns Hopkins Center for Clinical Trials, 615 N. Wolfe St., Ste. W5010, Baltimore, MD 21205 (bmartin{at}jhsph.edu).
  2. Reprints: Dr. Douglas A. Jabs, The Wilmer Eye Institute, 550 N. Broadway, Ste. 700, Baltimore, MD 21205 (djabs{at}jhmi.edu).

  • ↵Present affiliation: Department of Ophthalmology, The Mount Sinai School of Medicine, New York.

  • ↵Members of the Cytomegalovirus Retinitis and Viral Resistance Study Group are listed at the end of the text.

 
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Abstract

Background. In the mid-1990s, the incidence of cytomegalovirus (CMV) resistance to ganciclovir was estimated to be ∼25% by 1 year after diagnosis of retinitis in patients with acquired immunodeficiency syndrome.

Methods. Two hundred fifty-seven patients with CMV retinitis were enrolled in a prospective observational study during 1993–2003 and were treated with ganciclovir. Demographic characteristics and data on CMV disease, antiretroviral therapy, and ganciclovir resistance were recorded for all patients. Human immunodeficiency virus (HIV) load and CMV load were measured for patients enrolled in 1996 or later. Kaplan-Meier and Cox proportional hazards regression methods were used to examine incidence of resistance.

Results. The 2-year incidence of resistance was 28% among patients enrolled before 1996 and 9% among those enrolled in or after 1996 (P = .001). All cases of resistance occurred among patients with CD4+ T cell counts <50 cells/µL, and positive CMV culture results at baseline were associated with a ∼4-fold increase in resistance. Among patients whose CMV and HIV loads were measured, a detectable CMV load at baseline and during follow-up was associated with increased risk of resistance, but a detectable HIV load was not.

Conclusions. Rates of resistance have decreased from the high levels seen in the pre-HAART era. Better control of CMV replication may have contributed to this decrease.

During the early to mid-1990s, cytomegalovirus (CMV) retinitis was recognized as a common opportunistic infection among patients with AIDS. The reported frequency of CMV retinitis ranged from ∼20% to ∼45% of patients with AIDS [1–4]. Hoover et al. [5] estimated that the incidence of CMV retinitis was ∼25% by 4 years after the CD4+ T cell count had decreased to <100 cells/µL. Treatment of CMV retinitis required intravenous administration of ganciclovir [6], foscarnet [7], or cidofovir [8, 9]. Such long-term systemic therapy provided selective pressure for the emergence of viral mutations that conferred drug resistance, and HIV replication provided the opportunity for transactivation of CMV [10, 11]. Nonadherence to difficult anti-HIV and anti-CMV therapeutic regimens likely further increased viral loads and fostered the emergence of CMV resistance. We previously reported that the incidence of resistance to ganciclovir was >25% after 1 year of treatment [12].

In 1996, the picture of CMV retinitis was changed by 2 major events. The first event was the availability of the ganciclovir implant, which delivered sustained, high concentrations of drug to the eye [13] and resulted in a lower rate of retinitis progression [14]. However, local therapy alone was associated with high rates of visceral disease, mortality, and development of contralateral CMV retinitis [15]. Therefore, the implant was typically combined with oral ganciclovir treatment, thus continuing the selective pressure for drug resistance.

The second event was the use of protease inhibitors and nonnucleotide reverse-transcriptase inhibitors in HAART regimens. Use of HAART frequently resulted in a lowered HIV load—even to undetectable levels—and an elevated CD4+ T cell count. In some patients, it restored immunity to CMV [16] and other pathogens. In those with adequate immune reconstitution, it became possible to cease long-term anti-CMV therapy without a relapse of retinitis [17, 18]. These changes resulted in decreased mortality due to HIV infection [19] and a decreased incidence of opportunistic infection, including CMV retinitis [20].

Although the effect of HAART on CMV retinitis was dramatic, its potential effect on resistance to anti-CMV drugs among persons who still developed the disease was less clear. On one hand, the immunological benefits of HAART might be expected to reduce CMV replication and the emergence of drug-resistant virus. On the other hand, people who developed CMV retinitis after 1996 had typically received HAART before receiving this diagnosis [21], suggesting that HAART had failed as a result of difficulties with tolerating or adhering to treatment or of HIV resistance to antiretroviral drugs. In addition, patients who did not receive HAART at all likely had poor access or adherence to medical care. Therefore, it was possible that the benefits of HAART would not extend to persons who still developed CMV retinitis, and that the incidence of resistance would remain at previous levels.

In this article, we describe the incidence of resistance to anti-CMV therapy in the pre-HAART and HAART eras from the Cytomegalovirus Retinitis Viral Resistance (CRVR) study, a prospective observational study. We also evaluate the association of HAART use and other factors with incidence of resistance.

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Patients and Methods

Study population. Patients with AIDS and newly diagnosed CMV retinitis were enrolled at the Johns Hopkins University School of Medicine (Baltimore, MD; 1993–2003), the Northwestern University School of Medicine (Chicago, IL; 1997–2003), and the University of Miami School of Medicine (Miami, FL; 1998–2003). Follow-up continued through June 2004.

Data collection schedule. Before the start of anti-CMV therapy, blood and urine specimens were obtained for CMV culture, and CD4+ T cell counts were determined locally for all patients. Follow-up cultures were performed at 1 and 3 months after enrollment and every 3 months thereafter. Beginning in May 1996, blood specimens were obtained quarterly for determination of the CD4+ T cell count, the CMV DNA level, and the HIV RNA level. Anti-CMV therapy was recorded, and information on antiretroviral therapy was obtained from patients and from medical records, when possible. Receipt of a protease inhibitor or nonnucleotide reverse-transcriptase inhibitor was used to indicate HAART. Data on antiretroviral therapy were summarized as variables indicating whether HAART was being administered at the time of diagnosis of CMV retinitis or during intervals of follow-up centered around the visits at which specimens were obtained for CMV culture and susceptibility testing.

Definition of resistance. Culture isolates, rather than directly PCR-amplified blood specimens, were used to detect resistant CMV, because culture results are more predictive of clinical behavior [22]. For culture isolates, measures of phenotypic and genotypic resistance are highly correlated [23] and are similarly predictive of clinical behavior [24]. We chose phenotype as our primary outcome measure because it is a direct measure of CMV resistance to ganciclovir. Secondary analyses of genotypic resistance were conducted.

Cultures and phenotypic susceptibility testing. Culture specimens were processed at each clinical center, and isolates were sent to the Virology Laboratory of the Johns Hopkins Hospital for centralized susceptibility testing. Testing for ganciclovir susceptibility was performed with either a DNA hybridization assay (Hybriwix Probe System–CMV Susceptibility Test Kit; Diagnostic Hybrids) or the plaque reduction assay [25, 26]. We previously reported excellent correlation between the techniques [26–29]. Phenotypic resistance to ganciclovir was defined as an IC50 ⩾6 µmol/L for the blood isolate or an IC50 ⩾8 µmol/L for the urine isolate [26, 27, 29–31]. If CMV could not be isolated from either the blood or the urine specimen, the patient was assumed to harbor susceptible virus—an assumption supported by direct PCR and sequencing of blood specimens and clinical behavior [24].

CMV and HIV level quantification. Leukocyte and plasma aliquots were prepared locally and shipped to Johns Hopkins Hospital for centralized viral load quantification. Quantification of CMV load was performed with the Cobas Amplicor CMV Monitor test system (Roche Diagnostics) [32]. Quantification of HIV load was performed by quantitative PCR with the Amplicor HIV-1 monitor test, version 1.5 (Roche Diagnostics) [33].

Statistical analysis. For characteristics of patients in the CRVR study who received ganciclovir, frequencies of categorical variables and medians and interquartile ranges of continuous variables were calculated on the basis of the period of enrollment. We analyzed the following baseline characteristics: demographic characteristics, HIV disease characteristics and treatments, CMV retinitis characteristics and treatments, CMV culture results, and CMV and HIV loads; also provided were measures of follow-up, survival, progression, and resistance during the study. Summary statistics for these characteristics were provided for 3 enrollment periods: the pre-HAART era (1993–1995), the era of transition to HAART use (1996), and the HAART era (1997–2003). P values were obtained using the χ2 test or Fisher's exact test for categorical variables, the Kruskal-Wallis test for continuous variables, the log rank test for time-to-event variables, and the Poisson regression Wald test for rates.

In analyses of resistance, survival without resistance was graphed for 2 periods (before 1996 and 1996 and later) using the Kaplan-Meier method, and the log rank P value for the difference between the time periods was obtained. To explore factors that may have explained the difference by time period, the Kaplan-Meier method was used to estimate the cumulative incidence (first occurrence) of resistance by 1 and 2 years after CMV retinitis diagnosis according to baseline characteristics. For the total study population, these characteristics included demographic data, CMV retinitis measures, CD4+ T cell count, and CMV culture results; for the subgroup of patients enrolled in 1996 or later, additional characteristics included HAART use at the time of enrollment and baseline CMV and HIV load. Cox proportional hazards regression with the adaptation of Andersen and Gill [34] was used for analyses that included time-dependent HAART use (for all patients) and CMV and HIV load measurements (for patients enrolled in 1996 or later). Finally, exploratory analyses of resistance in the subgroup of patients who enrolled in 1996 or later but who did not take HAART during study follow-up (or before the incidence of resistance, for those who developed the outcome) were conducted.

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Results

Study population. Of the 309 patients enrolled in the CRVR study, 257 received some form of ganciclovir therapy (intravenous formulation, oral formulation, valganciclovir, or intraocular implant) during follow-up. As presented in table 1, 76 patients were enrolled during 1993–1995, 28 were enrolled in 1996, and 153 were enrolled during 1997–2003. Within these periods, 1.3%, 14.3%, and 53.6%, respectively, were receiving HAART at the time of diagnosis of CMV retinitis. For many demographic and clinical characteristics, 1996 represented a transition year between the pre-HAART and HAART eras. The percentages of female subjects, African-American subjects, and persons who reported heterosexual HIV exposure were highest during 1997–2003. In the same period, the median duration of survival increased by a few months. There was a large decrease in the proportion of patients who had positive CMV blood or urine culture results and an increase in the proportion of patients with CD4+ T cell counts ⩾50 cells/µL. For patients who enrolled in 1996 or later who underwent HIV load measurements, the plasma HIV load was detectable (⩾400 copies/mL) in 89%, and the CMV load was detectable in 67% of patients in leukocytes (⩾400 copies/million cells) and in 60% of patients in plasma (⩾400 copies/mL).

Figure 1
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Figure 1

Survival without ganciclovir resistance before and after 1996. Patients were enrolled prior to 1996 (hatched line) or in 1996 or later (solid line). P < .001, by log rank test.

Table 1
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Table 1

Characteristics of the study population, by period of diagnosis of cytomegalovirus (CMV) infection.

Resistance. Phenotypic resistance occurred in 24 patients. Fourteen of these patients were enrolled before 1996, 1 was enrolled in 1996, and another 9 were enrolled after 1996. The similarity in the rates of resistance in 1996 and 1997–2003 (data not shown) allowed us to treat this as a single HAART era. Data on survival without phenotypic resistance to ganciclovir prior to 1996 and in 1996 or later are shown in figure 1; before 1996, the 2-year incidence of ganciclovir resistance was 28.0%, whereas from 1996 on, it was only 8.8% (P < .001). Table 2 shows the 1- and 2-year cumulative incidences of resistance for other potential predictors. Age, race, sex, and injection drug use were not associated with resistance. The extent of retinitis at diagnosis (measured as presence of bilateral disease and as mean percentage of retinal area for both eyes) also was not associated with resistance. The factors measured for the entire study population that were associated with resistance were a CD4+ T cell count <50 cells/µL and a positive CMV culture result at baseline. For patients who were enrolled in 1996 or later, detectable CMV load at baseline also was associated with an increased incidence of resistance. However, neither exposure to HAART nor detectable HIV load at the time of CMV retinitis diagnosis was associated with increased resistance.

Table 2
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Table 2

Cumulative incidence of ganciclovir resistance at 1 and 2 years, by baseline characteristic.

Results of time-dependent Cox proportional hazards models of the association of HAART use, CD4+ T cell count, HIV load, and CMV load with phenotypic resistance to ganciclovir in the HAART era are presented in table 3. When HAART use was modeled both as exposure at diagnosis and as time-dependent use of HAART during the follow-up period, neither was significantly predictive of resistance. Detectable HIV load during follow-up also was not associated with resistance. However, a CD4+ T cell <50 cells/µL was associated with increased risk of resistance, and a detectable CMV load during the follow-up period had a large relative hazard and was highly statistically significant.

Table 3
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Table 3

Time-dependent models of ganciclovir resistance, 1996 or later.

Results were robust to the definition of resistance. Secondary analyses of the outcome of genotypic resistance (data not shown) produced similar results to those shown for phenotypic resistance.

Exploratory analyses revealed that 54 patients enrolled in the study in 1996 or later (30% of patients in that time period) were not receiving HAART at the time of or after the diagnosis of CMV retinitis, up to study closeout or the onset of phenotypic resistance (whichever came first). Seven of the 10 HAART-era cases of resistance occurred in this subgroup of patients. The 1- and 2-year incidences of resistance in this subgroup were 16% and 50%, respectively.

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Discussion

In this study, we investigated the incidence of ganciclovir resistance over more than a decade, spanning the pre-HAART and HAART eras. Our data show a decrease in the incidence of ganciclovir resistance that began in 1996 (the 2-year incidence was 28% among those enrolled before 1996 and 8.8% among those enrolled in or after 1996; P < .001).

Given the large decrease in ganciclovir resistance that coincided with the introduction of HAART, one also might have expected that, among patients enrolled in 1996 or later, there would have been a difference between those exposed and not exposed to HAART at the time of the diagnosis of CMV retinitis. In the multivariate, time-dependent model, receipt of HAART at the time of diagnosis of retinitis was associated with a 55% decrease in the hazard of developing drug-resistant CMV, but this result was not statistically significant (P = .25) because of the small number of cases of resistance. In addition, the effect of HAART is difficult to analyze, because although approximately one-half of patients were receiving HAART at the time of the diagnosis of CMV retinitis, ∼70% received HAART at some time before the diagnosis of CMV retinitis (estimates that are similar to those reported from another longitudinal study of ocular complications of AIDS [35]). Also, ∼80% of patients in the CRVR study received HAART during follow-up. Receipt of such treatment before the retinitis diagnosis and during follow-up, even if not sustained, may have therapeutic value beyond the short blocks of time in which we measured and analyzed, in a time-dependent fashion, antiretroviral therapy and resistance. Modeling the potentially complex relationship between HAART use and the development of resistance was not possible, given the small number of events. Furthermore, HAART use among patients who develop CMV retinitis may not be optimal, either before or after diagnosis, and our study data did not allow us to account for adherence. However, the exploratory subgroup analysis of the 54 patients enrolled in 1996 or later who did not receive HAART during follow-up (when at risk for the first occurrence of resistance) showed rates of resistance comparable to those from the pre-HAART era. This supports the idea that HAART use—even if suboptimal in this population of patients who develop CMV retinitis—reduces resistance to anti-CMV therapy.

We also investigated measures of immunologic benefit that patients may have received from antiretroviral therapy, even if therapy was suboptimal. In the HAART era, close to one-quarter of patients (up from only ∼7% from before 1996) had CD4+ T cell counts ⩾50 cells/µL at the time of diagnosis of CMV retinitis, and none of these patients developed resistance to ganciclovir. Nevertheless, their HIV loads were high (median, >105 copies/mL), and only 11% of patients had an undetectable HIV load at the time that CMV retinitis was diagnosed. Because we do not have measurements from before 1996 in this population, we do not know whether any differences in the HIV load occurred on the basis of period. In the HAART era, with only a few cases of resistance to analyze, the presence of a detectable HIV load either at baseline or during follow-up was not predictive of resistance. However, CD4+ T cell counts <50 cells/µL during follow-up produced a 6-fold increased risk of resistance.

The clearest associations with resistance involve measures of CMV (i.e., positive blood or urine CMV culture results and detectable CMV load in plasma or leukocytes). Of note is the negative predictive value of baseline CMV culture and CMV load—that is, only a very low incidence of resistance occurred among patients who had negative blood and urine culture results at the time of diagnosis of CMV retinitis, even when we included patients from the pre-HAART era. No cases of resistance occurred in the nearly 50% of the patient population who received a diagnosis of CMV retinitis in the HAART era and who had an undetectable CMV leukocyte load. Detectable CMV load during follow-up was associated with a large (>10-fold) risk of resistance. These data suggest that the immunological benefits of HAART—even if treatment is suboptimal, as is frequently the case in the CMV retinitis population—may contribute to better control of CMV replication. This is supported by other data showing a decreased CMV load when patients start to receive HAART [36].

Because the overall incidence of ganciclovir resistance in the HAART era is low, most patients who have detectable CMV load at baseline or during follow-up do not develop resistance to ganciclovir. That is, as we previously reported, the positive predictive value of detectable CMV load is low (range, 7%–9%) [37]. Therefore, testing for CMV load may be of some clinical utility in identifying persons who are unlikely to develop resistance to ganciclovir or those who are at increased risk, but testing does not readily identify when resistance occurs and a patient's treatment should be switched to an alternative anti-CMV regimen.

The incidence of ganciclovir resistance among patients with CMV retinitis has decreased by two-thirds in the HAART era. A CD4+ T cell count >50 cells/µL, negative CMV culture results, and an undetectable CMV load at the time of diagnosis of CMV retinitis are markers for patients who are unlikely to develop resistance. It is likely that immunological benefits of even suboptimal antiretroviral therapy have contributed to better control of CMV replication and to a decreased incidence of ganciclovir-resistant CMV.

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The Cytomegalovirus Retinitis and Viral Resistance Study Group

Clinical centers. The Johns Hopkins University School of Medicine (Baltimore, MD): Douglas A. Jabs (principal investigator), John G. Bartlett, Diane M. Brown, Lisa M. Brune, J. P. Dunn, Richard D. Semba, and Jennifer E. Thorne (former members: Stephen G. Bolton, John H. Kempen, Paul A. Latkany, Susan M. LaSalvia, Tracey Miller, Earline Nanan, Quan Dong Nguyen, Laura G. Neisser, Eva Rorer, George Peters, Qazi Faquir, and Armando Oliver); Northwestern University Medical School (Chicago, IL): David V. Weinberg, Alice T. Lyon, Annie Muñana, and Lori Kaminski; University of Miami (Miami, FL): Janet L. Davis, Elias Mavofrides, and Elizabeth Fuentes (former members: Elizabeth Cruz, Tina A. Rhee, and Patricia Vera).

Data center. The Johns Hopkins University School of Medicine and Bloomberg School of Public Health: Barbara K. Martin, Michelle O. Ricks, Lynn M. Hutt; former members: Cheryl Enger, Shirley Quaskey, and Judy Southall.

Flow cytometry laboratory. The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick and Fred Menendez.

Fundus photograph reading center. University of Wisconsin (Madison): Matthew D. Davis, Larry Hubbard, Jane Armstrong, Dolores Hurlburt, Sheri Glaeser, Jeff Joyce, Linda Kastorff, Nancy Robinson, and Marilyn Vanderhoof-Young (former member: Judy Brickbauer).

Virology laboratory. The Johns Hopkins Medical Institutions: J. Brooks Jackson, Michael Forman, and Linda Gluck (former members: Tamica Hamlin, Huiling Hu, Alicja Rylka, and Avareena Schools-Cropper).

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Acknowledgments

The CRVR Study Group acknowledges the laboratory of Dr. Thomas Quinn (Division of Infectious Diseases, Johns Hopkins University School of Medicine) in which the HIV load measurements were performed.

Financial support. National Eye Institute of the National Institutes of Health (EY10268 and EY015643 to D.A.J.), National Institute for Research Resources of the National Institutes of Health (M01-RR00052), and an unrestricted grant from Roche Laboratories.

Potential conflicts of interest. All authors: no conflicts.

  • Received September 1, 2006.
  • Accepted December 28, 2006.
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  1. Clin Infect Dis. (2007) 44 (7): 1001-1008. doi: 10.1086/512368
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