Cesar Ticona, MD

Cesar_Ticona

Nominated From: University of Washington

Research Site: Peru

Research Area: Infectious Disease

Primary Mentor: Joseph Zunt

Research Project

 

Cytomegalovirus viremia as a prognostic factor for poor outcome in AIDS patients

 

The impact of Cytomegalovirus (CMV) viremia upon the natural history of HIV/AIDS, and whether treatment of CMV viremia, in the absence of associated disease, is not known. Starting treatment after CMV has produced end-organ disease may be too late, yet the cost of prophylactic treatment may be too high, especially in developing countries. CMV infection is the most common viral infection in HIV-infected people (1). With the advent of antiretroviral treatment (ART) the incidence of CMV end-organ disease has declined significantly (2). However, in developing countries, where the majority of patients are still late presenters, (3) the incidence of CMV infection may be more likely to produce end-organ diseases and significant impact upon outcomes.

Subclinical CMV replication in HIV-infected patients has been associated with unfavorable outcomes. Durier et al, measured CMV viremia in Thai HIV patients who initiated ART at CD4 count <200 cells/mm3 to evaluate mortality and likelihood of developing a new AIDS-defining illness. The authors concluded that CMV DNA >500 copies/mL predicted increased mortality – despite ART initiation (4). Brantsaeter et al, used dried blood spots for detection of CMV viremia in HIV-infected patients with access to ART to examine the association of CMV viremia with outcomes; CMV≥200 copies/mL was an independent risk factor for death (HR 5; 95% CI: 2.1-11.9) (4). Moreover, unfavorable outcomes have been associated with HIV infection without AIDS. Fielding et al, showed that subclinical CMV viremia at baseline in HIV patients without AIDS was associated with a three-fold increase in mortality (HR 3.37; 95% CI: 1.60, 7.10) (6); the authors proposed the need for clinical trials to assess preemptive anti-CMV therapy in HIV-infected patients with subclinical CMV viremia.

In addition, CMV reactivation in critically ill patients suggests an immunologic or pathogenic role of CMV during severe illness (7). Frantzeskaki et al, evaluated CMV viremia in critically ill immunocompetent patients, and found CMV viremia occurred in 13.75% of patients and was associated with more severe organ dysfunction, but not with worse clinical outcome (8). In HIV-infected patients with CD4 counts <200 cells/mm3 in the intensive care unit, having high CMV viral load was associated with higher mortality compared to those with low viral load (HR 3.46; 95% CI: 1.55–7.71), especially in those who didn’t receive gancyclovir (100% mortality) (9). Despite these findings, preemptive treatment of CMV viremia in HIV-infected patients is not yet recommended, in contrast to the approach in stem cell transplant or solid organ transplant patients, where treatment is recommended. Mizushima et al, in a retrospective cohort study evaluated the efficacy of preemptive CMV therapy in HIV patients. They found that preemptive therapy significantly reduced CMV end organ disease by almost 25% (adjusted HR=0.170; 95%CI: 0.049–0.602; p=0.005), but there was no difference in mortality and some grade 4 adverse events were reported (10). Mattioni et al, in a retrospective study, found that preemptive therapy with valganciclovir was associated with a non-significant trend to reduced CMV end-organ disease, but was associated with significant toxicity (11). In a randomized placebo-controlled trial, Wohl et al evaluated preemptive therapy to prevent CMV end-organ disease in HIV-infected patients with CMV viremia; incidence of CMV end organ disease did not suggest a benefit of preemptive therapy (12). The current evidence is not strong enough to recommend preemptive therapy for CMV infection. Mainly due to methodologic factors (retrospective studies, small sample size, worse clinical conditions among patients evaluated with preemptive therapy, etc.), the ideal group of patients who may benefit from preemptive therapy has not yet been determined.

Specific Aims

Determine the association between CMV viremia and outcome of opportunistic infection, occurrence of immune reconstitution inflammatory syndrome, and mortality in the HIV/AIDS patients.

Research Significance

Cytomegalovirus (CMV) infection is a common complication during HIV infection in all countries. CMV detection in blood samples by PCR is economical and does not require biopsy tissue samples. Determining which patients with subclinical CMV viremia would benefit from preemptive antiviral therapy will be an important development that could prevent or reduce the devastating outcomes of CMV end-organ disease in HIV-infected patients living Peru and the United States without the need for tissue samples or other invasive, less accessible and expensive procedures.

Mentors

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