Human Cytomegalovirus Resistance to Antiviral Drugs

Human cytomegalovirus (HCMV) infections are common and lead to lifelong infections. In immunocompetent individuals, primary infections are mostly subclinical or they may be associated with a self-limited mononucleosis-like syndrome. In contrast, infections in immunocompromised hosts (either primary infections, reactivations from latency, or reinfections) are associated with important morbidity and mortality. In patients with AIDS, the introduction of highly active antiretroviral therapy (HAART) has decreased the overall incidence of HCMV disease, mainly retinitis and gastrointestinal infections, by about 80% (50, 105). However, the functional benefit of HAART (i.e., restoration of specific HCMV-specific immune responses) may take up to 3 to 6 months to occur, and some patients do not have access to or do not respond to HAART (3, 40, 67, 104). Thus, HCMV still remains a concern in AIDS patients with CD4 counts <50 to 100 cells/μl. A specific HCMV syndrome consisting of fever, malaise, arthralgia, and neutropenia may occur in solid-organ transplant (SOT) patients, in particular, those developing a primary HCMV infection (i.e., HCMV-seronegative recipient from a HCMV-seropositive donor [D+/R−]) during the first 3 months posttransplantation. In addition, invasive HCMV disease may involve different organs, such as the lungs, liver, and gastrointestinal tract. In the absence of antiviral intervention, symptomatic HCMV infections occur in approximately 39 to 41% of heart-lung transplant recipients, 9 to 35% of heart transplant recipients, 22 to 29% of liver and pancreas transplant recipients, 8 to 32% of kidney transplant recipients, 50% of kidney-pancreas transplant recipients, and 22% of small-bowel transplant recipients (114), with the highest incidence seen in D+/R− patients. Finally, active HCMV infections have been associated with indirect effects, such as dysfunction or rejection of the transplanted organ, an increased risk for bacterial or fungal opportunistic infections, and accelerated atherosclerosis in heart transplant recipients (109). Among allogeneic bone marrow transplant (BMT) or hematopoietic stem cell transplant (HSCT) recipients, pneumonia and enteritis are the most common clinical manifestations of HCMV disease. In HCMV-seropositive recipients, active HCMV infections occur in 70 to 80% of patients; and in the absence of antiviral intervention, disease develops in 20 to 35% of those individuals, whereas active infections occur in only 15% of seronegative recipients of marrow from a seropositive donor (102). HCMV pneumonia remains associated with a significant risk of mortality, even when specific antiviral treatment is administered (18, 101). Gastrointestinal disease, alone or in association with pulmonary disease, is the second most common clinical manifestation of HCMV infections in that setting (85). In addition to AIDS patients and transplant recipients, HCMV infections have been associated with serious complications in other immunocompromised hosts, such as cancer patients, mostly those suffering from hematologic malignancies (48), and children with congenital primary immunodeficiencies (135). Finally, congenital HCMV infections can result in severe sequelae in newborns or during the first years of life (22).