Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1-infected women. Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group

Abstract

Background and methods: Cytomegalovirus (CMV) has been implicated as a cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We assessed 440 infants (75 of whom were HIV-1-infected and 365 of whom were not) who had known CMV status and were born to HIV-1-infected women and who were followed prospectively. HIV-1 disease progression was defined as the presence of class C symptoms (according to the criteria of the Centers for Disease Control and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter by 1 year of age and less than 500 cells per cubic millimeter by 18 months of age.

Results: At birth the frequency of CMV infection was similar in the HIV-1-infected and HIV-1-uninfected infants (4.3 percent and 4.5 percent, respectively), but the HIV-1-infected infants had a higher rate of CMV infection at six months of age (39.9 percent vs. 15.3 percent, P=0.001) and continued to have a higher rate of CMV infection through four years of age (P=0.04). By 18 months of age, the infants with both infections had higher rates of HIV-1 disease progression (70.0 percent vs. 30.4 percent, P=0.001), CDC class C symptoms or death (52.5 percent vs. 21.7 percent, P=0.008), and impaired brain growth or progressive motor deficits (35.6 percent vs. 8.7 percent, P=0.005) than infants infected only with HIV-1. In a Cox regression analysis, CMV infection was associated with an increased risk of HIV-1 disease progression (relative risk, 2.59; 95 percent confidence interval, 1.13 to 5.95). Among children infected with HIV-1 alone, but not among those infected with both viruses, children with rapid progression of HIV-1 disease had higher mean levels of HIV-1 RNA than those with slower or no progression of disease.

Conclusions: HIV-1-infected infants who acquire CMV infection in the first 18 months of life have a significantly higher rate of disease progression and central nervous system disease than those infected with HIV-1 alone.

Figure 1

Estimated Cumulative Rates of CMV Infection over Time among HIV-1–Infected and HIV-1–Uninfected Children. At the end of follow-up, 52 HIV-1–infected children were confirmed to be CMV-infected, 23 were CMV-uninfected, and 18 were of unknown status. Of the 463 HIV-1–uninfected children, 144 were CMV-infected, 221 were CMV-uninfected, and 98 were of unknown status. I-bars indicate 95 percent confidence intervals.

Figure 2

Cumulative Rates of Morbidity and Mortality Due to AIDS in HIV-1–Infected Children According to CMV Status at 18 Months of Age. Forty children had CMV infection, and 23 did not. Thirty additional children had unknown CMV status. Panel A shows the cumulative incidence of disease progression (P=0.001) and of CDC class C symptoms or death (P=0.008). Panel B shows the cumulative incidence of central nervous system (CNS) disease (impaired brain growth or progressive symmetric motor deficits) (P=0.005).

Figure 3

Longitudinal Changes in Mean CD4 Counts (Panel A) and CD8 Counts (Panel B) According to HIV-1 Status, Age, and CMV Status (as a Time-Dependent Covariate). Children were classified according to CMV status at the time of each lymphocyte measurement. The trend lines represent the model-based means, with 95 percent confidence intervals. Children infected with both HIV-1 and CMV had lower mean CD4 counts at 15 months of age (P=0.008) than those infected only with HIV-1 (Panel A). Coinfected children had significantly higher mean CD8 counts at 1, 9, 30, 42, and 54 months of age (P<0.001, P=0.03, P=0.04, P=0.008, and P=0.002, respectively) than those infected only with HIV-1 (Panel B). Among the HIV-1–uninfected children, those with CMV infection had significantly higher mean CD8 counts at 3, 9, 15, 21, and 54 months of age (P=0.003, P<0.001, P=0.03, P=0.05, and P=0.04, respectively) than those without CMV infection.

Figure 4

Longitudinal Changes in Mean HIV-1 RNA Levels According to HIV-1 Disease-Progression Status, Age, and CMV Status (as a Time-Dependent Covariate). Children were classified according to CMV status at the time of each HIV-1 RNA measurement. The trend lines represent the modelbased means and 95 percent confidence intervals. Among CMV-uninfected children (Panel A), those with rapid progression of HIV-1 disease (29 children) had significantly higher mean levels of HIV-1 RNA than those with slower or no progression (37 children) at all ages (P=0.004, P=0.002, P=0.04, P=0.002, P=0.007, P=0.006, and P=0.08 at ages 6, 12, 18, 24, 30, 36, and 42 months, respectively). Among CMV-infected children (Panel B), there were no significant differences in HIV-1 RNA levels between those with rapid progression and those with slower or no progression of disease, except for children 24 months of age (P<0.001). Numbers above and below the bars indicate numbers of children.