RE-STIMULATING INTEREST IN CYTOMEGALOVIRUS AS A COFACTOR FOR HIV INFECTION

Monday, 4th of August 2014

RE-STIMULATING INTEREST IN CYTOMEGALOVIRUS AS A COFACTOR FOR HIV INFECTION

Vincent C. Emery

Professor of Translational Virology, Department of Microbial and Cellular Sciences, University of Surrey, Guildford, Surrey, GU1 7XH

Correspondence: Tel +44 1483 689119, Email v.emery@surrey.ac.uk

Journal of Infectious Diseases Advance Access published July 31, 2014

Excerpt below; full text, with figure, is at http://jid.oxfordjournals.org/content/early/2014/07/31/infdis.jiu419.full.pdf

Cytomegalovirus (CMV) is a complex virus that continues to contribute to morbidity in a range of patients. These include solid organ and stem cell transplant recipients where the virus is associated with both direct effects such as CMV hepatitis [1] and gastrointestinal disease and indirect effects including acute rejection, reduced long term graft function, accelerated post transplant vascular disease and in some cases death [2], In addition, CMV remains an important cause of congenital disease leading to a range of sequelae including microcephaly, mental retardation and sensorineural hearing loss [3]. In the HIV-infected individual, CMV was once one of the most feared pathogens since it led to sight threating retinitis in patients whose CD4 counts dropped below 50cells/ul, and despite anti-CMV therapy, recurrences were frequent, often due to drug resistant strains of CMV [4,5].

Fortunately, in HIV infected populations with access to effective antiretroviral therapy (ART), the incidence of CMV retinitis is now very rare and CMV disease in HIV patients has become a distant memory for many physicians.

Given the strong association of CMV with inflammation [6] and a skewing of the T-cell immune response [7], it is noteworthy that in the early days of the HIV epidemic, CMV was suggested as a cofactor for HIV disease progression. A seminal article in this area was published in 1989 by Webster et al [8]. This study investigated 108 HIV-1 infected hemophiliac men whose date of HIV seroconversion was accurately known; the men were then stratified according to their CMV IgG status. Individuals with prior CMV infection, as evidenced by serology, were 2.5 times more likely to progress to an AIDS defining disease compared to CMV seronegative individuals and, using survival analysis, the risk increased approximately 2 years after seroconversion. At the time this study was published, it created some controversy, not least because a mechanistic basis for the accelerating effects of CMV on HIV disease progression were not readily available. Nevertheless, a further publication from the same group in 1995 showed that after 13 years of follow-up, the risks of CMV positivity on progression to AIDS, death and a CD4 count below 50 cells/ul were 2.28, 2.42 and 2.34, respectively, although the risks were influenced by patient age [9]. Interestingly, a double blind, placebo controlled study of high dose acyclovir (800mg, four times a day) in AIDS patients with CD4 counts below 150 cells/ul blood showed no effect on the incidence of CMV disease between the arms, but a significant survival benefit to those patients exposed to acyclovir (Odds ratio reduced from 0.39 to 0.23; p=0.018) [10]. This survival effect was also observed in a meta-analysis of eight high-dose acyclovir trails involving some 2947 patient-years of follow up [11].

In the intervening years, especially with the advent of effective ART, interest in the CMV cofactor hypothesis for HIV progression has waned, even though studies in groups where ART is not widely available have shown that CMV DNAemia in HIV-infected mothers is a risk factor for 2-year mortality in both the mothers and their infants (adjusted HR=4.3) [12].

It is, thus, timely that the article by Litchener et al [13] in this issue of the Journal of Infectious Diseases revisits the issue of CMV co-infection in a large cohort of HIV infected individuals (n=6,111) participating in the the ICONA study. The latter was set up in 1997 as an Italian multicenter observational study of HIV-1 infected individuals, and the power of such cohorts is beautifully demonstrated by the findings presented in their current report.