July 10, 2002
Cytomegalovirus (CMV) is a DNA virus highly prevalent in populations worldwide. Although seroconversion in the general population is quite common, clinical disease is rare, transient and usually self-limited in immune competent individuals.
Prevalence of CMV seroconversion in the HIV population is higher than in the general population. Prior to the development of HAART, CMV disease in HIV was one of the most frequent opportunistic infections and was responsible for significant morbidity and mortality in patients suffering from AIDS. Today, CMV seroconversion in HIV patients remains common, but clinical disease manifestations are the exception, and occur mainly in patients off therapy, or non-responders with advanced immunosuppression.
Findings from in-vitro investigation suggest a synergistic effect of CMV and HIV on the development of immune suppression and co-infection of CD4+ T cells. CMV contributes to this effect, in part, through the transactivation of HIV-1 gene expression. In addition, CMV-infected cells are also known to release a range of different cytokines that could activate latent HIV proviral DNA and thus stimulate HIV-1 replication.
It is believed that in patients co-infected with CMV, a synergistic effect between both infections may serve to worsen the immunologic profile during early HIV infection, which, in the long term, could potentially translate into a more rapid disease progression. It is theorized that treating early HIV disease in these co-infected patients, at primary HIV infection (PHI), could reduce the chances of this synergistic effect, improving long-term prognosis.
The purpose of this study was to investigate the impact of CMV infection/reactivation on HAART response during the first 28 weeks of treatment in patients with PHI. To look at this, investigators from GlaxoSmithKline studied the effect of CMV on indices of HIV disease, prior initiation of treatment, and after 28 weeks of HAART in 125 treatment-naive PHI patients. These patients were part of a larger cohort of patients participating in the QUEST protocol, and receiving quadruple HAART (AZT/3TC/abacavir/amprenavir). PHI was defined as having a detectable HIV-RNA PCR and a negative or evolving HIV antibody test.
Patients were divided in two major groups based on the presence or absence of active CMV infection by positive CMV IgM or positive CMV DNA PCR. Seventy-nine patients were found to have active CMV infection, while 46 were negative for CMV IgM or DNA. Of these 46 CMV non-active patients, 38 had evidence of past seroconversion with positive IgG CMV antibodies.
CMV-active patients at baseline had a higher, significantly statistical median CD8+ and CD38+ counts than CMV non-active patients, despite equal absolute CD4+ counts. These CD8+ and CD38+ counts at baseline appear to correlate with the degree of CMV infection. At 28 weeks, the median HIV DNA was higher in CMV active patients than in CMV non-active. Equally, the time to achieve undetectable HIV-DNA was longer in these CMV-active patients.
The author concluded that CMV co-infection during HIV seroconversion is associated with higher pretreatment CD8+ and CD38+ activation that may reflect a cellular anamnestic or primary CMV response. CMV reactivation also appears to delay HAART response.
What are the implications of these results to us or to our patients? Bringing this work in perspective, the chances of encountering a patient with PHI is very low, because most of our patients already present long after HIV seroconversion has occurred. For those few whom we are lucky to encounter at this early stage, most of them have probably already been infected with CMV. For that group, there may be a value in assessing the presence of active CMV infection by measuring CMV IgM and CMV DNA PCR. But still the decision of starting early treatment is non-substantiated by these study results. It was interesting to see in this study that despite those differences in immunologic responses during the first 24 weeks, there were not significant differences in CD4+, CD8+ and CD38+ cell counts after 28 weeks of receiving HAART.
It is possible that CMV is not the only viral infection that may be acting synergistically in the immunopathology and progression of HIV infection. More studies assessing other potential co-factors are needed to determine with which infection it may be worthwhile to intervene by prevention or early initiation of HAART.
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