Detectable CMV predicts new AIDS events and deaths even with HAART

HIV-positive individuals with detectable cytomegalovirus (CMV) are more likely to experience new AIDS-defining illness and die, even in the era of HAART, according to a UK study published in the June 26^th edition of The Lancet. The study’s investigators, from London’s Royal Free Hospital, recommend that HIV-positive individuals with detectable CMV receive either more intensive HAART or anti-CMV therapy.

In addition, they call for a randomised controlled trial to be designed to evaluate if pre-emptive therapy for CMV in HIV-positive patients receiving HAART is justified. Interim data from the study were presented to the Ninth Retroviruses Conference in 2002 and were reported on aidsmap.

In the pre-HAART era, having detectable CMV in the blood was a predictor not only for future CMV disease, but for faster progression to a new AIDS-defining event and death as well. To see if these associations remained in the HAART era, the investigators conducted a prospective study involving 374 individuals who had a CD4 cell count below 100 cells/mm³ between 1997 and 2000. Individuals were seen every three months, when blood samples were taken to check for CMV using a PCR-based method.

At entry to the study, the median HIV viral load was 80,000 copies/ml and the median CD4 cell count was 80 cells/mm³. During the 36 months of the investigators’ analysis, 94.9% of patients took HAART. Baseline CMV tests were positive for 59 patients (15.8%). During the course of the study, 259 patients (69.3%) were persistently negative for CMV, 15 individuals (4%) were persistently positive, and CMV status changed in 100 patients (26.7%) on at least one occasion.

New CMV cases

On entry to the study, ten patients (2.7%) had been treated for CMV retinitis. There were a total of 14 new CMV events during the study, three events occurring in individuals who were negative for CMV at baseline. Patients who tested positive for CMV at baseline were eleven times more likely than those testing negative at this point to experience a new CMV event. The most recent CMV status was significantly related to a CMV event, even after the investigators controlled for CD4 cell count (p = 0.007) and HIV viral load (p = 0.008).

AIDS-defining events

At baseline, 206 (55.1%) individuals had already experienced an AIDS-defining event. During the three years of follow-up, 87 patients (23.3%) experienced a new AIDS-defining illness. Amongst the 315 individuals who were negative for CMV at baseline, there were 67 new AIDS events in a total of 797 patient years (rate 8.0 per 100 patient years). The incidence of new AIDS events was significantly higher among the patients who were positive for CMV on entry to the study. In these 59 patients, 18 new AIDS events occurred, an incidence of 16.4 per 100 patient years. The relationship between new AIDS events and a positive CMV PCR remained statistically significant after adjustment for both CD4 cell count and HIV viral load (p=0.04).

The investigators repeated their analysis excluding CMV as the cause of the new AIDS-defining event. The association between being PCR-positive for CMV and a new AIDS-defining event remained highly significant (p = 0.0001).

Death

During the study period, a total of 33 deaths occurred. Of these, 22 (7%) were negative for CMV at baseline and 11 (19%) were CMV PCR-positive. The death rate for individuals who were CMV-negative was 2.6 per 100 patient years. However, the rate for patients who were CMV-positive was 7.4 per 100 patient years. When these data were adjusted to take account of variables including CD4 cell count and HIV viral load, the presence of CMV in the blood remained significantly associated with death.

“We found that, even in the era of HAART, the presence of cytomegalovirus in the blood is independently associated with an increased risk of progression to cytomegalovirus disease, AIDS-defining illness and death,” comment the investigators. They stress that the increased risk of disease progression and death seen in their study was independent of CD4 cell count and HIV viral load.

Several reasons why CMV increases the rate of HIV disease progression and death are explored by the investigators. They suggest that CMV could activate latent reservoirs of proviral HIV. Another explanation could be that CMV directly causes disease and death without causing the signs of CMV end-organ disease. A lack of a functional immune response despite HAART could be an alternative explanation.

The investigators suggest that the detection of CMV in the blood could be a useful surrogate marker of immune function during treatment with HAART, with CMV reactivation being indicative of defects in immune reconstitution. In patients with detectable CMV during treatment with HAART, possible treatment strategies could be either the intensification of anti-HIV treatment or CMV therapy. The investigators conclude by calling for a randomised controlled trial to be conducted to determine the benefits of pre-emptive CMV treatment in patients receiving HAART.

A commentary on the Royal Free study in the same edition of The Lancet endorses this approach, arguing that the testing of blood for CMV using PCR “could provide a useful tool in the management of HIV patients. Specifically, patients failing current HIV treatments could be probed for persistent detection of CMV DNA.” Although this strategy would involve additional costs, there are benefits, particularly given the availability of oral CMV treatments such as valganciclovir. The commentary concludes by endorsing the Royal Free investigator’s call for a randomised clinical trial to assess the clinical benefit of this approach.

Further information on this website

CMV – overview

CMV viral load remains useful predictor of HIV disease risk - news story