CMV Viremia:
A Look at the Other Viral Load

Since current anti-CMV drugs are so costly, toxic and difficult to administer, it would make a lot of sense to single out those most at risk for CMV disease for early, preemptive treatment. CMV PCR assays may turn out to be the way of identifying this population. At this year's Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), researchers presented additional data that indicate CMV viremia is predictive of CMV disease progression and survival. The data suggest that CMV viral load can be a useful tool in tailoring CMV treatment options to suit each individual, just as HIV viral load is now.

CMV Viremia and Risk of Disease Development

Poster I-232 at ICAAC, by Stephen Spector, M.D., and colleagues at the University of California San Diego, reported on further analysis of plasma samples from over 600 participants in Roche study 1654. This CMV prophylaxis trial compared treatment with three grams of oral ganciclovir versus placebo in patients with advanced AIDS (see Treatment Issues, Sept. 1996).

Dr. Spector's group found that ability to detect CMV using PCR and quantity of virus correlated with development of CMV disease and survival. Participants with CMV present in their blood at baseline had a 3.4-fold increased risk of developing CMV disease and a 2.5-fold increased risk of death. With each 10-fold increase in CMV viral load at baseline, patients experienced a 3.1-fold increased risk of CMV disease and a 2.2-fold increased risk of death. This data was consistent with a recent article by Francis Bowen (EF Bowen et al. AIDS. June 1997; 11(7):889-93), which found that each 0.25 log10 (77%) increase in CMV viral load was associated with a 37% increased likelihood of developing CMV disease.

In the Spector study, among participants who were CMV PCR-positive at baseline, CMV disease developed in 43% receiving placebo versus 26% receiving oral ganciclovir. Participants receiving oral ganciclovir who switched from PCR-positive to -negative after two months of treatment had a 20% risk of developing CMV disease in one year, compared to the 48% risk found in those who remained PCR-positive. Of the 16 placebo patients who were CMV PCR-negative at baseline who developed CMV disease, 88% became PCR-positive prior to developing disease, and a switch from negative to positive correlated with a higher risk of CMV disease.

Dr. Spector's group concluded that CMV PCR-positivity increases the risk of developing CMV disease and decreases survival. Patients who clear CMV from their blood (in other words, become CMV PCR-negative) using oral ganciclovir exhibit a lower risk of disease progression and increased survival. This study also demonstrated that while HIV viral load did have some predictive value of risk of CMV disease progression and death, the predictive value of CMV viral load was much stronger. In addition, in the cohort of patients with CD4s below 50, there was not a statistically significant correlation between CD4 cell count and disease progression and death.

Looking at Preemptive Treatment

Furthering the Spector findings was a poster at ICAAC (H-58) by Paul Griffiths, M.D., and colleagues, of The Royal Free Hospital School of Medicine at the University of London, looking at preemptive treatment in CMV PCR-positive asymptomatic patients. Although preemptive treatment usually consists of the same steps as treatment for active CMV disease (induction with IV ganciclovir followed by lifelong maintenance therapy with oral or IV ganciclovir), the Griffiths' study was conducted to determine if oral ganciclovir alone could be used. The small pilot study compared 28 days of either three or six grams of oral ganciclovir in 20 patients. Participants in the three-gram arm took longer to clear CMV viremia than those in the six-gram arm. Patients taking three grams experienced viral rebound as soon as treatment terminated, while patients on six grams did not immediately rebound. The follow-up period for this trial was extremely short so it is impossible to say what will happen to the participants in the future. However, Dr. Griffiths expected that those who received six grams would also experience viral rebound some time after treatment terminated because CMV cannot be eradicated by present methods. Oral ganciclovir was well tolerated at both doses, but again, time on treatment was very short.

Dr. Griffiths noted data from previous work by his London group indicating IV ganciclovir was more effective at clearing viremia than either dose of oral ganciclovir. He stated, "If I were a patient with a positive viremia test, I would give myself a course of IV ganciclovir and then go on to oral." The dose and the amount of time on oral ganciclovir are still unclear. More trials are necessary to determine the best regimen. The disadvantage of IV induction is, of course, the inconvenience and the possibility of introducing blood infections. If IV is not used, this preliminary study suggests that six grams may be more effective than three in clearing viremia. (This makes sense, as a six-gram dose of the oral drug achieves blood levels of ganciclovir that are closer to what is achieved with IV infusions.)

Is Viremia Enough To Go On?

From the work Dr. Griffiths has done with transplant patients, he has seen that the presence of viremia in the blood identifies a risk for development of active disease in multiple organs. According to several studies in AIDS patients (EF Bowen et al. AIDS. op cit.; M Shinkai et al. Journal of Infectious Diseases. Feb. 1997; 175(2):302-8; KK Dodt et al. AIDS. March 1997; 11(3):F21-8), virtually everyone who is at risk for CMV will have CMV viremia beforehand. Dr. Griffiths tests all his patients with CD4 counts below 100 for the presence of CMV in the blood. If the results are negative, another test is performed at each subsequent visit. A positive test indicates that there is approximately a 60% risk of disease development in asymptomatic patients. Dr. Griffths suggests this risk is high enough to warrant, at least the consideration, of starting preemptive therapy.

Since oral ganciclovir is so expensive, its broad use as CMV prophylaxis is not cost effective (DN Rose and HS Sacks. AIDS. June 1997; 11(7): 883-7). By testing for CMV viremia in patients with CD4 cell counts below 100, only those most at risk are targeted for treatment. Dr. Griffiths stated that about 20% of patients tested will be CMV-positive, thus reducing by 80% the potential drug bill and providing medicine only to those who need it. Even though higher CMV viral loads indicate increased risk for disease development, Dr. Griffiths does not support waiting to start therapy. He advocates, instead, treating all patients who test positive for viremia in order to identify CMV before it seeds the retina and causes visual disturbances, or travels to another organ. He cited the 1997 Bowen article in AIDS that reports how rapidly disease can develop after a positive CMV PCR test, in as quickly as two to four months in some cases.

While Alejo Erice, M.D., of the University of Minnesota, agrees that detection of CMV viremia in plasma indicates risk of disease, he notes that not everyone with a positive qualitative test will develop active CMV. He feels it is also important to learn how to understand and use CMV viral load to make treatment decisions. Dr. Erice is the protocol chair of ACTG 360. This trial has just completed enrollment of 400 CMV-positive patients who have had no clinical symptoms of CMV, yet have high risk because of CD4 counts below 50. ACTG 360 is a three-year observational study with three primary objectives: 1) to define the relationship between HIV and CMV viral load and the risk of CMV disease associated with each; 2) to establish threshold CMV and HIV load values that are correlated with development of CMV end organ disease; and, 3) to determine the natural history of CMV infection in the context of highly active antiretroviral therapy (HAART). The study will also evaluate various commercial CMV PCR assays.

David Wohl, M.D., of the University of North Carolina, cautioned that, in general, "We really don't know yet what it means to have viremia. Anyone making judgements based on this is doing so by the seat of their pants." He points out that CMV can appear intermittently in the bloodstream. It may make more sense to target a sustained and, as yet, undetermined CMV viral load amount for treatment. Prescribing ganciclovir to everyone who is CMV PCR-positive could be overtreating. Dr. Wohl suspects that CMV viremia is only part of the equation and that CD4 count and HIV viral load may need to be considered as well in determining who is at most risk for development of active disease. "It's going to be a more complex picture than simply saying, you have CMV in your blood, we should act on this."

Translating Research into Clinical Practice

Ophthalmologists in this country are not as aggressive as Dr. Griffiths in the use of preemptive therapy at this point. This may be because no CMV PCR tests have yet been validated or are widely available, and there is no universally accepted method for interpreting test results. The investigators mentioned in this article, such as Drs. Griffiths and Spector, developed and used their own noncommercial "home brew" assays in their research. Some doctors argue that data from such noncommercial assays cannot be translated into clinical practice.

Also, not many patients would volunteer for a course of IV ganciclovir, or even oral ganciclovir at six grams a day, unless they had active disease, because of toxicity and expense (they might have difficulty getting reimbursed since preemptive treatment is not an FDA-approved indication for ganciclovir). It also needs to be clearly established that preemptive treatment does in fact increase survival. Mark Jacobson, M.D., at the University of California San Francisco, feels that it is premature to recommend such early treatment in clinical practice, "We don't know if preemptive treatment would ultimately benefit people. Starting treatment before disease might cause problems because of toxicity from the drugs." Bruce Polsky, M.D., of Memorial Sloan-Kettering in New York City added, "The data from the field are pretty far ahead of clinical practice from the point of view of what's available in terms of diagnostics, ease of therapy and reimbursement. I agree with Dr. Griffiths in the abstract, but in the clinic we don't have a way to apply it, in a practical sense. This is what we should be striving to do."

Finally, with the advent of HAART, there is less CMV around. The early participants in Dr. Griffiths' study who did not have access to HAART had higher CMV viral loads than those who enrolled later. This suggests that potent control of HIV-induced immunosuppression may reduce the incidence of asymptomatic CMV viremia as well as CMV disease. Just as transplant patients are at risk for CMV disease only while at their most immunocompromised, Dr. Griffiths and others in the field hope that HAART will restore the immune system of AIDS patients to the point that CMV ceases to be a threat. In fact, there have been reports of HAART patients with CMV retinitis on maintenance therapy who have not experienced reactivation of disease in the expected time frame. This is apparently due to HAART restoring immune competence. CMV PCR assays might be a useful tool to predict risk of CMV relapse for those patients who choose to go off their CMV treatment and maintain themselves on HAART.

Getting Tested

While there are other methods to detect the presence of CMV (viral cultures, serology, pp65 antigenemia), the PCR assays are the most sensitive (KK Dodt et al. AIDS. op cit.). There are two types of PCR tests: the viremia or qualitative assays that determine if a person is CMV-positive or -negative and the quantitative assays that measure viral load. Hoffman-La Roche and BioSource International have both developed these assays, which are available through certain labs (Biosource is offering both tests, while Roche is just offering the qualitative). Other companies are also working on methods of quantifying CMV DNA in plasma. Clinical trials for FDA approval of the PCR assays are not yet up and running. Persons interested in getting these tests should check with their physician to find a participating lab. Since they are not FDA-approved, insurance reimbursement is not guaranteed. Data from studies such as ACTG 360, that use standardized CMV PCR assays, will help determine how best to use these tests as diagnostic tools. To determine whom to treat, another study, being proposed to the ACTG by Drs. Jacobson and Wohl, would examine CMV viral load and randomize participants above a certain level to either treatment with the ganciclovir prodrug (see below) or placebo. What will then be needed is for those companies involved in the development of the assays to move quickly for FDA approval. An easy-to-take, highly effective medicine to combat CMV will be needed as well. One candidate for this role is the ganciclovir prodrug, once again under development by Hoffman-La Roche after a six-month hiatus (see "Improved Ganciclovir Regimens" in this issue). It represents a great improvement in ease and safety of administration, but will still be a very toxic compound. Glaxo Wellcome's 1263W94 is another promising new agent for CMV treatment (see Treatment Issues, Sept. 1997 ), although it is still in early development.