Exploring the dynamics of the herpesvirus family

Human herpesviruses have caused a great burden of disease in the United States for decades.

“The herpesvirus family is noted mainly because once you acquire them, they remain in your body,” Swathi Gowtham, MD, a pediatric infectious disease fellow at Johns Hopkins Children’s Center, told Infectious Disease News. “They have a stage called primary infection, which is the initial infection, and then they become latent or dormant in your body and can reactivate. Once reactivated, they may or may not cause any problems depending on how strong your immune system is at suppressing them.”

The human herpesvirus family is divided into three groups — the alpha herpesviruses, the beta herpesviruses and the gamma herpesviruses.

The alpha herpesviruses include the herpes simplex viruses and varicella-zoster virus (VZV; HHV-3); beta herpesviruses include cytomegalovirus (CMV; HHV-5), HHV-6A and HHV-6B, and HHV-7; and gamma herpesviruses include Epstein-Barr virus (EBV; HHV-4) and Kaposi’s sarcoma-associated herpesvirus (HHV-8).

The International Committee on Taxonomy of Viruses recognized HHV-6A and HHV-6B as two distinct species in 2012.

“They are about 90% identical, and there’s been a big battle for 20 years among virologists over whether they should be called separate viruses,” Charles Grose, MD, professor and director of infectious diseases at the University of Iowa Children’s Hospital in Iowa City, said in an interview. “There are now nine different human herpesviruses, although we only number them up to eight.”

Infectious Disease News spoke with several experts to discuss the details of the different human herpesviruses, excluding HSV-1 and HSV-2.

Varicella infections

Primary infection of VZV is highly contagious and causes chickenpox, one of the most common childhood diseases before the varicella vaccine (Varivax, Merck) was licensed in 1995. VZV also is responsible for herpes zoster in adults. Herpes zoster, or shingles, is a reactivation of latent VZV within the body.

“Twenty years ago, some people said that you can catch herpes zoster from somebody else but you really can’t,” Anne A. Gershon, MD, a professor of pediatrics at Columbia University Medical Center, told Infectious Disease News. “I think that has finally been laid to rest. The only way you can develop herpes zoster is by reactivating the latent infection already in your body.”

Chickenpox typically causes an itchy, blister-like rash within 10 to 21 days of acquiring the virus, and most patients will develop a low-grade fever before the virus is out of their system. Similarly, shingles typically presents as a rash, but only on one side of the body. It can spread to both sides, however, and appear to be chickenpox, Gershon said, but that is unusual.

There are some similarities between shingles and herpes simplex, so diagnostic testing with PCR may be necessary. Regardless, both infections can be treated with antiviral therapy such as acyclovir, valacyclovir and famciclovir.

“There was a lot of controversy with drug use when they first came out because the studies showed there was a benefit, but it wasn’t anything spectacular,” Gershon said. “A lot of people just said, ‘Why spend the money?’ Now, chickenpox is becoming so rare that many people will treat it, particularly if the person was not vaccinated. Treatment for shingles is pretty standard.”

Varicella vaccines

VZV is the only herpesvirus that has vaccines licensed for use in the United States. Currently, the varicella vaccines are live-attenuated vaccines, but according to Gowtham, there is ongoing research in inactive vaccines that appears to be promising.

The Advisory Committee on Immunization Practices recommends two doses of varicella vaccine for children aged 4 to 6 years, with the second dose being administered at least 3 months after the first dose. It also recommends catch-up second doses for older children.

The ACIP also recommends the herpes zoster vaccine (Zostavax, Merck) for adults 60 years and older unless they are substantially immunocompromised.

“It’s a near universal recommendation,” said William Schaffner, MD, professor of preventive medicine at Vanderbilt University and an Infectious Disease News Editorial Board member. “However, there are still many internists who are unaware of it, and even among those who are aware of it, there are some practical glitches.”

Most of the recommended population are aged 65 years and older and are covered by Medicare. Although the herpes zoster vaccine is covered by Medicare, it is not covered under Medicare part B, as influenza and pneumococcal vaccines are. Instead, herpes zoster vaccine is covered under Medicare part D.

There are a number of problems with this, Schaffner said. First, not everyone subscribes to part D. Second, each individual prescription drug plan under part D has different requirements for payment. They all are mandated to cover the herpes zoster vaccine, but some plans may require copays, while others require patients to pay full price upfront and submit the claim for reimbursement.

“All of these are barriers, even for those patients who do have part D,” Schaffner said. “Many physicians who are aware of the zoster vaccine and want their patients to benefit from it actually refer them to pharmacies to receive the vaccine because part D is structured with a pharmacy focus. That has been one of the difficulties in getting this vaccine accepted by the general population and by doctors.”

Long-term protection

The herpes zoster vaccine also is FDA-approved for adults aged 50 to 59 years, but the ACIP does not recommend it for people in this age group.

“When the vaccine was originally licensed, the ACIP considered it, but did not recommend the vaccine for this age group due to vaccine shortages and because of limited data on long-term protection,” Sandra Adamson Fryhofer, MD, internal medicine physician in private practice and an adjunct associate professor of medicine at Emory University, told Infectious Disease News. “Although vaccine shortage concerns have been resolved, the ACIP looked at this issue again in 2013, and did not change its recommendation.”

The vaccine does work among people aged 50 to 59 years, with a vaccine efficacy of 69.8% in the first year, Fryhofer said. However, its efficacy decreases over time.

“Incidence of shingles and risk of severe complications such as postherpetic neuralgia increase with age,” Fryhofer said. “There is concern that people who are vaccinated in their 50s may not be protected when they need it most.”

The vast majority of shingles occurs among people aged 65 years and older, Schaffner said. At the moment, the herpes zoster vaccine is a “one-shot deal” that does not require a booster. The ACIP zoster vaccine working group has looked at this issue extensively, Schaffner said, but there are not enough data to make a recommendation for a second dose of herpes zoster vaccine.

“Reimmunization has not been studied extensively, and in the studies that have been done, the second dose has not had the booster effect,” Schaffner said. “Because immunity after the vaccine does wane, and because there is not sufficient evidence to recommend booster doses, the ACIP recommendation is one dose, after age 60, so that the antibodies are highest when the patients are at the highest risk.”

Varicella in special populations

Immunocompromised patients are at a particularly high risk for severe disease related to VZV. For herpes zoster, the virus is latent inside of the body unless it is reactivated. Most people who develop herpes zoster are aged older than 50 years or immunocompromised.

“In people with normal immune systems, if the virus is reactivated, the immune system immediately smacks it down so they don’t develop symptoms,” Gershon said. “If the immune system can’t manage the virus, then it’s possible to develop symptoms — usually the characteristic rash.”

According to Gowtham, immunocompromised patients also can spread VZV through respiratory droplets.

“Of all the herpesviruses, VZV is the only one that can spread through respiratory particles, so it makes it a little more infectious compared to other herpesviruses,” she said. “Immunocompetent patients spread the virus mainly through contact, but immunocompromised patients can spread it through respiratory secretions. We put these patients in negative pressure rooms so they don’t spread the virus.”

When immunocompromised patients get the virus, it can have the normal skin manifestations, but it also can spread to other organs, particularly the lungs, which can result in pneumonia, Gowtham said. William Schaffner

Fryhofer said the shingles vaccine should not be given to pregnant women and it is also contraindicated for patients with severe immunodeficiency from hematologic and solid tumors, those receiving chemotherapy, those receiving long-term immunosuppressive therapy and severely immunocompromised patients with HIV and CD4 counts of less than 200 cells/mcL.

Immunocompromised patients are also at high risk of developing shingles and subsequent disseminated zoster infections, Schaffner said. For those who will undergo chemotherapy or other immunosuppressive treatment, the recommendation is that they receive the vaccine before beginning the treatment.

Cytomegalovirus

According to the CDC, 50% to 80% of adults in the US are infected with CMV by the time they are aged 40 years. Most healthy children and adults with CMV are asymptomatic and do not know they are infected. Like VZV, it lies dormant until it is reactivated.

“Reactivation of CMV in normal, healthy patients with a normal immune system doesn’t really cause any issues,” Gowtham said. “You don’t really notice it; small bouts of the virus could be present in the blood, but the body is able to control it.”

Reactivation of CMV is mainly a problem for immunocompromised patients, particularly those undergoing bone marrow and solid organ transplants. These patients experience high morbidity and mortality associated with CMV reactivation.

CMV infections can result in pneumonia in bone marrow transplant recipients. It also can result in viremia that causes significant disseminated disease in the blood, resulting in patients becoming ill and losing their grafts, Gowtham said. The graft itself can become infected, and in this case, the patient has a high likelihood of losing the graft, particularly a liver graft.

CMV also is the most common congenital infection, Gowtham said. Approximately one of 150 babies born each year are infected with CMV, according to the CDC, and one out of every five children born with congenital CMV develop permanent problems. The most significant manifestation, Gowtham said, is hearing loss.

At IDWeek 2013, David W. Kimberlin, MD, co-director of the division of pediatric infectious diseases at the University of Alabama at Birmingham, presented data that suggest 6 months of therapy with oral valganciclovir (Valcyte, Genentech) resulted in better audiologic outcomes compared with 6 weeks of therapy in infants with symptomatic congenital CMV.

CMV is passed through bodily fluids, including breastmilk, urine and saliva. Outbreaks of CMV are common in day care centers. Adults working in day care centers can prevent the infection by washing their hands often with soap and water, especially after potential exposure by changing diapers, feeding young children, wiping children’s noses or drool and handling children’s toys.

Kaposi’s sarcoma

HHV-8 is known as Kaposi’s sarcoma-associated herpesvirus. This novel herpesvirus was first reported in Science in 1994, when identified in tissue from patients with AIDS-related Kaposi’s sarcoma.

According to the NIH, the seroprevalence of HHV-8 among the general population in the US is 1% to 5%. It is higher among men who have sex with men, regardless of HIV infection.

As with CMV and VZV, most people with HHV-8 are asymptomatic, unless they are immunosuppressed, which is the reason Kaposi’s sarcoma is usually AIDS-related. It most commonly presents as reddish-brown plaque or nodular lesions on the skin, on oral mucosa or on internal organs. Serologic testing is not indicated for HIV-negative individuals.

According to Grose, HHV-8 infection in people with HIV seems to be mainly transmitted sexually, and thus, is rarely found in young children. In adults who are receiving adequate treatment for HIV infection, it does not appear as though HHV-8 causes any additional disease.

Grose said HHV-8 is commonly found around the Mediterranean, where it is present in both adults and children even if they do not have HIV. Transmission appears to occur by saliva exchange among family members.

“The virus does not seem to have any consequences in children,” Grose said. “In late adulthood, even people without HIV can sometimes develop Kaposi’s sarcoma. The reason it is prevalent among adults in the Mediterranean is still a medical mystery.”

According to Philip E. Pellett, PhD, professor of immunology and microbiology at Wayne State University School of Medicine in Detroit, half of adults were infected with HHV-8 early in their life in the central African region.

“It’s not exactly clear why there are more early life infections in Africa, and there are different hypotheses as to why it might be,” Pellett said. “There’s more than one mode of transmission for HHV-8, we just know less about them.”

Epstein-Barr virus

EBV presents as the classic mononucleosis and is mostly prevalent among adolescents. According to the American Academy of Pediatrics, most people will become infected with EBV at some point in their lives, but the virus typically remains latent in the system. EBV transmission occurs through infected saliva and presents with fever, sore throat, swollen lymph glands and fatigue.

“What has been talked about in the literature remains true,” Grose said. “Not a whole lot has changed with the virus over the last 5 to 10 years.”

However, of all of the human herpesviruses, EBV has the longest incubation period — at about 40 days. The long incubation often leads teenagers to blame the wrong person for giving them EBV, otherwise known as “kissing disease,” according to Grose.

Splenomegaly also is common in adolescents who acquire EBV infection.

“If an adolescent is involved in any contact sports, we do an ultrasound of the abdomen to check for splenomegaly,” Grose said. “If they have it, we do not allow them to play any contact sports during that time, which is usually 1 to 2 months. It’s usually advice that is not eagerly accepted.” Philip E. Pellett

Grose said EBV also can occur in younger children, typically in the day care setting.

“In general, it causes mild symptoms, usually a low-grade fever for perhaps 3 to 4 weeks,” he said. “There are no major problems, but it’s just bothersome. There are no other complications of having it at an earlier age.”

HHV-6 and HHV-7

HHV-6 was known for years to cause roseola. Once 6A and 6B were recognized as separate species, however, it became evident that 6B was the main cause of roseola, which 80% to 90% of children will have before they are aged 2 years. About 30% have the classic fever-rash presentation of roseola. The majority experience a variety of symptoms, such as fever without rash, rash without fever, and others.

“We actually don’t even know what disease HHV-6A causes,” Grose said. “It’s a real mystery with regard to those two viruses because they’re about 90% similar at a genetic level, but it appears that HHV-6B is the one that causes the disease that most of us will be familiar with in the United States and Europe.”

However, there are some geographic differences for the viruses.

“Studies done in South Africa found HHV-6A in children with fevers,” Grose said. “Symptomatically, those illnesses presented similarly to HHV-6B. In other parts of the world, however, roseola symptoms are mainly connected to HHV-6B.”

In a study published in Epilepsia in 2012, researchers found that one-third of all children who have severe febrile seizures also have an active infection with HHV-6B.

“This is a striking observation because febrile seizures are sort of the bane of parents who try to do everything right in the care of their children; they just pop up,” Grose said. “It’s frightening, and there hasn’t been, up to this point, any specific etiology associated with the fever.”

According to Pellett, about 5% of roseola cases are caused by HHV-7 and the virus also can cause other febrile illnesses. Whereas HHV-6B infections primarily occur between 6 months and 2 years of age, HHV-7 infections start a little later and go a little longer. Both viruses are common in the environment.

“HHV-7 has primary disease that basically makes it look like roseola and makes it indistinguishable from HHV-6B primary infection,” Pellett said. “A larger subset of those kids have febrile convulsions during their primary infections that can also occur for HHV-6B.”

Testing for both HHV-6 and HHV-7 can be done using cultures, but Pellett said that is rarely performed other than in research settings. – by Amber Cox and Emily Shafer

References:

CDC. MMWR. 2007;56(RR04):1-40.
Chang Y. Science. 1994;266:1865-1869.
Epstein LG. Epilepsia. 2012;53:1481-1488.
Grose C. J Virol. 2012;86:9558-9565.

For more information:

Sandra Adamson Fryhofer, MD, did not release contact information.
Anne A. Gershon, MD, can be reached at aag1@columbia.edu.
Swathi Gowtham, MD, did not release contact information.
Charles Grose, MD, can be reached at charles-grose@uiowa.edu.
David W. Kimberlin, MD, did not release contact information.
Philip E. Pellett, PhD, can be reached at ppellett@med.wayne.edu
William Schaffner, MD, can be reached at William.schaffner@vanderbilt.edu.

Should prophylaxis for cytomegalovirus be standard in bone marrow transplant recipients?

The case for prophylaxis: Do not open “Pandora’s Box.”

Human cytomegalovirus (CMV) is a herpes virus that has co-evolved with humans over millennia. Approximately 50% of adults in United States have evidence of past CMV infection. After stem cell transplantation (SCT), CMV reactivation occurs in 50-80% of SCT recipients with past CMV infection. Recipients of unrelated, HLA-mismatched or cord blood allografts are at particularly high risk. In these patients, prolonged CMV replication has been associated with antiviral resistance, multiple organ involvement, susceptibility to opportunistic infections, poor graft function, graft-versus-host disease and mortality. Like a ninja, CMV employs espionage, sabotage, infiltration and assassination to impact the quality of life of SCT recipients and poses a burden in the health care system.

Prophylaxis consists of measures taken for disease prevention, as opposed to disease treatment. In this case, prophylaxis refers to measures taken to prevent CMV reactivation as opposed to organ involvement by the virus. I would submit that CMV as a pathogen meets all criteria for prophylaxis: Infection is common, its consequences grave and its treatment carries substantial toxicity. Why then, is there a debate about CMV prophylaxis? One argument for a pre-emptive strategy is that CMV replication typically precedes organ involvement. By delaying initiation of treatment until CMV viremia is present, one may minimize pill burden and toxicities by 1) delaying treatment, and 2) reducing the number of patients treated. Using current molecular methods for CMV detection, we know that CMV reactivation commonly occurs early after transplant. Among high-risk patients, not many are “spared” treatment with anti-CMV antivirals. Preventing reactivation from latency is easier than controlling active replication. Asymptomatic CMV viremia carries substantial risks and poses an undue burden to patients and health care. In high-risk patients, pre-emptive therapy is often inadequate to control CMV viremia in a timely fashion. Prolonged, partially controlled viral replication fosters emergence of resistant virus, with limited options for treatment. In turn, these lead to increased utilization of health care resources and toxicities. Continuous CMV replication further sabotages immune recovery by contributing to graft-versus-host disease and other opportunistic infections and finally leading to direct organ involvement by CMV.  While a highly effective prophylaxis may prevent reimmunization with CMV, delaying reimmunization until immune recovery may be desirable.

Universal prophylaxis with acyclovir has been a success story in preventing infections and deaths by herpes simplex virus and varicella-zoster virus after SCT. Mold-active azoles are routinely used as antifungal prophylaxis in high-risk groups. In solid organ transplants, clinical studies support CMV prophylaxis for high-risk groups. To gain wide acceptance, a prophylaxis strategy has to pass the bars for safety and tolerability and efficacy. What has been sparking the debate for CMV prophylaxis in SCT is an astonishingly empty pipeline over the last 20 years. The status quo may be about to change: With two antiviral compounds and a DNA vaccine in phase 3 clinical trials, and neutralizing antibodies and cellular therapies following suit, we may soon be seeing the light at the end of the tunnel.

Genovefa Papanicolaou, MD, is a member of the infectious disease service at Memorial Sloan-Kettering Cancer Center. She is also an associate professor of medicine, Weill Cornell Medical College. Disclosure: Papanicolaou has been an investigator and advisor for Chimerix Inc., Merck and Viropharma/Shire.

Prophylaxis requires less patient monitoring and is effective.

Cytomegalovirus (CMV) is well known among transplant professionals as the most common opportunistic infection following solid organ transplantation. What is not in dispute is that CMV is an important cause of morbidity and mortality – our patients still die from it. There is increasing agreement about the best agent to use (valgancyclovir) and optimal duration (6 months), particularly for CMV-negative recipients of CMV-positive organs, and the best diagnostic strategies we can use to monitor (PCR). But what still polarizes the field is whether to administer antivirals prophylactically or pre-emptively. In universal prophylaxis, we administer antivirals to all patients for a defined period of time. The protocol is different in preemptive therapy where we monitor patients for CMV infection weekly or fortnightly, and institute short courses of therapy as needed. But for me there is really no argument.

In a systematic review of 17 trials, Small et al compared prophylactic and pre-emptive therapies. They found that there was a similar risk of CMV disease in prophylaxis trials and pre-emptive trials. They also found that only universal prophylaxis was associated with a reduction in bacterial and fungal infections and death. A more recent systematic review of 40 studies again showed similar outcomes in terms of the occurrence of CMV disease between strategies. The odds of CMV disease was not different between the two strategies. However, it was interesting that the odds of late-onset CMV infections (1-2 months after prophylaxis was discontinued) – not disease - were higher for the prophylactic group compared with a pre-emptive strategy.

If both approaches were truly non-inferior – even accounting for the potential cost benefits of fewer drugs (and attendant toxicities) administered in preemptive therapy – what moves me to choose prophylaxis is ultimately a pragmatic one. A pre-emptive strategy requires discipline and a nuanced choreography of monitor, start and stop, then monitor again. In centers such as ours with a large catchment area of hundreds of miles, multiple labs, rural and urban settings, medical ecosystems and health care organizations, it is no easy task to add another variable onto the transplant coordinators’ plate. Comparative effectiveness research with its emphasis on outcomes in routine clinical practice could yield important information in this regard. Newer antivirals with better toxicity profiles could also strengthen the argument for prophylaxis. Future CMV-specific immune monitoring strategies could potentially lead to a hybrid of universal prophylaxis to eliminate the bulk of disease, combined with a pre-emptive approach to continue monitoring in the highest risk patients to prevent late onset disease. But I still won’t give up prophylaxis for anything.

Peter Chin-Hong, MD, MAS, is an associate professor of medicine, University of California, San Francisco. He is also an Infectious Disease News Editorial Board member. Disclosure: Chin-Hong reports no relevant disclosures.

Prophylaxis is associated with toxicity and has never outperformed pre-emptive therapy in trials.

Pre-emptive therapy for CMV is based on viral load surveillance using state-of-the-art technology such as PCR. Although there are arguments for both prophylaxis and pre-emptive therapy, I think the argument is strongest for pre-emptive therapy in the stem cell transplant population because it is supported by several well performed randomized trials. Today, the technology and the methodology of pre-emptive therapy have been refined to a point where it is highly effective and can be done at any transplant center that has modern diagnostic technology available.

The key argument for pre-emptive therapy is that with the existing drugs (ie, valganciclovir, foscarnet, cidofovir), prophylaxis has never been shown in a randomized trial to outperform pre-emptive therapy. Pre-emptive therapy also reduces toxicity and potentially allows immune reconstitution to CMV faster than with prophylaxis. Pre-emptive therapy works particularly well in low- to intermediate-risk populations. There are some high-risk populations (eg, cord blood transplant recipients) where prophylaxis may provide better protection against CMV disease.

That said, there are some breakthrough cases of CMV associated with pre-emptive therapy, but those cases are usually treatable with existing drugs and are not typically associated with excess mortality. Specifically, since CMV gastrointestinal disease can occur without PCR positivity, those cases can be missed by pre-emptive therapy. However, they can be handled with antiviral drugs effectively, and are not associated with higher mortality.

The key points are that prophylaxis with the existing antiviral drugs has not been shown to be superior in terms of CMV disease, mortality or any other meaningful clinical endpoint so far. The take-home message is that if you have a CMV PCR assay available at your institution, then pre-emptive therapy is a well-studied and effective way of preventing CMV disease that minimizes toxicities and may foster CMV immune reconstitution.  In the future, once new drugs with an improved toxicity profile become available, the risk-benefit ratio may change in favor of prophylaxis. But we are not quite there yet.

Michael Boeckh, MD, PhD, is a member of the vaccine and infectious disease division at Fred Hutchinson Cancer Research Center. He is also professor of medicine at the University of Washington. Disclosure: Boeckh receives research support from and/or is a consultant for Astellas, Chimerix Inc., Clinigen, Gilead Sciences, Merck, Microbiotix and Viropharma Inc.

Pre-emptive therapy results in lower medication expenses and less drug toxicity

Prevention of CMV after solid organ transplantation (SOT) involves the use of either antiviral prophylaxis or preemptive therapy. Preemptive therapy utilizes routine monitoring for evidence of infection, generally by weekly CMV viral load assays on blood for the first 3 or 4 months after transplant or after periods of intensified immunosuppression such as treatment of rejection. Upon detection of significant CMV viremia, antiviral therapy is initiated, usually with valganciclovir orally or IV ganciclovir. After the initiation of such therapy, weekly viral load assays are sent to monitor a response to therapy. Once one or two negative assays have been obtained, antiviral treatment can be stopped. At that point, the clinicians may wish to restart weekly monitoring thus resuming preemptive therapy; alternatively, they may wish to initiate secondary prophylaxis with antiviral therapy. Duration of secondary prevention should correlate with the risk of CMV,

The merits of pre-emptive therapy include a decrease in late CMV infection, lower medication expense, less drug toxicity, and improvement in graft survival. Negative aspects of pre-emptive therapy include higher diagnostic costs, Pre-emptive therapy requires good organization, and patients must be willing to go for routine testing. There is no prevention against other herpes virus infections (herpes, varicella including disseminated disease) with pre-emptive therapy (unless antiviral therapy with an acyclovir-like agent is added).

Viral kinetics may allow for rapid viral expansion, especially in previously nonimmune (seronegative) transplant recipients, such that weekly monitoring may not be frequent enough to detect very rapid CMV expansion. The augmented risk of viremia, including high grade viremia, increases the risk of indirect effects which may result in higher rates of the following: other infections (bacterial, fungal, viral), post-transplant lymphoproliferative disorder, cardiovascular events, post-transplant diabetes, immunosenescence, rejection, and mortality.

Pre-emptive therapy has been shown to be quite effective at prevention, especially in lower risk CMV seropositive organ transplant recipients; recent guidelines recommend both approaches (pre-emptive therapy and prophylaxis) for prevention. Emerging data suggest that it is also effective as prevention in transplant recipients at higher risk for CMV infection, i.e. CMV seronegative organ transplant recipients who receive organs from seropositive donors. Pre-emptive therapy is useful when patients don’t tolerate prophylaxis due to leukopenia, cost, or other side effects. A novel approach to prevention involves a hybrid of the two techniques, first using prophylaxis for a period of time, followed by a preemptive therapy, especially in those at higher risk for infection after the end of prophylaxis. The hybrid tactic thus harnesses the strength of both methods. In conclusion, CMV prevention is a key element of SOT management, and pre-emptive therapy is a very effective approach.

Camille Nelson Kotton MD, is the clinical director of Transplant and Immunocompromised Host Infectious Diseases at Massachusetts General Hospital. He is also an associate professor at Harvard Medical School. Disclosure: Kotton has been a consultant for Genentech and Roche Diagnostics.