IHMF: Cytomegalovirus and Human Herpesvirus Type 6 Infections in the Immunocompromised (non-HIV) Host
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  Cytomegalovirus and Human Herpesvirus Type 6 Infections in the Immunocompromised (non-HIV) Host View Monograph Download Monograph


Background Information
Introduction
Chapter 1
Chapter 2
Chapter 3
Chapter 4
References

 
Introduction

This monograph was produced from a Workshop held in March 1996, whose recommendations were endorsed at the Annual Meeting in November 1996. Thus, nearly 5 years have elapsed since the recommendations were made, and the aim of this brief update is to draw attention to subsequent developments. Overall, a review of the monograph shows that the general principles it discusses remain appropriate. Furthermore, none of the recommendations is incorrect, although some, particularly research recommendations, have subsequently been achieved. The aim of this update is thus to provide additional details and references to recent publications which expand upon the principles set out in the monograph (see Background Information).

 
Chapter 1

The major change here has been extensive application of quantitative measures of cytomegalovirus (CMV) viral load to understand natural history and pathogenesis. Specifically, serial measures of viral load have defined the dynamics of CMV replication.1 The dynamics are far more rapid than had been envisaged, with a doubling-time (viral load on the increase) and half-life (viral load on the decrease in response to antiviral chemotherapy) of approximately 1 day. Thus, control of CMV replication will require rapid diagnosis, prompt introduction of potent antiviral compounds and so prevention of the high viral loads, which are associated with CMV disease. Although a high viral load coincides with CMV disease, it has now been shown that early measurements can predict those destined to develop high viral loads, i.e. can select patients likely to benefit from early antiviral therapy.2

 
Chapter 2 back to top

A further, large, double-blind, randomized, placebo-controlled trial of antiviral prophylaxis has been reported. Lowance et al.3 randomized renal transplant recipients to receive 90 days of valaciclovir, 2 g qds or placebo. The results demonstrated dramatic control of CMV disease while the drug was being taken, with a highly significant beneficial effect still being present when the patients were followed to 180 days. In addition, the trial showed a significant reduction in biopsy-proven acute graft rejection, consistent with the concept discussed in this monograph that CMV triggers some cases of graft rejection. Follow-up of the cardiac transplant patients who received 4 weeks of intravenous ganciclovir4 has shown reduced fungal septicaemia5 and reduced accelerated atherosclerosis.6 Taken together, the ability of antiviral drugs to control these ‘indirect effects’7 show that they are causally associated with CMV. Thus, while CMV end-organ disease is an important clinical outcome, the benefits of preventing CMV infection far exceed what is measured by this single parameter. Indeed, it has been shown that the medical costs associated with CMV disease are high 8 so providing a pharmaco-economic justification for preventing this infection.

In the monograph, the use of prophylaxis or pre-emptive therapy to control CMV infection and disease is discussed. Subsequent studies have confirmed that both of these are effective ways of controlling CMV, although their relative merits are hotly debated.9,10

The significance of resistance has increased. Once the dynamics of CMV replication were defined, it was possible to predict that resistance was a more frequent event and to explain why conventional cell cultures frequently fail to detect resistance in patients failing therapy.11 By avoiding the false-negative results from cell culture, it was possible to show that AIDS patients had an incidence of 22% of ganciclovir-resistant CMV 12 and a similar incidence of 20% has recently been reported in recipients of solid-organ transplants.13 Both of these studies show the problems of long-term maintenance antiviral therapy, particularly with oral ganciclovir which is poorly bioavailable and fails to control CMV replication.11

The only new drug to become available is valganciclovir, the valine ester of ganciclovir, which will allow induction doses to be given without intravenous administration, will allow higher doses to be given for maintenance therapy, so replacing oral ganciclovir, and will make the administration of pre-emptive therapy a more practical proposition. There is still an urgent need for safe and potent novel compounds that are able to treat CMV, including strains resistant to ganciclovir.

Finally, a research need has been met by a trial of combination therapy for CMV. Transplant patients requiring pre-emptive therapy were randomized to receive either iv ganciclovir or ganciclovir plus foscarnet, each at half-dose. The results show that the combination was not superior to standard ganciclovir therapy.14

 
Chapter 3 back to top

The need to invest in vaccine development for CMV highlighted in this chapter will hopefully be stimulated by a recent report from the Institute of Medicine showing the potential cost-effectiveness of a vaccine.15 The soluble recombinant glycoprotein B vaccine discussed is still being evaluated in investigator-driven studies.

It is now known that wild strains of CMV contain approximately 22 additional genes which are not present in the laboratory-adapted variants.16 It is possible that incorporation of these additional genes into a vaccine could confer some immunological protection against CMV. Accordingly, genetic techniques have been used to incorporate the missing genes into the Towne vaccine candidate background, with the expectation that a live, attenuated vaccine of proven safety can be made more immunogenic (reviewed in17).

 
Chapter 4 back to top

The monograph summarized the situation in the very early days of HHV-6. Since then, the genomes of various strains have been sequenced18–20 and much more is known about the natural history of this virus.21

Some of the early case reports of disease associations have not been confirmed, e.g. multiple sclerosis, pneumonitis post-transplant.

HHV-6 appears to cause some cases of encephalitis in the immunocompromised host,22 which is consistent with the proven neurotropism of this virus.23

Clinicopathological studies have shown statistical associations between HHV-6 infection and graft rejection following liver transplant,24 which is reminiscent of the indirect effects of CMV discussed above. HHV-6 is also associated statistically with CMV end-organ disease.9,25 Fortunately, HHV-6 and HHV-7 do not appear to produce CMV inclusion bodies, so that their histopathological identification remains specific for CMV.26

Clearly, much more work is needed to define the full impact of HHV-6, as well as for the more recently described and genetically closely related HHV-7 (reviewed in27).

 
References back to top

1. Emery VC, Cope AV, Bowen EF, Gor D, Griffiths PD. The dynamics of human cytomegalovirus replication in vivo. J Exp Med 1999; 190: 177–182.
2. Emery VC, Sabin CA, Cope AV, Gor D, Hassan-Walker AF, Griffiths PD. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 2000; 355: 2032–2036.
3. Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N Engl J Med 1999; 340: 1462–1470.
4. Merigan TC, Renlund DG, Keay S, Bristow MR, Starnes V, O'Connell JB et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N Engl J Med 1992; 326: 1182–1186.
5. Wagner JA, Ross H, Hunt S, Gamberg P, Gamberg P, Valantine H, Merigan TC et al. Prophylactic ganciclovir treatment reduces fungal as well as cytomegalovirus infections after heart transplantation. Transplantation 1995; 60: 1473–1477.
6. Valantine HA, Gao SZ, Menon SG, Renlund DG, Hunt SA, Oyer P et al. Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study. Circulation 1999; 100: 61–66.
7. Rubin RH. The indirect effects of cytomegalovirus infection on the outcome of organ transplantation. JAMA 1989; 261: 3607–3609.
8. Kim WR, Badley AD, Wiesner RH, Porayko MK, Seaberg EC, Keating MR et al. The economic impact of cytomegalovirus infection after liver transplantation. Transplantation 2000; 69: 357–361.
9. Hart GD, Paya CV. Prophylaxis for CMV should now replace pre-emptive therapy in solid organ transplantation. Rev Med Virol 2001; 11: 73–81.
10. Emery VC. Prophylaxis for CMV should not now replace pre-emptive therapy in solid organ transplantation. Rev Med Virol 2001; 11: 83–86.
11. Emery VC, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Natl Acad Sci U S A 2000; 97: 8039–8044.
12. Bowen EF, Emery VC, Wilson P, Johnson MA, Davey CC, Sabin CA et al. Cytomegalovirus polymerase chain reaction viraemia in patients receiving ganciclovir maintenance therapy for retinitis: correlation with disease in other organs, progression of retinitis and appearance of resistance. AIDS 1998; 12: 605–611.
13. Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 2000; 356: 645–649.
14. Mattes FM, Hainsworth E, Murdin-Geretti AM, et al. A randomized, controlled trial comparing ganciclovir or ganciclovir plus foscarnet (each at half dose) for pre-emptive therapy of cytomegalovirus infection in transplant recipients (abstract). 41st ICAAC, USA, December 2001.
15. Stratton KR, Durch JS (eds). Vaccines for the 21st Century: a Tool for Setting Priorities. National Academy Press, Institute of Medicine, 2001.
16. Cha TA, Tom E, Kemble GW, Duke GM, Mocarski ES, Spaete RR. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol 1996; 70: 78–83.
17. Prichard MN, Penfold ME, Duke GM, Spaete RR, Kemble GW. A review of genetic differences between limited and extensively passaged human cytomegalovirus strains. Rev Med Virol 2001; 11: 191–200.
18. Dominguez G, Dambaugh TR, Stamey FR, Dewhurst S, Inoue N, Pellett PE. Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol 1999; 73: 8040–8052.
19. Gompels UA, Nicholas J, Lawrence G, Jones M, Thomson BJ, Martin ME et al. The DNA sequence of human herpesvirus-6: structure, coding content, and genome evolution. Virology 1995; 209: 29–51.
20. Isegawa Y, Mukai T, Nakano K, Kagawa M, Chen J, Mori Y et al. Comparison of the complete DNA sequences of human herpesvirus 6 variants A and B. J Virol 1999; 73: 8053–8063.
21. Clark DA. Human herpesvirus 6. Rev Med Virol 2000; 10: 155–173.
22. Wang FZ, Linde A, Hagglund H, Testa M, Locasciulli A, Ljungman P. Human herpesvirus 6 DNA in cerebrospinal fluid specimens from allogeneic bone marrow transplant patients: does it have clinical significance? Clin Infect Dis 1999; 28: 562–568.
23. Hall CB, Long CE, Schnabel KC, Caserta MT, McIntyre KM, Costanzo MA et al. Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med 1994; 331: 432–438.
24. Griffiths PD, Ait-Khaled M, Bearcroft CP, Clark DA, Quaglia A, Davies SE et al. Human herpesviruses 6 and 7 as potential pathogens after liver transplantation: prospective comparison with the effect of cytomegalovirus. J Med Virol 1999; 59: 496–501.
25. Humar A, Malkan G, Moussa G, Greig P, Levy G, Mazzulli T. Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver transplant recipients. J Infect Dis 2000; 181: 1450–1453.
26. Mattes FM, McLaughlin JE, Emery VC, Clark DA, Griffiths PD. Histopathological detection of owl's eye inclusions is still specific for cytomegalovirus in the era of human herpesviruses 6 and 7. J Clin Pathol 2000; 53: 612–614.
27. Black JB, Pellett PE. Human herpesvirus 7. Rev Med Virol 1999; 9: 245–262.

 

Paul Griffiths
Royal Free Hospital School of Medicine
University of London
London, UK

 

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Last Updated : 23/02/2007 16:28:17