Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

The highest geometric mean titers of HHV-6 antibody occur during the first 3 years of life, indicating a clustering of primary infections in infants and toddlers (749Yoshikawa T, Suga S, Asano Y, et al. Distribution of antibodies to a causative agent of exanthem subitum (human herpesvirus-6) in healthy individuals. Pediatrics 1989;84:675-7., 750Brown NA, Sumaya CV, Liu CR, et al. Fall in human herpesvirus 6 seropositivity with age. Lancet 1988;2:396.). Approximately 90% of healthy children become infected with HHV-6 by 12 months of life (751Leach CT, Sumaya CV, Brown NA. Human herpesvirus-6: clinical implications of a recently discovered, ubiquitous agent. J Pediatr 1992;121:173-81.), and virtually 100% acquire infection by 3 years of age (750Brown NA, Sumaya CV, Liu CR, et al. Fall in human herpesvirus 6 seropositivity with age. Lancet 1988;2:396.). HHV-6 seroprevalence remains high throughout adulthood (750Brown NA, Sumaya CV, Liu CR, et al. Fall in human herpesvirus 6 seropositivity with age. Lancet 1988;2:396., 751Leach CT, Sumaya CV, Brown NA. Human herpesvirus-6: clinical implications of a recently discovered, ubiquitous agent. J Pediatr 1992;121:173-81.). Most children likely acquire infection through contact with the secretions of adult caretakers who shed the virus in saliva; approximately 85% of healthy or HIV-infected adults shed HHV-6 intermittently in their saliva (752Levy JA, Ferro F, Greenspan D, Lennette ET. Frequent isolation of HHV-6 from saliva and high seroprevalence of the virus in the population. Lancet 1990;335:1047-50.).

Primary HHV-7 infection also usually occurs during early childhood. Most adults have serologic evidence of previous HHV-7 infection. (753Di Luca D, Mirandola P, Ravaioli T, et al. Human herpesviruses 6 and 7 in salivary glands and shedding in saliva of healthy and human immunodeficiency virus positive individuals. J Med Virol 1995;45:462-8.). Eighty to ninety percent of HHV-7- infected adults, regardless of HIV status, shed HHV-7 intermittently in their saliva.

HHV-6B causes exanthem subitum (roseola), a common disease of childhood (754Ueda K, Kusuhara K, Hirose M, et al. Exanthem subitum and antibody to human herpesvirus-6. J Infect Dis 1989;159:750-2.). In addition, HHV-6B is a major cause of emergency room visits and hospitalizations for infants and young children (755Hall CB, Long CE, Schnabel KC CM et al. Human herpesvirus-6 infection in children: a prospective study of complications and reactivation. N Engl J Med;331:432-8. 1994.). HHV-6 also produces a spectrum of neurologic diseases, including encephalitis and febrile seizure (756Kimberlin DW, Whitley RJ. Human herpesvirus-6: neurologic implications of a newly-described viral pathogen. J Neurovirol 1998;4:474-85.). Although HHV-6 has been described as a cause of disease in other immunocompromised patients, it has not been identified as an important opportunistic pathogen in HIV-infected patients.

Both HHV-6 and HIV can simultaneously infect the same CD4⁺ cells under experimental conditions. Studies evaluating the effect of HHV-6 coinfection on active HIV viral replication in vitro have yielded contradictory results, with some investigations documenting enhanced HIV replication (757Lusso P, Ensoli B, Markham PD, et al. Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6. Nature 1989;337:370-3.), whereas others reported inhibition of HIV replication (758Asada H, Klaus-Kovtun V, Golding H, Katz SI, Blauvelt A. Human herpesvirus 6 infects dendritic cells and suppresses human immunodeficiency virus type 1 replication in coinfected cultures. J Virol 1999;73:4019-28.). In vivo studies have suggested a possible role for HHV-6 coinfection in the progression of HIV disease (759Chen H, Pesce AM, Carbonari M, et al. Absence of antibodies to human herpesvirus-6 in patients with slowly-progressive human immunodeficiency virus type 1 infection. Eur J Epidemiol 1992;8:217-21., 760Iuliano R, Trovato R, Lico S, et al. Human herpesvirus-6 reactivation in a longitudinal study of two HIV-1 infected patients. J Med Virol 1997;51:259-64.), but this remains unconfirmed.

HHV-7 has not been definitively documented to cause a specific disease, with no apparent correlation between HHV-7 and HIV plasma load, suggesting that HHV-7 infection might not be stimulated by or interact with HIV infection (761Boutolleau D, Bonduelle O, Sabard A, Devers L, Agut H. Detection of human herpesvirus 7 DNA in peripheral blood reflects mainly CD4+ cell count in patients infected with HIV. J Med Virol 2005;76:223-8.).

A fourfold or greater rise in anti-HHV-6 antibody titer between acute and convalescent serum samples suggests that active viral replication has occurred. Detection of HHV-6 IgM in infants and young children is a reliable marker of primary infection, although extrapolation to adults is problematic because IgM can be detected during HHV-6 reactivation. Detection of HHV-6 DNA in cell-free plasma specimens by PCR suggests active HHV-6 replication (762Secchiero P, Carrigan DR, Asano Y, et al. Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction. J Infect Dis 1995;171:273-80.).

HHV-6 and HHV-7 are ubiquitous universal infections, and prevention of exposure is not feasible.

Because of the ubiquity of HHV-6 and -7 during early childhood and the lack of an effective vaccine, prevention of primary HHV-6 and -7 infections or HHV-6 disease is not feasible.

Antiviral susceptibility patterns of HHV-6 resemble those of CMV. HHV-6 replication is readily inhibited by foscarnet, cidofovir, and ganciclovir at levels that are easily achievable in the human plasma. Indications for treatment of HHV-6 infection in HIV-seropositive patients are unclear. However, if disease in an HIV-infected person is determined to be caused by HHV-6, ganciclovir or foscarnet can be considered treatment options using treatment schedules and doses similar to those used for CMV disease (CIII). HHV-7 has not been recognized as a cause of disease in HIV-infected persons, and no recommendation for treatment can be made.

See CMV treatment recommendations for monitoring and adverse events. HHV-6 and -7 have not been demonstrated to be associated with IRIS.

Mutations conferring resistance of HHV-6 to ganciclovir, cidofovir, and foscarnet have been described (763De Bolle L, Manichanh C, Agut H, De Clercq E, Naesens L. Human herpesvirus 6 DNA polymerase: enzymatic parameters, sensitivity to ganciclovir and determination of the role of the A961V mutation in HHV-6 ganciclovir resistance. Antiviral Res 2004;64:17-25.). Theoretically, treatment failures could be managed by switching classes of antiviral medications (e.g., changing from ganciclovir to foscarnet), but data are completely lacking (CIII).

No data exist on prevention of HHV-6 or HHV-7 reactivation from latency in HIV-infected patients. Use of antiviral medications for this indication is not recommended (DIII).

Given the epidemiology of HHV-6 infection, symptomatic infection and indications for treatment in pregnancy are expected to be rare. See special considerations for CMV for a discussion of concerns regarding use of ganciclovir and foscarnet in pregnancy. Treatment of HHV-7 during pregnancy is not indicated.