What is the management of Human Herpesvirus (HHV) 6 and 7 infections, particularly in immunocompromised patients or those with severe disease?

HHV-6 and HHV-7: Clinical Overview and Management

For HHV-6 encephalitis in immunocompromised patients, treat with intravenous foscarnet (90 mg/kg twice daily) or ganciclovir (5 mg/kg twice daily) for at least 3 weeks until viral clearance from blood and CSF is documented. 1

Clinical Significance and Epidemiology

HHV-6

• HHV-6 is ubiquitous, with primary infection occurring in early childhood, and causes roseola infantum (exanthema subitum) in immunocompetent children 1, 2
• In immunocompromised patients, particularly hematopoietic stem cell transplant (HSCT) recipients, HHV-6B reactivation is the primary cause of infectious encephalitis post-transplant 1
• HHV-6 has not been identified as an important opportunistic pathogen in HIV-infected patients specifically, though it can cause disease in other immunocompromised populations 1

HHV-7

• HHV-7 has not been definitively documented to cause specific disease in immunocompromised patients, including those with HIV infection 1
• No apparent correlation exists between HHV-7 and HIV plasma load, suggesting minimal clinical interaction 1

Diagnosis

HHV-6 Diagnostic Approach

• Detection of HHV-6 DNA in cell-free plasma or CSF by PCR is the primary diagnostic test, with CSF PCR having 95% sensitivity for encephalitis 1, 3, 2
• A fourfold or greater rise in anti-HHV-6 antibody titer between acute and convalescent serum samples suggests active viral replication 1
• Detection of HHV-6 IgM is reliable in infants and young children for primary infection, but problematic in adults as IgM can be detected during reactivation 1
• Exclude chromosomally integrated HHV-6 (CIHHV-6) by testing blood PCR levels, as approximately 1% of the general population has integrated viral DNA that can confound diagnosis 3, 2

Clinical Presentation of HHV-6 Encephalitis

• Typical symptoms include acute-onset altered mental status, confusion, encephalopathy, short-term memory loss, seizures, or syndrome of inappropriate antidiuretic hormone secretion (SIADH) 3
• Rule out other pathogens including HSV-1/2, VZV, CMV, EBV, and other opportunistic infections before attributing disease to HHV-6 3

Treatment

HHV-6 Treatment Recommendations

For Confirmed HHV-6 Encephalitis:

• Intravenous foscarnet or ganciclovir are recommended as first-line agents, with drug selection dictated by side effects and patient comorbidities 1
• Recommended doses are foscarnet 90 mg/kg twice daily or ganciclovir 5 mg/kg twice daily 1
• Antiviral therapy should continue for at least 3 weeks and until testing demonstrates clearance of HHV-6 DNA from blood and, if possible, CSF 1
• Full-dose therapy (foscarnet ≥180 mg/kg/day or ganciclovir ≥10 mg/kg/day) is associated with better response rates than lower doses: foscarnet 93% vs. 74% (P=0.044); ganciclovir 84% vs. 58% (P=0.047) 1

Combination Therapy:

• Combined ganciclovir and foscarnet therapy can be considered, with one study showing 100% response rate in 10 patients, though small sample size limits definitive conclusions and drug toxicity must be weighed 1

Immunosuppression Management:

• Reduce immunosuppressive medications if possible during active HHV-6 disease 1

HHV-6 Treatment in HIV-Infected Patients

• If disease in an HIV-infected person is determined to be caused by HHV-6, ganciclovir or foscarnet can be considered using treatment schedules and doses similar to those used for CMV disease, though indications for treatment remain unclear 1
• HHV-6 antiviral susceptibility patterns resemble CMV, with ready inhibition by foscarnet, cidofovir, and ganciclovir at achievable plasma levels 1

HHV-6 Treatment for Other End-Organ Diseases

• For HHV-6B-associated end-organ diseases other than encephalitis, insufficient data exist to guide antiviral treatment recommendations 1

HHV-7 Treatment

• HHV-7 has not been recognized as a cause of disease requiring treatment in immunocompromised patients, and no recommendation for treatment can be made 1
• Treatment of HHV-7 during pregnancy is not indicated 1

Treatment Failure and Resistance

• Mutations conferring resistance of HHV-6 to ganciclovir, cidofovir, and foscarnet have been described 1
• Treatment failures can theoretically be managed by switching antiviral classes (e.g., changing from ganciclovir to foscarnet), though data are completely lacking 1
• Cidofovir has limited clinical data for HHV-6 encephalitis, with only two case reports available, and insufficient evidence to make a formal recommendation 1

Prophylaxis and Prevention

• HHV-6 and HHV-7 are ubiquitous universal infections, and prevention of exposure is not feasible 1
• No effective vaccine exists, making prevention of primary HHV-6 and HHV-7 infections or HHV-6 disease not feasible 1
• No data exist on prevention of HHV-6 or HHV-7 reactivation from latency in HIV-infected patients, and use of antiviral medications for this indication is not recommended 1
• Specific antiviral prophylaxis or preemptive therapy for HHV-6 infection is not recommended by the American Society of Transplantation Infectious Disease Community of Practice 4

Prognosis

• The prognosis for HHV-6 encephalitis is guarded, with memory defects and neuropsychological sequelae occurring in 20-60% of survivors 3
• Death from progressive encephalitis occurs in up to 25% of all HSCT recipients and up to 50% of cord blood recipients 3
• Risk factors for poor outcome include cord blood transplantation, acute graft-versus-host disease grades II-IV, mismatched unrelated donors, T-cell depleted allografts, and glucocorticoid treatment 3

Common Pitfalls

• Do not confuse chromosomally integrated HHV-6 (CIHHV-6) with active infection—always test blood PCR to distinguish, as 1% of the population has integrated viral DNA 3, 2
• Do not attribute disease to HHV-6 without excluding other pathogens, particularly in immunocompromised patients where multiple opportunistic infections can coexist 3
• Do not use suboptimal dosing—full-dose therapy is significantly more effective than lower doses for both foscarnet and ganciclovir 1
• Monitor for CMV-like adverse events during treatment, including nephrotoxicity with foscarnet and myelotoxicity with ganciclovir 1