Active ciHHV-6 linked to heart failure, a condition treatable by antiviral therapy

Antiviral therapy appears to benefit heart failure patients with active ciHHV-6

A group from one of the largest cardiology clinics in Europe, at Berlin’s renowned Charite Universitatsmedizin, has published a report demonstrating that heart failure patients with active chromosomally integrated HHV-6 (ciHHV-6) can be treated successfully with antivirals. The comprehensive study, led by Professor Uwe Kühl, systematically analyzed over 1600 endomyocardial biopsies from patients with persistent unexplained symptoms of heart failure for the presence of HHV-6 and ciHHV-6. Utilizing nested PCR, electron microscopy, and immunohistochemistry, the group identified HHV-6 infection in 16.5% (237 of 1656) of biopsy tissues and ciHHV-6 in 19 or 1.1%. Of the 19 ciHHV-6 patients, two-thirds had mRNA transcripts >10^5 copies/ug of RNA.

To demonstrate ciHHV-6 reactivation from latency, the group analyzed heart biopsy tissues and blood samples for the presence of HHV-6 mRNA and viral proteins. They also looked for virions by using an electron microscope. HHV-6 mRNA was found in both solid tissue and isolated PBMCs of the same patients, and late HHV-6 proteins (indicative of active replication) were identified in cardiac myocytes and interstitial cells of the myocardium, and mature cytoplasmic HHV-6 virions were visualized via electron microscopy.

Overall, HHV-6 was found in 16% of the biopsies, making it (along with parvovirus B19) one of the two most common viruses to be found in the cohort of heart failure patients. US cardiologists don’t routinely test for HHV-6 since it can only be found in the biopsy samples, and US cardiologists adopted guidelines in the 1980’s that have largely restricted routine endomyocardial biopsy surveillance for the presence of potential causative agents present in affected heart tissue. These guidelines were developed even before the discovery of HHV-6. In Germany, where this study was completed, heart tissue biopsies are routinely done as diagnostic procedure in patients suspected of heart failure, and thus can be treated definitively for the underlying pathogen (whether it is PVB19, CMV, HHV-6 or enterovirus) thought to be triggering the heart failure based on results from the procedure.

In the present study, although 37% of the patients with inherited virus had ciHHV-6A, only 5% of other patients with HHV-6 infections harbored HHV-6A. Patients with HHV-6B tended to improve on therapy, while those with HHV-6A had persistent inflammation. The authors note that HHV-6A can persist and cause inflammation in the absence of replication, via upregulation of a unique chemokine, U83A (Clark 2013). Of interest, only HHV-6A was found in degenerating myocytes, while HHV-6B was localized to the vascular endothelium.

The group also describes the successful antiviral-based treatment of heart failure in six ciHHV-6 patients, through a protocol that features 6+ months of ganciclovir treatment. Symptoms improved in all six patients, including a reduced frequency and duration of angina, palpitations, dyspnea, and fatigue, and improved physical capacity in daily life that coincided with a decreased level of HHV-6 mRNA transcripts. One ciHHV-6B patient and two ciHHV-6A patients remained asymptomatic until 12 months after treatment, when symptoms began to reappear. However, in the remaining three patients, symptoms began to reappear within days after treatment was removed. The group demonstrated that antiviral treatment in these individuals eliminated viral transcripts indicative of active HHV-6 replication, and that treatment coincided with an improvement of clinical symptoms. No RNA viral transcripts were detectable during antiviral treatment.

The group’s data demonstrates the importance of following ciHHV-6 patients with an assay that can measure mRNA transcripts. A coauthor on the report, Dirk Lassner, runs the only clinical lab in Europe, IDKT that performs this test. Coppe Labs in the US is the only lab in the US that can measure mRNA in blood and biopsy samples. The German group stresses the importance of long-term monitoring of HHV-6 transcripts in an even larger cohort of ciHHV-6 patients with cardiac disease, and hopes that such studies may reveal possible factors that could influence HHV-6 reactivation in ciHHV-6 patients.

Slightly less than 1% of the world’s population has the inherited ciHHV-6, and interest in this condition has escalated in the past year based on several reports that ciHHV-6 reactivation can cause severe symptoms in immunocompromised patients. Individuals born with ciHHV-6 may be vulnerable to HHV-6 reactivation from both their inherited and exogenous strains, due to tolerance. A landmark study published earlier this year demonstrated that ciHHV6-A could activate from its integrated state and result in a symptomatic infection in patients with severe combined immunodeficiency (SCID) (Endo 2014). Another report describes a ciHHV-6A transplant patient who developed severe HHV-6A encephalopathy, likely due to viral reactivation of the ciHHV6-A strain (Hill 2014). This prompted HHV-6 expert Louis Flamand, PhD, to call for screening of all donor organs and cells for ciHHV-6 status (Flamand 2014). Finally, it has recently been discovered that ciHHV-6 women can pass active virus from their inherited strains to their fetuses transplacentally (Gravel 2013).

Of interest, the group noted that one patient had HHV-6 viral reactivation in response to a proton pump inhibitor, pantoprazole on two occasions. HHV-6 reactivates commonly in severe drug hypersensitivity syndromes, as well as in response to high dose steroids.

For more information, read the full paper, and visit the HHV-6 Foundation’s webpage on HHV-6 & Myocarditis/Heart Disease