How I Manage Low-Level Viremia in Patients Receiving HBV Therapy

Robert S. Brown, Jr., MD, MPH

Gladys and Roland Harriman Professor of Medicine
Vice Chair,
Mentorship & Academic Development
Clinical Chief, Division of Gastroenterology and Hepatology
Weill Cornell Medicine
New York, New York


Robert S. Brown, Jr., MD, MPH, has disclosed that he has received consulting fees from Bristol-Myers Squibb and Gilead Sciences and funds for research support from Gilead Sciences.


View ClinicalThoughts from this Author

Released: September 24, 2018

An ongoing challenge is how to manage patients with HBV infection who have intermittent or persistent low-level viremia on treatment, but who do not meet the criteria for viral breakthrough. In my practice, I divide these patients into 2 groups: those with HBV that is detectable but not quantifiable (< 20 IU/mL) and those with HBV that is quantifiable (≥ 20 IU/mL).

Frequently, we see patients with test results reporting detectable but not quantifiable HBV levels, and I do not worry about these patients. In fact, many of these nonquantifiable readings are likely false positives.

However, I become concerned if the low-level viremia is quantifiable, even though this finding is much rarer in my practice. Although during the last 5 years the clinical community shifted from frequent use of combination therapy to monotherapy with entecavir or tenofovir even with intermittent low-level viremia, recent data indicate that quantifiable low-level viremia may be associated with worse outcomes, particularly in patients with cirrhosis.

A 2017 study reported that patients who had intermittent or persistent quantifiable HBV DNA levels between 12 and 2000 IU/mL while receiving entecavir had a significantly higher 5-year cumulative incidence of hepatocellular carcinoma vs those whose HBV DNA was always undetectable (14.3% vs 7.5%, respectively; P = .015). The hepatocellular carcinoma incidence was even higher among those with cirrhosis.

Similarly, a recent observational study reported significantly prolonged transplantation-free survival among those with decompensated cirrhosis who had consistently undetectable vs detectable HBV DNA on therapy.

These data indicate that effective strategies are needed to manage our rare patients who have quantifiable low-level viremia on treatment.

Assessing and Managing Low-Level Viremia
In patients with intermittent low-level viremia, I first ask about adherence and correct dosing. For example, entecavir must be taken on an empty stomach to be effective. Correct dosing may also be an issue in patients who have had a change in renal function, such as those who had previously had a dose adjustment for impaired renal function that has now improved.

If I can rule out issues surrounding adherence and dosing, the next step is to decide how to manage the patient’s low-level viremia. In such patients, I am most likely to recommend considering a change in HBV treatment if the patient has cirrhosis (especially decompensated cirrhosis) or if the patient’s viremia is persistent or frequent, not an isolated blip.

Another consideration is the patient’s treatment experience. I am more likely to recommend changing HBV treatment if there is uncertainty about the patient’s previous treatments or if the patient has been exposed to lamivudine and is now receiving entecavir, which may contribute to low-level resistance.

Treatment Choices
The primary decision is whether to switch monotherapy or start combination therapy. Both entecavir and tenofovir are very potent and well tolerated, so I usually go to combination therapy when I have to treat persistent viremia.

Combination therapy options combine a nucleotide and a nucleoside and include tenofovir disoproxil fumarate or alafenamide with either lamivudine, emtricitabine, or entecavir. Tenofovir plus entecavir has the advantage of the highest potency, although tenofovir plus emtricitabine are available as a single-tablet combination.

When I recommend switching monotherapy instead of using combination therapy, the switch is usually from entecavir to tenofovir if I suspect previous lamivudine exposure or if the patient is achieving suboptimal entecavir levels (by taking the drug inconsistently or on an empty stomach). Tenofovir, by contrast, can be taken with or without food.

The key reasons to instead switch from tenofovir to entecavir would be adverse events, which are infrequent, or because the patient has an estimated creatinine clearance < 15 mL/min, where entecavir is a better choice than switching from tenofovir disoproxil fumarate to tenofovir alafenamide. Entecavir may also be preferred over tenofovir alafenamide because it is available as a generic, although in some cases, generic agents may be more expensive if the manufacturer does not cover the patient’s copay.

Experts’ Selection of HBV Therapy
In Clinical Care Option’s decision support tool for first-line HBV therapy, you can see how other experts and I selected first-line HBV therapy for patients with cirrhosis, renal dysfunction, and many other scenarios.

Your Thoughts?
How do you manage patients with low-level viremia on HBV treatment? Does your approach change if the viremia is persistent vs intermittent? Please share your perspective in the comments box.

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