Most patients who have been infected with the Lyme disease bacterium, Borrelia burgdorferi, recover quickly after a short course of oral antibiotics. For some patients though, symptoms may persist for months or even longer. This has led to the question of whether such patients have “chronic Lyme disease,” a posited persistent infection despite standard antibiotic treatment, and the related question of whether longer-term antibiotic therapy can improve symptoms in such patients.

Recently, a major double-blind trial of long-term antibiotics was reported in the New England Journal of Medicine, showing an absence of benefit compared to placebo. The same researchers published a related study looking at the cost-effectiveness of such treatment, finding that a short course of antibiotics was as cost-effective as a longer course.

Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease

Berende et al. enrolled 281 patients in the Persistent Lyme Empiric Antibiotic Study Europe (PLEASE) study. Eligible patients had persistent symptoms related to a prior Lyme disease diagnosis, confirmed either by the presence of a rash, a tick bite in a Lyme-endemic area, or a positive IgM or IgG test. Patients received two weeks of open-label intravenous ceftriaxone, and were then randomized to one of three treatment arms: 12 weeks oral doxycycline, 12 weeks oral clarithromycin-hydroxychloroquine, or 12 weeks of placebo. Adherence was verified by pill counts and electronic monitoring of pill bottle opening.

The authors explained the decision to include a short course of open-label ceftriaxone, rather than a placebo-only arm, was made on ethical grounds, “because it was judged to be unethical to withhold treatment from patients who might have an infection at baseline that had not yet been treated.”

Patients in the study were about half female, were almost all white, had an average age of about 48 years, and had experienced symptoms for about 2.5 years. The most common symptoms, experienced by at least 70% of patients, included arthralgia, musculoskeletal pain, fatigue, sensory disturbances, and neurocognitive symptoms. Neuralgia was much less common, reported by less than 20% of patients.

About 90% of patients had received previous antibiotics, with a median of two courses, most for at least a month, with about 15% of patients receiving intravenous treatment.

The primary outcome measure of the study was health-related quality of life as measured by the physical component summary score on the SF-36 health survey. At baseline, the average patient score was about 31, and was well-balanced among the three treatment arms. This score is considered low, the authors pointed out, reflecting “the poor quality of life in these patients.”

About 90% of patients in each group completed the 12 weeks of treatment, with no differences among groups for adherence. While all groups improved significantly on the SF-36, there was no difference in the magnitude of improvement among the three arms (p=0.69) either after 12 weeks of therapy, or over the course of an additional 40 weeks of follow-up. Fatigue severity, a secondary outcome, was also not different among the groups.

Treatment-related adverse events were common on open-label ceftriaxone, reported by 45% of patients. Treatment-related adverse events during the oral therapy phase were reported by 49% of those on doxycycline, 44% of those on clarithromycin-hydroxychloroquine, and 35% of those on placebo.

“In this randomized, double-blind trial involving patients with persistent symptoms attributed to Lyme disease, prolonged antibiotic treatment (ceftriaxone followed by 12 weeks of either doxycycline or clarithromycin–hydroxychloroquine) did not lead to a better health-related quality of life than that with shorter-term treatment (ceftriaxone followed by placebo),” the authors concluded.

As to whether treatment was long enough, they noted that while there are diseases for which long-term antibiotic therapy is the standard, “the purpose of prolonged therapy for such diseases is for the prevention of microbiologic relapse rather than for a delayed onset of clinical alleviation of signs or symptoms. We are not aware of any infectious disease in which the initial effect on signs, symptoms, and laboratory findings is delayed beyond the first 3 months of effective therapy.”

Cost-effectiveness of longer-term versus shorter-term provision of antibiotics in patients with persistent symptoms attributed to Lyme disease

The same group of researchers, again led by Berende, evaluated the cost-effectiveness of longer-term treatment with antibiotics in the PLEASE study. “Regardless of clinical effect, it is important to assess the economic impact of the comparative antibiotic strategies,” they stated. “This is essential for policy makers, in order to prioritize and make complex decisions about healthcare interventions.”

Outcome measures in this study were cost and quality-adjusted life-years (QALYs), as determined by the EQ-5D. The EQ-5D is a health status assessment tool that comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Patient-reported and -weighted scores are combined with time to generate QALYs. Costs included direct medical costs and productivity losses.

Average QALYs yielded during the one-year follow-up was about 0.81 for all three treatment groups, with no significant differences among them (p=0.96). Total costs were also not different among the groups, ranging from 12,000 to 15,000 Euros per patient for the year-long study. The authors note that the study drug contributed relatively little to the total costs.

“Because the PLEASE study did not show any additional clinical benefit of longer-term compared to shorter-term treatment on health-related quality of life, we did not expect to find any large differences in costs and cost-effectiveness as the oral antibiotic treatment is low-priced,” they noted. However, “Costs of potential antibiotic resistance among both the patients’ intestinal flora and the environment were not included in our evaluation. If these costs could have been taken into account, the longer-term treatment regimens likely would have been less favorable in terms of costs and cost-effectiveness compared to the shorter-term treatment. Considering the growing concern to antibiotic resistance because of unnecessary use, the shorter-term provision of antibiotics should be preferred.”

References

  1. Berende, A., J.M. ter Hofstede, H., Vos, F., et al. (2016). Longer-Term Therapy for Symptoms Attributed to Lyme Disease. NEJM, 375(10), pp.997-998.
  2. Berende, A., Nieuwenhuis, L., ter Hofstede, H., et al. (2018). Cost-effectiveness of longer-term versus shorter-term provision of antibiotics in patients with persistent symptoms attributed to Lyme disease. PLOS ONE, 13(4), p.e0195260.