Longer therapy shows no added benefit for persistent Lyme disease symptoms

An additional 12 weeks of antibiotic therapy did not improve persistent symptoms of fatigue, musculoskeletal, neuropsychological or cognitive disorders attributed to Lyme disease, according to recent findings published in the New England Journal of Medicine.

“Patients with Lyme disease, which is caused by the Borrelia burgdorferi sensu lato complex (including B. afzelii and B. garinii in Europe), often report persistent symptoms,” Anneleen Berende, MD, of the department of medicine at Radboud University Medical Center, Nijmegen, Netherlands, and colleagues wrote. “Previous randomized, clinical trials have not shown convincingly that prolonged antibiotic treatment has beneficial effects in patients attributed to Lyme disease. Nonetheless, the debate about this issue has continued.”

The researchers conducted a randomized, double blind trial at two medical facilities in the Netherlands to determine whether longer-term antibiotic treatment improves health outcomes. They enrolled patients with symptomatic Lyme disease or B. burgdorferi antibodies who presented with persistent musculoskeletal pain, arthritis, arthralgia, neuralgia, sensory disturbances, dysesthesia, neuropsychological disorders or cognitive disorders from October 2010 to June 2013.

All participants received 2,000 mg of open-label intravenous ceftriaxone daily for 14 days. After the initial course, 280 participants were randomly assigned in a 1:1:1 ratio to receive a 12-week course of 100 mg doxycycline plus placebo twice daily, 500 mg clarithromycin plus 200 mg hydroxychloroquine twice daily, or two placebo capsules twice daily.

The primary outcome was quality of life (QOL) at the end of the treatment period, which was assessed by the RAND SF-36 score measuring physical functioning, role limitations due to physical health issues, pain and general health perceptions. Self-reported questionnaires were recorded at baseline and weeks 14, 26, 40 and 52. Safety assessments were conducted at weeks 2, 8 and 14.

Ninety percent of patients completed the oral drug regimen or placebo, including 88.4% of patients in the doxycycline group, 87.5% in the clarithromycin-hydroxychloroquine group and 93.9% in the placebo group. Treatment adherence was similar among the groups, ranging from 81.3% to 87.2%.

Health-related QOL did not significantly differ between groups, according to the researchers. The SF-36 summary score was 35 (95%CI, 33.5-36.5) in the doxycycline group, 35.6 (95% CI, 34.2-37.1) in the clarithromycin-hydroxychloroquine group and 34.8 (95% CI, 33.4-36.2) in the placebo group. The scores yielded a difference of 0.2 (95% CI, –2.4 to 2.8) in the doxycycline group and 0.9 (95% CI, –1.6 to 3.3) in the clarithromycin-hydroxychloroquine group compared with the placebo group.

Physical and mental aspects of health-related QOL among all participants increased from 31.8 at baseline to 36.4 at the end of treatment (P < .001); however, there were no significant changes in the SF-36 score for the remainder of the observation period. Sensitivity analyses produced similar results.

“Although we did not find a significant benefit of longer-term antibiotic therapy, we did find that there were side effects from the use of antibiotics; however, these side effects were similar among the study groups,” Berende and colleagues wrote.

While receiving the randomized treatments, 47.9% of participants reported at least one adverse event. The most common adverse events included photosensitivity and nausea in the doxycycline group, and diarrhea and nausea in the clarithromycin-hydroxychloroquine group.

“The current trial suggests that 14 weeks of antimicrobial therapy does not provide clinical benefit beyond that with shorter-term treatment,” the researchers concluded. “It may be argued that 14 weeks of treatment is insufficient to show a beneficial treatment effect. However, whereas prolonged antimicrobial treatment is not uncommon for various infectious diseases, 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.”

In a related editorial, Michael T. Melia, MD, associate director of the infectious diseases fellowship program and assistant professor of medicine at Johns Hopkins Medicine, and Paul G. Auwaerter, MD, vice president, and a member of the Board of Directors and Executive Committee of the Infectious Diseases Society of America (IDSA), and clinical director of the division of infectious diseases and professor of medicine at Johns Hopkins Medicine, agreed that arguments supporting delayed favorable outcomes with longer treatment courses are “weak.” In contrast, they wrote that the high number of adverse events related to prolonged antibiotic treatment should lessen physicians’ temptation to prescribe longer treatment courses.

“Patients with subjective, vexing symptoms attributed to Lyme disease should not anticipate that even longer courses of antibiotics will produce relief,” they wrote. “Though prolonged antibiotic therapy is not the answer, we do not know what is truly helpful. Our personal approach is centered on making thorough assessments for alternative diagnoses such as sleep disorders and providing recommendations borrowed from practices in general medicine.”

Melia and Auwaerter suggested that more innovative approaches to treat chronic health problems such as fatigue and pain are needed for the millions of people worldwide with these conditions, whether they are related to Lyme disease or not.

“One example of an innovative investigation is the recent finding of differential gene expression suggesting postinfectious cytokine or metabolic changes after Lyme disease, as compared with other acute infections,” they wrote. “Future research efforts should continue to explore such different strategies that may lead to proven options for helping our patients.” – by Stephanie Viguers

References:

Berende A, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1505425.

Melia MT, et al. N Engl J Med. 2016;doi:10.1056/NEJMe1502350.

Bouquet J, et al. mBio. 2016;doi:10.1128/mBio.00100-16.

Disclosures: One study author reports receiving grant support from the Netherlands Organization for Health Research and Development and reports a patent related to diagnostic testing for Lyme disease licensed to Oxford Immunotec. Auwaerter reports receiving personal fees from Biomerieux and for medical legal expert testimony regarding Lyme disease. Auwaerter also is a member of the ISDA panel for updating Lyme Disease Guideline.