The generalizability of clinical trials for Lyme disease treatment, particularly those conducted by Klempner et al., has come under scrutiny. A new analysis raises concerns that the findings from these trials may not be applicable to the broader population of patients with chronic Lyme disease. The original studies, which appeared in the New England Journal of Medicine, concluded that extended antibiotic treatment was no more effective than placebo for patients with persistent symptoms of Lyme disease. However, the review argues that the specific characteristics of the enrolled patients limit the extent to which these results can be applied to all individuals suffering from chronic Lyme disease.
Patient Selection Bias
The Klempner et al. trials focused on patients who had been ill for an average of 4.7 years and had already undergone an average of three previous courses of antibiotic treatment. This selection criterion raises questions about whether the treatment failure observed in the trials is representative of the outcomes for patients in earlier stages of chronic Lyme disease or those receiving treatment for the first time. The review points out that the authors did not adequately address the limitations imposed by this patient selection, potentially leading to misinterpretations of the results.
Impact of Treatment Delay
Another critical factor is the delay in treatment prior to enrollment in the trials. Some studies suggest that a significant proportion of Lyme disease patients develop chronic symptoms even after initial treatment. For example, one retrospective cohort study found that 62% of patients were still ill an average of 3.2 years after initial treatment, despite an average 6-week delay in getting treatment. The Klempner study did not consider the impact of treatment delay on long-term treatment failure.
Exclusion Criteria
The trials also excluded patients who had received parenteral antibiotic therapy for 60 days or more for their current symptoms, had active inflammatory synovitis, had a coexisting condition that could have accounted for their symptoms, or were unable to discontinue medication that could interfere with the evaluation of their response to the treatment regimen (e.g., narcotic analgesics or prednisone in a dose of 10 mg per day or more). Patients with a positive polymerase-chain-reaction (PCR) test for B. burgdorferi DNA in plasma or cerebrospinal fluid at baseline were also excluded. These exclusion criteria further narrow the population to which the trial results can be generalized.
Comparison with Previous Studies
The review highlights that previous studies of chronic Lyme disease have shown a benefit from retreatment with antibiotics, in contrast to the findings of the Klempner et al. trials. These earlier studies involved differing treatment regimens, durations, and broader patient populations. The authors suggest that the narrowly defined study population in the Klempner et al. trials should not be ignored when drawing general conclusions about effects in a broader target population.
Implications for Clinical Practice
The analysis suggests that caution should be exercised when applying the results of the Klempner et al. trials to all patients with chronic Lyme disease. The specific characteristics of the study population, including the duration of illness, prior treatment history, and exclusion criteria, limit the generalizability of the findings. Clinicians should consider these factors when making treatment decisions for patients with chronic Lyme disease.
