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1. Treatment of Lyme Disease
William R Bowie, MD, FRCPC
Professor of Medicine
University of British Columbia

2. Faculty/Presenter Disclosure
 Faculty: William R Bowie
 Relationships with commercial interests:
 Grants/Research Support:
• Pfizer Canada – Community Acquired Pneumonia Study
• GSK – Influenza studies
 Speakers Bureau/Honoraria: None
 Consulting Fees: None
 Other: Employee of the University of British Columbia, and
senior faculty at the Vancouver General Hospital

3. Disclosure of Commercial Support
 This program has received financial support from [organization name] in the
form of [describe support here – e.g. an educational grant].
 This program has received in-kind support from [organization name] in the
form of [describe support here – e.g. logistical support].
 Potential for conflict(s) of interest:
 Bowie has not received payment/funding, etc. from the organization supporting this
program AND/OR organization whose product(s) are being discussed in this program].
 [Supporting organization name] [developed/licenses/distributes/benefits from the sale
of, etc.] a product that will be discussed in this program: [insert generic and brand
name here].
 Bowie is a member of AMMI Canada and the IDSA, and is the AMMI Canada
representative on the ongoing revision to the Lyme management guidelines being
coordinated by the IDSA, American Academy of Neurology and American College of
Rheumatology


4. Mitigating Potential Bias
 No measures are required since there are no conflicts

5. Goals of Treatment of Infection
 Eradicate infection
 For the vast majority of infections this is a
realistic goal
 Return back to pre-illness baseline
 Improvement in symptoms and signs is usual
 recovery of signs may be partial
 Improvement of some symptoms, particularly
subjective symptoms, may be slow, and
incomplete, despite eradication of the
pathogen

6. What Constitutes High Quality
Evidence in Support of Treatment
Guidelines

7. Notes
 The plural of anecdotes, especially unevaluated
anecdotes, is not data
 Expert opinion is required to interpret data from
all sources, but expert opinion not based on
systematically collected and evaluated data
does not constitute data

8. BMJ 2003;327:1459–61

9. Recommended Antimicrobial
Treatment Regimens Should Have a
Strong Evidence Base
 Any recommended antimicrobial regimen is
amenable to evaluation using standard and well
developed methodologies
 Most typical is a randomized controlled trial
where regimen x is compared with a placebo or
regimen of known value
 Appropriately designed studies look not only at
efficacy using one or more pre-defined
endpoints, but also adverse events, and
ultimately an assessment of benefits vs risks

10. GRADE Methodology
 Grading of Recommendations Assessment,
Development and Evaluation system
 Become the most common and accepted way to
develop guidelines
 Has many advantages, including a special
emphasis on outcomes, including an emphasis
on patient centred wishes
 However, analyses start with high quality
data where defined regimens are assessed
and compared

11. Specific questions are incorporated in
PICO’s
 Population: clear articulation of the patient
population and question
 Intervention: specific regimen under study with a
drug, defined dose, and defined duration of the
drug
 Comparator: specific dose and duration of
another placebo or drug
 Outcome(s): pre-defined outcomes of
importance

12. Controversies around “Treatments” for
Lyme Disease
 Severe confusion (obfuscation) in terminology
around Lyme disease
 The term is being used to encompass those
where no one would dispute the diagnosis of
Lyme disease, all the way through to others
who have little or no objective evidence of
active infection
 Many “treatments” recommended by some have
never been subjected to the initial stage of
demonstrating activity of a specific proposed
regimen vs a standard, let alone demonstrating
that benefits exceed harm

13. IRRECONCILABLE RESULTS
Caught in the middle:
Patients and supporters
Health care providers
Public health officials
Media
Original Source: unknown to WRB. Modified (in red) by WRB

14. Moving Forward
 Clarify terminology
 Assess evidence according to the specific group
or presentation being discussed
 Looking further forward, define processes to fill
gaps of knowledge or hold accountable those
who promote “treatments” without conclusive
baseline supportive evidence

15. Categories Labelled “Lyme Disease”
1. people who have Lyme disease where disease
is diagnosed on appropriate clinical grounds in
early disease, or by reference laboratory testing in
disseminated Lyme disease, in accordance with
National Laboratory Guidelines (e.g. CDC, UK
PHS, ECDC, NML).
2. people who are given a label such as post
treatment Lyme disease, where they had clear
evidence of Lyme disease as in #1, but have
incomplete resolution of symptoms after standard
antimicrobial therapy

16. Categories Labelled “Lyme Disease”
3. people who have alternately diagnosed Lyme
disease where they are diagnosed on clinical
grounds, supported only by alternative laboratory
tests, the validity of which is questioned by major
reference laboratories
4. people who are diagnosed based purely on
clinical grounds, and if testing is done, test
seronegative at a time beyond the initial stage of
Lyme disease

17. Quality of Data Supporting Treatment
Recommendations – Group 1
 There are many well designed studies that
provide sufficient evidence to support treatment
guidelines, even though as with all guidelines
there are questions which remain inadequately
studied
 The IDSA guidelines are representative
 No recommendations are for more than 4 weeks
of therapy
 There is substantial improvement and usually
cure on these regimens

18. Quality of Data Supporting Treatment
Recommendations – Groups 2, 3, and
4
 None of several traditionally designed studies
have clearly demonstrated significant benefits of
longer courses of antimicrobials
 Many of these folk are “treated” according to
ILADS or similar guidelines
 For these non-IDSA “treatments”, there are no
studies demonstrating efficacy of those
“treatments”, let alone studies including
assessments of real or potential harm, and
overall cost-benefit of the studies.

20. Randomized, Double-blind Placebo
Controlled Trial in Europe
 P: 280 patients with persistent symptoms
attributed to Lyme disease – either related
temporally to proven Lyme disease or
accompanied by a positive IgG or IgM
immunoblot assay for Bb
 I + C: all received 2/52 IV ceftriaxone, followed
by 12 weeks of either doxycycline, clarithromycin
plus hydroxychloroquine, or placebo
 O: primary outcome was health-related quality of
life, as assessed by the physical-component
summary score of the RAND-36 Health Status
Inventory at the end of treatment

21. Patient Characteristics

23. ILADS, 2014 Recommendations for
Treatment of Erythema Migrans
 “Treatment regimens of 20 or fewer days of
phenoxymethylpenicillin, amoxicillin, cefuroxime
or doxycycline and 10 or fewer days of
azithromycin are not recommended for patients
with EM rashes because failure rates in the
clinical trials were unacceptably high. Failure to
fully eradicate the infection may result in the
development of a chronic form of Lyme disease,
exposing patients to its attendant morbidity and
costs, which can be quite significant.
(Recommendation, very low-quality evidence).”

24. ILADS, 2014 Continued
 “Clinicians should prescribe amoxicillin, cefuroxime or
doxycycline as first-line agents for the treatment of EM”
 “Initial antibiotic therapy should employ 4–6 weeks”
 “Clinicians should continue antibiotic therapy for patients
who have not fully recovered by the completion of active
therapy”
 “Strong-to-moderate responses favor extending the
duration of therapy of the initial agent; modest responses
may prompt an increase in the dose of the original
antibiotic or a switch to a different first-line agent or
tetracycline. Minimal or absent responses suggest a
need for a combination of first-line agents”
 “Recommendation, very low-quality evidence”

25. Non Evidence Based “Treatment” Can
do Harm
 Desperate and vulnerable individuals are given an
incorrect label and subjected to unproven “treatment” for
which there is no valid evidence of benefit, let alone of
benefits that exceed risk
 Focuses on Lyme rather than pursuing other possibilities
 Risk of antimicrobials to oneself
 Reactions, other toxicity, superimposed infection,
antimicrobial resistance
 Risks to others
 Antimicrobial resistance
 Undermines medicine and public health
 Scares people who have readily treatable acute Lyme
disease

26. Comment
 Given the large numbers of people who have
been subjected to such “treatments” over many
years, there has been ample opportunity to
actually evaluate many of those “treatments”
 This constitutes missed opportunities to help
provide better evidence based care

27. Example of a Potential Study
 Population: individuals who meet the criteria for
alternately diagnosed Lyme Disease
 Intervention: 6 months of doxycycline 100 mg
twice daily
 Comparator: 6 months of a matched placebo
 Outcomes:
 Primary – health related quality of life and
related measures
 Secondary – adverse events

28. Moving Forward
 Many of the people in categories 2 to 4 have
profoundly debilitating and life altering
symptoms
 They deserve formal evaluation of “treatments”
given to them, as well as efforts to better
understand the etiology of what for most is very
similar to presentations of chronic fatigue
 Focusing purely on a perceived diagnosis of
Lyme disease has the potential to be highly
detrimental

29. Recommendations
 Although this current process is fashioned
around Lyme disease, Health Canada could and
should use this opportunity to better understand
and support individuals with chronic, debilitating
manifestations, whether or not they have
anything to do with Lyme disease

30. Other Issues with Guidelines
 Guidelines will always be incomplete,
particularly as new tick transmitted pathogens
are found, ticks spread geographically and
numerically, and new knowledge accrues
 We all must be prepared to revise our
understanding of disease and treatments as
high quality new knowledge is acquired or
developed – this is at the core of the scientific
method

32. http://www.idsociety.org
http://www.journals.uchicago.edu/CID/journal/issues/v43n9/40897/40897.html

33. After multiple meetings, a public hearing, and extensive
review of research and other information, the Review
Panel concluded that the recommendations contained in
the 2006 guidelines were medically and scientifically
justified on the basis of all of the available evidence and
that no changes to the guidelines were necessary.

34. 2010 UK Health Protection Agency

35. Unconventional “treatments” for Lyme disease not supported by scientific evidence
Lantos PM et al, Clinical Infectious Diseases 2015; 60: 1776-1782