Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis

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Methodology for Preparation of These Guidelines

These guidelines were developed by the HIV-TB Drug Interaction Guideline Development Group (hereafter, Guideline Development Group). The Guideline Development Group consisted of experts in tuberculosis and HIV treatment and pharmacokinetics from CDC and other institutions (see listing of the Guideline Development Group at the end of this document on page 15). Members of the Guideline Development Group were selected by the chair and co-chairs. They sought to include as members some persons who had participated in preparation and review of the prior version of these guidelines. Particular effort was made to include staff from the U.S. National Institutes of Health (NIH), in order to coordinate these recommendations with those of the Federally-approved HIV/AIDS medical practice guidelines available online at http://www.aidsinfo.nih.gov/. No members of the Guideline Development Group were deemed to have substantial competing interests related to the recommendations in these guidelines. Guideline Development Group member competing interests are listed on page 16.

A literature search was conducted to extract articles that met the following inclusion criteria: clinical studies involving healthy volunteers or patients with HIV or HIV/TB co-infection with relevant PK, safety, or HIV (viral load suppression, change in CD4 count) endpoints. Our search strategy was as follows: (1) between March 2011 and May 2012 we searched in Pubmed and Embase for English and French articles published from 1990 to 2012. We used as MeSH terms "tuberculosis," "HIV," and the names of the drugs being evaluated. (2) After articles were extracted and selected, we hand-searched references at the end of included articles, and we searched trials listed at www.clinicaltrials.gov. (3) We reviewed abstracts from meetings (International AIDS Conference; International AIDS Society conference; Conference on Retroviruses and Opportunistic Infections; World Lung Health Conference; Workshop on Clinical Pharmacology of TB Drugs) at which data from HIV and/or TB clinical trials are commonly presented; these were included if they met the inclusion criteria cited above; most of these abstract reports had not yet completed the process of peer review and publication . (4) We reviewed package inserts for included drugs specifically looking for drug interaction data. Articles and abstracts were screened and selected using the inclusion criteria. One hundred seventeen articles and abstract met the inclusion criteria and were included in the body of evidence. These are included in the list of referenced articles and abstracts at the end of this document. The body of evidence was not graded for quality.

The chair of the Guideline Development Group reviewed the previous version of these guidelines (at http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/default.htm), and then reviewed the references accumulated through the search strategy and inclusion criteria described above. The chair then drafted an updated revision of the guideline, which was reviewed and discussed with the two Guideline Development Group co-chairs. Agreed revisions were made, and the revised document was then submitted to the rest of the members of the Guidelines Development Group Each member of the Guideline Development Group reviewed the revised guideline draft and provided written comments and suggested revisions. Final recommendations were developed by the Guideline Development Group; the strength of each recommendation was not graded. In one instance where the Guideline Development Group’s view conflicted with that of the product manufacturer, the chair and co-chairs of the Guideline Development Group held two teleconferences with representatives of the manufacturer, staff of NIH, and staff of the U.S. Food & Drug Administration (FDA), to share and discuss unpublished data underlying the different views [see Rifampin and Efavirenz].

Following this discussion, and with the concurrence of NIH and FDA members, the Guideline Development Group chose to include the following clarification, which is quoted directly from the introduction to the U.S. adult AIDS treatment guidelines, where it was intended to address similar issues: "... the science [underlying this guideline] evolves rapidly, [and] the availability of new agents and new clinical data may change therapeutic options and preferences. Information included in these guidelines may not be consistent with approved labeling for the particular products or indications in question, and the terms “safe” and “effective” may not be synonymous with the Food and Drug Administration (FDA)-defined legal standards for product approval. The guidelines are updated [periodically].... However, the guidelines cannot always keep pace with the rapid evolution of new data in this field, and they cannot provide guidance for all patients. Clinicians should exercise clinical judgment in management decisions tailored to unique patient circumstances."¹