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Maglione M, Goetz MB, Wang Z, et al. Antiretroviral (ARV) Drug Resistance in the Developing World. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Sep. (Evidence Reports/Technology Assessments, No. 156.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Antiretroviral (ARV) Drug Resistance in the Developing World

Antiretroviral (ARV) Drug Resistance in the Developing World.

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Original Proposed Key Questions

This project was suggested by the Fogarty International Center (Fogarty) at the National Institutes of Health (NIH) on behalf of several institutes at NIH with the aim of guiding the research agenda on the development of ARV resistance in developing countries by identifying critical gaps in the published research. A secondary aim was to identify issues for clinicians rolling out HIV medications in the developing world. The following key questions were proposed:


What is the prevalence of resistance? Does the prevalence of resistance differ between adults and children? Between men and women? Between groups with differing modes of transmission?


What are the factors associated with the development of resistance? How do the factors differ among varying population groups?


Viral factors


Host factors


Specific ARVs


Resistance assay (whether resistance identified depends on the type of test used)


Health service associated


What are effective strategies to prevent or reduce the development of resistance in different population groups (prevention of Mother To Child Transmission (pMTCT); people receiving ARV, etc.)?


What is the likely impact of low-level or partial resistance on subsequent therapy? What is the impact on response to subsequent PMTCT interventions?

Technical Expert Panel

In designing the study questions and methodology at the outset of this report, the EPC consulted several technical and content experts. Broad expertise and perspectives were sought. The following scientists and clinicians participated in the TEP for this report: David Bangsberg, John Baxter, Lisa Frenkel, David Katzenstein, Shahin Lockman, Douglas Richman, Robert Shafer, Steve Spector, and Jonathan Uy. Appendix A * provides a list of their names, degrees, and affiliations.

Divergent and conflicting opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore, the final study questions, design, and/or methodologic approaches do not necessarily represent the views of all technical and content experts.

The TEP's participation in the preparation of the report began with a meeting conducted via conference call on February 27, 2006. The purpose of this meeting was to obtain TEP input on the scope of the project. The TEP expressed the strongly held belief that we focus on the ARV resistance picture in developing counties. During the course of the worldwide spread of HIV, the main virus (M) evolved into multiple clades. Most approved ARV medications were developed in studies of clade B, the most common clade in the Western world. Since clade B viruses account for only about 10 percent of HIV cases worldwide,94 knowledge of how ARVs affect the other clades is of critical importance. Thus, the TEP suggested that we provide an overview of the prevalence of resistance world-wide and how it differs by region. They asked us to address both resistance acquired through taking ARV drugs as well as drug resistance transmitted to treatment-naïve persons through infection.

A second TEP meeting was held by telephone on May 26, 2006. To better match the scope of the project with resources, the panel agreed that we should focus on key question one and on parts a, b, c, and e of key question two. They expressed the belief that comparing types of resistance assays was beyond the scope of the project. They again emphasized the focus on developing countries. Specific concerns were MTCT and prevalence of ARV resistance in treatment-naïve populations.

Literature Search

Our search for studies began in November, 2005 with an electronic search of PubMed® and Embase for reports of resistance to ARV medications. We also searched the Cochrane Controlled Clinical Trials Register Database and the Cochrane Database of Reviews of Effectiveness (DARE). (The Cochrane Collaboration is an international organization that helps people make well-informed decisions about health care by preparing, maintaining, and promoting the accessibility of systematic reviews on the effects of heath care interventions.)

We ordered all articles on resistance to ARVs, regardless of study design, language, or publication date. Search terms included the generic and trade names of every available NNTRI, NRTI, and Protease Inhibitor (PI), regardless of U.S. Food and Drug Administration (FDA) approval status. We also searched for studies of resistance to fusion inhibitors. We included only studies of humans; no animal studies or in vitro passage studies were included. Appendix B * shows our specific search terms.

Additional Sources of Evidence

Stanford University HIV Drug Resistance Database

The HIV RT and Protease Sequence Database is an on-line relational database that catalogs sequence variation in HIV reverse transcriptase (RT) and protease enzymes, the molecular targets of anti-HIV therapy. The database was developed in order to help physicians and researchers determine clinical cross-resistance among current and experimental anti-HIV drugs and to identify any drug regimens that retain their effectiveness against drug-resistant HIV-1 isolates. The database links HIV-1 RT and protease sequence data, drug treatment histories, drug susceptibility, and clinical parameters.

One part of the database provides copies of or links to published papers, meeting abstracts, and GenBank entries that have not yet been published as a paper or abstract. We searched the publications list in January, 2006, and downloaded relevant studies. We did not conduct our own analysis of the patient-level data stored in the RT and Protease Sequence database.

WATCH: Worldwide Analysis of Resistance Transmission over Time of Chronically and Acute Infected HIV-1 infected persons

Located in Europe, the WATCH project aims to collect HIV-1 RT and protease sequences from treatment-naïve participants all over the world and analyse them together in a standardised manner, in order to be able to make a good comparison of resistance figures. We found two WATCH conference abstracts and contacted the authors about additional research in progress.

Presentation - Preventing Mother-to-Child HIV Transmission and ARV Drug Resistance

Dr. Lynne Mofenson of the National Institute of Child Health and Human Development provided us with a copy of an overview she presented on March 16, 2006; this excellent overview contained nearly 100 slides, from which we obtained all relevant studies cited.

Article - The Global Status of Resistance to ARV Drugs

In 2005, Vella and Palmisano published an overview in the journal Clinical Infectious Diseases.18 They searched for published studies on the incidence and prevalence of drug resistance in persons recently infected with HIV in all regions of the world. We retrieved the one study from a developing country (Ivory Coast).

We also searched the proceedings of the following conferences for the past 2 years. (We chose a 2 year cut-off because we expected that in general, abstracts and presentations would be published in journals within 2 years of the conference.)

Conference on Retroviruses and Opportunistic Infections (CROI)

The most recent CROI conference was held in Denver, Colorado on February 5–8, 2006. The CROI is a scientifically based meeting of leading HIV/AIDS researchers from around the world, and the 2006 conference was sponsored by the Foundation for Retrovirology and Human Health, the National Institute of Allergy and Infectious Diseases, the Centers for Disease Control and Prevention, and the University of California, San Diego School of Medicine. Participants included scientists actively engaged in basic science or clinical studies examining retroviral diseases and their complications or full-time academic clinician-teachers responsible for HIV/AIDS training and research programs. The aim of the conference was to enable researchers to present, discuss, and critique their investigations with the ultimate goal of translating their research into progress in the fight against HIV/AIDS.

International AIDS Conference

The most recent International AIDS Conference was held in Toronto, Canada on August 13–18, 2006. The conference is the largest HIV/AIDS meeting in the world; participants include scientists; health care providers; political, community and business leaders; journalists; government, non-governmental and intergovernmental representatives; and people living with HIV/AIDS. The goal of the conference is to allow for the exchange of ideas, research, and knowledge to help strengthen HIV/AIDS programs worldwide, with an emphasis on evidence, outcomes, and best practices. The theme of the 2006 conference was A Time to Deliver, underscoring the still urgent need to bring effective prevention and treatment programs to communities worldwide.

IAS Conference on HIV Pathogenesis and Treatment

The International AIDS Society (IAS) is a professional society with over 6,000 members, including scientists, health care workers, and others involved in the prevention and treatment of HIV/AIDS. Every 2 years, IAS sponsors a conference to disseminate knowledge that can accelerate the response to HIV/AIDS worldwide. We examined the proceedings from the July 24–27, 2005 conference, which took place in Rio de Janeiro, Brazil and was co-sponsored with the Universidad de Federal do Rio de Janeiro and the Brazilian Society of Infectious Diseases. The specific aim of the conference was to focus on new insights into HIV disease development, prevention, and care and their practical applications in developing countries.

Meetings of the Infectious Diseases Society of America (IDSA)

The meetings of the Infectious Diseases Society of America (IDSA) are geared towards physicians, scientists, and other health care professionals involved in research, patient care, public health, disease prevention, and education in the field of infectious diseases (ID). The meetings are designed to disseminate current knowledge and advancements in the field, bridge the gaps among various medical disciplines, and promote multidisciplinary dialogues and communications that will facilitate the prevention and treatment of ID. The 2006 meeting of the IDSA took place on October 12–15 in Toronto, Canada, and included four program tracks: investigative infectious diseases (ID), adult ID, HIV, and pediatric ID. The IDSA website also provides a meetings archive that enabled us to examine the proceedings.

Article Review

Study Inclusion

Our initial search was unrestricted by study design. The studies included in the review are of one of the following types of designs.

Review articles identified by the search were classified as either systematic (including meta-analyses) or nonsystematic. Systematic reviews were identified by reading the methods section of the article to determine whether an acceptable method was employed to identify evidence (such as a description of the name of the computerized database searched and the full set of search terms used, as well as details about the method for accepting and rejecting identified articles).

Randomized controlled trials (RCTs) are studies where the participants are definitely assigned prospectively to one of two (or more) alternative forms of intervention, using a process of random allocation (e.g., random number generation, coin flips).

Controlled clinical trials (CCT) s are studies where participants (or other units) are either


definitely assigned prospectively to one of two (or more) alternative forms of health care using a quasi-random allocation method (e.g., alternation, date of birth, patient identifier)



possibly assigned prospectively to one of two (or more) alternative forms of health care using a process of random or quasi-random allocation.

Observational studies (such as cohort, case-control, and cases series) are those where the investigators do not control who gets the interventions. Much of the data included in this report comes from observational studies. To avoid reviewing potentially numerous case reports, we initially set a threshold of 50 or more participants per series for inclusion in our review. After discussion with our TEP, we reduced this number to 20 for studies of populations in developing countries, so as not to exclude potentially important data.


Using a single-page “screening form” (included in Appendix C *), we reviewed the studies retrieved from the various sources against our exclusion criteria. Two reviewers, each trained in the critical analysis of scientific literature, independently reviewed each study and resolved disagreements by consensus. The lead investigators resolved any disagreements that remained unresolved after discussions between the reviewers.

To be included in our report, a study had to focus on human resistance to ARV. Studies of cell lines or animals were excluded. There were no language limitations; we included many non-English studies Studies of obsolete therapies were also excluded at this time, if it was very unlikely that such therapies would never be used again, even in resource-limited regions.

After the TEP further narrowed the scope of the project, we created a second one-page screening form. Using this form, we tracked articles on treatment-naïve patients, pregnant women and children. We also used this form to identify studies of entire geographic regions, large hospitals, and specific medications.

During this phase of screening, we were asked to exclude studies not set in the developing world. “Developing” generally refers to economic growth and social development in areas such as health care, literacy, life expectancy, and fertility. Some less-developed regions could actually be considered non-developing, as a number have experienced years of decline rather than development. However, the United Nations (UN) allows each country to decide for itself whether it will be designated as “undeveloped” or “developing.” For the purposes of our report, we chose to include the following “undeveloped” and “developing” regions: Latin America, sub-Saharan Africa, India, and all other areas of Asia except Hong Kong, Macau, Singapore, and Japan.

Extraction of Study-Level Variables and Results

We abstracted data from the articles that passed our screening criteria onto a specialized Quality Review Form (included in Appendix C *). The form collects data on geographic region, number of participants, subject demographics, HIV viral clade (clade), medications taken (if any), years of data collection, how people were selected for resistance testing, and how and when resistance was assessed. Data for all abstracted studies are presented in Evidence Tables (Appendix D). Trained reviewers, working in groups of two, extracted data from the same articles and resolved disagreements by consensus. A senior researcher resolved any disagreements not resolved by consensus.

Synthesis of Results

Results for a) treatment- naïve populations and b) pregnant women and their children are presented in separate tables. Because of study heterogeneity, pooling was not possible; thus, we summarize the data qualitatively. Differences by region, population group, and HIV viral clade are described. We also include a separate summary of resistance studies that reported adherence data.

Peer Review

A draft of this report was prepared in December, 2006 and sent to the TEP members and eight additional national and international experts for review. Peer reviewer comments were considered by the EPC in preparation of this final report. A list of peer reviewers and TEP members is included as Appendix A. Synthesis of the scientific literature presented here does not necessarily represent the views of individual reviewers.



Appendixes cited in this report are provided electronically at http://www​​.htm


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