Materials and Links

Background:

While very effective in slowing the progression of HIV disease in many people, HAART is not a cure for AIDS and, because of the development of resistance to anti-viral drugs, many patients see their viral loads rebound, CD4 cells decline and clinical symptoms of AIDS develop despite HAART. Treatment failure can occur for multiple reasons - poor adherence, poor absorption, sub-optimal anti-viral therapy, etc. To address these issues, the Forum has focused on how and why therapy fails people, the design of clinical studies to develop salvage therapy regimens, and the need for studies to understand the long-term clinical effectiveness of anti-viral therapies.

Treatment Failure

Of primary importance to the Forum is long-term management of patients on anti-retroviral therapy, particularly management of patients for whom therapy is failing.

As a first step in 1998, the Forum produced "HIV Anti-Retroviral Treatment Failure: A Review of Current Clinical Research," which focuses on four central issues:

• How is treatment failure defined in current clinical research?
• How are estimates of treatment failure developed for the design of clinical studies?
• What factors may predict treatment failure?
• What strategies are being examined for managing treatment failure?

The FCHR updated the report with a second paper entitled "HIV Anti-Retroviral Treatment Failure: A Review of Current Clinical Research," which includes data summaries from the 12th World AIDS Conference in Geneva, Switzerland, the 1999 ICAAC Conference, and the 4th International Conference on HIV Drug Therapy in Glasgow, Scotland.

Salvage Therapy

The Forum convened a meeting to review the scientific and logistical issues in the design and implementation of studies of salvage therapy regimens in heavily pre-treated patients in whom current anti-viral therapy is no longer working. The meeting, held in conjunction with the 2nd International Workshop on Salvage Therapy for HIV Disease, provided an opportunity for discussion about the differing needs, priorities and challenges faced by industry, researchers, regulators and patients conducting and participating in this research and resulted in the publication of The Challenges of Clinical Trial Design in Assessing the Effects of Anti-HIV Therapy in Heavily Pre-treated Patients.

Drug Resistance

The Forum convened members from both the pharmaceutical industry and government research groups to discuss the issues surrounding drug resistance at a "Roundtable on HIV Drug Resistance," where the following issues were discussed:

1. the potential sharing of data and resistant isolates between companies and research groups;
2. the need for standardized methodology of resistance testing, and
3. the need for clinical studies to learn how to apply data on resistant mutations to clinical decision-making.

When to Start Feasibility Evaluation

When in the course of HIV disease progression to begin anti-viral therapy remains a key question for researchers, care providers and people with HIV, but conducting clinical trials to answer that question presents a number of significant challenges.

A January 2000 conference on "Long-Term Clinical Studies in HIV-1 Infection" sponsored by the National Institute of Allergy and Infectious Diseases was the first phase in a feasibility evaluation on conducting such trials. At the meeting, an expert panel agreed that such studies would require large, randomized trials with clinical endpoints and long-term follow-up of participants. Specific factors related to overall feasibility of the studies include recruitment and retention of patients, ethics, and applicability/interpretability.

To maintain the momentum on this research question, the second phase of the feasibility evaluation, to be conducted by the Forum requires a comprehensive analysis of the state-of-the-art in this arena, followed by discussion and recommendations from leaders of the groups involved in the design and implementation of and participation in the studies. The focus of this phase will be on the identification and discussion of issues that must be addressed to ensure successful enrollment, implementation, and completion of the studies. They include:

• Do providers and patients believe that questions about when to initiate therapy are important and still unanswered? Do beliefs vary in different communities?
• Will patients consent to randomization in an early vs. deferred treatment study?
• How will physician attitudes effect patient enrollment?
• Given a patient population that is increasingly poor, young, under-educated, and faced with co-morbidities, what support mechanisms could best ensure long-term retention of patients in a study?
• How can such studies be promoted to patients and providers?
• Will the different types of healthcare delivery systems impact enrollment and retention?
• What resources and structures are needed to conduct a long-term follow-up study of 5 years or longer?
• How will changes in the HIV treatment guidelines, data from other completed studies or interim data impact this study?
• What educational strategies will be effective in conducting the study?

To answer these questions, the Forum will conduct a four-part feasibility evaluation, which includes:

Literature review
This extensive review will summarize what long-term clinical trials on questions similar to when to initiate therapy in other diseases have been done. The review will describe:

• study designs,
• implementation efforts,
• methods used to recruit and retain patients,
• reported difficulties, and
• study results.

It will also provide background information on strategies for determining if patients and providers are uncertain as to when to start treatment (equipoise). Detailed information on strategies used to recruit and retain patients for extended time periods, the success of those strategies, the effect of different health care delivery systems of study implementation, and the applicability of study results will also be included.

Structured Interviews
The Forum will develop a survey instrument to determine provider attitudes towards the use of anti-viral therapy, their degree of uncertainty about the early use of anti-viral drugs, and their willingness to refer patients to a long-term study and recommend randomization to either early or deferred treatment. The survey will also provide information about the participant's method of health care delivery and the ways in which those varied methods may effect study enrollment and retention. The survey will be conducted using a database of geographically diverse health care providers serving a variety of populations affected by HIV.

Patient Focus Groups
The Forum will conduct a series of focus groups with patients in five areas of the U.S. The focus groups will investigate patients' attitudes about starting therapy, their interests and concerns about clinical studies, their willingness to enroll in "when to start" studies, and what factors would influence their decision to enter and remain in a long-term study.

Data Collection and Analysis
The Forum will perform an analysis of the Centers for Disease Control and Prevention's SHAS database to determine when in the course of their HIV disease patients are learning about their infection and when they are accessing care. This data analysis will provide essential information to determine if a substantial number of patients are learning about their infection early in the course of their disease and are, therefore, eligible for a study of when to initiate HAART. If a large population of patients are finding out late in the course of their infection, then study enrollment will be more difficult and the underlying question of when to begin therapy less relevant. The analysis will also examine differences in HIV testing rates and care access based on race, gender, age and population.

The results of these activities will result in a final publication widely distributed to the scientific community. The publication can assist and guide individual efforts to develop protocols examining the initiation of HAART.

Structured Treatment Interruptions (STI)

In October 2000 the Forum for Collaborative HIV Research, Foundation for AIDS & Immune Research (FAIR), Project Inform, and Treatment Action Group (TAG) sponsored a collaborative project on STI. Clinicians, researchers and community advocates from multiple disciplines met to explore STI as a way to enhance HIV specific immune responses, limit drug exposure, prevent drug-related toxicity, allow a shift to a more drug-susceptible "wild type virus", and improve the quality of life for people infected with HIV. The presenters addressed issues specific to patient populations in the areas of primary infection, chronic suppressed infection and chronic unsuppressed drug resistant infection. The workshop summary provides details of the meeting.