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What the HIV community thinks about when to start--and START.

The question of when antiretroviral therapy (ART) should ideally be started has been a flash-point for controversy ever since the first anti-retroviral drug, zidovudine (Retrovir, AZT), won approval in 1987. That question has recently come to the fore once again because of accumulating data-particularly from the large SMART treatment interruption trial (1)--showing that people with HIV infection face health risks that fall outside the historical definition of AIDS-related clinical events. These data have informed the design of the new START trial by the INSIGHT clinical trials network. START aims to assess the impact of earlier ART not only on AIDS-defining diseases, but also on cardiovascular, liver, and kidney disease and mortality from any cause.

Burning the bulb early?

Historically, community opinions on the when-to-start question have tended to divide along lines similar to those of clinicians; some have leaned toward supporting early treatment while others have expressed caution, arguing that antiretroviral use should be delayed until late in disease when the risk of clinical illness is greatest.

Over a decade ago, Treatment Action Group's Mark Harrington offered a famously lucid description of why he fell into the latter camp at the 1994 International AIDS Conference in Yokohama: "Using AZT when your immune system is still holding HIV in check, and your lymph nodes are still trapping virus, may be like using your last light bulb at noon: it may be burnt out by dusk, and you'll be left in the dark." This view was underpinned by data from several large studies of early intervention with AZT monotherapy, which failed to reproduce the clinical benefit reported in individuals with advanced disease. (2,3) The advent of combination ART in 1996 reignited the debate about when to start. Data from trials of dual and triple combinations showed dramatic, stepwise improvements in the incidence of clinical illness and survival but did not answer the question of when ART should begin. Some researchers and community activists called for a trial that would specifically address the issue, and a protocol was developed for the government-sponsored AIDS Clinical Trials Group (ACTG) called the "Strategic Timing of ART" trial (ACTG 355). But ACTG leadership ultimately dubbed the protocol "overly ambitious" and withdrew the trial in March 1997. As a result, the historically unreliable resource of "expert opinion" was left to make recommendations for starting ART which, in the United States, came in the form of a panel that generated what is now called the "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents." (4)

As work began on the first iteration of this document (released in 1997), the panel--which included researchers, clinicians, and community representatives--faced a near-meltdown caused by the controversy around the when-to-start question. Several researchers wanted to recommend treatment for almost everyone with HIV, and it took the threat of a walkout by an opposing group of activists and clinicians to ensure that diverging viewpoints were acknowledged and that "some experts" (as the document phrased it) would defer treatment until CD4 counts reached 350 cells/[mm.sup.3]. The more aggressive approach comprised a recommendation to begin treatment if the CD4 count fell below 500 cells/[mm.sup.3] or if viral load crested above 20,000 copies/mL (regardless of CD4 count).

By the turn of the millennium, increased awareness of the potential long-term side effects of ART (such as lipodystrophy) caused the debate about a when-to-start trial to bubble back to the top of the research agenda. Over 2 days in January 2000, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored a workshop on ART and the feasibility and desirability of a NIAID-sponsored trial was first on the agenda. Again, opinions were divided, although some objections to the concept derived from concerns that a when-to-start trial was simply not feasible because people would not want to enroll. Some community members also argued that the results, by the time they were obtained, would likely be irrelevant because newer antiretrovirals with potentially improved side effect profiles would be available. Ultimately, the idea fell by the wayside once more.

SMART helps jumpstart START

Now the idea is back with much broader support and, ironically, exactly the same acronym as ACTG 355: START (Strategic Timing of AntiRetroviral Therapy). The driving force comes from results of the large SMART study, which evaluated continuous versus intermittent ART among 5472 participants. (1) Crucially, SMART revealed that immune activation--long known to correlate strongly with disease progression in people with HIV--has health consequences that have until now been poorly recognized. Understandably, before the advent of combination ART, the focus was on preventing opportunistic infections, which were clearly the biggest threat to the health of individuals with HIV. Studies suggested immune activation (and associated inflammation) played a role in the development of dementia, but the impact of chronic inflammation on other health outcomes received relatively little attention. Conditions associated with chronic inflammation in uninfected people, such as cardiovascular, liver, and kidney disease, tended to be considered ART side effects when they occurred in HIV-infected individuals.

The results of SMART, which showed a significantly increased risk of these non-AIDS-defining problems in people who interrupted ART--strongly associated with increases in inflammatory markers such as the cytokine IL-6--have challenged the assumption that these events were all treatment-related and brought the clinical consequences of immune activation into sharp relief. Furthermore, an analysis of the small subset of SMART participants who entered the trial naive to ART suggests that fewer events occurred in people randomized to start immediately compared with those who waited until their CD4 counts declined below 350. (5)

Taken together, these findings have provided a strong impetus for the START trial, which is designed to be large enough to definitively test whether starting ART immediately is better than waiting until the CD4 count is less than 350. Similar to SMART, START includes a pilot phase that will enroll 900 people in order to assess feasibility. Only if the pilot is successful will the trial expand.

Time to "stow our opinions" and get data

Community opinion on the proposed START trial is varied. Long-time supporters of the idea of studying when to start are, unsurprisingly, enthused. "It's hard to believe it's finally happening" says Lynda Dee from AIDS Action Baltimore, who has been among those calling for a when-to-start trial for more than a decade. "For years the scientific community professed that it was impossible to enroll and complete such a study. I believe the pilot is a great way to ascertain if it is in fact possible. Let's get it done and try and finally resolve this extremely important strategic treatment question."

The experience of Paul Simmons from Houston's Center for AIDS causes him some concern about the feasibility of START. "Here in Houston, the mean CD4 T-cell count at presentation is about 100. If that's also the case elsewhere, then a when-to-start study is not recruitable." He also wonders if the availability of improved antiretrovirals has impacted the rationale for the study. "When people were dosing a toxic protease inhibitor three times daily on an empty stomach, you had reason to wonder whether the benefits of early treatment outweighed its dangers and inconvenience. But when you can take a relatively safe medication once a day without regard to meals, your biggest negative to early treatment is probably cost. So while I think when-to-start is still valid as a public policy question, it's probably not as clinically valuable a question as it used to be."

Despite those reservations, Simmons does not oppose the idea. "I don't feel strongly about stopping the study. Over the course of this epidemic, both professional and community 'experts' have been wrong repeatedly in their estimations and projections. So where possible, we should collect data and stow our opinions. The pilot phase will tell us whether the study is feasible."

Paul Dalton from Project Inform in San Francisco has been skeptical in the past about this type of trial, based on the concern that the data would be inextricably linked to the regimens in use at the time the trial began. If a trial had been launched in '97, he notes, "we would just be getting final results, and we would have a lot of information on d4T, Crixivan and Viracept regimens [stavudine (Zerit), indinavir, and nelfinavir]. Not only would that information be of little value, but it would likely argue for delaying treatment as long as possible."

But Dalton also acknowledges that this concern may be leavened in 2008: "I think this might be a good time to try a trial such as START. For one thing, the pipeline is thin and unlikely to generate anything of a game-changing nature for years to come. Also, we might luck out and have another SMART-like situation, where we get meaningful information in short order. As a member of the DHHS guidelines panel, I very much want randomized, controlled when-to-start data. But I remain quite skeptical about whether we can get that information in a workable time flame."

The plan for the START trial involves international trial sites, and Simon Collins from i-Base in the UK is a member of the INSIGHT Network's community advisory board (CAB). Collins has been a long-time supporter of addressing the question of when to start in a large randomized trial and believes START is critically important for many reasons.

"One of the things that changes how people see the benefits of the study," Collins notes, "is the trend for baseline CD4 count to determine how high CD4 counts are likely to recover. Over 30 to 50 years those extra CD4s may protect against potential long-term health issues including heart disease, organ failure, and cancer that currently run higher in HIV-positive people compared to HIV-negative people from similar circumstances. We need the trial to find out whether this may be true. No one has ever looked at this question in a study that is sufficiently powered to get an answer. I want to know if earlier treatment closes the gap between how long an HIV-positive person can live compared to an HIV-negative person."

Collins acknowledges that recruitment could be problematic--"It's one of the reasons that we need a large trial network"--but also points out that "the study seems less difficult if thought of as just starting treatment a year or two earlier than otherwise. Given the 30, 40, or even 50 years that we currently think of with indefinite treatment, a couple of years early is not so big a difference, especially if CD4 counts have a much higher chance of normalizing."

Another INSIGHT CAB member, San Francisco's Claire Rappaport, also stresses the importance of the trial: "Current data available are insufficient to inform whether the benefits of initiating ART at CD4 cell counts above 500 outweigh the risks. It is critical to evaluate risks and benefits of early ART with a randomized trial." Rappaport thinks "the split within the community about this issue also speaks to the need to conduct the START trial. We need to know the answer of when is the best time to start treating HIV disease for both the HIV and non-HIV disease outcomes."

Although there remains some skepticism in the community about START, there is also clearly much support. After many delays, the pilot phase of the trial is about to get under way. Concerns remain about the commitment of the National Institutes of Health (NIH) to fully support the trial--for example, concerns that funding for important components such as baseline kidney function tests may not be made available.

Fourteen years on from his light bulb metaphor, Mark Harrington used the opportunity of a speech at the most recent International AIDS Conference to raise the START funding issue, directly addressing NIAID Director Anthony Fauci: "Right now there is only $5 million available for the INSIGHT pilot. Please fund the full study.

References

(1.) The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296

(2.) Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet. 1994;343:871-881.

(3.) Volberding PA, Lagakos SW, Grimes JM, et al. The duration of zidovudine benefit in persons with asymptomatic HIV infection. Prolonged evaluation of protocol 019 of the AIDS Clinical Trials Group. JAMA. 1994;272:437-442.

(4.) Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. January 2008 (http://AIDSinfo.nih.gov/Guidelines).

(5.) The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008; 197:1133-1144.

Richard Jefferys is Coordinator of the Michael Palm Basic Science, Vaccines and Prevention Project, Treatment Action Group, New York, NY.
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Title Annotation:Perspectives; antiretroviral therapy
Author:Jefferys, Richard
Publication:Research Initiative/Treatment Action!
Article Type:Report
Geographic Code:1USA
Date:Sep 22, 2008
Words:2149
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