In December 2009, a panel of government officials, academic researchers and HIV/AIDS activists revised the U.S. Department of Health and Human Services (DHHS) official recommendations for when to start HIV treatment. The new Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents strongly encourage treatment for all people living with HIV with CD4 counts between 350 and 500. Previously, treatment was only advised for patients with CD4 counts of 350 or lower—as remains the recommendation in most other developed nations.
A patchwork of data suggests that starting treatment earlier can benefit the health and longevity of people living with HIV, as it may better defend the immune system, lower the risk of non-AIDS diseases and further reduce the risk of death. It is this research that has sparked tremendous interest in the personal benefits of early antiretroviral (ARV) therapy.
Early treatment may also benefit the greater good of the public health. Some research suggests that undetectable viral loads in a large swath of the HIV population can potentially slow the spread of the virus. In turn, public health officials are considering whether widespread, immediate ARV therapy could be an effective HIV prevention tactic.
Few experts and activists argue that the research supporting early treatment is anything less than encouraging. Where there is less agreement, however, is whether enough sound, scientific research has been conducted to spell out the benefits and risks—the increased (or decreased) likelihood of short- and long-term side effects, adherence challenges and the development of drug resistance, for example—of early treatment and to warrant major changes to public policy. In fact, some of the most experienced and trusted sources of HIV prevention and treatment policy are struggling to make the right call.
Case in point is Project Inform’s recent switch on where it stands on the issue. On April 13, the prominent San Francisco–based HIV advocacy organization issued a policy statement containing a series of when-to-start recommendations. One in particular seemed to advise treatment at any CD4 cell count. A few weeks later—without acknowledgment or explanation in a revised policy statement—Project Inform changed its position.
In its April 13 policy statement, the organization stated, “Based upon a careful review of currently available data, Project Inform believes that all HIV-positive people who are ready to begin treatment should start before their CD4 counts fall below 500.” This exceeded the start recommendation in the DHHS guidelines, which only promoted treatment when the CD4 cell count is 500 or below, and was more along the lines of a recent San Francisco Department of Public Health (SFDPH) policy recommending immediate treatment for everyone diagnosed with HIV.
But, in a revised policy statement dated May 2010, they wrote: “Based upon a review of currently available data, Project Infom believes that all HIV-positive people who are ready to begin treatment should start if their CD4 counts fall below 500” [emphasis added]. This put the organization’s position more in line with the DHHS guidelines.
“Based on feedback and in an effort to be clearer in our positions, we made small changes [to our policy statement] and re-dated it,” said Dana Van Gorder, Project Inform’s executive director. When asked if he cared to elaborate, pointing out that some may consider the CD4 change to the policy statement to be rather significant, Van Gorder simply responded, “No.”
Project Inform is not the only group to struggle with the question of when to start treatment. Even the panel of experts who revised the DHHS treatment guidelines were somewhat divided—if not over their final recommendation, then certainly about how strongly they supported it. Though more than two thirds of the DHHS panelists who revised the treatment guidelines voted to change the CD4 starting point (from 350 and below to between 350 and 500), there wasn’t universal agreement on the strength of the recommendation. Fifty-five percent of the panel voted that the recommendation be “strong,” and 45 percent voted that it be “moderate.”
The rationale behind recommending treatment for those with up to 500 CD4s comes primarily from two large cohort studies. The North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study and the ART Cohort Collaboration (ART-CC) study suggested that people who waited to start treatment until CD4s dropped below 350 faced a higher risk of premature death, from any cause, than people who start treatment at a CD4 count above 350.
Further evidence in support of early treatment—again from cohort studies—suggests that uncontrolled HIV replication might be associated with a number of illnesses not traditionally associated with AIDS. These include non-AIDS-related cancers, cardiovascular disease, liver disease, kidney disease and immune inflammation.
Simon Collins of HIV i-Base, an HIV treatment education and advocacy group in London, argues that these data need to be interpreted with a critical eye. Not only are the observed differences marginal, but the data reported thus far only come from studies with important limitations.
“The few studies involving patients starting at 350 and 500 show both options are very safe and very effective,” Collins says. “In [NA-ACCORD], 19 out of 1,000 people died in the first year of treatment if they started at 350, compared with 16 out of 1,000 people who started above 500. The absolute risk of death in both groups was very small. The difference in the absolute risk between the groups—0.3 percent—could easily have been due to confounding factors [factors unrelated to HIV] that [cohort study limitations] can’t account for.”
As for people living with HIV with CD4s above 500, the guidelines’ panelists were again split down the middle, this time as to whether to recommend treatment or not. Whereas NA-ACCORD did suggest a benefit associated with very early treatment, ART-CC did not. Even with NA-ACCORD, the guidelines’ authors themselves note important limitations, “including the small number of deaths”—which makes detailed comparisons extremely difficult—“and the potential for unmeasured confounders that might have included outcomes independent of antiretroviral therapy.”
“This brings us to why randomization is key to the quality of the evidence,” Collins says, pointing out that cohort studies lack this tried-and-true scientific device that can help neutralize confounding factors in studies. “Randomized trials generally get a balance of all factors in the two groups being compared. This includes the things we think might affect the results, but also the things we have no control over, like genetics or personal behavior.”
There is a dearth of data from randomized clinical trials to demonstrate that the benefits of starting treatment when the CD4 cell count is above 350 outweigh the potential risks. Despite this paucity, a groundswell of support for early treatment is already growing.
As mentioned earlier, the San Francisco Department of Public Health (SFDPH) is now recommending ARV therapy be started as soon as HIV is diagnosed, regardless of the person’s CD4 cell count. Project Inform quickly followed suit, noting the potential personal and public health benefits that may come from early HIV treatment. Though Project Infom has quietly changed one its more controversial initial recommendations, Project Inform’s position statement continues to read as a strong endorsement for early treatment.
Bob Huff, a member of the AIDS Treatment Activists Coalition (ATAC), supports Project Inform’s original April 13 statement. “Based on what I understand about the evidence, and on what I understand about the potential benefits of treating HIV whenever it is diagnosed, I agreed with the position PI has taken,” Huff says. “I commended them for it because other AIDS organizations have avoided—or even actively resisted—supporting programs to greatly expand testing and treatment in their cities. I think PI understood it would be controversial but chose to make the statement anyway, and in doing so, I think, have showed some welcome leadership.”
Huff adds that immediate-treatment-for-prevention is a “reasonable approach” in an area like San Francisco, where the epidemic affects mainly gay men and where there has been “significant progress in expanding treatment access, which may have resulted in lowering community viral load rates. [Given results to date,] it makes sense [that public health officials] would press forward to try and achieve even more success. The potential payoff for the campaign would be halting the spread of new HIV infections in the area—an amazing outcome. Because the upside is so profound, it’s necessary that they try to achieve that goal.”
Mark Milano, another ATAC member and an activist with ACT UP New York, sees things differently. “I was unhappy with the simplistic advice the PI paper gave,” he says. “Unlike [deceased Project Inform founding director] Martin Delaney's vision of empowering people with HIV to take an active part in their health care decisions, PI just said, ‘We looked at the data, and we think you should start at 500.’ There was no attempt to educate people about the lack of data, nothing about the split on the DHHS panel, nothing about the ongoing debate over when to start. That’s not the approach I think Marty would have taken—he would have respected people with HIV enough to give them all points of view so they could decide for themselves.”
Milano also remains skeptical of the test-and-treat approach to combating the ongoing spread of HIV. “If these decisions were motivated by epidemiologic concerns—and I hope they weren’t—I disagree [with them]. Urging [people to start] treatment at higher CD4 counts when we don’t know the long-term effects, in an attempt to lower community-wide transmission rates [of HIV], does a real disservice to individuals making this life-changing decision. Especially if we don’t tell them [that protection of public health is] part of the motivation [for the recommendation].”
Collins adds: “An undetectable viral load on an individual level reduces the risk of transmission—this is supported by the data. But rolling out early treatment as a public health policy is different. An individual taking treatment primarily has to derive personal benefit, given that they face an individual risk from treatment. The discussion for individual treatment and public health cannot just be lumped together.”
The potential benefits of early treatment, as spelled out by the data reported thus far, are encouraging to say the least. But the only way to know these benefits are what they seem to be is to conduct a scientific study. In fact, a massive study exploring the potential health benefits and risks of early HIV therapy is currently under way. It’s called the Strategic Timing of Antiretroviral Treatment (START) study, and it’s being conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT).
The START trial is ambitious in its goal, yet simple in its basic design. Taking place at roughly 90 sites in nearly 30 countries, it seeks to randomize more than 4,000 antiretroviral-naive HIV-positive individuals with CD4s above 500 cells to either begin treatment immediately or defer treatment until their CD4s are less than 350 cells.
Some researchers associated with START are concerned that the revised DHHS guidelines will lead to conclusions among people living with HIV and their care providers that deferring treatment until the CD4 cell count hits 350 is too great of a safety gamble. “We are concerned that some may interpret the new [U.S.] recommendations as implying that the deferral group of this trial is no longer ethical,” Andrew Phillips, PhD, a statistician for the START trial, and his colleagues write in the February 20 issue of The Lancet. The authors add: “Such an interpretation would endanger the future of the trial in the USA.”
In an effort to challenge such interpretations, members of START’s Community Advisory Board (CAB) issued a sign-on letter highlighting the controversy surrounding the DHHS recommendations, allaying safety concerns and reiterating the need for sound, scientific data to determine, once and for all, when treatment should be started.
“We wanted to see whether there was still strong community support for getting proper evidence before changing policy so dramatically,” says Collins, a lead author of the letter. “We also wanted to emphasize that it is still a very safe study, whether someone is randomized to the immediate or deferred treatment groups.”
Collins and his fellow START CAB members—roughly 260 signatures have been added to the letter including more than 150 organizations—express a number of grievances with the revised DHHS guidelines and, indeed, the promotion of treatment at any CD4 cell count.
According to the sign-on letter, the new U.S. recommendation “is based on poor evidence and therefore might not be in the best interest of patients.”
Collins comments that the sign-on letter has actually shown how widely the study is supported. “Getting a study like START has been an activist priority for at least 10 years, and luckily, it is now being run when treatment is at its safest. Many activists continue to believe in the importance of this study, probably many more than those who think we already know enough without the data it will provide.”
Researchers are also on board with the study. “Researchers in the U.S. still see the study as safe and important,” Collins adds. “Many of the experts on the guidelines panel are also on the steering committee for START.”
START is proceeding in two phases. The pilot phase will ultimately enroll at least 900 participants, followed by a definitive phase, which will expand enrollment to an estimated 4,000 participants.
In addition to the primary study objective—to determine whether or not those who start therapy immediately are less likely to develop a serious AIDS illness, a serious non-AIDS illness or death from any cause—some patients enrolled in the trial will be followed closely to answer more specific questions about early treatment, including its effects on neurological, arterial, pulmonary and bone diseases.
“START is a randomized study, which isn’t just a technical detail,” Collins stresses. “It means the results will be solid and is the gold-standard for research. Otherwise, we have nothing other than guesses—and those guesses, even by experts, have been wrong too often in the past.”
START isn’t just about evaluating the potential benefits of treatment for practically everyone living with HIV, but also about its potential risks. “Cohort studies show the potential benefits of earlier treatment, but they haven’t been able to look at the risks of drug resistance or side effects,” Collins points out. “If we are asking people to start treatment when they feel well, we need to be able to know the risks too. The risks may turn out to be low, but we don’t know. Even aspirin does more harm than good if you give it to everyone, and this could easily be the case for HIV drugs.”
Collins also points out that, for people in the United States, the study provides free treatment. “This may in fact guarantee access to newer drugs and earlier treatment than they would have access to otherwise.”
Is it possible that enrollment in START, with its deferred treatment arm, will be considered unethical in light of the DHHS guidelines revisions and specific groups pushing for immediate treatment? Collins doesn’t think so, despite the fact that the potential for an ethics conundrum was raised in the START CAB sign-on letter. “After speaking with a wide range of advocates and researchers in the U.S., it’s clear that many take what they want from the guidelines and do what they want otherwise,” he says. “It would be nice if this were publicly known, however.”
Milano agrees and says the language employed by the guidelines panel and other groups is tricky and should be clarified, so that people living with HIV and their care providers know that they do in fact have options. “The DHHS guidelines say over and over again that they are just that—guidelines,” he says. “If doctors would stop using them as rules, it would not affect enrollment of START. If the panel members felt that cohort studies argue for earlier treatment, it would be unethical to withhold their ‘recommendation’ just to help START enroll. But they need to emphasize that the new guidelines are—as they have usually been—a best guess, and that START should move forward.”
Huff doesn’t doubt the merits of START. “I agree that a large clinical trial of this question is essential, but I don’t think communities should be restricted from doing what they think is best at this point based on available data.”
He also argues that the push for early treatment by some cities and local organizations shouldn’t be viewed as a direct threat to the study, but rather an opportunity for supplemental learning. “I don’t think a nationwide recommendation by the CDC or the guidelines committee is warranted by the evidence at this point, and neither does the committee, apparently,” he says.
“The experience [in San Francisco] will feed into the forming and shifting ‘cloud of consensus’ on this question over the next several years,” he says. “I expect researchers in the city health department and elsewhere will report on the impact of the campaign. I hope Project Inform also reports on its experiences with communicating its position in the community and what it learns about the range of individual experiences with quality of care, protection of rights and respect for people with HIV as this program goes forward. If universal testing and treating become the standard of care in the future, other cities and organizations will look to the experiences in San Francisco and other pioneer cities to learn what worked and what didn’t.”
Project Inform stresses that it supports the need for, and completion of, START. “The study’s main endpoints and data from its many planned sub-studies can only help to define the best time to start therapy.” When asked why it didn’t include a reference to START—and the controversies it hopes to settle—in its position paper, Van Gorder says that it didn’t mention the study “because START, among other study data, will be more carefully discussed [elsewhere on Project Inform’s website].
“Given recent changes in earlier treatment advocacy, concern for fully enrolling START is understandable,” he adds. “Project Inform wants to see START fully enrolled and completed, and will work with its CAB to support successful implementation of the study.”
Collins says he hopes the sign-on letter will lead to an even larger national dialog about the DHHS recommendations and emerging public policy favoring immediate treatment. “This is almost creating a panic to get on treatment, when we already know that at high CD4 counts there is rarely any urgency for treatment. We are saying that we want to see the evidence of both the risks and the benefits.”