To Start or Not to Start? Still Looking for Answers
The question of when it's best to begin antiretroviral therapy may be as controversial and frustrating as any of the many HIV treatment questions to which we have no clear answers. The US Department of Health and Human Services (DHHS) HIV treatment guidelines were revised in February, and the biggest change in the guidelines addresses this question.
Since their first appearance in 1997, the guidelines have been relatively aggressive in their recommendations about when people with no symptoms should consider starting treatment. They've recommended that treatment be considered once CD4 counts fall below 500 or viral load rise above 20,000 copies/mL by PCR, the most commonly used test. The newly revised guidelines lean more toward delaying therapy in people without symptoms -- they now recommend considering therapy if CD4s fall below 350 or viral load rises above 55,000. Many people living with HIV and their healthcare providers have been delaying treatment despite the guidelines' previous recommendations, but this is still a big change.
When combination therapy first went into widespread use in 1996, people increasingly needed help figuring out how to best use the drugs. The DHHS guidelines, often simply referred to as the federal treatment guidelines, were created to offer people a roadmap to help them navigate their way through their options. Developed by a group of researchers, physicians and community members, the guidelines can help in the process of determining if and when to start therapy, what drugs to start with, when to stop or switch, and how best to use available diagnostic tests. They reflect our current understanding of HIV progression and treatment and are periodically revised as ongoing research increases our understanding of HIV.
Clearly, current anti-HIV drugs can't rid the body of HIV. Even when viral load is undetectable, HIV is still reproducing at low levels. The realization that treatment with current drugs will probably be lifelong is the impetus behind the change in the guidelines. The change also reflects an appreciation of long-term drug side effects, the recognition that these drugs require an almost impossible level of adherence, and the likely development of drug-resistant virus while on lifelong therapy. If we had drugs that completely suppressed HIV, caused no short or long-term side effects, and were easy to take, everyone would start them soon after infection. But that's unfortunately not the case.
As much as we'd like a clear answer about when to start treatment, the debate continues. In the rush to get to the tables and charts, it can be easy to overlook the guidelines' thoughtful discussion of some of the benefits and risks of starting treatment later rather than earlier. Possible benefits of delaying treatment include better quality of life, no drug-related side effects, putting off the development of drug-resistant virus, and having more drug options later on, when you might need them more. On the other hand, the risks of delaying treatment include the possibility that your immune system might have suffered irreversible damage and it might be harder to achieve an undetectable viral load.
But starting treatment early requires a consideration of risks and benefits, too. The stronger your immune system is when you start, the easier it is to achieve and maintain an undetectable viral load -- and drug resistance is less likely to develop when your viral load is undetectable. Earlier treatment might also delay or even prevent damage to the immune system. Conversely, possible risks of starting treatment early include a reduced quality of life due to short and long-term side effects, the development of drug resistance if viral load doesn't stay undetectable, and limited treatment options in the future.
The information we have to help us answer the question of when to start comes from retrospective studies based on patients' medical records, rather than from prospective studies designed specifically to answer the question. Such a prospective trial is extremely difficult to design. It would have to run for years and enroll thousands of people. And a trial that started now would, at best, answer the question of when to start therapy in 2001, with the treatments available in 2001. By the time the trial ended years from now, new, hopefully better drugs and strategies would be available and our understanding of HIV disease would be more complete.
At the 8th Conference on Retroviruses and Opportunistic Infections (CROI) in February, there were many reports on retrospective studies that looked at the relationship between disease progression and CD4 counts and/or viral load levels of people when they first started combination therapy. A retrospective study from Johns Hopkins University looked at what happened to 1,014 patients who began two- or three-drug combinations after July 1, 1999. There was a strong correlation between disease progression and starting therapy with CD4 counts below 200. The higher rate of disease progression in these patients may be at least partly explained by observations made by the Johns Hopkins group (and other studies) that people are less likely to achieve undetectable viral load if they start treatment with a CD4 count below 200. Progression rates in people who started therapy with CD4 counts between 200 and 350 didn't differ substantially from those who started when their CD4s were above 350. Interestingly, pre-treatment viral load levels, independent of CD4 count, didn't predict clinical outcome. The study looked at pre-treatment viral loads less than or greater than 20,000, 100,000, and 200,000, and found no differences in disease progression between the groups.
A study from the Centers for Disease Control and Prevention (CDC) looked at more than 5,100 people who started two- or three-drug combinations in 1994 or later. The risk of death was significantly higher for people who started treatment when their CD4s were below 200 compared to those who started treatment when their CD4s were above 200. The study showed a trend for better clinical outcomes in people who started treatment with CD4 counts between 200 and 350, but the difference wasn't statistically significant. And people who started treatment with CD4 counts above 350 showed no clear benefit.
These and other studies show pretty convincingly that people who begin therapy before their CD4s dip below 200 do better clinically. So is it best to consider treatment before you reach that point? Probably. But what's the cutoff? Somewhere between 200 and 350, perhaps. But even then, there are so many factors to consider. Is someone whose CD4 count has dropped from 700 to 300 in a year in the same situation as someone whose CD4s have remained steady at 300 for five years? Clearly not. This is where the individual flexibility called for within the text of the guidelines comes into play.
As people living with HIV and their healthcare providers make complicated treatment decisions -- including the decision about when to start therapy -- the federal guidelines can be enormously helpful. But the guidelines have limitations, and it's important that we recognize those limitations. They are guidelines, a tool. They include recommendations, suggestions, information and discussion. They are not a "one-size-fits-all" formula for treatment, nor are they intended to be.
The data we have on HIV disease progression are based on what seems to happen to groups of people -- populations, not individuals. These data and the real-life experience of people living with HIV support the revision to the guidelines, that therapy be considered by people without symptoms when the CD4 count is below 350 (rather than 500 as previously recommended), or the viral load is above 55,000 (rather than 20,000). But if there's one thing we've learned over the last twenty years, it's that HIV disease varies widely from person to person. The percentages and probabilities don't necessarily apply to you, your very particular situation, and the many factors that contribute to who you are -- a unique individual.
James Learned is CRIA's Director of Treatment Education and Editor of CRIA Update.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.