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Massive Change in U.S. Treatment Guidelines

January 2010

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Earlier Initiation of Therapy Recommended

According to the DHHS, the goals of anti-HIV therapy are supposed to be:

  • to maximally and durably suppress HIV in the blood
  • to reduce HIV-associated illness and prolong survival
  • to improve quality of life
  • to restore and preserve the immune system
  • to prevent HIV transmission

Readers should note that the effectiveness of treatment in preventing the sexual transmission of HIV is controversial and is still being studied.

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Additionally, the authors of the guidelines hope that HIV suppression with anti-HIV therapy may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other health conditions that affect HIV-positive people.

Perhaps the most controversial changes to the DHHS guidelines are in the section on when to start anti-HIV therapy. Over most of the past decade, the DHHS has encouraged doctors to delay starting therapy until later in the course of HIV disease. This was mostly because regimens were cumbersome and had side effects.

However, in the past several years, newer treatments have become more commonly available and co-formulations -- putting two or more drugs into one pill -- have become standard. This means that the number of pills a person has to take each day, at least when starting therapy, is reduced. Indeed, there is even one pill containing three potent anti-HIV drugs that only has to be taken once daily. Also, medicines used today are generally better tolerated than those a decade ago. So doctors and their patients have more options.


Deep Divisions

The usual procedure for the creation and revision of the guidelines is for the guidelines committee or panel to make recommendations and there is usually consensus for these recommendations. However, when revising the recent guidelines, the panel members found that there was no consensus about several major issues. For the first time, decisions of the panel are accompanied by a breakdown in the vote. We will explain these as we cover key issues in the guidelines.


When to Start?

For the past several years, major HIV treatment guidelines in the United States and Europe have generally recommended that therapy begin when a key marker of the immune system -- the level of CD4+ cells in the blood -- has fallen below a threshold of 350 cells. Certainly the panel continues to recommend this. However, they now go beyond this.

Recent results from large observational studies were considered when formulating the new guidelines. These results suggest that the risk of major disease-related events were greatly reduced when HIV-positive people began therapy when their CD4+ counts were between 350 and 500 cells. The events that were avoided were as follows:

  • death
  • AIDS-related illnes
  • illness from causes unrelated to AIDS

Based on these results the panel now recommends that HIV-positive people begin therapy when their CD4+ count falls below the 500-cell mark.

However, it is important to note that the panel was deeply divided on this issue: 55% of members voted to strongly recommend this change while 45% felt that starting early deserved only a moderate recommendation.


Should All HIV-Positive People Be on Therapy?

One question the panel dealt with was: What about starting therapy when the CD4+ count is above 500 cells (essentially this would recommend immediate therapy for all HIV-positive people)? On this issue the panel was again divided. Half of the panel was in favour of starting therapy at this stage, while the other 50% felt that therapy at high cell counts should be "optional."

There are several reasons why therapy might start very early, such as the following arguments made by some panel members:

  • Results from one large observational study clearly show improved health with early therapy.
  • In the present era, emerging data suggest that untreated HIV infection is associated with an increased risk for diseases not usually considered AIDS-related, such as cardiovascular, kidney and liver diseases, as well as certain cancers including liver, lung and skin tumours.
  • Currently available therapies are better tolerated, more effective and more convenient than older therapies.
  • There are hints that some people who take anti-HIV therapy may be less infectious, although the evidence is not conclusive.

The other half of the panel made the following arguments against early therapy:

  • There is no conclusive evidence that early anti-HIV therapy will benefit every person whose CD4+ count is more than 500 cells.
  • Though treatments are more tolerable today than they were 15 years ago, these drugs still carry both short-term and long-term risk for side effects.
  • As anti-HIV therapy has to be taken for the rest of a person's life, there may be problems maintaining adherence over the long-term in people who begin therapy when they are largely symptom-free, as are most people who have CD4+ counts above 500 cells. Difficulty maintaining adherence may give rise to drug-resistant and therefore hard-to-treat strains of HIV, reducing future treatment options.


The Psychology of Shock

One issue apparently not considered by the panel members is the psychological shock many otherwise healthy and symptom-free HIV-positive people would have if the panel, however divided, had indeed recommended that all HIV-positive people start therapy regardless of CD4+ count or other factors.

At best, receiving a diagnosis of HIV infection is a traumatizing event; people, their friends and family need time to adjust to this. For some HIV-positive people such adjustment can take years. Even with acceptance of a changed health status, the additional shock of the news about having to take a complex drug regimen for the rest of one's life may cause additional distress.

Also, today in high-income countries, many people who are HIV-positive may have other unrecognized, undiagnosed or unacknowledged pre-existing health issues that they may also need support to manage, such as:

  • depression
  • hepatitis B and C virus co-infection
  • addiction

The news of their HIV status and the fact that they have to start medication very soon and deal with other health issues could overwhelm some people.


A Note on Study Design

Data from observational studies suggest that there is a benefit from the early initiation of therapy. However, observational studies, by their nature, can only find associations; they cannot prove that taking therapy at high CD4+ counts will ultimately benefit people. What's more, confounding or channeling bias is a problem with observational studies that makes drawing firm and accurate conclusions when interpreting data difficult.

Observational studies can produce interesting results and be very useful. These results can then be used to inform studies of a more robust design, such as randomized, controlled clinical trials. We will now take a brief look at a couple of the large observational studies that underpin recent decisions by the guidelines' panel. This exercise will highlight some of the issues of relying on these trials and may explain some of the panel's voting patterns.


The NA-ACCORD

A large Canada-U.S. study called the NA-ACCORD found that among 2,200 HIV-positive participants who began therapy when their CD4+ count was greater than 500 cells, the risk of death was significantly lower than seen in 6,935 HIV-positive participants who began therapy when their counts fell below 500 cells. The panel notes that although the difference in death rates was statistically significant, the number of deaths that occurred was relatively small.


ART-CC

Another large observational study, the ART-CC has a database with health-related information on more than 60,000 HIV-positive people. In analysing its data, the ART-CC research team found that there was no benefit to starting therapy when the CD4+ count was greater than 450 cells. This analysis also found that the number of people who entered the study with a cell count between 451 and 550 cells and who later developed AIDS or died before their CD4+ count slipped below the 450-cell mark was low.

As previously mentioned, observational studies cannot produce definitive results. And despite the lack of definitive results, 50% of the panel felt that therapy should be started when the CD4+ count is more than 500 cells. In effect, half the panel thinks that all HIV-positive people should be on therapy.


What to Do?

When discussing the possibility of starting therapy at high CD4+ counts (more than 500 cells), the panel stated this:

"Clinicians should inform patients that data on the clinical benefit of starting treatment at such [CD4+ cell] levels is not conclusive. There is a need for further ongoing research (both with randomized clinical trials and cohort studies) to assess the short- and long-term clinical and public health benefits and cost-effectiveness of starting therapy at higher CD4+ counts."


Special Considerations for Early Treatment

The American panel, like similar committees in the European Union (EU), recommends that anti-HIV therapy begin regardless of CD4+ count in HIV-positive people with the following circumstances or conditions:

  • pregnancy -- to prevent mother-to-child transmission
  • HIV-related kidney damage
  • hepatitis B virus (HBV) co-infection when there is a need to begin anti-HBV therapy -- because several drugs that are used to treat HIV infection also have activity against HBV


Other Conditions

The panel stated that in some cases the initiation of therapy may take on added urgency because of special circumstances, including these:

  • the diagnosis of a life-threatening infection
  • having low CD4+ counts (less than 200 cells)
  • having CD4+ counts that decline rapidly from year to year, in other words, losing more than 100 CD4+ cells per year
  • having a high viral load (more than 100,000 copies).


Reference

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161. [Accessed 10 December 2009].

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This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.
 
See Also
Read the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
More News and Analysis on HIV Treatment Guidelines


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