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Study uncovers new ground about when to start HIV therapy
12 Jan 2015 - A major question that has recurred since the availability of potent combination anti-HIV therapy (commonly
ART or HAART) is when this therapy should be initiated to ensure the optimal health of HIV-positive people.
New research has revealed that early therapy may be highly beneficial.
About starting ART
Over the past 15 years, leading treatment guidelines have increased the immunological threshold at which
treatment should be started in adults—from 200 cells/mm 3 to 350 cells/mm 3 to 500 cells/mm 3, and now
many guidelines recommend offering treatment soon after diagnosis regardless of CD4+ count (immediate
therapy).
The recommendation to offer earlier therapy is based on a large body of research on both the health
and prevention benefits of ART. Furthermore, initiating ART when there is less immunological damage
generally enables better preservation and enhancement of the immune system. What is more,
starting ART when the immune system is not greatly weakened ensures that treatment is
generally well tolerated.
Clinical trials and observational studies have shown that keeping CD4+ counts at 500 cells/mm 3 or higher
with ART significantly reduces the chances of developing AIDS-related complications and other unfortunate
events.
Emerging research suggests that starting ART at the threshold of 500 cells/mm 3 may, in some cases,
be insufficient for normalizing the functioning of the immune system. A new study has shown that
starting ART within 12 months of becoming HIV positive results in measureable and significant
immunological benefits. This study also provides insight into the normal range for CD4+
cells that has implications for therapeutic goals in HIV treatment.
What is a normal CD4+ cell count?
A team of scientists in California and Texas has recently reviewed studies from Australia, North America
and Western Europe in the current era and sought to clarify the normal range for CD4+ cell counts among
healthy HIV-negative people. To their surprise, researchers found that data from more than 16,000
people suggested that the normal range for CD4+ cells was between 700 and 1,100 cells/mm 3.
In this range, 900 CD4+ cells/mm 3 would be considered the mid-point or average CD4+ cell count.
This figure of 900 cells/mm 3 is much greater than 500 cells/mm 3 .
Thus, it appears that the figure of 500 CD4+ cells/mm 3 underestimates what a normal CD4+ count should be.
Unmeasured immunological injury
Assessing CD4+ cell counts only captures some of the changes brought about by HIV infection. However, there are many complex and
sometimes subtle changes to the immune system that historically have not received as much attention as the CD4+ cell count,
including the following:
- excessive activation and inflammation of the immune system
- immunological exhaustion
These and other changes begin shortly after HIV infection and ultimately have an adverse effect on a person's health.
Timing
Here is another issue: Relying on CD4+ cell counts alone may underestimate the injury caused to the immune system by HIV. Emerging
research suggests that delaying the initiation of ART until the CD4+ count falls to a level of 500 cells/mm 3 may not reverse
immunological injury caused by HIV. In other words, starting ART shortly after HIV infection may be highly beneficial
because waiting for the CD4+ count to fall allows HIV more time to injure the immune system. The U.S. researchers
suggest that in part this problem arises because using the CD4+ cell count as an indicator of the overall
health of the immune system is not a highly accurate way to assess the subtle injury caused by HIV.
What also needs to be taken into account, they say, is the duration of HIV infection.
Historically, the duration of HIV infection has not been factored into the
decision-making process for deciding when to start ART.
A large study
To gain a better understanding of the impact of HIV infection and early or delayed initiation of ART, the researchers in California and
Texas also analysed health-related information from the U.S. Military HIV Natural History Study (NHS). Participants in the NHS are from
the U.S. military and include spouses and children. What is important to note about the NHS is that participants received regular
and extensive assessments (checkups and blood tests). As a result, the estimated dates when they became HIV positive are
relatively accurate.
Researchers used data captured from 1,119 HIV-positive participants in the NHS. Most of them were male (95%) and relatively young
(31 years) and came from the major ethno-racial groups in the U.S.
In their analysis, researchers found that nearly 40% of NHS participants achieved a CD4+ count of about 900 cells/mm 3 when ART was
initiated within 12 months of becoming HIV positive. In contrast, among participants who began ART 12 months or more after becoming
HIV positive, only about 30% were able to achieve a CD4+ count within the normal range. This difference was statistically
significant; that is, not likely due to chance alone.
Sophisticated tests revealed that the closer participants' counts rose to 900 cells/mm 3 , the more their immune systems were like
those of HIV-negative people—with very low levels of immune activation, inflammation and immunological dysfunction. Such
participants also had improved responses to vaccination against hepatitis B virus compared to HIV-positive people
whose CD4+ counts did not approach the 900-cell mark. However, it is important to note that the immune systems
of early initiators of ART never became identical to those of HIV-negative people. We explore this point later.
The researchers concluded that delaying the initiation of ART beyond 12 months of the estimated date of becoming HIV positive “diminishes
the likelihood of restoring immunologic health in HIV-1-infected individuals.”
Close but not there
There are likely several reasons that underlie the failure of ART to fully heal the immune system. Here are just a few:
- ART can reduce the production of HIV in the blood; however, sophisticated research has found that ART does not fully penetrate the lymph nodes and lymphatic tissues that are a major part of the immune system. As a result, HIV can infect cells within these tissues throughout the body and continue to produce new viruses and viral proteins that impair the immune system and perhaps other organ-systems.
- Members of the herpes virus family, including CMV (cytomegalovirus) and human herpes virus-8 (HHV-8), are likely sexually transmitted, particularly among men who have sex with men. These viruses can cause low-level infection in some HIV-positive people and scientists suspect that co-infection with CMV and/or HHV-8 may play a role in the excess inflammation seen in ART users.
- Other scientists suspect that HIV causes subtle changes to the immune system that are difficult to fully reverse.
Teams of researchers in North America and Western Europe are busy trying to find ways to safely reduce
excess inflammation in ART users. Results of some research on HIV-related inflammation appear
in TreatmentUpdate 205 and
additional reports will appear later in 2015 on the CATIE website.
Implications of the present study
According to the research team, its findings have “broad implications for the management of care for HIV-1-infected patients, as well
as public policy,” as follows:
Restoring the immune system
If a major goal of treatment is to restore the immune system, the researchers stated: “Our data indicate that normalization of CD4+
counts may be an important therapeutic target.” This statement is supported by their findings that getting the CD4+ count to about
900 cells/mm 3 and keeping viral loads low greatly reduces the risk of subsequently developing AIDS and also reduces
immunological dysfunction and activation and inflammation of the immune system. More studies need to be done to
find safe ways to further reduce the excess inflammation that persists in ART users and to help raise their CD4+ cell counts.
Normalizing CD4+ cell counts
The researchers found that participants had “the capacity for CD4+ cell normalization” if the following two conditions were met:
- the duration of untreated HIV infection is short (less than 12 months)
- the CD4+ count when ART is initiated is 500 cells/mm 3 or greater
In the present study, researchers found that participants whose CD4+ counts were at least 500 cells/mm 3 when they initiated ART generally
had large subsequent increases in cell counts. However, the advantage of starting ART with a high CD4+ count was, according to the
researchers, “greatly diminished” if participants initiated ART more than 12 months after they became HIV positive.
The present study has uncovered what some scientists and doctors had suspected: Untreated HIV infection can cause significant injury to
the immune system in a relatively short span of time, long before CD4+ counts fall and AIDS symptoms appear.
Public policy—reaping the benefits of early ART
Most people are not aware when they became infected with HIV. In large part this problem arises because the symptoms of initial
HIV infection are generally similar to a cold or flu and in some cases can be very mild. However, if newly diagnosed people are
to be in a position to take advantage of the benefits of early ART, sexually active adults need to have frequent access to
barrier-free and confidential counselling and HIV testing. The U.S. researchers hope that such testing will uncover
some previously unrecognized HIV infections so that after counselling and swift referral to care “prompt
initiation of ART after diagnosis occurs.” According to the U.S. researchers, “such a strategy may
offer the best chance for [quickly halting injury to the immune system that can otherwise occur because of untreated HIV infection].”
The researchers also stated that “an added advantage of earlier [initiation of] ART would be reductions in HIV transmission” because,
in their experience, early ART quickly reduces the amount of HIV in the blood. People who test negative for HIV need to take steps
to continue to stay that way. Such steps include the correct and consistent use of condoms and, in some cases, discussion with
their doctor about the use of pre-exposure prophylaxis (PrEP).
Limitations
It is important to bear in mind that the present U.S. study was observational in design. Such studies cannot provide definitive results.
Another limitation is that participants were overwhelmingly male and relatively young. Finally, participants were not randomly
assigned to received early ART or delayed initiation of ART.
Another important study
A well-designed international study called START (Strategic Timing of Antiretroviral Therapy) is underway. START has enrolled more than 4,500 participants. This study is exploring the effect of starting ART when CD4+ counts are greater than 500 cells/mm 3 vs. deferring initiation of ART until CD4+ counts fall around the 350-cell mark. START's results are not expected until 2016.
Resources
HIV, the immune system, ART and inflammation:
Lymph nodes reveal HIV's hiding place—scientists call for new drugs
TreatmentUpdate 205
Inflammation – TreatmentUpdate 201
Reduced inflammation linked to survival – Treatment Update 170
The START study:
START study – HIV i-Base
START – International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
— Sean R. Hosein
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From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE
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