The results of the START study have confirmed what some researchers have suspected for some time -- the CD4+ cell count is an imperfect measure of the immune system's health. As a result of START, we expect scientists to engage in further work to find out more accurate ways of assessing the health of the immune system. To accompany that work, we present some findings from another study that raised issues about what constitutes a normal or acceptable CD4+ count and some of the immunological injury that can occur early in the course of HIV disease. This information appeared earlier this year in CATIE News and we have adapted it for presentation here.
Results from START and other research strongly suggest that starting potent combination anti-HIV therapy (ART) at the threshold of 500 cells/mm3 is insufficient for normalizing the functioning of the immune system. An American 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 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/mm3. In this range, 900 CD4+ cells/mm3 would be considered the mid-point or average CD4+ cell count. This figure of 900 cells/mm3 is much greater than the figure of 500 cells/mm3,which was the figure used in many treatment guidelines before the results of START were known. Furthermore, it appears that the figure of 500 CD4+ cells/mm3 significantly 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.
Here is another issue: Relying on CD4+ cell counts alone underestimates the injury caused to the immune system by HIV. New research suggests that delaying the initiation of ART until the CD4+ count falls to a level of 500 cells/mm3 does 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.
Timing of Therapy
In their analysis, researchers found that nearly 40% of NHS participants achieved a CD4+ count of about 900 cells/mm3 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/mm3, 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.
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.
- Some 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 on the CATIE website.
Implications of the U.S. 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/mm3 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/mm3 or greater
In the U.S. study, researchers found that participants whose CD4+ counts were at least 500 cells/mm3 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 long 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 "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).
The analysis from the U.S. study is supported by the results of the START study, discussed earlier in this issue of TreatmentUpdate.
- Fletcher CV, Staskus K, Wietgrefe SW, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proceedings of the National Academy of Sciences USA. 2014 Feb 11;111(6):2307-12.
- Okulicz JF, Le TD, Agan BK, et al. Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals. JAMA Internal Medicine. 2015 Jan;175(1):88-99.
- Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. New England Journal of Medicine. 2013 Jan 17;368(3):218-30.