This article by Sean Hosein previously appeared on the CATIUE website here.
Une version française est disponible ici.
A major question that has recurred since the availability of potent combination anti-HIV therapy (commonly called 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/mm3 to 350 cells/mm3 to 500 cells/mm3, 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/mm3 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/mm3 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/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 500 cells/mm3.
Thus, it appears that the figure of 500 CD4+ cells/mm3 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 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/mm3 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/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. 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/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 present 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 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).
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/mm3 vs. deferring initiation of ART until CD4+ counts fall around the 350-cell mark. START’s results are not expected until 2016.
HIV, the immune system, ART and inflammation:
Lymph nodes reveal HIV’s hiding place—scientists call for new drugs
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
1. 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; in press.
2. 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.
3. 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.
4. Thornhill J, Inshaw J, Oomeer S, et al. Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection. Journal of the International AIDS Society. 2014 Nov 2;17(4 Suppl 3):19480.
5. Vassileva V, Piquette-Miller M. Inflammation: the dynamic force of health and disease. Clinical Pharmacology and Therapeutics. 2014 Oct;96(4):401-5.
6. Pawelec G, Goldeck D, Derhovanessian E. Inflammation, ageing and chronic disease. Current Opinion in Immunology. 2014 Aug;29:23-8.
7. Saracino A, Bruno G, Scudeller L, et al. Chronic inflammation in a long-term cohort of HIV-infected patients according to the normalization of the CD4:CD8 ratio. AIDS Research and Human Retroviruses. 2014; in press.
8. S Metkus T Jr, Brown TT, S Post W, et al. Cardiovascular disease associated with the human immunodeficiency virus: an update. Current Treatment Options in Cardiovascular Medicine. 2014 Nov;16(11):346.
9. d’Ettorre G, Ceccarelli G, Giustini N, et al. Taming HIV-related inflammation with physical activity: a matter of timing. AIDS Research and Human Retroviruses. 2014 Oct;30(10):936-44.
10. Anzinger JJ, Butterfield TR, Angelovich TA, et al. Monocytes as regulators of inflammation and HIV-related comorbidities during cART. Journal of Immunological Research. 2014;2014:569819.
11. De Pablo-Bernal RS, Ruiz-Mateos E, Rosado I, et al. TNF-α levels in HIV-infected patients after long-term suppressive cART persist as high as in elderly, HIV-uninfected subjects. Journal of Antimicrobial Chemotherapy. 2014 Nov;69(11):3041-6.
12. Seddiki N, Brezar V, Draenert R. Cell exhaustion in HIV-1 infection: role of suppressor cells. Current Opinion in HIV/AIDS. 2014 Sep;9(5):452-8.
13. Poudel-Tandukar K, Bertone-Johnson ER, Palmer PH, et al. C-reactive protein and depression in persons with Human Immunodeficiency Virus infection: The Positive Living with HIV (POLH) Study. Brain, Behaviour and Immunity. 2014 Nov;42:89-95.
14. Hileman CO, Labbato DE, Storer NJ, et al. Is bone loss linked to chronic inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study. AIDS. 2014 Jul 31;28(12):1759-67.
15. Tsoukas C. Immunosenescence and aging in HIV. Current Opinion in HIV/AIDS. 2014 Jul;9(4):398-404.
16. Wilson EM, Singh A, Hullsiek KH, et al. Monocyte-activation phenotypes are associated with biomarkers of inflammation and coagulation in chronic HIV infection. Journal of Infectious Diseases. 2014 Nov 1;210(9):1396-406.
17. Masiá M, Robledano C, Ortiz de la Tabla V, et al. Coinfection with human herpesvirus 8 is associated with persistent inflammation and immune activation in virologically suppressed HIV-infected patients. PLoS One. 2014 Aug 18;9(8):e105442.
18. Cockerham LR, Jain V, Sinclair E, et al. Programmed death-1 expression on CD4⁺ and CD8⁺ T cells in treated and untreated HIV disease. AIDS. 2014 Jul 31;28(12):1749-58.
19. Mandell DT, Kristoff J, Gaufin T, et al. Pathogenic features associated with increased virulence upon Simian immunodeficiency virus cross-species transmission from natural hosts. Journal of Virology. 2014 Jun;88(12):6778-92.
20. Pedersen KK, Manner IW, Seljeflot I, et al. Monocyte activation, but not microbial translocation, is independently associated with markers of endovascular dysfunction in HIV-infected patients receiving cART. Journal of Acquired Immune Deficiency Syndromes. 2014 Dec 1;67(4):370-4.
21. Savva GM, Pachnio A, Kaul B, et al. Cytomegalovirus infection is associated with increased mortality in the older population. Aging Cell. 2013 Jun;12(3):381-7.
22. Terrazzini N, Bajwa M, Vita S, et al. A novel cytomegalovirus-induced regulatory-type T-cell subset increases in size during older life and links virus-specific immunity to vascular pathology. Journal of Infectious Diseases. 2014 May 1;209(9):1382-92.
23. Barnes LL, Capuano AW, Aiello AE, et al. Cytomegalovirus infection and risk of Alzheimer’s disease in older blacks and whites. Journal of Infectious Diseases. 2015 Jan 15;211(2):230-7
24. Lichtner M, Cicconi P, Vita S, et al. CMV co-infection is associated with increased risk of severe non-AIDS events in a large cohort of HIV-infected patients. Journal of Infectious Diseases. 2015 Jan 15;211(2):178-86.
25. Emery VC. Re-stimulating interest in cytomegalovirus as a cofactor for HIV infection. Journal of Infectious Diseases. 2015 Jan 15;211(2):169-71.
26. Barrett L, Stapleton SN, Fudge NJ and Grant M. Immune resilience in HIV-infected individuals seronegative for cytomegalovirus. AIDS. 2014 Sep 10;28(14):2045-9.