Pre-infection Immunological Health Achieved in Some Cases
By Annette M. Boyle
SAN ANTONIO — For years, clinicians have not recommended treating human immunodeficiency virus (HIV) patients with antiretroviral therapy (ART) before they saw a significant drop in T-cell levels.
Starting early offers significant benefits, however, including halving the risk of developing acquired immune deficiency syndrome (AIDS) and increasing the likelihood that patients can achieve pre-infection immunological health, according to new research.
The main lesson of the study, published late last year in JAMA Internal Medicine, is “never tell a patient to not start therapy immediately,” said senior author Sunil K. Ahuja, MD, director of the VA Center for HIV and AIDS Texas Veterans Health Care System and professor of medicine at the School of Medicine Infection and the VA Center for Personalized Medicine at the South at the University of Texas Health Science Center, all in San Antonio.1
The VA provides care to more than 40,000 veterans with HIV, one of the largest HIV-infected patient cohorts in the world. About 11% of diagnosed patients were not taking antiretroviral medications as of 2013, according to the VA.
About 1 in 5,000 active duty personnel are HIV positive, according to the DoD. According to a May 23, 2013, article in Stars and Stripes, the Navy reported 315 HIV-positive sailors in 2012, while the Air Force said it had 210 HIV-positive servicemembers, the Marines 90 and the Army 333.
Historically, clinicians have focused almost exclusively on suppression of the virus. The increased potency of newer, well-tolerated ART regimens has made durable viral suppression “readily attainable,” according to the authors.
Now, “we are suggesting that achieving normalization of immunologic health comparable to that of an uninfected person, and making it stick for the long term, is also a critical goal,” said first author Jason F. Okulicz, MD, director of the HIV Medical Evaluation Unit at the San Antonio Military Medical Center.
The study was led by researchers from the School of Medicine at The University of Texas Health Science Center at San Antonio, the VA Research Center for AIDS and HIV Infection, the VA Center for Personalized Medicine at the South Texas Veterans Health Care System and the Uniformed Services University of Health Sciences. The study evaluated data on 1,119 HIV-1 infected U.S. Army, Air Force, Marines and Navy personnel and beneficiaries in the observational U.S. Military HIV Natural History Study.
The researchers categorized the participants in two dimensions: early vs. late treatment starters and those with vs. without high (above 500) CD4+ counts at initiation of therapy. The study found that participants who started ART with higher CD4+ counts and earlier in the course of the disease were more likely to achieve the threshold of 800-900 cells per cubic millimeter than those who started later or with lower counts.
“That’s important, because people who achieve the threshold of 900 are much less likely to develop AIDS and are more likely to have parameters indicating restoration of their immune system,” Ahuja explained. Patients who started therapy within the first year of infection had a 7.8% risk of developing AIDS, compared with 15.3% for those who began ART later.
While it is not easy to determine exactly when someone was first infected, the researchers were able to estimate the duration of untreated infection based on previous negative tests and first positive screens. “Early” treatment in the study was defined as that starting within the first 12 months following seroconversion.
Starting ART after 12 months of infection reduced participants’ odds of CD4+ normalization by 80%, compared with those who started earlier. “These data indicate that the integrity of functional immune responses is substantially compromised if the duration of untreated HIV infection is greater than 12 months,” the study authors wrote.
Earlier treatment did not increase the normalization rates of those with CD4+ counts below 400 cells per cubic millimeter, however.
Okulicz noted that normalizing CD4+ T-cell counts might also reduce the risk of non-AIDS-related diseases frequently seen in infected servicemembers and veterans. Individuals with higher CD4+ counts had a stronger response to hepatitis B virus vaccine, an indicator of in vivo immune function.
A 2013 study by many of the same researchers answered the question of what normalizing CD4+ counts represents.
“No one had even established a benchmark for what normality means,” Ahuja told U.S. Medicine. “If someone had a CD4 count above 500 cells per cubic millimeter, we were happy in days gone by. By surveying a large number of HIV negative people, we established that the normal CD4 count is about 900 and then asked, ‘Does treating HIV positive individuals early allow them to get back to those levels?’”2
Ahuja added that some patients with high CD4+ counts did not achieve normal rates, even with treatment. “There may be other immunologic defects not captured when looking just at CD4 counts and we can’t predict whether any particular patient will be a good or poor responder,” he said.
The research supports regular screening for HIV and prompt treatment for infected individuals. Servicemembers are screened every two years and on return from deployment. Veterans are encouraged to be screened at least once, regardless of risk factors, and voluntary HIV testing is recommended as a part of routine medical care for all veterans.
Initiating therapy promptly also minimizes the spread of the virus. According to the study authors, “earlier compared with later ART was associated with a more rapid suppression of [viral load], which is a key determinant of transmission rates.”
- Okulicz JF, Le TD, Agan BK, Camargo JF, Landrum ML, Wright E, Dolan MJ, Ganesan A, Ferguson TM, Smith DM, Richman DD, Little SJ, Clark RA, He W, Ahuja SK. Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals. JAMA Intern Med. 2015;175(1):88-99.
- Le TD, Wright EJ, Smith DM, He W, Catano G, Okulicz JF, Young JA, Clark RA, Richman DD, Little SJ, Ahuja SK. Enhanced CD4+ T-Cell Recovery with Earlier HIV-1 Antiretroviral Therapy. N Engl J Med 2013; 368:218-230.