Initiation of Antiretroviral Therapy in Early HIV Infection

Ahroom Youk, Mercer University College of Pharmacy

The Department of Health and Human Services (DHHS) reports an increased risk of morbidity and mortality in patients who defer antiretroviral therapy (ART) until CD4 T lymphocyte (CD4) cell counts are less than 350 cells/mm3.  They explain that this is due to the direct correlation of the pre-treatment CD4 count to CD4 recovery.  In their guidelines for the use of ART, the DHHS recommends all treatment-naïve patients with human immunodeficiency virus type 1 (HIV-1) infections to make a willing commitment to ART, especially in patients with CD4 cell counts less than 350 cells/mm3.  Their rating system suggests that this recommendation is strongly supported by data from well-designed trials of patients with CD4 cell counts less than 500 cells/mm3, and moderately supported by expert opinion of patients with CD4 counts greater than 500 cells/mm3.  According to the guidelines, the lack of randomized trial data is the reason why the DHHS cannot strongly recommend the early initiation of ART, i.e. when pre-treatment CD4 is greater than 500 cells/mm3.1

The following study conducted on treatment-naïve patients fulfills this gap in knowledge.2

Title                Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection2
Design Multi-continental, randomized study; N = 4,685
Objective To determine the risks and benefits of the immediate initiation of ART in asymptomatic HIV-positive patients who have a CD4+ count of greater than 500 cells/mm3, as compared with deferring initiation until the CD4+ count is 350 cells/mm3
Study Groups Immediate-initiation group (n = 2,326) or deferred-initiation group (n = 2,359)
Methods The Strategic Timing of Antiretroviral Treatment (START) investigators selected approved antiretroviral therapies based on the United States DHHS guidelines.  Follow-up occurred at the first and fourth months, then every four months thereafter.  Each of these visits included an assessment of health history, any ART changes, and adherence to therapy; a health examination, CD4+ cell count, and HIV RNA levels were also obtained.  Lipid panels, liver function tests, glucose and creatinine measurements, 12-lead electrocardiograms, and non-acquired immune deficiency syndrome (AIDS) risk factors were assessed annually.
Duration Three years
Primary Outcome Measure Composite outcome of serious AIDS-related events (death from AIDS, any AIDS-defining event, or Hodgkin’s lymphoma) and serious non-AIDS-related events (death from causes other than AIDS)
Baseline Characteristics Characteristic Immediate-Initiation Group (n = 2,326) Deferred-Initiation Group (n = 2,359) All Patients
(n = 4,685)
Median age, years (IQR) 36 (29 – 44) 36 (29 – 44) 36 (29 – 44)
Female sex, number (%) 624 (26.8) 633 (26.8) 1,257 (26.8)
Self-reported race or ethnic group*, number (%)
     Caucasian 1,015 (43.6) 1,071 (45.4) 2,086 (44.5)
     African 702 (30.2) 708 (30.0) 1,410 (30.1)
     Hispanic or Latino 320 (13.8) 318 (13.5) 638 (13.6)
     Asian 198 (8.5) 190 (8.1) 388 (8.3)
     Other 91 (3.9) 72 (3.1) 163 (3.5)
Mode of infection with HIV, number (%)
     Sexual contact
          Men with men 1,300 (55.9) 1,286 (54.5) 2,586 (55.2)
          Opposite sex 873 (37.5) 917 (38.9) 1,790 (38.2)
     Injection drug use 37 (1.6) 27 (1.1) 64 (1.4)
     Other 116 (5.0) 129 (5.5) 245 (5.2)
Median time since HIV diagnosis, years (IQR) 1.0 (0.4 – 3.0) 1.1 (0.4 – 3.1) 1.0 (0.4 – 3.1)
Median CD4+ count, cells/mm3 (IQR) 651 (585 – 765) 651 (582 – 764) 651 (584 – 765)
Median HIV RNA, copies/mL (IQR) 13,000

(3133 – 43,808)


(2963 – 42,567)


(3019 – 43,391)

Tobacco smokers, number (%) 730 (31.4) 766 (32.5) 1,496 (31.9)
Median CHD risk at 10 years, percent (IQR) 1.9 (0.5 – 5.0) 1.9 (0.5 – 5.3) 1.9 (0.5 – 5.1)
*Among all patients, 1,539 (32.8%) were from Europe and Israel, and 507 (10.8%) were from North America.

IQR = interquartile range; CHD = coronary heart disease

Results The lead investigators and the National Institute of Allergy and Infectious Diseases terminated the deferred-initiation strategy early because the primary question was answered.
Primary Outcome Immediate-Initiation Group
(n = 2,326)
Deferred-Initiation Group
(n = 2359)
Hazard Ratio*
(95% CI)
Number Number per 100 person-years Number Number per 100 person-years
Composite primary outcome 42 0.60 96 1.38 0.43
(0.30 – 0.62)
< 0.001
     Serious AIDS-related event 14 0.20 50 0.72 0.28
(0.15 – 0.50)
< 0.001
     Serious non-AIDS-related event 29 0.42 47 0.67 0.61
(0.38 – 0.97)
     Death from any cause 12 0.17 21 0.30 0.58
(0.28 – 1.17)
*Immediate-initiation group compared to deferred-initiation group
Adverse Events Common Adverse Events: cardiovascular disease, non-AIDS-defining cancer, tuberculosis
Serious Adverse Events: unexpected adverse events in the immediate-initiation group included wrist fracture, psychosis, atheroma, suicide attempt, cholecystolithiasis, rectal bleeding, hallucinations, transient polyneuropathy, febrile pancytopenia, acute delirium, and Bell’s palsy; in the deferred-initiation group, eruptive xanthomas, febrile syndrome, ureterolithiasis, unknown cause of death, and normochromic normocytic anemia occurred.
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions The immediate initiation of ART in HIV-positive adults provided net benefits over the deferred initiation of ART, regardless of CD4+ count.

Recommended regimens for HIV-positive treatment-naïve patients generally consist of two nucleoside reverse transcriptase inhibitors and a third antiretroviral medication (an integrase strand transfer inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor plus cobicistat or ritonavir).  Due to the variety of effective options, the DHHS suggests to utilize the efficacy, safety, resistance, and patient-specific factors when determining the treatment regimen.1

An editorial published in the New England Journal of Medicine describes the overall results of the START study (in the table above) and the TEMPRANO study, a similar study of 2,050 patients in Ivory Coast, Africa.  The author of this editorial emphasizes the increased rates of viral suppression in both trials, as well as the decreased rate of tuberculosis and minimal or no increases in adverse events after early ART in both trials.  According to this editorial, early ART can also provide benefits to public health; it can reduce the transmission of HIV, reduce the risk of acquiring herpes simplex virus type 2 infections, and act as treatment of viral hepatitis B infections.  However, the author explains that it is difficult to implement effective programs supporting early ART due to insufficiencies in funding, quality of care, adherence, accessibility, and from patients unaware of their HIV status.  Therefore, the author suggests that innovative resources (such as home test kits) and simplified treatment protocols can alleviate some of these issues.3


  1. 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. Accessed September 2, 2015.
  2. INSIGHT START Study Group. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795-807. doi: 10.1056/NEJMoa1506816.
  3. Abdool karim SS. Overcoming Impediments to Global Implementation of Early Antiretroviral Therapy. N Engl J Med. 2015;373(9):875-6.

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