Starting antiretroviral therapy (ART) has significant benefits and entails few risks for individuals with a low pre-treatment viral load, according to analysis of results from a large treatment initiation study. Prompt initiation of ART was associated with robust increases in CD4 cell count, sustained viral suppression and favourable changes in inflammatory biomarkers. The investigators also calculated that treatment would have public health benefits by almost eliminating the risk of onward HIV transmission.
The study involved patients with a baseline viral load below 3000 copies/ml recruited to the START (Strategic Timing of Antiretroviral Treatment) study. This unequivocally established the benefits of ART for patients with higher CD4 cell counts (above 500 cells/mm3). Treatment guidelines around the world now recommend ART for all individuals, regardless of CD4 cell count.
However, a small number of individuals with HIV have a persistently low viral load even without the use of ART, leading some to question whether ART is necessary.
Investigators from the START study led by Matthew G Law at the faculty of medicine, Kirby Institute, University of New South Wales in Australia, examined their data to see if these patients benefit from therapy.
A total of 4684 adult HIV-positive patients were recruited to the study. All had a CD4 cell count above 500 cells/mm3 and were randomised to start immediate ART or to defer therapy until their CD4 cell count fell below this level.
The current analysis was restricted to the 1134 individuals (25% of the total study population) who had a pre-treatment viral load below 3000 copies/ml. The investigators compared clinical outcomes (serious non-HIV-related illnesses, hospitalisations and all-cause mortality), viral load, CD4 cell count and biomarkers (including those indicating inflammation) between the immediate and deferred ART groups.
The median baseline CD4 cell count was 714 cells/mm3, average age was 37 years and the majority of participants (60%) were male. A small sub-set of patients (n = 93) had a pre-treatment viral load below 50 copies/ml.
Participants were almost equally randomised to immediate (n = 555) or deferred therapy (n = 579).
A serious clinical outcome was observed in 64 patients in the immediate and 61 patients in the deferred group, a non-significant difference.
Immediate therapy had clear benefits in terms of viral suppression. After twelve months of follow-up, 93% of patients in the immediate compared to 22% of those in the deferred group had a viral load below 200 copies/ml. There was evidence that viral load suppression below 50 copies/ml would not be maintained without ART. During the first year of follow-up, 55% of individuals in the deferred group with a baseline viral load below 50 copies/ml experienced an increase in viraemia above this level.
CD4 cell counts increased among the patients who started immediate ART but declined among the patients deferring treatment. After twelve months of follow-up, mean CD4 cell count was 125 cells/mm3higher in the immediate ART group and by month 36 this had increased to a mean difference was 235 cells/mm3. Nonetheless, regardless of study arm, CD4 cell count remained stable in the sub-group of patients with a baseline viral load below 50 copies/ml.
There was little difference over three years of follow-up between the immediate and deferred groups in the proportion experiencing serious changes in haemoglobin, platelet count, creatinine, ALT and kidney function.
However, there were beneficial changes in several biomarkers indicating systemic inflammation in the immediate study arm, but not among patients who deferred treatment. In the sub-group with a baseline viral load below 50 copies/ml, these differences were not significant.
Finally, immediate treatment was calculated to have significant public health benefits. The investigators estimated that over twelve months the rate of onward HIV transmission would be 0.2 per 100 patients in the immediate group but 3.2 per 100 patients in the deferred group.
Even with just 93 individuals with a pre-treatment viral load below 50 copies/ml included, Dr Irini Sereti at the National Institute of Allergy and Infectious Diseases (NIAID)/National Institute of Health (NIH) and colleagues say that this is the largest randomised study of such individuals to date. For this group, a clear clinical benefit to starting ART was not observed, but neither was there evidence of harm. As clinical trials do not provide clear guidance on how to treat individuals with such rare disease phenotypes, they recommend that clinical decision making should be individualised and based on a partnership with the patient.
“In conclusion,” write the authors, “for most HIV-positive people with HIV RNA below 3000 copies/ml, although there are low numbers of clinical events, our analyses show that immediate ART results in suppressed HIV RNA, CD4 cell count increases, little evidence of increased serious clinical outcomes, and an estimated modest decrease in onward HIV transmission.”
Background: The benefit of immediate antiretroviral therapy (ART) at CD4 >500 cells/μL was established in the Strategic Timing of Antiretroviral Treatment (START) study. The benefits and risks of immediate ART in participants with low pretreatment viremia, including virologic suppressors, were further assessed.
Setting: Randomized prospective international study.
Methods: START participants with enrollment viremia <3000 c/mL were included. We compared clinical outcomes (grade 4 adverse events, hospitalizations, or death), plasma viremia, CD4 counts, and changes in biomarkers in immediate versus deferred ART groups.
Results: Participants (N = 1134 including 93 with viremia ≤50 c/mL) had a median age of 37 years, 40% were women, and median CD4 was 713 cells/µL. Ninety-seven percent in the immediate and 29% in the deferred arm initiated ART at a median of 6 and 699 days, respectively. Clinical outcomes were experienced in 64 versus 61 patients in immediate and deferred arms (hazard ratio 1.10, 95% confidence interval: 0.77 to 1.56). The CD4 count difference was 125 cells/µL at 12 and 235 cells/µL at 36 months higher in the immediate versus deferred groups. D-dimer and VCAM levels decreased, and C-reactive protein increased, in the immediate arm at month 8. No significant changes in CD4 counts or biomarkers were observed in persons who maintained spontaneous virologic suppression.
Conclusions: START participants with low enrollment viremia experienced higher CD4 counts, greater proportion with suppressed viremia, and decreases in D-dimer levels on immediate ART despite the lack of difference in serious clinical outcomes. These data support immediate ART in people with low viremia, although equipoise remains for suppressors.
Sereti, Irini; Gulick, Roy M; Krishnan, Sonya; Migueles, Stephen A; Palfreeman, Adrian; Touzeau-Römer, Veronique; Belloso, Waldo H; Emery, Sean; Law, Matthew G for the INSIGHT START Study Group