Early antiretroviral therapy significantly reduced the risk of AIDS and HIV-related illness in a large study in low and middle-income countries, according to the final results of the HPTN 052 study published in Lancet Infectious Diseases. Participants in this large multi-site study were randomised to take immediate or delayed HIV therapy. Overall, participants in the early treatment arm had a lower risk of AIDS, tuberculosis, symptomatic HIV disease and also some non-HIV-related illnesses.
The investigators had previously shown that early antiretroviral treatment reduced the risk of HIV transmission by 96%.
“Coupling clinical benefits with a striking effect on transmission risk gives additional strength to the argument for early initiation of antiretroviral treatment,” write the authors.
Thanks to antiretroviral therapy, many people living with HIV now have a normal life expectancy.
However, there is uncertainty about the best time to start HIV treatment.
Investigators from the HPTN 052 study hoped their data could clarify this important question.
The randomised controlled trial was conducted at 13 sites in nine countries. HIV serodiscordant couples (in which one person has HIV and the other does not) were eligible for enrolment if the HIV-positive partner had a CD4 count between 350 and 550 cells/mm3.
The HIV-positive participants were randomised on a 1:1 basis to start immediate HIV therapy or to delay treatment until their CD4 count fell to 250 cells/mm3 or the development of symptomatic HIV-related disease.
A total of 1763 HIV-positive participants were randomised. Median CD4 cell count at baseline was 436 cells/mm3. The median duration of follow-up was 2.1 years.
Primary outcomes were death, progression to AIDS, tuberculosis, severe bacterial infections, cardiovascular disease, serious liver and kidney disease, non-AIDS cancers and diabetes.
Secondary outcomes included symptomatic HIV disease (WHO stage 2 and stage 3), malaria, renal and hepatic dysfunction, hypertension, lipodystrophy, dyslipidaemia, peripheral neuropathy and some blood disorders.
In total, 57 participants (6%) in the early treatment group and 77 participants (9%) in the delayed therapy arm experienced a primary outcome. The cumulative two-year probability of a primary outcome was 4.8% for participants receiving early treatment compared to 7.9% for those who delayed therapy. Early treatment reduced the risk of a primary event by a non-significant 27% (p = 0.074).
An AIDS event was diagnosed in 5% of participants in the early treatment arm compared to 7% of people in the delayed therapy arm. The cumulative two-year probability of AIDS was 3.3% for those who received early treatment and 6% for individuals delaying treatment. Early treatment reduced the risk of developing an AIDS-defining illness by 36% (0.64; 95% CI 0.43-0.96, p = 0.031).
Tuberculosis was diagnosed in 2% of participants in the early treatment arm and 4% of participants randomised to delay therapy. Early treatment was associated with a 1.2% two-year probability of TB, whereas the probability was 3.7% for people who delayed treatment. The authors calculated that early treatment reduced the risk of TB by 51% (p = 0.018).
As regards secondary outcomes, serious non-HIV-related events were rare, occurring in twelve participants who started early treatment compared to nine individuals in the delayed treatment arm.
The overall incidence of primary events for people taking early treatment was 3.5 per 100 person-years, compared to an incidence of 4.5 per 100 person-years for people in the delayed therapy arm. This difference was not significant. However, there was a significantly lower incidence of tuberculosis in the delayed treatment arm (0.8 vs 1.8 events per 100 person years, p = 0.009).
The frequency of secondary outcomes was similar between the early and delayed treatment arms (36 vs 34%, respectively).
Combining primary and secondary outcomes showed that these occurred in 37% of people taking early treatment and in 40% of people in the delayed therapy arm. Combined incidence rates were significantly lower among people in the early versus the delayed treatment arm (24.9 vs 26.5 per 100 person-years, p = 0.025).
Primary and secondary events were not concentrated in people with low CD4 counts; in fact most occurred in people with CD4 counts above 350 cells/mm3. The median CD4 count at which primary events occurred was 353 cells/mm3 for people in the delayed treatment arm and 502 cells/mm3 for people taking immediate treatment.
“Early antiretroviral treatment…can be expected to delay the time to AIDS-defining events, tuberculosis, and WHO stage 2 and 3 events and significantly reduce the incidence of these events,” comment the authors.
They acknowledge the differences in outcomes between the study arms were small, but believe “they offer the potential for reduced morbidity among millions of people with HIV-1 infection.”
Grinsztejn B et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes in HIV-1 infection: results of from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis 14: 281-90, 2014.