The present randomized trial provides the strongest evidence to date of a clinical benefit of temporary cART initiated during PHI. Early cART transiently lowered the viral set point by 0.5–0.8 log10 copies/ml, increased the CD4 cell count, and deferred the need for initiation of cART during chronic HIV infection by 1.1–2.3 y. Both viral set point and CD4 cell count measured at viral set point were associated with time to (re)start of cART. The duration of temporary early cART was not predictive, suggesting that 24 wk of cART would be sufficient. The time off therapy was longer in the 24-wk treatment arm than in the 60-wk treatment arm, but in the per protocol analysis, and in the Cox models, which were adjusted for possible confounders, there was no statistically significant difference between the 24- and 60-wk treatment arms.
Overall, these findings are in agreement with the data of the SETPOINT study and SPARTAC trial, in which, respectively, 36 and 48 wk of cART during early HIV infection modestly delayed the need for subsequent initiation of cART 
An important strength of our study is that it showed a significant benefit of temporary early cART as compared to deferred therapy even using conservative mITT analyses, in which patients who discontinued cART earlier than planned remained in the analyses and those who did not discontinue cART at the scheduled TI date were considered as having reached the study end point.
The study has several limitations. First, despite the random allocation of patients to the different study arms, the mean baseline CD4 cell count was by chance higher in the 24-wk treatment arm, which might have affected the time to restart in this group. However, the mean baseline CD4 cell count was not different between the no treatment and 60-wk treatment arms, whereas the time off therapy was significantly longer in the patients treated for 60 wk (p
0.02). More importantly, after adjusting for baseline CD4 cell count in the Cox models, temporary early cART remained associated with a longer time to subsequent reinitiation of cART. Second, by providing the option of randomizing patients over the two treatment arms only, we might have introduced selection bias, as patients with more severe symptoms might have been less likely to be enrolled in the three-way randomization. However, we observed that the baseline characteristics, viral set point, CD4 cell count measured at viral set point, and the time to (re)start of cART did not differ between the three- and two-way randomized treated patients. Additionally, the adjusted Cox models also showed that the time to (re)start of cART was not different for the treated patients randomized over three or two study arms. Third, according to current treatment guidelines zidovudine/lamivudine was replaced by tenofovir/emtricitabine halfway through the trial, which is a potential source of variability in baseline characteristics between treatment groups. However, the proportion of PHI patients treated with both drugs was comparable in both treatment arms ().
The rate of HIV disease progression in our study was high: the median time off therapy in the no treatment arm was less than 1 y. More than 80% of patients presented with an acute retroviral syndrome, which is a strong predictor of HIV disease progression 
, suggesting that our results may not be generalizable to asymptomatic seroconverters. Our findings are consistent with a German cohort study in which 56 patients with untreated PHI had a median time to CD4 cell count <350 cells/mm3
of 8.3 mo after seroconversion 
. Data from the CASCADE cohort, a collaboration of international cohorts of patients with a well-estimated date of HIV seroconversion 
, demonstrated that in 179 untreated seroconverters the median time to initiation of cART or reaching a CD4 cell count below 350 cells/mm3
was approximately 1.5 y 
. However, it was not reported whether patients were symptomatic or not during the acute stage of the disease.
The stage of PHI was not associated with time to (re)start of cART. This is in contrast with findings from two previous cohort studies. In one study, initiation of cART within 2 wk of antibody seroconversion was associated with viral and immunological benefits during at least 24 wk after TI as compared to starting therapy between 2 wk and 6 mo after HIV seroconversion 
. The second study reported that if early cART was initiated within 60 d after estimated HIV infection, it resulted in reduced pVL and proviral HIV DNA levels as compared to later starters (between 61 and 120 d) or untreated controls for more than 1 y after TI 
. The treated patients in our study had a median delay of 5 (IQR 3–7) wk between the diagnosis of PHI and the start of early cART, which means that the golden hour, in which the greatest benefits of early cART could have been achieved, was possibly already missed. Nevertheless, even with this delay we observed a clear benefit of initiating cART during PHI.
Temporary cART initiated during PHI deferred the subsequent restart of cART, which, according to the Cox models, was most likely caused by the effects of the CD4 gain during treatment and the transient lowering of the viral set point. The question remains how the latter might be explained. We know that two critical events in PHI are the massive destruction of CD4 T cells in the gastrointestinal tract and the establishment of latent HIV reservoirs. Early treatment may result in viral suppression and immune restoration in gut-associated lymphoid tissue 
. Alternatively, it may have an effect on the cellular HIV proviral load and limit the size of the viral reservoirs 
. Others have postulated that early treatment enables virus-specific CD8+ T cells to mature into fully differentiated effector cells, which might be important in viral control 
. Early treatment is also suggested to help preserve specific anti-HIV responses 
, though we previously found that HIV-specific CD4 T cell responses provided no explanation for the lower viral set point in patients treated during PHI 
. Recently, we reported that HIV-1 dual infection (coinfection or superinfection) was the main factor associated with CD4 cell count decline in a cohort of 37 untreated men with subtype B PHI 
. A potential benefit of temporary early cART may therefore be the prevention of early HIV-1 superinfection.
The gain in treatment-free years must be weighed against potential disadvantages of starting cART in the acute stage of the disease, a period in which patients are often physically and emotionally distressed and adherence may be suboptimal. In addition, early cART is often initiated before baseline resistance test results are available and therefore may require “overtreatment” to ensure an effective drug regimen, which may increase the risk of drug toxicity. In our study, patients were started on a triple-class therapy. In any case, if early treatment is considered, it should at least include a boosted protease inhibitor until resistance testing results are available 
. Another concern may be the risk of developing drug resistance after TI. Extended follow-up studies will be needed to address this question.
Structured TI studies in chronic HIV infection have fallen into disfavor after the SMART trial demonstrated that CD4-guided TI was associated with adverse outcomes and a rapid CD4 cell count decline as compared to continuous therapy 
. The question is whether this also holds true for patients who have initiated cART shortly after seroconversion, before the development of severe immunological dysfunction 
. The ANRS PRIMO cohort reported that a larger increase in CD4 cells during early cART was associated with a markedly steeper decline after TI, and the benefit of a limited course of cART was questioned 
. In our study, after an initial rapid, but limited CD4 cell decline during the first 8 wk following TI in both the 24- and 60-wk treatment arms, the slope of CD4 cell decline was comparable between all three study arms.
Nonetheless, even in the patients in our study who received temporary early cART, the total time off therapy was relatively short. The lowering of the viral set point was transient, suggesting loss of protective immune functions and the emergence of viral escape mutants. Therefore, a reasonable question is whether early cART should not be interrupted but continued for life, given the concern that uncontrolled HIV replication and chronic immune activation carry an increased risk of morbidity and mortality at all stages of HIV infection 
. Additionally, the continuation of cART may have a public health benefit as it decreases infectiousness 
In conclusion, this randomized study demonstrates a clear clinical benefit of temporary cART initiated during PHI. Early cART transiently lowered the viral set point and deferred the need for restart of cART during chronic HIV infection. Although extended follow-up studies are needed to evaluate the long-term benefits of such early treatment, starting cART when the patient is ready to do so seems the most reasonable advice for patients with PHI.