In this study, we observed that virological response was reached in the great majority of naïve PLWH patients (beyond 99%) by 12th month of ART, without being influenced by the timing of its initiation. This result is important considering that assessment of long-term efficacy and acceptability of rapid ART in the real-life practice remains challenging, especially in developed countries.
In our study the proportion of patients receiving rapid ART, as within 7 days from first HIV medical referral, was higher in inpatients’ cohort (62.3%) rather than outpatients’ one (23.4%). This observation might be due to the greater probability of inpatients to be diagnosed late with HIV namely in advanced stage of infection, as demonstrated by patients with AIDS defining events representing more than half (55.3%) of inpatients’ group. These clinical conditions are already recognized by major national and international guidelines to require an immediate start of adequate therapy [22–25]. Recently, small cohorts from high-income settings also provided increasing evidence of safety and acceptability of rapid ART initiation in very early stage of infection out of clinical trials. For example, one cohort from London showed rapid viral suppression and high ART uptake by 24 weeks (99%) among those initiated ART at first medical appointment . Similarly, another cohort from San Diego demonstrated increased ART uptake and higher likelihood to virally suppress (91%) by 24 weeks for participants initiating ART within 7 days .
Nonetheless, clear evidence that certain timing of ART initiation impacts or not on long-term care engagement and virologic suppression still lacks  and previous studies carried out in high-income settings sometimes highlighted discordant results. On one hand, researchers from ICONA Foundation Study Cohort did not observed any clear benefit of rapid ART start in term of virological success after one year of follow up . On the other, one cohort study from France even showed that longer time between first medical visit and first ART prescription was associated with a better 1-year retention in care . By contrast, a real-life world retrospective study in Taiwan demonstrated a higher rate of attrition from care together with lower rate of LTFU at 12 months in population receiving ART within 7 days .
Our Clinic follows around 4000 HIV-infected patients from the province of Brescia (Lombardy), which counts one of the highest incidences of HIV/AIDS diagnosis  and the fourth largest migrant population in Italy . Another study carried out in our HIV Clinic during a 6-year-period (2012-2018) estimated a rate of 86.7% outpatients retained in care with a rate of viral suppression (HIV RNA < 37 copies/ml) more than 94% . Although current study corroborates our previous findings, with low rate of LTFU (< 10%) and almost 90% (87.5%) of patients still linked to care after 1 year of follow up, we did not find a connection between time of ART start and likelihood of durable viral suppression over time. We observed a great rate of viral suppression (up to 99%) among people remained in care regardless of timing of ART initiation (rapid, intermediate and late).
Shortening time to ART initiation leads towards faster virologic suppression [3, 4, 14] with incontrovertible benefits regarding both individual patients’ health and “community viremia”, due to prevention of sexual and perinatal HIV-transmission [15, 30]. Indeed, although timing of ART initiation does not seem to be a successful guarantee of long-term retention in care [5, 13], one of the greatest goals of rapid ART start remains faster control of “community viremia” aimed at reducing time in which naïve HIV patients continue to be contagious. In our population each week spent waiting for therapy start brought to 4% less probability to reach undetectable HIV viral load (see Table 4). This finding might be concerning from a “public health” point of view if we consider that in our study the majority of patients (41.8%) still began ART after 30 days from their first medical encounter with, overall, almost 3 months as median time from ART prescription to first undetectable HIV RNA, clearly more than what observed by other cohorts [19, 20, 26]. Thus, in our real-life practice this time is still too wide and there is a room for improvement.
Obviously, fast initiation of treatment requires first removal of any cultural, financial and structural barriers which might prevent patients from diagnosis and care engagement [21, 31] and optimizing strategies able to guarantee easy prompt access to HIV care remains a crucial topic. Compared with published data [14, 18–20] and very far from WHO recommendations, in our Clinic time from HIV diagnosis to linkage to care tends to be still too long (around two weeks), as well as interval from first HIV referral to ART initiation is even wider, especially for outpatients who might have to wait for ART initiation up to 1 month (median time 34 days). As previously underlined by d’Arminio Monforte and colleagues, this lag time could be due not only to prescription policy of the Centre but also to the fact that HIV diagnosis often occurs outside hospital settings (i.e. private laboratories, community-based checkpoints) and the process to refer HIV positive patients to an ID Center might be delayed .
It is broadly recognized that predictors of virologic success include low baseline viremia, highly potent ART regimen, drug tolerability, convenience of the regimen and appropriate adherence to the treatment . Thus, as shown already by other cohorts [4, 18–20, 26], in our study the achievement of viral suppression was more likely associated to patients’ lower HIV RNA viral load and initial INSTI-containing regimens, the latter proven safe, non-inferior and less toxic in dual therapy for naïve HIV patients by GEMINI trials . In our cohort, anyway, even though DTG turned out to be largely prescribed (66.6%), its use in dual therapy continues to lack, resulting paltry compared with its proportion in three-drug regimen.
Our study has several limitations. First, its single-centre retrospective, observational design might present bias related to retrospective data collecting as well as poor generalizability of findings to other settings. Second, these data may suffer from prescription habits of physicians from the same medical center and HIV care experience. Third, we did not characterize initial AIDS defining events, including eventual TB co-infections, which have probably influenced differently the choice of ART start timing. Therefore, we cannot draw precise conclusions regarding reasons behind clinician’s decisions of ART timing initiation in such cases. Also, since September 2015, when the study period began, several aspects of our HIV continuum of care have changed. On one hand, bureaucratic procedures have been simplified, on the other national and international guidelines have progressed and our clinical practice in HIV care and ART prescription attitudes too, going beyond latest version of HIV care Italian guidelines from 2017 , which recommended clinicians offering rapid ART initiation primarily to those highly motivated patients; however, dual-therapy (DTG-based) in naïve patients has been implemented only in the last 24 months, due to the availability of single tablet regimen and according to the results of newer randomized clinical trials in this topic. Nowadays, main guidelines in HIV care share and strongly recommend offering rapid strategy in all but very few exceptions.
The strength of our study is mainly due to its perspective of “real -life” setting over 4-year period in a field of HIV care still deeply unexplored. Moreover, another point to be underlined is that, differently from most published studies, we included both in-and outpatients’ cohorts reflecting our clinical practice even in severely ill patients.