Between January 2005 and June 2017, a total of 8788 PLWH met the inclusion criteria and were eligible for our analyses (Figure S1). Baseline characteristics are presented in Table 1. The median age was 38 years (IQR 31–46), and patients were predominantly male (n = 7040; 80.1%). Among male patients, 4470 (63.5%) reported sex with men (MSM) as the main transmission risk factor. In the total study population, the median pretreatment CD4+ T-cell count was 241 cells/µL (IQR 111–369 cells/µL), and 39.6% of patients had a CD4+ T-cell count below 200 cells/µL. The median pretreatment HIV RNA was 65,000 copies/mL (IQR 13,903–213,000), and 38.9% of patients had a pretreatment viral load greater than 100,000 copies/mL. A total of 338 (3.8%) patients died over the observation period, of whom 177 (52.4%) were on a PI-based regimen, 105 (31.1%) on a nucleotide reverse-transcriptase inhibitor (NRTI)/non-nucleotide reverse-transcriptase inhibitor (NNRTI) regimen, and 22 (10.1%) on an INSTI-based regimen.
The most common prescribed first-line cART regimens were TDF/FTC/EFV (n = 1734/8788; 19.7%) and TDF/FTC/DRV/r (n = 1180/8788; 13.4%). Within the early period of 2005–2010, TDF/FTC/EFV accounted for almost one third (n = 1285/4450; 28.2%) of all prescribed cARTs, while TDF/FTC/DRV/r (n = 860/4238; 20.3%) was the most frequent cART during the late period of 2011–2017. Most of the common first-line drug class combinations were NRTI/PI/boosted (n = 3682/8788; 41.9%), NRTI/NNRTI (n = 2951/8788; 33.6%), and NRTI/INSTI (n = 1676/8788; 19.1%), shown in Table 1. Since 2010, treatment initiation with NRTI/PI/boosted or NRTI/NNRTI decreased continuously and dropped below 5% in 2017. In comparison, treatment initiation with INSTI-based regimens increased constantly since 2008 and amounted to 85% of all patients initiating cART in 2017. Changes over time are shown in detail in Fig. 1.
Durability of the first-line cART regimen
During 44,439 patient-years of follow-up and a median follow-up time of 3.83 years (IQR 1.30–7.81) per patient, the overall rate of first-line cART modification was 25 per 100 person-years. In total, 4210 (47.9%) patients modified their first-line therapy during follow-up. The median durability was 63 months (IQR 59–66), and was significantly longer in the early period compared to the late period (68 months, 95% CI 64–72 vs. 52 months, 95% CI 48–55; log-rank test p = 0.002) (Table S1).
The reason for modifying first-line therapy was recorded in 3597/4210 (85.4%) patients. The most commonly reported causes in men and women were side effects of drugs 792/3597 (22.0%), simplification of therapy 394/3597 (11.0%), patients’ choice 267/3597 (7.4%), decision of the responsible physician 259/3597 (7.2%), non-adherence 212/3597 (5.9%), comorbidities 136/3597 (3.8%), and virological failure 133/3597 (3.7%). Among women, side effects of drugs 152/588 (25.9%), patients’ choice 75/588 (12.8%), simplification of therapy 70/588 (11.9%), and pregnancy 51/588 (8.7%) were the most common causes to modify first-line therapy.
Physicians’ choice to modify first-line therapy was reported in 4.9% (128/1609) of patients during the early period and increased to 8.1% (131/2601) during the late period. The percentage of patients who modified first-line cART due to the simplification of therapy was lower in the early period than in the late period (192/2601; 7.4% vs. 202/1609; 12.6%).
Of the 4210 patients who modified their first-line cART, 21.5% (701/3259) switched from a MTR to a STR. The proportion increased from 19.4% (384/1981) in the early period to 24.8% (317/1278) during the late period (p < 0.001). A total of 31.3% (1084/3464) switched from a non-INSTI towards an INSTI-based regimen, the proportion increased from 24.6% (564/2297) to 44.6% (520/1167; p < 0.001) comparing the early to the late period.
Factors associated with first-line cART durability
Time-to-event analyses revealed prognostic factors to modify the first-line regimen, illustrated in the KM plots in Fig. 2a–d and Supplementary Figures S2 A and B and Table S1. For the duration of the first-line regimens, significant differences were identified among sex (p < 0.001), different drug classes (p < 0.001), and the year of cART initiation (p = 0.002). The median durability of the first-line regimen was significantly shorter in patients on MTR than in patients on STR (median 51 months, 95% CI 47–53 vs. 93 months, 95% CI 87–97; p < 0.001) (Table S1). KM analyses also revealed an increasing trend of first-line cART modification with a lower pre-cART CD4+ T-cell count (< 350 µL) (p < 0.001). These differences remained significant in the adjusted multivariable Cox regression model.
Women were more likely to modify the first-line regimen than men (aHR 1.24; 95% CI 1.12–1.37). Patients on a STR were significantly less likely to modify the first-line regimen compared to patients on an MTR (aHR 0.91; 95% CI 0.70–0.94). In addition, the frequency of tablet intake twice daily compared to once daily was significantly associated with treatment modification (aHR 1.34; 95% CI 1.22–1.48). We found that being on a NRTI/NNRTI (aHR 0.75; 95% CI 0.67–0.84) or a NRTI/INSTI (aHR 0.44; 95% CI 0.39–0.50) first-line regimen was associated with lower rates of modification, compared to being on a NRTI/PI/boosted first-line regimen. Modification of first-line regimen increased in the late period (2011–2017) compared to the early period (2005–2010) (aHR 1.45; 95% CI 1.33–1.58) (Table 2).
We also identified significant differences for modification of the discontinuation of first-line cART among transmission risk groups and different INSTI regimens. Patients on RAL and EVG were significantly more likely to modify therapy compared to those on DTG (HR 2.01; 95% CI 1.59–2.53 and HR 1.46; 95% CI 1.08–1.96, respectively). However, the transmission risk group did not remain significant in the adjusted multivariable Cox regression model, and INSTI regimens were excluded due to multicollinearity. Uni-and multivariable analyses were also performed separately for the early and late period. Details are displayed in supplementary table S2–S4.
Antiviral efficacy and immunological recovery after first-line initiation
Among patients with an available HIV-1 RNA assessment at month 12 (± 6 months), 5745/6089 (95.4%) achieved viral suppression (< 200 copies/mL).
Pre-cART viral load was significantly higher in patients who modified their first-line cART regimen within 12 months (± 6 months) (median 70,324 copies/mL; IQR 12,812–257,914 copies/mL) than in patients who remained on their first-line regimen (median 63,126 copies/mL; IQR 14,078–200,000; p = 0.013). In the whole group, the median decrease in viral load after 12 months on cART was 3.4 log copies/mL (IQR 2.8–4.0 log copies/mL) and was greater in those who remained on their first-line cART than in patients who modified the initial treatment (4.0 vs. 3.5 log copies/mL, respectively). The overall pre-cART CD4+ T-cell count increased with a median gain of 205 cells/µL (IQR 180–374 cells/µL) at month 12 (± 6 months), a relative increase of 84%. No differences were observed between individuals who remained on their first-line regimen compared to those who modified their first-line regimen (p = 0.843).