Abstract
Objective:
To assess outcomes of heavily treatment experienced people with HIV (PWH) who received the antiretroviral therapy salvage regimen containing raltegravir, etravirine, and darunavir/ritonavir (known as TRIO).
Methods:
Data were from the ART Cohort Collaboration; a collaboration of European and North American HIV cohort studies. Adult PWH were eligible if they had: history of virologic failure (VF) while receiving nonnucleoside reverse-transcriptase inhibitors (NNRTI); ≥3 primary protease inhibitor and nucleoside reverse transcriptase inhibitor mutations; ≤3 darunavir and NNRTI mutations; received TRIO between 2007–2018; VF at TRIO start; and not received any TRIO drugs previously. Follow-up began at TRIO start. We examined rates of: virologic suppression on TRIO, AIDS/death, receipt of drug-reducing regimens post-TRIO in those virologically suppressed, and subsequent virologic response. We used a competing risks framework to estimate 5-year cumulative incidence of outcomes.
Results:
Among 126 eligible PWH, 24% were female and median age was 46 years (Interquartile range[IQR]:41–50). Median follow-up was 7.9 years (IQR:5.1–9.3). 94(74.6%) were virologically suppressed on TRIO. Of these, 26(28%) subsequently switched to a drug-reducing regimen, of whom 19/26(73.1%) were virologically suppressed at their next VL measure. The 5-year cumulative incidence of outcomes was: stop TRIO and start another ≥3 drug regimen 39.1%; simplify 16.0%; stop TRIO without switch 8.8%; death on TRIO 7.2%.
Conclusions:
Although the most common outcome after TRIO was switch to another ≥3 drug regimen, almost one third of virologically suppressed PWH under TRIO (with a history of multi-drug resistance) switched to a drug-reducing regimen, the majority of whom maintained suppression.
Keywords: multi-drug resistant HIV, cohort, drug-reducing regimen, salvage therapy
1. Introduction
Heavily treatment experienced (HTE) people with HIV (PWH), and their treating physicians, can have few treatment options (1, 2). A commonly used definition of HTE is having two or fewer antiretroviral (ARV) classes available for use with limited fully active ARV agents within each class (1). Fortunately, prevalence of HTE PWH has decreased since the introduction of integrase inhibitors (INSTIs) in 2007. A US study reported a <1% annual prevalence of HTE PWH between 2012 to 2017 (3).
Despite its low prevalence, the issue of treating HTE PWH remains and salvage therapies are required (4). In 2009, the French ANRS 139 TRIO trial (5) reported evidence for the safety and efficacy of a salvage therapy called TRIO containing raltegravir (a first generation INSTI FDA-approved in 2007), etravirine (a non-nucleoside reverse transcriptase inhibitor (NNRTI)), and darunavir/ritonavir (a boosted protease inhibitor (PI)) for HTE PWH with multidrug-resistant HIV and HIV-1 RNA viral load (VL) >1000 copies/ml. TRIO was well tolerated with a similar rate of virologic suppression (VS) as treatment-naïve PWH. 96-week results showed sustained efficacy of TRIO (6), and longer-term follow-up reported that one-third of HTE PWH on TRIO would subsequently be eligible for drug-reducing treatment strategies (7).
Since the advent of second-generation INSTIs in 2013 (8) and improved options for treatment simplification there is interest in management of HTE PWH in real-life settings (2). We hypothesised that new generations of ART allow simplified regimens for this population. Using data from the Antiretroviral Therapy Cohort Collaboration (ART-CC) (9) we aimed to describe: the proportion of HTE PWH treated with TRIO who were subsequently virologically suppressed; the type of drug-reducing strategies implemented and proportion of virologic failure (VF) after each; and clinical outcomes (AIDS events, deaths) after TRIO start.
2. Materials and Methods
2.1. Setting
We analysed data from the 2019 update of ART-CC. Established in 2000, ART-CC combines data from 20 HIV observational cohort studies across North America and Europe (9). Fourteen cohorts with HIV resistance data participated (Appendix). Cohorts ascertained mortality until the end of 2019, through linkage with vital statistics agencies, hospitals, physician report, and active follow-up of participants (10).
2.2. Eligibility criteria
Adult (≥16 years old) PWH were eligible if they had: ever received the TRIO regimen; a history of VF (1 measure of VL>200 copies/ml) while receiving NNRTIs; VF at TRIO start defined as VF within 3 months prior to TRIO start and up to one week after; not received any individual TRIO drugs prior to starting TRIO between 2007 and 2018; ≥3 primary PI and nucleoside reverse transcriptase inhibitor (NRTI) mutations; and ≤3 darunavir and NNRTI mutations.
2.3. Outcomes
Outcomes of interest were: VS (VL<50 copies/ml) on TRIO; switching from TRIO to an alternative regimen (either a drug-reducing regimen containing <3 drugs, or another ≥3 drug regimen); first AIDS-defining event after starting TRIO; and death.
2.4. Covariates of interest
We assessed associations of the following covariates with outcomes: sex (male/female), age at TRIO start (<50 years, ≥50 years), mode of HIV acquisition (sex between men, injection drug use (IDU), sex between men and women, other/unknown), CD4 cell count at TRIO start (<200, ≥200 cells/mm3), and calendar year of TRIO start (≤2009, 2010–2017).
2.5. Statistical analysis
Baseline characteristics of the eligible population were described. A survival analysis approach was used to estimate outcome rates. TRIO start date was the baseline date, and follow-up ended at the earliest date of: outcome of interest; death; loss to follow-up; and cohort database close. For analyses concerning only time spent on TRIO, follow-up ended at TRIO end date where this date was available. Cox models, with baseline hazards stratified by cohort, were used to estimate hazard ratios for associations of covariates with outcomes. Validity of the proportional hazards assumption was assessed using Schoenfeld residuals.
We used a competing risks framework (Aalen-Johansen method) to non-parametrically estimate 5-year cumulative incidence of outcomes after TRIO (11). The main event of interest was switching from TRIO to a drug-reducing regimen, with competing events ‘stopped TRIO and switched to a ≥3 drug regimen’, ‘Stopped TRIO’, and ‘Died while on TRIO’. Competing risks regression models using the Fine and Gray approach (12) were used to estimate associations of covariates with these outcomes allowing for competing events.
2.6. Sensitivity analyses
As definitions of VF varied over time and across international organisations (13, 14), we assessed the sensitivity of our findings to these definitions. A first sensitivity analysis increased the assay threshold to require 1 VL measure of >500 copies/ml in steps 2 and 3 of the eligibility criteria (Appendix Figure 1). A second sensitivity analysis required 2 consecutive VL measures >200 copies/ml to define VF. A third sensitivity analysis required 2 consecutive VL measures >500 copies/ml. Stata version 18.0 (15) was used for all analyses.
3. Results
3.1. Eligible population
1193 PWH across 14 cohorts received TRIO salvage therapy, regardless of whether they started ART on a three-drug regimen. PWH were excluded according to the eligibility criteria defined (Appendix Figure 1). 126 PWH were eligible for analyses. Median age was 46 years (interquartile range [IQR]: 41–50), 24% were female, median CD4 at TRIO start was 96 (IQR: 18–315 cells/mm3), and 64% started TRIO prior to 2010 (Table 1). 73.8% started their first ART regimen with mono or dual therapy, rather than triple therapy. Those who started on mono or dual therapy, had a median of 13.2 years between ART start and TRIO start. Those who started on triple therapy (mostly on PI-based regimens) started TRIO a median of 8.7 years after first ART start. Total follow-up time (from TRIO start to death, loss to follow-up, or administrative censoring) was 859.2 years, with a median follow-up duration of 7.9 years (IQR: 5.1–9.3) per person.
Table 1:
Characteristics of eligible PWH, N=126
| N (%) | |
|---|---|
| Sex | |
| Male | 95 (75.4%) |
| Female | 30 (23.8%) |
| Missing | 1 (0.8%) |
| Age (years) at TRIO start | |
| <50 | 93 (73.8%) |
| 50+ | 33 (26.2%) |
| Median (IQR) | 46 (41–50) |
| CD4 (cells/mm 3 ) at TRIO start | |
| <200 | 73 (57.9%) |
| 200+ | 44 (34.9%) |
| Missing | 9 (7.1%) |
| Median (IQR) | 96 (18–315) |
| Mode of acquisition | |
| Sex between men | 50 (39.7%) |
| IDU | 26 (20.6%) |
| Sex between men and women | 40 (31.8%) |
| Other | 10 (7.9%) |
| Calendar year of TRIO start | |
| 2007–2009 | 80 (63.5%) |
| 2010–2017 | 46 (36.5%) |
| First ART regimen | |
| Mono/dual therapy | 93 (73.8%) |
| Triple therapy | 33 (26.2%) |
| First ART start year (median, IQR) | |
| Mono/dual therapy | 1995 (1993–1998) |
| Triple therapy | 2001 (1999–2004) |
| Time (years) from first ART to TRIO (median, IQR) | |
| Start on mono/dual therapy | 13.2 (11.5–16.7) |
| Start on triple therapy | 8.7 (6.0–11.7) |
| Time (years) spent on TRIO (median, IQR) | 1.7 (0.4–4.9) |
3.2. Virologic suppression in PWH treated with TRIO
120/126 eligible (95.2%) PWH had a VL recorded whilst receiving TRIO. 94 (75%) PWH achieved VS, at a rate of 217.8 per 100 person-years (95% Confidence Interval (CI): 178.0–266.6). In general, associations between covariates and outcomes were imprecisely estimated due to low numbers of events (Table 2). There was strong evidence that CD4 counts ≥200 cells/mm3 were associated with increased hazards of VS on TRIO (aHR 2.21, 95% CI 1.28–3.82) compared to CD4 < 200 cells/mm3. Additionally, there was moderate evidence that HIV acquired via IDU was associated with lower hazards of VS on TRIO (aHR 0.43, 95% CI 0.21–0.90) compared to acquisition via sex between men. There was no evidence against the proportional hazards assumption for any covariate.
Table 2:
Adjusted* hazard ratios (aHR) for associations with time to first virologic suppression, AIDS, Death and combined endpoint of AIDS/death, N=125**
| Virologic suppression | AIDS | Death | AIDS/death | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Characteristic at TRIO start | N | # events | aHR (95% CI) | # events | aHR (95% CI) | # events | aHR (95% CI) | # events | aHR (95% CI) | |
| Sex | Female | 30 | 21 | 1.29 (0.68, 2.46) | 9 | 1.07 (0.42, 2.73) | 5 | 1.81 (0.55, 5.98) | 11 | 1.27 (0.55, 2.94) |
| Age, years | <50 | 92 | 69 | 1 | 20 | 1 | 14 | 1 | 27 | 1 |
| ≥50 | 33 | 24 | 0.77 (0.45, 1.33) | 12 | 2.31 (1.01, 5.29) | 8 | 1.48 (0.49, 4.43) | 15 | 2.07 (0.96, 4.46) | |
| CD4 count, cells/mm 3 | <200 | 73 | 52 | 1 | 22 | 1 | 18 | 1 | 29 | 1 |
| ≥200 | 44 | 36 | 2.21 (1.28, 3.82) | 9 | 0.59 (0.25, 1.41) | 3 | 0.06 (0.01, 0.51) | 11 | 0.46 (0.20, 1.02) | |
| Missing | 8 | 5 | 2.93 (0.95, 9.03) | 1 | 0.20 (0.02, 2.12) | 1 | 0.55 (0.06, 5.20) | 2 | 0.37 (0.07, 2.03) | |
| Probable mode of HIV acquisition | Sex between men | 49 | 40 | 1 | 10 | 1 | 7 | 1 | 14 | 1 |
| IDU+ | 26 | 20 | 0.43 (0.21, 0.90) | 4 | 1.36 (0.35, 5.33) | 3 | 2.45 (0.33, 18.08) | 6 | 1.27 (0.37, 4.37) | |
| Sex between men &women | 40 | 27 | 0.73 (0.40, 1.31) | 15 | 2.05 (0.81, 5.15) | 11 | 3.49 (1.01, 12.07) | 19 | 1.97 (0.88, 4.42) | |
| Other/Unknown | 10 | 6 | 0.63 (0.23, 1.72) | 3 | 0.68 (0.14, 3.39) | 1 | 0.29 (0.03, 2.98) | 3 | 0.46 (0.09, 2.20) | |
| Calendar year | 2007–2009 | 79 | 60 | 1 | 18 | 1 | 16 | 1 | 24 | 1 |
| 2010–2017 | 46 | 33 | 1.09 (0.63, 1.88) | 14 | 1.70 (0.79, 3.63) | 6 | 0.33 (0.09, 1.15) | 18 | 1.30 (0.64, 2.63) | |
adjusted for all variables displayed in the table, and stratified by cohort
N=125 because of 1 participant with missing gender
injection drug use
3.3. Clinical outcomes in PWH treated with TRIO
Among PWH treated with TRIO, 23 died during follow-up, a mortality rate of 2.7 (95% CI: 1.8, 4.0) per 100 person-years. 32 experienced an AIDS event, a rate of 4.3 (95% CI: 3.1, 6.1) per 100 person-years. Considering the composite outcome first AIDS event/death after starting TRIO, there were 43 events, a rate of 5.8 per 100 person-years (95% CI: 4.3–7.8). There was weak evidence that age ≥50 years was associated with increased hazards of AIDS (aHR: 2.31, 95% CI 1.01, 5.29) compared to age <50 years. CD4 ≥200 was associated with lower hazards of death compared to CD4<200 (aHR: 0.06, 95% CI: 0.01, 0.51) (Table 2). There was no evidence against the proportional hazards assumption for any covariate.
3.4. Drug-reducing strategies in PWH treated with TRIO
Of those virologically suppressed on TRIO (n=94, 74.6%), 26 (27.7%) switched to a drug-reducing regimen. Where a reason for switch was available (n=15), 53% were due to there being a ‘Simplified treatment available’. Most switches were to a darunavir-based regimen (Appendix Table 1): these happened earlier (median July 2012) than simplifications to non-darunavir based regimens (median Dec 2016). Among those who switched to a drug-reducing regimen, 19/26 (73.1%) were virologically suppressed at their next VL measure. None subsequently experienced a new AIDS event.
3.5. Cumulative incidence of outcomes after TRIO
The 5-year cumulative incidence of competing outcomes following TRIO was: start another ≥3 drugs regimen 39.1%; simplify 16.0%; stop TRIO without switch 8.8%; death whilst receiving TRIO 7.2% (Figure 1). 95% CIs for the sub-distribution hazard ratios (SHR) from the competing risks regression were wide due to small event numbers (Appendix Table 2). There was weak evidence that age ≥50 years were more likely to simplify than age <50 years (aSHR 2.26, 95% 0.90–5.66). Those with missing CD4 counts were more likely to simplify than those with CD4 counts <200 (aSHR 6.50, 95% 1.44–29.40).
Figure 1: Outcomes after TRIO start.
*Generated with the Aalen-Johansen method
Among 88 participants who switched away from TRIO, a reason for stopping was available for 66 of them. The most common reason for switching was that a simplified treatment was available. When stratified by type of switch (to a ≥3-drug regimen, or to a drug-reducing regimen), switching for simplification was still common in both groups, though in the ≥3-drug regimen group there are more with unknown reasons for switching (see Appendix Table 3).
3.6. Sensitivity analysis
For each sensitivity analysis, the sample size decreased as eligibility criteria became more restrictive, dropping from 126 to 70. As sensitivity analyses became more restrictive, the proportion of females became smaller, as did the proportion IDU, and starting TRIO in 2010–2017 (Appendix Table 4). Also, event rates increased, with the highest event rate in sensitivity analysis 2 (Appendix Table 5). Estimates of covariate associations with clinical outcomes were consistent across sensitivity analyses, with wide CIs due to low event numbers (Appendix Table 6). The 5-year cumulative incidence of outcomes after TRIO were also similar across sensitivity analyses (Appendix Table 7, Appendix Figure 2).
4. Discussion
4.1. Main results
In this study of HTE PWH starting TRIO with VF, the most common outcome was to switch to another 3-drug regimen. Over 5-years, almost 40% of HTE PWH switched to another 3-drug regimen following TRIO. However, overall 16% switched to a drug-reducing regimen, and of those virologically suppressed on TRIO almost one third switched to a drug-reducing regimen. Among those switching to a drug-reducing regimen, the majority (73.1%) remained suppressed. There was moderate evidence that HIV acquisition via IDU was associated with lower hazards of VS (aHR 0.43, 95% CI 0.21–0.90) compared to acquisition via sex between men. CD4 counts ≥200 cells/mm3 were strongly associated with increased hazards of VS (aHR 2.21, 95% CI 1.28–3.82) when compared to CD4 <200 cells/mm3. We saw weak evidence that age ≥50 years was associated with increased hazards of AIDS (aHR 2.31, 95% CI 1.01, 5.29) compared to age <50 years, and evidence that CD4 ≥200 cells/mm3 was associated with decreased hazards of death compared to CD4 <200 cells/mm3 (aHR 0.06, 95% CI: 0.01, 0.51).
4.2. Comparison with other literature
The TRIO regimen was evaluated in the ANRS 139 TRIO trial (5, 6), and also within a study of the Aquitaine region of France (7). The extension to the ANRS trial published in 2012, showed that TRIO produced a sustained virologic response (VL<50 copies/ml) at week 96 for 88% of participants. Similarly, in our observational study, we observed virologic response in 75% of PWH on TRIO over a median 1.7 years on TRIO per person.
The Aquitaine study also showed favorable longer-term virologic responses among PWH on TRIO (7), and also assessed the number of PWH receiving TRIO who subsequently switched to a drug-reducing regimen. At the last visit, 25% of PWH with VF at TRIO start subsequently received dual therapy. In the present study, we estimated a 5-year cumulative incidence of 16% of PWH stopping TRIO to simplify their regimen. When drawing comparisons with the Aquitaine study, we must be aware that criteria for the present study are stricter. For example, the present study restricted to PWH with a history of VF (1 measure of VL>200 copies/ml) while receiving NNRTIs; additionally we defined VF at TRIO start as 1 VL measure >200 copies/ml within 3 months prior to TRIO start and up to one week after, whereas the Aquitaine study used a 1-year window period prior to TRIO. Unlike the Aquitaine study, we required that PWH had not received any individual TRIO drugs prior to starting TRIO between 2007 and 2018.
A 2023 US study reported on virologic responses among people on salvage therapy who did and did not simplify their ART regimen (16). They found comparable virologic responses across the two groups. While this study did not focus explicitly on TRIO, most participants had salvage therapy of darunavir/ritonavir, etravirine plus an INSTI. Suppression rates were similar to those in the present study.
4.3. Strengths and limitations
A major strength of this study was the breadth of data collected across diverse settings in Europe and North America, in particular, ascertainment of mortality across these varied cohorts (10). Within large-scale observational studies it can be difficult to obtain data on resistance profiles (17). A large amount of effort is appreciated from cohort teams to make this study possible with additional data extraction to obtain HIV resistance data. As with all observational studies, we have limitations. The sample size was relatively small due to the eligibility criteria utilised. However, the sample size was comparable to other studies of the TRIO regimen.
4.4. Further research
The 2015 US-based OPTIONS study reported development of a ‘web-based utility’ to assist clinicians in regimen selection decisions (2). They reported that drug resistance, prior ARV experience and race-ethnicity were characteristics which led to more complicated treatments being chosen. However, their study was completed before Dolutegravir was approved which may have helped to simplify regimens for more individuals. Our study also had limited data after the introduction of Dolutegravir, and few PWH were observed to switch from TRIO to a regimen with Dolutegravir. The therapeutic landscape has since evolved and the current era of treatments include second generation INSTIs, long-acting injectables, and newer agents for multidrug resistance (e.g., fostemsavir, ibalizumab, lenacapavir). However, we hypothesise that this will improve outcomes for HTE PWH who have received TRIO by providing more treatment options with higher genetic barriers to resistance. For a subset of participants (n=61) in the current study, in a post-hoc analysis, we were able to link to more recent cohort data up until 2022. We found that 27 patients (44%) subsequently took a regimen containing DTG, and 3 (5%) subsequently took a regimen containing BIC, demonstrating that 2nd generation INSTIs are being utilised by this group. Additionally, among those who had switched to a drug-reducing regimen immediately post-TRIO and had more recent data (n=14), all were observed to remain on a drug-reducing regimen at their last follow-up. Future studies evaluating long-term outcomes of modern treatment strategies in HTE populations would provide more contemporary and clinically informative evidence to guide regimen selection and sequencing in this complex population.
4.5. Implications
Treatment recommendations for HTE PWH remain complex (1, 18), however among those who switched to simplified regimens after TRIO, rates of VS were comparable to rates while on TRIO and therefore simplification could be considered.
5. Conclusions
In this observational cohort study, the most common outcome after starting TRIO while being in VF and HTE was to switch to another regimen containing at least 3 drugs. PWH with long treatment histories prior to starting TRIO had few options to switch to less burdensome regimens in this period, although one third of those virologically suppressed did switch to drug-reducing regimens and maintain suppression.
Supplementary Material
Message:
TRIO remains an effective salvage regimen in triple-class resistant HIV, and among those achieving suppression, selected patients may safely transition to simplified regimens.
Acknowledgements
We would like to thank all patients, and the clinical teams associated with the participating cohort studies.
Funding:
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of this report.
The ART-CC was funded by the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026209) during 2017-2024, and by the US National Institute of Allergy and Infectious Diseases (R01-AI181733) during 2024-2029. JACS is funded by National Institute for Health Research Senior Investigator award NF-SI-0611-10168. AT is funded by the Wellcome Trust under a Sir Henry Wellcome Postdoctoral Fellowship (222770/Z/21/Z).
Declarations of Interest:
MJG. is an ad hoc member of the Canadian National HIV advisory board to Merck, Gilead. and ViiV. C.S. received payments for lectures/scientific advice from the following pharmaceutical companies: Gilead Sciences, Johnson&Johnson (formerly Janssen Cilag), MSD Sharp & Dohme, Shionogi, Theratechnologies, and ViiV Healthcare, further on travel grants for scientific conferences from AbbVie, Gilead Sciences, MSD Sharp & Dohme, and Johnson&Johnson (formerly Janssen-Cilag). CB received honoraria for lectures and/or consultancies from AbbVie, Astra Zeneca, Bavarian Nordic, Gilead, Janssen, MSD, Pfizer, ViiV. Funding from DFG, Dt. Leberstiftung, DZIF, Hector Stiftung, NEAT ID. PFR reports NIH grant funding to support research (money paid to institution). GT has received grants unrelated to this study from Gilead Sciences Europe, UCL, EU, and National funds, all paid to her institution. FB reports non-financial support from Gilead Sciences, Janssen, ViiV Healthcare, and MSD, research grants from Gilead Sciences, ViiV Healthcare, and MSD and personal fees from Gilead Sciences, ViiV Healthcare and MSD outside the submitted work. MH reports non-financial support and personal fees from Gilead Sciences, ViiV Healthcare, and MSD outside the submitted work. HMC reports grant funding to their institution from ViiV.
All other co-authors have no interests to declare.
Footnotes
Previously presented as a poster at CROI 2025.
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