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Abstract

Heavily treatment-experienced (HTE) persons with HIV have limited options for antiretroviral therapy and face many challenges, complicating their disease management. There is an ongoing need for new antiretrovirals and treatment strategies for this population. We reviewed the study designs, baseline characteristics, and results of clinical trials that enrolled HTE persons with HIV. A PubMed literature search retrieved articles published between 1995 and 2020, which were grouped by trial start date (1995–2009, N = 89; 2010–2014, N = 3; 2015–2020, N = 2). Clinical trials in HTE participants markedly declined post-2010. Participant characteristics and study designs showed changes in trends over time. As treatment strategies for HTE persons with HIV progress, we must look beyond virologic suppression to consider the broader needs of this complex heterogeneous population.

Keywords

study design virologic failure optimized background therapy multidrug resistance HIV therapies

Introduction

Heavily treatment-experienced (HTE) persons with HIV are among those who have been left behind by continuing improvements in the treatment of HIV infection. Since the initial approval of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the introduction of combination antiretroviral therapy (cART) in the late 1990s,^1–3 more than two decades of relentless progress have seen the development of five additional classes of antiretrovirals (ARVs), numerous fixed-dose combinations and once-daily single-tablet regimens, and a long-acting injectable 2-drug regimen.^1,4 In parallel, rates of morbidity and mortality have fallen dramatically, and the focus has shifted away from antiviral potency to quality-of-life improvements through better-tolerated, more convenient cART regimens.^5,6 While these advances mean that, in high-income countries, undetectable plasma HIV RNA is an achievable goal, for others, problems with side effects, drug-drug interactions (DDIs), and barriers to treatment adherence and retention in care mean that suppression to below detectable limits is challenging.¹ In these individuals, failure of successive cART regimens with accumulation of viral resistance to multiple ARVs, often accompanied by an increasing burden of comorbidities, can leave few remaining treatment options so that switching to a viable new cART regimen is not possible.¹ Those who survived the earlier era of suboptimal ART with poor tolerability, complex dosing, and less sophisticated monitoring likely experienced persistence of viral replication and subsequent resistance to several different classes and regimens; this complex heterogeneous population still faces numerous clinical challenges (Figure 1).^7–10 HTE persons are often prescribed complex regimens, potentially further hindering long-term adherence and leading to persistent viral replication with increased risk of morbidity, immunodeficiency, reduced quality of life, and onward transmission of multidrug-resistant HIV. In this population, there is a need to develop therapies with novel mechanisms of action and formulate optimal management strategies. High rates of efficacy with first-line ART, simplified dosing regimens, and increased tolerability have focused attention on optimizing long-term HIV management for individuals with suppressed viral replication rather than developing novel agents for those with persistent detectable viral load. Developing new treatments for the HTE population has been challenging because of the extensive variability in prior treatment experience, viral resistance, and drug tolerance.^7–9,11 Although genotypic and phenotypic resistance testing can help guide ARV selection, it can be difficult to select an optimal regimen that accommodates other clinical factors.¹² HTE persons with HIV require individually constructed regimens that may include combinations that have not been clinically evaluated for efficacy, safety, or DDIs. The potential for DDIs between comedications of individually constructed cART regimens, often including pharmacokinetic enhancers, is a particularly important consideration. These complexities, along with inconsistent regulatory guidance, have led to inconsistency in the design of clinical studies evaluating new therapies for HTE persons.

Figure 1.

Clinical challenges to optimal ARV treatment in heavily treatment-experienced persons with HIV. ART, antiretroviral therapy; ARV, antiretroviral; NRTI, nucleoside reverse transcriptase inhibitor.

In this article, we review the evolution of study design and participant characteristics for clinical trials evaluating treatment strategies for persons with HIV who have experienced virologic failure on multiple cART regimens and/or have multidrug-resistant HIV-1, with the aim of understanding how changes in the treatment landscape have influenced trial design for HTE individuals and providing perspectives on appropriate clinical trial endpoints that can inform the future care of this population.

Methods

Articles published from January 1995 to December 2020 were retrieved from PubMed in April and December of 2020, using search terms listed in Supplemental Table S1. Reference lists of retrieved articles and trial records on ClinicalTrials.gov were also reviewed.

Articles describing primary analyses of prospective clinical trials and interventional studies evaluating the efficacy of cART in adults with HIV-1 and virologic failure during ART were included. Secondary reports of long-term outcomes were considered for safety and efficacy data.

Exclusion criteria and eligibility assessment

Retrospective studies, real-world studies, and those with young paediatric patients (aged <12 years) were excluded. Studies conducted in treatment-experienced participants with virologic suppression (switch studies) or in treatment-naive participants were also excluded as were studies evaluating therapies for co-infection. Studies with a single treatment arm and/or <100 participants that were published before 2005 were only included if the authors deemed that the study was well designed and represented an advancement in study design.

Data abstraction

Data were abstracted using a form. Information included (1) number of overall and HTE participants, (2) clinical trial phase, (3) publication date, (4) experimental drug regimen and comparator group, (5) definitions of and inclusion criteria for HTE, (6) participant baseline characteristics, and (7) efficacy measurements assessed. A sub-analysis of included articles describing phase 3 studies of new antiretrovirals was conducted to analyze virologic, immunologic, resistance, and safety outcomes in HTE populations. This information included (1) primary study endpoint result; (2) proportion of participants with HIV-1 RNA below the limit of detection at various time points; (3) proportion of participants who met virologic failure criteria as described in the study; (4) change in CD4⁺ cell count; (5) proportion of participants with treatment-emergent resistance associated with reduction in susceptibility; and (6) proportion of participants with drug-related adverse events (AEs), serious AEs, AEs leading to discontinuation, AIDS-defining events, and deaths. Data were analyzed using descriptive statistics.

Trials were grouped into the following three periods by year of initiation (when participant inclusion started) or year of primary publication if study initiation date was not available: Period 1, 1995–2009 (triple-agent cART became standard clinical practice after the introduction of PIs and NNRTIs); Period 2, 2010–2014 (multiple ARV classes and single-tablet regimens available; guidelines recommend treatment initiation regardless of CD4⁺ cell count); and Period 3, 2015 or later (implementation of the latest US Food and Drug Administration [FDA] guidance for the development of ARVs; widespread availability of dolutegravir in the HTE setting).

Results

A total of 100 articles describing results from 94 clinical studies were included in the review (Supplemental Figure S1; Supplemental Table S2). Table 1 provides an overview of study designs, inclusion criteria, and participant baseline demographic and disease characteristics for included studies grouped according to year of initiation (n = 77 studies) or year of primary publication where study start date was not available (n = 17 studies). Most studies were in Period 1 (1995–2009; 95%, n = 89; Table 1, Figure 2).

Table 1.

Overview of inclusion criteria, study designs, and participant demographic and disease characteristics at baseline.

		Period 1 (N = 89)		Period 2 (N = 3)	Period 3 (N = 2)
		1995–2009		2010–2014	2015–2020
		n/N (%)^a	References	n ^a	n ^a
Study design^b
	Phase 2	19/89 (21)	^{35,40,43,45,47,50,51,53,56,62,63,66,76,81,83,93,94,103,104}	—	—
	Phase 3 or 3b	24/89 (27)	^{12,14,16–22,28,32,34,39,41,46,52,55,57,65,75,105}	3^23–25	2^26,27
	Randomized (fully or partially)	59/89 (66)	^{13,14,16–22,30,31,34,37,39–43,45,46,48–53,57,59–62,66–68,71,74–76,80,81,83,86,91–93,103,105–112}	2^24,25	1²⁷
	Blinded (fully or partially)	21/89 (24)	^{12,14,17,19,20,39–41,43,45,51–53,62,66,67,103,106}	1²⁴	1²⁷
	Non-inferiority	9/89 (10)	^{19,34,41,42,46,50,57,105,111}	—	—
	Single-arm	27/89 (30)	^{29,32,33,35,36,44,47,55,56,63–65,70,72,77–79,82,84,85,87–90,94,104,113}	1²³	1²⁶
Core ARVs investigated
Protease inhibitors	Lopinavir	12/89 (13)	^{29,30,38,57,75,76,78,79,82,91,94,106,108}	—	—
	Saquinavir	13/89 (15)	^{30,37,43,46,60,61,64,72,78,79,88,90,114}	—	—
	Darunavir	9/89 (10)	^{17,19,32,33,40,45,47,56,58}	—	—
	Tipranavir	6/89 (7)	^{21,22,34,83,93,113}	—	—
NNRTIs	Efavirenz	11/89 (12)	^{29,54,62,63,67,74,77,86,88,94,103}	—	—
NNRTIs	Etravirine	6/89 (7)	^{17,19,50,55,56,87}	—	—
Integrase inhibitors	Raltegravir	5/89 (6)	^20,56,66,87	—	—
Integrase inhibitors	Dolutegravir	1/89 (1)	³⁵	2^23,24	—
Fusion inhibitor	Enfuvirtide	7/89 (8)	^{16,18,33,48,59,85,89}	—	—
CCR5 antagonist	Maraviroc	4/89 (4)	^15,65,87	1²⁵	—
CCR5 antagonist	Vicriviroc	2/89 (2)	^14,53	—	—
Post-AI	Ibalizumab	—	—	—	1²⁶
AI	Fostemsavir	—	—	—	1²⁷
Comparator and BT^c
	Optimized BT^d	5/89 (6)	^{13,16,18,31,81}	—	—
ARV/Dose^e	+ Fixed BT	4/89 (4)	^49,54,86,107	—	—
	+ Selected BT	19/89 (21)	^{30,37,41,42,46,57,60,68,73,74,76,93,103,105,106,108–110,114}	—	—
	+ Optimized BT	15/89 (17)	^{21,22,34,40,45,50,58,59,61,75,83,91,92,111,112}	—	—
Placebo	+ FR	3/89 (3)	^39,51,52	1^24,f	1^27,f
	+ Fixed BT	3/89 (3)	^43,62,80	—	—
	+ Selected BT	3/89 (3)	^17,19,67	—	—
	+ Optimized BT	10/89 (11)	^{14,15,20,48,53,66,71}	—	—
Single arm	FR	0	—	1^23,f	1^26,f
	Fixed BT	8/89 (9)	^{29,63,77,79,87,90,104}	—	—
	Selected BT	11/89 (12)	^{55,64,70,72,78,82,84,85,88,94,113}	—	—
	Optimized BT	7/89 (8)	^{32,33,47,56,65,89,97}	3^23–25,f	2^26,27,f
Inclusion criteria: Viral load, copies/mL
	Not specified	16/89 (18)	—	—	—
	≥400 or 500	8/89 (9)	^{34,39,51,52,54,59,63,103}	2^23,25	1²⁷
	≥1000	37/89 (42)	^{14,20–22,30–32,35,37,40–43,45–48,50,53,56–58,61,65,75,76,82,83,92,94,105,106,111,113}	1²⁴	1²⁶
	≥2000 or 2500	3/89 (3)	^33,112,114	—	—
	≥5000	17/89 (19)	^{12,16–19,29,49,66,68,70,72,80,88,93,108,110}	—	—
	≥10,000	7/89 (8)	^{36,64,67,71,81,91,104}	—	—
Inclusion criteria: CD4⁺ cell count, cells/mm³
	Not specified	76/89 (85)	—	3^23–25	2^26,27
	>50 or ≥50	4/89 (4)	^42,44,46,67	—	—
	> Or ≥100 or 200	5/89 (6)	^{29,31,39,104,112}	—	—
	<50	1/89 (1)	¹⁰⁹	—	—
	<200 or <500	3/89 (3)	^49,81,91	—	—
Inclusion criteria: Prior ART experience
Duration	Not specified	38/89 (43)	—	3^23–25	1²⁷
	≥8–16 weeks	29/89 (33)	^{17–19,30,32,34,40,43,45,47,51–54,56–58,64,66–69,80,83,91,106,107,111,112}	—	—
	≥5–9 months	17/89 (19)	^{12,14,16,21,22,37,41,59,60,63,70,92,93,109,114}	—	—
	≥1–4 years	4/89 (4)	^{71,74,103,108}	—	—
ARV classes	Not specified	26/89 (29)	—	—	—
	≥1 class	11/89 (12)	^{44,62,67,70,73,74,90,94,103,106,107}	—	—
	≥2 classes	27/89 (30)	^{13,14,17,19,30–32,37,41,43,50,56,58,60,61,63,64,77,82,86,91,93,110–112}	—	—
	≥3 classes	25/89 (28)	^{12,16,18,20–22,33–36,40,45–47,55,59,66,68,71,78,87,89}	3^23–25	1²⁶
	≥4 classes	0	—	—	1²⁷
Resistance^g	Not required	61/89 (69)	—	1²⁵	—
	≥1 class	8/89 (9)	^{21,22,34,40,45,47,50,83}	—	—
	≥2 classes	8/89 (9)	^{13,14,17,19,41,53,56}	—	—
	≥3 classes	12/89 (13)	^{12,16,18,20,36,59,66,68,89,97}	2^23,24	1²⁶
	≥4 classes	0	—	—	1²⁷
Inclusion criteria: Available ARV treatment options for BT
	No restrictions	68/89 (76)	—	—	—
	ARV class naive^h	5/89 (6)	^{44,67,86,94,114}	—	—
	Min fully active	15/89 (17)	^{13,19,31,34,35,41,42,48,55,62,81,93,103,104,106}	3^23–25	2^26,27
	Max fully active	0	—	—	1²⁷
Demographics at baseline
Age	Median ≥45 years	11/56 (20)	^{17,19,20,33,35,55,56,81,85,113}	3^23–25	2^26,27
Age	Mean ≥45 years	4/27 (15)	^12,45,68	—	—
Race	≥50% non-White	6/46 (13)	^{32,42,50,62,68,108}	1²⁴	—
Sex	≥30% female	10/82 (12)	^{14,30,32,37,48,50,57,74,92,107}	—	—
Disease characteristics at baseline
Viral load, log₁₀ copies/mL
Median	≥5	12/66 (18)	^{16,18,36,63,73,79–81,83,85,109,110}	—	—
	≥4.5 to <5	24/66 (36)	^{17,19,20,22,29,43,55,59,61,64,66,75,76,78,82,89–91,93,104,108,113}	—	1²⁶
	<4.5	30/66 (45)	^{13,31,35,39,41,42,44,46,48–50,52,54,56,58,60,70–72,84,86–88,92,93,103,105–107,111,112,114}	3^23–25	1²⁷
Mean	≥4.5 to <5	14/21 (67)	^{14,21,32,33,40,45,47,53,68,77}	—	—
Mean	<4.5	7/21 (33)	^{30,34,37,51,57,62,67,74}	—	—
CD4⁺ cells/mm³
Median	>200	35/72 (49)	^{13,29,31,34–36,39,41–44,46,48–50,52,54,56,58,60,66,84,86–88,90–93,103–105,111–113}	1²⁵	—
	>100 to ≤200	24/72 (33)	^{12,17,19,20,40,47,55,61,63–65,68,70,72,73,79,82,83,107,108,114}	2^23,24	—
	>50 to ≤100	10/72 (14)	^{16–19,30,45,78,80,81,105}	—	2^26,27
	≤50	4/72 (6)	^59,85,89,106	—	—
Mean	>200	9/15 (60)	^{14,22,37,51,53,57,67,77}	—	—
Mean	>100 to ≤200	5/15 (33)	^{32,33,62,74,76}	—	—
AIDS or CDC category C
	At baseline in ≥50%	16/40 (40)	^{13,17,19,21,30,47,51,55,64,72,78,81,82,87,109}	2^23,24	NR
	History of in ≥50%	10/15 (67)	^{16,18,20–22,36,66,68,110}	NR	1²⁷ (1²⁶ NR)
Treatment history
Prior ART
Median	≥10 years	8/42 (19)	^{20,35,47,48,56,87,105}	3^23–25	1²⁷ (1²⁶ NR)
	≥5 to <10 years	17/42 (40)	^{16,18,36,45,46,52,58,66,71,79,85,90,91,103,104,108,110}	—	—
	ARVs ≥10	16/31 (52)	^{16,18–20,34–36,40,45,48,66,78,83,85}	2^23,24 (1²⁵ NR)	1²⁷ (1²⁶ NR)

AI, attachment inhibitor; ART, antiretroviral therapy; ARV, antiretroviral; BT, background therapy; FR, failing regimen; NNRTI, non-nucleoside reverse transcriptase inhibitor; NR, not reported; VL, viral load.

^an = number of studies reporting the parameter/N = number of studies.

^bStudy design criteria are not mutually exclusive.

^cFixed BT included the same protocol-specified ARVs for all participants in each study group; Selected BT included some study-specified ARVs and some investigator-selected ARVs with some additional restrictions; Optimized BT was selected by the investigator based on clinical history and resistance testing with minimal protocol-defined restrictions.

^dStudy regimen plus optimized BT was compared with optimized BT alone. This includes one trial where a fixed study regimen was compared with an optimized study regimen.¹³

^eStudy drug was compared with another ARV or different formulation or dose of the study ARV combined with the indicated BT.

^fShort-term functional monotherapy to assess the antiviral effect of the investigational ARV, followed by open-label treatment in combination with a new OBT.

^gRequirement for documented resistance.

^hProtocol specified that participants must be naive to a specified ARV class but did not otherwise require availability of ARVs.

Figure 2.

Included studies and key ARV approvals (United States, red circles; European Union, blue circles) over time. Only studies with published start dates are included. AI, attachment inhibitor; ARV, antiretroviral; ATV, atazanavir; DTG, dolutegravir; FI, fusion inhibitor; FTR, fostemsavir; EFV, efavirenz; ENF, enfuvirtide; ETR, etravirine; IBA, ibalizumab; INI, integrase inhibitor; LPV, lopinavir; MVC, maraviroc; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PAI, post-attachment inhibitor; PI, protease inhibitor; R5A, CCR5 antagonist; RAL, raltegravir; RCT, randomized controlled trial; SQV, saquinavir; TPV, tipranavir. ^aOnly phase 3 studies in treatment-experienced participants with treatment failure are included. Approval dates were taken from the US Food and Drug Administration¹⁰¹ and European Medicines Agency websites,¹⁰² and clinical trial start and primary finish dates (indicated by coloured bars) were taken from ClinicalTrials.gov. ^bFinal guidance document published November 2015.⁹⁹

Period 1 studies included 19 phase 2 trials (six single arm), 21 phase 3 trials (including six pairs of parallel trials with similar study designs: BENCHMRK-1/2 [raltegravir], DUET-1/2 [etravirine], MOTIVATE-1/2 [maraviroc], TORO-1/2 [enfuvirtide], RESIST-1/2 [tipranavir], VICTOR-E3/E4 [vicriviroc]),^14–22 three phase 3b/early-access trials, and 25 other randomized controlled or comparative studies (Table 1). The remaining 21 studies were post-registration, single-arm studies and prospective cohort studies. All studies included in Periods 2 and 3 were phase 3 or 3b clinical trials: VIKING-3²³ and VIKING-4²⁴ (dolutegravir) and OSCAR²⁵ (maraviroc) in Period 2, TMB-301²⁶ (ibalizumab) and BRIGHTE^27,28 (fostemsavir) in Period 3.

Inclusion criteria

Participants in included studies were described as treatment-experienced (n = 33)^{14,17,19,20,23,25,29–58}; highly, heavily, or extensively treatment-experienced (n = 31)^{13,24,27,59–83}; receiving salvage therapy (n = 11)^16,84–92; and multidrug, multiclass, or triple-class experienced (n = 11).^{21,33,48,55,76,84,85,87,93–95}

In Period 1, 50 (56%) studies specified a duration of previous ARV therapy for inclusion, 63 (71%) specified a minimum number of prior ARV classes, and 28 (31%) required documented resistance (Table 1). All 11 studies requiring experience with a minimum of one ARV class (mostly NRTIs) were initiated no later than 2000 and none required documentation of resistance. In contrast, all 25 studies requiring experience with ≥3 ARV classes were initiated in 2000 or later and 19 also required documented resistance to ≥1 ARV class. Only 15 studies in Period 1 specified a minimum number of active ARVs or ARV classes available to use in background therapy (Table 1).

In Periods 2 and 3, all four phase 3 studies required extensive experience and resistance to ARVs. In the VIKING studies, participants had to be taking raltegravir or elvitegravir and have screening or historical resistance to integrase inhibitors (INIs) and ≥1 ARV from ≥2 other classes.^23,24 In TMB-301, participants were required to have documented resistance to ≥1 ARV from ≥3 classes.²⁶ BRIGHTE required that participants had eliminated all ARV options from ≥4 classes for resistance, previous side effects, contraindications, or unwillingness to use enfuvirtide (a twice-daily injectable).^27,28 All five studies in Periods 2 and 3 required that participants had ≥1 fully active ARV that could be used in the background regimen, but only BRIGHTE limited inclusion to those who had active agents from only one or two ARV classes (in the Randomized Cohort). BRIGHTE also included a Non-randomized Cohort for participants with no remaining active treatment options who were allowed to include other investigational agents in their optimized background therapy (OBT). TMB-301 also allowed participants to use other investigational agents.²⁶

Most studies (77/94 [82%]) specified a minimum viral load for inclusion, most commonly HIV-1 RNA 1000 copies/mL (Table 1). All 27 studies with minimum viral load criteria >1000 copies/mL were in Period 1. All studies with minimum viral load criteria of 5,000 or 10,000 copies/mL (n = 24) were initiated no later than 2005. Conversely, all studies in Periods 2 and 3 had viral load inclusion criteria of HIV-1 RNA 400, 500, or 1,000 copies/mL. Only 13 studies specified baseline CD4⁺ cell count inclusion criteria (all in Period 1; Table 1).

Participant baseline characteristics

In Period 1, there was a slight trend toward greater median age with increasing year of publication (Figure 3(a)). Only 15/83 (18%) studies reported median or mean age ≥45 years (Table 1). Median age was ≥45 years in all three studies in Period 2 and ≥50 years in both studies in Period 3. Demographic diversity among study participants was low in most studies, with the exception of those designed to assess specific populations (e.g., women). Across all included studies, most participants were men. Only 10 studies (all in Period 1; Table 1) had ≥30% women. Similarly, among 50 studies reporting race (including four in Periods 2 and 3), only seven enrolled ≥50% of participants who were of non-White non-Hispanic race (Table 1).

Figure 3.

Baseline parameters^a by year of study initiation^b: (A) median and mean (as reported) age of study participants, (B) median and mean (as reported) baseline viral load, (C) median and mean (as reported) baseline CD4⁺ cell count, (D) median duration of prior ART,^c and (E) median number of prior ARVs.^c Each symbol represents one study. The dashed line is the linear trend line for median values by study start year only. ART, antiretroviral therapy; ARV, antiretroviral. ^aData are shown for studies that reported the given parameter. ^bBy year of primary publication where study start date was not available. ^cIn BRIGHTE, 71% of participants had >15 years of ARV experience and 85% had received >5 ARV regimens, but medians were not reported.

Just over half of studies (50 [56%]) in Period 1 had populations with median or mean baseline viral load ≥4.5 log₁₀ copies/mL, and among studies reporting median baseline viral load, 12/66 (18%) had ≥5 log₁₀ copies/mL (Table 1). There was a trend in baseline viral load in studies over time (Figure 3(b)). In Periods 2 and 3, median viral load was <4.5 log₁₀ copies/mL in all studies except TMB-301 (4.6 log₁₀ copies/mL).²⁶ Among studies in Period 1 that reported baseline CD4⁺ cell count, 29/87 (33%) had a median or mean of >100 to ≤200 cells/mm³ and 4/72 (6%) had a median baseline CD4⁺ cell count of ≤50 cells/mm³. There was a slight trend toward lower baseline CD4⁺ cell count in studies over time (Figure 3(c)). In Periods 2 and 3, all studies except OSCAR²⁵ had median baseline CD4⁺ cell counts <200 cells/mm³.

Prior ART experience was inconsistently reported; nevertheless, a trend could be observed toward increasing levels of ART experience with increasing year of study initiation (Figure 3(d) and (e)). In all studies in Periods 2 and 3 reporting data, participants had received a median of ≥10 years of ART or ≥10 different ARVs, or both. In the VIKING studies, participants had received a median of 14 ARVs over a median of 13 (VIKING-4) or 14 (VIKING-3) years.^23,24 Across both studies, the OBT included ≤2 fully active ARVs in 86% of participants and ≤1 fully active ARV in 46%. In TMB-301, participants had experience with a median of 10 ARVs and a high frequency of resistance to all ARVs in a class (24% for fusion inhibitors to 65% for NRTIs and NNRTIs).²⁶ In BRIGHTE, most participants had received ≥5 ARV regimens (85%) over >15 years of treatment (71%) with a correspondingly high frequency of ARV class exhaustion (in all ARV classes except INIs, >75% of participants had no remaining options).^28,96 Most participants in BRIGHTE had ≤1 fully active ARV in the OBT (58% of participants in the Randomized Cohort and all participants in the Non-randomized Cohort).^27,28 Notably, both TMB-301 and BRIGHTE specifically allowed use of other investigational ARVs for participants who had no other way to ensure at least one fully active ARV in the OBT.^26,27

Study design

Core ARVs assessed in the included studies are summarized in Table 1. Consistent with approval dates (Figure 2), PIs and NNRTIs were most frequently studied in Period 1, while Periods 2 and 3 feature more recent ARV classes such as second-generation INIs and different classes of entry inhibitors.

In Period 1, 15 (17%) studies used a fixed background therapy of protocol-specified ARVs, 33 (37%) used a selected background therapy, and 32 (36%) used an OBT selected by the investigator based on clinical history and resistance testing with minimal protocol-defined restrictions. Among 62 comparative studies in Period 1, 38 (61%) compared the study ARV(s) with another ARV or a different formulation or dose of the study ARV, 19 compared with placebo, and five compared with OBT alone (Table 1).

All five studies in Periods 2 and 3 used open-label treatment with the investigational ARV with an OBT (Tables 1 and 2). These studies are described in more detail in the next section.

Table 2.

Efficacy and safety data from phase 3 studies evaluating new ARVs.

Trial (N) [start date]^a,b	Study cohorts and treatment arms (n)	Primary endpoint^c	Long-term efficacy and safety^d
Trial (N) [start date]^a,b	Study cohorts and treatment arms (n)	Primary endpoint^c	Study week	VL <50 c/mL, %^d	MeanΔCD4 cells/mm³(n)^e	PDVF, %^f	SAEs, %	Deaths, %^g	ADE, %^g
Period 3
BRIGHTE (371) [2015]^27,28	Cohort 1 (RC): 1-2 FAA^hFTR + OBT (272)	Mean ΔVL (log₁₀ c/mL), D8^i,jFTR + FR (n = 203) −0.79PBO + FR (n = 69) −0.17	48/96	(S)54/60	139 (228)/205 (213)	18/23	31/34	7/8	10/10
BRIGHTE (371) [2015]^27,28	Cohort 2 (NRC): 0 FAA^hFTR + OBT (99)	NA	—	38/37	64 (83)/119 (65)	46/49	44/48	—	—
TMB-301 (40) [2015]²⁶	IBA + OBT (40)	% With ≥0.5 log₁₀ ↓VL (S)^i,kFR only D0 to D7 3%^l IBA + FR D7 to D14 83%	25	(S)43	62 (27)	25	23	10	10
Period 2
VIKING-4 (30) [2012]²⁴	DTG + OBT (30)	Mean ΔVL (log₁₀ c/mL), D8ⁱDTG + FR (n = 14) −1.06PBO + FR (n = 16) 0.10	48	(S)40	125 (21)^m	23	30	7	NR
VIKING-3 (183) [2011]^23,35	DTG + OBT (30)	Mean ΔVL (log₁₀ c/mL), D8^i,nDTG + FR −1.43% With VL <50 c/mL, Wk24DTG + OBT 69%	48	(S)63	110 (145)^m	NR	25	1	5
Period 1
GS-US-183-0145 (702) [2008]⁴¹	EVG QD + BT^o (351)RAL BID + BT^o (351)	VL <50 c/mL, Wk48 (T)59%^†58%^†	48	(T/S)59/6058/58	(NC = F)119^m127^m	2022	NR	10	NR
VICTOR-E3/E4 (721) [2007]¹⁴	VVC + OBT (486)PBO + OBT (235)	VL <50 c/mL, Wk4864%^‡62%^‡	48	(NC = F)6462	(NC = F)138129	NRNR	109	1	<1
BENCHMRK-1/2 (699) [2006]^20,97	RAL + OBT (462)PBO + OBT (237)	VL <400 c/mL, Wk1677.5%41.9%	48/156	(NC = F)62/5133/22	109 (439)/164 (396)48 (228)/63 (208)	NR/36NR	18/2919/23	2/4	4/5
M06-802 (599) [2006]⁵⁷	LPV/r QD + ≥2 NRTI (300)LPV/r BID + ≥2 NRTI (299)	VL <50 c/mL, Wk48 (T)55.3%^†51.8%^†	48	(T)55.351.8	135 (195)122 (193)	NRNR	NRNR	5	NR
DUET-1/2 (612/591) [2005]^{17,19,115,116}	ETR + BT^p (304/295)PBO + BT^p (308/296)	VL <50 c/mL, Wk24 (T)56%^§/62%39%^§/44%	48/96	(T)61/5740/36	(NC = F)98/12873/86	NRNR	20/2623/26	3/3	8/NR
TITAN (595) [2005]⁵⁸	DRV/r + OBT (298)LPV/r + OBT (297)	VL <400 c/mL, Wk4877%67%	48	(T)7160	(NC = F)8881	1022	910	1	1
TRIAD (74) [2005]⁷⁵	FPV/r standard dose (24)FPV/r high-dose (25)FPV/LPV/r (25)	AAUCMB VL (log₁₀ c/mL), Wk24^q−0.98^‡−1.00^‡−1.05^‡	24	(T)212420	124 (9)39 (18)21 (17)	636860	0816	0	1
MOTIVATE-1/2 (pooled) (1049) [2004]¹²	MVC QD + OBT (414)MVC BID + OBT (426)PBO + OBT (209)	Mean ΔVL (log₁₀ c/mL), Wk48−1.68−1.84−0.79*	48	(NC = F)434617	(LOCF)11612461	222354	182118	2	6
RESIST-1/2 (620/539) [2003]^21,22,117	TPV/r + OBTCPI/r + OBT	ΔVL ≥1.0 log₁₀ c/mL, Wk2441.5%/41.0%22.3%/14.9%	48	(NC = F)22.810.2	(LOCF)4521	1140	/100py33.735.8	/100py2.42.8	NR
BMS 045 (358) [2001]⁴⁶	ATV/r QD + BT^r (120)ATV + SQV QD + BT^r (115)LPV/r BID + BT^r (123)	TAD^s ΔVL (log₁₀ c/mL), Wk480.13 (mean ΔVL −1.93)^†0.33 (mean ΔVL −1.55)^‖Mean ΔVL −1.87	48	(NC = F)382646	(NS)11072121	NR	10129	<1	NR
TORO-1/2 (491/504) [2000]^{16,18,118,119}	ENF + OBT (326/335)OBT (165/169)	Mean ΔVL (log₁₀ c/mL), Wk24^t−1.70/−1.43−0.76/0.65	48	(NC = F)18.3/7.8	(LOCF)9145	5278	/100py3653	2	NR
CNA3002 (185) [1999]^39,u	ABC + SBG (92)PBO + SBG (93)	VL <400 c/mL, Wk1639%8%	16	(NC = F)202	(NC = F)^v301	NR	NR	NR	0
GS-99-907 (520) [1999]⁵²	TDF + SBG (368)PBO + SBG (184)	TWA ΔVL (log₁₀ c/mL), Wk24−0.61−0.03	24	(NC = M)221	(TWA)13−11	NR	NR	NR	NR

Δ, change from baseline; AAUCMB, average area under the curve minus baseline; ABC, abacavir; ADE, AIDS-defining event; ARV, antiretroviral; ATV, atazanavir; BID, twice daily; BT, background therapy (partially selected); c/mL, copies per mL; CPI, comparator protease inhibitor; cPSS, continuous phenotypic susceptibility score; DTG, dolutegravir; DRV, darunavir; EFV, efavirenz; ENF, enfuvirtide; ETR, etravirine; EVG, elvitegravir; FAA, fully active ARV; FDA, US Food and Drug Administration; FPV, fosamprenavir; FR, failing regimen; FTR, fostemsavir; IBA, ibalizumab; IV, intravenously; LOCF, last observation carried forward; LPV, lopinavir; MVC, maraviroc; NC = F, non-completer = failure; NC = M, non-completer = missing; NR, not reported; NRC, Non-randomized Cohort; NRTI, nucleoside reverse transcriptase inhibitor; NS, not specified; OBT, optimized background therapy; OR, optimized regimen; PBO, placebo; PDVF, protocol-defined virologic failure; py, patient-years; QD, once daily; r, ritonavir-boosted; RC, Randomized Cohort; SAE, serious adverse event; SBG, stable background therapy; SQV, saquinavir; TAD, time-averaged difference; TDF, tenofovir disoproxil fumarate; TPV, tipranavir; TLOVR, time to loss of virologic response; TWA, time-weighted average; VF, virologic failure; VL, viral load; VVC, vicriviroc. *Significant difference between treatment groups/periods, p < 0.001. ^†Met criteria for non-inferiority. ^‡Difference between treatment groups/periods not significant. ^§Significant difference between treatment groups/periods, p < 0.05. ^‖Did not meet criteria for non-inferiority.

^aFor parallel trials with identical study designs, pooled results are shown where available. N represents the intention-to-treat population.

^bYear in which participant enrolment started.

^cUnless otherwise indicated, virologic response endpoints are for the intention-to-treat population with NC = F. Where indicated, the FDA Snapshot algorithm (S) or the FDA TLOVR algorithm (T) were used. For BRIGHTE, the HIV-1 RNA cutoff was 40 c/mL.

^dResults are reported for Week 48 where available and the latest on-study time point for which published data were identified after Week 48. For parallel studies, results from the pooled analyses are shown.

^eResults of observed analysis unless otherwise indicated.

^fNote that definitions varied between studies. Definitions included the requirement for confirmation on repeat measure and criteria for incomplete response (<1 log₁₀ drop in HIV-1 RNA by Week 12 or 16), virologic rebound (HIV-1 RNA >200 or >400 c/mL after prior suppression and/or >1 log₁₀ increase in HIV-1 RNA above nadir), and lack of virologic suppression (HIV-1 RNA >200 or >400 c/mL at or after Week 24 or 48).

^gPresented for the total study population.

^hFAA status was based on current and historical resistance, tolerability, eligibility, and willingness to use ENF.

ⁱThese early primary endpoints measure virologic response during a limited period of functional monotherapy added to the failing ART regimen.

^jIn the RC, participants were randomized 3:1 to FTR or PBO for the first 8 days of study, then all participants received FTR + OBT after Day 8.

^kIBA was added to FR from Day 7.

^l1 participant initiated OBT prematurely during this period.

^mMedian (mean not reported).

ⁿThere was no comparator group for the primary endpoint for VIKING-3.

^oA fully active, ritonavir-boosted protease inhibitor and a second agent.

^pDRV/r + 2 NRTIs.

^qAAUCMB calculated using last AAUCMB carried forward analysis strategy.

^rTDF + 1 NRTI.

^sTAD through Week 48 between each study group and the LPV/r group.

^tCalculated using LOCF.

^uBased on publication date.

^vMedian change from baseline.

Efficacy and safety analysis of phase 3 trials

Twenty-three phase 3 trials evaluating new ARVs were included in the review of efficacy results (including six sets of parallel studies considered as single studies in this section; Table 2). Studies in Period 1 were superiority studies (n = 10) or non-inferiority studies (n = 3), comparing the investigational ARV with placebo (n = 6), an alternative standard-of-care ARV (n = 6), or OBT alone (n = 1; Table 2). Among the earliest seven studies, six used a measure of viral load change from baseline to Week 24 or 48 as the primary endpoint: GS-99-907,⁵² TORO-1/2,^16,18 BMS 045,⁴⁶ RESIST-1/2,^21,22 MOTIVATE-1/2,¹² and TRIAD.⁷⁵ Although most studies met their primary endpoint, rates of virologic response (HIV-1 RNA <50 copies/mL) at Weeks 16, 24, or 48 were consistently low (<50%; Table 2).

The primary endpoint for the remaining studies in Period 1 was virologic response (HIV-1 RNA <400 or <50 copies/mL) at Weeks 16, 24, or 48 (Table 2). These studies used a more consistent non-completer = failure approach to missing data, mostly applying FDA time to loss of virologic response (TLOVR) algorithm for calculating virologic response rates. The most recent study in this period, GS-US-183-0145 (elvitegravir), used both TLOVR and the more recently developed FDA Snapshot algorithm. Most of these studies met their primary endpoints, and rates of virologic response (HIV-1 RNA <50 copies/mL) at Week 48 were consistently higher than the earlier studies (all >50%).

The phase 3 studies in Periods 2 and 3 differed from those in Period 1 in that, after a short functional monotherapy phase with the investigational ARV added to failing regimen, participants received open-label treatment with the investigational agent plus OBT. The earliest of these studies, VIKING-3, had no placebo control during the monotherapy period; therefore, short-term antiviral activity attributable to dolutegravir could not be evaluated.²³ An additional phase 3 study, VIKING-4, was conducted to address this omission and included a randomized placebo control in the functional monotherapy phase.²⁴ In Period 3, the BRIGHTE study used the same placebo-controlled approach to assess short-term antiviral activity of fostemsavir.²⁷ TMB-301 used an alternative approach, measuring viral load change over 7 days of treatment with the failing ART regimen alone before initiating 7 days of functional monotherapy with ibalizumab and comparing changes in viral load over the two periods.²⁶ All three of these comparative studies met their primary endpoint and showed significant short-term antiviral activity. In all four Period 2 and 3 studies, rate of virologic response (HIV-1 RNA <40 or <50 copies/mL) after approximately 6 months of treatment with the investigational agent plus OBT was a secondary (or co-primary) endpoint, and in all cases, it was calculated using the FDA Snapshot algorithm with missing values counted as failures (Table 2). Virologic response rates at Week 48 were comparable to rates seen in the later studies in Period 1 (Table 2). One notable observation in BRIGHTE in Period 3 was that in the Randomized Cohort, there was a continuous increase in virologic response rates by Snapshot analysis in the ITT-E population from Week 24 (144/272 [53%]) through 96 (163/272 [60%]).^28,96 The inevitable discontinuations seen in any clinical trial, and particularly in trials involving participants with advanced disease, usually results in a gradual reduction in virologic response rates over time, as seen in the BENCHMRK trials where virologic response rates in the raltegravir group decreased from 62% at Week 16 to 57% at Week 96 and 51% at Week 156.⁹⁷ Another interesting finding from both BRIGHTE and VIKING-3 was that the association between virologic response rates and the susceptibility score of the OBT (i.e., the number of active agents in the OBT according to genotypic and phenotypic resistance testing) was much more apparent when only new (not previously used) ARVs were considered in the score.^23,96

Across all phase 3 studies evaluated, increases from baseline in CD4⁺ cell count showed a similar trend to that seen with virologic response rates, with participants in earlier studies showing smaller increases from baseline versus later studies (Table 2).

Safety results were largely comparable across studies in all periods (Table 2) and consistent with what would be expected in a treatment-experienced population who are more likely than treatment-naive or less treatment-experienced persons with HIV to be older and to have pre-existing comorbidities requiring concomitant therapies.^9,10,98 Serious AEs and deaths in these studies were often reported to be mostly attributable to complications of advanced HIV disease.

Discussion

For HTE persons, multidrug ARV resistance is just one of many barriers to effective viral suppression, including accumulated ARV toxicity, ageing, comorbidities, and polypharmacy.^7–10 This review showed a dramatic reduction in the number of studies conducted in HTE participants after 2010. This likely coincides with a focus on the development and testing of new ARVs designed to offer comparable efficacy with less toxicity, better tolerability, and greater dosing convenience, and there has been remarkable progress in these areas. However, new ARVs and strategies are still needed to provide a viable range of personalized treatment options to overcome the barriers faced by HTE individuals.

The definition and composition of the HTE population has changed dramatically since the introduction of cART. Available ARVs in the 1990s often had inadequate antiviral potency, low barriers to resistance, and poor tolerability. Hence, many persons with HIV experienced the sequential failure of several ARVs in a short space of time. Development of better ART regimens after 2000 has meant fewer individuals experiencing treatment failure but after longer periods of treatment and for more complex and diverse reasons. This is reflected in the studies reviewed; participants in more recent clinical studies tended to be older and to have longer durations of previous treatment with more ARVs. Consistent with longer duration of disease and multiple treatment failures, participants in more recent studies also tended to have lower baseline CD4⁺ cell counts, suggesting a more advanced disease.

When developing inclusion criteria for trials in HTE participants, careful balances must be struck: broad inclusion criteria allowing recruitment of a larger study population and including a heterogeneous mix of participants reflective of the real-world population versus more restrictive criteria enrolling a smaller but more standardized group of participants in whom results may be more easily interpreted. Early superiority and non-inferiority studies aimed to demonstrate superior or comparable reductions in viral load over 24 or 48 weeks relative to placebo or standard-of-care therapy (in line with contemporary FDA advice and knowledge about surrogate markers).⁹⁹ These studies needed participants with high baseline viral loads to allow a sufficient magnitude of HIV-1 RNA change to be seen before reaching unquantifiable levels and sufficient numbers of participants to provide adequate statistical power to demonstrate superiority or non-inferiority. Later studies used lower baseline viral load criteria to allow participants to benefit from new agents at the earliest stages of treatment failure. Long-term, placebo-controlled comparisons are no longer appropriate for assessing the efficacy of antiretrovirals in any setting because the continued use of suboptimal regimens increases the risk of emergent resistance and disease progression. Non-inferiority trials have also not generally been feasible in studies assessing new agents for HTE persons because extensive multidrug resistance means that each study participant requires a highly individualized OBT and, thus, there is currently no appropriate active control to use for defining a non-inferiority margin.⁹⁹ An alternative approach to assessing the antiviral potency of the investigational agent over a short time, without compromising benefits to study participants, has been to include a limited period, during which the investigational agent is added to the failing ART regimen, followed by an open-label period with an optimized background regimen. In TMB-301²⁶ (ibalizumab) and BRIGHTE²⁷ (fostemsavir), this period of “functional monotherapy” lasted for 1 week with a primary endpoint analysis before optimization of the background regimen. In TMB-301,²⁶ there was no placebo control for this period, thus the possibility of uncontrolled factors influencing changes in viral load cannot be excluded, particularly since there were only 40 participants in the study. It could be argued that the urgent need for new therapies for HTE persons at the time, and the potential difficulty of recruiting from a comparatively small subgroup, justifies a small single-arm design for a registrational trial; however, the need to confirm the efficacy and safety results of TMB-301 in a larger population remains. BRIGHTE,²⁷ which ran concurrently with TMB-301, did include a placebo group during the functional monotherapy period and also recruited a considerably larger study population. More recently, the capsid inhibitor lenacapavir has been approved on the basis of the results from the CAPELLA (NCT04150068) study, which included a longer 14-day placebo-controlled period, albeit in a small number of participants (N = 72).¹⁰⁰ The nucleoside analogue reverse transcriptase translocation inhibitor islatravir is also being evaluated (P019 Illuminate HTE, NCT04233216) using a similar design. This longer period is the maximum suggested in the FDA guidance and, while providing more information about the antiviral potency of the investigational agent, may also increase the risk of resistance.⁹⁹

The individualized OBT, used in the longer-term analysis period in the recent phase 3 studies, is more reflective of how new agents will be used in the real world and is needed to establish the safety and tolerability of new agents, which is particularly important in the HTE population. However, the use of multiple different OBT regimens complicates the longer-term analysis of efficacy. This complexity is further added to in CAPELLA by the transition from daily oral treatment with lenacapavir to 6-monthly subcutaneous treatment, with a secondary endpoint after just one injection (at Week 26).¹⁰⁰ In this case, longer-term follow-up may be needed to adequately determine the role of long-acting lenacapavir versus that of the OBT. Complete long-acting injectable treatment regimens could be particularly beneficial for some HTE persons who have faced problems with adherence; however, mixed treatment combinations of conventional oral agents and long-acting injectable agents may carry a high risk of resistance selection, particularly given the potential for a long pharmacokinetic tail with long-acting agents (up to 12 months or longer for lenacapavir). In this case, maximizing treatment adherence to all components of the regimen should continue to be a priority to minimize the development of resistance. Because of these added complications, we need to learn how to approach the analysis of complex data to better understand the correlates of response. This will involve collecting and recording the most complete clinical history possible for study participants, providing a foundation on which to build viable subgroup analyses to assess prognostic factors, and ensure the best chance of tailoring a successful OBT to the needs of each individual. The importance of historical data is highlighted in VIKING-3/4 and BRIGHTE, showing that consideration of historical ARV use improves the prognostic value of OBT susceptibility scores.^23,96 To ensure the statistically valid identification of prognostic markers, we will need data from sufficient numbers of patients to carry out meaningful subgroup and multivariate analyses. It is notable that both ibalizumab and lenacapavir have been approved on the basis of clinical studies with fewer than 100 participants (40 and 72 participants, respectively). Approval based on studies with few participants also raises the question of adequate safety monitoring; in these cases, diligent post-approval monitoring of AEs, including injection site reactions, will be crucial.

There are some limitations to this review. The literature search and identification of papers to include was susceptible to bias, particularly given the selective inclusion of trials that were considered to represent an advancement in study design but with single treatment arms or low participant numbers published before 2005. The focus on clinical trials may have further increased bias in the results, as real-world patient demographics are likely to differ from those in clinical trial settings. Inclusion of several studies that used single-arm designs, which may be necessary for HTE individuals, may limit interpretation of results. Interpretation is also limited because the review was not systematic, and results are descriptive, with no formal statistics to test observed trends.

With the approval of fostemsavir, ibalizumab, and lenacapavir, there are now several options for constructing effective combination regimens for the treatment of HTE people living with HIV, and more agents are in development (including islatravir, albuvirtide, maturation inhibitors, a variety of monoclonal antibodies, and others earlier in the pipeline). The design of clinical trials for new agents for this population is likely to continue to evolve, for example, with the use of factorial designs assessing two new agents simultaneously or, potentially, active comparators with established non-inferiority margins. Ongoing guidance and support from regulatory authorities, such as the FDA and European Medicines Agency, will be crucial to ensure an appropriate and standardized approach. As we move forward with developing effective new strategies for HTE persons, we need to look beyond just potent suppression of resistant virus to consider maximum adherence, a lack of DDIs, which should be essential in this population, a long-term safety profile that will not exacerbate comorbidities, and a high level of tolerability across a range of age groups and demographics. Ideally, future clinical trials should include endpoints that address these considerations, such as metabolic and immunologic biomarkers and measures of treatment adherence and quality of life.

Supplemental Material

Supplemental Material - The evolution of clinical study design in heavily treatment-experienced persons with HIV: A critical review

Supplemental Material for The evolution of clinical study design in heavily treatment-experienced persons with HIV: A critical review by Judith A Aberg, Anthony Mills, Santiago Moreno, Jill Slater, Manyu Prakash, and Andrew Clark in Antiviral Therapy

Footnotes

Acknowledgements

The authors would like to dedicate this manuscript to Charles Boucher, MD, PhD, who passed away on 26 February 2021, and to acknowledge his valuable contribution to the early stages of the literature review.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JAA has received grants from Atea, Emergent BioSolutions, Frontier Technologies, Gilead Sciences, GSK, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare, which were paid to her institution, and has participated in scientific advisory boards for GSK, Merck, and ViiV Healthcare. AM has received research funding from Gilead Sciences, ViiV Healthcare, Janssen, Merck, and Sangamo Therapeutics and has served on advisory boards for Gilead Sciences, ViiV Healthcare, Janssen, and Merck. SM has participated in speaking activities and received grants for research from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GSK, Janssen-Cilag, Merck, Pfizer, Roche, and Schering Plough. JS, MP, and AC are employees of ViiV Healthcare and own stock in GSK.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by ViiV Healthcare.

Data availability

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

ORCID iDs

Judith A Aberg

Manyu Prakash

Supplemental material

Supplemental material for this article is available online.

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