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Abstract

Fostemsavir, a prodrug of the first-in-class gp120-directed attachment inhibitor temsavir, is indicated in combination with other antiretrovirals for the treatment of multidrug-resistant HIV-1 in adults who are heavily treatment-experienced (HTE). Temsavir binds to HIV-1 gp120, close to the CD4 binding site, preventing the initial interaction of HIV-1 with CD4 on the host cell. Amino acid substitutions at four positions in gp120 have been identified as important determinants of viral susceptibility to temsavir (S375H/I/M/N/T/Y, M426L/P, M434I/K, M475I), with a fifth position (T202E) recently described. For most currently circulating group M HIV-1 subtypes, the prevalence of these resistance-associated polymorphisms (RAPs) is low. As with many other antiretrovirals, the impact of RAPs is modified by other changes in the target molecule. Different regions of gp120 interact to modify the temsavir binding pocket, with multiple amino acids playing a role in determining susceptibility. Extensive variability of HIV-1 gp120 means the susceptibility of clinical isolates to temsavir is also highly variable. Importantly, in vitro measurement of the susceptibility of clinical isolates to temsavir does not necessarily capture the range of susceptibilities of the heterogeneous mix of viruses generally present in each isolate. Due to these factors and limited phenotypic clinical data, thus far, no relevant phenotypic cutoff or genotypic algorithms have been derived that reliably predict response to fostemsavir-based therapy in individuals who are HTE; therefore, pre-treatment temsavir resistance testing may be of limited benefit. In the phase III BRIGHTE study, re-suppression after virologic failure was observed in some participants despite treatment-emergent genotypic and/or phenotypic evidence of reduced temsavir susceptibility, and substantial CD4+ T-cell count increases occurred even among participants with HIV-1 RNA ⩾40 copies/mL at Week 240. Clinical management of people who are HTE and experience virologic failure during treatment with fostemsavir-based regimens requires an individualized approach with consideration of potential benefits beyond virologic suppression.

Keywords

fostemsavir heavily treatment-experienced multidrug resistance

Introduction

Fostemsavir (Rukobia; ViiV Healthcare, Durham, NC), a prodrug of the first-in-class gp120-directed attachment inhibitor temsavir, is indicated for use in combination with other antiretrovirals (ARVs) for the treatment of multidrug-resistant HIV-1 in adults who are heavily treatment-experienced (HTE).^1–7 Temsavir binds to HIV-1 gp120, close to the CD4 binding site, locking the molecule into a “closed” conformational state that prevents the initial interaction of HIV-1 with the host CD4+ T cell and subsequent HIV-1 binding and entry.^8–11 With this unique mechanism of action, temsavir is active against both CCR5- and CXCR4-tropic viruses and shows no cross-resistance with other ARV classes, including other viral entry inhibitors, with the possible exception of context-dependent cross-resistance with ibalizumab.^12–16 The clinical efficacy and safety of fostemsavir have been demonstrated in a phase IIb study, in combination with raltegravir and tenofovir disoproxil fumarate (TDF), in adults who were treatment-experienced (AI438011),^4,6 and in a phase III study, in combination with optimized background therapy (OBT), in adults who were HTE with limited treatment options (BRIGHTE).^1–3,5,7 Results through Week 240 of the BRIGHTE study showed that fostemsavir 600 mg twice daily plus OBT resulted in durable virologic suppression and clinically meaningful improvements in CD4+ T-cell count and CD4+/CD8+ ratio in a population with advanced disease and multidrug-resistant HIV-1.²

People with HIV-1 who are HTE make up a heterogeneous population who often face multiple clinical and social challenges, including multidrug-resistant virus, cumulative drug toxicity, comorbidities, polypharmacy, and barriers to treatment adherence and retention in care.^17–23 With no consensus on the definition of HTE status, reports of prevalence range from 2% to 16%.^19–22 Treatment regimens for individuals who are HTE should optimally include well-tolerated ARVs with mechanisms of action distinct from previously existing classes and few drug–drug interactions.²³ The assessment of new ARV agents and/or strategies for this population is complicated by the range of individualized treatment needs and the lack of a standardized regimen to act as a control.¹⁷ This presents challenges in designing experiments with a placebo group and has resulted in variable and complex study designs that can be difficult to interpret.¹⁷ Nevertheless, as of January 2025, there are three first-in-class ARVs indicated for the treatment of multidrug-resistant HIV-1 in individuals who are HTE: fostemsavir (first approved in the United States in July 2020),²⁴ ibalizumab (a CD4-directed post-attachment inhibitor, first approved in the United States in March 2018),²⁵ and lenacapavir (an HIV-1 capsid inhibitor, first approved in the European Union in August 2022²⁶).²³ Constructing treatment regimens that incorporate these new classes of ARV requires an individualized approach with careful consideration of multiple factors to achieve maximum benefit. In a population in which there is already a high frequency of multidrug-resistant HIV-1, minimizing the risks and consequences of further drug resistance is an important consideration.²³

Specific amino acids at four HIV-1 gp120 positions surrounding the temsavir binding site (375, 426, 434, and 475) are the most important determinants of viral susceptibility to temsavir.^{1,7,9,13,14,27,28} Substitutions at gp120 amino acid positions 116(P), 202(E), and 204(D) have also been reported to have a measurable impact on susceptibility to temsavir, but these are extremely rare in the population.^14,16,29,30 For most currently circulating HIV-1 subtypes, the prevalence of resistance-associated amino acid polymorphisms (RAPs) at positions 375, 426, 434, and 475 is low (<10%), and most (~80%) clinical isolates from individuals naive to fostemsavir show a high degree of susceptibility to temsavir, with half-maximal inhibitory concentrations (IC₅₀s) of <10 nM.^7,29,31 The exceptions to this are group O viruses (consensus H375), group N viruses (consensus M375, L426, I434), and the circulating recombinant form CRF01_AE (consensus H375, I475), which show high levels of reduced susceptibility to temsavir.^14,29 The extensive variability of HIV-1 gp120 means that in vitro measurements of temsavir susceptibility vary widely among clinical isolates of HIV-1 both with and without RAPs or resistance-associated substitutions (RASs).^14,27,31,32 In this narrative review, we describe the mechanisms and context dependency of reduced susceptibility to temsavir and summarize available data on the emergence and potential consequences of genotypic and phenotypic changes in gp120 during treatment with fostemsavir in clinical trials.

Mechanisms of reduced susceptibility to temsavir

Temsavir mechanism of action

HIV-1 gp120, the target of temsavir, is a complex, heavily glycosylated protein crucial for the process of viral attachment and entry into host cells.^33–35 Situated on the viral surface, with highly conserved host protein binding sites that are exposed during the viral entry process, gp120 is a primary target for humoral immune responses. To avoid humoral responses, HIV has developed extensive variability in overall gp120 amino acid sequence and glycosylation patterns and a high degree of structural heterogeneity and conformational flexibility that masks conserved receptor-binding sites.^33–36 Because of this, gp120 can be a difficult molecule to target with ARVs.³⁵

Modeling and crystallographic studies suggest that temsavir binds to gp120 in a structurally conserved hydrophobic pocket below and on the opposite side of the β20-21 loop to that recognized by CD4 (Figure 1).^8,9 This binding acts to inhibit HIV-1 entry into host cells through two mechanisms of action: at higher concentrations, temsavir binding allosterically interferes with CD4 binding; at lower concentrations, temsavir binding stabilizes the molecule in a “closed” or “State 1” conformation that prevents the CD4-induced conformational rearrangements required for the next steps in the viral entry process.^8–10,33,37 These mechanisms prevent the initial interaction of gp120 with the host cell, thus inhibiting subsequent HIV-1 binding and entry.^8–10,37

Figure 1.

Chemical structures of (a) fostemsavir and (b) temsavir and homology models of (c) CD4 (protein data bank code 2NXY), in brown, and (d) temsavir (protein data bank code 5U7O), in magenta, bound to wild-type HIV-1 JR-FL gp120, in green, with annotation to show key amino acid positions. Models illustrate the distinct CD4 and temsavir binding sites on opposite sides of the β20-21 loop (in blue).^8,9,38

Amino acid substitutions associated with reduced susceptibility to temsavir

Extensive preclinical studies with temsavir and related experimental attachment inhibitors (BMS-378806 and BMS-488043), and genotypic and phenotypic analysis of clinical isolates of HIV-1 from multiple sources, including clinical trials of fostemsavir, initially identified four amino acid positions in conserved regions of HIV-1 gp120 that play an important role in reducing the susceptibility of the virus to temsavir: positions 375, 426, 434, and 475 (Table 1 and Figure 1).^{1,14,27,28,32,39,40} Amino acid substitutions L116P and A204D were also shown to decrease temsavir susceptibility in vitro; however, changes at these positions have not been observed in vivo in fostemsavir clinical studies, and both 116P and 204D are very rare among circulating subtypes of HIV-1 (only four and five of 10,733 full-length sequences, respectively, in the Los Alamos National Laboratory (LANL) HIV sequence database).^14,29,30 Based on these studies, the amino acid substitutions (relative to HIV-1 HXB2) S375H/I/M/N/T, M426L/P, M434I/K, and M475I were pre-specified for monitoring in the BRIGHTE study.^1,7,27 In an HIV-1 LAI background, most of these identified RAPs individually result in less than 100-fold reductions in susceptibility to temsavir, with double amino acid substitutions being required to achieve greater than 1000-fold reductions (Tables 1 and 2). Subsequently, S375Y was identified as a novel RAP present at baseline in two participants in BRIGHTE (although there are only 12 examples in the LANL database) and found to be associated with a substantial decrease in temsavir susceptibility when introduced into an HIV-1 LAI background.^1,2,27,30 After further analysis of data from BRIGHTE, the amino acid substitutions S375H/I/M/N/Y, M426L, and M434K were designated as “most relevant” based on their impact on temsavir susceptibility and/or association with an HIV-1 RNA reduction of <0.5 log₁₀ copies/mL from Day 1 to Day 8 of functional fostemsavir monotherapy (Table 1). More recently, gp120 amino acid position 202 has also been reported to have an impact on temsavir susceptibility. Although previous studies supported a lack of cross-resistance between temsavir and the CD4-directed post-attachment inhibitor ibalizumab,¹³ two envelope clones from the Monogram Biosciences collection have been identified that show reduced susceptibility to both agents.¹⁶ In one of these clones, 202E was shown to be a key substitution resulting in reduced susceptibility to temsavir and ibalizumab.¹⁶ Like 116P and 204D, 202E is rarely observed in clinical isolates of HIV-1, with only two examples in the 2022 version of the LANL database.³⁰

Table 1.

Impact of gp120 amino acid substitutions introduced by site-directed mutagenesis on in vitro susceptibility to temsavir of HIV-1 LAI (subtype B) in a cell–cell fusion assay and HIV-1 JR-FL in a pseudovirus assay.

Amino acid substitution^a	FC-IC₅₀		Frequency in LANL database 2022, %^d	Comments
Amino acid substitution^a	HIV-1 LAI^b	HIV-1 JR-FL^c	Frequency in LANL database 2022, %^d	Comments
L116P	>340	NR	<0.1	• Four in LANL database (no subtype B); selected during in vitro passage with temsavir but not seen in fostemsavir clinical studies^14,29
T202E	NR^e	NR	<0.1	• Two in LANL database (no subtype B); associated with reduced susceptibility to both temsavir (>400-fold) and ibalizumab in 1 cloned envelope from the Monogram Biosciences library¹⁶ • Emerged in an isolate from 1 (<1%) participant with PDVF^f in BRIGHTE¹⁶
A204D	⩾340	NR	<0.1	• Five in LANL database (no subtype B); selected during in vitro passage with temsavir but not seen in fostemsavir clinical studies^14,29
S375H*	48	890	14^g	• Associated with temsavir resistance in CRF01_AE¹⁴ • Emerged in isolates from 4 (3%) participants with PDVF in BRIGHTE²
S375I*	17	99	1.2	• Associated with reduced susceptibility to BMS-488043 in clinical isolates³² • Emerged in an isolate from 1 (<1%) participant with PDVF in BRIGHTE²
S375M*	47	12,551	1.2	• Associated with reduced susceptibility to temsavir in a clinical isolate from the phase IIa fostemsavir study^14,40 • Emerged in isolates from 4 (3%) participants with PDVF in BRIGHTE²
S375N*	1	25	1.5	• Associated with reduced susceptibility to BMS-488043 in clinical isolates³² • Associated (as part of a mixed population) with reduced susceptibility to temsavir in two isolates from participants meeting resistance testing criteria during treatment with fostemsavir + raltegravir + TDF in the phase IIb study^28,h • Emerged in isolates from 30 (23%) participants with PDVF in BRIGHTE²
S375T	1	NR	9.3	• Emerged in isolates from 5 (4%) participants with PDVF in BRIGHTE²
S375Y*	>10,000	NR	0.1	Twelve in LANL database (no subtype B); detected in isolates from two participants at baseline in BRIGHTE²⁷
M426L*	81	433	5.8	• Selected during in vitro passage with BMS-378806³⁹ and temsavir¹⁴ • Associated with reduced susceptibility to BMS-488043 in clinical isolates³² • Associated with a lack of virologic responseⁱ to fostemsavir monotherapy over 8 days in the phase IIa study⁴⁰ • Associated with reduced susceptibility to temsavir in five isolates from participants meeting resistance testing criteria during treatment with fostemsavir + raltegravir + TDF in the phase IIb study^28,h • Emerged in isolates from 36 (27%) participants with PDVF in BRIGHTE²
M426P	6	NR	<0.1	• Three in LANL database (no clade B); detected at baseline in an isolate from 1 participant in the phase IIb study, subsequently found to decrease temsavir susceptibility in HIV-1 LAI²⁸ • Not detected in any baseline or on-treatment samples in BRIGHTE²⁷
M426R	<1	NR	8.3	• Relatively common among HIV-1 B subtype isolates (22%) but not associated with reduced susceptibility to temsavir^28,29
M434I	11	4	9.5	• Selected during in vitro passage with BMS-378806³⁹ • Emerged in isolates from 9 (7%) participants with PDVF in BRIGHTE²
M434K*	NR	NR	<0.1	• Seven in LANL database (two from subtype B); associated with >20,000-fold reduced susceptibility to temsavir in an isolate from a participant meeting resistance testing criteria during treatment with fostemsavir + raltegravir + TDF in the phase IIb study^h; impact confirmed by SDM in a single clone²⁸ • Emerged in an isolate from 1 (<1%) participant with PDVF in BRIGHTE²
M434T	15	NR	0.4	• Emerged (as part of a mixed population) in an isolate from 1 (<1%) participant with PDVF in BRIGHTE²
M475I	5	70	11^g	• Selected during in vitro passage with BMS-378806³⁹ and temsavir^1,14 • Associated with lack of temsavir susceptibility in CRF01_AE isolates^1,14 • Emerged in isolates from 14 (11%) participants with PDVF in BRIGHTE²

Amino acid substitutions numbered according to the HIV-1 HXB2 reference sequence. In the phase III BRIGHTE study, substitutions shown in bold font were pre-specified for monitoring at all time points (S375Y was pre-specified for monitoring from Week 240), and substitutions marked with * were considered to be most relevant based on impact on temsavir susceptibility or association with an HIV-1 RNA reduction of <0.5 log₁₀ copies/mL from Day 1 to Day 8 of functional fostemsavir monotherapy in clinical studies.

Fold change in temsavir IC₅₀ between wild-type HIV-1 LAI reference virus and HIV-1 LAI with the single amino acid substitution indicated in the first column in a cell–cell fusion assay.^1,7,14,28

Fold change in temsavir IC₅₀ between wild-type HIV-1 JR-FL reference virus and HIV-1 JR-FL with the single amino acid substitution indicated in the first column in a pseudovirus assay.⁴¹

Frequency among 10,733 HIV-1 envelope sequences in the LANL HIV sequence database through December 31, 2022.³⁰

In a cloned envelope from the Monogram Biosciences library, E202 was associated with a >400-fold reduction in temsavir susceptibility compared with T202 in the same background.¹⁶

PDVF was defined as the following: before Week 24, confirmed (or last available before discontinuation) plasma HIV-1 RNA ⩾400 copies/mL after prior confirmed suppression to <400 copies/mL or >1 log₁₀ copies/mL increase in HIV-1 RNA at any time above nadir, where nadir is ⩾40 copies/mL; at or after Week 24, confirmed (or last available before discontinuation) HIV-1 RNA ⩾400 copies/mL.²

CRF01_AE sequences contributed most of the instances of 375H (72%; 1081/1511) and 475I (73%; 841/1152) in the LANL database.

29/66 fostemsavir-treated participants who met criteria for resistance testing had a temsavir susceptibility result, 13/29 had virus with a >3-fold increase in FC-IC₅₀ from baseline, and population gp120 sequencing was successful for 11/13 participants.²⁸

Virologic response was defined as a maximal decline in plasma HIV-1 RNA of ⩾1 log₁₀ copies/mL from Day 1 to Day 8.⁴⁰

FC, fold change; IC50, half-maximal inhibitory concentration; LANL, Los Alamos National Laboratory; NR, not reported; PDVF, protocol-defined virologic failure; SDM, site-directed mutagenesis; TDF, tenofovir disoproxil fumarate.

Table 2.

Impact of gp120 amino acid substitutions at positions 375, 426, 434, and 475 introduced by site-directed mutagenesis into two different viral envelope clones.

Amino acid substitution^a	FC-IC₅₀^b
Amino acid substitution^a	HIV-1 LAI^1,7,14,29	27-ENV-B-N4-25
S375H	48	1633
S375I	17	82
S375M	47	297
S375N	1	18
S375T	1	3
M426L	98	38
M434I	2	1
M475I	11	8
S375H + M426L	>20,000	>20,000
S375H + M434I	3391	4585
S375H + M475I	>16,937	1924
S375I + M426L	7376	1214
S375I + M434I	203	163
S375I + M475I	456	1029
S375M + M426L	>20,000	>20,000
S375M + M434I	841	502
S375M + M475I	4239	565
S375N + M426L	315	789
S375N + M434I	6	26
S375N + M475I	67	53
S375T + M426L	471	204
S375T + M434I	5	7
S375T + M475I	26	18
M426L + M434I	324	115
M426L + M475I	>20,000	220
M434I + M475I	91	30

Amino acid substitutions numbered according to the HIV-1 HXB2 reference sequence.

Fold change in temsavir IC₅₀ in a cell–cell fusion assay between wild-type reference virus and the same virus with the indicated amino acid substitution(s).

FC, fold change; IC₅₀, half-maximal inhibitory concentration.

The effects of amino acid substitutions at positions 375, 426, 434, and 475 on temsavir susceptibility are consistent with the proposed binding site and mechanism of action.^8–10 All four positions reside in or close to the modeled temsavir binding site.⁸ Leucine and isoleucine have branched side chains that are predicted to sterically reduce the size of the temsavir binding site at positions 426 and 475, respectively.^8,9 Although direct interactions between temsavir and S375 are minimal, bulky amino acid side chains at this position extend into the temsavir binding site and physically interfere with temsavir binding.¹⁰ Prévost et al.¹⁰ showed that in a subtype B HIV-1 envelope (JR-FL) the size of amino acid residue at position 375 correlated with the activity of temsavir in a single round neutralization assay; for the smallest amino acids (serine (S) or threonine (T)), temsavir IC₅₀s were <1 nM, while for the largest amino acids (phenylalanine (F), tyrosine (Y), histidine (H), or tryptophan (W)), IC₅₀s were >100 nM. M434 packs against the azaindole ring of temsavir bound to gp120, and the branched side chain of isoleucine at this position would require an alteration of the orientation of temsavir in the binding pocket.⁹ In a biophysical analysis, the affinity (equilibrium dissociation constant (K_D)) of temsavir for JR-FL gp120 molecules carrying RAPs (either alone: S375H/I/M/N, M426L, M434I, M475I, or in combination: S375H + M475I) varied from 0.7- to 74-fold compared with wild-type JR-FL gp120.⁴¹ There was a strong correlation between temsavir IC₅₀ in a pseudovirus assay and temsavir affinity and binding on-rate (r = −0.8940; p = 0.0011; Table 3). Importantly, for all tested gp120 molecules, temsavir was still able to completely block CD4 binding in a competition assay (at concentrations of 20 × K_D for M434I, S375H, S375M, S375N, and S375H + M475I or 40 × K_D for M426L, M475I, and S375I).⁴¹ Amino acid position 202 is also located next to the temsavir binding site in gp120 and a glutamic acid (E) at this site likely sterically hinders temsavir binding.¹⁶ Ionic interactions may also play a role since the virus carrying gp120 202K (lysine), a positively charged amino acid with a longer side chain than the negatively charged glutamic acid, retains susceptibility to temsavir.¹⁶

Table 3.

Comparison of the on-rate (k_a) of temsavir binding to gp120 carrying the indicated amino acid substitutions versus temsavir IC₅₀ for pseudotyped viruses with the same amino acid substitutions.⁴¹

Substitution	Mean antiviral IC₅₀, nM	k_a of temsavir binding, M⁻¹ s⁻¹
Wild-type (JR-FL)	0.19	61,000
M426L	86.7	15,000
M434I	0.8	129,000
M475I	14.0	22,000
S375H	178	11,000
S375M	2510	12,000
S375N	5.1	31,000
S375I	19.8	16,000
S375H + M475I	5945	6000

IC₅₀, half-maximal inhibitory concentration.

Given that temsavir binds to gp120 in a conserved region close to the CD4 binding site, it might be expected that amino acid substitutions that impact temsavir binding could also impact virus infectivity or “fitness.” Indeed, as previously noted, the substitutions that have the greatest individual impact on temsavir susceptibility in vitro (>100-fold, L116P, T202E, A204D, S375Y, and M434K) are all extremely rare (⩽0.1% in the LANL HIV sequence database) and have infrequently been observed in fostemsavir clinical studies.^2,29 In BRIGHTE, there have been no reports of L116P or A204D, one case each of T202E and M434K, and two cases of S375Y.

Context dependency of temsavir susceptibility

While the key amino acids described above clearly result in measurable reductions in temsavir susceptibility, their impact in clinical isolates is highly variable. This suggests that the effects of changes at these positions are highly dependent on other polymorphisms in the HIV envelope (the envelope context), in which they occur, as has been described for neutralizing antibodies.^16,31,42

When RAPs at positions 375, 426, 434, and 475 were introduced by site-directed mutagenesis into two different viral envelope clones (the subtype B laboratory strain LAI and an envelope derived from a subtype B clinical isolate from a participant in the phase IIa clinical study), several of the inserted amino acid substitutions had different effects on temsavir susceptibility in the two envelopes (Table 2; M. Gartland, personal communication). This was true for single substitutions (S375H/I/M/N) and double substitutions (S375M + M475I, M426L + M475I). Even within single clinical isolates (derived from participants in the phase IIa fostemsavir study), multiple clones, all carrying the same RASs in gp120, had in vitro temsavir susceptibilities spanning a 2- to 3-log range (Figure 2).¹⁴ For example, 12 functional clones from participant 12, each containing S375H, had fold change (FC)-IC₅₀s ranging from 7 to 1138, while the population assay gave a FC-IC₅₀ of 19. Similar results were seen for participant 21, where all 30 clones contained M426L. Even for viruses with high (participant 27) or low (participant 16) levels of temsavir susceptibility, there was a wide range of FC-IC₅₀s seen across multiple clones.¹⁴

Figure 2.

Variability of in vitro susceptibility to temsavir among individual clones from the same clinical isolate population with the same key amino acid substitutions. Clinical isolates were derived from participants at baseline in the phase IIa fostemsavir clinical study.

In an investigation into the correlates of temsavir resistance in subtype CRF01_AE (which carries naturally occurring, conserved H375 and I475), wide ranges of in vitro temsavir susceptibility within groups of clinical isolates of various subtypes based on the amino acid at position 375 were observed (Figure 3(a)).¹⁰ Furthermore, introducing an H375S into CRF01_AE viruses did not completely restore temsavir susceptibility and, in addition to I475, amino acids at five other co-evolved positions within the inner gp120 domain layers (H61, Q105, V108, N474, and K476) were found to be involved in the observed lack of susceptibility to temsavir in CRF01_AE viruses. Further structure–function analyses showed that the temsavir binding pocket in gp120 is shaped by cooperation between distal regions of gp120 and that temsavir is able to adjust its conformation in the binding pocket to accommodate minor changes in Env conformation.

Figure 3.

Variability of in vitro susceptibility to temsavir among different clinical isolates of HIV-1 (N = 208 biologically independent viral strains) grouped by (a) identity of the polymorphic residue at position 375 of gp120 and (b) virus subtype. Horizontal lines indicate median IC₅₀, dotted line indicates maximum detectable IC₅₀, % coverage indicates percentage of tested isolates with measurable IC₅₀ within detectable range.

Another element to consider for context dependency of temsavir susceptibility is glycosylation. Potential N-linked glycosylation sites in gp120 have been shown to play a role in reduced susceptibility to the CD4-directed post-attachment inhibitor ibalizumab.^16,43 In studies assessing the impact of gp120 202E on reduced susceptibility to temsavir and ibalizumab, loss of a highly conserved N-linked glycosylation site close to position 202, through the introduction of the substitution N197D, resulted in complete restoration of susceptibility to ibalizumab and partial restoration of susceptibility to temsavir.¹⁶

Virologic failure in clinical studies of fostemsavir

Phase IIb study

In the phase IIb study (NCT01384734) in adults with HIV-1 who were treatment-experienced, fostemsavir at doses of 400 mg twice daily, 800 mg twice daily, 600 mg once daily, or 1200 mg once daily was well tolerated and resulted in similar antiviral efficacy and immunologic responses relative to the active comparator, ritonavir-boosted atazanavir (both in combination with raltegravir and TDF), through Weeks 24 and 48.^4,6,28 Eligibility criteria for this study included a clinical isolate temsavir IC₅₀ of <100 nM at baseline; nevertheless, amino acid polymorphisms at positions 375, 426, 434, or 475 were detected at baseline in 42% of participants in the fostemsavir group.^4,28 There was no correlation between the presence of these baseline polymorphisms and meeting on-treatment resistance testing criteria through Week 48.²⁸ Among 66 participants in the fostemsavir group who met criteria for resistance testing, 29 had a successful temsavir susceptibility result (using the PhenoSense^® Entry assay, Monogram Biosciences, South San Francisco, CA, USA), and for 13/29, there was a >3-fold increase in FC-IC₅₀ from baseline.²⁸ Population sequencing of gp120 was successful for samples from 11 of these 13 participants, 7 of which showed emergent changes at positions 375, 426, or 434, most commonly M426L (n = 5).²⁸ Emergence of reduced susceptibility to temsavir did not preclude re-suppression; among 13 participants for whom decreased susceptibility to temsavir was detected during treatment, five achieved re-suppression to HIV-1 RNA <50 copies/mL during the study, regardless of S375S/N and M426L substitutions.²⁸

Phase III BRIGHTE study

In the ongoing phase III BRIGHTE study (NCT02362503), fostemsavir 600 mg twice daily plus OBT has been well tolerated and has demonstrated durable virologic and immunologic responses through 240 weeks of treatment in adults who were HTE with advanced disease and limited treatment options (⩽2 non-investigational ARVs available).^2,3,5 BRIGHTE enrolled participants in two cohorts: a Randomized Cohort (RC) of participants with one or two fully active ARVs that could be included in the OBT, and a compassionate-use Non-randomized Cohort (NRC) of participants who had no remaining fully active approved ARVs at the beginning of the study. At baseline, most participants (85%; 316/371) had received at least five prior ARV regimens, 86% (320/371) had a history of AIDS, and 30% (112/371) had CD4+ T-cell count <20 cells/mm³.⁴⁴

The presence of RAPs at baseline may explain some of the differences in virologic response in the BRIGHTE study. In a subset of participants without evidence of any residual activity from their failing regimen, the baseline presence of at least one RAP designated as “most relevant” (S375H/I/M/N/Y, M426L, M434K) was significantly associated with lower odds of a Day 8 virologic response (>0.5 log₁₀ copies/mL decrease in HIV-1 RNA).⁴⁵ At Week 192, 53% (145/272) of participants in the RC achieved Snapshot virologic response, and the presence of at least one “most relevant” RAP was associated with significantly lower odds of virologic response.⁴⁶

Rates of protocol-defined virologic failure (PDVF) through Weeks 96 and 240 were as expected in this population with multidrug-resistant HIV-1: 23% (63/272) and 29% (80/272), respectively, in the RC and 49% (49/99) and 54% (53/99), respectively, in the NRC.^2,27 Protocol-defined virologic failure was most frequent among participants with baseline CD4+ T-cell count <20 cells/mm³ and a history of AIDS (Table 4).² Among the 133 participants with PDVF through Week 240, 122 had available population genotypic and phenotypic temsavir susceptibility results.² Pre-specified RASs were emergent in samples from 52% (n = 63) of participants, with S375N or M426L being the most frequent (Table 5). In most cases (89%; 56/63), emergent pre-specified RASs were associated with a >3-fold reduction in in vitro temsavir susceptibility relative to the baseline sample. There were also nine cases of a >3-fold reduction in temsavir susceptibility in the absence of detectable emergent pre-specified RASs. Thus, 59% (72/122) of participants with PDVF had detectable genotypic or phenotypic evidence of a change in temsavir susceptibility from baseline. Notably, like the phase IIb study, these emergent changes did not preclude virologic re-suppression. Among 75 participants with treatment-emergent RASs or >3-fold change in temsavir susceptibility who remained in the study after PDVF, 20% (n = 15) had HIV-1 RNA <40 copies/mL, seven of whom had no changes to their OBT regimen. Importantly, substantial increases in CD4+ T-cell count were observed even among study participants with HIV-1 RNA ⩾40 copies/mL at Week 240 (mean increase, 251 cells/mm³).²

Table 4.

Incidence of PDVF by baseline characteristics through Week 240.²

Category, n/N (%)	Randomized Cohort (N = 272)	Non-randomized Cohort (N = 99)
Baseline HIV-1 RNA, copies/mL
<400	4/21 (19)	2/5 (40)
400 to <1000	2/10 (20)	0/4 (0)
1000 to 10,000	8/44 (18)	12/24 (50)
10,000 to <30,000	10/42 (24)	13/25 (52)
30,000 to <100,000	20/75 (27)	18/26 (69)
100,000 to <500,000	23/59 (39)	7/13 (54)
⩾500,000	13/21 (62)	1/2 (50)
Baseline CD4+ T-cell count, cells/mm³
<20	29/72 (40)	27/40 (68)
20 to <50	8/25 (32)	6/14 (43)
50 to <100	12/39 (31)	6/14 (43)
100 to <200	20/63 (32)	4/11 (36)
200 to <350	8/44 (18)	10/15 (67)
350 to <500	1/14 (7)	0/3 (0)
⩾500	2/15 (13)	0/2 (0)
History of AIDS
Yes	77/231 (33)	50/89 (56)
No	3/41 (7)	3/10 (30)

PDVF, protocol-defined virologic failure (before Week 24: confirmed (or last available before discontinuation) plasma HIV-1 RNA ⩾400 copies/mL after prior confirmed suppression to <400 copies/mL or >1 log₁₀ copies/mL increase in HIV-1 RNA at any time above nadir, where nadir is ⩾40 copies/mL; at or after Week 24: confirmed (or last available before discontinuation) HIV-1 RNA ⩾400 copies/mL).

Table 5.

Summary of emergent genotypic changes resulting in amino acid substitutions of interest in gp120 (PDVF population through Week 240).^2,a

n (%)	Randomized Cohort (N = 80)	Non-randomized Cohort (N = 53)	Total (N = 133)
Sequenced	71 (89)	51 (96)	122 (92)
Pre-specified substitutions^b,c	30 (42)	33 (65)	63 (52)
Most relevant substitutions^b,d	24 (34)	32 (63)	56 (46)
S375	17 (24)	21 (41)	38 (31)
S375H	0	1 (2)	1 (<1)
S375H/N	1 (1)	1 (2)	2 (2)
S375M	0	3 (6)	3 (2)
S375N	8 (11)	8 (16)	16 (13)
S375N/T	1 (1)	2 (4)	3 (2)
S375S/H	1 (1)	0	1 (<1)
S375S/I	0	1 (2)	1 (<1)
S375S/M/T	1 (1)	0	1 (<1)
S375S/N	4 (6)	5 (10)	9 (7)
S375S/T	1 (1)	0	1 (<1)
M426	16 (23)	20 (39)	36 (30)
M426L	10 (14)	13 (25)	23 (19)
M426M/L	6 (8)	7 (14)	13 (11)
M434	6 (8)	4 (8)	10 (8)
M434I	1 (1)	1 (2)	2 (2)
M434K	1 (1)	0	1 (<1)
M434M/I	3 (4)	3 (6)	6 (5)
M434M/I/T	1 (1)	0	1 (<1)
M475	8 (11)	6 (12)	14 (11)
M475I	4 (6)	2 (4)	6 (5)
M475M/I	4 (6)	4 (8)	8 (7)

Sequencing results at additional on-treatment time points around the time of PDVF are included where available (not limited to only the PDVF time point).

Denominator for proportions with substitutions is the number sequenced for each cohort and overall.

S375H/I/M/N/T, M426L, M434I/K, M475I.

S375H/I/M/N/Y, M426L, M434K.

PDVF, protocol-defined virologic failure (before Week 24: confirmed (or last available before discontinuation) plasma HIV-1 RNA ⩾400 copies/mL after prior confirmed suppression to <400 copies/mL or >1 log10 copies/mL increase in HIV-1 RNA at any time above nadir, where nadir is ⩾40 copies/mL; at or after Week 24: confirmed (or last available before discontinuation) HIV-1 RNA ⩾400 copies/mL).²

Polymorphisms and temsavir susceptibility in global clinical isolates

Data from the BRIGHTE study, in which most participants had HIV-1 subtype B, show that high in vitro temsavir FC-IC₅₀s and/or RAPs at baseline in some cases did not preclude a virologic response to treatment with fostemsavir-based regimens.²⁹ This may in part be due to the relatively high 600-mg twice-daily fostemsavir dose, which was selected based on exposure-response modeling that incorporated the variability in temsavir pharmacokinetics and baseline protein binding–adjusted temsavir IC₅₀ observed in the phase IIa and IIb studies.³ Nevertheless, it is important to be aware of natural variations in temsavir susceptibility and prevalence of RAPs that could affect the efficacy of fostemsavir in the global population with HIV-1.²⁹

Wide variability in susceptibility to temsavir has been observed overall and within subtypes (Figures 3(b) and 4). In an analysis of 1337 individual envelopes tested using the PhenoSense Entry assay, IC₅₀s ranged from 0.018 to >5000 nM (Figure 4).³¹ Overall, median and geometric mean temsavir IC₅₀s were 0.8 and 1.7 nM, respectively, and IC₅₀s were <10 nM for 80% of isolates and >100 nM for 9% of isolates. IC₅₀s were <10 nM for most subtype B isolates (84%), with 6% having IC₅₀s >100 nM. Subtypes BF, F1, and BF1 had higher proportions (21%–38%) of isolates with IC₅₀s >100 nM, and 5 of 5 (100%) CRF01_AE isolates had IC₅₀s >100 nM.

Figure 4.

Range of temsavir susceptibility observed within subtypes. Viruses with >5 isolates grouped by subtype. Horizontal solid lines indicate geometric mean. Symbols on dotted horizontal line had IC₅₀s above the highest concentration tested.

In a genotypic analysis of 10,733 full-length gp160 sequences from all available isolates in the LANL HIV sequence database (through December 31, 2022), the most prevalent amino acids at relevant positions were the same as those seen in the subtype B consensus (S375, 72%; M426, 83%; M434, 88%; M475, 89%; Table 6).³⁰ The only amino acid polymorphism at these positions in ⩾10% of subtype B isolates was S375T (19% of isolates), which does not play a major role in determining temsavir susceptibility in vitro.^14,28,30 S375H (99%) and M475I (77%) were predominant in subtype CRF01_AE. Among non-M HIV-1 groups, the consensus for group N isolates (N = 16) was 375M, 426L, and 434I, and 80 of 82 group O isolates carried S375H (in 10 cases in combination with M434I).³⁰ The impact of these amino acids on temsavir susceptibility in a group N or O background has not been confirmed; however, it seems likely that the efficacy of fostemsavir would be reduced in these viruses. The results from this analysis are consistent with other studies assessing the frequency of amino acid polymorphisms at positions 375, 426, 434, and 475 in clinical isolates of HIV-1.^29,47–50 No major differences were reported in the distribution of RAPs or in vitro susceptibility to temsavir between isolates from individuals naive to ARVs or with prior ARV experience, or between CXCR4- and CCR5-tropic isolates.^47–51

Table 6.

Frequencies of relevant gp160 amino acid polymorphisms^a at positions 375, 426, 434, and 475 in the LANL HIV sequence database.^30,b

Polymorphisms, n (%)			Subtypes
Position	AA	All isolates(N = 10,733)	B(N = 3583)	C(N = 1937)	CRF01_AE(N = 1097)	A1(N = 355)	CRF02_AG(N = 274)
S375	S	7733 (72)	2668 (74)	1764 (91)	7 (0.6)	329 (93)	245 (89)
	H	1511 (14)	20 (0.6)	3 (0.2)	1081 (99)	0	0
	T^c	995 (9.3)	664 (19)	91 (4.7)	0	16 (4.5)	15 (5.5)
	N	159 (1.5)	115 (3.2)	14 (0.7)	1 (<0.1)	0	0
	I	125 (1.2)	63 (1.8)	27 (1.4)	0	0	4 (1.5)
	M	125 (1.2)	32 (0.9)	18 (0.9)	0	9 (2.5)	9 (3.3)
	Y	12 (0.1)	0	1 (<0.1)	4 (0.4)	0	0
M426	M	8932 (83)	2419 (68)	1811 (93)	1052 (96)	323 (91)	260 (95)
	L	626 (5.8)	300 (8.4)	83 (4.3)	37 (3.4)	9 (2.5)	10 (3.6)
	P	3 (<0.1)	0	0	0	0	0
M434	M	9487 (88)	3361 (94)	1634 (84)	1043 (95)	225 (63)	227 (83)
	I	1018 (9.5)	181 (5.1)	272 (14)	45 (4.1)	122 (34)	46 (17)
	K	7 (<0.1)	2 (<0.1)	0	2 (0.2)	0	0
M475	M	9514 (89)	3537 (99)	1916 (99)	232 (21)	345 (97)	270 (99)
	I	1152 (11)	42 (1.2)	13 (0.7)	841 (77)	7 (2.0)	3 (1.1)

The top row for all amino acid positions shows the reference HXB2 sequence.

S375H/I/M/N/T/Y, M426L/P, M434I/K, M475I.

LANL database entries through December 31, 2022. Accessed August 23, 2024.

S375T has no measurable effect on in vitro temsavir susceptibility in an LAI *S375T background.

AA, amino acid; LANL, Los Alamos National Laboratory.

Clinical response to fostemsavir in study participants with subtype CRF01_AE

As described above, HIV-1 subtype CRF01_AE, which is predominant in Southeast Asia but uncommon elsewhere, shows considerably reduced susceptibility to temsavir in vitro. The RC of the BRIGHTE study included two participants with CRF01_AE virus.^1,7 The baseline virus isolate for the first participant had a temsavir FC-IC₅₀ of 298 along with a gp120 S375N substitution. This participant had HIV-1 RNA <40 copies/mL at Week 96 while receiving fostemsavir in combination with an OBT that included twice-daily dolutegravir. The baseline isolate for the second participant had a temsavir FC-IC₅₀ of >4747 and gp120 S375H and M475I substitutions. This participant had an increase in HIV-1 RNA (0.473 log₁₀ copies/mL) after 8 days of fostemsavir monotherapy but subsequently achieved HIV-1 RNA <40 copies/mL at Week 96 with fostemsavir plus OBT that included dolutegravir. It is not clear to what degree fostemsavir contributed to response in these individuals.

Discussion

The in vitro and clinical trial data described here are consistent in terms of (1) the wide ranges of in vitro temsavir susceptibility seen across clinical isolates of HIV-1, between different isolates of the same subtype, and between different individual clones from the same isolate^9,10,14,31; (2) the occurrence of some cases of PDVF in the absence of detectable changes in in vitro temsavir susceptibility or emergent relevant amino acid substitutions^2,27; (3) detectable treatment-emergent changes in in vitro temsavir susceptibility in the absence of detectable known RASs^2,27; and (4) re-suppression after virologic failure in some participants who were HTE despite treatment-emergent genotypic and/or phenotypic evidence of reduced temsavir susceptibility.^2,28 These observations highlight the complexity of accurately quantifying the role of gp120 mutations in cases of virologic failure during treatment with fostemsavir-based regimens in people with HIV-1 who are HTE.

Prior observations have shown that the impact of genotypic changes in gp120 on in vitro temsavir susceptibility is highly contextual, that different regions of the gp120 molecule interact to modify the temsavir binding pocket such that multiple amino acid substitutions play a role in determining susceptibility,¹⁰ that variation in N-linked glycosylation sites could also impact temsavir susceptibility,¹⁶ and that our current tools for measurement of the susceptibility of clinical isolates to temsavir do not capture the range of susceptibilities of the multiple different viruses present in the isolate.¹⁴ Furthermore, binding studies show that temsavir can still inhibit the binding of CD4 to gp120 even in the presence of RAPs that have an impact on the in vitro temsavir susceptibility of pseudoviruses.⁴¹ As a consequence of the large variability, limited clinical data, and context dependency of temsavir susceptibility, to date, no clinically relevant phenotypic cutoff or genotypic algorithms have been derived that reliably predict response to fostemsavir-based therapy in the HTE population; thus, pre-treatment resistance testing may currently offer limited value and is not stipulated in the product label.^1,52 Given the marked reduction in susceptibility to temsavir among non-M HIV-1 groups and HIV-1 subtype CRF01_AE viruses, the European Medicines Agency product label advises against the use of fostemsavir to treat these strains, and the US label notes reduced in vitro antiviral activity.^1,7 Due to the reduced susceptibility of CRF01_AE and the absence of an available resistance assay, the role of fostemsavir is limited in areas of the world where CRF01_AE is the prevalent strain, including Southeast Asia. For all other subtypes, there are currently no commercially available temsavir resistance tests,²³ and most online genotype interpretation tools do not provide updates that include the latest fostemsavir data.^53–56 However, the HIV-GRADE online tool does provide an interpretation of env sequencing results based on an algorithm developed using multiple regularly updated data sources.⁵⁷ The current version of this interpretation may overestimate temsavir resistance and should be considered in the context of the potential activity of other ARVs that could be included in the regimen. In any case, guidelines encourage clinicians to consult with specialists in HIV drug resistance when interpreting genotypic test results and designing optimal ARV regimens.²³

The potential clinical benefits of fostemsavir therapy beyond virologic suppression should also be considered, particularly with regard to immunologic recovery. Guidelines recommend that, in the face of extensive ARV resistance, ongoing regimens should be designed to maintain CD4+ T-cell count, delay clinical progression, and minimize toxicity.²³ In BRIGHTE, fostemsavir plus OBT resulted in steady and substantial increases in CD4+ T-cell count and CD4+/CD8+ ratio through 240 weeks in both study cohorts, achieving levels that might not have been expected in participants with such advanced disease. Notably, the largest increases were seen among participants who were the most immunosuppressed at baseline, and substantial increases were seen in those who had Week 240 HIV-1 RNA ⩾40 copies/mL.^2,5

Management of detectable virologic failure during treatment with fostemsavir will require a holistic approach, assessing not just viral load but also immunologic responses, pharmacokinetics, concomitant medications, tolerability, and resistance to other components in the regimen. In the absence of available options to construct a completely new regimen, there may be other changes that could be implemented, for example, improving treatment adherence or reducing drug–drug interactions.²³

Further analyses of long-term results and correlates of response in the ongoing BRIGHTE study, new data from the ongoing phase I/II SHIELD study (NCT04648280, fostemsavir in children and adolescents), and emerging data from real-world HTE cohorts⁵⁸ may yield further valuable information on the mechanisms and consequences of temsavir resistance and on the potential breadth of clinical benefits of fostemsavir.

Conclusion

The mechanisms of reduced susceptibility to temsavir are complex and highly context-dependent, currently precluding definitions of clinically relevant genotypic and phenotypic cutoffs. Despite this, many individuals show potent virologic response to fostemsavir-based regimens without baseline resistance testing,⁵ and findings from clinical trials show that individuals who experience PDVF and emergent RASs can later re-suppress on fostemsavir.^2,28 Furthermore, the unique mode of action of temsavir targeting gp120 before CD4 binding may provide clinical benefit beyond virologic suppression. Considerable and steady immunologic improvements through Week 240 were observed in the BRIGHTE study, even among individuals with viremia.² Thus, an individualized and holistic approach to the clinical management of people who are HTE and experience virologic failure during treatment with fostemsavir-based regimens is encouraged.

Footnotes

Acknowledgements

Editorial assistance was provided under the direction of the authors by Esther Race, PhD, Race Editorial Ltd, and Jennifer Rossi, MA, ELS, MedThink SciCom, and funded by ViiV Healthcare.

Declarations

ORCID iD

Jose R. Castillo-Mancilla

References

ViiV Healthcare. Rukobia (US prescribing information). Durham, NC: ViiV Healthcare, 2024.

Aberg

Shepherd

Wang

, et al. Week 240 efficacy and safety of fostemsavir plus optimized background therapy in heavily treatment-experienced adults with HIV-1. Infect Dis Ther 2023; 12: 2321–2335.

Kozal

Aberg

Pialoux

, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med 2020; 382: 1232–1243.

Lalezari

Latiff

Brinson

, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. Lancet HIV 2015; 2: e427–e437.

Lataillade

Lalezari

Kozal

, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study. Lancet HIV 2020; 7: e740–e751.

Thompson

Lalezari

Kaplan

, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviral-experienced subjects: week 48 analysis of AI438011, a phase IIb, randomized controlled trial. Antivir Ther 2017; 22: 215–223.

ViiV Healthcare BV. Rukobia (EU summary of product characteristics). Amersfoort, Netherlands: ViiV Healthcare BV, 2023.

Langley

Kimura

Sivaprakasam

, et al. Homology models of the HIV-1 attachment inhibitor BMS-626529 bound to gp120 suggest a unique mechanism of action. Proteins 2015; 83: 331–350.

Pancera

Lai

Y-T

Bylund

, et al. Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529. Nat Chem Biol 2017; 13: 1115–1122.

10.

Prévost

Chen

Zhou

, et al. Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir. Nat Commun 2023; 14: 6710.

11.

Meanwell

Krystal

Nowicka-Sans

, et al. Inhibitors of HIV-1 attachment: the discovery and development of temsavir and its prodrug fostemsavir. J Med Chem 2018; 61: 62–80.

12.

Zhou

Sun

, et al. Activity of the HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068, against CD4-independent viruses and HIV-1 envelopes resistant to other entry inhibitors. Antimicrob Agents Chemother 2013; 57: 4172–4180.

13.

Rose

Gartland

, et al. Clinical evidence for a lack of cross-resistance between temsavir and ibalizumab or maraviroc. AIDS 2022; 36: 11–18.

14.

Zhou

Nowicka-Sans

McAuliffe

, et al. Genotypic correlates of susceptibility to HIV-1 attachment inhibitor BMS-626529, the active agent of the prodrug BMS-663068. J Antimicrob Chemother 2014; 69: 573–581.

15.

Nowicka-Sans

Gong

Y-F

McAuliffe

, et al. In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068. Antimicrob Agents Chemother 2012; 56: 3498–3507.

16.

Gartland

Stewart

Zhou

, et al. Characterization of clinical envelopes with lack of sensitivity to the HIV-1 inhibitors temsavir and ibalizumab. Antiviral Res 2024; 228: 105957.

17.

Aberg

Mills

Moreno

, et al. The evolution of clinical study design in heavily treatment-experienced persons with HIV: a critical review. Antivir Ther 2023; 28: 13596535231174774.

18.

Cutrell

Jodlowski

Bedimo

The management of treatment-experienced HIV patients (including virologic failure and switches). Ther Adv Infect Dis 2020; 7: 2049936120901395.

19.

Pelchen-Matthews

Borges

ÁH

Reekie

, et al. Prevalence and outcomes for heavily treatment-experienced individuals living with human immunodeficiency virus in a European cohort. J Acquir Immune Defic Syndr 2021; 87: 806–817.

20.

Hsu

Fusco

Henegar

, et al. Heavily treatment-experienced people living with HIV in the OPERA^® cohort: population characteristics and clinical outcomes. BMC Infect Dis 2023; 23: 91.

21.

Priest

Hulbert

Gilliam

, et al. Characterization of heavily treatment-experienced people with HIV and impact on health care resource utilization in US commercial and Medicare Advantage health plans. Open Forum Infect Dis 2021; 8: ofab562.

22.

Henegar

Vannappagari

Viswanathan

, et al. Identifying heavily treatment-experienced patients in a large administrative claims database. In: 10th IAS Conference on HIV science, Mexico City, Mexico, 21–24 July 2019, poster no. MOPEB236.

23.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV, https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-arv/guidelines-adult-adolescent-arv.pdf (2024, accessed 12 September 2024).

24.

US Food and Drug Administration. FDA approves new HIV treatment for patients with limited treatment options, https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-treatment-patients-limited-treatment-options (2020, accessed 8 January 2025).

25.

US Food and Drug Administration. FDA approves new HIV treatment for patients who have limited treatment options, https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-treatment-patients-who-have-limited-treatment-options (2018, accessed 8 January 2025).

26.

Gilead Sciences Ireland UC. Sunlenca (EU summary of product characteristics). Carrigtohill, Ireland: Gilead Sciences Ireland UC, 2024.

27.

Gartland

Cahn

DeJesus

, et al. Week 96 genotypic and phenotypic results of the fostemsavir phase 3 BRIGHTE study in heavily treatment-experienced adults living with multidrug-resistant HIV-1. Antimicrob Agents Chemother 2022; 66: e0175121.

28.

Lataillade

Zhou

Joshi

, et al. Viral drug resistance through 48 weeks, in a phase 2b, randomized, controlled trial of the HIV-1 attachment inhibitor prodrug, fostemsavir. J Acquir Immune Defic Syndr 2018; 77: 299–307.

29.

Gartland

Arnoult

Foley

, et al. Prevalence of gp160 polymorphisms known to be related to decreased susceptibility to temsavir in different subtypes of HIV-1 in the Los Alamos National Laboratory HIV Sequence Database. J Antimicrob Chemother 2021; 76: 2958–2964.

30.

Los Alamos National Laboratory HIV Sequence Database. HIV sequence alignments, https://www.hiv.lanl.gov/content/sequence/NEWALIGN/align.html (2024, accessed 23 August 2024).

31.

Gartland

Zhou

Stewart

, et al. Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense^® Entry assay. J Antimicrob Chemother 2021; 76: 648–652.

32.

Zhou

Nowicka-Sans

Zhang

, et al. In vivo patterns of resistance to the HIV attachment inhibitor BMS-488043. Antimicrob Agents Chemother 2011; 55: 729–737.

33.

Nguyen

Wang

Anang

, et al. Characterization of the human immunodeficiency virus (HIV-1) envelope glycoprotein conformational states on infectious virus particles. J Virol 2023; 97: e0185722.

34.

Munro

Gorman

, et al. Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. Science 2014; 346: 759–763.

35.

Acharya

Lusvarghi

Bewley

, et al. HIV-1 gp120 as a therapeutic target: navigating a moving labyrinth. Expert Opin Ther Targets 2015; 19: 765–783.

36.

Wang

Finzi

Sodroski

The conformational states of the HIV-1 envelope glycoproteins. Trends Microbiol 2020; 28: 655–667.

37.

Zou

Zhang

Gaffney

, et al. Long-acting BMS-378806 analogues stabilize the state-1 conformation of the human immunodeficiency virus type 1 envelope glycoproteins. J Virol 2020; 94: e00148-20.

38.

Zhou

Dey

, et al. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 2007; 445: 732–737.

39.

Lin

P-F

Blair

Wang

, et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc Natl Acad Sci U S A 2003; 100: 11013–11018.

40.

Ray

Hwang

Healy

, et al. Prediction of virological response and assessment of resistance emergence to the HIV-1 attachment inhibitor BMS-626529 during 8-day monotherapy with its prodrug BMS-663068. J Acquir Immune Defic Syndr 2013; 64: 7–15.

41.

Wensel

Gartland

Beloor

, et al. The sensitivity of HIV-1 gp120 polymorphs to inhibition by temsavir correlates to temsavir binding on-rate. Antiviral Res 2024; 229: 105953.

42.

Malherbe

Sanders

van Gils

, et al. HIV-1 envelope glycoprotein resistance to monoclonal antibody 2G12 is subject-specific and context-dependent in macaques and humans. PLoS One 2013; 8: e75277.

43.

Toma

Weinheimer

Stawiski

, et al. Loss of asparagine-linked glycosylation sites in variable region 5 of human immunodeficiency virus type 1 envelope is associated with resistance to CD4 antibody ibalizumab. J Virol 2011; 85: 3872–3880.

44.

Ackerman

Thompson

Molina

J-M

, et al. Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1. AIDS 2021; 35: 1061–1072.

45.

Gartland

Wang

Liao

, et al. A multivariate analysis of the phase 3 BRIGHTE trial, through week 24, to identify predictors of virologic response to fostemsavir in heavily treatment-experienced people living with HIV. In: HIV Drug Therapy Glasgow, Glasgow, Scotland, 23–26 October 2022, poster no. P064.

46.

Gartland

Wang

Liao

, et al. Expanded multivariable models to identify predictors of virologic response to fostemsavir in BRIGHTE. In: European Meeting on HIV & Hepatitis, Barcelona, Spain, 22–24 May 2024, poster no. 75.

47.

Bouba

Berno

Fabeni

, et al. Identification of gp120 polymorphisms in HIV-1 B subtype potentially associated with resistance to fostemsavir. J Antimicrob Chemother 2020; 75: 1778–1786.

48.

Lepore

Fabrizio

Bavaro

, et al. Gp120 substitutions at positions associated with resistance to fostemsavir in treatment-naive HIV-1-positive individuals. J Antimicrob Chemother 2020; 75: 1580–1587.

49.

Soulié

Lambert-Niclot

Fofana

, et al. Frequency of amino acid changes associated with resistance to attachment inhibitor BMS-626529 in R5- and X4-tropic HIV-1 subtype B. J Antimicrob Chemother 2013; 68: 1243–1245.

50.

Saladini

Giannini

Giammarino

, et al. In vitro susceptibility to fostemsavir is not affected by long-term exposure to antiviral therapy in MDR HIV-1-infected patients. J Antimicrob Chemother 2020; 75: 2547–2553.

51.

Zuze

BJL

Radibe

Choga

, et al. Fostemsavir resistance-associated polymorphisms in HIV-1 subtype C in a large cohort of treatment-naïve and treatment-experienced individuals in Botswana. Microbiol Spectr 2023; 11: e0125123.

52.

Cluck

Chastain

Murray

, et al. Consensus recommendations for the use of novel antiretrovirals in persons with HIV who are heavily treatment-experienced and/or have multidrug-resistant HIV-1: endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy. Pharmacotherapy 2024; 44: 360–382.

53.

Max Planck Institut Informatik. Geno2pheno, https://www.geno2pheno.org/ (2024, accessed 12 August 2024).

54.

Stanford University. HIV drug resistance database, https://hivdb.stanford.edu/ (2024, accessed 12 August 2024).

55.

Wensing

Calvez

Ceccherini-Silberstein

, et al. 2022 Update of the drug resistance mutations in HIV-1, https://www.iasusa.org/wp-content/uploads/2022/10/30-4-559.pdf (2022, accessed 12 August 2024).

56.

HIV French Resistance. HIV-1 genotypic drug resistance interpretation’s algorithms, www.hivfrenchresistance.org (2024, accessed 12 August 2024).

57.

HIV-GRADE. Improving interpretation for antiviral drug resistance, https://www.hiv-grade.de/cms/grade/ (2024, accessed 12 August 2024).

58.

Hsu

Brunet

Lackey

, et al. Immunological and virological response to fostemsavir in routine US clinical care: an OPERA cohort study. HIV Med 2025; 26: 17–25.

Fostemsavir resistance in clinical context: a narrative review

Abstract

Keywords

Introduction

Mechanisms of reduced susceptibility to temsavir

Temsavir mechanism of action

Amino acid substitutions associated with reduced susceptibility to temsavir

Context dependency of temsavir susceptibility

Virologic failure in clinical studies of fostemsavir

Phase IIb study

Phase III BRIGHTE study

Polymorphisms and temsavir susceptibility in global clinical isolates

Clinical response to fostemsavir in study participants with subtype CRF01_AE

Discussion

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References