AIDS.

Drug Evaluation

Raltegravir as antiretroviral therapy in HIV/AIDS

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Library of Health Sci-Univ of Il on 02/05/14 For personal use only.

Malika Sharma & Sharon L Walmsley† †

1.

Introduction

2.

Overview of the market

3.

Introduction to the compound

4.

Clinical efficacy

5.

Safety and tolerability

6.

Conclusion

7.

Expert opinion

Toronto General Research Institute, Toronto General Hospital, Division of Experimental Therapeutics -- Infection and Immunity, Toronto, ON, Canada

Introduction: HIV, a major cause of morbidity and mortality worldwide has been transformed by antiretroviral (ARV) therapy into a manageable condition. Drug resistance, tolerability and drug interactions remain major concerns when choosing ARV therapy. Raltegravir, the first integrase inhibitor in the armamentarium against HIV, has been shown to be efficacious in both treatment-naı¨ve and treatment-experienced patients when used in combination as part of nucleoside-reverse transcriptase inhibitor-containing regimens. Its key advantages include safety, tolerability and fewer drug interactions but it has some important limitations such as a lower barrier to resistance and a twice-daily dosing schedule. Its role in nucleoside-sparing regimens is under investigation. Areas covered: PubMed was searched for publications in English from 2004 to September 2013 using the terms ‘raltegravir’, ‘integrase inhibitor’ and ‘MK-0518’. Relevant publications were reviewed and reference lists were examined for further publications. Conference abstracts from the Conference on Retroviruses and Opportunistic Infections, Interscience Conference on Antimicrobial Agents and Chemotherapy, and International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention for 2013 were also reviewed. Expert opinion: Raltegravir is an important agent for both naı¨ve and experienced HIV patients. Its key features include its tolerability, efficacy and lack of significant drug interactions. Keywords: antiretroviral, HIV/AIDS, integrase inhibitor, raltegravir Expert Opin. Pharmacother. (2014) 15(3):395-405

1.

Introduction

Human immunodeficiency virus (HIV) affects 34 million people worldwide, the majority of whom live in low- and middle-income countries [1]. As WHO guidelines now recommend treatment for all HIV-positive people with a CD4 < 500/mm3 to prevent disease progression and transmission, ~ 26 million additional people worldwide will now be eligible for treatment [2]. Current guidelines recommend antiretroviral (ARV) therapy for treatment-naı¨ve adults with combinations of two nucleoside reverse-transcriptase inhibitors (NRTI) and a third agent, either a non-nucleotide reverse-transcriptase inhibitor (NNRTI), ritonavir-boosted protease inhibitor (PI) or any of the three integrase strand transfer inhibitors [3,4]. 2.

Overview of the market

Transmitted drug resistance (particularly for NNRTIs) limits options in treatmentnaı¨ve patients, while extensive drug resistance requires agents in new classes [5-7]. The tolerability, potential for drug interactions and short- and long-term safety profiles of many agents remain suboptimal [8-10]. Comorbid illness and the contribution of long-term ARV exposure to cardiac, liver, renal and bone health are being 10.1517/14656566.2014.868884 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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M. Sharma & S. L. Walmsley

Box 1. Drug summary. Drug name (generic) Phase (for indication under discussion) Indication (specific to discussion)

Raltegravir III In combination with other ARV agents for the treatment of treatment-naı¨ve and treatment-experienced HIV/AIDS patients Integrase strand-transfer inhibitor Oral; chewable and film-coated tablets available N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl)propan-2-yl) Protocol 004, BENCHMRK 1 and 2, STARTMRK, SWITCHMRK, QDMRK, SPRING-2, SAILING

Pharmacology description/mechanism of action Route of administration Chemical formula


Pivotal trial(s)

explored [11-15]. Thus, there is ongoing need to develop new drugs and strategies to minimize toxicity. Three integrase inhibitors are currently on the market [16]. Raltegravir (RAL) (Box 1), the first agent in the class, has well-established indications and safety data for treatmentnaı¨ve and experienced patients. Elvitegravir (EVG) is available as a cobicistat-boosted fixed-dose combination with emtricitabine (FTC) and tenofovir (TDF) in a single tablet and has performed favorably relative to recommended first-line therapy in treatment-naı¨ve patients [17,18]. Dolutegravir (DTG) was recently approved by the United States Food and Drug Administration for treatment-naı¨ve and experienced patients [19,20]. 3.

Introduction to the compound

Previously known as MK-0518, RAL was first approved for use in treatment-experienced adults, and later as first-line therapy in ARV-naı¨ve patients and pediatric populations [21,22]. It is available as 400 mg film-coated tablets and a chewable form is approved for use in patients aged 2 -- 11 years. Chemistry HIV-1 replication requires three enzymes: nucleoside reverse transcriptase, protease and integrase. Integration involves two key processes: 3¢ processing and strand transfer. Integrase first binds to the viral DNA to form a stable pre-integration complex with specific DNA sequences at the end of long terminal repeat regions. This complex moves to the cell nucleus followed by viral DNA processing and transfer to the host cellular DNA [23-25]. Currently approved integrase inhibitors block integrase’s active site and prevent the pre-integration complex from binding to host DNA, resulting in inactive nonintegrated proviral HIV DNA [24,26]. RAL’s chemical name is N-[(4-fluorophenyl)methyl]-1, 6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt. It is a pyrimidine carboxamide integrase inhibitor structurally based on a diketo acid chemical moiety [27]. The b-hydroxy-ketone structural motif allows blocking of integrase’s active site through interaction with divalent cations bound within it [28]. RAL is the 3.1

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result of several modifications and improvements upon earlier diketo-acid based inhibitors, resulting in improved stability, pharmacokinetics, resistance profile and toxicity [27]. Pharmacokinetics/pharmacodynamics RAL is rapidly absorbed and is 83% protein-bound. Its variable pH-dependent absorption results in variable pharmacokinetics. The area under the curve (AUC0 -- 12) is 9.97 -14.4 umol/l·h, Cmax ranges from 2.85 to 4.5 umol/l and Cmin ranges from 129 to 142 nmol/l [26]. Data from singleand multiple-dose escalation studies demonstrate that plasma concentrations decrease biphasically, with an initial t1/2 of 1 h and terminal t1/2 of 9 h [29]. Steady state is achieved after 2 days after multiple dose administration. Trough levels were greater than the IC95 (the 95% inhibitory concentration in 50% human serum) in a pharmacokinetic assessment of 35 treatment-naı¨ve patients randomized to doses of 100 -- 600 mg RAL monotherapy twice-daily (b.i.d.), Cmax and AUC remained similar when dosing of ‡ 400 mg was achieved [30]. Pharmacokinetic data from a Phase III trial examining RAL 800 mg once daily (q.d.) versus 400 mg b.i. d. found similar AUC but sixfold lower Ctrough concentrations with once-daily dosing. Failure to achieve viral suppression was associated with lower values of Ctrough in the 800 mg/day arm [31]. Pharmacokinetic parameters have been found to be similar among African-American populations [32]. Current recommendations that RAL can be given without regard to food are supported by an open-label randomized trial on 20 HIVnegative volunteers who received RAL 400 mg b.i.d. in four diet states [33]. RAL is primarily metabolized by hepatic glucuronidation (UGT 1A1) and excreted in the feces and urine [34]. In vitro it does not inhibit UGT 1A1 or UGT 2B7. RAL levels may be decreased by UGT 1A1 inducers and increased by UGT 1A1 inhibitors. It does not affect CYP isoenzymes. RAL pharmacokinetics are not impacted by moderate hepatic or severe renal dysfunction [35]. RAL is ~ 76% bound by plasma proteins [36]. Its diffusion into the cerebrospinal fluid is variable, with only 50% of tested specimens exceeding the IC95 levels required to inhibit HIV-1 in one study [37]. It has been found to accumulate in seminal plasma with a seminal plasma to blood plasma ratio 3.2

Expert Opin. Pharmacother. (2014) 15(3)


Raltegravir

of 4.32 (interquartile range = 4.1 -- 5.0), perhaps due to higher availability of unbound drug in the male genital tract. Semen plasma trough concentrations were 12-fold higher than the IC95 for wild-type HIV-1 [38]. In vitro, RAL blocks HIV replication with an IC95 of 33 ± 23 nmol/l and demonstrates synergistic antiviral activity when combined with other ARVs [39]. In a pilot study of patients with multidrug-resistant virus, it decreased proviral DNA with a more dramatic decay in patients with lower median Ctrough levels [40]. RAL has a distinct pattern of viral decay with a slower (0.563/day) first phase and a longer duration (median 15.1 days) [41]. The prolonged first-phase decay is explained by RAL’s activity against formation of the preintegration complex, preventing cells from becoming productively infected and is recognized by a faster decline in plasma viral load (VL) [41,42]. RAL also demonstrates activity against HIV-2 [43]. Dosing Although pharmacokinetic data suggested that RAL 800 mg/day dose was sufficient to achieve Ctrough exceeding the IC95 for wild-type HIV-1 strains, lower values of Ctrough are seen [31,44]. Doses from 100 to 600 mg b.i.d. were similarly effective in earlier data, but subsequent trials used 400 mg b.i.d. dosing to ensure an adequate buffer for potential drug interactions [30,42,45,46]. A randomized trial in treatment-naı¨ve patients (QDMRK) could not confirm noninferiority of RAL 800 mg q.d. to 400 mg b.i.d. combined with TDF/FTC, with 83% patients receiving RAL once-daily dosing suppressing to < 50 copies/ml compared to 89% of twice-daily dosing (p = 0.044). Plasma Cmin predicted viral response in terms of VL < 50 copies/ml, < 400 copies/ml and virological failure at 48 weeks. Among those with baseline VL > 100,000 copies/ ml, only 74% achieved suppression in the once-daily arm compared to 84% in the twice-daily arm. Emergence of resistance was higher in the once-daily arm, especially those with lower Ctrough levels. These findings have resulted in 400 mg b.i.d. being the only approved and recommended dosing strategy [31,47]. A recent open-label randomized crossover study in 36 healthy subjects evaluated the single dose pharmacokinetics of two different RAL formulations with findings indicative that further clinical trials investigating once-daily regimens are warranted [48]. 3.3

Drug--drug interactions As RAL is not a substrate of cytochrome P450, it has relatively few drug--drug interactions [26]. It does, however, interact with atazanavir due to atazanavir’s inhibition of UGT 1A1, thus resulting in higher levels of RAL. Despite the increase seen, standard dosing of both drugs is recommended. Similarly, standard dosing of most other ARVs is also recommended. An important interaction may occur with the concomitant use of rifampin, a UGT 1A1 inducer. Pharmacokinetic studies suggest that coadministration of rifampin and RAL results in lower plasma RAL concentrations, with caution advised 3.4

with concomitant use [49]. An important interaction occurs with the concomitant use of omeprazole, which can result in higher RAL plasma levels given its pH-dependent absorption [50]. 4.

Clinical efficacy

RAL was initially studied in treatment-experienced patients but has now been studied in those with variable degrees of drug resistance. It is increasingly used in treatment-naı¨ve patients and is a preferred first-line regimen [4]. Phase I studies Phase I data is previously summarized [26]. RAL monotherapy was compared to placebo in 35 treatment-naı¨ve patients with HIV-1 RNA ‡ 5000 copies/ml and CD4 counts ‡ 100 cells/mm3. All doses of RAL had greater ARV activity than placebo and were well tolerated, with a decline in VL ranging from --1.9 to --2.2 log10 copies/ml at 10 days. Mean trough concentrations exceeded IC95 (33 nmol/l) for all doses [30]. 4.1

Phase II studies In a multicenter, double-blind, randomized, dose-finding study, RAL twice-daily dosing was compared to efavirenz (EFV) 600 mg/day in 198 treatment-naı¨ve participants, both in combination with TDF and lamivudine. Patients in the RAL arm were more likely to achieve VL suppression at weeks 2, 4 and 8, but rates were similar at 24 and 48 weeks. RAL was better tolerated than EFV, particularly with regard to neuropsychiatric symptoms and lipid profile [51]. Its potency, durability and tolerability persisted to 96 weeks, with 83% of patients in the RAL arm and 84% in the EFV arm maintaining viral suppression [45,51]. In 179 treatment-experienced patients, RAL was added to optimized background therapy (OBT) and compared to placebo in a multicenter, randomized, triple-blind, dose-ranging trial. At week 24, RAL was superior to placebo at all doses in achieving viral suppression (56 -- 67% and 13%, respectively) and had a similar safety profile [52]. In a cohort (TRIO) of 103 treatment-experienced patients with multidrug-resistant virus failing ARV therapy (ART), a regimen of RAL, etravirine and ritonavir-boosted darunavir (DRV/r) with or without NRTI demonstrated HIV RNA < 50/ml in 86% of patients at week 48 [53]. RAL (400 mg b.i.d.) was studied in an open-label Phase IIb trial of 112 treatment-naı¨ve patients (ACTG A5262) as part of a NRTI-sparing regimen with DRV/r (800/100 mg q.d.). Virological failure occurred in 26% of patients by week 48, most commonly in those with a baseline VL > 100,000 copies/ml and lower baseline CD4 count [54]. An ongoing randomized open-label study (RADAR) compared RAL plus DRV/r to DRV/r plus TDF/FTC in treatment-naı¨ve patients. At 48 weeks, only 62.5% of patients in the RAL arm had a VL < 48 copies/ml versus 83.7% of patients in the 4.2


397


TDF/FTC arm [55]. Reasons for this inferior efficacy are unclear. A larger, powered, randomized trial of these two strategies is ongoing (ANRS143/NEAT001) examining DRV/r + TDF/FTC versus DRV/r plus RAL [56].

WHO stage 4 events or death, CD4 count > 250 cells/mm3 and VL < 10,000 copies/ml or > 10,000 copies/ml without PI resistance mutations at week 96 [62]. Treatment-naı¨ve studies The STARTMRK trial, an international multicenter, doubleblind, randomized controlled trial (RCT), compared the safety and efficacy of RAL with EFV in treatment-naı¨ve patients in combination with TDF and FTC. At the week 48 primary end point, 86.1% in the RAL arm and 81.9% in the EFV arm achieved HIV RNA < 50 copies/ml. VL suppression occurred more rapidly in patients on RAL [42]. Modest changes in serum lipids, serum glucose and body fat were seen with both regimens at 96 weeks [63]. At 5 years, 71% of RAL recipients and 61.3% of EFV recipients had a VL < 50 copies/ml, superiority largely driven by the greater tolerability of RAL [64]. The SPRING-2 trial was a randomized, multinational, double-blind, noninferiority trial of 411 treatment-naı¨ve patients comparing RAL or DTG plus TDF/FTC or abacavir/lamivudine. About 88% of patients in the DTG group and 85% in the RAL group achieved a VL of < 50 copies/ ml at 48 weeks, demonstrating noninferiority with similar rates of adverse events but higher rates of treatment-emergent resistance in the RAL group [20]. A randomized, open-label trial compared RAL plus LPV/r to LPV/r plus TDF/FTC in 206 treatment-naı¨ve patients to evaluate the role of RAL in a nucleoside-sparing regimen (PROGRESS). VL suppression < 40 copies/ml at week 48 (83.2% in the RAL group and 84.8% in the TDF/FTC group) or at 96 weeks (66.3% in the RAL group and 68.6% in the TDF/FTC group) met the definition of noninferiority. Tolerability was similar in both groups, with greater increases in peripheral fat in the RAL arm but greater reductions in estimated glomerular filtration rate and bone mineral density in the TDF/FTC arm [65]. In contrast, the SPARTAN trial investigating RAL and unboosted atazanavir versus boosted atazanavir with TDF/FTC found good viral suppression but unacceptable rates of drug resistance to RAL and hyperbilirubinemia [66]. 4.3.2

4.3

Phase III studies (Table 1)


These have been summarized in a recent systematic review and meta-analysis of 48 integrase inhibitor studies [57]. Data from pivotal trials are summarized below. Treatment-experienced studies BENCHMRK 1 and 2 were identical international randomized trials, where RAL or placebo was combined with OBT in a total of 699 patients. At the 16-week primary end point, 61.8% of RAL recipients and 34.7% of placebo recipients had HIV-1 RNA < 50 copies/ml (p < 0.001) with similar rates of drug-related adverse events [46]. The superior virological response to RAL was irrespective of baseline RNA level, CD4 cell count, virological resistance, demographics and use of DRV or enfuvirtide in the OBT. As BENCHMRK 1 and 2 were not powered to make statistically significant inferences from subgroup analysis, they should be interpreted cautiously [58]. At week 156, 51% of RAL group had < 50 copies/ml compared to 22% in the placebo group (p< 0.0001), with a mean CD4 cell count increase of 164 versus 63 cells/mm3. After week 156, all patients were offered open-label RAL until week 240, and 6% of all patients had virological failure in the open-label phase at 240 weeks [59]. Comparisons have also occurred within classes. RAL was compared to EVG in treatment-experienced patients when combined with a PI/r and a third agent (Study 145). Oncedaily EVG was noninferior to twice-daily RAL with 47.6% of patients in the EVG arm and 45% in the RAL arm achieving a VL < 50 copies/ml at 96 weeks, with similar safety profiles [60]. The SAILING study compared once-daily DTG and twice-daily RAL in treatment-experienced patients. This randomized, double-blind, controlled, noninferiority trial of 715 patients combined DTG or RAL with at least two active ARV. About 71% of patients in the DTG arm versus 64% in the RAL arm had a HIV RNA < 50 copies/ml at 48 weeks (p = 0.03). Significantly fewer patients developed treatment-emergent integrase-inhibitor resistance on DTG compared to RAL [19]. The SECOND-LINE study was a randomized, open-label, noninferiority multinational trial comparing lopinavir/ ritonavir (LPV/r) plus two to three NRTIs to LPV/r plus RAL in 541 patients with prior NNRTI failure. About 81% of patients in the NRTI group and 83% in the RAL group achieved the primary end point of VL < 200 copies/ml at 48 weeks, confirming noninferiority [19,61]. An open-label trial in African sites (EARNEST) compared PI/r plus two to three NRTIs to PI/r plus RAL to PI/r monotherapy in 1277 patients failing therapy. About 60% of patients in the NRTI group, 65% in the RAL group, and 57% in the PI/r monotherapy group achieved the primary composite end point of no new 4.3.1

398

Switch studies in those with viral suppression These studies were designed to determine the safety and efficacy of switching in those with viral suppression but with issues related to tolerability or preference. SWITCHMRK 1 and 2 compared substitution of RAL for LPV/r with continuation of LPV/r in those with viral suppression on LPV/r-based therapy. A total of 707 patients were randomized in this multicenter, double-blind, double-dummy trial. Switching to RAL resulted in significant improvement in lipid profile (the primary endpoint) but inferior virological efficacy compared to continuation of LPV/r therapy (84.4% with VL < 50 copies/ml vs 90.6%, respectively) and the studies were terminated. Of note, 84% (27 of 32) of patients with confirmed virological failure in the RAL group were on at 4.3.3


Regimen or backbone

RAL 400 mg b.i.d. TDF/FTC vs EFV 600 mg q.d. RAL 100, 200, TDF/3TC 400 and 600 mg b.i.d. vs EFV 600 mg q.d. RAL 400 mg b.i.d. TDF/FTC vs RAL 800 mg q.d.

Comparator therapies

RAL 400 mg b.i.d. TDF/FTC or ABC/3TC vs DTG 50 mg q.d. Treatment-experienced patients with virological failure RAL 400 mg b.i.d. or Optimized background BENCHMRK [46,58,59] placebo RAL 400 mg b.i.d. Optimized background SAILING [19] vs DTG 50 mg q.d. Treatment-experienced patients as part of a switch strategy RAL (400 mg b.i.d.) 2 NRTI SWITCHMRK [67] vs LPV/r (400/100 mg) b.i.d. RAL (400 mg b.i.d.) 2 NRTI SPIRAL [68] vs PI/r As part of an NRTI-sparing strategy in treatment-naı¨ve patients RAL 400 mg b.i.d. LPV/r (400 mg/100 mg) b.i.d. PROGRESS [65] vs TDF/FTC ATV vs ATV/r RAL 400 mg b.i.d. (with SPARTAN [66] ATV) vs TDF/FTC (with ATV/r) As part of an NRTI-sparing strategy in treatment-experienced patients RAL 400 mg b.i.d. LPV/r (400/100 mg) b.i.d. SECOND LINE [61] vs 2NRTI

SPRING-2 [20]

QDMRK [47]

[30,45,51]

Protocol 004

[42,45,63,64]

Treatment-naı¨ve patients STARTMRK

Study acronym [Refs.]

Table 1. Summary of pivotal raltegravir trials.

88% (DTG) vs 85% (RAL)

61.8/62.1% vs 34.7/32.9% placebo 71% (DTG) vs 64% (RAL)

80.8% (RAL) vs 87.4% (control)

89.2% (RAL) vs 86.6% (PI/r)

83.2% (RAL) vs 84.8% TDF/FTC 74.6% (RAL) vs 63.3% (ATV/r)

83% (RAL) vs 81% control

< 50 copies/ml at week 16/week 48 < 50/ml at week 48

< 50 copies/ml at week 48


< 40 copies/ml week 48 < 50 copies/ml at week 24


89% (b.i.d.) vs 83% (q.d.)

83 -- 88% (RAL) vs 87% (EFV)

86.1% (RAL) vs 81.9% (EFV)

Analysis





Primary outcome (VL)



At 96 weeks, responses 66.3 vs 68.6%

Study terminated at week 24 by DSMB

At 5 years, 51% RAL < 50 copies/ml vs 22% placebo

For those with VL > 100,000 copies/ml at baseline, 74% (q.d.) vs 84% (b.i.d.) met primary end point Similar results at week 96: 81% (DTG) vs 76% (RAL)

At 5 years, 71% RAL and 61.3% EFV < 50 copies/ml Fewer adverse events with RAL (55%) than EFV (76%)

Comments

Raltegravir

399



least their second ART regimen and 66% (18 of 27) reported a history of prior virological failure [67]. The SPIRAL study was a similarly designed randomized, multicenter, open-label trial of 273 patients with HIV RNA < 50 copies/ml (for at least 6 months) on a PI/r-based regimen. Switching to RAL was noninferior to continuing PI/r-based treatment at 48 weeks (89.2 vs 86.6% free of treatment failure, respectively), with an improvement in plasma lipids [68]. The ROCnRAL study was a single-arm study of 44 CCR5 tropic patients with suppressed VL who were switched from suppressive ART to maraviroc and RAL. Five patients experienced virological failure with this NRTIsparing regimen, resulting in premature study discontinuation [69]. Taken together, these studies support switching the third agent only if adequately supported by an active NRTI backbone [67-70]. Resistance profile While major resistance mutations remain rare in integraseinhibitor-naı¨ve patients, RAL use is associated with emergent resistance with treatment failure. Known integrase inhibitor resistance-associated mutations (RAMs) include N155H, Q148H/R/K, Y143C/R and G140S and can confer crossresistance between RAL and EVG [54,58,71,72]. Integrase inhibitor RAMs can occur and accumulate rapidly, in as early as 2.6 months [73]. In the STARTMRK study, the overall incidence of virological failure was low with 55 of 281 patients randomized to RAL developing protocol-defined virological failure at 5 years [64]. Of those that could be assessed 7 of 23 (3%) patients had integrase inhibitor RAMs. In the SPRING-2 study, 1 of 18 (6%) RAL subjects with protocol-defined failure whose virus could be amplified showed evidence of integrase resistance at 48 weeks [20]. In BENCHMRK 1 and 2, 23% of RAL recipients had virological failure at 48 weeks, with integrase mutations found in 68%. About 75% of participants with integrase mutations had two or more mutations, with mutations at Y143, Q148 or N155 associated with virological failure. Participants with higher baseline HIV-1 RNA levels or those receiving background therapy with a genotypic or phenotypic sensitivity score of 0 were more likely to develop integrase mutations [58]. In the trial of EVG versus RAL in treatment-experienced patients, emergent integrase RAMs were found in 7.4% of all RAL patients at 96 weeks [60]. The VIKING studies have provided early data that viral strains resistant to RAL may be treated with salvage combinations containing DTG. However, the studies are small and the predictors of response are still under investigation [74]. Because of the potential for accumulation of RAMs that may confer cross-resistance to other integrase inhibitors, the continuation of RAL in the presence of known integrase RAMs is not recommended [75]. The 96-week data from the SPRING-2 trial have demonstrated no emergent integrase inhibitor resistance mutations to DTG and in 6% (n = 1) of patients with virological failure in the RAL group [76]. 4.4

400

5.

Safety and tolerability

RAL is well tolerated. In studies of ARV-naı¨ve subjects, 48-week discontinuation rates for drug-related adverse events is 1 -- 3% and in STARTMRK < 5% of patients discontinued therapy at 5 years [20,64]. In treatment-experienced patients, rates of clinical or laboratory adverse events were similar to placebo [46]. Most common drug-related adverse events were diarrhea, nausea and headache. Central nervous symptoms have been reported in up to 10% of patients on RAL and may be related to higher concentrations with concomitant TDF or proton-pump inhibitor use [77]. The most common laboratory changes with RAL were elevations in serum cholesterol, triglyceride or aminotransferase levels [42,59,63]. Elevation in liver transaminases is more commonly seen in patients with hepatitis B or C coinfection, where up to 67% of patients have some degree of elevation with RAL use (compared to 50% with EFV) [63]. Rates of serious clinical adverse events are similar between RAL and comparator drugs and represent < 2% of all patients studied [42,64]. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been described, and rashes or severe hypersensitivity reactions are possible [78,79]. Myopathy and rhabdomyolysis are described [79,80]. In a cross-sectional study, 37% of patients on RAL (vs 19% of control patients) presented with skeletal muscle toxicity, ranging from myalgia to proximal myopathy. Muscle toxicity was independent of RAL duration or levels [81]. Prior elevation of creatine kinase (CK), abnormal baseline CK and male gender are all risk factors for CK elevation [82]. Early data suggested a disproportionate number of malignancies with the use of RAL compared to placebo. Data from four Phase II -- III trials of RAL was combined to yield a relative risk of cancer of 1.2 (95% CI: 0.4 -- 4.1) with RAL use [46]. Subsequent data failed to show higher rates of malignancy with RAL when compared to other agents [63]. RAL is currently classified as pregnancy category C due to a lack of safety and pharmacokinetic data. However, it has been used in pregnancy to prevent maternal to child transmission, particularly among women presenting at advanced gestational age. RAL may be especially well suited to this indication due to its higher rate of first and second phase viral decay, high placental transfer with fetal accumulation and its ability to accumulate in cervicovaginal secretions [83,84]. Current evidence to support this indication relies primarily on case reports and case series, and further data is needed [85,86]. 6.

Conclusion

RAL is the first and most extensively studied integrase inhibitor. It is a potent and durable component of first-line therapy in treatment-naı¨ve patients and in treatment-experied patients failing ART when combined with OBT. Data are emerging on its role as part of a nucleoside-sparing regimen but it



Raltegravir

should only be used in this combination in patients with few other treatment options. Its key advantages include safety, tolerability, few drug interactions, as well as its clear potency and long-term efficacy. The primary disadvantages remain the need for twice-daily dosing and high cost compared to other agents, particularly limiting its usefulness in lower-income settings. Given its lower barrier to resistance compared to boosted PIs, it must be supported by an adequate backbone, and failing regimens should be discontinued promptly to prevent the emergence of additional mutations that could compromise future options. 7.

Expert opinion

RAL is the first integrase inhibitor for the management of HIV. Its introduction revolutionized the management of multidrug-resistant viruses. When used in combination with OBT, many treatment-experienced patients were able to achieve and maintain viral suppression for the first time in years. This advance changed treatment guidelines and practices and highlighted the importance of including a new class of agent in salvage regimens. Many physicians continue to comment on the success of the ‘TRIO’ regimen (RAL, etravirine and DRV/r) in their own patients. Subsequently RAL has been studied in treatment-naı¨ve patients and those with lesser drug resistance. Its efficacy and tolerability have led to its inclusion at 400 mg b.i.d. as one of the preferred options in international treatment guidelines for initial therapy. RAL provides a potent, safe and welltolerated therapeutic option, and drug discontinuations for adverse events are uncommon. It has fewer neuropsychiatric, gastrointestinal and lipid-related adverse effects compared to other commonly used agents. It provides a switch option for those unable to tolerate other agents but who have adequate viral suppression and a supportive NRTI backbone. The twice-daily dosing needs to be balanced against its improved tolerability as demonstrated by the 71% response rate at 5 years in the STARTMRK study. New formulations including an oral compressed tablet are under evaluation. Pharmacokinetic studies support their once-daily use and clinical studies are underway. It has several potential uses in special populations. Given its favorable lipid profile, it may be a good option for individuals with increased cardiovascular risk. Its minimal risk for drug interactions makes it ideal for those requiring chemotherapy for malignancy, immunosuppression for transplantation, antidepressants, direct-acting agents for hepatitis C, anti-seizure medications or for those who are impacted by the cytochrome

P450 enzyme activity of NNRTI and PI/r [87]. The HIV population is aging and the long-term impact of NRTIs on bone, kidney, heart and brain are of increasing concern. The development of new strategies that include integrase inhibitors but spare NRTIs could be useful in the future. Early evidence suggests that RAL may have antiinflammatory properties, and data have shown improvement in inflammatory biomarkers and T-cell activation when PI/r are switched to RAL [88]. Although intriguing, more research is required to address the clinical relevance of these changes and whether this could contribute to a decrease in cardiac risk or the HIV viral reservoir. Last, the rapid viral decline on therapy needs further exploration as to its clinical relevance. This could prove to be valuable for management of the late presenter, for decreasing VL rapidly in late-stage pregnancy, or as a component of post-exposure prophylaxis. Two other integrase inhibitors are also on the market, including EVG as part of a single-tablet regimen (STR) (EVG + cobicistat + TDF + FTC) and DTG. These other compounds will compete with RAL in the first-line ARV market. The integrase inhibitor containing STR has comparable activity to the STR containing TDF/FTC/EFV but without the CNS adverse events [17]. It has not been compared directly to RAL but has the disadvantage of the need for boosting with cobicistat which could lead to more gastrointestinal side effects and may also cause early increases in serum creatinine due to the inhibition of renal transporters. DTG and RAL were comparable in a head-to-head clinical trial (SPRING 2) of ARV-naı¨ve subjects with a similar adverse event profile [20,76]. The advantages to DTG were the once-daily dosing and the lack of emergence of any drug resistance with viral failure. In treatment-experienced patients, DTG was superior to RAL (SAILING) when used in combination with an OBT, especially with lower genotype/phenotype scores in the backbone [19]. The VIKING trials have demonstrated that some RAL failures may respond to a new combination that includes DTG [74].

Declaration of interest Sharon Walmsley has served on advisory boards and spoken at CME events for Merck & Co, ViiV, Abbvie, Janssen, Gilead, Bristol-Myers Squibb. She has received funding for an investigator study for ViiV. She has participated in clinical trials sponsored by Merck & Co, ViiV, Gilead, Abbvie, Janssen and Bristol-Myers Squibb. Malika Sharma has no conflicts of interests.


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Affiliation Malika Sharma1 MD FRCPC & Sharon L Walmsley†2 MSc MD FRCPC † Author for correspondence 1 University of Toronto, Division of Infectious Diseases, Toronto, Canada 2 Toronto General Research Institute, Toronto General Hospital, Division of Experimental Therapeutics -- Infection and Immunity, Eaton North Wing - 13th floor Rm. 13E-214, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada E-mail: [email protected]

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