A safety evaluation of raltegravir for the treatment of HIV
Rosa de Miguel, Rocio Montejano, Natalia Stella-Ascariz & Jose R Arribas
To cite this article: Rosa de Miguel, Rocio Montejano, Natalia Stella-Ascariz & Jose R Arribas (2017): A safety evaluation of raltegravir for the treatment of HIV, Expert Opinion on Drug Safety, DOI: 10.1080/14740338.2018.1411903
To link to this article: https://doi.org/10.1080/14740338.2018.1411903

 
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Journal: Expert Opinion on Drug Safety DOI: 10.1080/14740338.2018.1411903
A safety evaluation of raltegravir for the treatment of HIV

1 + 1,+ ,
Rosa de Miguel Buckley , Rocio Montejano Natalia Stella-Ascariz1, Jose R Arribas1,*
*Both authors contributed equally

 

Affiliations
1 HIV Unit, Internal Medicine Service, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain
*Corresponding author
Tel: +34-91-207-1676; Email: [email protected]

 

Accepted

 

 

 

Abstract
Introduction: Raltegravir (RAL) was the first commercialized agent from a new drug class with an innovative target, the integrase. Since its introduction in clinical practice RAL has become widely used for the treatment of HIV-1 infected patients. A decade after its approval, this article reviews key evidence from RAL with a special interest on safety outcomes.
Areas covered: Pharmacologic, safety and efficacy data of RAL from clinical trials and post-commercialization published reports are hereby summarized after a literature review including PubMed search, relating proceedings and abstracts from relevant international HIV conferences, assessment reports from European and United States regulatory agencies and treatment guidelines (World Health Organization, United States Department of Health and Human Services and European AIDS Clinical Society), up to October 2017. Most frequent search terms were “raltegravir”, “safety”, “adverse
events”, “efficacy” and “integrase-inhibitors”.
Expert opinion: Despite the arrival of new integrase strand transfer inhibitors (INSTIs) with advantages in terms of dosing convenience (elvitegravir, ELV) and higher genetic barrier (dolutegravir, DTG), RAL has stood the test of time and its overall favourable safety profile, without significant appearance of unexpected adverse events, vouch for its relevance in the antiretroviral armamentarium.
Keywords: antiretrovirals, efficacy, HIV infection, integrase-inhibitors, MK-0518, raltegravir, safety.

 

 

 
List of abbreviations AEs= adverse events
ALT= alanine aminotransferase ARV= antiretroviral
AST= apartate aminotransferase ATV=atazanavir
ATV/r= ritonavir-boosted ATV BIC= bictegravir
bPIs= boosted protease inhibitors CAB= cabotegravir
CK= creatine kinase
DDI = drug-drug interactions
DRESS= drug reaction with eosinophilia and systemic symptoms DRV= darunavir
DRV/r = ritonavir-boosted darunavir DTG= dolutegravir
EFV= efavirenz ELV= elvitegravir
FTC= emtricitabine FTC
GSS= genotypic sensitivity score HCV= hepatitis C
INSTI= integrase strand transfer inhibitor LPV/r= ritonavir-boosted lopinavir NPAEs= neuropsychiatric adverse events
NRTIs= nucleoside reverse transcriptase inhibitors OBT = optimized background therapy
PI= protease inhibitor RAL= raltegravir
RAMs= resistance-associated mutations TDF= tenofovir disoproxil fumarate TT= triple therapy

VF= virologic failure VL= viral load
1.Introduction
It is estimated that over 36 million people worldwide live with HIV [1]. The primary goal to control the infection is to suppress HIV viral load (VL), which for now translates into lifetime treatment. New drugs with novel targets and less toxicity have appeared over the last decade. Raltegravir (RAL) was the first integrase strand transfer inhibitor (INSTI) approved for HIV treatment in 2007. INSTIs inhibit the integrase, an HIV enzyme that allows integration into the DNA of host cells. Two other drugs from this class are currently available, elvitegravir (ELV) and dolutegravir (DTG). Additionally bictegravir (BIC) and injectable long-acting cabotegravir (CAB) are in advanced preclinical development.
INSTIs combine high efficacy with good safety and tolerability, characteristics that despite their relatively recent introduction have placed them as one of the preferred drugs used in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) for HIV treatment [2, 3].
This review summarizes RAL pharmacology and efficacy, with specific attention to key safety data.
2.Overview of RAL pharmacology
Several years of thorough investigation [4,5] led to the development of RAL (MK- 0518), which effectively binds to the active site of the integrase enzyme preventing its activity. The integrase primes HIV-DNA in the cytoplasm (3′-processing), accompanies it to the nucleus and allows for its integration (strand transfer) within the cell’s own genome to access the host’s transcription machinery [6-8].
RAL is administered orally as 400 mg BID in adults and has recently been approved for naïve patients in a single QD formulation of 1200 mg (two 600 mg tablets). This new QD formulation is also approved for patients who are virologically suppressed on an initial regimen of RAL 400 mg BID. Tmax absorption in the fasted state is approximately 3 hours (h) for the BID dosing, with a half-life of around 9h. Tmax for the 1200 mg qd dose in the fasted state is 1.5 -2h. The drug binds in 83% to plasma proteins and is cleared mainly via UGT1A1 glucorinidation. Faecal and urine elimination is 51% and 32%, respectively.

RAL does not require boosting and neither inhibits nor inducts cytochrome P450, which contributes to its low potential for significant drug-drug interactions (DDI) [9,10]. RAL is affected by UGT1A1 inductors like rifampicin [11], and current recommendation is to consider RAL 800 mg bid when co-administered with this drug. UGT1A1 inhibitor atazanavir (ATV) moderately increases RAL plasma levels, no dose adjustment for the BID formulation is needed [12] but 1200 mg qd formulation should be avoided [13]. Although omeprazole can be prescribed, RAL should not be co-administered with
metal-containing antacids [9,10]. No clinically meaningful DDIs requiring dose adjustment have been disclosed with methadone, oral contraceptives or hepatitis C (HCV) direct antivirals [2, 14-16].
RAL does not have any specific food requirements and is considered safe without any dose adjustments when moderate hepatic insufficiency or severe renal impairment is present [17]. Based on accumulated safety and efficacy, 2016 HHS guidelines include RAL as the INSTI of choice for the treatment of antiretroviral (ARV)-naive pregnant women [18] and there is new evidence that supports its use for women presenting late in pregnancy [19-21]. RAL can be administered in paediatric population aged >4 weeks and adequate dosing for neonates is currently being tested [22]
3.Efficacy in clinical trials
3.1.- Treatment naive
STARTMRK randomised patients to RAL or efavirenz (EFV), combined with daily tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). After 5 years VL <50 copies/mL was 71% in RAL and 61.3% in EFV recipients, showing RAL superiority [23]. RAL produced significant increases in CD4 and faster VL decay, but resistance- associated mutations (RAMs) to integrase, FTC or both arose in some patients when virologic failure (VF) occurred [23-25].
ACTG A5257 [26] allocated patients to TDF+FTC plus ritonavir-boosted ATV (ATV/r), ritonavir-boosted darunavir (DRV/r) or RAL with equivalent results: in the intention to treat analysis 88.3% of ATV/r, 89.4% of DRV/r and 93.9% of the RAL group achieved VL< 50 copies/mL after 96 weeks. A combined endpoint of virologic efficacy and tolerability favoured RAL over the two boosted protease inhibitors (bPIs). In the RAL arm 18/85 developed RAMs, more than half to both NRTI and INSTI and two with intermediate-level resistance to DTG.
SPRING-2 determined DTG was non-inferior to RAL, combined with 2NRTIs: at 96

weeks 81% in the DTG and 76% in the RAL arm had VL<50 copies/mL, and higher number of patients in the RAL group had RAMs compared to DTG [27,28]. ONCEMRK study demonstrated non-inferiority of RAL 1200 mg qd vs. RAL 400 mg bid. After 96 weeks VL < 40 copies/mL was 81.5% for the new dose vs. 80.1% for RAL bid. Resistance to integrase was found in 0.8% of participants in each category and most patients with VF at 48 weeks subsequently regained viral suppression without any change of treatment [29,30].
The PROGRESS study (although underpowered to detect non-inferiority) showed similar virologic efficacy of RAL + ritonavir-boosted lopinavir (LPV/r) to triple therapy with TDF/FTC and LPV/r [31]. RAL+ DRV/r exhibited non-inferiority to triple therapy with TDF/FTC + DRV/r in the NEAT 001 study [32], but efficacy was reduced if CD4
< 200 cells/μL or viral load > 100,000 copies/mL at baseline, and more RAMs emerged in patients with initial high VL.
3.2.- Treatment experienced
BENCHMRK-1 & 2 [33-36] randomised patients with VF and triple-ARV class resistance to RAL or placebo plus an optimized background therapy (OBT). At 48 weeks RAL was superior to placebo irrespective of baseline CD4, VL or phenotypic and genotypic sensitivity scores (GSS) [34]. After 5 years, efficacy was sustained in 42% of patients initially allocated to RAL, but integrase RAMs developed in 64% of VF [36]. Observed risk factors for resistance were high baseline VL and OBT with 0 genotypic or phenotypic score[34].. Typical resistance pathways are mutations at positions N155 (N155H), Q148 (Q148 H/K/R) and Y143 (Y143C/R). Primary mutations generally reduce viral fitness, but this is frequently alleviated with secondary mutations resulting in decreased susceptibility to RAL [37-41].
In the switch scenario, SWITCHMRK failed to prove non-inferiority of RAL over LPV/r-containing therapy [42], yet in the SPIRAL study switching to RAL was non- inferior to continuing with a PI-based regimen [43]. SWITCHMRK investigators hypothesized that prior VF could have led to an insufficiently robust OBT, increasing RAL susceptibility to failure. Both studies included similar proportions of previous VF, but viral suppression was more prolonged before inclusion in SPIRAL.
Several studies have successfully tested RAL+ bPI in VF [44-46]. A network meta- analysis [47] provided evidence to include RAL + LPV/r as an alternative to the traditional 2NRTIs+bPI recommendation by the World Health Organization for second-

line therapy [48].
ELV was non-inferior to RAL, both combined with a bPI plus a third-active agent: after 96 weeks 47.6% of patients on ELV vs. 45% in the RAL group had VL<50 copies/mL [49, 50]. Integrase resistance was observed in 6.6% of ELV and 7.4% of the RAL patients, and phenotypic cross-resistance was detected. SAILING study [51] determined that DTG was superior when compared to RAL (both combined with 1-2 other active ARVs): VL < 50 copies/mL after 48 weeks was 71% in the DTG group vs. 64% in the RAL arm, with more clinically relevant integrase resistance in the RAL group.
4.Safety evaluation
4.1Safety in clinical trials
4.1.1Clinical adverse events (AEs)
In naive, STARTMRK study showed a significant difference supportive of RAL regarding clinical drug-related AEs after a five-year follow-up (52% RAL vs. 80.1% EFV, p< 0.001)[23]. The difference was most evident in patients reporting neuropsychiatric symptoms relating to EFV. Other common symptoms described in both groups, but overall more noted in the EFV group were: headache, abnormal dreams, nausea, fatigue, insomnia, diarrhoea, and rash. No significant differences in terms of serious AEs or drug discontinuations were globally observed [23-25].
In ACTG A5257 study tolerability in terms of study-drug discontinuation due to toxicity was better for RAL compared to bPIs. Discontinuations due to non-biliary gastrointestinal symptoms were more frequent in both ATV/r and DRV/r than RAL
(26%, 44% and 25% respectively) [26]. Recently approved 1200 mg qd formulation has a similar safety profile as the BID formulation. At 96 weeks, low rate of discontinuations because of clinical AEs was observed in the ONCEMRK study (0.9% in the QD group vs. 2.3% in the RAL BID group). Most frequently reported side effect was nausea (7.5% for both groups), the rest of clinical AEs (headache, diarrhoea, dizziness, vomiting) had a similar distribution in both arms, except for a slightly higher proportion of patients referring abdominal pain in the 1200 mg qd group [29-30].
Trials evaluating RAL on treatment-experienced patients [33-36,42,43] depict similar AEs than those in naïve [23-30]. A surprisingly higher rate of malignancies was found in the RAL group in BENCHMRK report [33] but ulterior comprehensive review of 96- week data from clinical trials ruled out carcinogenicity related to RAL [52]. After exposure-adjustment, data from the BENCHMRK study at 5 years showed similar

proportion of patients with clinical AEs (nausea, headache, diarrhoea) in placebo and RAL-exposed patients. The rate of AIDS defining conditions was 1.8/100 person-years vs. 2.9/100 person-years for patients allocated to initial RAL vs. placebo regimens, respectively [36].
4.1.2Laboratory AEs
Grade 3-4 toxicity was uncommon in STARMRK and ONCEMRK [23-25,29,30]. Laboratory abnormalities in BENCHMRK appeared in similar proportion between groups, although creatine kinase (CK) elevation was more frequent among RAL participants, but did not result in drug discontinuation [33,35,36,52]. In the week 96 analysis of ONCERMRK [30], grade 4 CK elevations were detected in 3.4% of patients with 1200 mg qd formulation compared to the 1.9% observed with RAL 400 mg bid (and to the <1% described in the ACTG A5257 study). In ACTG A5257 RAL better tolerability was mostly because of withdrawals due to jaundice or hyperbilirubinemia that were more prevalent amongst patients on ATV/r (originating 48% of ATV discontinuations) [26].
4.1.2.1Metabolic effects
RAL showed minor changes in lipid profile from baseline compared to EFV in STARTMRK [23-25]. In ACTG A5257 a favourable effect in lipid parameters compared to ATV/r and DRV/r was observed, although risk of developing metabolic syndrome was comparable across groups because of RAL effect in increasing waist circumference [53]. A comparative beneficial effect on lipids was also demonstrated in the SWITCHMRK and SPIRAL studies, where patients switched from a PI-containing regimen to RAL [42,43].
4.2Post-commercialization safety data
4.21.Drug reaction with eosinophilia and systemic symptoms (DRESS) Several post-marketing case reports have linked RAL to DRESS syndrome [54-56].
Although highly infrequent, most cases appeared in African patients and resolved after drug withdrawal and sometime steroid treatment. A recent study exhibited the association of RAL-related DRESS to the HLA-B*53:01 allel, which is more prevalent in Africans than other ethnic groups [57].
4.2.2Rhabdomyolysis

CK elevations have been detected and routinely monitored in pivotal trials, although most were non-severe and clinically irrelevant. There have been cases of rhabdomyolysis in patients taking RAL that have prompted analysis in observational studies [58-63]. Reports are not homogeneous but CK elevations range between 11%- 21%, the majority being mild and not leading to RAL discontinuation. No cases of rhabdomyolysis were observed in these cohorts. Presence of muscle symptoms is also variable, described in 1.5 to 23% of patients taking RAL, and not always associated to increased CK levels. The SCOLTA project found patients taking ATV and with CNS symptoms more likely to have muscle manifestations. Proposed risk factors for RAL skeletal muscle toxicity are prior treatment with zidovudine, history of increased CK, male sex and higher body mass index, although to date no definite causative agent has been identified. Notwithstanding, regulatory agencies and the manufacturer recommended exerting caution when combining RAL to other drugs known to produce CK elevations or patients at risk of myopathy.
4.2.3Safety in coinfected patients: hepatitis and tuberculosis
Other than occasionally increasing alanine aminotransferase (ALT) and apartate aminotransferase (AST), no outstanding hepatotoxicity was observed in clinical trials. Although underrepresented, hepatitis B and/or C patients were included and had similar rates of virologic efficacy than monoinfected in the BENCHMRK and STARTMRK studies [64]. Observational studies show that coinfected patients are more likely to have baseline liver enzyme alterations and to present subsequent increases after RAL introduction, irrespective of severity and mostly appearing early after treatment initiation. However, severe abnormalities are globally rare and hardly warrant RAL discontinuation. It is generally accepted that RAL is overall a safe ARV in coinfected patients [65-68].
The REFLATE study [69] has shown that RAL 400 mg or 800 g twice daily can be used in patients co-infected with HIV and tuberculosis although still is not completely clear which is the preferred dosing. In REFLATE doubling the dose of RAL overcompensated the effect of rifampicin induction. However, the standard dose had only small decreases in AUC0-12 and C12 [70].
5.Comparison with safety of other drugs

It has already been mentioned that RAL showed some advantages when compared to bPIs (less lipid and gastrointestinal side effects, ACTG A5257) and EFV (lesser neuropsychiatric symptoms, STARMRK). A large network meta-analysis comparing various ARV in naive evidenced RAL and DTG to be the only ones superior to
standard-dose EFV in preventing all-cause discontinuations [71]. Another meta-analysis including more than 8000 treatment-naive patients indicated a higher relative risk (RR) of treatment discontinuation with EFV than RAL (RR 2.7%, 95% IC 1.1 to 6.9%) although no significant difference in severe neuropsychiatric AEs was noted [72]. A
trial evaluating a switch from EFV to RAL demonstrated decreases in the degree of steatosis in non-alcoholic fatty liver disease patients (mostly HCV co-infected) that received the latter [73]. Conversely, a trial of a switch from an EFV-containing regimen (both with TDF/FTC) showed a small decrease in estimated creatinine clearance and estimated glomerular filtration rate in the RAL group [74]. Small increases in serum creatinine could be observed in RAL pivotal trials but no overt nephrotoxicity
developed [23-25,29,30], contrarily to widely reported TDF adverse renal outcomes that also affect, to some extent, to bPIs (ATV) [75]. Most of RAL pivotal studies have been conducted with 2NRTIs as backbone therapy and therefore it is difficult to find straight head-to-head safety comparisons of RAL with this drug class. Studies evaluating NRTI- sparing strategies showed that RAL combined to DRV/r or nevirapine were kinder towards bone health than a TDF-containing regimen [76-78].
5.1 Comparison with commercialized INSTIs.
DTG and RAL had very similar safety profile in the SPRING-2 and SAILING studies, with comparable proportion of any grade or discontinuation because of AEs [27, 28, 51]. Most common side effects were headache, diarrhoea, upper tract respiratory
infection or nasopharyngitis, and nausea. RAL and ELV had similar safety profile in the Study 145 [49,50], except for diarrhoea that was more prevalent in ELV and grade 3 or 4 ALT or AST elevations which where more frequent in the RAL group. Although
DTG and COBI interfere with tubular creatinine handling, the INSTI class as a whole do not seem to poise a substantial risk towards severe renal AEs [79].
After the controversy arisen from real-life data reporting a higher number of neuropsychiatric AEs (NPAEs) with DTG than depicted in trials [80-83], there has been an increased interest on this particular subset of symptoms. A recent meta-analysis found INSTIs overall risk for NPAEs was low, similar to that of bPIs and with a

tendency to a reduced risk compared to EFV [84]. A large Swiss cohort reported low rate of treatment discontinuation for RAL and DTG (<5%), neuropsychiatric symptoms being the most common reason for treatment modification and more frequently observed in DTG [85]. Two Spanish studies of patients receiving INSTI coincided that
DTG neuropsychiatric toxicity was more frequent in patients discontinuating because of AEs, but no statistically significant differences in toxicity-related drug withdrawals was detected between RAL, ELV or DTG [86,87]. Contrariwise, no higher risk of discontinuation because of NPAEs with DTG was detected in a United States cohort, despite a higher number of patients with prior psychiatric disease at baseline [88]. Results are therefore inconclusive and additional data is awaited.
6.Conclusion
RAL has demonstrated efficacy in naive, treatment-experienced patients with VF and also in switch studies, albeit careful selection of accompanying ARV is warranted due to RAL low genetic barrier. As a whole RAL can be considered a safe drug: very low potential for DDI, good tolerability and scarcity of severe AEs, without the appearance of unexpected side effects after a decade, have helped to position this drug in most preferred regimens endorsed by guidelines.
7.Expert opinion
RAL has demonstrated efficacy in virologic control and immunologic recovery. Rapid VL decay is a desirable effect and can be especially useful for acute infection or in late- presenting pregnant women. However, it is important to note that in some patients this rapid control of viral load can increase de risk of immune reconstitution syndrome People living with HIV have increased life expectancy so comorbidities and increasing pill burden are to be expected. has a low potential for DDIs, its overall benign metabolic effects, and safety in hepatic or renal insufficiency make it a suitable candidate for an ageing population, or patients with concomitant diseases. Retention in care and drug adherence are crucial to achieving optimal outcomes, and in this scenario is where a drug’s safety and tolerability is uttermost important. A major strength of RAL is that AEs tend to be mild and rarely prompt drug withdrawal. It is reassuring that RAL unexpected and potentially severe AEs unearthed outside clinical trials are confined to case reports and abate after drug discontinuation. RAL is a versatile and reliable drug that can be part of very successful regimens when combined with adequately robust

ARVs that surmount RAL main pitfall, low genetic barrier. This low genetic barrier implies a higher risk of development of resistance mutations in case of failure compared to second generation INSTIs such as DTG. in the setting of virological failure Being widely accepted since its introduction, RAL has to compete against DTG and ELV that are available in always-attractive single-tablet regimens. However, ELV boosting with cobicistat comes along with DDIs and long-term results are needed to confirm if tenofovir alafenamide can definitely overcome TDF disadvantages regarding bone and renal outcomes. Notably, cross-resistance precludes ELV and RAL sequential use. DTG high genetic barrier has been one of its unquestionable assets when compared to other available drugs but the need for HLA-B5701 testing when coformulated with ABC and the debate over unexpected AEs may restrict its use. To our knowledge no study
directly compares CAB or BIC to RAL, yet both drugs show promising results. One of RAL drawbacks was the inconveniency of twice-daily formulation, but RAL 1200 mg QD has already been approved for naive patients and for patients who are virologically suppressed on an initial regimen of RAL 400 mg BID. Long-term safety and if this posology will substitute the BID formulation cannot be predicted at this point.
A decade after its first approval there are reasons to maintain RAL amongst the preferred ARVs but, with newer INSTIs in the pipeline and the development of drugs with innovative targets, whether it can preserve its current position is a matter of time. Funding
Supported by Red Temática Cooperativa de Investigación en Sida Instituto de Salud Carlos III. N.S.-A. is supported by a predoctoral fellowship from Fondo de Investigaciones Sanitarias. R.dM.B is supported by a Río Hortega fellowship from Fondo de Investigaciones Sanitarias.
Declaration of interest
Arribas reports personal fees from Gilead, VIIV, Janssen, MSD, Teva, grants from Gilead, outside the submitted work. Montejano reports grants from Fondo de Investigaciones Sanitarias, personal fees from Janssen, outside the submitted work. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or

other relationships to disclose.

 

 

 

 
Drug summary box
Drug name (generic) RAL
Phase (for indication under discussion) Launched Indication (specific to discussion)
Pharmacology description/mechanism of action HIV integrase-strand inhibitor
Route of administration Orally Chemical structure
N-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-2-{2-[(5-methyl-
1,3,4-oxadiazol-2-yl)formamido]propan-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Pivotal trial(s) . Naive: STARMRK [23-25]
ACTG A5257 [26]
SPRING-2 [27,28]
ONCEMRK [29,30]
NEAT 001 [32]
.Treatment experienced: BENCHMRK [33-36]
SWITCHMRK [42]
SPIRAL [43]
SAILING [51]
Study 145 [49,50]

 

 

 

 

 

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23.- Rockstroh JK, DeJesus E, Lennox JL, Yazdanpanah Y, Saag MS, Wan H et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013; 63: 77–85. doi: 10.1097/QAI.0b013e31828ace69
24.- Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009 Sep 5;374(9692):796-806. doi: 10.1016/S0140- 6736(09)60918-1
** STARTMRK study: RAL non-inferior to EFV in combination with TDF/FTC for naive patients.

25.- DeJesus E, Rockstroh JK, Lennox JL, Saag MS, Lazzarin A, Zhao J et al. Efficacy of Raltegravir Versus Efavirenz When Combined With Tenofovir/ Emtricitabine in Treatment-Naive HIV-1– Infected Patients: Week-192 Overall and Subgroup Analyses From STARTMRK. HIV Clin Trials. 2012 Jul-Aug;13(4):228-32. doi: 10.1310/hct1304-228
26..- Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial.Ann Intern Med. 2014 Oct 7;161(7):461-71. doi: 10.7326/M14-1084.
* RAL equivalent to DRV/r and ATV/r in naive, superior to both in a combined endpoint including tolerability and efficacy.

 

27.- Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C et al. Once-
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* DTG non-inferior to RAL for naive patients, RAMs more frequent on the RAL arm

28.- Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, et al.Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double- blind, non-inferiority trial. Lancet Infect Dis. 2013 Nov;13(11):927-35. doi: 10.1016/S1473-3099(13)70257-3.
29- Cahn P, Kaplan R, Sax PE, Squires K, Molina JM, Avihingsanon A, et al. Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial. Lancet
HIV. 2017 Sep 11. pii: S2352-3018(17)30128-5. doi: 10.1016/S2352-3018(17)30128-5 ** First trial demonstrating daily RAL formulation (1200 mg qd) non-inferior to RAL 400 mg bid, for naive patients

30.- Cahn P, Kaplan R, Sax PE, Squires K, Molina JM , Ratanasuwan W et al. Raltegravir (RAL) 1200 mg once daily (QD) versus RAL 400 mg twice daily (BID), in combination with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), in previously untreated HIV-1 infection through week 96. 9th International AIDS Society (IAS) Conference on HIV Science (IAS 2017). Paris, 23-26th July 2017. Poster TULBPEB20
31.-Reynes J, Trinh R, Pulido F, Soto-Malave R, Gathe J, Qaqish R et al. Lopinavir/Ritonavir Combined with Raltegravir or Tenofovir/Emtricitabine in Antiretroviral-Naive Subjects: 96-Week Results of the PROGRESS Study. AIDS Res Hum Retroviruses. 2013 Feb;29(2):256-65. doi: 10.1089/AID.2011.0275

32.- Raffi F, Babiker AG, Richert L, Molina JM, George EC, Antinori Aet al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir–emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. 2014 Nov 29;384(9958):1942-51. doi: 10.1016/S0140-6736(14)61170-3
* DRV/r + RAL non-inferior to DRV/r + TDF/FTC, results less favourable if CD4<200/μL or high VL at baseline.

33.- Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz Met al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359: 339–54.
** BENCHMRK, pivotal trial where RAL had superior virologic efficacy vs. placebo in treatment-experienced multi-resistant patients with VF.

34- Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni Pet al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008; 359: 355–65.
35.- Steigbigel RT, Cooper DA, Teppler H, Eron JJ, Gatell JM, Kumar PN et al. Long- term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase III trials. Clin Infect Dis 2010; 50: 605–12
36.- Eron JJ, Cooper DA, Steigbigel RT, Clotet B, Gatell JM, Kumar PN, et al. Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. Lancet Infect Dis. 2013 Jul;13(7):587-96. doi: 10.1016/S1473-3099(13)70093-8
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38.- Fransen S, Gupta S, Frantzell A, Petropoulos CJ, Huang W. Substitutions at Amino Acid Positions 143, 148, and 155 of HIV-1 Integrase Define Distinct Genetic Barriers

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46.- La Rosa AM, Harrison LJ, Taiwo B, Wallis CL, Zheng L, Kim P, ET AL. Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study. Lancet HIV. 2016 Jun;3(6):e247-58. doi: 10.1016/S2352-3018(16)30011-X
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* Study 145: ELV non-inferior to RAL in integrase-naive patients with VF. Overlapping RAMs were detected between drugs, precluding sequential use.

50.- Elion R, Molina JM, Ramón Arribas López J, Cooper D, Maggiolo F, Wilkins E, et al. A Randomized Phase 3 Study Comparing Once-Daily Elvitegravir With Twice-Daily Raltegravir in Treatment-Experienced Subjects With HIV-1 infection: 96-Week Results. J Acquir Immune Defic Syndr. 2013 Aug 1;63(4):494-7. doi: 10.1097/QAI.0b013e318298469c
51.- Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor- naive adults with HIV: week 48 results from the randomised, double-blind, non-

inferiority SAILING study. Lancet. 2013 Aug 24;382(9893):700-8. doi: 10.1016/S0140-6736(13)61221-0
** Major study documenting DTG superiority over RAL, treatment-experienced (integrase-naive) patients with VF. RAMs more frequent with RAL, exposing DTG high genetic barrier.

52.- Teppler H, Brown DD, Leavitt RY, Sklar P, Wan H, Xu X, et al. Long-Term Safety from the Raltegravir Clinical Development Program. Current HIV Research, 2011, 9,
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Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Session Number: P-O2. Abstract 651.
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Accepted