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Integrase inhibitors: a clinical review of raltegravir and elvitegravir.


An essential step in the life cycle of all retroviruses, including HIV, is the insertion of a double-stranded DNA copy of the viral RNA genome into the host cell DNA by integrase. HIV integrase was recognised as a possible target early in the HIV epidemic [1], but development of an effective integrase inhibitor was haltingly slow due to issues of potency, protein binding and toxicity.

Due to high rates of viral replication and an error-prone reverse transcriptase, HIV is unique in its prodigious ability to create viral mutants. For patients with extensive resistance to existing medications, the FDA approval of the well-tolerated and effective integrase inhibitor, raltegravir, was a welcome event. The majority of viraemic patients with multi-drug-resistant HIV can now be suppressed when raltegravir is combined with other active agents. The role of raltegravir in patients naive to antiretroviral agents or with toxicity related to current antiretroviral drugs has yet to be fully established. Elvitegravir, another integrase inhibitor, is currently undergoing Phase III trials and holds promise as an effective agent and will also be discussed in this review.


The HIV integrase catalyses a multi-step process that allows the double-stranded cDNA to be irreversibly incorporated within the host DNA. Within the cytoplasm of the cell, integrase fastens onto specific sequences on the ends of HIV cDNA and recruits cellular and viral factors to create a pre-integration complex. Integrase then excises two nucleotides from each 3??end, exposing reactive ends in preparation for strand transfer. Cellular co-factors allow the pre-integration complex to enter the host nucleus. The preintegration complex binds to specific regions within the host DNA, and integrase nicks both strands of host DNA and executes the process of strand transfer, covalently bonding the primed viral ends to the cleaved host DNA. The host's own cellular repair enzymes seal the HIV cDNA into the host genome. Both raltegravir and elvitegravir specifically inhibit the step of strand transfer catalysed by integrase.



Grinsztejn et al. established the safety and efficacy of raltegravir over 24 weeks in a Phase II randomised dose finding study known as Protocol 005 [2]. In this study, 179 patients with extensive drug resistance and a viral load >5000 copies/ml were randomised in a 1:1:1:1 fashion to twice-daily raltegravir 200 mg, 400 mg, 600 mg or placebo plus optimised background therapy (OBT). All patients were required to have documented resistance to at least one nucleoside reverse transcriptase inhibitor (NRTI), one nonnucleoside reverse transcriptase inhibitor (NNRTI) and one protease inhibitor (PI). Mean CD4 count and [log.sub.10] viral load was 240 cells/[mm.sup.3] and 4.7 [log.sub.10] copies/ml, respectively. Enfuvirtide was given to 36% of the patients, with 25% of patients receiving enfuvirtide as a new drug. Apart from enfuvirtide, 72% of the treated patients had no active drugs in their OBT based on genotypic resistance testing while 48% had no active drugs based on phenotypic resistance testing. Tipranavir and darunavir were not available at the time of enrolment to this protocol. The results are shown in Table 1.

Two large ongoing Phase III 156-week randomised studies, BENCHMRK-1 and -2, have reported 48-week results [3,4]. These pivotal studies compared raltegravir against placebo in combination with OBT in patients with triple-class resistance and viral load >1000 copies/ml. The two studies differ only in the geographic distribution of enrolled patients. BENCHMRK-1 enrolled patients from Europe, Peru and Asia/Pacific, and BENCHMRK-2 enrolled patients primarily from North and South America. Raltegravir at 400 mg twice daily was chosen as the dose for these studies due to inter-patient variability in drug levels and potential drug interactions with co-administered antiretroviral drugs.

At 48 weeks, 64% of patients receiving raltegravir achieved a viral load <50 copies/ml versus 34% receiving placebo (P<0.001). Subgroup analysis showed patients with lower baseline viral load and higher CD4 cell count had an improved response (see Figure 1). As expected, with increasing number of active drugs in the OBT, virological response improved. In the raltegravir versus the placebo arm, 45% versus 3%, 67% versus 37%, and 75% versus 59% of patients achieved a viral load <50 copies/ml with 0, 1, and 2 or more active drugs, respectively, in the OBT based on the genotypic susceptibility score (see Figure 2). Evaluating responses based on phenotypic susceptibility scoring showed a similar increase in response based on increasing number of active drugs in the OBT. Impressively, in those patients receiving darunavir and enfuvirtide for the first time along with raltegravir, 89% of patients achieved a viral load <50 copies/ml at 48 weeks. Etravirine was not available during this study.


The FDA indication for raltegravir is for patients with ongoing viraemia on current antiretroviral therapy. However, another unmet need is for patients who have intolerance to current antiretroviral drugs but who also have a suppressed viral load. Two small retrospective studies in patients on enfuvirtide with a viral load <50 copies/ml and suffering from injection site reactions have reported success in switching from enfuvirtide to raltegravir while maintaining background antiretroviral agents. Harris et al. reported that 34/35 patients maintained a viral load <50 copies/ml at a median of 7 months of follow-up [5]. Talbot et al. reported 11/11 patients remained suppressed at 12 weeks on raltegravir with resolution of the injection site reactions from enfuvirtide in all patients [6].


Protocol 004 treated 198 treatment-naive patients for 48 weeks with twice-daily raltegravir at 100 mg, 200 mg, 400 mg, 600 mg, or efavirenz combined with lamivudine and tenofovir [7]. At 48 weeks, 83-88% of patients achieved a viral load <50 copies/ml with no differences between the arms. Interestingly, the decline in the viral load was more rapid in the raltegravir arms than the efavirenz arms with 60-80% versus 25% achieving viral load <50 copies/ml at 4 weeks (lower bound of 95% confidence interval [CI]>0; see Figure 3). The clinical importance of this finding is not known at this time, but this rapid decline in viral loads has also been seen in treatment-experienced patients receiving integrase inhibitor-containing regimens.


In clinical studies to date, raltegravir has been shown to be a safe and well-tolerated antiretroviral drug. In Protocol 005 and the BENCHMRK studies, where raltegravir was compared to placebo, the addition of raltegravir to the OBT was not associated with increased rates of clinical or laboratory adverse effects. Rates of rash, hepatic and CK-related adverse effects were similar between raltegravir and placebo. In Protocol 004, clinical adverse effects were fewer in the raltegravir arms versus the efavirenz arm (48% versus 71%, P=0.04) especially with respect to abnormal dreams (7% versus 21%) and nightmares (0% versus 11%). Laboratory adverse events were similar other than lipid abnormalities, which were found more commonly in the efavirenz arm with increased total cholesterol, LDL and triglycerides (P<0.001) with the use of raltegravir associated with little change in lipid values.

Early studies of raltegravir showed a non-significant increase in the numbers of malignancies in patients treated with raltegravir versus comparator or placebo. However, the malignancies reported were those commonly seen in patients with advanced HIV. Many represented recurrences of previous cancers or occurred during the first 3 months on the study drug. At a later date, during submission for FDA approval, Merck pooled all available randomised studies of raltegravir and found the relative risk of malignancy in the raltegravir versus comparator arms to be 1.2 (95% CI 0.4-4.1). The rates of malignancy will be continued to be followed in post-marketing studies but at this point, raltegravir appears to be safe.


Raltegravir is primarily metabolised by glucuronidation via uridine diphosphate glucuronosyltransferase (UGT) 1A1. Raltegravir can be taken without respect to food, does not interact with the P450 system, and does not require altered dosing for renal or hepatic dysfunction. Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of raltegravir is required when co-administered with other antiretroviral agents. Atazanavir which inhibits UGT1A1 glucuronidation, increases raltegravir blood levels, but when co-administered with raltegravir there was no increase in adverse effects [3]. Co-administration of strong inducers of UGT1A1 (e.g. rifampin) with raltegravir should be avoided due to reduced plasma levels of raltegravir. The effect of the less potent inducers (e.g. phenytoin and phenobarbital) on the drug levels of raltegravir is unknown. However, other less potent inducers (e.g. efavirenz, nevirapine, rifabutin and St John's wort) can be safely used with the recommended dose of raltegravir [8].



In 278 treatment-experienced patients with virological failure, Zolopa et al. compared daily ritonavir-boosted elvitegravir at 20, 50, or 125 mg versus a ritonavir-boosted PI (PI/r), each combined with OBT in a study known as GS 183-0105 [9]. Enrolment criteria included viral load >1,000 copies/ml and at least one protease mutation. OBT consisted of NRTIs and enfuvirtide, if needed. The use of NNRTIs was not allowed and, initially, the use of PIs was excluded from the elvitegravir arms. At baseline, mean viral load was 4.59 [log.sub.10] copies/ml, the CD4 cell count was 185 cells/[mm.sup.3]. In addition, 49% of patients had a GSS of 0 for all NRTIs in the OBT with a median of 11 protease mutations and 22% used enfuvirtide for the first time. Darunavir and tipranavir were used by 49% and 27% of those in the PI/r arm, respectively.

At week 8, the data and safety monitoring board recommended stopping the 20-mg boosted elvitegravir arm because of a high rate of virological failure. As a result of new data indicating lack of drug--drug interactions, darunavir or tipranavir could be added to the ongoing elvitegravir arms, if clinically warranted. Before week 16, only 3% of patients added a PI to their regimens, however, by week 24, 26% of patients in the 50-mg and 125-mg boosted elvitegravir arms added a PI to their regimens. As a result, week 16 was the last time point for a true comparison between boosted elvitegravir and PI/r. At week 16, the mean change from baseline in viral load was -1.2 [log.sub.10] copies/ml in the PI/r arm and -1.5 and -1.7 [log.sub.10] copies/ml in the 50-mg and 125-mg boosted elvitegravir arms, respectively (Figure 4). Viral load changes were similar after week 24. Results from the 125-mg boosted elvitegravir arm were shown to be statistically superior to the PI/r arm at both weeks 16 and 24. At week 16, 30% of patients in the PI/r arm achieved viral load < 50 copies/ml compared with 38% and 40% of patients in the 50-mg and 125-mg boosted elvitegravir arms, respectively (P-value not reported). Not surprisingly, the patients with more active drugs in the OBT had improved responses on elvitegravir [10]. In patients receiving enfuvirtide for the first time in the 125-mg boosted elvitegravir arm, 74% of patients had a viral load <50 copies/ml versus only 25% of patients who received enfuvirtide for the first time in the PI/r arm (P=0.01)


There were few toxicity-driven drug discontinuations in GS 183-0105, and similar numbers in patients in each group had grade 3 or 4 clinical or laboratory adverse effects. Elvitegravir is metabolised through a combination of cytochrome P450 3A4 and glucuronidation pathways. A benefit of this interaction is that, when boosted with ritonavir, it allows for once-daily dosing.


The integrase inhibitors appear to have a relatively low barrier to resistance, and there seems to be substantial cross-resistance between raltegravir and elvitegravir. In the BENCHMRK studies at 24 weeks, 32 of 41 patients with virological failure on raltegravir developed integrase resistance--often with multiple mutations at initial virological rebound [11,12]. The signature mutations were N155H, Q148H/R/K and infrequently Y143R/C. Associated with N155H were the secondary mutations of E29Q, V151I, T97A, G163R and L74M. Associated with Q148H/R/K were secondary mutations at G140S/A and E138K. Increasing phenotypic resistance is seen with three or more mutations and, generally, the Q148 pathway leads to higher levels of phenotypic resistance [13].

In the GS 183-0105 protocol, integrase genotyping and phenotyping was performed on 28 of 30 patients experiencing virological failure in the 125-mg boosted elvitegravir arm by week 24 [14]. The most common integrase mutations observed in these patients were E92Q, E138K, Q148H/R/K and N155H, each of which was observed in 39% of patients experiencing virological failure. The other most commonly noted mutations were S147G (observed in 32%) and T66I/A/K (observed in 18%). The mean elvitegravir and raltegravir fold changes were >151 and >28, respectively. Interestingly, replication capacity decreased from a median of 108% at baseline to 54% at virological failure, reflecting a decrease in fitness associated with integrase resistance. Evidence of clinical cross-resistance between the integrase inhibitors was reported by DeJesus et al. when two patients who had failed elvitegravir were switched to raltegravir and did not demonstrate a virological response [15].


Raltegravir is a potent and well-tolerated addition to the HIV treatment armamentarium. With the availability of raltegravir and other new agents, current HIV guidelines now emphasise maximal virological suppression for treatment-experienced patients [16]. Currently, the known side-effect profile of raltegravir is quite favourable, and with more study, the use of raltegravir may expand to patients who are antiretroviral naive or are intolerant or have toxicities to their current antiretroviral therapy.

Elvitegravir is currently undergoing a Phase III non-inferiority study versus raltegravir. If approved, the once-daily dosing may be an attractive option to many patients, particularly those on a ritonavir-boosted PI regimen.


[1.] Bushman FD, Fujiwara T, Craigie R. Retroviral DNA integration directed by HIV integration protein in vitro. Science, 1990, 249, 1555-1558.

[2.] Grinsztejn B, Nguyen BY, Katlama C et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet, 2007, 369, 1261-1269.

[3.] Cooper DA, Gatell J, Rockstroh J et al. 48-week results from BENCHMRK-1, a phase III study or raltegravir in patients with failing antiretroviral therapy with triple-class resistant HIV-1. 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 2008. Abstract 788.

[4.] Steigbigel R, Kumar P, Eron J et al. 48-week results from BENCHMRK-2, a phase III study or raltegravir in patients with failing antiretroviral therapy with triple-class resistant HIV-1. 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 2008. Abstract 789.

[5.] Harris M, Larsen G, Montaner J. Outcomes of patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen. 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 2008. Abstract 799.

[6.] Talbot A, Marcotte S, Thomas R et al. Retrospective analysis of a switch from enfuvirtide to raltegravir in patients with undetectable viral load: efficacy at 12 weeks in a Montreal cohort. 17th Annual Canadian Conference on HIV/AIDS Research, Montreal, April 2008.

[7.] Markowitz M, Nguyen BY, Gotuzzo E et al. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007, 46, 125-133.

[8.] accessed 24th June 2008.

[9.] Zolopa A, Mullen M, Berger D et al. The HIV integrase inhibitor GS9137 demonstrates potent ARV activity in treatment-experienced patients. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007. Abstract 143LB.

[10.] Zolopa AR, Lampiris H, Blick G et al. The HIV integrase inhibitor elvitegravir (EVG/r) has potent and durable activity in treatment-experienced patients with active optimized background therapy (OBT). 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 2007. Abstract H-714.

[11.] Cooper D, Gatell J, Rockstroh J et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007. Abstract 105aLB.

[12.] Steigbigel R, Kumar P, Eron J et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007. Abstract 105bLB.

[13.] Hazuda DJ, Miller MD, Nguyen BY, Zhao J for the P005 Study Team. Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a Phase II study in patients with triple-class resistant HIV-1 infection. 16th International HIV Drug Resistance Workshop, Barbados, June 2007. Abstract 8.

[14.] McColl DJ, Fransen S, Gupta S et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a phase II study of elvitegravir (GS-9137). 16th International HIV Drug Resistance Workshop, Barbados, June 2007. Abstract 9.

[15.] DeJesus E, Cohen C, Elion R et al. First report of raltegravir (RAL, MK-0518) use after virological rebound on elvitegravir (EVT, GS 9137). 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, July 2007. Abstract TUPEB032.

[16.] Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1-128. Available at AdultandAdolescentGL.pdf. Accessed 25th June 2008.

Correspondence to: Dr Philip Grant, Division of Infectious Diseases and Geographic Medicine, Stanford University, 300 Pasteur Drive, Grant Building Room S-169, Stanford, CA 94305-5107, USA.

Table 1: Results from Protocol 005.

 Raltegravir arms Placebo P value

 200 mg 400 mg 600 mg

Decrease in viral load -1.80 -1.87 -1.84 -0.35 <0.0001
at 24 weeks

Percentage achieving 65 56 67 13 <0.0001
viral load <50

CD4 cell count 63 113 94 5 <0.0001
increases (cells/

Figure 1: BENCHMRK-1 and -2 combined efficacy: percentage of patients
with HIV-RNA <50 copies/ml at week 48 by genotypic susceptibility score
(GSS) [3,4] ( Raltegravir + OBT), ( Placebo + OBT).


 (n = 443) 64
 (n = 228) 34
Baseline >100,000 (n = 156) 48
HIV-RNA (n = 76) 16
(copies/ml) [less than
 or equal to] 100,000 (n = 287) 73
 (n = 152) 43
 [less than
 or equal to] 50 (n = 139) 50
 (n = 75) 20
Baseline >50 and (n = 167) 67
CD4 [less than or
 or equal to] 200 (n = 82) 39
(cells/[mm.sup.3]) (n = 136) 76
 [greater than
 or equal to] 200 (n - 71) 44

Note: Table made from bar graph.

Figure 2: BENCHMRK-1 and -2 combined efficacy:
percentage of patients with HIV-RNA <50 copies/ml at week
48 by genotypic susceptibility score (GSS) [3,4] (Raltegravir
+ OBT), (Placebo + OBT).

Total: (n = 443) 64
 (n = 228) 34
GSS = 0 (n = 112) 45
 (n = 65) 3
GSS = 1 (n = 166) 67
 (n = 92) 37
GSS = >2 (n = 158) 75
 (n = 68) 59

Note: Table made from bar graph.
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Title Annotation:LEADING ARTICLE
Author:Grant, Philip; Zolopa, Andrew
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:1USA
Date:Jun 1, 2008
Previous Article:New drugs.
Next Article:New protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

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