The use of HIV-1 integrase inhibitors in antiretroviral naive patients

Lennox, Jeffrey L.

doi: 10.1097/COH.0b013e3283562a27
INTEGRASE INHIBITORS: Edited by Charles Hicks and Esteban Martinez

Purpose of review: In this review we will discuss recent findings on the use of inhibitors of the HIV-1 integrase enzyme for the treatment of antiretroviral naive patients. We will also discuss differences between integrase inhibitors, and comment on the use of this class of drugs in the future.

Recent findings: Raltegravir when taken twice daily is as effective and well tolerated as efavirenz. Once daily dosing of raltegravir is virologically inferior to raltegravir taken twice daily. A novel nucleoside-free regimen of raltegravir in combination with a once daily ritonavir-boosted protease inhibitor did not produce adequate viral suppression, although raltegravir with a twice daily protease inhibitor yielded better results. Subset analyses have demonstrated a favorable impact of raltegravir on lipid levels and body fat composition. Two once daily integrase inhibitors not yet Food and Drug Administration-approved, elvitegravir and dolutegravir, have completed phase-2 testing and are also virologically noninferior to efavirenz.

Summary: Integrase inhibitors provide potent antiretroviral activity, little short-term toxicity and excellent tolerability. For patients with preexisting atherosclerosis or cardiac risk factors this class of therapy is a logical preferred treatment choice. Raltegravir is a preferred option for those in whom therapy for hepatitis C virus infection is anticipated.

Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA

Correspondence to Jeffrey L. Lennox, MD, Professor of Medicine, Division of Infectious Disease, Emory University School of Medicine, Glenn Memorial Building, 69 Jesse Hill Jr. Drive, SE, Suite 202, Atlanta, Georgia 30303, USA. Tel: +1 404 251 8784; e-mail:

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In the modern antiretroviral therapy (ART) era combination therapy including two nucleoside analog reverse transcriptase inhibitors (NRTI) and either a protease inhibitor or a nonnucleoside analog reverse transcriptase inhibitor (NNRTI) are recommended as preferred treatment options for individuals with human immunodeficiency virus type-1 (HIV-1) infection [1,2]. These ‘standard’ combinations are less than ideal due to associated hyperlipidemia and other metabolic toxicities [3,4]. The first HIV-1 integrase inhibitor, raltegravir (Merck Inc., Whitehouse Station, New Jersey, USA), was approved in 2007 for patients who had failed previous antiretrovirals [5,6]. This was soon followed by promising results in a small population of treatment-naive patients [7]. A larger Phase-3 study then confirmed the noninferiority of raltegravir to efavirenz (Bristol-Myers Squibb, New York, New York, USA) [8]. In this review we will discuss the recent findings from this ongoing treatment-naive study, review the treatment experience with the investigational integrase inhibitors elvitegravir (Gilead Sciences Inc., Foster City, California, USA) and dolutegravir (ViiV Healthcare, Brentford, Middlesex, United Kingdom) and discuss the future directions for the use of HIV-1 integrase inhibitors in ART-naive patients.

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The Phase-3 STARTMRK study demonstrated that raltegravir was noninferior to efavirenz, both in combination with fixed dose tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, Gilead Sciences Inc., Foster City, California, USA) in antiretroviral treatment-naive patients [8,9]. There was a more rapid viral suppression in the raltegravir arm, more modest lipid elevations, and fewer patients had serious drug-related adverse events. The 3–4-year results extended these observations and provided additional metabolic data [10▪▪,11]. After 3 years of blinded treatment raltegravir produced a virologic suppression rate of 75.4%, versus a rate of 68.1% for efavirenz, using intent-to-treat analysis in which missing data equals failure. In an analysis counting treatment-related discontinuations as failure, 85.1% of the patients in the raltegravir arm did not experience treatment failure, versus 77.1% in the efavirenz arm. All raltegravir failures with integrase inhibitor resistance occurred in the first year of the study, whereas four additional efavirenz failures with NNRTI resistance developed after the first year. Few participants developed lipid abnormalities in the third year of follow-up. The addition of therapy for hyperlipidemia after baseline through year 3 occurred in 4% of patients in the raltegravir arm, versus 7% of patients in the efavirenz arm. In a subgroup of 57 participants who had dual energy X-ray absorptiometry (DEXA) scans performed annually the mean total body fat gain in the raltegravir arm was 19%, versus 31% in the efavirenz arm. Only three of the 57 patients developed lipoatrophy, as defined by a greater than 20% appendicular fat loss, by DEXA scanning. These results are supported by recent in-vitro experiments showing little effect of raltegravir on cellular adipogenesis and lipolysis [12].

After 4 years of blinded treatment the rate of viral suppression was superior in the raltegravir arm versus the efavirenz arm [76.2% versus 67.0%, 95% confidence interval (CI), 1.6–16.4], using intent-to-treat analysis. No new raltegravir or efavirenz resistance emerged during the fourth year of the study. Given differences in the integrase sequence between subtype-b and non-b subtypes of HIV-1, an analysis was undertaken in patients from STARTMRK to compare virologic responses in nonb subtype viruses to subtype-b viruses [13]. The non-b subtype infected participants had a 94.5% virologic suppression rate, versus 88.7% in the patients with subtype-b viruses.

As there were no differences in antiviral effect observed for lower dose raltegravir in the early dose ranging study, and as raltegravir had a prolonged in-vitro occupancy time on the viral integrase enzyme, a trial of once daily raltegravir was judged to be appropriate. This QDMRK study was a randomized comparison of once daily versus twice daily raltegravir, both in combination with TDF/FTC [14▪▪]. At week 48, 88.9% of the patients in the twice daily treatment group had achieved virologic suppression versus 83.2% of participants in the once daily group. This difference of −5.7 (95% CI −10.7 to −0.83) proved the inferiority of once daily raltegravir treatment in this population (P = 0.044). In addition, the time to achieve confirmed virologic response was longer for the once daily group, and 14% of patients in the once daily group experienced virologic failure versus 9% in the twice daily group. Participants who had a baseline HIV-1 RNA more than 100 000 copies/ml or CD4 T-cell count 200 cells/μl or less had lower virologic response rates with once daily dosing. Approximately, 4.5% of the participants developed grade 3 or 4 elevations in serum creatine kinase. No cases of rhabdomyolysis or severe myositis were reported, an adverse event that has been reported with raltegravir use in clinical practice [15]. An important caveat to this study is that the requirement for a placebo nullified any potential adherence advantages of once daily dosing.

Given the established rapid virologic suppression produced by raltegravir (and other HIV integrase inhibitors) there has been speculation that it may be beneficial in the setting of acute HIV infection. Koelsch et al.[16] studied the HIV RNA and DNA decay characteristics in plasma, CD4 T-cells and colon tissue biopsies for eight patients with acute HIV infection and eight patients with chronic HIV infection treated with TDF/FTC and raltegravir. Both groups had rapid suppression of plasma viral load, and simultaneous increases in episomal HIV DNA, indicating that raltegravir was blocking HIV integration. Integrated HIV-1 DNA levels were lower at baseline in the acutely infected patients, and decreased even further with treatment. However, this single arm study does not establish whether raltegravir exerts a differential effect on these kinetic parameters than would be expected with non-integrase-based antiretroviral therapy.

An innovative nucleoside-sparing regimen containing raltegravir and 800 mg once daily of darunavir (Janssen Therapeutics, Titusville, New Jersey, USA) and 100 mg of daily ritonavir (Abbott Laboratories, Abbott Park, Illinois, USA) was studied by the AIDS clinical trials group (ACTG 5262) [17▪]. In this single arm study a virologic failure rate of 16% was observed by week 24, which increased to 26% by week 48. Having a baseline viral load of more than 100 000 copies/ml or a lower CD4 T-cell count increased the likelihood of failure. Of the 28 patients who experienced virologic failure, five of 25 in whom the integrase enzyme could be amplified developed integrase resistance mutations.

A similar, but comparative and randomized trial was presented at the 2011 International AIDS Society Meeting [18]. Eighty participants received daily darunavir/ritonavir and were randomized to receive either raltegravir or TDF/FTC. At 24 weeks the rate of HIV viral suppression was equivalent in both arms. However, two of 40 patients in the raltegravir arm experienced virologic failure, whereas none of the patients in the TDF/FTC arm experienced virologic failure. The results of these two studies raise the question of whether darunavir once daily, when given with raltegravir, might yield subtherapeutic levels. A study in which patients who were taking darunavir were switched from enfuvirtide (Hoffmann-La Roche Inc., Basel Switzerland) to raltegravir demonstrated a slight decrease in darunavir concentrations [19]. In a second study, patients were administered two NRTIs and raltegravir twice daily for 21 days followed by the addition of darunavir/ritonavir 800/100 mg once daily [20]. Darunavir concentrations were not different from those obtained from previous studies. When raltegravir was stopped, however, the darunavir area under the curve increased. The failure of once daily darunavir–raltegravir may, therefore, either be due to the asynchronous dosing schedule, or to slight reductions in darunavir concentrations.

The nucleoside-sparing strategy of raltegravir with a twice-daily boosted protease inhibitor was investigated in the PROGRESS (PROtease/InteGRasE Simplification Study) study [21]. In this randomized, open-label trial, 206 patients were randomized to receive a twice daily lopinavir/ritonavir fixed dose (LPV/r, Abbott Laboratories Inc.) and raltegravir or twice daily LPV/r+TDF/FTC. At week 48, 83.2% of participants in the nucleoside–sparing arm achieved virologic suppression versus 84.8% in the standard-of-care arm. The twice daily dosing of both the integrase inhibitor and the protease inhibitor may account for the success of this study.

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Elvitegravir is an investigational integrase inhibitor in a single pill formulation combined with cobicistat (a pharmacologic inhibitor of elvitegravir metabolism developed by Gilead Sciences and similar in action to ritonavir) and TDF/FTC, referred to hereafter as the ‘Quad’. In a small Phase-2 study 48 patients were randomized to treatment with the Quad and 23 patients to treatment with a fixed dose combination of EFV/TDF/FTC (Atripla, Gilead sciences Inc.) [22▪▪]. At week 48 both arms achieved an 83% viral suppression rate. Psychiatric disorders occurred in 17% of the participants in the Quad arm versus 26% in the EFV/TDF/FTC arm (P = 0.02). The study was not powered to detect differences in changes in lipids. A 14% decline from the baseline estimated glomerular filtration rate (EGFR) was observed in the quad arm only. The majority of this decline in EGFR occurred within the first 2 weeks of study treatment. The manufacturer reported that this change in serum creatinine does not affect actual glomerular filtration rate when measured by iohexol clearance, and postulated that the change in serum creatinine was due to an inhibiting effect on tubular secretion of creatinine by cobicistat. As detailed elsewhere in this issue, cobicistat also affects other medications that are metabolized by cytochrome enzymes.

Two larger studies comparing the Quad regimen to EFV/TDF/FTC and to atazanavir/ritonavir are ongoing. The 48-week data were presented at the 2012 Retrovirus Conference [23,24]. The Quad was found to be noninferior to both efavirenz and to atazanavir boosted with ritonavir, in both studies producing approximately 89% virologic suppression. In the head to head comparison with efavirenz the Quad produced less neuropsychological side effects, but did have a statistically significantly higher rate of nausea (21% versus 14%). The rates of nausea were equivalent between the Quad and boosted atazanavir. These results indicate that the Quad has about the same gastrointestinal tolerability as low-dose ritonavir. The Quad produced less elevation in triglycerides than boosted atazanavir, with no difference in the cholesterol fractions. Conversely, there was no difference between the Quad and efavirenz for triglyceride elevations, but all cholesterol fractions were higher in those who received efavirenz. Twenty-six patients between the two studies developed virologic failure on the Quad regimen. Twelve failed with integrase inhibitor resistance and emtricitabine resistance, and in four cases tenofovir resistance. Patients infected with an HIV-1 possessing this resistance profile have limited remaining NRTI treatment options. In comparison, of 17 patients who experienced virologic failure on efavirenz, eight had NNRTI resistance and two of these had emtricitabine or tenofovir resistance. None of the eight patients who experienced virologic failure on atazanavir boosted with ritonavir had any drug resistance detected. In the STARTMRK study, after 4 years of follow-up, no tenofovir resistance has been detected in samples from patients with virologic failure on raltegravir [11].

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Dolutegravir is being jointly developed by ViiV Healthcare and Shionogi Pharmaceuticals (Osaka, Japan). Dolutegravir, without any pharmacologic booster, given once daily achieves trough levels above the predicted 50% inhibitory concentration (IC50) for wild type HIV-1 [25]. Dolutegravir in vitro has a higher barrier to the development of resistance, and retains activity against certain raltegravir-resistant viruses [26]. A small Phase-2a randomized, double-blind dose-ranging study of dolutegravir has been completed [27▪▪]. The mean decrease from baseline in plasma HIV-1 RNA levels after 10 days of monotherapy was more than 1.51 log10 copies/ml for all three doses tested up to 50 mg daily. In addition, seven of the nine patients given the 50 mg dose achieved a viral load of less than 50 copies/ml by Day 11, versus only one of 18 of the patients in the combined lower dose arms.

The SPRING-1 study is a Phase-2b comparison of two nucleoside analogues and dolutegravir at doses of 10 mg, 25 mg, or 50 mg per day to EFV/TDF/FTC. The 96-week results have been presented at the 2011 Conference on Retroviruses and Opportunistic Infections [28]. At week 48, 139 of 155 patients (87%) in the combined dolutegravir arms and 41 of 50 patients (82%) in the EFV/TDF/FTC arm achieved a viral load less than 50 copies/ml. Although there was no overall difference in adverse events between the dolutegravir arms and the EFV arm, this was a small study. The SPRING-2 study is a larger, phase 3 comparison of dolutegravir to raltegravir. The 48-week results showing that dolutegravir was not inferior to raltegravir were announced in a press release, but have not yet been presented or published.

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In the March, 2012 Department of Health and Human Services Antiretroviral Therapy Guidelines the integrase inhibitor-based regimen of raltegravir+TDF/FTC is one of four preferred first-line options for treatment naive, nonpregnant adults [1]. However, the guidelines’ authors emphasize that this recommendation is based on one study, and that there has not yet been a comparative study of raltegravir to a boosted protease inhibitor. An 1800 person, 3-arm study comparing raltegravir with two different once daily protease inhibitor containing regimens is ongoing (ACTG 5257). The European AIDS Clinical Society treatment guidelines, last published in October 2011, include raltegravir as one of six recommended first-line treatment options [2]. At the time these two guidelines were published neither elvitegravir nor dolutegravir had been approved for use in the USA or Europe. If both are approved as single-pill combination therapies, the number of available single-pill therapies will increase to four. Table 1 presents a summary of some of the key differences between the two currently available once daily treatments and these investigational therapies.

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Raltegravir is effective, well tolerated, and has little metabolic toxicity. The 4-year results of STARTMRK are reassuring in that no additional virologic failures occurred in which integrase inhibitor resistance was detected. Raltegravir also has few potential drug interactions, and is therefore particularly appealing for patients who may require the use of direct inhibitors of hepatitis C virus replication. Despite these advantages, the twice daily dosing of raltegravir and lack of coformulation with NRTIs are considered by some to be impediments to its use in clinical practice.

The investigational once daily elvitegravir-based Quad appears promising. The slight increase in serum creatinine in patients who received the Quad is concerning, especially as the combination tablet includes the known nephrotoxin tenofovir. The published results of the small Phase-2 study, and the oral presentation from the larger study, indicate that the cobicistat-induced serum creatinine increases reach maximum levels within 2 weeks and then stabilize. Practitioners will need to develop a tolerance for following patients forward from this ‘new baseline,’ and for gastrointestinal side effects and medication interactions due to the cobicistat component of this combination. The development of resistance to elvitegravir, emtricitabine, and tenofovir among four of 12 of the patients with failure and resistance in this study is also concerning. Longer-term follow-up is necessary to determine how commonly failure of the Quad regimen leads to combined integrase and NRTI resistance.

The antiviral potency and pharmacokinetics of dolutegravir are promising, although limited safety data are available for this agent and the results from the comparison to raltegravir are only available via press release. The resistance profile of dolutegravir, as covered elsewhere in this journal, shows potential ability to salvage some of the commonly observed resistance mutations observed after raltegravir or elvitegravir failure. However, as most patients who develop virologic failure on first-line regimens also have nucleoside resistance, this salvage therapy would by necessity contain two other active antiretrovirals.

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The currently available integrase inhibitor raltegravir offers a potent, well tolerated and safe therapy option for antiretroviral treatment-naive patients. Raltegravir use is associated with infrequent lipid elevations, low rates of metabolic abnormalities, and evidence of long-term antiretroviral durability when compared with efavirenz. When a coformulated, once daily integrase inhibitor containing combination becomes available many providers may switch to this as their first-line treatment of choice, based on reduced pill burden and improved convenience. However, the use of the Quad will be constrained by its associated drug–drug interactions and lipid abnormalities.

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Conflicts of interest

The author is an investigator on the STARTMRK study, and was formerly a member of the Merck antiretroviral advisory board.

No funding was received for this work from any agency or organization.

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 488–489).

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This study demonstrates the long-term antiretroviral activity of raltegravir. Raltegravir was not only virologically noninferior to efavirenz, but was also better tolerated. Lipid abnormalities were less common in patients receiving raltegravir. Patients in the raltegravir arm also gained less total body fat over 3 years.

11. DeJesus E, Rockstroh JK, Lennox JL, et al. Raltegravir (RAL)-based Therapy Demonstrates Superior Virologic Suppression and Immunologic Response Compared with Efavirenz (EFV)-based Therapy, with a Favorable Metabolic Profile, Through 4 Years in Treatment-naïve Patients: 192 Week Results from STARTMRK [Abstract 405]. In: IDSA 49th Annual Meeting. Boston; 20–23 October, 2011.
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In this study once daily raltegravir took longer than twice-daily raltegravir to produce virologic suppression, and was more likely to result in virologic failure. Despite this, 83.2% of participants in the once daily group achieve virologic suppression. This may be a treatment option for patients with a low viral load and a T-cell count more than 200 cells/μlif no other first-line options are available.

15. Croce F, Vitello P, Dalla Pria A, et al. Severe Raltegravir Associated Rhabdomyolysis: a Case Report and Review of the Literature. Int J STD AIDS 2010; 21:783–785.
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Once daily darunavir, when given with twice daily ritonavir, did not produce adequate virologic suppression.

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22▪▪. Cohen C, Elion R, Ruane P, et al. Randomized, Phase 2 Evaluation of Two Single Tablet Regimens Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Versus Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate for the initial treatment of HIV infection. AIDS 2011; 25:F7–F12.

In this small trial the fixed-dose combination that contained elvitegravir appeared equivalent to a fixed-dose combination containing efavirenz. The elvitegravir containing combination was also better tolerated. These results indicated that the ‘Quad’ pill had sufficient antiviral activity to move forward into larger clinical trials.

23. Sax P, DeJesus E, Mills A, et al. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir (Quad) Has Noninferior Efficacy and Favorable Safety Compared to Efavirenz/Emtricitabine/Tenofovir in Treatment-Naïve HIV-1 + Subjects [Abstract 101]. In: 19th Conference on Retroviruses and Opportunistic Infections. Seattle; 5–8 March, 2012.
24. DeJesus E, Rockstroh J, Henry K, et al. Week 48 Results of an Ongoing Global Phase 3 Study Comparing Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate with Atazanavir/Ritonavir Boosted Plus Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment Naïve HIV-1 + Subjects Showing Efficacy, Safety, and Pharmacokinetics [Abstract 627]. In: 19th Conference on Retroviruses and Opportunistic Infections. Seattle; 5–8 March, 2012.
25. Song I, Borland J, Chen S, et al. Effect of Food on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir. Antimicrob Agents Chemother 2012; 56:1627–1629.
26. Canducci F, Ceresola ER, Boeri E, et al. Cross-resistance Profile of the Novel Integrase Inhibitor Dolutegravir (S/GSK1349572) Using Clonal Viral Variants Selected in Patients Failing Raltegravir. J Infect Dis 2011; 204:1811–1815.
27▪▪. Min S, Sloan L, DeJesus E, et al. Antiviral Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Dolutegravir as 10 day monotherapy in HIV-1-infected adults. AIDS 2011; 25:1737–1745.

In this dose ranging study, a 50 mg dose of dolutegravir given as monotherapy reduced viral load by greater than 1.5 log10. This result was achieved without any pharmacologic booster, and with once daily dosing of the dolutegravir. Lower doses of the dolutegravir were less effective, so the 50 mg dose moved forward into phase 2 clinical trials.

28. van Lunzen J, Maggiolo F, Arribas JR, et al. Once Daily Dolutegravir (S/GSK 134-9572) in Combination Therapy in Antiretroviral-Naïve Adults with HIV: Planned Interim 48 Week Results from Spring-One, a Dose Ranging, Randomized, Phase 2b Trial. Lancet Infect Dis 2012; 12:111–118.

HIV-1; integrase inhibitor; treatment naive

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