Median CD4+ cell counts increased from baseline to week 96 in all treatment groups and were numerically greater with DTG than EFV (Fig. 2). The median increase from baseline in CD4+ cells was 338 cells/μl with DTG (all treatment groups combined) compared with 301 cells/μl with EFV (P = 0.155).
Through week 96 of the study, six participants reported new HIV-associated conditions: four participants had Herpes zoster [DTG 10 mg (n = 2), DTG 50 mg (n = 1), and EFV (n = 1)], one participant (DTG 50 mg) developed Burkitt's lymphoma, and one participant (DTG 10 mg) died (in a traffic accident). Two cases of Herpes zoster and the development of Burkitt's lymphoma were previously reported in the 48-week analysis .
The adverse event profile overall was similar to what was seen at week 48. At week 96, adverse events were reported by 92% of participants each who received DTG (all groups combined) and who received EFV (Table 2). There were no clinically significant dose-related trends in adverse events in participants who received DTG. Drug-related adverse events were reported for a smaller proportion of participants who received DTG compared with EFV (47 and 62%, respectively; Table 2). Nausea and headache occurred more frequently with DTG, whereas dizziness, rash, insomnia, and fatigue occurred more frequently with EFV. Between weeks 48 and 96, two participants receiving DTG (motor vehicle accident and lipoatrophy) and one participant receiving EFV (fatigue) withdrew due to adverse events. A total of 24 participants (12%) reported SAEs through week 96 (11 and 14% with DTG and EFV, respectively; Table 2). SAEs leading to permanent discontinuation of study drug included Burkitt's lymphoma (DTG 50 mg), suicide attempt (EFV), and multiple injuries/road traffic accident (DTG 10 mg). Two SAEs were considered possibly related to study drug: myocardial infarction in a individual with a smoking history and hyperlipidemia who received DTG 50 mg along with TDF/FTC, and a suicide attempt in a participant who received EFV along with ABC/3TC, which was previously described .
A summary of treatment-emergent clinical chemistry toxicities for selected laboratory parameters is presented in Table, Supplemental Digital Content 2, http://links.lww.com/QAD/A338. Two participants had grade 3 or 4 elevations in alanine aminotransferase (ALT; without concomitant bilirubin elevations) and were subsequently diagnosed with acute hepatitis C infection: one participant who received DTG 25 mg had a grade 3 elevation in ALT and continued the study, and one participant who received EFV had a grade 4 elevation in ALT and was discontinued from the study at week 84 for meeting the liver toxicity stopping criteria. A similar proportion of participants who received DTG and EFV had grade 3 or 4 lipase elevations (5 vs. 4%, respectively), all of which were asymptomatic and spontaneously resolved. Grade 1 to 2 increases in bilirubin were noted with DTG but did not correlate with changes in other liver chemistries (e.g. ALT). Grade 3 and 4 elevations in creatine kinase were only reported in participants who received DTG and were without a dose-related trend. Most elevations in creatine kinase were asymptomatic and related to preceding exercise, resolved spontaneously, and did not lead to discontinuation of study drug.
As noted in the 48-week analysis, a small mean increase in serum creatinine was observed at week 1 with DTG that remained stable through week 24 and then declined by week 48 (see Table, Supplemental Digital Content 3, http://links.lww.com/QAD/A338, which shows a summary of serum creatinine and urine protein) . At week 96, there was a relative increase in mean serum creatinine from week 48 in both the DTG and EFV groups. However, the mean change from baseline in creatinine at week 96 was similar to that observed at week 24 for all DTG doses and for EFV. As previously reported at week 48 , the mean change from baseline in creatinine did not appear to be driven by NRTI backbone therapy. Quantitative assessments of urine albumin:creatinine ratio indicated that there was no evidence of higher levels of urinary albumin in patients who received DTG compared with EFV at week 96 (see Table, Supplemental Digital Content 3, http://links.lww.com/QAD/A338).
At 96 weeks, mean changes in cholesterol parameters were lower with DTG than EFV, but mean changes in triglycerides were variable across the DTG treatment groups and the EFV group. There were no clinically significant differences in maximum toxicity changes in lipid parameters noted between treatment with DTG and EFV.
No clinically significant changes in corrected QT or vital signs were noted for either DTG or EFV.
SPRING-1 is the first long-term (96-week) study of DTG in treatment-naive individuals with HIV-1. The high early response rate for DTG (≥90% had HIV-1 RNA <50 copies/ml ) was sustained for the selected 50 mg q.d. dose through 96 weeks. The proportion of participants with HIV-1 RNA less than 50 copies/ml at 96 weeks was 88% with DTG 50 mg, the dose selected for phase III evaluation, and 79 and 78% for DTG 10 and 25 mg, respectively (using TLOVR). The DTG response rates compared favorably with that observed for EFV (72%), which was consistent with previously reported EFV response rates . When using MD = F, the response rates for the lower doses are typically higher than the TLOVR response rates (87, 80, and 86% for DTG 50, 25, and 10 mg, respectively) and still better than the corresponding virologic response seen in the EFV arm (78%). The MD = F analysis is a close approximation to the FDA Snapshot analysis, which was used in the DTG phase III studies [14,15]. The response rates for DTG in this participant population are similar to those reported for RAL and EVG at the marketed dose in studies of similar design [8,16]. Thus, the response rates for all doses of DTG assessed in this study were similar to those observed with other potent antiviral therapies in a treatment-naive population.
Data from recent DTG phase III studies SPRING-2 and SINGLE, both conducted in treatment-naive individuals and utilizing the selected DTG 50 mg q.d. dose, also compare favorably with data reported for other INIs and support the selected DTG dose from SPRING-1. The response rate for DTG in the SPRING-2 study was noninferior to RAL at 48 weeks (88% for DTG vs. 85% for RAL) using the FDA Snapshot analysis . The response rate for a regimen of DTG along with ABC/3TC in the SINGLE study was superior to TDF/FTC/EFV (Atripla; Bristol-Myers Squibb, Princeton, New Jersey, USA, and Gilead Sciences Inc.) at 48 weeks (88 vs. 81%, respectively; P = 0.003) .
There were no confirmed PDVFs (HIV-1 RNA ≥400 copies/ml) in participants who received the phase III-selected dose (DTG 50 mg). Furthermore, the rates of confirmed PDVF in participants who received DTG 10 mg, DTG 25 mg, or EFV were low , and there were no new cases after week 48. No INI resistance was observed in participants receiving any of the DTG doses through week 96, and in the 25 and 50 mg DTG dose arms, no participants developed NRTI resistance. In contrast, half of participants with PDVF in a similar study of RAL developed INI resistance by week 96 , and over half of the participants meeting criteria for resistance testing in a similar and recent study of EVG developed INI resistance by week 96 .
The safety profile of DTG at 96 weeks was favorable, with no dose-response relationship with adverse events and fewer discontinuations due to adverse events and fewer drug-related adverse events than EFV. Tolerability was also generally better with DTG in comparison with EFV, as higher rates of drug-related dizziness, rash, insomnia, and fatigue were noted with EFV, events known to be associated with the drug .
Our dose-selection strategy for DTG was to select the maximum tolerated dose to compensate for potential reductions in exposure caused by drug interactions without the need for dose adjustment, specifically in the treatment-experienced, INI-naive patient population. Additionally, higher doses could provide a pharmacological barrier to the development of antiviral resistance. Therefore, the DTG 50 mg q.d. dose was selected for phase III studies with INI-naive patient populations. At week 96, the safety profile was comparable across DTG doses, and the efficacy at the 50 mg q.d. selected dose continued to be robust. Additionally, no participants at this dose developed PDVF or evidence of resistance to either INIs or the NRTI backbone. The data at week 96 and the data from the DTG phase III studies, thus, continue to support the phase III dose selection of DTG 50 mg q.d. for the INI-naive population. As all participants randomized to DTG were given the opportunity to switch to the 50 mg q.d. dose at week 96, longer-term safety evaluation is ongoing in this study.
Small, nonprogressive increases in serum creatinine observed with DTG through 96 weeks were similar to those described previously at 48 weeks  and have been observed in other studies [12,18]. Based on the week 96 data from SPRING-1, the small, nonprogressive increases (∼12% or 10.1 μmol/l for 50 mg) in creatinine observed with DTG represent a resetting of the baseline creatinine level due to nonpathologic blockade of the organic cation transporter 2 responsible for tubular creatinine secretion  rather than nephrotoxicity, as evidenced by the lack of withdrawals due to renal adverse events and lack of significant increases (e.g. grade 3 or 4) in creatinine. This has been confirmed in two large phase III studies of DTG in treatment-naive individuals [14,15].
Although changes in urine protein (dipstick) results were observed, without time-dependency or dose-dependency to these results at week 48 , quantitative assessments (spot urine albumin:creatinine ratio) were similar across DTG doses and between DTG and EFV at week 48 and week 96. Further evaluation is being conducted in the adult phase III and pediatric phase II studies.
The study did have some limitations. First, the study population was not fully representative of the global HIV population. Participants with advanced immunosuppression (screen CD4+ cell count <200 cells/μl) and chronic active hepatitis B (as evidenced by hepatitis B surface antigen) were excluded. The study was conducted predominately in high-income countries (i.e. United States and western Europe) and had requirements for frequent visits, which resulted in a relatively low representation of women and nonwhite participants. Second, as this was a phase IIb study, the sample size was not large, and the study was not powered for direct statistical testing vs. EFV nor within subgroups. Third, EFV served as a control arm, and as such, participants and investigators were not blinded to treatment assignment of DTG or EFV. As the purpose of the study was dose-finding for DTG, only the dose of DTG was blinded to allow for comparisons. The ongoing phase III studies involve a greater number of participants in general, and in particular, a greater diversity in terms of race and sex. The sample sizes in the phase III studies also make subgroup explorations more reasonable.
In conclusion, once-daily DTG with two NRTIs was efficacious through 96 weeks at all doses studied, with 88% of participants who received the phase III-selected dose of 50 mg achieving plasma HIV-1 RNA less than 50 copies/ml. No INI mutations had emerged by 96 weeks with any dose of DTG, and no participants receiving DTG 50 mg q.d. developed PDVF or resistance mutations to INIs or NRTIs. DTG had a favorable safety profile to 96 weeks. Overall, the durable efficacy and tolerability of DTG 50 mg q.d. in combination with two NRTIs at 96 weeks support the selection of this dose for continued phase III development in INI-naive individuals.
All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Author contributions were as follows: H-J.S., J.R., A.L., E.V., F.P., and F.F. were SPRING-1 investigators and wrote and critically reviewed the article; S.A. performed the statistical analysis and wrote and critically reviewed the article; M.S.C. was the protocol virologist and wrote and critically reviewed the article; N.F. was the clinical study lead and wrote and critically reviewed the article; and S.M. was the dolutegravir lead physician and wrote and critically reviewed the article.
The authors wish to thank the SPRING-1 study participants and their families and caregivers for participation in the study. The authors also wish to acknowledge the following individual for editorial assistance during the development of this article: Patricia Zipfel.
Conflicts of interest
This work was supported by ViiV Healthcare.
H.-J.S. has received consulting fees or honorarium from Pfizer, ViiV Healthcare, and GlaxoSmithKline; has been provided support for travel to meetings for the study or other purposes from GlaxoSmithKline and ViiV Healthcare; has had writing support from ViiV Healthcare; has been provided documentation fees for clinical trial documentation from GlaxoSmithKline; has been an advisory board member for Abbott, Gilead Sciences, ViiV Healthcare, Boehringer-Ingelheim, Merck Sharp & Dohme, and Janssen-Cilag; has been a consultant for Gilead Sciences, ViiV Healthcare, Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen-Cilag, and Boehringer-Ingelheim; has provided expert testimony for Bristol-Myers Squibb; has received payment for lectures including service on speakers bureaus from Abbott, Bristol-Myers Squibb, ViiV Healthcare, Gilead Sciences, Janssen-Cilag, and Boehringer-Ingelheim; and has received payment for development of educational presentations from Bristol-Myers Squibb, Janssen-Cilag, and ViiV Healthcare.
J.R. has received an educational grant from GlaxoSmithKline and ViiV Healthcare; has board membership with Abbott, Astellas, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Tibotec-Janssen, and ViiV Healthcare; is employed by the University of Montpellier and the Hospital of Montpellier; has grants/grants pending from the French National Agency for Research on AIDS and viral hepatitis (ANRS); has received payment for lectures including service on speakers bureaus for Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Tibotec, and ViiV Healthcare; and has been provided travel/accommodations/meeting expenses from Abbott, Astellas, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Tibotec-Janssen, and ViiV Healthcare.
A.L. has been an advisor and speaker for Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, ViiV Healthcare, Pfizer, Roche, GlaxoSmithKline, and Janssen-Cilag; and has participated as principal investigator for several trials sponsored by Abbott, Bristol-Myers Squibb, Pfizer, Merck Sharp & Dohme, Tibotec, Roche, ViiV Healthcare, and GlaxoSmithKline.
E.V. has no conflicts of interest to disclose.
F.P. has received grants from GlaxoSmithKline; has fulfilled board membership for Abbott, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, and ViiV Healthcare; and has received payment for lectures including service on speakers bureaus from Abbott, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, and ViiV Healthcare.
F.F. has grants/grants pending from ViiV Healthcare, Abbott, Boehringer-Ingelheim, Gilead Sciences, Janssen, and Vertex; and has received payment for lectures including service on speakers bureaus from Janssen, Merck Sharp & Dohme, and ViiV Healthcare.
S.A., M.S., N.F., and S.M. are employees of GlaxoSmithKline and as a result receive stock options and support for travel to study-related meetings.
The SPRING-1 Team included the following investigators: J.R., I. Cotte, F. Raffi, C. Katlama, P. Yeni, J-M. Molina, J. van Lunzen, H-J.S., M. Stoll, T. Lutz, G. Carosi, F. Maggiolo, G. Rizzardinin, A. Lazzarin, O Tsybakova, E Voronin, A Rakhmanova, F Pulido, J Arribas, S Moreno-Guillen, J Gatell, B. Lotet, E. DeJesus, F. Felizarta, T. Hawkins, J. Lalezari, I. McCurdy, G. Rischmond, S. Schneider, L. Sloan, J. Torres, B. Young, T. Vanig, and M. Mustafa.
1. Powderly WG. Integrase inhibitors in the treatment of HIV-1 infection
. J Antimicrob Chemother
2. DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, et al. for the 183-0101 Study TeamAntiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients
. J Acquir Immune Defic Syndr
3. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al. for the BENCHMRK Study TeamsRaltegravir with optimized background therapy for resistant HIV-1 infection
. N Engl J Med
4. Zolopa AR, Berger DS, Lampiris H, Zhong L, Chuck SL, Enejosa JV, et al. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial
. J Infect Dis
5. Lennox JL, DeJesus E, Berger DS, Lazzarin A, Pollard RB, Ramalho Madruga JV, et al. for the STARTMRK InvestigatorsRaltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses
. J Acquir Immune Defic Syndr
6. Markowitz M, Nguyen B-Y, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al. the Protocol 004 Part II Study TeamRapid 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
7. Eron JJ Jr, Rockstroh JK, Reynes J, Andrade-Villanueva J, Ramalho-Madruga JV, Bekker L-G, et al. for the QDMRK InvestigatorsRaltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 noninferiority trial
. Lancet Infect Dis
8. Zolopa A, Sax PE, DeJesus E, Mills A, Cohen C, Wohl D, et al.A randomized, double-blind comparison of co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir DF versus efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr
2013. [Epub ahead of print]
9. Blanco J-L, Varghese V, Rhee S-Y, Gatell JM, Shafer RW. HIV-1 integrase inhibitor resistance and its clinical implications
. J Infect Dis
10. Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults
11. Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, et al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor
. Antimicrob Agents Chemother
12. Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A, et al. for the VIKING Study GroupSafety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING study
. J Infect Dis
13. van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial
. Lancet Infect Dis
14. Raffi F, Rachlis A, Stellbrink H-J, Hardy WD, Torti C, Orkin C, et al. for the SPRING-2 study groupOnce-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, noninferiority SPRING-2 study
15. Walmsley S, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, et al.Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results – SINGLE (ING114467) [abstract H-556b].
In: Program and abstracts of the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 9–12 September 2012; San Francisco, California, USA.
16. Markowitz M, Nguyen B-Y, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al. for the Protocol 004 Part II Study TeamSustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection
. J Acquir Immune Defic Syndr
17. Sustiva [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2011.
18. Koteff J, Borland J, Chen S, Song I, Peppercorn A, Koshiba T, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects
. Br J Clin Pharmacol
Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
antiretroviral agents; HIV integrase; HIV integrase inhibitors; HIV-1; reverse transcriptase inhibitors