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Virologic suppression and CD4+ cell count recovery after initiation of raltegravir or efavirenz-containing HIV treatment regimens

Edwards, Jessie K.a; Cole, Stephen R.a; Hall, H. Ireneb; Mathews, W. Christopherc; Moore, Richard D.d; Mugavero, Michael J.e; Eron, Joseph J.f For the CNICS investigators

Author Information
doi: 10.1097/QAD.0000000000001668

Abstract

Introduction

Integrase inhibitors have expanded first-line treatment options for people living with HIV. Randomized trials have demonstrated that patients initiating regimens containing integrase inhibitors experience more rapid plasma HIV RNA suppression following treatment initiation and fewer adverse events than patients initiating other first-line regimens [1–9]. Furthermore, addition of an integrase inhibitor to an initial treatment regimen improves tolerability for patients with treatment-limiting toxicity with reverse transcriptase or protease inhibitors [10] and increases treatment efficacy for patients with prior treatment failure [7,11–14].

For these reasons, many patients new to antiretroviral therapy (ART) have initiated regimens containing integrase inhibitors since the first drug in this class, raltegravir, was approved on 12 October 2007. Here, we use observational data on ART-naïve patients from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) to compare virologic suppression [15,16] and CD4+ cell count recovery over 30 months after initiation of an ART regimen containing raltegravir in combination with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) with a regimen containing efavirenz and the same reverse transcriptase inhibitor backbone. We account for differences in patient characteristics between treatment groups (i.e., channeling bias) and between patients in CNICS and the population of people with diagnosed HIV in the United States (lack of generalizability) using inverse probability weighting. Examining the immunologic trajectories of patients in an observational clinical setting reflects the performance of these regimens in clinical care, free from Hawthorne effects, and selective enrollment into a trial population.

Methods

Study sample

Patients with a detectable viral load who initiated an ART regimen containing TDF and FTC and raltegravir or efavirenz at a CNICS site between 12 October 2007 and 31 December 2014 and had not previously initiated combination ART, defined as treatment with three or more antiretroviral drugs, were eligible for inclusion in this analysis (N = 3060). Patients were excluded if they were missing information on transmission risk factor, race, sex, or baseline CD4+ cell count (n = 217), leaving 2843 patients in the cohort.

Patients were followed from initiation of one of the regimens of interest until death, loss to follow-up, or administrative censoring at 2.5 years (30 months) after study entry or on 31 December 2014. Patients were considered to be lost to follow-up after 12 months without a documented clinic visit in which CD4+ cell count or viral load was measured. Each CNICS site semiannually queries the United States Social Security Death Index and/or National Death Index to confirm reported deaths and record deaths not captured by the sites. Viral loads and CD4+ cell counts were collected during the course of routine HIV care at each CNICS site.

We present results of both an intent-to-treat analysis, in which patients remained in their initial treatment group regardless of whether or not they later switched regimens, and a per protocol analysis, in which patients were censored at any change in treatment regimen, with two exceptions: changes from the raltegravir regimen to another integrase inhibitor-based regimen (including fixed-dose combination of elvitegravir, cobicistat, TDF, and FTC or dolutegravir); and changes from the efavirenz regimen to the nonnucleoside reverse transcriptase inhibitor regimen of rilpivirine, TDF, and FTC.

Institutional review boards at each site approved CNICS study protocols, and patients provided written informed consent to be included in the CNICS cohort or contributed administrative and/or clinical data with a waiver of written informed consent where approved by local institutional review boards.

Target population

Results were generalized to a target population defined by all people with diagnosed HIV in the Unites States between 2008 and 2014 to extrapolate study findings to the larger population of people living with HIV in the United States. Characteristics of this population, including race/ethnicity, sex, age group, and likely mode of transmission (i.e., MSM, IDU) were provided by the Centers for Disease Control and Prevention from national HIV surveillance data [17,18].

Statistical methods

We compared the proportion of patients alive and virally suppressed and the mean CD4+ cell count improvement over 30 months after ART initiation between patients initially prescribed the raltegravir and efavirenz regimens. We estimated the difference in CD4+ cell count recovery between treatment groups by comparing the mean CD4+ cell count at baseline to the mean CD4+ cell count 30 months later in each treatment group. The proportion of patients alive and suppressed at each timepoint was estimated using the method formally described by Gouskova et al.[15,16], adapted to account for nonrandom treatment assignment and the competing event of death, and the 30-month restricted mean time alive and suppressed was the sum of this proportion over the 30-month follow-up period.

We accounted for differences between patients in the study sample and the US population of people with diagnosed HIV, differences in baseline characteristics between patients prescribed each regimen, and informative censoring because of loss to follow-up or regimen switching using inverse probability weights. Technical details can be found in Appendix 1, http://links.lww.com/QAD/B177.

Results

Of the 2843 patients included in the study, 2476 initiated the efavirenz-containing regimen and 367 initiated the raltegravir-containing regimen (Table 1). In the intent-to-treat analysis weighted to account for sampling, nonrandom treatment assignment, and informative censoring, patients initiating efavirenz spent an average of 556 days of the 913-day study period alive and suppressed, while patients initiating raltegravir spent an average of 630 days in this state, for a difference of 74 [95% confidence interval (CI): 41, 106] days in favor of raltegravir. This difference in time suppressed is primarily driven by more rapid suppression under raltegravir than efavirenz. The probability of being alive and suppressed after 2 years was similar in the efavirenz group (70.3%) and in the raltegravir group (71.5%) (Fig. 1). The advantage of raltegravir in terms of number of days virally suppressed was even greater in the ‘per protocol’ analysis, in which patients were censored at a change in regimen (difference: 80 days; 95% CI: 50, 117).

Table 1
Table 1:
Demographics and clinical characteristics at study entry of 2843 patients who initiated an antiretroviral therapy regimen containing efavirenz or raltegravir in combination with tenofovir DF/emtricitabine at a CNICS site between 12 October 2007 and 31 December 2014 at eight US clinical sites.
Fig. 1
Fig. 1:
Probability of being alive and in a state of suppression before viral rebound in the intent to treat analysis for 2476 patients who initiated the efavirenz-containing regimen and 367 patients who initiated the raltegravir-containing regimen in the Centers for AIDS Research Network of Integrated Clinical System between 12 October 2007 and 31 December 2014 over 30 months of follow-up, weighted to generalize results to the US population of people with HIV diagnosed between 2008 and 2014 and to account for nonrandom treatment assignment and informative censoring.

CD4+ cell count improved over time from treatment initiation for both groups. In the weighted intent-to-treat analysis, CD4+ cell count improvement over the 30-month period was 215 cells/μl for the efavirenz group and 247 cells/μl for raltegravir group, for a difference of 32 (95% CI: 14, 49) cells/μl in favor of raltegravir. Results were similar in the per protocol analysis (difference: 30 cells/μl; 95% CI: 3, 57). Full tabular and graphical results are presented in Appendix 2, http://links.lww.com/QAD/B177.

Discussion

Patients receiving raltegravir had a modest advantage in terms of the mean time spent alive and virally suppressed over patients receiving efavirenz during the 30-month period following treatment initiation. As might be expected, this advantage was driven by initial viral suppression; patients initiating the raltegravir regimen experienced a shorter time to a measured viral load under 50 copies/ml than patients receiving efavirenz. The clinical impact of the difference in days suppressed for an individual patient is uncertain, but this difference may have an impact on onward transmission. In addition, reducing viral burden over time may play a role in reducing HIV-related inflammation [19,20] and other negative effects of chronic HIV infection [21–23].

Our result that patients initiating raltegravir experienced more rapid viral suppression than patients initiating efavirenz aligns with findings from randomized trials comparing efavirenz and raltegravir [1,24]. In the STARTMRK trial, long-term viral suppression over 5 years appeared to be superior in the raltegravir arm than the efavirenz arm, though much of this difference was because of treatment discontinuation in the efavirenz arm, which was treated as virologic failure [25]. The difference in CD4+ cell count improvement was similar between this study (30 cells/μl over approximately 130 weeks) and the STARTMRK trial (37 cells/μl over 156 weeks) [26], though participants in STARTMRK who changed therapy, had virologic rebound, or experienced intolerance were discontinued from study, which may have influenced CD4+ response results. The clinical benefits of relatively small but significant differences in CD4+ cell response are unknown in the context of long-term (decades long) ART.

The current study complements the results from randomized trials. Here, we estimated that raltegravir was associated with superior viral suppression among patients in routine care settings under real-world adherence patterns, despite its higher pill burden. Even trials reporting results from intent-to-treat analyses, which typically do not account for nonadherence, are subject to Hawthorne effects in which participants may display different adherence patterns than they would under real world conditions. Accordingly, these trials may over or underestimate the effectiveness of a given treatment regimen in routine clinical care [27]. In addition, results from this study in the CNICS cohort were generalized to the US population of people with diagnosed HIV to provide a population-level estimate of observed study effects [28]. Finally, because regimen switches for reasons other than virologic failure (e.g., tolerability, toxicity, or convenience) are increasingly common [29], we did not consider regimen switch to be virologic failure.

The potential for regimen switches in the context of routine care may explain why the estimated effect of raltegravir in the intent-to-treat analysis appeared to be attenuated compared with results from STARTMRK. For example, in the intent-to-treat analysis, positive results from patients who switched from efavirenz to an alternative therapy for reasons of toxicity or tolerability would be seen as beneficial outcomes for initial prescription of efavirenz. Therefore, these results may show efavirenz to perform better than it appeared to perform in trials that treated regimen switch as virologic failure. In addition, initiating therapy with a regimen that had suboptimal outcomes in clinical trials may have improved outcomes in clinical practice, where switching therapy is frequently used to manage even mild or moderate adverse events. Such frequent switching may result in a smaller clinical impact of the initial therapy choice than seen in trials that treat regimen switching as failure. Switching therapy for intolerance has little clinical impact provided the switch is not accompanied by rebound in plasma HIV RNA, which carries a resistance risk that can be considered a life-long adverse event. Appendix 3, http://links.lww.com/QAD/B177 reports counts of patients in each arm who switched regimens. As expected, the estimated benefit of the raltegravir regimen in terms of number of days suppressed was greater when patients were censored at these changes in treatment regimen in the per-protocol analysis than in the intent-to-treat analysis.

In this study, patients receiving raltegravir spent more days alive and virally suppressed and had superior CD4+ cell count recovery than patients receiving efavirenz over the 30 months following treatment initiation. Optimizing the amount of time spent in a state of viral suppression is important when considering antiretroviral treatment plans not only to improve survival among people living with HIV [30] but also to reduce onward transmission from people living with HIV to their HIV-uninfected partners [31–36].

Acknowledgements

The research was supported in part by the National Institutes of Health (grants K01AI125087, R01AI100654, P30AI50410, and R24AI067039); roles of authors: J.K.E., S.R.C., H.I.H., and J.J.E. designed the study. R.D.M., W.C.M., J.J.E., S.R.C., and M.J.M. played a role in development of the CNICS cohort. J.K.E. drafted the manuscript. All authors revised the manuscript.

Conflicts of interest

There are no conflicts of interest.

References

1. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. STARTMRK investigators. 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; 374:796–806.
2. Lennox JL, Dejesus E, Berger DS, Lazzarin A, Pollard RB, Ramalho Madruga JV, et al. STARTMRK Investigators. Raltegravir versus Efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune Defic Syndr 2010; 55:39–48.
3. Young B, Vanig T, DeJesus E, Hawkins T, St Clair M, Stancil B, Ha B. Shield Study Team. 96-week results of a pilot study of abacavir/lamivudine and raltegravir in antiretroviral-naïve HIV-1-infected patients: the SHIELD trial. HIV Clin Trials 2011; 12:228–233.
4. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al. Protocol 004 Part II Study Team. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir Immune Defic Syndr 2009; 52:350–356.
5. Eron JJ, Rockstroh JK, Reynes J, Andrade-Villanueva J, Ramalho-Madruga JV, Bekker LG, et al. ONCEMRK Study Group. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 noninferiority trial. Lancet Infect Dis 2011; 11:907–915.
6. Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, et al. GS-US-236-0102 study team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379:2439–2448.
7. Raffi F, Wainberg MA. Multiple choices for HIV therapy with integrase strand transfer inhibitors. Retrovirology 2012; 9:110.
8. Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, et al. SINGLE Investigators. Dolutegravir plus abacavir–lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013; 369:1807–1818.
9. Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, et al. ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; 383:2222–2231.
10. Nguyen A, Calmy A, Delhumeau C, Mercier I, Cavassini M, Mello AF, et al. A randomized cross-over study to compare raltegravir and efavirenz (SWITCH-ER study). AIDS 2011; 25:1481–1487.
11. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359:339–354.
12. Eron JJ, Cooper DA, Steigbigel RT, Clotet B, Gatell JM, Kumar PN, et al. BENCHMRK Study Teams. 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; 13:587–596.
13. Buchacz K, Wiegand R, Armon C, Chmiel JS, Wood K, Brooks JT, Palella FJ Jr. Long-term immunologic and virologic responses on raltegravir-containing regimens among ART-experienced participants in the HIV Outpatient Study. HIV Clin Trials 2015; 16:139–146.
14. Dow DE, Bartlett JA. Dolutegravir, the second-generation of integrase strand transfer inhibitors (INSTIs) for the treatment of HIV. Infect Dis Ther 2014; 3:83–102.
15. Gouskova NA, Cole SR, Eron JJ, Fine JP, Carolina N. Viral suppression in HIV studies: combining times to suppression and rebound. Biometrics 2014; 70:441–448.
16. Edwards JK, Cole SR, Adimora A, Fine J, Martin J, Eron J. Illustration of a measure to combine viral suppression and viral rebound in studies of HIV therapy. J Acquir Immune Defic Syndr 2015; 68:241–244.
17. Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data-United States and 6 dependent areas-2013; 2015
18. Cohen SM, Gray KM, Ocfemia MC, Johnson AS, Hall HI. The status of the National HIV Surveillance System, United States, 2013. Public Health Rep 2014; 129:335–341.
19. Tebas P, Henry WK, Matining R, Weng-Cherng D, Schmitz J, Valdez H, et al. Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk. PLoS One 2008; 3:e2021.
20. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
21. Schrack JA, Jacobson LP, Althoff KN, Erlandson KM, Jamieson BD, Koletar SL, et al. Effect of HIV-infection and cumulative viral load on age-related decline in grip strength. AIDS 2016; 30:2645–2652.
22. Mugavero MJ, Napravnik S, Cole SR, Eron JJ, Lau B, Crane HM, et al. Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) Cohort Study. Viremia copy-years predicts mortality among treatment-naive HIV-infected patients initiating antiretroviral therapy. Clin Infect Dis 2011; 53:927–935.
23. Cole SR, Napravnik S, Mugavero MJ, Lau B, Eron JJ, Saag MS, et al. Copy-years viremia as a measure of cumulative human immunodeficiency virus viral burden. Am J Epidemiol 2010; 171:198–205.
24. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al. Protocol 004 Part II Study Team. 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. J Acquir Immune Defic Syndr 2007; 46:125–133.
25. Rockstroh JK, DeJesus E, Lennox JL, Yazdanpanah Y, Saag MS, Wan H, et al. STARTMRK Investigators. 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.
26. Rockstroh JK, Lennox JL, DeJesus E, Saag MS, Lazzarin A, Wan H, et al. Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis 2011; 53:807–816.
27. Westreich D, Edwards JK. Invited commentary: every good randomization deserves observation. Am J Epidemiol 2015; 182:857–860.
28. Lesko CR, Cole SR, Hall HI, Westreich D, Miller WC, Eron JJ, et al. CNICS Investigators. The effect of antiretroviral therapy on all-cause mortality, generalized to persons diagnosed with HIV in the USA, 2009-11. Int J Epidemiol 2016; 45:140–150.
29. Eaton EF, Tamhane AR, Burkholder GA, Willig JH, Saag MS, Mugavero MJ. Unanticipated effects of new drug availability on antiretroviral durability: implications for comparative effectiveness research. Open Forum Infect Dis 2016; 3:ofw109.
30. Lesko CR, Edwards JK, Moore RD, Lau B. A longitudinal HIV care continuum: 10-year restricted mean time in each care continuum stage after enrollment in care, by history of injection drug use. AIDS 2016; 30:2227–2234.
31. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 2000; 342:921–929.
32. Attia S, Egger M, Müller M, Zwahlen M, Low N. Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS 2009; 23:1397–1404.
33. Marks G, Gardner LI, Rose CE, Zinski A, Moore RD, Holman S, et al. Time above 1500 copies. AIDS 2015; 29:947–954.
34. Hernán MA, Mcadams M, Mcgrath N, Lanoy E, Costagliola D. Observation plans in longitudinal studies with time-varying treatments. Stat Methods Med Res 2009; 18:26–52.
35. Westreich D, Edwards JK, Stuart EA, Lesko CR, Cole SR. Transportability of trial results using inverse odds of sampling weights. Am J Epidemiol 2017; In press.
36. Howe CJ, Cole SR, Westreich DJ, Greenland S, Napravnik S, Eron JJ. Splines for trend analysis and continuous confounder control. Epidemiology 2011; 22:874–875.
Keywords:

efavirenz; HIV; HIV integrase inhibitors; sustained virologic response; viral load

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