Most modern combination antiretroviral therapies (cARTs) include 3 drugs from at least 2 drug classes and therefore the regimens often are triple-tablet regimens (TTR). Good adherence to cART is among the key determinants of successful HIV treatment and is essential to minimize virological failure and emergence of drug resistance.1 Reducing the pill burden by combining different drugs into fewer pills in fixed-dose combinations has been widely introduced into clinical practice to address this problem. Of importance, fixed-dose combinations reduce the potential for selective noncompliance and thus decrease the risk of development of virological resistance. Tenofovir, efavirenz, and emtricitabine have proved to be an efficient first-line cART regimen.2,3 The first once-daily single-tablet regimen (STR) including tenofovir, efavirenz, and emtricitabin (STR-TEE) (Atripla; Gilead Sciences Inc, Foster City, CA, and Bristol-Myers Squibb, New York City, NY), was approved in the US in 2006.4 Despite the fact that STR-TEE is not licensed in Europe for use in cART-naive patients, it is included in international recommendations and Danish national guidelines for initial cART.5–7
In a mathematical simulation, Walensky et al8 recently demonstrated that a switch from STR to TTR in the United States would initially yield annual savings of $920 million. The saving may however be a tradeoff in terms of a potential risk of decreased adherence, which may lead to virological failure and poor outcome.9–12 However, few clinical data support the effectiveness of STR versus TTR.
To obtain economic savings, HIV-infected patients in the Capital Region of Denmark in treatment with STR-TEE were switched from April 1, 2011 to a cheaper TTR including tenofovir, efavirenz, and lamivudine (TTR-TEL) and also cART-naive patients eligible for STR-TEE were started on TTR-TEL. We aimed to estimate the impact of the switch to TTR-TEL on antiretroviral effectiveness.
The study was divided in 2 parts and both included 2 time periods (period 1: April 1, 2010 to March 31, 2011; period 2: April 1, 2011 to March 31, 2012). Part 1 included cART-naive HIV-infected patients and compared individuals who initiated STR-TEE in period 1 with individuals who initiated TTR-TEL in period 2. Part 2 compared cART-experienced HIV-infected patients on STR-TEE in period 1 with patients on STR-TTE who were shifted to TTR-TEL in period 2. The main outcomes in both studies were virological suppression, development of 184V/I resistance mutation, CD4 cell count, and time to change of cART regimens.
The study included the 3 HIV treating centers in the region of Copenhagen, Denmark, and its suburbs that treat two-thirds of Danish HIV patients (Hillerød Hospital, Hvidovre Hospital, and Rigshospitalet). To obtain economic savings, all patients in these centers on STR-TEE were on the first visit after April 1, 2011 intended switched to TTR-TEL unless they had explicit adherence problems (defined by treating physician). The patients were informed that the changes were because of economic savings. As the changes were not part of a clinical trial but induced by regional guidelines, no ethical approval or consent was obtained. Also, cART-naive patients who after April 1, 2011 were eligible for start of STR-TEE were started on TTR-TEL. It was not an option for the patients to compensate the hospital for the price differences and thereby obtain STR-TEE.
The region of Copenhagen had a population of 1.7 million as of December 31, 2011, with an estimated HIV prevalence of approximately 0.2% in the adult population. Treatment including antiretroviral treatment is provided free of charge to all Danish HIV-infected patients, and HIV care and antiretroviral treatment are only provided at HIV treating centers.
The Danish HIV Cohort Study is a population-based prospective nationwide cohort study of all HIV-infected individuals 16 years or older at HIV diagnosis who are treated at Danish HIV centers after January 1, 1995. Individuals are consecutively enrolled, and multiple registrations are avoided through the use of the unique person identification number. Data are updated yearly and includes demographics, date of HIV diagnosis, route of HIV infection, AIDS defining events, date and cause of death, and antiretroviral treatment. CD4 cell counts and HIV-RNA measurements are extracted electronically from laboratory data files. The study is described in detail elsewhere.13
Genotypic HIV-1 resistance tests were obtained from the Danish HIV Sequence Database.14 All sequencing was performed using 04J94-32 ViroSeq HIV-1 Genotyping System, version 2.0 (Applied Biosystems, Foster City, CA) and analyzed according to the list of recommended mutations for surveillance of transmitted drug resistance by genotypic HIV-1 resistance.15
Prices for the 4 drugs and the number of STR-TEE tablets dispensed in the Capital region per month in the period April 1, 2010 to April 1, 2012 were obtained from the Hospital Pharmacy of the Capital Region.16 Generic lamivudine was not used in neither of the periods.
From Danish HIV Cohort Study, we identified all adult HIV-infected patients followed at 1 of the 3 HIV centers in the region of Copenhagen. For part 1, we included all patients who were cART naive and initiated treatment with STR-TEE in period 1, or initiated treatment with TTR-TEL in period 2. For this patient population study, inclusion was the date of STR-TEE/TTR-TEL initiation. Patients who did not have a viral load (VL) and CD4 test within 6 weeks before or after study inclusion were excluded. For part 2, we included all patients who were treated with STR-TEE on April 1, 2010 (date of study inclusion) or were treated with STR-TEE on April 1, 2011 and subsequently switched to TTR-TEL (study inclusion was date of switch to TTR-TEL). In part 2, patients who had not been continuously on STR-TEE for 1 year before study inclusion or did not have a VL and CD4 test within 6 weeks before or after study inclusion were excluded.
Demographics and characteristics of the study were tabled presenting as numbers, medians, and interquartile ranges. VL tests and CD4 cell measurements were grouped in 12-week intervals as described previously and the proportions with VL ≥50 copies per milliliter with 95% confidence intervals (CI) and the median CD4 cell count from 24 weeks before 48 weeks after study inclusion were determined.17 These analyses were stratified on gender and mode of transmission.
We also estimated the number of HIV patients experiencing virological failure in part 1 and part 2 of the study. In part 1, virological failure was defined as 1 VL >1000 copies per milliliter within 4 to 6 months or 1 VL >500 copies per milliliter in first VL test 6 months after date of cART initiation (date of study inclusion). In part 2, virological failure was defined as 2 consecutive VL >500 copies per milliliter within 1 year after date of study inclusion (HIV patients with VL ≥50 copies/mL at study inclusion were excluded from the analysis). If any of these HIV patients with viral failure had a genotypic resistance test performed, this was examined for 184V/I mutations.
We used cumulative incidence function to estimate the probability of switch to any new cART regimen 1 year after study inclusion, recognizing death as a competing risk.18 In these analyses, time was calculated from study inclusion to the first date of last clinical observation, 1 year after study inclusion, or date of death or emigration. The difference between probabilities with 95% CI for switch to any cART regimen was calculated in 2 ways: (1) not including a switch back to STR-TEE from TTR-TEL and (2) including a switch back to STR-TEE from TTR-TEL before April 1, 2012 (the date after which presumably all patients on TTR-TEL were switched back to STR-TEE). Differences in the number of cART-naive HIV patients initiating TTR-TEL and STR-TEE were evaluated by the χ2 test.
The study was approved by the Danish Data Protection Agency. SPSS statistical software, version 15.0 (Norusis; SPSS Inc, Chicago, IL) and R software, version 2.8.1 (R Development Core Team) was used for data analysis.
In part 1, 183 cART-naive patients initiated antiretroviral therapy in the period April 1, 2010 to March 31, 2011. A total of 120 (65.6%) of these patients initiated STR-TEE and 9 were excluded because of no available VL or CD4 leaving 111 (60.7%) in the study with a total of 73.0 person-years of follow-up (Fig. 1). Between April 1, 2011 and March 31, 2012, 141 initiated cART of whom 58 (41.1%) initiated TTR-TEL and 2 patients were excluded because of no available VL or CD4, leaving 56 (39.7%) in the study with a total of 39.2 person-years of follow-up. The fraction of cART-naive patients who initiated TTR-TEL in the period April 1, 2011 and March 31, 2012 was thereby lower than the fraction who initiated STR-TEE in the period April 1, 2010 to March 31, 2011 (P < 0.001).
For part 2, 570 and 695 patients were on STR-TEE on the April 1, 2010 and 2011, respectively, of whom 195 and 162 were excluded as they had not been continuously on STR-TEE for 1 year before study inclusion, 19 and 1, because they had no VL and CD4 available and 20, as they were not shifted to TTR because of anticipated compliance problems, leaving 356 and 512 patients in the study with 343.6 and 444.2 person-years of follow-up, respectively. Of the 532 candidate patients, 512 (96.2%) were thereby shifted to TTR-TEL.
Most of the study populations were men who have sex with men with a median age of 41–43 years. Other characteristics of the study populations are shown in Table 1.
The dispensing of STR-TEE from the Hospital Pharmacy of the Capital Region decreased dramatically around April 1, 2011 (Fig. 2). The price difference between defined daily doses of STR-TEE and TTR-TEL after April 1, 2011 was $9.8 (see Supplemental Digital Content 2, http://links.lww.com/QAI/A526).
Viral Load and CD4 Counts in the cART-Naive Population
For the cART-naive populations (part 1), the fractions with VL ≥50 copies per milliliter in the patients who initiated TTR-TEL was not increased compared with the cohort who initiated STR-TEE (7.0%, 95% CI: 1.4 to 19.0; 8.3%; 95% CI: 0.2 to 38.5; difference: −1.3, 95% CI: −22.4 to 19.8 at week 48 for those who initiated STR-TEE and TTR-TEL, respectively) (Fig. 3A). Also, the median CD4 count was not lower in the TTR-TEL population compared with the population initiating STR-TEE (Fig. 4A).
Viral Load and CD4 Counts in the cART-Experienced Population
The equivalent analyses for the cART-experienced population (part 2) are shown in Figures 3B and 4B and also in these populations the response to TTR-TEL was not hampered compared with patients who continued STR-TEE (4.0%, 95% CI: 2.2 to 7.1; 4.4%; 95% CI: 2.6 to 8.4; difference −0.4, 95% CI: −4.2 to 3.4 had VL ≥50 copies/mL at week 48, respectively). Analysis of the fractions with VL≥50 copies per milliliter in the cART-experienced population stratified on gender and route of infection showed comparable results (see Supplemental Digital Content 1, http://links.lww.com/QAI/A526).
Virological Failure and Genotypic Resistance
In part 1, 3.6% (4/111) HIV patients experienced virological failure after initiation with STR-TEE and none (0/56) after initiation with TTR-TEL. One of the 4 HIV patients with virological failure after initiation with STR-TEE had genotypic resistance testing performed, which did not demonstrate a 184V/I mutation. In part 2, none (0/326) and 0.6% (3/478) of the STR-TEE and TTR-TEL patients experienced virological failure within 1 year after study inclusion. All 3 TTR-TEL patients with virological failure had genotypic resistance testing performed and 1 had the 184V/I mutation detected.
Switch of Antiretroviral Regimens in the cART-Naive Population
Among the cART-naive individuals, 26 and 14 of those who initiated STR-TEE and TTR-TEL respectively were shifted to other regimes within 1 year of cART initiation (24 versus 12 were switched to a non–efavirenz containing cART regimen, respectively). The cumulated 1-year incidences of switch to any new cART regimes were 28.9% (95% CI: 19.5% to 39.0%) and 26.9% (95% CI: 15.5% to 39.6%) for HIV patients initiating STR-TEE and TTR-TEL (difference: −2.0%, 95% CI: −17.5% to 13.5%). None of the patients who initiated TTR-TEL were shifted to STR-TEE.
Switch of Antiretroviral Regimens in the cART-Experienced Population
Among the individuals in treatment with STR-TEE per April 1, 2010, 27 were shifted to other regimes within 1 year after study inclusion compared with 42 in the TTR-TEL population (25 versus 38 were switched to a non–efavirenz containing cART regimen, respectively). The cumulated 1-year incidences for switch to any new cART regimes (not including a switch back to STR-TEE for those on TTR-TEL) were 7.6% (95% CI: 5.2% to 10.7%) and 9.1% (95% CI: 6.7% to 12.1%) for HIV patients treated with STR-TEE and TTR-TEL, respectively (difference: 1.5%, 95% CI: −2.4% to 5.4%). A shift back to STR-TEE occurred in 3.9% (20/512) of the patients who were switched to TTR-TEL. In the analysis including a shift back from TTR-TEL to STR-TEE as change in cART regimen, the cumulated 12-month incidence for switch to any new cART regimes was 13.1% (95% CI: 10.2% to 16.4%) for HIV patients treated with TTR-TEL and compared with the cumulated 12-month incidence for those on STR-TEE, the difference was 5.5% (95%CI: 1.4% to 9.6%).
In this population-based cohort study, we demonstrated that the antiretroviral effectiveness of cART was not hampered by a switch from a single-tablet regimen to a triple-tablet regimen. Also, the risk of subsequent shift to other antiretroviral regimens was not substantially affected by the switch. To our knowledge, no other studies have examined the impact on virological response of a switch from a 1 daily fixed-dose combination to a triple-tablet regimen.
Major strengths of the study are the population-based design, almost complete follow-up, and the high fraction (>96%) that was shifted from STR-TEE to TTR-TEL. The latter aspect was confirmed by the fact that patients did not have the option to compensate the hospital for the price differences between the 2 antiretroviral regimens and thereby obtain STR-TEE, and this was confirmed by a dramatic decrease in STR-TEE dispensed in the region (Fig. 2).
Since the approval of the first antiretroviral drugs in Denmark, focus has been on efficacy, tolerability, compliance, and reduction of adverse events. A main characteristic of the study is that the switch in cART regimens was based exclusively on economic incentives. The population-based design and the fact, that more than 96% of the STR-TEE regimens were switched in the study period makes our results generalizable to other western world settings with HIV care programs comparable with the Danish. In Denmark, antiretroviral drugs are only dispensed from hospital pharmacies, why our estimates of cART type and amount dispensed are highly reliable and confirms the effectiveness of the shift from single- to triple-tablet regimens in the region. We did not perform a formal cost-effectiveness analysis as it was beyond the scope of the study.
Our study was observational and not randomized and although no changes in Danish national guidelines for HIV treatment were made during the 2-year study period, minor changes in prescription practices may have occurred. Fewer antiretroviral-naive patients were initiated on efavirenz-containing regimens in the later study period. We do not know the exact reason behind this, but a contributing factor could be increased focus on central nervous system side effects caused by efavirenz and pinpointed in recently published randomized studies.19 Also, the fact that STR were not available in the later study period may have decreased the incentives to use efavirenz-containing regimens in treatment-naive patients. Still, we observed no statistically significant differences in the fractions of HIV patients on STR-TEE and TTR-TEL who were switched to non–efavirenz containing regimens. Virological failure was defined as VL >500 copies per milliliter, thus allowing for virological blips. This could have led to an underestimation of the degree of virological failure although virological blips in this magnitude (≤500 copies/mL) are not associated with virological rebound.20
As the patients were later switched back to STR-TEE, the economic incentive disappeared and we will not be able to present long-term follow-up on TTR-TEL regimens. As the economic incentive disappeared, the physicians decided that the convenience of 1 pill a day was preferred over the TTR regime.
In the Capital Region of Copenhagen, HIV treatment is centralized in 3 departments of infectious diseases and a recent report has demonstrated a high effectiveness of antiretroviral treatment in Denmark.21 The patients were provided careful oral and written instructions before the switch from STR-TEE to TTR-TEL and all antiretroviral drugs were dispensed by experienced nurses. We presume that these aspects are important and we cannot exclude that the effectiveness of multitablet regimens may be decreased in settings that differ from the Danish structure of HIV care.
Although STR regimens are widely recommended as first-line therapy, very few data are available on clinical outcomes comparing STR and regimens including the separate components.5,6,22 Only 3 studies, of which 1 focused on short-term financial effects and the other 2 were performed among marginally housed individuals and women have investigated the impact on virological parameters of a switch from single-tablet to triple-tablet regimens in a clinical setting.8,23,24
Recently, Beck et al24 showed that treatment with STR-TEE compared with several multitablet regimens displayed similar effectiveness in terms of virological suppression and CD4 cell count increase. In that study, decreased health care costs for non-AIDS individuals was observed for patient on STR; however, the basis for this is obscure and the study may be substantially confounded.
In our study, the STR-TEE and TTR-TEL regimens differed not only in the number of daily tablets, but also had emtricitabine substituted by lamivudine. A recent publication from World Health Organization states that the 2 drugs can be regarded as equivalent that concerns antiretroviral potency.25 The only randomized study comparing emtricitabine and lamivudine included accompanying antiretroviral drugs that differed from the regimens used in our study and observed no significant differences in virological response between the 2 drugs (FTC 302).26 There are, however, reports suggesting emtricitabine to be more potent or associated with less development of resistance mutations than lamivudine,27–30 but the quality of the evidence is limited.31 We experienced very few virological failures and almost no patients developed resistance mutations after shift to TTR-TEL. Even if all virological failures were considered to harbor the 184V/I mutation, it still remained below 1% of the exposed. Also, as we did not see any differences in fractions with detectable viral loads between the lamivudine and the emtricitabine-containing regimens, we conclude that in the actual clinical setting a potential difference in antiretroviral potency between the 2 drugs is limited and do not affect our conclusions.
From a mathematical model, Walensky et al8 estimated that almost $1 billion could be saved annually in United States from switching STRs to generic multitablet regimens. In the model, the authors presumed that the TTR containing lamivudine was slightly less effective, a presumption the present study does not confirm suggesting the savings could be even larger. Our study indicates that these estimated savings can be realized without substantial impact on antiretroviral effectiveness.
The switch strategy was adopted after a tender (motivated by higher antiretroviral drug prices in Denmark compared with neighboring European countries) had resulted in considerable price differences between STR-TEE and TTR-TEL. The drugs were not generic, but the price differences that motivated the study may be driven from the potential availability of generic lamivudine. The switch was not because of general austerity measure, but it was assumed that the economic savings justified the switch.
It has been augured that the simplicity of STR increases compliance.31 Although we did not systematically generate data on compliance in the 2 study periods, we are aware of a few patients who for some weeks took double doses of 1 antiretroviral drug and missed out another drug. These mistakes did not lead to virological failure but illustrates the risk of decreased compliance in the initial period after switch to multitablet regimens.
Our results demonstrate that in individuals without known or anticipated compliance problems prescribing TTR-TEL as a substitute for STR-TEE does not affect antiretroviral effectiveness and imply that the economic savings estimated in the mathematical model of Walensky et al can be realized with negligible short-term risk of adverse outcomes.
The authors thank the staff of our clinical departments for their continuous support and enthusiasm. Centers in the Danish HIV Cohort Study: Departments of Infectious Diseases at Copenhagen University Hospitals, Rigshospitalet (J.G., N.O.) and Hvidovre (G.K.) and Nordsjællands Hospital (L.N.N.).
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HIV; cohort study; virological failure; switch; fixed-dose combination; triple-tablet regimen
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