Background and objectives While randomised controlled trials in HIV-infected patients have shown that certain dual antiretroviral therapy (DAT) regimens are non-inferior in terms of efficacy compared with classical triple-drug regimens, few real clinical experiences have been described. The aim of the study was to investigate, in real clinical practice, DAT effectiveness, durability, and risk factors for treatment discontinuation.
Methods This was a prospective cohort study that included HIV-infected patients treated with DAT (2015–2020). DAT was considered effective when patients achieved or maintained virological suppression and was assessed at 24 and 48 weeks. DAT durability was evaluated using the Kaplan-Meier method. Adherence and treatment cost were compared with patients’ previous antiretroviral regimens.
Results 51 patients were included, 27.5% with HIV-1 RNA ≥50 copies/mL at baseline, treated with a wide range of dual combinations. At 48 weeks follow-up, 83.8% and 50.0% of patients who started DAT with HIV-1 RNA <50 copies/mL and ≥50 copies/mL, respectively, were suppressed. 39 out of 51 patients (76.5%) maintained DAT for a mean treatment duration of 40.5±14.8 weeks. Full adherence was observed in 78.4% of patients compared with 70.2% in the previous regimen. Mean daily cost was €18.6±4.3 compared with €16.1±7.9 in the previous regimen (p=0.008).
Conclusion DAT effectiveness and durability were higher in patients who were virologically suppressed at baseline. DAT is a possible alternative for virologically non-suppressed patients who cannot be treated with a triple-drug regimen.
- Drug Monitoring
- PHARMACY SERVICE, HOSPITAL
- Quality of Health Care
- Practice Guideline
Data availability statement
No data are available.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
The current clinical practice guidelines recommend some dual therapies as an initial or maintenance combination regimen for HIV infected patients according to recent data provided by randomised and observational studies.
WHAT THIS STUDY ADDS
This work describes a real-world clinical experience with HIV-infected patients on different dual antiretroviral therapy regimens followed up over 48 weeks between 2015 and 2020.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These findings may help hospital physicians resolve clinical concerns that arise outside the controlled environment of clinical trials.
Antiretroviral therapy has modified the prognosis of HIV-infected patients in recent decades, while newer classes of antiretrovirals have improved efficacy and safety profiles.1 A main challenge facing HIV health providers in both low- and high-income countries is to improve the quality of life of HIV-infected patients on antiretroviral therapies while achieving the best health outcomes.1 2 In this context, any therapy that improves tolerability and simplifies the treatment regimen is of high value. Dual antiretroviral therapy (DAT) is based on two antiretroviral agents that are used in the treatment-naïve patients or as maintenance therapy in virologically suppressed patients.3 4
In randomised controlled trials, non-inferior efficacy has been demonstrated for DAT in comparison with triple-drug therapy, mainly based on two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third drug.5 The single-arm pilot AtLaS (Atazanavir and Lamivudine for Treatment Simplification) study of virologically suppressed patients initially showed encouraging results for long-term efficacy and safety of simplified antiretroviral therapy compared with the atazanavir/ritonavir (ATV/r) plus lamivudine (3TC) combination.6 In virologically suppressed HIV-infected patients, non-inferior efficacy has been demonstrated for DAT regimens combining 3TC with ATV/r,7 lopinavir/ritonavir (LPV/r),8 or darunavir/ritonavir (DRV/r)9 compared with triple-drug regimens. DAT regimens with integrase strand transfer inhibitors (INSTIs) have also been investigated10–12; regimens with dolutegravir (DTG) combined with rilpivirine (RPV),10 3TC,11 or DRV/r12 have shown non-inferior efficacy compared with the continuation of triple- or quadruple-drug regimens in patients virologically suppressed at baseline. In HIV-infected treatment-naïve adult patients, DAT regimens with DTG plus 3TC showed non-inferior efficacy compared with triple antiretroviral regimens.13
Given the available evidence, both triple antiretroviral and DAT regimens are considered standard treatments and are recommended in clinical practice guidelines.3 4 The main benefits of a DAT regimen are that the simplification of treatment and the reduction in treatment-related toxicities may improve adherence and reduce costs.5 14 However, data on real-world clinical practice regarding the effectiveness of DAT regimens for HIV-infected patients are scant.
The main objective of this study was to investigate DAT effectiveness in HIV-infected patients by measuring viral load suppression at 24 and 48 weeks after treatment initiation. Secondary objectives were to investigate DAT durability, risk factors, and reasons for discontinuation, and to compare DAT adherence and DAT cost compared with patients’ previous antiretroviral regimens.
A prospective cohort study was performed using data collected retrospectively from hospital electronic clinical records.
Adult (≥18 years old) HIV-infected patients, who initiated oral DAT regimens between January 2015 and August 2019, were included. Any patients who started treatment in other centres for whom the corresponding data were not available were excluded. Patients could be treatment-naïve or previously treated with any combination of antiretrovirals before inclusion in the study. The follow-up period was 48 weeks from DAT initiation.
Demographic and clinical data
The following data were collected from clinical histories (patient data) and from the hospital pharmacy department (dispensing and billing data): demographic data (age and gender); clinical characteristics (time since HIV diagnosis, history of intravenous drug use, previous Centers for Disease Control and Prevention (CDC) category C); CD4 +T cell count and HIV-1 RNA at baseline and at 24 and 48 weeks follow-up; treatment data (previous antiretroviral regimen, reason for switch to DAT, DAT used, time to discontinuation, and reason); treatment adherence data (Simplified Medication Adherence Questionnaire (SMAQ), pharmacy dispensations, and number of tablets/day); and treatment cost data.
DAT effectiveness and durability
Virological suppression was defined as HIV-1 RNA <50 copies/mL as measured 24 and 48 weeks after DAT initiation. Blips of <200 copies/mL were accepted if the next measurement showed virological suppression.4 Subgroup analyses were performed according to baseline virological suppression (HIV-1 RNA <50 or ≥50 copies/mL). Durability was evaluated based on treatment start date and end date or at 48 weeks. Treatment discontinuation was defined as treatment interruption or any change in or addition to the antiretroviral treatment regimen. Reasons for discontinuation were recorded. Patients transferred to other centres were considered lost to follow-up.
Adherence was evaluated during follow-up or until treatment interruption using two indirect methods: medication counts from the dispensations register (DR), and a dichotomously adapted SMAQ. To calculate adherence according to the DR, the real number of dispensations over the planned number of dispensations was obtained as a percentage (higher percentages reflected higher adherence). For the SMAQ, adherence was considered correct if the patient responded appropriately to all items in all follow-up visits to the Infectious Diseases Unit. Full adherence was defined as a DR score ≥90% plus a correct SMAQ result.15 DAT adherence was compared with patients’ previous antiretroviral regimens, evaluated using the same method as for DAT.
Drug costs (direct healthcare costs based on laboratory sale prices), in 2020 euros, were obtained from the published public prices of reference of the Spanish Health Service applicable in terms of ambulatory dispensing hospital drugs16 and measured from the hospital perspective. A mean daily theoretical cost was calculated per patient.
The main outcomes of interest were DAT effectiveness and durability. Treatment effectiveness was measured using intention-to-treat (ITT) analysis, also performed for the baseline virological suppression subgroups. Statistical analysis of the sample was descriptive. Continuous variables were described by mean±SD, while categorical variables were described by number of events and percentages. To measure effect, hazard ratio (HR) values were calculated by Cox regression. An initial bivariate analysis was conducted of the studied risk factors (gender, age, previous CDC category C, time since HIV diagnosis, baseline virological suppression, and full adherence), and variables with values of p<0.20 were included in a multivariate Cox regression analysis based on the stepwise method. DAT discontinuation-free survival was calculated using the Kaplan-Meier method, and survival curves for risk factors were compared using the log rank test. Statistical significance was set at p<0.05. Due to the observational, non-comparative structure of this study a sample size calculation was not performed to meet the main study objective.
Sample recruitment and main characteristics
Of 57 patients on a DAT regimen, 51 were considered eligible for inclusion in the study (figure 1), two of whom were treatment-naïve and 49 treatment-experienced. Demographic and clinical characteristics are summarised in table 1. The reasons for switching from a previous antiretroviral regimen were as follows: treatment simplification (13; 26.5%); virological failure (13; 26.5%); clinical conditions or comorbidities (12; 24.5%); adverse effects (6; 12.2%); drug–drug interactions (3; 6.1%); pregnancy (1; 2.0%); and participation in a clinical trial (1; 2.0%). Of the 51 patients, 37 (72.5%) were virologically suppressed before starting DAT, and 14 (27.5%) started with HIV-1 RNA ≥50 copies/mL (eight with HIV-1 RNA >200 copies/mL). Mean baseline CD4 +T cell count was 567.5±304.8 cells/µL (one patient had under 200 cells/μL).
DAT combinations, shown in table 2, were INSTI plus NRTI or INSTI plus non-NRTI (NNRTI) (29; 56.9%), boosted protease inhibitor (PI/b) plus NRTI or PI/b plus NNRTI (15; 29.4%), and INSTI plus PI/b (7; 13.7%).
Virological suppression effectiveness
Forty-two (82.4%) and 38 (74.5%) patients were virologically suppressed at 24 and 48 weeks follow-up, respectively; 91.9% and 83.8% of patients who started DAT with HIV-1 RNA <50 copies/mL versus 57.1% and 50.0% of patients who started DAT with HIV-1 RNA ≥50 copies/mL were virologically suppressed at 24 and 48 weeks follow-up, respectively (table 3). Mean CD4 +T cell counts were 657.5±274.8 and 656.4±304.1 cells/µL at 24 and 48 weeks follow-up, respectively; at 48 weeks no patient had values under 200 cells/µL. During the follow-up period, two cases of virological failure occurred in patients who had started DAT with virological suppression: one treated with RPV plus DTG and the other with 3TC plus boosted DRV. The patient treated with RPV plus DTG developed high-level resistance to RPV (M230L mutation in genotype), while treatment resistance in the other patient could not be evaluated due to a low viral load that could not be amplified. In both cases, virological suppression was achieved after a switch to a triple-drug regimen.
At 48 weeks follow-up, 39 out of 51 (76.5%) patients maintained DAT, for a mean treatment duration of 40.5±14.8 weeks. Of patients with baseline HIV-1 RNA <50 copies/mL, 32 (86.5%) maintained DAT. Figure 2 depicts treatment durability according to the Kaplan-Meier survival analysis. Reasons for discontinuation were as follows: treatment simplification, that is, fewer pills (3; 6.1%); treatment abandonment (2; 4.1%); drug–drug interactions (2; 4.1%); virological failure (1; 2.0%); renal function deterioration (1; 2.0%); and death (1; 2.0%). Two patients were lost to follow-up. Table 4 summarises the effect (HR) of study factors on DAT durability in the crude analysis. After adjusting for gender, age, previous CDC category C, time since HIV diagnosis, and baseline virological suppression, being male was the only protective factor for DAT discontinuation.
No difference in full adherence was observed between DAT and previous antiretroviral regimens (78.4% vs 70.2%; p=0.125). Eliminated from the comparative analysis were two cases, as their adherence before DAT initiation was not measured due to a lack of data, and two naïve patients, as they had not been previously treated. During the DAT regimen, adherence was maintained in 32 out of 33 patients (97.0%), while six out of 14 non-adherent patients (42.9%) became adherent after the switch. Mean tablet intake by patients on DAT was 2.0±1.0 tablets/day compared with 2.6±1.4 tablets/day for the previous antiretroviral regimen. More patients were treated with a single tablet on DAT versus the previous antiretroviral regimen (33.3% vs 20.4%), and fewer patients on DAT versus the previous antiretroviral regimen were treated with three or more pills (21.6% vs 40.8%).
The estimated mean daily treatment cost for DAT was €18.6±4.3 compared with €16.1±7.9 for the previous antiretroviral regimen (p=0.008).
This study investigates long-term real-world clinical practice with a DAT regimen in a heterogeneous sample of patients, given that clinical trials in recent decades have mainly investigated DAT efficacy in virologically suppressed HIV-infected patients. Treatment simplification, virological failure, comorbidities, and drug adverse effects were the most frequent reasons for switching to DAT. Different drug combinations were used depending on the clinical characteristics of each patient.
We report a high level of DAT effectiveness in patients who were virologically suppressed at baseline. Among these patients, two cases of virological failure occurred during the follow-up period. DAT was less effective in patients not virologically suppressed at baseline, although DAT was discontinued for reasons other than virological failure.
The experience described in this study is similar to that of other recent studies reporting data on DAT in real-world clinical practice.17–19 Contrasting with our findings are those of an observational retrospective study of 30 HIV-infected patients (73.3% virologically suppressed at baseline) treated for at least 48 weeks with different DAT combinations, which reported that 90% and 100% of patients were virologically suppressed at 24 and 48 weeks follow-up, respectively.17 The difference in findings is partly explained by eligibility criteria, ITT analysis, and different percentages of cases switching due to treatment simplification or due to virological failure. For example, some patients in our cohort were switched to a DAT combination without NRTI due to suspected NRTI resistance (suspected because HIV amplification for genotypic resistance could not be performed due to a very low viral load). An observational prospective study of 35 previously treated HIV-patients (91.4% virologically suppressed at baseline) switched to a DAT regimen based on DTG plus RPV reported 91.4% effectiveness in virological suppression at 48 weeks18; the same study also reported higher effectiveness for baseline virological suppression compared with non-suppression. More recently, an ITT analysis for a multicentre observational retrospective study of 177 virologically suppressed HIV-infected patients showed that 82.4% of included patients treated with the DTG plus 3TC combination had HIV-1 RNA <50 copies/mL at 48 weeks follow-up19; that study, of a cohort of patients treated with a single combination of antiretrovirals, reported an effectiveness rate comparable to ours, and used—as we did in most cases—an INSTI combined with a second drug. Drug combinations using an INSTI are a current recommendation of a clinical practice guideline for DAT regimens.4
In our study, 76.5% of all patients and 86.5% of those with baseline HIV-1 RNA <50 copies/mL maintained DAT at 48 weeks follow-up. Treatment durability in real clinical practice has previously been compared between DAT and triple-drug regimens. At 96 weeks follow-up of 1666 virologically suppressed patients at baseline, significantly higher treatment durability was reported for patients on an INSTI-based dual-drug versus an INSTI-based triple-drug regimen (probability of treatment discontinuation for any reason, 11.2% vs 20.6%; p<0.001).20 Our study also showed that being male was an independent protective factor for treatment durability, although this finding needs to be considered in the context of our small sample.
We observed a slight increase in adherence among the small proportion (33.3%) of our patients treated with a single-tablet antiretroviral regimen, possibly related to a reduction in the tablet burden of previous more complex antiretroviral regimens. We also observed an increase in adherence in patients not adherent to their previous regimen. Several studies have shown that one-tablet regimens are associated with significantly better adherence than multiple-tablet regimens.21 At the outset of our study (January 2015), one-pill DAT formulations were not available, but their use would likely have improved our adherence findings. As for treatment costs, significant differences were found for DAT compared with previous antiretroviral regimens; a possible explanation may be that patients were switching from generic formulations of older antiretroviral drugs to more recently commercialised, and therefore more expensive, drugs.22
This real-world study has some limitations, mainly that retrospectively collected data were used and the sample was small. Another limitation is that no comparison was made with a matched sample of patients treated with conventional triple-drug regimens. Our study was also heterogeneous in including both virologically suppressed and virological non-suppressed patients at baseline, and patients with different reasons for switching to DAT. Finally, the heterogeneity of the antiretroviral combinations made it difficult to draw conclusions about the effectiveness of any specific DAT formulation. Nonetheless, the study fulfilled its main goal of investigating the effectiveness and durability of DAT in real-world clinical practice.
Our study suggests that DAT can be an effective alternative for HIV-infected patients in certain clinical scenarios, as we found that treatment effectiveness and durability was greater for patients with baseline virological suppression who initiated DAT. Future studies with larger sample sizes are needed to further investigate effectiveness, durability, adherence, and cost savings in patients who switch to DAT for reasons other than treatment simplification. Finally, the recently approved one-pill regimen may contribute to understanding the real impact of this new DAT treatment strategy for HIV-infected patients.
Data availability statement
No data are available.
Patient consent for publication
The study protocol was evaluated and approved by the Drug Research Ethics Committee of Mataró Hospital (protocol number 17/20).
EAHP Statement 4: Clinical Pharmacy Services.
Contributors LP-C, AS, SM, LF, MS-P and LC participated in the conception, planning, design, methodology, conduct, supervision, data acquisition and analysis, reporting and writing (original draft preparation and subsequent review and editing) of this article. MS-P and EP provided expertise in epidemiology and statistics. LP-C, AS, SM, LF, MS-P, EP and LC have read and agreed to final version of this manuscript. LP-C is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.