Simplification of Antiretroviral Treatment from Darunavir/Ritonavir Monotherapy to Darunavir/Cobicistat Monotherapy: Effectiveness and Safety in Routine Clinical Practice

Abstract

Our aim was to evaluate the effectiveness and safety of darunavir/cobicistat (DRV/c) monotherapy as an antiretroviral treatment simplification strategy in HIV-infected patients already on suppressive darunavir/ritonavir (DRV/r) monotherapy in routine clinical practice. We conducted a retrospective multicenter study including all adult patients switched from DRV/r monotherapy to DRV/c monotherapy while HIV-1 RNA was <50 copies/mL and who had at least one follow-up visit. The primary endpoint was the percentage of patients remaining free of treatment failure (TF), defined as discontinuation of monotherapy for any reason, including loss of follow-up. Virological failure (VF) was defined as a confirmed HIV-1 RNA ≥50 copies/mL or any change in the regimen after a single determination with HIV-1 RNA ≥50 copies/mL. Changes in renal function parameters and lipid profile were also evaluated. Factors associated with VF were analyzed using Cox regression. In this study, 173 subjects were included. The median (interquartile range) time of follow-up was 58 (50–67) weeks. Overall, 90% of patients remained free of TF during follow-up. Ten (6%) patients discontinued DRV/c monotherapy for nonvirological reasons and eight (5%) developed VF. No DRV-related mutations were identified in patients with VF. A decrease in triglyceride levels (p = .006) and estimated glomerular filtration rate (p = .005) were observed during follow-up. The presence of blips and CD4+ nadir <100 cells/mm³ were predictors of VF. In conclusion, switching to DRV/c monotherapy seems to be safe and effective in routine clinical practice in HIV-infected patients undergoing suppressive DRV/r monotherapy.

Introduction

Treatment simplification with ritonavir-boosted protease inhibitor (PI) monotherapy has been widely used in Europe in recent years.^1,2 Although increased risk of virological failure (VF) with PI monotherapy³ makes this strategy no longer recommended by scientific societies, there are patients on long-term PI monotherapy^4

–9 who maintain sustained viral suppression without tolerability or drug–drug interaction-related issues. So, this group of patients could continue using PI monotherapy as a strategy to save future antiretroviral drug options and antiretroviral treatment (ART)-associated costs. Among boosted PIs, darunavir (DRV) is particularly suitable for PI monotherapy, and data from clinical trials and cohort studies have shown high efficacy and favorable safety profile of ritonavir-boosted DRV (DRV/r) monotherapy.^9
–11

Cobicistat is a new pharmacoenhancer used to boost antiretroviral drugs. Compared with ritonavir,^12,13 it has no antiviral activity, is more selective in terms of inhibition of different isoenzymes of the cytochrome P450 system, and does not induce CYP isoenzymes or glucuronidation.¹⁴ Cobicistat can be co-formulated and a fixed-dose combination of DRV plus cobicistat (DRV/c) has been recently developed, resulting in bioequivalent DRV concentrations in plasma compared with DRV/r.^14
–16 Nevertheless, DRV trough concentrations are 30% lower with cobicistat than with ritonavir.¹⁵ This difference seems not be clinically relevant in patients treated with triple ART and no DRV-associated resistance mutations.¹⁷ However, a possible lack of efficacy in patients treated with DRV/c monotherapy may be a concern, and data in this regard remain scant.

The aim of this study was to evaluate the effectiveness and safety of DRV/c monotherapy as a treatment simplification strategy in HIV-infected patients on suppressive DRV/r monotherapy in routine clinical practice.

Materials and Methods

This was a multicenter retrospective observational study including all adult HIV-infected patients on DRV/r (800/100 mg once daily) monotherapy who had been switched to DRV/c (800/150 mg once daily) monotherapy between November 2015 and June 2017, with HIV-1 RNA load <50 copies/mL, and at least one follow-up visit. All switches were performed in the routine clinical setting according to the medical criteria. Data were retrieved from electronic medical records. The study was performed at the Hospital Universitari Germans Trias i Pujol (Badalona, Spain) and at the Hospital Universitari Vall d'Hebron (Barcelona, Spain). The study was approved by the Ethics Committee of Hospital Germans Trias i Pujol, Badalona, Spain (FLS-DAR-2017-01) and performed according to the stipulations of the Declaration of Helsinki (Brasil, 2013). All patients gave their written informed consent for their medical information to be used in scientific research.

The primary endpoint of the study was the proportion of patients remaining free of treatment failure (TF) during follow-up, defined as a discontinuation of DRV/c monotherapy for any reason, including VF, adverse events, or loss to follow-up. VF was defined as two consecutive determinations of HIV-1 RNA ≥50 copies/mL, or any change in the ART regimen or loss of follow-up after a single determination with HIV-1 RNA ≥50 copies/mL. Secondary endpoints included the proportion of patients and factors associated with VF, reasons for treatment discontinuation, development of protease resistance-associated mutations after VF, percentage of patients experiencing blips (single determination of HIV-1 RNA 50–200 copies/mL), and changes in CD4+ T cell count, serum creatinine levels, estimated glomerular filtration rate (eGFR), and fasting lipid profile.

Demographic and clinical characteristics including HIV-1 RNA, CD4+ T cell count, serum creatinine levels, eGFR (according to Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] calculation), and fasting lipid profile [total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides] were recorded when DRV/c monotherapy was initiated (baseline) and during follow-up, in accordance with standards of clinical care. Adverse events leading to discontinuation of DRV/c and genotypic tests performed at VF were also evaluated, when available. The study was approved by the ethics committee of the participating hospitals and complied with the stipulations of the Declaration of Helsinki (Seoul, 2008).

The statistical analysis was performed using SPSS version 15.0 (SPSS, Chicago, IL). Creatinine levels, eGFR, and fasting lipid profile were compared between baseline and 12 weeks of follow-up. The Kaplan–Meier method was applied to calculate the time to TF. Factors associated with VF were evaluated by means of a Cox regression and multivariate logistic regression analyses.

Results

A total of 173 patients with a median (interquartile range) age of 49 (41–45) years and a median time of 7 (4–11) years on virological suppression fulfilled inclusion criteria and were included in the study. Patient characteristics are summarized in Table 1.

Table 1.

Baseline Characteristics (N = 173)

	General cohort
Male	132 (76)
Age (years)	49 (41–55)
HCV coinfection	45 (26)
Time since HIV diagnosis (years)	17 (7–24)
Time on treatment (years)	14 (6–20)
Time on DRV/r monotherapy (years)	5 (2–6)
Time on virological suppression (years)	7 (4–11)
Number of previous ARV regimens	4 (2–7)
Patients with previous failure to PIs	46 (27)
Number of patients with CD4+ nadir <100 cells/mm³	43 (25)
CD4+ nadir (cells/mm³)	280 (183–359)
CD4+ T cell count at baseline (cells/mm³)	695 (533–916)

All values are expressed as median (interquartile range) or n (%).

HCV, hepatitis C virus; DRV/r, darunavir/ritonavir; ARV, antiretroviral; PI, protease inhibitor.

The median time of follow-up was 58 (50–67) weeks. The overall proportion of patients who remained free of TF was 90% (155/173 subjects) with a median time to TF of 32 (24–39) weeks (Fig. 1). Reasons for discontinuation included VF in 8 (5%) patients and nonvirological reasons in 10 (6%).

FIG. 1.

Median time to TF in HIV-1-infected patients with DRV/c monotherapy. DRV/c, darunavir/cobicistat; TF, treatment failure; IQR, interquartile range.

Focusing on the eight patients with VF, the median of HIV-1 RNA at failure was 281 (123–557) copies/mL and poor adherence was reported in three (38%) cases. The description of these patients is given in Table 2. Fifteen (9%) patients experienced blips during follow-up. Factors found to be predictors of VF in the multivariate analysis were experiencing blips [hazard ratio (HR) = 12.4; 95% confidence interval (CI) = 3.1–49.5; p < .001] and a nadir of CD4+ cell count <100 cells/mm³ (HR = 8.1; 95% CI = 1.8–36.1; p = .006). Viral load was resuppressed in seven of eight cases either by reintroduction of the previous nucleoside reverse transcriptase inhibitors (NRTI) backbone (emtricitabine/tenofovir-DF in two cases and abacavir/lamivudine in one patient) or other antiretroviral drugs (four cases). In one patient the treatment was completely changed to dolutegravir plus two NRTIs, but this patient had no further follow-up visits. Genotypic data were available at VF in two patients with measurements of HIV-1 RNA of 6,963 and 430 copies/mL, respectively. The first patient had no resistance-associated mutations in the protease gene, whereas the other patient showed the following: L10I, K14R, K20R, M36I, R41K, I62V, L63P, and A71T, and in the reverse transcriptase gene had the E138A. These patients had experienced previous failure in response to ritonavir and saquinavir/ritonavir-containing regimens, respectively. Although no previous genotypes were available to establish comparisons, none of these mutations have been associated with DRV resistance.

Table 2.

Clinical and Virological Data of Patients Experiencing Virological Failure to Darunavir/Cobicistat Monotherapy (N = 8)

Patient	Number of previous ART regimens	Previous failure to PIs	Time on previous virological suppression (years)	Time on previous DRV/r monotherapy (weeks)	Time to VF on DRV/c monotherapy (weeks)	HIV-1 RNA at VF (copies/mL)	CD4+ nadir (cells/mm³)	CD4+ T cell count at baseline (cells/mm³)	Historical genotypes (protease gene)	Genotypes at VF (protease gene)	Comments
1	7	Yes	8	229	24	430	328	1,047	—	L10I, K14R, K20R, M36I, S37N, R41K, I62V, L63P, A71T	—
2	1	No	2	71	23	773	493	692	WT	NA	—
3	1	No	4	22	74	132	489	818	—	—	—
4	4	No	6	23	24	97	247	829	—	—	Suboptimal ART adherence
5	5	No	12	315	45	51	50	690	WT	—	Suboptimal ART adherence
6	4	Yes	13	299	42	485	12	603	—	—	—
7	6	No	16	254	30	6963	11	735	—	WT	Suboptimal ART adherence
8	3	No	3	134	31	132	409	1,125	WT	—

ART, antiretroviral treatment; DRV/c, darunavir/cobicistat; VF, virological failure; WT, wild type; NA, not amplified.

Nonvirological reasons for treatment discontinuation included adverse effects (n = 2, 1%), enrolment in clinical trials (n = 3, 2%), prevention of future ART-related toxicities (n = 2, 1%), drug–drug interactions with recreational drugs (n = 1, 1%), immune discordance with CD4 count persistently <500 cells/mm³ despite suppressed viremia (n = 1, 1%), and loss of follow-up (n = 1, 1%). All these patients, except for the subject who missed follow-up, maintained HIV viral load <50 copies/mL at the moment of DRV/c discontinuation.

Adverse events leading to DRV/c discontinuation included gastrointestinal disturbances in one subject and hypersensitivity to cobicistat in another. This last patient had been previously treated with DRV/r for 231 weeks. Five days after switching to DRV/c monotherapy, the patient experienced grade II urticaria. DRV/c was then stopped and the patient was put back up on DRV/r. The symptoms dissipated 2 days after DRV/r reinitiation.

There was a significant decrease in triglyceride levels at week 12 (p = .006), whereas total-, HDL-, and LDL-cholesterol remained stable (Table 3). In addition, a significant reduction in eGFR at week 12 (p = .005) was also observed (Table 2). Four (2%) patients experienced a reduction >25% in eFGR. There were no significant changes in the median level of CD4+ cell count at week 48 (p = .855).

Table 3.

Changes in CD4 Cell Count, Lipid Profile, Creatinine, and CKD-EPI After Switching to Darunavir/Cobicistat Monotherapy (N = 173)

	Baseline	Week 12	p Value
CD4 cell count, cells/mm³	695 (533–916)	715 (573–940)	.855
Serum lipid profile, mg/dL
Total cholesterol	181 (154–206)	179 (152–205)	.684
HDL-cholesterol	43 (36–52)	44 (36–52)	.637
LDL-cholesterol	108 (89–127)	110 (88–130)	.960
Triglycerides	137 (106–190)	128 (95–184)	.006
Kidney parameters
Serum creatinine, mg/dL	0.87 (0.76–0.97)	0.92 (0.81–1.06)	<.001
CKD-EPI, mL/min/1.73 m²	95 (81–102)	88 (75–101)	.005

Data are expressed as median (interquartile range).

HDL, high-density lipoprotein; LDL, low-density lipoprotein; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.

Discussion

This study shows that simplification of ART with DRV/c monotherapy in HIV-1-infected patients on stable and suppressive DRV/r monotherapy is effective and well tolerated in routine clinical practice. This strategy may be useful to simplify the ART regimen to a more comfortable fixed-dose combination of DRV/c, reducing the pill burden and the risk of selective adherence.

Observational studies evaluating DRV/r monotherapy as a simplification strategy have reported an effectiveness similar to that observed in clinical trials.^{4

–7,9,18,19} Our results are in line with these studies, showing a high rate of virological suppression after switching to DRV/c monotherapy. In addition, similar to previous studies,^{4

–7,9,18,19} the development of VF in response to DRV/c monotherapy in our cohort was not associated with the loss of future therapeutic options, it was rarely associated with resistance to PIs, and the reintroduction of NRTIs or other ART achieved virological suppression in all failing patients. Therefore, our data also suggest that the efficacy of DRV monotherapy remains independent of the pharmacokinetic enhancer, confirming that a lower DRV trough concentration using cobicistat compared with ritonavir is not clinically relevant in patients simplified to DRV/c monotherapy.¹⁷ It is important, however, to keep in mind that PI monotherapy may be associated with increased risk of VF compared with standard triple ART, especially if patients are not properly selected.³ In addition, at present there are other drug-saving strategies available (dual therapies) with promising results in well-powered clinical trials.^20,21 However, DRV/c monotherapy may still be a valid option for a subgroup of HIV-1-infected patients who are already on suppressive PI monotherapy without safety or drug–drug interaction issues.

We found that experiencing blips and a CD4+ nadir <100 cells/mm³ were factors associated with VF. It is important to note that blips were more frequently reported in other studies than in our study, but they have not been associated with VF in response to PI monotherapy.^5,9,22
–24 In our opinion, the presence of blips could be regarded as an indirect measure of poor adherence, which is a critical factor associated with the response to ART.^24,25 Of interest, consistent with previous reports,^6,9,18 we also did not find a significant relationship between previous failure of PI therapy and failure of DRV/c monotherapy. In fact, no DRV-related mutations were observed in those failing patients with genotypic tests available.

Similar to studies that have evaluated cobicistat-containing ART,^16,26,27 we found that DRV/c monotherapy was well tolerated and few patients discontinued therapy owing to mild adverse events. Switching to cobicistat caused a small and expected decrease in the eGFR.^16,26,28,29 These changes, however, were not considered to be clinically significant, because they were relatively small and <5% of patients experienced a reduction >25% in eGFR. In addition, consistent with other studies,³⁰ we observed a mild but significant improvement in triglyceride levels, suggesting that DRV/c may confer advantages in the management of metabolic disorders in subjects on ART with poorer lipid profiles and hypertriglyceridemia.

Our study is subject to certain limitations. Its retrospective and uncontrolled design and the lack of a comparative arm may have introduced bias or unmeasurable confounding factors. In fact, patients had been on suppressive therapy with DRV/r monotherapy for years, which might have been a selection bias with a positive influence in our efficacy and safety results. Nonetheless, to our knowledge, this is the first study reporting the safety and effectiveness of DRV/c monotherapy in routine clinical practice. Our results, therefore, provide important insights into this strategy, which could be useful in a selected group of patients without hepatitis B virus coinfection who still remain on PI monotherapy, especially those on DRV/r, with good treatment adherence, with no historical resistance mutations associated to PI, and who have never had a CD4 cell count <200 cell/mm³.

In conclusion, simplification to DRV/c monotherapy seems to be safe and effective in selected HIV-infected patients already on treatment with suppressive DRV/r monotherapy in routine clinical practice.

Footnotes

Acknowledgments

The authors thank Nuria Pérez-Álvarez for support with the statistical analysis, Oriol Noguer for help with coordinating and recording all data, and Michael Kennedy-Scanlon for editorial assistance. This study was supported in part by grants from Lluita contra la SIDA Foundation (Barcelona, Spain), the Spanish AIDS Network ‘Red Temática Cooperativa de Investigación en SIDA’ (RIS, RD16/0025/0041, NEAT (European AIDS Treatment Network), Ministerio de Economía y Competitividad of Spain (MINECO/FEDER, MTM2015-64465-C2-1-R), and GRBIO (Grup de Recerca en Bioestadística i Bioinformàtica; 2017 SGR 622). The funders had no role in study design, data collection and analysis, the decision to publish, or drafting of the article.

Author Disclosure Statement

J.R.S. has received research funding, consultancy fees, and lecture sponsorships from and has served on advisory boards for Abbott, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, and ViiV Healthcare. A.C. has received research funding, consultancy fees, and lecture sponsorships and has served on advisory boards for AbbVie, Boehringer Ingelheim, Gilead Sciences, GSK, Janssen-Cilag, BMS, ViiV Healthcare, MSD, and Pfizer. J.N.-M. has received research funding, consultancy fees, and lecture sponsorships from AbbVie, Boehringer Ingelheim, Gilead Sciences, GSK, Janssen-Cilag, BMS, ViiV Healthcare, and Merck Sharp and Dohme. B.C. has received research funding, consultancy fees, and lecture sponsorships from and has served on advisory boards for Abbott, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Merck Sharp and Dohme, Panacos, Pfizer, Roche, and Tibotec. R.P. has received research funding and consultancy fees from and has served on advisory boards for Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck Sharp and Dohme, Pfizer, and ViiV Healthcare. J. M. has received research funding, consultancy fees, and lecture sponsorships from and has served on advisory boards for Abbott, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Bristol-Myers Squibb, ViiV Healthcare, and Pfizer. All other authors declare no conflicts of interest.

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