Abstract
Background
Methods
Results
Conclusions
Introduction
Salvage regimens with the combination of multiple antiretroviral drugs were able to fully suppress HIV replication in patients infected with multidrug-resistant virus [1,2]. Nevertheless, high pill burden and concerns about toxicity and costs made dual therapy strategies interesting options to maintain viral suppression [3], especially in patients with poor compliance or comorbidities. Dolutegravir and darunavir are potent drugs with high genetic barrier and low rates of adverse effects. The use of dolutegravir plus boosted-darunavir reduces pill-burden, avoiding the toxicity of multiple-drug regimens without compromising viral suppression. However, no or limited data are available regarding this regimen for simplification of salvage therapies [4]. Accordingly, we assessed the efficacy and safety of dual regimens containing dolutegravir plus boosted-darunavir as switching strategies in patients with history of virological failure.
Methods
We performed a Phase IV, prospective, single-arm, open-label cohort study at the HIV Unit of a tertiary university hospital from January 2015 through December 2017. Patients with previous virological failures to different classes of antiretroviral drugs, but virologically suppressed in a salvage regimen for at least 24 weeks, were included if switched to a once-daily regimen of dolutegravir 50 mg plus darunavir/cobicistat (DRV/c) 800 mg/150 mg, or darunavir/ritonavir (DRV/r; 800 mg/100 mg). Pregnant or HBV-infected patients were excluded. Also, previous failure to integrase inhibitors (InSTI) was not permitted. The study was approved by our Institutional Review Board (EC 280/15), and patients gave their written informed consent (NCT02491242).
Demographic, HIV-related and laboratory variables were recorded at baseline and every 12 weeks until week 48, including levels of triglycerides, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c) and high-density lipoprotein-cholesterol (HDL-c); estimated glomerular filtration rate (eGFR) calculated with the Chronic Kidney Diseases-Epidemiological collaboration formula [5], proteinuria expressed as urine protein to creatinine ratio (uPCR), tubular reabsorption of phosphate (TRP); nadir and baseline CD4+ and CD8+ T-cell counts, CD4+/CD8+ ratio, and HIV RNA level by using Versant® HIV-1 RNA 1.5 assay (kPCR; Siemens Healthcare, Erlangen, Germany), threshold 37 copies/ml. HCV coinfection was defined as HCV antibodies plus HCV-RNA-positivity.
The Stanford HIVdb genotypic resistance interpretation system was used to obtain the genotypic susceptibility score (GSS) of darunavir from previous genotypic tests. The algorithm uses five categories of resistance: high-level, intermediate, low-level, potential low-level and susceptible. These categories were correlated with a GSS of 0, 0.25, 0.50, 0.75 and 1, respectively [6]. A value of 1 was assigned to dolutegravir since no patient had virological failure while on InSTI-based therapy, as defined.
The primary end point was the proportion of patients with HIV RNA plasma viral load <37 copies/ml at week 48. Treatment failure was defined as virological failure (two consecutive detectable HIV RNA levels), discontinuation or reintroduction of triple therapy. Secondary end points included changes in laboratory parameters.
Mean, median and IQRs or frequencies (%) were calculated. For GSS, the sum of the individual scores provided the total GSS (maximum, 2 points). Results were assessed as intention-to-treat (including all patients enrolled) and per-protocol analyses (including only those who had virological failure or discontinuation due to adverse events). Missing data were considered as failure. Analysis of paired observations was performed using the Wilcoxon-rank test. Statistical significance was defined at two-sided P-values <0.05. Analyses were performed with IBM SPSS Statistics version 18 (Chicago, IL, USA).
Results
Overall, 51 patients switched to dolutegravir plus boosted-darunavir (29 patients received DRV/c, and 22 DRV/r) and they were followed-up over a median of 29.4 months (IQR 20.6–35.1; cumulative time of follow-up, 67.58 patient-years). Baseline characteristics are shown in Table 1. Baseline HIV RNA level was undetectable in 43 patients (83%); in 8 cases HIV RNA level was detectable at inclusion due to non-adherence or recent discontinuation of the previously suppressive antiretroviral regimen.
Baseline characteristics of the patients switching to dolutegravir plus boosted-darunavir
ART, antiretroviral; DRV/r, darunavir plus ritonavir; eGFR, estimated glomerular filtration rate; GSS, genotypic susceptibility score; HDL-c, high-density lipoprotein-cholesterol; LDL-c, low-density lipoprotein-cholesterol; TC, total cholesterol; TG, triglycerides; TRP, tubular reabsorption of phosphate; uPCR, urine protein to creatinine ratio.
Patients had received a median of 8 (IQR 4–12) regimens over 18.4 years (IQR 13.9–21.16) before switching and had previous virological failure to ≥2 antiretroviral classes at baseline. Median time of virological suppression with the previous regimen was 37 months (IQR 18–90). The reasons for switching were simplification, toxicity to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI; renal/bone toxicity) and metabolic abnormalities (dyslipidaemia). Baseline genotypic testing was available in 42 (82%) patients. The mean number of primary resistance mutations was 3.5 for protease inhibitors (PIs; in positions I54 and V82 predominantly), 1.2 for non-nucleoside reverse transcriptase inhibitors (mostly in positions Y181 and K103) and 2.4 for NRTI (mainly in positions T215, M184 and M41). However, the mean GSS of dual therapy was 1.95 (range: 1–2), with only 5 patients having a reduced GSS to DRV.
At week 48, there were no virological failures and the efficacy was 90% (95% CI 82, 99%) in the intention-to-treat analysis and 94% (95% CI 87, 100%) in the per-protocol analysis. Five patients had discontinued dual therapy: two because of loss to follow-up, and three because of central nervous system adverse events (insomnia, headache and severe anxiety). These patients were receiving DRV/c and were HCV-coinfected, two of them with fibrosis 4/cirrhosis. Median CD4+ T-cell count increased from 551 to 650 cells/mm3 (P=0.04), median CD4+/CD8+ ratio increased from 0.55 to 0.65 (+18%; P=0.80), and CD8+ T-cell count decreased by 5% (P=0.45). Therefore, the variation in CD4+/CD8+ ratio was primarily driven by the improvement in CD4+ T-cell count. The proportion of patients with CD4+ T-cell counts <200 cell/mm3 decreased by 16% at week 48 (P<0.01). The median number of pills per day decreased from 4 (IQR: 1–6) to 2 (IQR: 2–3).
No other severe adverse events were recorded during follow-up. Mean eGFR decreased by 8.8 ml/min/1.73 m2 (P<0.01). The decline in the eGFR was similar or even lower in patients receiving dolutegravir plus cobicistat, both inhibitors of creatinine tubular secretion, than with dolutegravir plus ritonavir (−7.6 versus −11.9 ml/min/1.73 m2; P=0.24). Globally, mean proteinuria improved from 91.1 to 87.2 mg/dl (P=0.86) and mean TRP from 78.8% to 80.1% (P=0.8). There was also a non-significant increase in mean TC (1.9%), LDL-c (1.4%) and HDL-c (4.3%), with reduction in mean TG levels (−10.3%). Noteworthy, tenofovir disoproxil fumarate discontinuation also caused non-significant increases in TC (4.9%; P=0.26), LDL-c (10%; P=0.25), HDL-c (12.4%; P=0.14) and decrease in TG (−15.1%; P=0.25). Changes in laboratory parameters during follow-up in the overall cohort and in patients receiving DRV/c versus DRV/r are shown in Figure 1A and 1B.
Mean percentage of change in different analytical parameters during the 48 weeks of follow-up
Discussion
Our data show the high efficacy expected with the simultaneous use of two drugs with high genetic barrier such as dolutegravir and boosted-darunavir as simplification regimen, maintaining a 90% virological suppression in patients with history of multiple failures harbouring multidrug-resistant strains. The simplicity of this strategy could be advantageous in heavily pre-treated patients without affecting efficacy, since both drugs maintain viral suppression when administrated once-daily as two pills [7,8].
Dual therapy as simplification of salvage regimens based on InSTI plus boosted-darunavir has been investigated mostly with raltegravir. In the SPARE study, there was no significant difference between DRV/r plus raltegravir and lopinavir/ritonavir plus tenofovir/emtricitabine [9]. Several observational studies further assessed this combination and demonstrated viral success in 75.5% to 97.6% of patients [10–12]. The use of raltegravir, a drug with relatively low genetic barrier and twice-daily administration at that time, could have affected the overall results, as described in other studies [9].
With respect to the dual combination used in this study, Capetti et al. [4] found that 76% reached undetectable viral load at week 48 in a cohort of treatment-experienced patients switched for multiple reasons. Noteworthy, they include viral failure, 9% of patients had resistance mutations to InSTI, 15% had reduced susceptibility to darunavir, and it was unclear which patients received darunavir in a twice-daily regimen. Indeed, our study provides further support about the efficacy of darunavir once daily in treatment-experienced patients, even in presence of PI-resistant viruses, as previously described [8,13].
This dual regimen had adequate tolerance, with less than 6% of patients discontinuing the drugs at week 48, due to neuropsychiatric adverse events that resolved after changing dolutegravir. This is in line with previously reported rate of dolutegravir-treatment interruptions in observational studies [14]. Moreover, the regimen led to a non-significant improvement of proteinuria and tubular reabsorption of phosphate, related to tenofovir disoproxil fumarate discontinuation [15], and on the other hand, to an unexpected HDL-c and triglyceride level improvement [16]. Interestingly, the decrease in eGFR in patients receiving dolutegravir and cobicistat was similar to the use of dolutegravir individually [17], showing a lack of additive effects on the inhibition of the tubular secretion of creatinine, a fact suggesting the existence of compensatory renal mechanisms for creatinine secretion [18].
The limitations of this study include the observational design, decreasing the generalizability of the findings; the absence of a triple therapy comparison group; a rather heterogeneous population, though representative of clinical practice; and the lack of pharmacokinetic determinations. In previous pharmacokinetic studies, DRV/r co-administration resulted in non-clinically significant reductions of dolutegravir concentrations in healthy individuals [19], while a significant increase in dolutegravir exposure has been reported after changing from DRV/r to DRV/c individuals [20]. In any case, we did not observe higher rates of adverse events in the group receiving cobicistat.
In conclusion, in this real-life study in treatment-experienced patients, we demonstrated the maintenance of viral suppression with the combination of dolutegravir plus boosted-darunavir, even in patients with previous failure to several class of drugs and in presence of mutations against PI, improving renal and lipid comorbidities, and reducing the number of pills. This strategy is appealing to reduce toxicity and pill-burden in patients harbouring multidrug-resistant strains, although the relative short follow-up make it mandatory to be cautious in the wide application of these results.
Footnotes
Acknowledgements
We would like to thank Ana Abad (Department of Infectious Diseases, Ramón y Cajal Hospital) for her contribution in the database management.
This work was supported by internal funding.
JLC, PV and MF conceived and designed the study, and were responsible for patient enrolment, data analysis and drafted and finalized the article. MM, MJV and AR, were responsible for patient enrolment, clinically followed-up patients and helped to write the work. All co-authors revised the manuscript, read and approved the final version.
All research was conducted within the guidelines of ethical principles and local legislation.
The authors declare no competing interests.