Safety and Effectiveness of Switching to Abacavir/Lamivudine Plus Rilpivirine for Maintenance Therapy in Virologically Suppressed HIV-1 Patients in Singapore (SEALS)

The ecacy and tolerability of an antiretroviral regimen are important considerations for selection of HIV-1 infection maintenance therapy. Abacavir/lamivudine plus rilpivirine (ABC/3TC+RPV) has been shown in international studies to be effective and well-tolerated in virologically suppressed patients. This study evaluated the effectiveness and safety of switching to ABC/3TC+RPV as maintenance therapy in virologically suppressed HIV-1 infected patients in Singapore.


Abstract Background
The e cacy and tolerability of an antiretroviral regimen are important considerations for selection of HIV-1 infection maintenance therapy. Abacavir/lamivudine plus rilpivirine (ABC/3TC+RPV) has been shown in international studies to be effective and well-tolerated in virologically suppressed patients. This study evaluated the effectiveness and safety of switching to ABC/3TC+RPV as maintenance therapy in virologically suppressed HIV-1 infected patients in Singapore.

Methods
In this retrospective, single-centre study, we included patients who were prescribed ABC/3TC+RPV, had HIV-1 RNA <50 copies/ml immediately pre-switch, and had no documented history of resistance mutations or virologic failure to any of the components. Patients were followed up for 48+12 weeks. The primary outcome was the proportion of patients who maintained virologic suppression of HIV-1 RNA <50 copies/ml at the end of follow-up period based on on-treatment analysis. The secondary outcomes were the resistance pro les associated with virologic failure, changes in immunologic and metabolic parameters, and the safety pro le of ABC/3TC+RPV.

Results
A total of 222 patients were included in the study. The primary outcome was achieved in 197 patients [88.8%, 95% con dence interval: 83.7%-92.4%]. There were 21 patients (9.5%) who discontinued treatment for non-virologic reasons. The remaining 4 patients experienced virologic failure, of whom, 3 of these patients had developed emergent antiretroviral resistance and had HIV-1 RNA >500 copies/ml at the end of the 48+12 weeks follow-up period. The remaining patient experienced sustained low level viremia and subsequently achieved viral suppression without undergoing resistance testing. A total of 49 adverse events were observed in 31 out of 222 patients (14.0%), which led to 13 patients discontinuing therapy.
Neuropsychiatric adverse events were most commonly observed (57.1%). A statistically signi cant increase in CD4 was observed (p<0.01), with a median absolute change of 31 cells/uL (interquartile range: -31.50 to 140.75). No signi cant changes in lipid pro les were detected.

Conclusion
ABC/3TC+RPV is a safe and effective switch option for maintenance therapy in virologically suppressed HIV-1 patients with in Singapore.

Background
Modern combination antiretroviral therapy (ART) regimens have generally demonstrated potency and e cacy in achieving virologic suppression. 1 Owing to the chronic nature of HIV infection, maintenance therapy is required even after initial virologic suppression. 1 In addition to e cacy, the cost-effectiveness, convenience and long-term tolerability of the ART are important considerations in selecting a suitable maintenance therapy. 1 The current standard for HIV treatment is combination ART, which comprise of two nucleos(t)ide reverse transcriptase inhibitors (NRTI) as backbone, paired with a third agent from another class, including integrase strand transfer inhibitors (INSTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), or protease inhibitors (PI). 1 Tenofovir and emtricitabine (TDF/FTC) are recommended as a rst-line NRTI backbone for their effectiveness, but the combination of abacavir and lamivudine (ABC/3TC) may be used as maintenance therapy for its cost-effectiveness and better safety pro le. [1][2][3][4] Compared to tenofovir-based regimens, ABC/3TC offer the advantage of avoiding potential renal and bone toxicity and is suitable for use in individuals with renal insu ciency and osteoporosis. [1][2][3][4] In Singapore, the price of ABC/3TC is roughly half that of TDF and 3TC (as separate components), and one-fth the cost of a TDF/FTC xed dose combination tablet. Rilpivirine (RPV) is a second-generation NNRTI approved for use with NRTIs in treatment-naïve HIV-1 infected patients. [5][6][7][8][9] Its use is recommended to be limited to patients with pre-treatment CD4 counts exceeding 200 cells/uL and pre-treatment viral loads of less than 100,000 copies/ml. 1 RPV has been shown to have fewer neuropsychiatric adverse effects (AEs) when compared with efavirenz, a more favourable metabolic pro le compared with PI, and better cost-effectiveness due to its relatively lower cost. [5][6][7][8][9] In Singapore, the cost of RPV is 25% compared to that of a PI or INSTI.
The SIMRIKI retrospective study has demonstrated the long-term effectiveness and safety of ABC/3TC + RPV as a switch therapy with a follow-up period of up to 48 weeks. 10 The results of the SIMRIKI study are corroborated by several similar Spanish studies. [11][12][13] A local study has also shown the e cacy and safety of this regimen in treatment naïve HIV-1 infected adults, 14 but to our knowledge, there have not been any studies on the effectiveness and safety of ABC/3TC + RPV as a switch regimen in Singapore.
The aim of this study was to evaluate the effectiveness and safety of switching to ABC/3TC + RPV as maintenance therapy for virologically suppressed HIV-1 infected patients in Singapore.

Methods
This study was a retrospective, single-centre evaluation conducted at National Centre for Infectious Diseases (NCID), which provides HIV care for the majority of HIV-infected individuals in Singapore. The study was conducted between June 2014 and September 2018. Approval from Domain Speci c Review Board of the National Healthcare Group (Reference Number: 2012/00438-SRF0006) was obtained prior to study commencement.
The inclusion criteria were as follows: i) documented HIV-1 infection, ii) age ≥ 18 years, iii) use of combination of ABC/3TC (600/300 mg xed dose combination once daily) plus RPV (25 mg once daily) as maintenance therapy between June 2014 and September 2018 inclusive, iv) virologically suppressed (de ned as having at least 1 reading of HIV-1 RNA < 50 copies/ml) immediately before switching to ABC/3TC + RPV, and v) no documented history of resistance mutations or virologic failure to ABC, 3TC, FTC or RPV. Exclusion criteria were CD4 count < 200 cells/uL and pregnancy. As adherence could not be determined for patients who either obtained external supply of ART with no pharmacy dispensed records and/or with erratic clinic attendance, patients with proportion of days covered (PDC) for adherence of < 95% were also excluded. PDC was calculated by the following formula: [Number of days with medication supply in study period / number of days in the study period] x 100, capped at 100%. PDC is a known, validated and stringent measure of patient adherence. 15,16 The cut-off for PDC was chosen to be 95% as it is a widely used standard for optimal ART. 17 Eligible patients were identi ed from the NCID HIV Clinical Database, a standardised computerised database containing records of demographic information, HIV transmission route, and ART history. Data collected from electronic medical records included AEs attributed to ART, reasons for ART switch, and other laboratory readings which were not available on the Clinical Database. Data were anonymised upon extraction. Intervals for follow-up were determined by individual attending physicians per in-house clinical care guidelines.
The primary outcome measured was the proportion of patients who maintained virologic suppression on ABC/3TC + RPV after 48 ± 12 weeks of follow-up and had no therapy discontinuation due to non-virologic reasons such as adverse drug reactions. Patients were considered to have maintained virologic suppression if they had no virologic failure. Virologic failure was de ned as: i) 2 consecutive HIV-1 RNA readings of > 50 copies/ml, ii) any HIV-1 RNA reading of > 50 copies/ml that resulted in discontinuation of ABC/3TC + RPV, or iii) any HIV-1 RNA reading of > 500 copies/ml. This de nition for virological failure is similar to the SIMRIKI study, 10 but also included any HIV-1 RNA reading of > 500 copies/ml to detect any potential emergent antiretroviral resistance. Patients who had a one-off HIV-1 RNA reading between 51 copies/ml and < 199 copies/ml that was followed by a return to virologic suppression were considered virologic blips. 1 For all patients, HIV-1 RNA was measured at least twice throughout the follow-up period.
The secondary outcomes were the resistance pro les associated with virologic failure, changes in immunologic and metabolic parameters, and the AE pro le of ABC/3TC + RPV. For the immunologic and metabolic parameters, only patients who had both baseline and follow-up values were analyzed for secondary outcomes. The 95% con dence intervals (CI) were calculated based on the Newcombe-Wilson hybrid score. 18 We checked whether the continuous variables were normally distributed using the Kolmogorov-Smirnov test (for n ≥ 50) and Shapiro-Wilk test (for n < 50). We then used the paired samples t-test to analyze variables with normal distribution, and the Wilcoxon Signed Rank test to analyze variables with non-normal distribution. All statistical tests were two-sided, and p-values < 0.05 were considered statistically signi cant. Statistical analysis was carried out using the IBM SPSS Statistics for Windows, version 24.0 (Armonk, NY: IBM Corp).

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A total of 346 patients were screened. We included 222 patients for analysis. The inclusion process of the study was detailed in Fig. 1. Baseline characteristics of the patients included in the study were displayed in Table 1.

Discussion
Our results showed that a high proportion of patients (88.8%) who switched to ABC/3TC + RPV had maintained virologic suppression. In several studies in Spain, 86-88% of HIV patients maintained virologic suppression and avoided therapy discontinuation at 48 weeks or 12 months. [11][12][13] The SIMRIKI study also saw 91.2% of their study population achieving the same outcome at 48 weeks. 10  AEs were observed amongst 31/222 patients (14.0%) and resolved either spontaneously or upon discontinuation of the medication. These results were comparable to the favourable results of SIMRIKI study, 10 as well as the local study on treatment-naïve HIV-infected patients, 14 which reported only 15.6% and 13.5% of patients with observed AEs respectively. The AE pro le seen in our study was also very similar to the local study which saw mostly neuropsychiatric AEs at a rate of 46.4% of all observed AEs compared to our study which saw 57.1% of observed AEs being neuropsychiatric. 14 These ndings further support the well-established safety and tolerability of ABC/3TC + RPV.
Our patients had a signi cant improvement of absolute CD4 count at the end of the 48 ± 12 weeks followup. The increase in the CD4 count can possibly be attributed to maintained virologic suppression, and was also seen in other switch studies with increases ranging from + 48 to + 262 cells/uL. [11][12][13] We observed a statistically signi cant decrease in eGFR but not in eCrCl. The median absolute changes in eGFR and eCrCl were deemed to be of little or no clinical relevance, 20,21 as a median change of -4 ml/min/1.73 m 2 in eGFR or -1 ml/min in eCrCl is unlikely to affect the staging of chronic kidney disease or acute kidney injury. We also observed a statistically signi cant decrease in ALT, but the magnitude of the change is clinically insigni cant, 22 as the median change of -6 U/L is insu cient to warrant any clinical action. Signi cant changes in eCrCl, eGFR and ALTs were rarely noted in other studies on ABC/3TC + RPV, and it is likely that the regimen has no signi cant effect on these laboratory parameters. [11][12][13][14] While no statistically signi cant changes were detected for lipids, fasting blood glucose and HbA1c, the Our study has several limitations. The absence of a control group prevented us from comparing the effectiveness and safety in patients who would have continued with the prior regimen. As we excluded patients who were < 95% adherent by PDC, our ndings may not be generalizable to patients with suboptimal adherence or who are compliant to ART despite irregular clinic attendance or who purchase external supplies of ART. In practice, it will be crucial to take into account the relatively low genetic barrier to resistance and the caloric requirements of RPV when selecting this regimen. The frequency of adverse events may also have been under-reported, as only adverse events that were reported and explicitly attributed to the regimen in the patients' clinical documentation were included in the study.

Conclusion
In conclusion, this study shows that ABC/3TC + RPV is an effective and safe switch option for maintenance therapy in virologically suppressed HIV-1 patients in Singapore.