No Significant Changes to Residual Viremia After Switch to Dolutegravir and Lamivudine in a Randomized Trial.

In the ASPIRE trial, antiretroviral therapy (ART) switch to dolutegravir plus lamivudine (DTG+3TC) was comparable to 3-drug ART in maintaining viral suppression by standard viral load assays. We used an ultrasensitive assay to assess whether this switch led to increased residual viremia. At entry, levels of residual viremia did not differ significantly between arms (DTG+3TC vs 3-drug ART: mean, 5.0 vs 4.2 HIV-1 RNA copies/mL; P = .64). After randomization, no significant between-group differences were found at either week 24 or 48. These results show no evidence for increased viral replication on DTG+3TC and support its further investigation as a dual ART strategy.

RCT Entities:   Population Interventions Outcomes

Two-drug antiretroviral treatment (ART) is an investigational strategy to maintain HIV suppression while reducing long-term antiretroviral drug exposure, cost, and adverse events. The Antiretroviral Strategy to Promote Improvement and Reduce Exposure (ASPIRE) study was a randomized, 48-week, controlled pilot trial that assessed the efficacy of the 2-drug regimen of dolutegravir and lamivudine (DTG+3TC) in participants who were virologically suppressed on a standard 3-drug ART regimen [1]. Virologic outcomes showed that switching to DTG+3TC was comparable to continuation of standard 3-drug maintenance therapy in maintaining viral suppression. This was supported by the Food and Drug Administration snapshot analyses, in which 93% of DTG+3TC participants maintained viral suppression at week 24 vs 91% for 3-drug ART, and 91% vs 89% at week 48, respectively. One case of virologic failure was detected in each arm, with no emergence of resistance mutations.

One potential concern about reducing treatment from 3 to 2 drugs is loss of complete viral suppression. This may be detected by use of a more sensitive viral load assay [2]. Furthermore, viral blips have been reported after switching to DTG+3TC, although this was not observed in the ASPIRE trial [1, 3]. Thus, we quantified longitudinal changes in residual viremia by the ultrasensitive integrase single-copy viral load assay to determine whether ART switch to DTG+3TC in ASPIRE participants resulted in increased low-level viral replication.

METHODS

Study Population and Samples

ASPIRE was an open-label, randomized, multicenter, 48-week clinical trial that enrolled HIV-1-infected adults who were virologically suppressed on any US Department of Health and Human Services (DHHS)–recommended/alternative or other 3-drug regimen for at least 48 weeks (NCT02263326) [1]. Inclusion criteria included age ≥18 years, ≥2 HIV-1 RNA measurements <50 copies/mL within 48 weeks of study entry, and a screening HIV-1 RNA <20 copies/mL. Exclusion criteria included a history of virologic failure (VF) after 1 year of treatment, pretreatment reverse transcriptase (RT) resistance mutation, or known integrase resistance mutations. Participants were randomized 1:1 to switch to open-label oral DTG 50 mg plus 3TC 300 mg once daily or to continue their current 3-drug ART. Postentry monitoring included plasma HIV-1 RNA using the COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, v2.0 (lower detection limit, 20 copies/mL; Roche Molecular Systems), safety labs, and 4-day adherence recall. The institutional review board of each participating institution approved this study, and each participant provided informed consent.

Quantification of Residual Viremia

Low-level plasma HIV viremia were measured on plasma at study entry and at weeks 24 and 48 of treatment using the validated ultrasensitive integrase single-copy assay (iSCA; limit of detection, 0.5 HIV-1 RNA copies/mL) [4], commonly used to assess levels of residual viral load [5-12]. Plasma from the participants was spiked with an internal replication-competent ASLV long terminal repeat with a splice acceptor (RCAS) virion as a control for RNA extraction efficiency [13]. Real-time polymerase chain reactions were performed with a Roche LightCycler 480 system using primers and probes specific to a conserved region of the HIV integrase gene [4].

Statistical Methods

Differences in residual viremia between the treatment groups were analyzed by fitting a linear model accounting for possible within-patient correlation using a generalized least squares fit. We included the study time point and treatment arm in the model. Those who discontinued ART during the study or in which iSCA measurement was not available at at least 1 time point were excluded from this analysis. The participant characteristics between treatment groups were compared using the Mann-Whitney U test for continuous variables and chi-square test for categorical variables.

RESULTS

Of the 89 participants randomized to the ASPIRE study, 7 discontinued their randomized ART due to virologic rebound (n = 2), adverse events (n = 1), or noncompliance (n = 4). Additionally, 10 participants were excluded due to the lack of iSCA measurement at one or more time points. A total of 72 participants with iSCA data at study entry, week 24, and week 48 were included in the current analysis. The median CD4+ count was 663 cells/mm3, and prior ART exposure (median, 6.0 years) consisted of integrase inhibitors (40%), non-nucleoside reverse transcriptase inhibitors (29%), and protease inhibitor–based regimens (31%) at the time of study entry (Table 1).

Table 1.

Participant Characteristics

Characteristic	DTG+3TC (n = 36)	3-Drug ART (n = 36)	P
Age, median, y	45.5	50.5	.67
Male sex, %	92	86	.71
Ethnicity, %			.33
White	58	72
Black	39	28
Asian	3	0
CD4+ cell count, median, cells/mm3	677	637	.09
Duration of viral suppression, median, y	5.37	6.04	.82

Abbreviations: 3TC, lamivudine; ART, antiretroviral therapy; DTG, dolutegravir.

At baseline, the mean residual viremia did not differ significantly between study arms (DTG+3TC vs 3-drug ART: mean, 5.0 vs 4.2 HIV-1 RNA copies/mL; P = .64). After ART switch, no significant differences were found in the residual viremia when comparing the DTG+3TC vs 3-drug ART arms, adjusting for baseline values (mean viral load change at week 24, 1.6 copies/mL; 95% confidence interval [CI], –1.9 to 5.2; P = .37; mean viral load change at week 48, 0.5 copies/mL; 95% CI, –3.0 to 4.1; P = .76) (Figure 1). Furthermore, no significant changes in residual viremia were found after stratification by duration of prior ART treatment or CD4+ count (Supplementary Figure 1). Finally, we analyzed residual viremia as a dichotomous variable (detectable or undetectable) and found no significant differences in residual viremia detectability status between baseline and either 24 or 48 weeks in the DTG+3TC arm vs 3-drug ART arm (Supplementary Table 1).

Figure 1.

Levels of HIV viral load by the ultrasensitive integrase single-copy assay by treatment arm at study entry, 24 and 48 weeks after antiretroviral therapy switch. Tukey’s box and whisker plots; box limits: interquartile range (IQR); middle line: median; diamond: mean; vertical lines: adjacent values (1st quartile −1.5 IQR; 3rd quartile +1.5 IQR). Abbreviations: 3TC, lamivudine; ART, antiretroviral therapy; DTG, dolutegravir.

CONCLUSIONS

We have previously reported that in the ASPIRE randomized trial, switching to the 2-drug DTG+3TC regimen was comparable to continuation of a standard 3-drug maintenance therapy [1]. Using the ultrasensitive iSCA viral load assay, we found no evidence for increased low-level viral replication after a switch to DTG+3TC, as reflected by stable levels of residual viremia.

There has been a concerning report that ART switch to a 2-drug regimen may lead to increased low-level viral replication, which could eventually select for drug resistance or lead to virologic rebound [2]. Data from studies using 2-drug regimens as maintenance therapy are mixed. In a study of switching suppressed patients to raltegravir (RAL) plus maraviroc (MVC), increased virologic failure was observed despite preswitch assessment of viral tropism [2]. By contrast, switching to DTG+rilipvirine (RPV) [14] or a boosted PI+3TC [15, 16] has been a successful strategy. In addition, no significant changes in levels of systemic inflammation [17] or differences in HIV DNA decline [18] were observed. It is possible that the success of certain 2-drug regimens results from at least 1 of the agents having a high resistance barrier, a characteristic shared by DTG and boosted PIs. Our results support the virologic efficacy of selected 2-drug regimens and are consistent with multiple studies now demonstrating that DTG+3TC is an effective option either for treatment-naïve individuals [19, 20] or as a maintenance therapy [1, 21].

The use of DTG+3TC as a maintenance regimen likely has several benefits, including decreasing costs [21, 22] and avoidance of side effects associated with abacavir or tenofovir. For example, the switch to a 2-drug therapy has been reported to improve renal function and bone mineral density when tenofovir disoproxil fumarate is avoided [15], and improvements in immune function and metabolic markers have also been found with decreased nucleos(t)ide reverse transcriptase (NRTI) exposure [21, 23]. It is important to note that the ASPIRE trial excluded individuals with any history of NRTI genotypic resistance mutations, especially in light of a recent report showing that a history of M184V resistance was associated with an increased probability of viral blips in those switching to DTG+3TC [24]. This was not associated with a significantly increased risk of virologic failure, but the sample size was relatively limited, and DTG+3TC treatment should not be recommended in those with a history of resistance mutations against 3TC. Another limitation of this study is that sampling of nonperipheral blood compartments was limited to the genital tract. A combined genital tract analysis was performed for the ASPIRE participants and those in the AIDS Clinical Trials Group A5353 study of DTG+3TC for ART-naïve individuals. The frequency of genital HIV RNA shedding while virologically suppressed was similar between those on a standard 3-drug ART and those on DTG+3TC as either initial or maintenance therapy [25].

In summary, the ASPIRE trial has demonstrated that DTG+3TC is effective in maintaining viral suppression, as measured either by conventional or ultrasensitive viral load assays. These results support further investigation of DTG+3TC dual therapy for maintenance of viral suppression, as is being done in the fully powered TANGO study (NCT03446573).

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Click here for additional data file.