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Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO)
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May 2020 - Rosa De Miguela,#, David Rial-Crestelob,#, Lourdes Dominguez-Dominguezb, Rocío Montejanoa, Andres Esteban-Cantosa, Paula Aranguren-Rivasb, Natalia Stella-Ascariza,
Otilia Bisbalb, Laura Bermejo-Plazab, Monica Garcia-Alvarezb, Belen Alejosc,Asuncion Hernandod, Mireia Santacreu-Guerrerob, Julen Cadi~nanosa, Mario Mayorala,
Juan Miguel Castroa, Victoria Morenoa, Luz Martin-Carboneroa, Rafael Delgadob, Rafael Rubiob, Federico Pulidob,*,##, Jose Ramon Arribasa,**,##, ART-PRO, PI16/00837-PI16/00678 study group
a Hospital Universitario La Paz IdiPAZ. Paseo de la Castellana 261, 28046, Madrid, Spain b Hospital Universitario 12 de Octubre - Imas12, Av. de Cordoba, s/n, 28041, Madrid, Spain c Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain d Universidad Europea de Madrid- Imas12, Calle Tajo, s/n, 28670 Villaviciosa de Odon, Madrid, Spain
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Commentary
Dolutegravir plus lamivudine for hiv treatment: Does the historical genotype really matter?
June 2020 - Andrea Giacomellia,b,*, Federico Contia,b, Stefano Rusconia,b
a Department of Infectious Diseases, ASST Fatebenefratelli-Sacco, Luigi Sacco University Hospital, Milan, Italy
b Luigi Sacco Department of Biomedical and Clinical Sciences (DIBIC), University of Milan, Italy
The paradigm of antiretroviral therapy shifted in the last few years from the “mantra” of triple therapy to the possibility of using two-drug combination initially as maintenance strategies [1], and in fact as first-line regimens [2]. The possibility of such a shift was allowed by the availability of compounds with a high genetic barrier to resistance as “core agents”, protease inhibitors, and the second-generation integrase inhibitor dolutegravir. This strategy looks at the avoidance of untoward long-term effects related to the exposure of antiretrovirals with regards to nucleos(t)ide reverse transcriptase inhibitors with potential metabolic [3], bone and renal toxicities[4]. Nevertheless, for a relevant percentage of patients, the possibility to switch to regimens composed of fewer drugs is challenged by the presence of archived genotypic mutations in their historical genotype.
In the recent article published in EBioMedicine, De Miguel and co-workers assessed the switch to dolutegravir plus lamivudine in patients without previous exposure to integrase inhibitors with and without previously acquired lamivudine resistance [5]. The study addresses a topic that continues to challenge physicians involved in the treatment of people living with HIV. In particular, the possibility of switching patients with a lamivudine containing dual regimen with and without previously archived lamivudine resistance in the historical RNA genotype. The authors selected only patients without a lamivudine resistance detectable at the time of the switch in the proviral DNA by Sanger sequencing. The authors concluded that dolutegravir plus lamivudine was effective in maintaining virological suppression despite the presence of lamivudine resistance mutations in the historical genotype and the presence of archived mutations assessed by next-generation sequencing.
Some limitations related to the pilot-study design warrant a mention. First, the small study population warrants us to interpret the findings with caution. The probability of virological failure at 48 weeks, which was the primary and endpoint is not a frequent event in patients who switch under virological control. The limited sample size may have influenced the results toward showing no difference between the groups. Second, the convenience sample from patients enrolled in a previous study (GEN-PRO [6]) could have introduced a selection bias by enrolling patients with a good adherence to antiretrovirals and with higher probability of treatment success. Third, the use of proviral DNA to guide clinical decision to change an antiretroviral regimen could be questionable. This strategy may not be feasible for the majority of clinical centers that manage people living with HIV including some high income countries, especially when we consider the use of next-generation sequencing. On one hand, the assumption that a negative detection of resistance at the time of the switch in the proviral DNA correlate with the time of viral suppression before the switch may sound reasonable, but on the other side, it may be questionable due to the possible presence of archived mutations not detected by the test or the fading away of latently infected cells. Nonetheless, the increased sensitivity provided by a next-generation sequencing facilitates more informed decision making to make the therapeutic switch is still a matter of debate. The findings of the present study confirm that there is no difference in virological failure in those with and without lamivudine resistance detected by next-generation sequencing [7].
Data from observational studies suggest that the time of viral suppression before the switch in patients under virological control with previous NRTIs resistance could be one of the most important factors in determining the risk of virological failure [8]. The study by De Miguel et al. underlines that patients with previous lamivudine resistance had a longer duration of viral suppression before the switch compared to those without lamivudine resistance (7.7 years vs 5.3 years) [5]. Thus, the prolonged viral suppression in patients with archived lamivudine resistance could have increased the probability of virological success when compared to those without resistance.
We also have to consider the growing evidence that NRTIs can contribute to treatment success in the presence of previous resistance, in the reverse transcriptase or other enzymes, when combined with a high-genetic-barrier anchor drug. While this effect could be class- or drug-specific, M184V/I data suggest that the duration of virological suppression has a critical role in decreasing the amount of previously resistant variants below a clinically relevant threshold.
Although these findings are preliminary, after combining them with those coming from observational studies [9,10] we can suggest the possibility to simplify patients who have archived in their historical genotype lamivudine resistance to dolutegravir plus lamivudine as a maintenance regimen.
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Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO)
Rosa De Miguela,#, David Rial-Crestelob,#, Lourdes Dominguez-Dominguezb, Rocío Montejanoa, Andres Esteban-Cantosa, Paula Aranguren-Rivasb, Natalia Stella-Ascariza,
Otilia Bisbalb, Laura Bermejo-Plazab, Monica Garcia-Alvarezb, Belen Alejosc,Asuncion Hernandod, Mireia Santacreu-Guerrerob, Julen Cadi~nanosa, Mario Mayorala,
Juan Miguel Castroa, Victoria Morenoa, Luz Martin-Carboneroa, Rafael Delgadob, Rafael Rubiob, Federico Pulidob,*,##, Jose Ramon Arribasa,**,##, ART-PRO, PI16/00837-PI16/00678 study group
a Hospital Universitario La Paz IdiPAZ. Paseo de la Castellana 261, 28046, Madrid, Spain b Hospital Universitario 12 de Octubre - Imas12, Av. de Cordoba, s/n, 28041, Madrid, Spain c Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain d Universidad Europea de Madrid- Imas12, Calle Tajo, s/n, 28670 Villaviciosa de Odon, Madrid, Spain
ABSTRACT
Background
We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA population sequencing.
Methods
Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/μL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224.
Findings
41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71⋅4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92⋅7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation.
Interpretation
In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results.
Results
Between September 25, 2017, and April 9, 2018, we assessed the eligibility to participate in this study. Participants were selected among the 102 participating subjects of our prior study GEN-PRO, of whom 45 were offered to participate in ART-PRO to achieve our intended sample size (Figure 1). Forty-one participants on suppressive ART were included and switched to dolutegravir plus lamivudine: based on historical RNA genotype 21 had a history of resistance to lamivudine and 20 had not. Median time between the historical RNA genotype and baseline proviral DNA sequencing was 12⋅9 years (IQR: 6⋅7-14⋅4).
Baseline demographic characteristics at study entry were overall similar between groups (Table 1). Participants with previous lamivudine resistance had a non-statistically significant longer duration of HIV infection and lower CD4+ nadir count and had received a greater number of prior treatment regimens and were less likely to be receiving treatment with lamivudine or emtricitabine prior to entering the study compared to those without historical lamivudine resistance. Median duration of HIV viral suppression was 6 years (IQR 3⋅3-11) in both groups, which was also higher in the group with historical lamivudine resistance (7⋅7 years versus 5⋅3 years in the group without history of lamivudine resistance).
Proviral DNA next-generation sequencing genotypes from baseline samples obtained before switching ART were retrospectively available in all cases except for one participant belonging to the non-historical lamivudine resistance group, in whom amplification was unsuccessful. Seven participants with historical lamivudine resistance had the M184V/I and/or K65R/E/N mutations detected over the 20% threshold at baseline by next generation sequencing. When considering over a 5% threshold more than half of the participants with history of lamivudine resistance (15/21) had these mutations, and almost all participants in this group had lamivudine resistance-associated mutations when the 1% threshold was applied (20/21). Among participants without historical lamivudine resistance, none presented the K65R/E/N mutation but in three and seven cases the M184I mutation was detected with over a 5% or 1% threshold, respectively, including one participant harboring the M184I mutation with a 99% frequency. Reads with lamivudine resistance-associated mutations detected through next-generation sequencing (1% threshold) were subjected to hypermutation analysis, showing that 16/27 samples harbored retrotranscriptase defective viral genomes due to APOBEC-induced mutations. After removal of reads identified as hypermutated, lamivudine resistance-associated mutations remained present in 22 of the 27 initial samples.
Two participants in the history of lamivudine resistance group -initially misclassified as lacking lamivudine resistance-associated mutations- had the M184V mutation detected in proviral DNA Sanger sequencing at baseline (protocol violation).
38/41 patients completed the 48 weeks of study. There were three participants that prematurely discontinued: the two protocol violations (week 12) and one withdrawal due to an adverse event (week 8), all doing so with HIV RNA below 50 copies per mL. At week 48, 92⋅7% of participants (38/41) remained with HIV RNA below 50 copies per mL (FDA-snapshot intention- to- treat- exposed analysis). All participants completing 48 weeks reached the primary efficacy endpoint of HIV RNA below 50 copies per mL following the FDA-snapshot algorithm (Figure 2, Table 2). The three participants that did not complete the study belonged to the historical lamivudine resistance group: primary efficacy endpoint in this group was 85⋅7 % in the intention- to- treat- exposed analysis (18/21 of participants with HIV RNA below 50 copies per mL at week 48) and 94⋅7% in the per-protocol analysis (18/19 HIV RNA below 50 copies per mL at week 48) (Table 2). The three non-completers abandoned the study before reaching week 24, hence, efficacy at week 24 does not differ from the results presented for week 48.
Ten participants - four from the historical lamivudine resistance and six from the non- lamivudine resistance group- had a transient low-level viral rebound followed by a re-test HIV RNA below 50 copies per mL (Table 3). Two of these occurred on day 1 of the study (before switching treatment), and in half of the cases the person admitted to temporary low adherence or was suffering a concomitant mild infection. All cases of transient viral rebound re-suppressed without changing treatment. We were able to obtain Sanger sequencing in two participants with history of M184V/I mutation who had a transient viral rebound, including one individual rebounding to 1120 copies/mL at week 36 (Figure 3): there was no re-emergence of lamivudine-resistance associated mutations nor did we identify any newly acquired integrase mutations. Three of the six participants without historical lamivudine resistance who had transient low-level viral rebound had the M184I mutation detected through next-generation sequencing in baseline proviral DNA, including the participant who had this mutation detected at a frequency above 99%. Notably, this participant's viral rebound occurred on day 1 of the study when he had not yet received the first dose of dolutegravir plus lamivudine, and remained without any blips throughout the study.
Through week 48, there were no cases of withdrawal due to virologic failure and no emergence of resistance mutations. None of the 21 participants who had either history of lamivudine resistance or detection of lamivudine resistance-associated mutations above the 5% threshold in proviral DNA had virologic failure after 48 weeks of follow-up (IC95% 0-14%). At 48 weeks, there was not a significant difference in mean change of CD4 count from baseline (23⋅84 cells/mm3, p=0⋅686, IC95% -94⋅88-142⋅56).
There were 28 treatment related adverse events (Table 4). Most drug related adverse events were mild cases of flatulence or insomnia that spontaneously resolved in the first weeks after the switch. One participant had newly acquired insomnia attributed to dolutegravir leading to treatment discontinuation on week 8, after which his symptoms disappeared. The only laboratory grade 3 drug-related adverse event occurred in one participant in the group with historical lamivudine resistance (hypercholesterolemia). We found no difference in total cholesterol, HDL, LDL mean changes by group. Mean weight change from baseline was 1⋅36 kg (95% CI -1⋅11; 3⋅84) without significant differences by group.
Discussion
In this pilot trial dolutegravir plus lamivudine maintained virologic suppression through 48 weeks despite history of lamivudine resistance and detection of archived lamivudine resistance-associated mutations in proviral DNA by next generation sequencing but not by population sequencing. These results provide preliminary evidence supporting the combination of dolutegravir plus lamivudine as a reduced-drug regimen for maintenance of HIV suppression in integrase naïve persons with historical lamivudine resistance, without lamivudine resistance-associated mutations detected by proviral DNA Sanger sequencing.
Our results and those of others do no support the assumption that dolutegravir plus lamivudine in patients with prior history of lamivudine resistance is functional dolutegravir monotherapy. In ART-PRO none of the 21 participants reaching week 48 who had either history of lamivudine resistance or detection of lamivudine resistance mutations above the 5% threshold in proviral DNA experienced virologic failure. In two other clinical trials a total of 21 participants with history of lamivudine resistance or detection of lamivudine resistance-associated mutations in proviral DNA did not experience virologic failure 48 weeks after switching to dolutegravir plus lamivudine.
Adding the results of these three trials, none of a total of 42 participants with history and/or detection of lamivudine resistance-associated mutations have developed virologic failure after switching to dual therapy with dolutegravir plus lamivudine. In contrast, pooled data from dolutegravir monotherapy studies for maintenance treatment revealed a proportion of virologic failure of 8⋅9% (95% CI 4⋅7-16⋅2) at 48 weeks.
These differences in the rates of virological failure suggest that lamivudine might provide significant antiviral activity to dolutegravir despite the presence of archived lamivudine resistance mutations. Additional support for this hypothesis comes from two retrospective cohort studies in which a historical plasma genotype detecting the M184V mutation was not predictive of virologic failure in participants switching to lamivudine- based dual therapies with either a protease inhibitor or an integrase inhibitor.
The residual antiviral efficacy of lamivudine was demonstrated more than a decade ago in a study showing a viral load increase of 0⋅5 log10 after discontinuing lamivudine despite the presence of the M184V mutation.
Another study reported lower viral rebound in persons harboring the M184V who received lamivudine monotherapy compared to patients interrupting treatment. In addition to the antiviral effect of lamivudine, the maintenance of the M184V/I mutations might contribute to the success of dolutegravir plus lamivudine by sustaining a diminished viral fitness and preventing the emergence of resistance mutations against dolutegravir.
Another factor that might have contributed to the success of the dolutegravir plus lamivudine regimen in this pilot trial is the exclusion of participants if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. In our study GEN-PRO we found that when lamivudine resistance-associated mutations were absent in proviral DNA by population genotyping, the percentage of lamivudine resistance-associated mutations detected by next-generation sequencing was much lower than when proviral DNA population sequencing did detect lamivudine resistance-associated mutations. Only 17⋅1% of the participants in ART-PRO had detection of lamivudine resistance-associated mutations by next generation sequencing with a threshold over 20%. This is in contrast with GEN-PRO, where 78⋅5% or participants with lamivudine resistance-associated mutations detected in proviral DNA by population genotyping had these mutations detected by next generation sequencing with a threshold of 20%.
We believe baseline proviral DNA population sequencing renders at least some assurance that past lamivudine resistance-associated mutations are not persisting at high levels and thus, increases the probability of response to dolutegravir plus lamivudine. In our study, the hypermutation analysis showed that 18⋅5% of mutations associated with lamivudine resistance detected at baseline through next-generation sequencing were from hypermutated viral sequences, and therefore, not clinically relevant. However, this analysis does not completely exclude that the archived resistance mutations found in our study may be related to defective viral genomes for other reasons different to hypermutation, such as large internal deletions.
In our study the group with historical lamivudine resistance had longer duration of viral suppression (7⋅7 vs 5⋅3 years) compared to the group without historical lamivudine resistance. It has been postulated that the duration of virologic suppression could have some role in the dynamics of lamivudine resistance. The small sample size prevents us from inferring if this had a significant impact in our results, however, in the study by Gagliardini et al. dual therapy with either boosted protease inhibitor or integrase inhibitor plus lamivudine in persons with past M184V demonstrated only a statistically higher risk of virological failure for those with a viral suppression equal or under three years, which is inferior to the median viral suppression duration in our study.
The most important limitations of our study are the small sample size-characteristic of a pilot proof-of-concept clinical trial and the relative short follow-up. We intentionally recruited a small number of participants because treatment with dolutegravir plus lamivudine in suppressed persons with prior history of resistance to lamivudine had never been prospectively tested before. A 144-week extension of our study is currently ongoing, but further studies are necessary to confirm our findings.
To our knowledge, our study is the only specifically designed to address the outcomes of dolutegravir plus lamivudine for maintenance of viral suppression in patients with historical resistance to lamivudine. Our results generate the hypothesis that a switch to dolutegravir plus lamivudine in integrase-inhibitor naïve persons with historical lamivudine resistance-associated mutations could be effective in preserving virologic suppression at 48 weeks, under the condition that, before switching to dual therapy, proviral DNA population sequencing does not detect the persistence of lamivudine resistance-associated mutations. The findings of this pilot trial call for a larger, fully-powered study to confirm our results.
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