FeaturePerspective

Dolutegravir monotherapy ’not a valid option’ for patients with HIV

Laurent Hocqueloux, MD
Laurent Hocqueloux

Study results showed that dolutegravir monotherapy “is not a valid option” to keep patients with chronic HIV infection virologically suppressed and should not be considered a treatment option, researchers said.

Laurent Hocqueloux, MD, from the department of infectious and tropical diseases at the Regional Hospital Center of Orléans in France, and colleagues published results from the MONCAY trial in Clinical Infectious Diseases.

“Dolutegravir (DTG) monotherapy is not indicated as a maintenance therapy for long-term

suppressed people living with HIV because of a significant risk of virological failure with mutation to the class of [integrase strand transfer inhibitor (INSTI)]. Our study adds strong evidence for that conclusion,” Hocqueloux told Infectious Disease News.

MONCAY trial

In an editorial also published in Clinical Infectious Diseases, Bart J.A. Rijnders, MD, PhD, and Casper Rokx, MD, PhD, from the section of infectious diseases at Erasmus University Medical Center in Rotterdam, the Netherlands, noted that when DTG-based combination ART (cART) was approved in the United States in 2013 and in Europe in 2014, evaluating DTG monotherapy as a maintenance treatment strategy “made sense.” However, three prospective clinical trials have showed that DTG monotherapy, while effective in the short term, is “clearly inferior” to cART in the long term, they said.

Hocqueloux and colleagues investigated the ability of DTG monotherapy to maintain virologic suppression in people living with HIV on a successful DTG-based triple therapy. In the 48-week multicenter, randomized, open-label, 12% noninferiority margin trial, patients with a CD4 nadir of more than 100/L, HIV viral load of less than 50 copies/mL for 12 months or more, and a stable dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) regimen were randomly assigned to continue their regimen or switch to DTG monotherapy.

According to Hocqueloux and colleagues, the primary endpoint was the proportion of patients with an HIV viral load of less than 50 copies/mL at week 24 in the intent-to-treat snapshot analysis. They defined virologic failure as two consecutive counts of a viral load of more than 50 copies/mL within 2 weeks apart.

The researchers assigned 78 patients to DTG monotherapy and 80 to continue the DTG-based triple therapy. In the DTG arm, two patients experienced virologic failure without resistance to the INSTI class by week 24 and one patient from the DTG/ABC/3TC arm discontinued because of an adverse event. At week 24, the success rate in the DTG group was 93.6% compared with 96.3% in the DTG/ABC/3TC group, a difference of 2.7% (95% CI, –5 to 10.8).

Virologic failure occurred five additional times among those receiving DTG monotherapy during follow-up, and of those, two had an emerging resistance mutation to INSTI. At week 48, Hocqueloux and colleagues observed a 9.7% (95% CI, 2.8-16.6) cumulative incidence of virologic failure in the DTG arm compared with no observed virologic failure in the DTG/ABC/3TC arm (P = .005). The experimental DTG arm of the study was stopped based on recommendations from the data safety monitoring board, Hocqueloux and colleagues reported.

“The MONCAY trial demonstrated that DTG monotherapy was not a valid option to maintain virological suppression over time in [people living with HIV] with chronic infection on a successful DTG/ABC/3TC regimen, even though it met non-inferiority to DTG/ABC/3TC at week 24,” they wrote.

Swiss study

Hocqueloux said he believes — “personally, not as the leader of the MONCAY study” — that patients with HIV who receive DTG monotherapy at the time of primary infection “may have much better outcomes.” He noted findings from a pilot study also published in Clinical Infectious Diseases that showed DTG monotherapy is noninferior to cART among patients who initiated cART within 180 days after the estimated day of documented primary HIV infection and who were virally suppressed for at least 48 weeks.

Domin ique L. Braun, MD, from the division of infectious diseases and hospital epidemiology at University Hospital Zurich, and colleagues conducted EARLY-SIMPLIFIED, a randomized, open-label, noninferiority trial, from Nov. 30, 2015, to March 10, 2017, including 101 patients in the study. The primary endpoint was the proportion of patients without virologic failure on or before week 48, and the noninferiority margin was 10%.

Braun and colleagues randomly assigned 68 patients to receive once-daily DTG 50 mg and 33 patients to continue cART. The virologic response in both arms at week 48 was 100% (95% CI, –100% to 4.76%).

Braun and co-author Huldrych F. Günthard, MD, from the division of infectious diseases and hospital epidemiology at University Hospital Zurich, told Infectious Disease News that patients who initiated cART during the chronic phase of HIV infection should not consider DTG monotherapy as a treatment option. However, a specific subset of patients may still be considered for DTG monotherapy as long as cART was initiated during primary HIV infection, there are no resistance-associated mutations to integrase inhibitors, viral loads are closely monitored and therapy is immediately switched back to a cART regimen if viral suppression is not achieved on two consecutive tests measured 2 weeks apart.

Braun and Günthard explained that because all HIV-infected patients must now be treated promptly, regardless of CD4 count or viral load, the number of patients initiating cART early will increase, resulting in an increase in patients eligible for DTG monotherapy.

“However, if our treatment policies will not be adapted in the future to more personalized approaches, we may overtreat large numbers of patients for decades,” they said. “Hence, future simplification studies should optimally use a stratification according to the time of HIV infection until start of first cART and also including measurements of the latent HIV-1 reservoir, immune activation parameters and anti-HIV immune responses.”

In their editorial, Rijnders and Rokx explained that the smaller genetic diversity of HIV in the patients in Braun and colleagues’ study may be one explanation for the lack of virologic failures. The reservoir size and its association with the success of DTG monotherapy is “uncertain and is a question that cannot easily be answered,” they wrote. They suggested viewing the findings of Braun and colleagues only as a first proof-of-concept study and recommend a longer follow-up period for future studies.

“DTG as maintenance monotherapy should no longer be considered a treatment option for patients outside or even inside the context of a clinical trial,” Rijnders and Rokx concluded. – by Marley Ghizzone

References:

Braun DL, et al. Clin Infect Dis. 2019;doi:10.1093/cid/ciy1131.

Hocqueloux L, et al. Clin Infect Dis. 2019;doi:10.1093/cid/ciy1132.

Rijnders BJA, Rokx C. Clin Infect Dis. 2019;doi:10.1093/cid/ciy1136.

Disclosures: Braun, Günthard, Hocqueloux, Rijnders and Rokx each report numerous ties to industry. Please see the studies for all other authors’ relevant financial disclosures.

Laurent Hocqueloux, MD
Laurent Hocqueloux

Study results showed that dolutegravir monotherapy “is not a valid option” to keep patients with chronic HIV infection virologically suppressed and should not be considered a treatment option, researchers said.

Laurent Hocqueloux, MD, from the department of infectious and tropical diseases at the Regional Hospital Center of Orléans in France, and colleagues published results from the MONCAY trial in Clinical Infectious Diseases.

“Dolutegravir (DTG) monotherapy is not indicated as a maintenance therapy for long-term

suppressed people living with HIV because of a significant risk of virological failure with mutation to the class of [integrase strand transfer inhibitor (INSTI)]. Our study adds strong evidence for that conclusion,” Hocqueloux told Infectious Disease News.

MONCAY trial

In an editorial also published in Clinical Infectious Diseases, Bart J.A. Rijnders, MD, PhD, and Casper Rokx, MD, PhD, from the section of infectious diseases at Erasmus University Medical Center in Rotterdam, the Netherlands, noted that when DTG-based combination ART (cART) was approved in the United States in 2013 and in Europe in 2014, evaluating DTG monotherapy as a maintenance treatment strategy “made sense.” However, three prospective clinical trials have showed that DTG monotherapy, while effective in the short term, is “clearly inferior” to cART in the long term, they said.

Hocqueloux and colleagues investigated the ability of DTG monotherapy to maintain virologic suppression in people living with HIV on a successful DTG-based triple therapy. In the 48-week multicenter, randomized, open-label, 12% noninferiority margin trial, patients with a CD4 nadir of more than 100/L, HIV viral load of less than 50 copies/mL for 12 months or more, and a stable dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) regimen were randomly assigned to continue their regimen or switch to DTG monotherapy.

According to Hocqueloux and colleagues, the primary endpoint was the proportion of patients with an HIV viral load of less than 50 copies/mL at week 24 in the intent-to-treat snapshot analysis. They defined virologic failure as two consecutive counts of a viral load of more than 50 copies/mL within 2 weeks apart.

The researchers assigned 78 patients to DTG monotherapy and 80 to continue the DTG-based triple therapy. In the DTG arm, two patients experienced virologic failure without resistance to the INSTI class by week 24 and one patient from the DTG/ABC/3TC arm discontinued because of an adverse event. At week 24, the success rate in the DTG group was 93.6% compared with 96.3% in the DTG/ABC/3TC group, a difference of 2.7% (95% CI, –5 to 10.8).

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Virologic failure occurred five additional times among those receiving DTG monotherapy during follow-up, and of those, two had an emerging resistance mutation to INSTI. At week 48, Hocqueloux and colleagues observed a 9.7% (95% CI, 2.8-16.6) cumulative incidence of virologic failure in the DTG arm compared with no observed virologic failure in the DTG/ABC/3TC arm (P = .005). The experimental DTG arm of the study was stopped based on recommendations from the data safety monitoring board, Hocqueloux and colleagues reported.

“The MONCAY trial demonstrated that DTG monotherapy was not a valid option to maintain virological suppression over time in [people living with HIV] with chronic infection on a successful DTG/ABC/3TC regimen, even though it met non-inferiority to DTG/ABC/3TC at week 24,” they wrote.

Swiss study

Hocqueloux said he believes — “personally, not as the leader of the MONCAY study” — that patients with HIV who receive DTG monotherapy at the time of primary infection “may have much better outcomes.” He noted findings from a pilot study also published in Clinical Infectious Diseases that showed DTG monotherapy is noninferior to cART among patients who initiated cART within 180 days after the estimated day of documented primary HIV infection and who were virally suppressed for at least 48 weeks.

Domin ique L. Braun, MD, from the division of infectious diseases and hospital epidemiology at University Hospital Zurich, and colleagues conducted EARLY-SIMPLIFIED, a randomized, open-label, noninferiority trial, from Nov. 30, 2015, to March 10, 2017, including 101 patients in the study. The primary endpoint was the proportion of patients without virologic failure on or before week 48, and the noninferiority margin was 10%.

Braun and colleagues randomly assigned 68 patients to receive once-daily DTG 50 mg and 33 patients to continue cART. The virologic response in both arms at week 48 was 100% (95% CI, –100% to 4.76%).

Braun and co-author Huldrych F. Günthard, MD, from the division of infectious diseases and hospital epidemiology at University Hospital Zurich, told Infectious Disease News that patients who initiated cART during the chronic phase of HIV infection should not consider DTG monotherapy as a treatment option. However, a specific subset of patients may still be considered for DTG monotherapy as long as cART was initiated during primary HIV infection, there are no resistance-associated mutations to integrase inhibitors, viral loads are closely monitored and therapy is immediately switched back to a cART regimen if viral suppression is not achieved on two consecutive tests measured 2 weeks apart.

Braun and Günthard explained that because all HIV-infected patients must now be treated promptly, regardless of CD4 count or viral load, the number of patients initiating cART early will increase, resulting in an increase in patients eligible for DTG monotherapy.

“However, if our treatment policies will not be adapted in the future to more personalized approaches, we may overtreat large numbers of patients for decades,” they said. “Hence, future simplification studies should optimally use a stratification according to the time of HIV infection until start of first cART and also including measurements of the latent HIV-1 reservoir, immune activation parameters and anti-HIV immune responses.”

In their editorial, Rijnders and Rokx explained that the smaller genetic diversity of HIV in the patients in Braun and colleagues’ study may be one explanation for the lack of virologic failures. The reservoir size and its association with the success of DTG monotherapy is “uncertain and is a question that cannot easily be answered,” they wrote. They suggested viewing the findings of Braun and colleagues only as a first proof-of-concept study and recommend a longer follow-up period for future studies.

“DTG as maintenance monotherapy should no longer be considered a treatment option for patients outside or even inside the context of a clinical trial,” Rijnders and Rokx concluded. – by Marley Ghizzone

References:

Braun DL, et al. Clin Infect Dis. 2019;doi:10.1093/cid/ciy1131.

Hocqueloux L, et al. Clin Infect Dis. 2019;doi:10.1093/cid/ciy1132.

Rijnders BJA, Rokx C. Clin Infect Dis. 2019;doi:10.1093/cid/ciy1136.

Disclosures: Braun, Günthard, Hocqueloux, Rijnders and Rokx each report numerous ties to industry. Please see the studies for all other authors’ relevant financial disclosures.

    Perspective
    Paul E. Sax

    Paul E. Sax

    ART agents with high resistance barriers have an important place in HIV therapy. Specifically, they have demonstrated no emergent resistance when used as part of an initial treatment regimen a highly desirable trait, especially for patients who may not be fully adherent. Historically, this property was held only by boosted protease inhibitors (PIs); we now know that the second-generation integrase inhibitors DTG and bictegravir have this characteristic as well.

    Because of this high resistance barrier, researchers have speculated that monotherapy with boosted PIs or DTG may be sufficient to maintain viral suppression. For boosted PIs, more viral failure occurred in monotherapy than with continued combination treatment, although generally without development of PI resistance, provided the nucleoside reverse transcriptase inhibitors were reintroduced. For DTG monotherapy, similar results have been found, most recently in a paper published in Clinical Infectious Diseases. In the MONCAY study by Hocqueloux and colleagues, 78 patients with viral suppression were assigned to DTG monotherapy and 80 to continue DTG/ABC/3TC. After 48 weeks, 9.7% in the monotherapy arm experienced virologic failure two with resistance to integrase inhibitors vs. none in the triple-therapy arm, prompting early discontinuation of the study. These data clearly show that DTG monotherapy should not be used, even in patients with viral suppression.

    A second study conducted in patients who started treatment during primary HIV infection also tested DTG monotherapy, with the hypothesis that those patients would have lower viral reservoirs and less diversity, and hence be easier to treat with a single agent. Here, 68 patients were assigned to DTG monotherapy and 33 patients to continuation of combination therapy. At week 48, none of the patients in either arm experience viral rebound or resistance. As per the title of the study, the DTG monotherapy study was “noninferior” to continued combination ART based on the 10% noninferiority margins.

    However, despite the title and results of this second study, there are several reasons for clinicians to avoid using DTG monotherapy in all settings, regardless of when patients initiated ART. First, as shown in the MONCAY study of patients with established (not primary) HIV infection, the risk of treatment failure and development of resistance is unacceptably high. This is particularly important given the central role integrase inhibitors play in preferred ART regimens. Second, the second study’s conclusions must be tempered by the small sample size, short follow-up time, and wide noninferiority margins (10%), which certainly could come into play with greater follow-up. Finally, the driving motivation behind DTG monotherapy, which is to avoid the toxicity of tenofovir and abacavir, has become less relevant with the availability of tenofovir alafenamide (which has less renal and bone toxicity) and the promising results of DTG plus lamivudine.

    In summary, DTG monotherapy as a treatment strategy should be avoided.

    • Paul E. Sax, MD
    • Clinical director, HIV program and division of infectious diseases Brigham and Women’s Hospital Boston

    Disclosures: Sax reports serving as a scientific advisory board member/consultant for Gilead Sciences, GlaxoSmithKline/ViiV, Janssen and Merck; receiving research support from Gilead, GlaxoSmithKline/ViiV and Merck; and serving in editorial positions at UpToDate, Medscape, NEJM Journal Watch and Open Forum Infectious Diseases.