Meeting News

HIV drugs show promise in phase 3 trials

Joel Gallant
Joel Gallant

Several investigational HIV drugs or drug regimens showed promise in recent phase 3 trials, according to findings presented at the International AIDS Society conference.

Gilead Sciences, Janssen and Merck each spotlighted new medicines or treatments aimed at simplifying regimens or addressing the problem of HIV drug resistance. Experts who presented the findings extolled the progress that has been made in treating patients with HIV, but they insisted better options are still needed.

“In an era when we can treat almost all patients with safe, effective and convenient regimens, it may no longer be possible to talk about ‘urgent needs’ with respect to treatment,” Joel Gallant, MD, MPH, medical director of specialty services at Southwest Care Center in Santa Fe, New Mexico, told Infectious Disease News. “However, drug development in our field is still exciting, with the potential for long-acting agents and regimens. Of course, the search continues for both a preventive vaccine and a cure.”

Kathleen Squires, MD, professor and director of infectious diseases at Thomas Jefferson University in Philadelphia, also mentioned the need for drugs that can be taken less frequently. World health officials issued a warning on the eve of the conference about a “worrying” rise in HIV drug resistance that is largely tied to nonadherence.

“We have come a long way in our treatment regimens for HIV-infected patients. However, all of these regimens require daily dosing of the drugs because of their half-life,” Squires said in an interview. “Despite the fact that we have a number of medications that are once-daily regimens, there are some people who, for a number of reasons, simply can’t adhere to taking a pill a day.

“In many cases, I’ve had patients who have said to me, ‘Every time I look at the medication, it reminds me that I have HIV infection and I don’t want to be reminded of that,’” Squires continued. “They can’t deal with that, so they don’t take the medication.”

Gilead’s bictegravir-containing regimen

Gilead announced 48-week results of two phase 3 trials showing that a fixed-dose combination containing the novel integrase inhibitor bictegravir was noninferior to regimens containing Tivicay (dolutegravir, GlaxoSmithKline; DTG) in treatment-naive adults with HIV. Both trials studied the effect of a once-daily single-tablet regimen of bictegravir (BIC) in combination with Descovy (emtricitabine/tenofovir alafenamide, Gilead; FTC/TAF).

In the first trial, Gallant and colleagues randomly assigned 629 patients 1:1 to receive either BIC/FTC/TAF (50/200/25 mg) or Triumeq (abacavir/dolutegravir/lamivudine, ViiV Healthcare; ABC/DTG/3TC; 600/50/300 mg). At 48 weeks, 92.4% of patients taking BIC/FTC/TAF achieved viral suppression with HIV-1 RNA levels less than 50 copies/mL compared with 93% of patients in the ABC/DTG/3TC arm. Moreover, no resistance mutations emerged in either group, and bone and renal safety profiles were similar, Gallant and colleagues reported.

In the second trial, Paul E. Sax, MD, clinical director of the HIV program at Brigham and Women’s Hospital, and colleagues randomly assigned 645 patients 1:1 to receive BIC/FTC/TAF (50/200/25 mg) or DTG (50 mg) plus FTC/TAF (200/25 mg). At 48 weeks, 89.4% patients in the BIC/FTC/TAF arm had HIV-1 RNA levels less than 50 copies/mL compared with 92.9% of patients taking the combination with dolutegravir. Like the first trial, no resistance was observed to any the study drugs and BIC/FTC/TAF was safe and well-tolerated, according to Sax and colleagues.

“[BIC/FTC/TAF] is a promising option for initial antiretroviral therapy, with advantages over existing first-line choices, including other single-tablet regimens,” Gallant said. “Because it can be given to patients with [glomerular filtration rates] as low as 30 mL/min and to patients with chronic hepatitis B, and because it does not require pre-screening for HLA-B5701, it could be an attractive choice for ‘rapid start’ approaches in which patients are treated at the time of diagnosis, before baseline laboratory results are available.”

Janssen’s darunavir-based regimen

According to findings announced by Janssen, virologically suppressed adult patients with HIV who switched from a standard boosted-protease inhibitor regimen to a once-daily single-tablet regimen containing Janssen’s protease inhibitor darunavir had a low cumulative virologic rebound rate and high virologic suppression rate at 24 weeks.

Jean-Michel Molina, MD, professor at the University of Paris Diderot and physician in the department of infectious diseases at Saint-Louis Hospital in Paris, single-tablet regimens with boosted protease inhibitors can help address the issue of HIV drug resistance.

“Single-tablet regimens are useful because they facilitate adherence to the regimens,” Molina told Infectious Disease News. “We know it’s critical that patients adhere to their regimens, so any improvement in the convenience of the regimen is important.”

Molina and colleagues compared the outcomes of 1,141 patients randomly assigned 2:1 to be treated with a regimen containing either 800 mg of darunavir combined with 150 mg of cobicistat, 200 mg of emtricitabine and 10 mg of tenofovir alafenamide (D/C/F/TAF) or a boosted protease inhibitor plus emtricitabine and tenofovir disoproxil fumarate (F/TDF).

Midway through the 48-week study, cumulative virologic rebound was 1.8% among patients taking D/C/F/TAF (n = 14) vs. 2.1% in the control group (n = 8), of which 10 and five patients, respectively, eventually achieved viral suppression again, with no confirmed rebounds of more than 200 copies/mL, according to Molina and colleagues. Virologic suppression was 96.3% in patients taking D/C/F/TAF and 95.5% in the control arm, with virologic failure occurring in 0.5% and 0.8% of patients, respectively. There were no discontinuations for virologic failure and no detected resistance to any study drug, Molina and colleagues reported. Moreover, safety was similar between both groups, with low incidences of grade 3-4 adverse events (AEs), serious AEs and treatment discontinuations.

According to Janssen, D/C/F/TAF is currently undergoing European regulatory review by the European Medicines Agency under the brand name Symtuza. If approved, it would be the first darunavir-based complete regimen for the treatment of HIV-1.

Merck to submit NDA for doravirine

Merck said it plans to submit a new drug application to the FDA in the fourth quarter of 2017 after a second phase 3 trial showed the effectiveness of its investigational non-nucleoside reverse transcriptase inhibitor doravirine in the treatment of HIV.

In the DRIVE-AHEAD trial, Squires and colleagues compared doravirine with efavirenz in ART-naive adult patients with pretreatment viral loads of at least 1,000 copies/mL. They randomly assigned 734 patients 1:1 to receive a once-daily fixed-dose regimen of 100 mg of doravirine, 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate (DOR/3TC/TDF) or 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (EFV/FTC/TDF) for up to 96 weeks.

At 48 weeks, 84.3% of patients receiving DOR/3TC/TDF achieved viral suppression, with HIV-1 RNA levels under 50 copies/mL compared with 80.8% of patients in the EFV/FTC/TDF study arm for a difference of 3.5% (95% CI, –2.0 to 9.0), according to Squires and colleagues. The study also met its primary safety endpoint, with fewer patients reporting neuropsychiatric AEs like dizziness, sleep disorders and disturbances and inability to think clearly or concentrate.

“This was a second phase 3 trial of the drug, and so the next development would really be for the drug to be approved,” Squires said. – by Gerard Gallagher and Stephanie Viguers

References:

Gallant J, et al. A phase 3 randomized controlled clinical trial of bictegravir in a fixed dose combination, B/F/TAF, vs. ABC/DTG/3TC in treatment-naive adults at week 48. Presented at: IAS Conference on HIV Science; July 23-26, 2017; Paris.

Molina J-M, et al. Efficacy and safety of switching from boosted-protease inhibitor plus emtricitabine/tenofovir disoproxil fumarate regimens to the single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in virologically suppressed, HIV-1-infected adults through 24 weeks: EMERALD Study. Presented at: IAS Conference on HIV Science; July 23-26, 2017; Paris.

Sax PE, et al. Phase 3 randomized, controlled clinical trial of bictegravir coformulated with FTC/TAF in a fixed-dose combination (B/F/TAF) vs. dolutegravir (DTG) + F/TAF in treatment-naive HIV-1 positive adults: week 48 results. Presented at: IAS Conference on HIV Science; July 23-26, 2017; Paris.

Squires KE, et al. Fixed dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naive adults with HIV-1 infection: week 48 results of the phase 3 DRIVE-AHEAD study. Presented at: IAS Conference on HIV Science; July 23-26, 2017; Paris.

Disclosures: Gallant reports research support from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Sangamo and ViiV, and serves on advisory boards for Bristol-Myers Squibb, Gilead, Merck, Theratechnologies and ViiV. Molina reports receiving research grants from Gilead and Merck, serving on advisory boards for Bristol-Myers Squibb, Gilead, Janssen, Merck, Teva and ViiV, and on a speaker’s bureau for Gilead. Squires has received research grants from Gilead and has served on advisory boards for Bristol-Myers Squibb, Gilead, Janssen, Merck/MSD and ViiV. Please see the studies for a list of all other authors’ relevant financial disclosures.

Joel Gallant
Joel Gallant

Several investigational HIV drugs or drug regimens showed promise in recent phase 3 trials, according to findings presented at the International AIDS Society conference.

Gilead Sciences, Janssen and Merck each spotlighted new medicines or treatments aimed at simplifying regimens or addressing the problem of HIV drug resistance. Experts who presented the findings extolled the progress that has been made in treating patients with HIV, but they insisted better options are still needed.

“In an era when we can treat almost all patients with safe, effective and convenient regimens, it may no longer be possible to talk about ‘urgent needs’ with respect to treatment,” Joel Gallant, MD, MPH, medical director of specialty services at Southwest Care Center in Santa Fe, New Mexico, told Infectious Disease News. “However, drug development in our field is still exciting, with the potential for long-acting agents and regimens. Of course, the search continues for both a preventive vaccine and a cure.”

Kathleen Squires, MD, professor and director of infectious diseases at Thomas Jefferson University in Philadelphia, also mentioned the need for drugs that can be taken less frequently. World health officials issued a warning on the eve of the conference about a “worrying” rise in HIV drug resistance that is largely tied to nonadherence.

“We have come a long way in our treatment regimens for HIV-infected patients. However, all of these regimens require daily dosing of the drugs because of their half-life,” Squires said in an interview. “Despite the fact that we have a number of medications that are once-daily regimens, there are some people who, for a number of reasons, simply can’t adhere to taking a pill a day.

“In many cases, I’ve had patients who have said to me, ‘Every time I look at the medication, it reminds me that I have HIV infection and I don’t want to be reminded of that,’” Squires continued. “They can’t deal with that, so they don’t take the medication.”

Gilead’s bictegravir-containing regimen

Gilead announced 48-week results of two phase 3 trials showing that a fixed-dose combination containing the novel integrase inhibitor bictegravir was noninferior to regimens containing Tivicay (dolutegravir, GlaxoSmithKline; DTG) in treatment-naive adults with HIV. Both trials studied the effect of a once-daily single-tablet regimen of bictegravir (BIC) in combination with Descovy (emtricitabine/tenofovir alafenamide, Gilead; FTC/TAF).

In the first trial, Gallant and colleagues randomly assigned 629 patients 1:1 to receive either BIC/FTC/TAF (50/200/25 mg) or Triumeq (abacavir/dolutegravir/lamivudine, ViiV Healthcare; ABC/DTG/3TC; 600/50/300 mg). At 48 weeks, 92.4% of patients taking BIC/FTC/TAF achieved viral suppression with HIV-1 RNA levels less than 50 copies/mL compared with 93% of patients in the ABC/DTG/3TC arm. Moreover, no resistance mutations emerged in either group, and bone and renal safety profiles were similar, Gallant and colleagues reported.

In the second trial, Paul E. Sax, MD, clinical director of the HIV program at Brigham and Women’s Hospital, and colleagues randomly assigned 645 patients 1:1 to receive BIC/FTC/TAF (50/200/25 mg) or DTG (50 mg) plus FTC/TAF (200/25 mg). At 48 weeks, 89.4% patients in the BIC/FTC/TAF arm had HIV-1 RNA levels less than 50 copies/mL compared with 92.9% of patients taking the combination with dolutegravir. Like the first trial, no resistance was observed to any the study drugs and BIC/FTC/TAF was safe and well-tolerated, according to Sax and colleagues.

“[BIC/FTC/TAF] is a promising option for initial antiretroviral therapy, with advantages over existing first-line choices, including other single-tablet regimens,” Gallant said. “Because it can be given to patients with [glomerular filtration rates] as low as 30 mL/min and to patients with chronic hepatitis B, and because it does not require pre-screening for HLA-B5701, it could be an attractive choice for ‘rapid start’ approaches in which patients are treated at the time of diagnosis, before baseline laboratory results are available.”

PAGE BREAK

Janssen’s darunavir-based regimen

According to findings announced by Janssen, virologically suppressed adult patients with HIV who switched from a standard boosted-protease inhibitor regimen to a once-daily single-tablet regimen containing Janssen’s protease inhibitor darunavir had a low cumulative virologic rebound rate and high virologic suppression rate at 24 weeks.

Jean-Michel Molina, MD, professor at the University of Paris Diderot and physician in the department of infectious diseases at Saint-Louis Hospital in Paris, single-tablet regimens with boosted protease inhibitors can help address the issue of HIV drug resistance.

“Single-tablet regimens are useful because they facilitate adherence to the regimens,” Molina told Infectious Disease News. “We know it’s critical that patients adhere to their regimens, so any improvement in the convenience of the regimen is important.”

Molina and colleagues compared the outcomes of 1,141 patients randomly assigned 2:1 to be treated with a regimen containing either 800 mg of darunavir combined with 150 mg of cobicistat, 200 mg of emtricitabine and 10 mg of tenofovir alafenamide (D/C/F/TAF) or a boosted protease inhibitor plus emtricitabine and tenofovir disoproxil fumarate (F/TDF).

Midway through the 48-week study, cumulative virologic rebound was 1.8% among patients taking D/C/F/TAF (n = 14) vs. 2.1% in the control group (n = 8), of which 10 and five patients, respectively, eventually achieved viral suppression again, with no confirmed rebounds of more than 200 copies/mL, according to Molina and colleagues. Virologic suppression was 96.3% in patients taking D/C/F/TAF and 95.5% in the control arm, with virologic failure occurring in 0.5% and 0.8% of patients, respectively. There were no discontinuations for virologic failure and no detected resistance to any study drug, Molina and colleagues reported. Moreover, safety was similar between both groups, with low incidences of grade 3-4 adverse events (AEs), serious AEs and treatment discontinuations.

According to Janssen, D/C/F/TAF is currently undergoing European regulatory review by the European Medicines Agency under the brand name Symtuza. If approved, it would be the first darunavir-based complete regimen for the treatment of HIV-1.

Merck to submit NDA for doravirine

Merck said it plans to submit a new drug application to the FDA in the fourth quarter of 2017 after a second phase 3 trial showed the effectiveness of its investigational non-nucleoside reverse transcriptase inhibitor doravirine in the treatment of HIV.

In the DRIVE-AHEAD trial, Squires and colleagues compared doravirine with efavirenz in ART-naive adult patients with pretreatment viral loads of at least 1,000 copies/mL. They randomly assigned 734 patients 1:1 to receive a once-daily fixed-dose regimen of 100 mg of doravirine, 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate (DOR/3TC/TDF) or 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (EFV/FTC/TDF) for up to 96 weeks.

At 48 weeks, 84.3% of patients receiving DOR/3TC/TDF achieved viral suppression, with HIV-1 RNA levels under 50 copies/mL compared with 80.8% of patients in the EFV/FTC/TDF study arm for a difference of 3.5% (95% CI, –2.0 to 9.0), according to Squires and colleagues. The study also met its primary safety endpoint, with fewer patients reporting neuropsychiatric AEs like dizziness, sleep disorders and disturbances and inability to think clearly or concentrate.

“This was a second phase 3 trial of the drug, and so the next development would really be for the drug to be approved,” Squires said. – by Gerard Gallagher and Stephanie Viguers

PAGE BREAK

References:

Gallant J, et al. A phase 3 randomized controlled clinical trial of bictegravir in a fixed dose combination, B/F/TAF, vs. ABC/DTG/3TC in treatment-naive adults at week 48. Presented at: IAS Conference on HIV Science; July 23-26, 2017; Paris.

Molina J-M, et al. Efficacy and safety of switching from boosted-protease inhibitor plus emtricitabine/tenofovir disoproxil fumarate regimens to the single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in virologically suppressed, HIV-1-infected adults through 24 weeks: EMERALD Study. Presented at: IAS Conference on HIV Science; July 23-26, 2017; Paris.

Sax PE, et al. Phase 3 randomized, controlled clinical trial of bictegravir coformulated with FTC/TAF in a fixed-dose combination (B/F/TAF) vs. dolutegravir (DTG) + F/TAF in treatment-naive HIV-1 positive adults: week 48 results. Presented at: IAS Conference on HIV Science; July 23-26, 2017; Paris.

Squires KE, et al. Fixed dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naive adults with HIV-1 infection: week 48 results of the phase 3 DRIVE-AHEAD study. Presented at: IAS Conference on HIV Science; July 23-26, 2017; Paris.

Disclosures: Gallant reports research support from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Sangamo and ViiV, and serves on advisory boards for Bristol-Myers Squibb, Gilead, Merck, Theratechnologies and ViiV. Molina reports receiving research grants from Gilead and Merck, serving on advisory boards for Bristol-Myers Squibb, Gilead, Janssen, Merck, Teva and ViiV, and on a speaker’s bureau for Gilead. Squires has received research grants from Gilead and has served on advisory boards for Bristol-Myers Squibb, Gilead, Janssen, Merck/MSD and ViiV. Please see the studies for a list of all other authors’ relevant financial disclosures.

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