Small study: Drug combo achieves negative bacterial culture in all TB patients

SEATTLE – An all-oral drug combination achieved negative bacterial culture in 100% of patients with extensively drug resistant (XDR) or multidrug resistant (MDR) tuberculosis at 4 months, according to a study.

The drugs used were bedaquiline (400 mg once daily for 2 weeks followed by 200 mg three times per week), pretomanid (200 mg once daily), and linezolid (600 mg twice daily). The study, Nix-TB, was an open-label, two-site trial that examined a simplified and shortened all-oral regimen. Pretomanid is an experimental drug, while bedaquiline and linezolid are both approved medications.

The mortality rate among study participants was less than 6%.

“I was surprised at how successful this study was. These are patients who are generally very ill, with a very poor prognosis,” noted Francesca Conradie, MD, deputy director of the clinical HIV unit at the University of Witwatersrand (Johannesburg, South Africa), who presented the results at a poster session at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.

To date, the trial has enrolled 72 subjects (51% HIV positive, 65% XDR-TB, 35% MDR-TB). HIV-infected subjects had to have CD4 counts of at least 50 cell/mcL. The researchers evaluated clinical, laboratory, and sputum liquid cultures at baseline and at weeks 1, 2, 4, 6, and 8, and then every 4-6 weeks throughout the 6-month treatment period.

Forty patients have finished 6 months of therapy and 31 have completed 6-months of posttherapy follow-up.

Four patients died during the first 8 weeks of therapy. Of the survivors, 74% were culture negative at 8 weeks, and all were culture negative at 4 months. Two patients experienced relapses or reinfections at 6 months following therapy.

Twenty-seven percent of patients experienced serious adverse events, but no patients withdrew from the trials for clinical adverse events or laboratory abnormalities.

Linezolid-associated peripheral neuropathy and myelosuppression occurred, with 71% of patients having experienced at least one dose interruption as a result. Seven patients experienced grade 3 or 4 transaminitis, but all such cases resolved and those patients continued the study regimen.

Some hepatic enzyme changes were seen among patients. A total of 14.1% developed alanine transaminase levels greater than 3 times the upper limit of normal (ULN), and 7.0% had levels greater than 5 x ULN. A total of 14.9% had aspartate transaminase (AST) enzymes at greater than 3 x ULN, and 2.8% had AST levels greater than 5 x ULN. A total of 4.2% had alkaline phosphatase levels reaching greater than 3 x ULN. In all cases, the values returned to normal with a pause in therapy.

Dr. Conradie characterized these results as reassuring, in light of the fact that the STAND study of pretomanid in combination with moxifloxacin and pyrazinamide was ended prematurely because of liver safety concerns.

The linezolid side effect profile is concerning, and the study will continue with modified linezolid doses, Dr. Conradie acknowledged. “We’re looking to see if we could do a study with a lower dose” of linezolid or a study that doesn’t involve giving linezolid for the entire period of the treatment, she noted.

Dr Conradie has served on advisory boards for ViiV, Janssen, Merck, GSK, Mylan, and Sanofi Aventis. The study was funded by the TB Foundation.

SEATTLE – An all-oral drug combination achieved negative bacterial culture in 100% of patients with extensively drug resistant (XDR) or multidrug resistant (MDR) tuberculosis at 4 months, according to a study.

The drugs used were bedaquiline (400 mg once daily for 2 weeks followed by 200 mg three times per week), pretomanid (200 mg once daily), and linezolid (600 mg twice daily). The study, Nix-TB, was an open-label, two-site trial that examined a simplified and shortened all-oral regimen. Pretomanid is an experimental drug, while bedaquiline and linezolid are both approved medications.

The mortality rate among study participants was less than 6%.

“I was surprised at how successful this study was. These are patients who are generally very ill, with a very poor prognosis,” noted Francesca Conradie, MD, deputy director of the clinical HIV unit at the University of Witwatersrand (Johannesburg, South Africa), who presented the results at a poster session at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.

To date, the trial has enrolled 72 subjects (51% HIV positive, 65% XDR-TB, 35% MDR-TB). HIV-infected subjects had to have CD4 counts of at least 50 cell/mcL. The researchers evaluated clinical, laboratory, and sputum liquid cultures at baseline and at weeks 1, 2, 4, 6, and 8, and then every 4-6 weeks throughout the 6-month treatment period.

Forty patients have finished 6 months of therapy and 31 have completed 6-months of posttherapy follow-up.

Four patients died during the first 8 weeks of therapy. Of the survivors, 74% were culture negative at 8 weeks, and all were culture negative at 4 months. Two patients experienced relapses or reinfections at 6 months following therapy.

Twenty-seven percent of patients experienced serious adverse events, but no patients withdrew from the trials for clinical adverse events or laboratory abnormalities.

Linezolid-associated peripheral neuropathy and myelosuppression occurred, with 71% of patients having experienced at least one dose interruption as a result. Seven patients experienced grade 3 or 4 transaminitis, but all such cases resolved and those patients continued the study regimen.

Some hepatic enzyme changes were seen among patients. A total of 14.1% developed alanine transaminase levels greater than 3 times the upper limit of normal (ULN), and 7.0% had levels greater than 5 x ULN. A total of 14.9% had aspartate transaminase (AST) enzymes at greater than 3 x ULN, and 2.8% had AST levels greater than 5 x ULN. A total of 4.2% had alkaline phosphatase levels reaching greater than 3 x ULN. In all cases, the values returned to normal with a pause in therapy.

Dr. Conradie characterized these results as reassuring, in light of the fact that the STAND study of pretomanid in combination with moxifloxacin and pyrazinamide was ended prematurely because of liver safety concerns.

The linezolid side effect profile is concerning, and the study will continue with modified linezolid doses, Dr. Conradie acknowledged. “We’re looking to see if we could do a study with a lower dose” of linezolid or a study that doesn’t involve giving linezolid for the entire period of the treatment, she noted.

Dr Conradie has served on advisory boards for ViiV, Janssen, Merck, GSK, Mylan, and Sanofi Aventis. The study was funded by the TB Foundation.

SEATTLE – An all-oral drug combination achieved negative bacterial culture in 100% of patients with extensively drug resistant (XDR) or multidrug resistant (MDR) tuberculosis at 4 months, according to a study.

The drugs used were bedaquiline (400 mg once daily for 2 weeks followed by 200 mg three times per week), pretomanid (200 mg once daily), and linezolid (600 mg twice daily). The study, Nix-TB, was an open-label, two-site trial that examined a simplified and shortened all-oral regimen. Pretomanid is an experimental drug, while bedaquiline and linezolid are both approved medications.

The mortality rate among study participants was less than 6%.

“I was surprised at how successful this study was. These are patients who are generally very ill, with a very poor prognosis,” noted Francesca Conradie, MD, deputy director of the clinical HIV unit at the University of Witwatersrand (Johannesburg, South Africa), who presented the results at a poster session at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.

To date, the trial has enrolled 72 subjects (51% HIV positive, 65% XDR-TB, 35% MDR-TB). HIV-infected subjects had to have CD4 counts of at least 50 cell/mcL. The researchers evaluated clinical, laboratory, and sputum liquid cultures at baseline and at weeks 1, 2, 4, 6, and 8, and then every 4-6 weeks throughout the 6-month treatment period.

Forty patients have finished 6 months of therapy and 31 have completed 6-months of posttherapy follow-up.

Four patients died during the first 8 weeks of therapy. Of the survivors, 74% were culture negative at 8 weeks, and all were culture negative at 4 months. Two patients experienced relapses or reinfections at 6 months following therapy.

Twenty-seven percent of patients experienced serious adverse events, but no patients withdrew from the trials for clinical adverse events or laboratory abnormalities.

Linezolid-associated peripheral neuropathy and myelosuppression occurred, with 71% of patients having experienced at least one dose interruption as a result. Seven patients experienced grade 3 or 4 transaminitis, but all such cases resolved and those patients continued the study regimen.

Some hepatic enzyme changes were seen among patients. A total of 14.1% developed alanine transaminase levels greater than 3 times the upper limit of normal (ULN), and 7.0% had levels greater than 5 x ULN. A total of 14.9% had aspartate transaminase (AST) enzymes at greater than 3 x ULN, and 2.8% had AST levels greater than 5 x ULN. A total of 4.2% had alkaline phosphatase levels reaching greater than 3 x ULN. In all cases, the values returned to normal with a pause in therapy.

Dr. Conradie characterized these results as reassuring, in light of the fact that the STAND study of pretomanid in combination with moxifloxacin and pyrazinamide was ended prematurely because of liver safety concerns.

The linezolid side effect profile is concerning, and the study will continue with modified linezolid doses, Dr. Conradie acknowledged. “We’re looking to see if we could do a study with a lower dose” of linezolid or a study that doesn’t involve giving linezolid for the entire period of the treatment, she noted.

Dr Conradie has served on advisory boards for ViiV, Janssen, Merck, GSK, Mylan, and Sanofi Aventis. The study was funded by the TB Foundation.