News
Highlights of the 44th Union World Conference on Lung Health Mehau Kulyk/Science Photo Library
Rifapentine and bedaquiline for tuberculosis
Published Online November 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70224-8 For the abstracts from the Union conference see http://www.worldlunghealth. org/conf2013/images/1_ Paris2013/Forms/ABSTRACT_ BOOK_2013_Web.pdf For more on whether e-cigarettes should be regulated as a medicinal device see Comment Lancet Respir Med 2013; 1: 429–31 For more on the regulatory challenges for refined nicotine products see Comment Lancet Respir Med 2013; 1: 431–33
762
A multicentre phase 2 clinical trial enrolling participants at 18 sites across Brazil, Hong Kong, Kenya, Peru, South Africa, Spain, Uganda, USA, and Vietnam showed that a treatment regimen containing high-dose rifapentine (sanofi aventis) in place of rifampicin, along with other standard tuberculosis drugs during the first 8 weeks of treatment had very potent antimicrobial activity. Susan Dorman (Johns Hopkins University, Baltimore, MD, USA) and colleagues assessed 334 adults (69% male, 77% with chest cavitation on radiograph) with smear-positive pulmonary tuberculosis, who were randomly assigned to rifapentine 10 mg/kg, 15 mg/kg, or 20 mg/kg per dose or rifampicin 10 mg/kg per dose administered once-daily for 8 weeks, along with isoniazid, pyrazinamide, and ethambutol. Culture conversion rates on solid media ranged from 81% for the rifampicin group to 89–95% for the three rifapentine groups, while for liquid media the rates were 56% and 70–83%, respectively. Rifapentine is closely related to rifampicin but stays in the body much longer. Both belong to rifamycin drug class. “All the regimens were well tolerated and safe,” concludes Dorman. “The rifapentine regimens were substantially more active than the rifampicin regimen based on the surrogate endpoint of culture conversion at the end of the 8 week treatment period. These results support further evaluation of high dose rifapentine regimens for [tuberculosis] treatment shortening.” Elsewhere, Andreas Diacon (University of Stellenbosch, Cape Town, South Africa) and colleagues reported final 120 week data from their phase 2 study into bedaquiline for treatment of multidrug-resistant tuberculosis (MDR-TB). The drug, which was granted accelerated
approval by the US Food and Drug Administration (FDA) in December, 2012, has a novel mechanism of action compared with presently available anti-tuberculosis drugs. Other data from this trial had already shown a reduced culture conversion time from 125 days to 83 days for bedaquiline versus existing regimens. Patients with smear-positive confirmed MDR-TB received 400 mg bedaquiline once-daily for 2 weeks, followed by 200 mg bedaquiline three times a week for 22 weeks (79 patients) or placebo (81 patients). All patients also received a background regimen of standard MDR-TB therapy. The researchers noted that bedaquiline gave a culture conversion rate of 62% at 120 weeks, compared with 44% with placebo. Nausea, arthralgia, and headache were the prominent adverse events, with five deaths due to MDR-TB and five deaths not related to tuberculosis in the bedaquiline group, compared with two deaths in the placebo group. Testing revealed new resistance to one or more anti-tuberculosis drug in two patients in the bedaquiline group compared with 16 cases in the placebo group. Diacon suggests: “The addition of bedaquiline to a background regimen resulted in a higher culture conversion rate over 120 weeks, indicating that response at 24 weeks may be a reliable indicator of durable cure at 120 weeks. Bedaquiline was generally well tolerated.” In a separate study, Alexander Pym (KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa) looked at results from another trial of bedaquiline to treat MDR-TB, extensively drug-resistant tuberculosis (XDR-TB), and pre-XDRTB. 233 patients aged 18 years or older (median 34 years; 64% male) received bedaquiline (400 mg per day for 2 weeks followed by 200 mg three times per week for 22 weeks) along with an individualised background
regimen. At week 24, 80% of patients had sputum culture conversion (87% in MDR-TB group, 77% in the pre-XDR-TB group, and 56% in the XDR-TB group). 120 week data were also presented, showing an overall conversion rate of 72%. Five grade 4 adverse events occurred during therapy, with hyperuricaemia, nausea, headache, arthralgia, diarrhoea, and vomiting the most common adverse events of any grade. Pym says: “The addition of bedaquiline to treatment of MDRTB will probably allow simplification and maybe shortening of treatment. This will be of great benefit to the commonest form of resistance and treating MDR-TB patients more effectively will prevent the evolution to XDR-TB and possibly reduce transmission as patients convert their sputum to negative more rapidly.” He concludes: “One new drug is probably not sufficient for successfully combating XDR-TB but there are other drugs in clinical development, and the combination of two new drugs along with better use of existing drugs could have a big impact on the outcome of patients with XDR-TB.”
Union Council says e-cigarettes should face tough regulation Rapid expansion of the market for e-cigarettes and electronic nicotine delivery systems (ENDS) is of increasing concern in all countries: overall rates of use in current and former tobacco users in 2010–11 was about 6% in the USA, 4% in the UK, 1% in Canada and Australia and 0·5% in Indonesian men. The pace of growth was underlined by a recent report by the UK Medicines and Healthcare Products Regulatory Agency, which found that a tenth of UK smokers now use e-cigarettes, and the number of UK users has risen to around 1·3 million in 2013, up from 700 000 in 2012. “e-cigarette and ENDS manufacturers and vendors have been vocal
www.thelancet.com/respiratory Vol 1 December 2013
about the supposed benefits of their products and quick to shout down calls for regulation or questions about their contents”, says José Luis Castro, Interim Executive Director of The Union. “Based on our review of the available evidence, we strongly support the regulation of the manufacture, marketing and sale of electronic cigarettes or electronic nicotine delivery systems; and our preferred option is to regulate these products as medicines.” Major concerns include wide variation in the amount of nicotine and other chemicals that e-cigarettes and ENDS deliver. Data are also lacking on adverse effects for third parties exposure— important since the products emit fine and ultrafine particles, including nicotine into indoor air. Particular concerns surround use of e-cigarettes and ENDS by young people, including potential negative effects of nicotine on adolescent brain development, and risk for nicotine addiction and prompting use of conventional cigarettes or other tobacco products. A recent study by the US Centers for Disease Control and Prevention showed that e-cigarette experimentation and recent use doubled in US school students during 2011–12, resulting in an estimated 1·78 million students having ever used e-cigarettes as of 2012. “No matter how its marketed, I, for one, cannot help but believe that the profusion of e-cigarette shops near universities and schools, and the use of social marketing, does anything but target children, adolescents, and the young as an entrance to tobacco addiction”, says Union President E Jane Carter. Until conclusive evidence exists, to keep ENDS under sufficient scrutiny and control the Union proposes a ban on all advertising, removal of devices from shop displays, forbidding purchase by minors, and not selling products in flavours that are appealing to children, and listing all product ingredients. “We also propose that ENDS should not be used in public places, workplaces or on public transportation”, adds Castro.
“Consumer safety standards should be established, including ensuring manufacturing consistency and regulating the maximum quantity and dosage of nicotine they may contain.”
Tuberculosis in prisons Bringing tuberculosis in prisons under control was a major theme of this year’s Union conference. In theory, controlling tuberculosis in prisoners should be much easier than doing so in the general population, because the prison population has strictly limited movement and continuous supervision in most cases, which should facilitate delivery of directly observed therapy (DOT). However, in several symposia, experts discussed how the grim reality is far different—many prisons are old, poorly ventilated buildings, boosting transmission of tuberculosis and other infectious diseases. Drug users are particularly susceptible to infection and high rates in those entering prison inevitably leads to increased transmission inside the system. Conditions of prison life, including malnutrition and stress, also increase tuberculosis transmission, and many prisoners released into society with tuberculosis do not get the continuity of care they need. Masoud Dara, of WHO Europe and also Chair of the Union’s TB in Prisons Working Group, discussed how wide global variation exists regarding tuberculosis programmes in prison. “The days of seven or eight prisoners to a cell are more or less in the past in Europe, and as such transmission rates in prisons have come down here”, says Dara. “However, the horrendous conditions in much of Asia and Africa mean it is sadly a different story there.” In many developed countries, efforts are being made to reduce total prisoner populations, contributing to falls in national tuberculosis incidence. But Dara adds that the actual incidence per 100 000 prisoners is also coming down. Despite this, across Europe notifications of new tuberculosis cases in prisons are four to 180 times that in
www.thelancet.com/respiratory Vol 1 December 2013
the general population depending on the country studied. In eastern Europe, Dara points to Azerbaijan as a success story since the country now boasts an MDR-TB cure rate in prisoners of 65–81%, in a prison population where up to a third of all cases are MDR-TB. He also highlights Kazakhstan, where the Ministry of Health funds non-governmental organisations that offer support to prisoners while incarcerated and after release, to help them receive continuity of care for tuberculosis and other infectious and chronic conditions. “The Union is now calling on its global network to collect information on best practice for tuberculosis care in prisons and hopes to publish guidelines on this during 2014”, adds Dara. These new guidelines will to add to the Union’s 2012 statement Time to Act to Prevent and Control Tuberculosis Among Inmates, which calls on health authorities, civil society organisations, donor agencies and all other relevant parties to prioritise tuberculosis prevention and control in penitentiary settings. In another prison-related talk, John Stephens, a legal researcher with Section 27, a South African social justice advocacy organisation, highlighted the case of Dudley Lee, a former South African detainee who was acquitted after more than 4 years awaiting trial. He was infected with tuberculosis during his incarceration. He took his case to the Constitutional Court of South Africa, which in December 2012 ruled that the country’s Department of Correctional Services (DCS) was liable for causing his infection. Despite this ruling, Stephens suggests: “We have not seen real political commitment from the DCS to tackle [tuberculosis] in prisons and ensure that rights are fulfilled. Rather, the DCS is in denialist mode. We are unlikely to make progress until the DCS is honest with the public and itself.”
Reuters/CORBIS
News
For the Union statement on electronic cigarettes and ENDS see http://theunion.org/images/ stories/Newsroom/E-cigarette_ statement_FULL.pdf For the Time to act to prevent and control tuberculosis among inmates statement see http:// www.theunion.org/images/ stories/resources/Union_Official_ Statement_TB_Control_in_ prisons_Nov2012_FINAL.pdf For the South Africa Guidelines see http://www.section27.org.za/ wp-content/uploads/2013/05/ Guidelines-for-themanagement-of-TuberculosisHuman-ImmunodeficiencyVirus-and-Sexually-TransmittedInfections-in-CorrectionalCentres-2013.pdf
Tony Kirby 763
Highlights of the 44th Union World Conference on Lung Health Mehau Kulyk/Science Photo Library
Rifapentine and bedaquiline for tuberculosis
Published Online November 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70224-8 For the abstracts from the Union conference see http://www.worldlunghealth. org/conf2013/images/1_ Paris2013/Forms/ABSTRACT_ BOOK_2013_Web.pdf For more on whether e-cigarettes should be regulated as a medicinal device see Comment Lancet Respir Med 2013; 1: 429–31 For more on the regulatory challenges for refined nicotine products see Comment Lancet Respir Med 2013; 1: 431–33
762
A multicentre phase 2 clinical trial enrolling participants at 18 sites across Brazil, Hong Kong, Kenya, Peru, South Africa, Spain, Uganda, USA, and Vietnam showed that a treatment regimen containing high-dose rifapentine (sanofi aventis) in place of rifampicin, along with other standard tuberculosis drugs during the first 8 weeks of treatment had very potent antimicrobial activity. Susan Dorman (Johns Hopkins University, Baltimore, MD, USA) and colleagues assessed 334 adults (69% male, 77% with chest cavitation on radiograph) with smear-positive pulmonary tuberculosis, who were randomly assigned to rifapentine 10 mg/kg, 15 mg/kg, or 20 mg/kg per dose or rifampicin 10 mg/kg per dose administered once-daily for 8 weeks, along with isoniazid, pyrazinamide, and ethambutol. Culture conversion rates on solid media ranged from 81% for the rifampicin group to 89–95% for the three rifapentine groups, while for liquid media the rates were 56% and 70–83%, respectively. Rifapentine is closely related to rifampicin but stays in the body much longer. Both belong to rifamycin drug class. “All the regimens were well tolerated and safe,” concludes Dorman. “The rifapentine regimens were substantially more active than the rifampicin regimen based on the surrogate endpoint of culture conversion at the end of the 8 week treatment period. These results support further evaluation of high dose rifapentine regimens for [tuberculosis] treatment shortening.” Elsewhere, Andreas Diacon (University of Stellenbosch, Cape Town, South Africa) and colleagues reported final 120 week data from their phase 2 study into bedaquiline for treatment of multidrug-resistant tuberculosis (MDR-TB). The drug, which was granted accelerated
approval by the US Food and Drug Administration (FDA) in December, 2012, has a novel mechanism of action compared with presently available anti-tuberculosis drugs. Other data from this trial had already shown a reduced culture conversion time from 125 days to 83 days for bedaquiline versus existing regimens. Patients with smear-positive confirmed MDR-TB received 400 mg bedaquiline once-daily for 2 weeks, followed by 200 mg bedaquiline three times a week for 22 weeks (79 patients) or placebo (81 patients). All patients also received a background regimen of standard MDR-TB therapy. The researchers noted that bedaquiline gave a culture conversion rate of 62% at 120 weeks, compared with 44% with placebo. Nausea, arthralgia, and headache were the prominent adverse events, with five deaths due to MDR-TB and five deaths not related to tuberculosis in the bedaquiline group, compared with two deaths in the placebo group. Testing revealed new resistance to one or more anti-tuberculosis drug in two patients in the bedaquiline group compared with 16 cases in the placebo group. Diacon suggests: “The addition of bedaquiline to a background regimen resulted in a higher culture conversion rate over 120 weeks, indicating that response at 24 weeks may be a reliable indicator of durable cure at 120 weeks. Bedaquiline was generally well tolerated.” In a separate study, Alexander Pym (KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa) looked at results from another trial of bedaquiline to treat MDR-TB, extensively drug-resistant tuberculosis (XDR-TB), and pre-XDRTB. 233 patients aged 18 years or older (median 34 years; 64% male) received bedaquiline (400 mg per day for 2 weeks followed by 200 mg three times per week for 22 weeks) along with an individualised background
regimen. At week 24, 80% of patients had sputum culture conversion (87% in MDR-TB group, 77% in the pre-XDR-TB group, and 56% in the XDR-TB group). 120 week data were also presented, showing an overall conversion rate of 72%. Five grade 4 adverse events occurred during therapy, with hyperuricaemia, nausea, headache, arthralgia, diarrhoea, and vomiting the most common adverse events of any grade. Pym says: “The addition of bedaquiline to treatment of MDRTB will probably allow simplification and maybe shortening of treatment. This will be of great benefit to the commonest form of resistance and treating MDR-TB patients more effectively will prevent the evolution to XDR-TB and possibly reduce transmission as patients convert their sputum to negative more rapidly.” He concludes: “One new drug is probably not sufficient for successfully combating XDR-TB but there are other drugs in clinical development, and the combination of two new drugs along with better use of existing drugs could have a big impact on the outcome of patients with XDR-TB.”
Union Council says e-cigarettes should face tough regulation Rapid expansion of the market for e-cigarettes and electronic nicotine delivery systems (ENDS) is of increasing concern in all countries: overall rates of use in current and former tobacco users in 2010–11 was about 6% in the USA, 4% in the UK, 1% in Canada and Australia and 0·5% in Indonesian men. The pace of growth was underlined by a recent report by the UK Medicines and Healthcare Products Regulatory Agency, which found that a tenth of UK smokers now use e-cigarettes, and the number of UK users has risen to around 1·3 million in 2013, up from 700 000 in 2012. “e-cigarette and ENDS manufacturers and vendors have been vocal
www.thelancet.com/respiratory Vol 1 December 2013
about the supposed benefits of their products and quick to shout down calls for regulation or questions about their contents”, says José Luis Castro, Interim Executive Director of The Union. “Based on our review of the available evidence, we strongly support the regulation of the manufacture, marketing and sale of electronic cigarettes or electronic nicotine delivery systems; and our preferred option is to regulate these products as medicines.” Major concerns include wide variation in the amount of nicotine and other chemicals that e-cigarettes and ENDS deliver. Data are also lacking on adverse effects for third parties exposure— important since the products emit fine and ultrafine particles, including nicotine into indoor air. Particular concerns surround use of e-cigarettes and ENDS by young people, including potential negative effects of nicotine on adolescent brain development, and risk for nicotine addiction and prompting use of conventional cigarettes or other tobacco products. A recent study by the US Centers for Disease Control and Prevention showed that e-cigarette experimentation and recent use doubled in US school students during 2011–12, resulting in an estimated 1·78 million students having ever used e-cigarettes as of 2012. “No matter how its marketed, I, for one, cannot help but believe that the profusion of e-cigarette shops near universities and schools, and the use of social marketing, does anything but target children, adolescents, and the young as an entrance to tobacco addiction”, says Union President E Jane Carter. Until conclusive evidence exists, to keep ENDS under sufficient scrutiny and control the Union proposes a ban on all advertising, removal of devices from shop displays, forbidding purchase by minors, and not selling products in flavours that are appealing to children, and listing all product ingredients. “We also propose that ENDS should not be used in public places, workplaces or on public transportation”, adds Castro.
“Consumer safety standards should be established, including ensuring manufacturing consistency and regulating the maximum quantity and dosage of nicotine they may contain.”
Tuberculosis in prisons Bringing tuberculosis in prisons under control was a major theme of this year’s Union conference. In theory, controlling tuberculosis in prisoners should be much easier than doing so in the general population, because the prison population has strictly limited movement and continuous supervision in most cases, which should facilitate delivery of directly observed therapy (DOT). However, in several symposia, experts discussed how the grim reality is far different—many prisons are old, poorly ventilated buildings, boosting transmission of tuberculosis and other infectious diseases. Drug users are particularly susceptible to infection and high rates in those entering prison inevitably leads to increased transmission inside the system. Conditions of prison life, including malnutrition and stress, also increase tuberculosis transmission, and many prisoners released into society with tuberculosis do not get the continuity of care they need. Masoud Dara, of WHO Europe and also Chair of the Union’s TB in Prisons Working Group, discussed how wide global variation exists regarding tuberculosis programmes in prison. “The days of seven or eight prisoners to a cell are more or less in the past in Europe, and as such transmission rates in prisons have come down here”, says Dara. “However, the horrendous conditions in much of Asia and Africa mean it is sadly a different story there.” In many developed countries, efforts are being made to reduce total prisoner populations, contributing to falls in national tuberculosis incidence. But Dara adds that the actual incidence per 100 000 prisoners is also coming down. Despite this, across Europe notifications of new tuberculosis cases in prisons are four to 180 times that in
www.thelancet.com/respiratory Vol 1 December 2013
the general population depending on the country studied. In eastern Europe, Dara points to Azerbaijan as a success story since the country now boasts an MDR-TB cure rate in prisoners of 65–81%, in a prison population where up to a third of all cases are MDR-TB. He also highlights Kazakhstan, where the Ministry of Health funds non-governmental organisations that offer support to prisoners while incarcerated and after release, to help them receive continuity of care for tuberculosis and other infectious and chronic conditions. “The Union is now calling on its global network to collect information on best practice for tuberculosis care in prisons and hopes to publish guidelines on this during 2014”, adds Dara. These new guidelines will to add to the Union’s 2012 statement Time to Act to Prevent and Control Tuberculosis Among Inmates, which calls on health authorities, civil society organisations, donor agencies and all other relevant parties to prioritise tuberculosis prevention and control in penitentiary settings. In another prison-related talk, John Stephens, a legal researcher with Section 27, a South African social justice advocacy organisation, highlighted the case of Dudley Lee, a former South African detainee who was acquitted after more than 4 years awaiting trial. He was infected with tuberculosis during his incarceration. He took his case to the Constitutional Court of South Africa, which in December 2012 ruled that the country’s Department of Correctional Services (DCS) was liable for causing his infection. Despite this ruling, Stephens suggests: “We have not seen real political commitment from the DCS to tackle [tuberculosis] in prisons and ensure that rights are fulfilled. Rather, the DCS is in denialist mode. We are unlikely to make progress until the DCS is honest with the public and itself.”
Reuters/CORBIS
News
For the Union statement on electronic cigarettes and ENDS see http://theunion.org/images/ stories/Newsroom/E-cigarette_ statement_FULL.pdf For the Time to act to prevent and control tuberculosis among inmates statement see http:// www.theunion.org/images/ stories/resources/Union_Official_ Statement_TB_Control_in_ prisons_Nov2012_FINAL.pdf For the South Africa Guidelines see http://www.section27.org.za/ wp-content/uploads/2013/05/ Guidelines-for-themanagement-of-TuberculosisHuman-ImmunodeficiencyVirus-and-Sexually-TransmittedInfections-in-CorrectionalCentres-2013.pdf
Tony Kirby 763
