Dec 2, 2009 - Khayat R, Patt B, Hayes D Jr. Obstructive sleep apnea: the new cardio- .... only in the intensive phase); the new trial is offering ART to all.
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2. Parati G, Lombardi C, Narkiewicz K. Sleep apnea: epidemiology, pathophysiology, and relation to cardiovascular risk. Am J Physiol Regul Integr Comp Physiol 2007;293:R1671–R1683. 3. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82–93. 4. Davies CW, Crosby JH, Mullins RL, Barbour C, Davies RJ, Stradling JR. Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects. Thorax 2000;55:736–740. 5. Baguet JP, Barone-Rochette G, Pepin JL. Hypertension and obstructive sleep apnoea syndrome: current perspectives. J Hum Hypertens 2009; 23:431–443. 6. Khayat R, Patt B, Hayes D Jr. Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the pathogenesis of vascular disease. Heart Fail Rev 2009;14:143–153. 7. Dopp JM, Reichmuth KJ, Morgan BJ. Obstructive sleep apnea and hypertension: mechanisms, evaluation, and management. Curr Hypertens Rep 2007;9:529–534. 8. Narkiewicz K, Wolf J, Lopez-Jimenez F, Somers VK. Obstructive sleep apnea and hypertension. Curr Cardiol Rep 2005;7:435–440. 9. Cortelli P, Parchi P, Sforza E, Contin M, Pierangeli G, Barletta G, Lugaresi E. Cardiovascular autonomic dysfunction in normotensive awake subjects with obstructive sleep apnoea syndrome. Clin Auton Res 1994;4:57–62. 10. Bonsignore MR, Parati G, Insalaco G, Castiglioni P, Marrone O, Romano S, Salvaggio A, Mancia G, Bonsignore G, Di RM. Baroreflex control of heart rate during sleep in severe obstructive sleep apnoea: effects of acute CPAP. Eur Respir J 2006;27:128–135. 11. Lombardi C, Parati G, Cortelli P, Provini F, Vetrugno R, Plazzi G, Vignatelli L, Di RM, Lugaresi E, Mancia G, et al. Daytime sleepiness and neural cardiac modulation in sleep-related breathing disorders. J Sleep Res 2008;17:263–270. 12. Logan AG, Perlikowski SM, Mente A, Tisler A, Tkacova R, Niroumand M, Leung RS, Bradley TD. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001;19:2271–2277.
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13. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, et al. Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–1187. 14. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr., et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–2572. 15. Alajmi M, Mulgrew AT, Fox J, Davidson W, Schulzer M, Mak E, Ryan CF, Fleetham J, Choi P, Ayas NT. Impact of continuous positive airway pressure therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a meta-analysis of randomized controlled trials. Lung 2007;185:67–72. 16. Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50:417–423. 17. Giles TL, Lasserson TJ, Smith BH, White J, Wright J, Cates CJ. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006;3:CD001106. 18. Haentjens P, Van MA, Moscariello A, De WS, Poppe K, Dupont A, Velkeniers B. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials. Arch Intern Med 2007;167:757–764. 19. Bonsignore MR, Parati G, Insalaco G, Marrone O, Castiglioni P, Romano S, Di RM, Mancia G, Bonsignore G. Continuous positive airway pressure treatment improves baroreflex control of heart rate during sleep in severe obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002;166:279–286.
DOI: 10.1164/rccm.201001-0031ED
A Trial Involving HIV-Tuberculosis in India The Minute Particulars In this issue of the Journal (pp. 743–751), Swaminathan and colleagues report on a significant clinical trial involving persons with HIV-tuberculosis (HIV-TB) in India (1). The trial was organized by the Tuberculosis Research Centre in Chennai (TRC), which has a long history of addressing important issues in TB care (2). This trial sought to evaluate the efficacy of the standard 6-month thrice-weekly regimen, which has been applied nationally in India’s National Tuberculosis Program, for the treatment of high-risk persons with HIV-associated TB (3). The clinical study compares a standard duration of 6 months to an extended 9-month treatment period. A number of investigations have sought to determine whether HIV-associated TB responds to therapy as well as TB in HIV-negative persons, and some recent evaluations suggest that it may not (4–6). The findings of the trial are notable for (1) high rates of failure during therapy; (2) high rates of acquired rifampin resistance; (3) substantial rates of recurrence after completion of therapy, with lower rates of recurrent TB in those treated for the longer period; (4) high mortality; and (5) a significant association of acquired rifampin resistance (ARR), with the presence of baseline isoniazid (INH) resistance. These are important observations; if confirmed in other settings, they could have substantial influence on TB control programs worldwide. The authors have carefully sought to respond to many of the questions that arise for the informed reader: d
They have compared the results of modified intention-totreat analyses to those of Protocol Correct analyses, and
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they have analyzed outcomes in several manners (crude, Kaplan-Meier, proportional hazards regression). These approaches demonstrate consistency within their findings. They have reported on extensive genotyping of the large majority of failure and recurrence isolates, permitting in most cases the distinction of endogenous failure or relapse from exogenous reinfection. They have addressed concerns about supervision of trial therapy (all doses in intensive phase; one of every three doses in continuation phase) and about adherence (through pill counts and multiple spot urine checks). They have carefully assessed the impact of baseline characteristics, such as drug resistance, to limit any unrecognized confounding. They have satisfied many of the CONSORT criteria (7). They are helpfully transparent in acknowledging the potential for nosocomially transmitted reinfection to explain some of the TB recurrences, noting that several patients with rifamycin-resistant failure or recurrence underwent prolonged hospitalizations during which others might have been infected.
Nonetheless, there remain a few sources of uncertainty. One concerns the fact that genotyping results were not available for many of the failure or recurrence isolates and, in particular, were not available for any of the rifampin-resistant recurrence
Editorials
isolates. It would have been helpful if the authors had indicated which patients underwent extended hospitalizations, which other failure or recurrence patients were exposed to them during that time, and whether there was any clustering of the rifampinresistant events (which would favor the hypothesis that these events did not represent relapse of the same strain with acquired drug resistance, but rather reinfection with a different strain). This is an important issue, since the appropriate response to prevent development of more rifampin-resistant cases is different, depending on whether the issue is insufficiency of therapy or lack of infection control. However, genotyping did confirm identity of the rifampin-resistant failure strain with the baseline strain in 11 of 19 failure patients, and exogenous reinfection was confirmed in only 4. These findings support the hypothesis that rifampin resistance was selected during the intensive phase of therapy, when presumably very large numbers of bacilli were exposed to inadequate concentrations of rifampin as a result of intermittent dosing. The fact that others have reported acquired rifampin-resistant failure or relapse in the setting of advanced HIV disease suggests that we should not easily disregard this finding (5, 6, 8). A second source of uncertainty in this trial concerns HIVassociated malabsorption and pharmacokinetics of the medications used for treatment of HIV. No pharmacokinetic data are available, nor are data on the quality of trial medications presented. It has been the practice at TRC to perform a laboratory assessment of each batch of study drugs to assure their quality (Dr. S. Swaminathan, personal communication); if done in the context of this study, it should be reported. Otherwise, the reader wonders if there was failure to achieve adequate blood levels of treatment medications due to unsuspected problems with drug quality. Future trials should include such information. This concern might have been partly allayed by the inclusion of a control arm of patients receiving daily therapy. This trial began in 2001 and required 4 years to complete enrollment. No patient in this trial received antiretroviral therapy (ART) until TB treatment was complete, and most never received ART during the trial, because access was still quite limited. Since many had advanced HIV disease (median CD4 count at entry was below 170/mm3 in both arms), it is not surprising that mortality was high in both arms. Response to thrice-weekly therapy, as well as survival, might be substantially better in patients on ART (6). It is thus relevant that TRC has recently begun a similar new HIV-TB trial that includes a thrice-weekly arm plus two control arms of daily therapy (one with daily dosing throughout and one with daily dosing only in the intensive phase); the new trial is offering ART to all qualifying patients, per the Indian national guidelines (9, 10). The finding of an association of ARR with baseline INH resistance is important. Menzies and colleagues and Lew and colleagues have recently published reports which indicate that INH resistance is a frequent precursor to development of multidrug resistance (MDR) in studies of rifampin-based treatment regimens (11, 12). The new World Health Organization Tuberculosis Treatment Guidelines appropriately recommend the use of a 6-month rifampin-based regimen as the treatment of choice for primary episodes of TB around the world (13). Due to the rarity of baseline drug-susceptibility testing, this may increase the exposure of INH-resistant strains to rifampin; in some settings this will occur in conjunction with use of intermittent intensive phase regimens and in the presence of advanced HIV disease. This may be, paradoxically, both life-saving and a recipe for the creation of more MDR-TB. Intermittent regimens are of great interest to TB control programs, because they greatly ease the burdens of supervision. If they should be avoided in select patient populations, then
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published guidelines should carefully explain this. In the United States, the CDC has recommended that highly intermittent dosing during the intensive phase should be avoided in persons with advanced HIV disease (i.e., CD4 count below 100/mm3) (14, 15). The results of this trial add to concerns that have been raised about thrice-weekly intensive phase therapy in such persons. Surveillance for drug resistance should be carefully implemented wherever patients with advanced HIV disease and TB are being managed. Some of the new anti-TB agents under development offer promise of intermittency due to their long half-lives (16), but these agents will not soon be available for programmatic use in drug-susceptible TB. Contrary to the belief that one regimen can fit all, we are learning again that optimal patient management—even in programmatic settings—sometimes requires the tailoring of therapy to circumstance: ‘‘He who would do good to another must do it in Minute Particulars. General Good is the plea of the scoundrel, hypocrite, and flatterer; For Art and Science cannot exist but in minutely organized Particulars . . .’’(17) Conflict of Interest Statement: A.V. directs a TB research branch at CDC. The branch houses the coordinating and data center for a TB clinical trials activity, which sometimes collaborates with drug manufacturers; several have provided drugs or other support for TB trials. One company (sanofi aventis, through its Access to Medicines program) has provided substantial support (.$1 million) for multiple pharmacokinetic and genetics studies, data management, and other activities related to rifamycin development.
Andrew Vernon, M.D., M.H.S. Centers for Disease Control and Prevention Atlanta, Georgia
References 1. Swaminathan S, Narendran G, Venkatesan P, Iliayas S, Santhanakrishnan R, Menon P, Padmapriyadarsini C, Ramachandran R, Chinnaiyan P, Suhadev M, et al. Efficacy of a 6 vs. a 9-month intermittent treatment regimen in HIV-infected TB patients: a randomized clinical trial. Am J Respir Crit Care Med 2010(181):743–751. 2. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1959;21:51–144. 3. Khatri GR, Frieden TR. Controlling tuberculosis in India. N Engl J Med 2002;347:1420–1425. 4. Nahid P, Gonzalez LC, Rudoy I, de Jong BC, Unger A, Kawamura LM, Osmond DH, Hopewell PC, Daley CL. Treatment outcomes of patients with HIV and tuberculosis. Am J Respir Crit Care Med 2007;175:1199–1206. 5. Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet 1999;353:1843–1847. 6. Burman W, Benator D, Vernon A, Khan A, Jones B, Silva C, Lahart C, Weis S, King B, Mangura B, et al.; Tuberculosis Trials Consortium. Acquired rifamycin resistance with twice-weekly treatment of HIVrelated tuberculosis. Am J Respir Crit Care Med 2006;173:350–356. 7. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallelgroup randomised trials. Lancet 2001;358:585. 8. Li J, Munsiff SS, Driver CR, Sackoff J. Relapse and acquired rifampin resistance in HIV-infected patients with tuberculosis treated with rifampin- or rifabutin-based regimens in New York City, 1997–2000. Clin Infect Dis 2005;41:83–91. 9. Tuberculosis Research Centre, India. Comparing daily versus intermittent regimen of ATT (ethambutol, pyrazinamide, INH, rifampicin) in HIV with pulmonary tuberculosis (TB). Clinical trial entered at www. ClinicalTrials.Gov, as NCT00933790. 10. National AIDS Control Organisation. Antiretroviral therapy guidelines for HIV-infected adults and adolescents including post-exposure
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[Internet]. Accessed 5 December 2009. Available from: http://www. nacoonline.org/NACO/About_NACO/Policy__Guidelines Menzies D, Benedetti A, Paydar A, Martin I, Royce S, Pai M, Vernon A, Lienhardt C, Burman W. Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: a systematic review and meta-analysis. PLoS Med 2009;6:e1000146. Lew W, Pai M, Oxlade O, Martin D, Menzies D. Initial drug resistance and tuberculosis treatment outcomes: systematic review and metaanalysis. Ann Intern Med 2008;149:123–134. World Health Organization. Treatment of tuberculosis: guidelines for national programmes. 4th edition. Available from: http://whqlibdoc. who.int/publications/2010/9789241547833_eng.pdf Centers for Disease Control and Prevention (CDC). Acquired rifamycin resistance in persons with advanced HIV disease being treated for
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active tuberculosis with intermittent rifamycin-based regimens. MMWR Morb Mortal Wkly Rep 2002;51:214–215. 15. American Thoracic Society; CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52:1–77. 16. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223. 17. Blake W. The holiness of minute particulars, from Jerusalem. Accessed online on December 2, 2009 at http://users.compaqnet.be/cn127848/ blake/collected/chap-29.html
DOI: 10.1164/rccm.200912-1822ED
