XDR tuberculosis can be cured with aggressive treatment

XDR tuberculosis can be cured with aggressive treatment

Comment from them. He has also received research support from Pfizer, has been an investigator on clinical trials sponsored by this company, and has r...

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from them. He has also received research support from Pfizer, has been an investigator on clinical trials sponsored by this company, and has received payments to support the conduct of these trials. 1

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Chaturvedi N, Porta M, Klein R, et al, for The DIRECT Programme Study Group. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 2008; published online Sept 26. DOI:10.1016/S0140-6736(08)61412-9. Sjølie AK, Klein R, Porta M, for the DIRECT Programme Study Group. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 2008; published online Sept 26. DOI:10.1016/S01406736(08)61411-7. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: A systematic review. JAMA 2007; 298: 902–16. Cheung N, Wong TY. Diabetic retinopathy and systemic vascular complications. Progr Retin Eye Res 2008; 27: 161–76. Cheung N, Rogers S, Couper DJ, Klein R, Sharrett AR, Wong TY. Is diabetic retinopathy an independent risk factor for ischemic stroke? Stroke 2007; 38: 398–401. Cheung N, Wang JJ, Klein R, Couper DJ, Sharrett AR, Wong TY. Diabetic retinopathy and the risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Diabetes Care 2007; 30: 1742–46.

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Wong TY, Rosamond W, Chang PP, et al. Retinopathy and risk of congestive heart failure. JAMA 2005; 293: 63–69. UK Prospective Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13. Sjolie AK. Prospects for angiotensin receptor blockers in diabetic retinopathy. Diabetes Res Clin Pract 2007; 76 (suppl 1): S31–39. Chatervedi N, Sjolie AK, Stephenson AM, et al, and the EUCLID Study Group. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet 1998; 351: 28–31. Schreier RW, Savage S. Appropriate blood pressure control in type II diabetes (ABCD trial): Implications for complications. Am J Kidney Dis 1992; 20: 653–57. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829–40. Wong TY, Liew G, Tapp R, et al. Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based cross-sectional studies. Lancet 2008; 371: 736–43. Wong TY, Mitchell P. The eye in hypertension. Lancet 2007; 369: 425–35. Keech AC, Mitchell P, Summanen PA, et al, for the FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370: 1687–97. Simo R, Hernandez C. Fenofibrate for diabetic retinopathy. Lancet 2007; 370: 1667–68.

XDR tuberculosis can be cured with aggressive treatment Multidrug-resistant (MDR) tuberculosis, once thought of as a problem largely confined to Russia and eastern Europe, has emerged as a substantial threat to treatment and control programmes for tuberculosis worldwide. Between 2002 and 2006, 81 countries reported cases of MDR tuberculosis, with about 490 000 cases emerging worldwide in 2006 alone.1 Although MDR tuberculosis can be effectively treated with second-line regimens,2 improvements in resistance testing have revealed what is now defined as extensively drug-resistant (XDR) tuberculosis,3 with cases recorded in 45 countries.1 XDR tuberculosis, defined as MDR tuberculosis with additional resistance to the two most important second-line classes (fluoroquinolones and the second-line injectable agents), is often referred to as untreatable, and as such has provoked fear among health staff, patients, and affected communities.4,5 The Russian Federation has one of the highest prevalences of MDR tuberculosis in the world, estimated at 19% of all tuberculosis cases and rising to 50% in prisoners with tuberculosis.1,6 Unsurprisingly, a considerable proportion (about 7%) of these cases are found to have XDR tuberculosis when tested.1 In today’s Lancet, Salmaan Keshavjee and colleagues7 report the outcome of treatment for 29 patients with XDR tuberculosis in part of a larger treatment www.thelancet.com Vol 372 October 18, 2008

programme for MDR tuberculosis in Tomsk, Russia. 14 (48%) patients were successfully treated in this setting. Despite the small number of patients, there are lessons to be learnt from this experience. Patients with XDR tuberculosis were not differentiated from those who had MDR tuberculosis and enrolled in the treatment programme. All patients were treated with a regimen that aimed to include five effective antituberculosis drugs on the basis of in-vitro testing of drug susceptibility and previous treatment. Additionally, a fluoroquinolone (ofloxacin or levofloxacin), together with the second-line injectable capreomycin, was included in regimens even when drug resistance was found (although not counted as part of the five effective drugs). In Keshavjee and colleagues’ study, this aggressive approach, which included the full range of available second-line agents from the outset, contributed to the successful treatment of two-thirds of patients with MDR tuberculosis but without the XDR form, and nearly half of those with XDR tuberculosis. This result was achieved despite extensive disease and previous treatment, high consumption of alcohol and use of other illicit drugs, and high rates of current or previous imprisonment (all factors likely to complicate treatment of MDR tuberculosis). However, none of the patients with XDR

Published Online August 25, 2008 DOI:10.1016/S01406736(08)61205-2 See Articles page 1403

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Guard at gate of ward for XDR tuberculosis, Brooklyn Infectious Disease Hospital, Cape Town

tuberculosis and only 1% of the remaining patients with the MDR form had HIV infection in Tomsk. The programme in Tomsk is the result of a partnership between regional tuberculosis and prison services, an international tuberculosis laboratory able to test for second-line drug susceptibility, and an international medical non-governmental organisation that provided good clinical support and resources. Such a partnership reveals the elements needed to effectively treat both forms of tuberculosis (MDR and XDR): ownership and commitment of local treatment services for tuberculosis, sufficient laboratory capacity, specific clinical skills, and dedicated resources. Perhaps the most important lesson for drug-resistant programmes elsewhere is a commitment by tuberculosis services to provide the best possible care and treatment for individual patients. Although international organisations can provide technical assistance and help to mobilise funds, effective patient-centred treatment is up to governments to provide, because the only way to reduce further transmission of highly resistant strains will be to diagnose and successfully treat as many patients as possible. XDR tuberculosis attained international prominence in 2006 after an outbreak in South Africa8 in which all of the 53 reported cases eventually died. All patients with known HIV serostatus were positive. Although the overall proportion of MDR tuberculosis in tuberculosis cases is low in many settings with high HIV prevalence, 1364

the incidence of MDR and XDR tuberculosis might be very high because of much higher overall incidence of tuberculosis. On the basis of the latest worldwide estimates, the annual incidence of MDR tuberculosis in Russia is 26 per 100 000 population. By contrast, although MDR tuberculosis is estimated at only 2·6% of tuberculosis cases in South Africa, this equates to an incidence of 32 per 100 000 every year, of which an estimated 6% of patients have XDR tuberculosis.1 In view of this high burden, Keshavjee and colleagues’ results need to be urgently replicated in other settings, particularly for HIV-positive individuals. At present less than 5% of the estimated 490 000 patients with MDR and XDR tuberculosis arising every year are likely to receive effective treatment, which highlights the urgent need to scale-up treatment worldwide.1,9,10 Toxic effects of the drugs and long duration of treatment contribute to the problem, and the development of new drugs to treat both drugsusceptible and drug-resistant tuberculosis should be adequately supported.11 Until these new drugs are developed, we are responsible for effective use of available drugs. Keshavjee and colleagues have shown that both MDR and XDR tuberculosis can be cured with aggressive treatment, with use of the most effective antituberculosis drugs available. Although we should be cautious in our hope to attain such success rates in settings with a high prevalence of HIV, aggressive treatment is the logical strategy to provide the best chance of cure while avoiding the creation of additional drug resistance. *Helen Cox, Cheryl McDermid Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, VIC 3004, Australia (HC); and Médecins Sans Frontières, Cape Town, South Africa (HC, CMcD) [email protected] We declare that we have no conflict of interest. 1

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WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. Anti-tuberculosis drug resistance in the world: report No 4. 2008. http://www.who.int/tb/publications/2008/drs_report4_26feb08. pdf (accessed July 4, 2008). Nathanson E, Lambregts-van Weezenbeek C, Rich ML, et al. Multidrug-resistant tuberculosis management in resource-limited settings. Emerg Infect Dis 2006; 12: 1389–97. Migliori GB, Besozzi G, Girardi E, et al. Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur Respir J 2007; 30: 623–26. Singh JA, Upshur R, Padayatchi N. XDR-TB in South Africa: no time for denial or complacency. PLoS Med 2007; 4: e50. Raviglione M. XDR-TB: entering the post-antibiotic era? Int J Tuberc Lung Dis 2006; 10: 1185–87. Ruddy M, Balabanova Y, Graham C, et al. Rates of drug resistance and risk factor analysis in civilian and prison patients with tuberculosis in Samara Region, Russia. Thorax 2005; 60: 130–35.

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Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; published online Aug 25. DOI:10.1016/S0140-6736(08) 61204-0. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368: 1575–80. Green Light Committee. GLC program applications, as at the end of the GLC 48th review cycle. 2008. http://www.who.int/tb/challenges/mdr/ greenlightcommittee/report_glc_applications_cycle_48.pdf (accessed July 4, 2008).

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WHO, Stop TB Partnership. The global MDR-TB and XDR-TB response plan 2007–2008. 2007. http://www.stoptb.org/events/world_tb_day/2008/ assets/documents/news/WHO_HTM_TB_2007.387_eng.pdf (accessed July 4, 2008). Feuer C. Tuberculosis research and development: a critical analysis. October, 2006. http://www.aidsinfonyc.org/tag/tbhiv/tbrandd.pd (accessed July 4, 2008).

From Alma-Ata to Almaty: a new start for primary health care On Oct 14, Now more than ever, the World Health Report for 2008, was launched at Almaty, a city formerly called Alma-Ata and well known for the 1978 WHO declaration on primary health care.1 Although many countries tried to put primary care into practice, the declaration’s goal of Health for All was not achieved. Will all countries now establish strong and efficient primary care as an integral component of their health systems? Is 2008 different from 1978? Both the 1978 declaration and the 2008 report are underpinned by social justice, equity, and solidarity, although these values are increasingly under pressure in a context of globalisation and a growing gap between rich and poor nations. The most important difference between 2008 and 1978 is that today there is more evidence about the effectiveness and efficiency of primary health care. This evidence may inspire action at different levels with greater safety, effectiveness, efficiency, patient-orientation, timeliness, and equity of health services. Evidence at the macro level (eg, policy, payment, regulations) is now overwhelming: countries with a strong service for primary care have better health outcomes at low cost. Systems that explicitly distribute resources according to population health-needs (rather than demands), that eliminate co-payments, that assume responsibility for the financing of services, and that provide a broad range of services within the primary care sector are more cost effective.2 The evidence is robust across time and place, including middle-income countries and countries of the Organisation for Economic Co-operation and Development (OECD), with similar findings in more limited studies in developing countries. Essential features of a strong health system led by primary care are: accessibility (with no out-of-pocket www.thelancet.com Vol 372 October 18, 2008

payments), a person (not disease) focus over time, universality, a broad range of services in primary care, and coordination when people do have to receive care elsewhere. There are large variations, even among developed countries, in exposure to primary care services.3 Focusing on just a few diseases or health problems interferes with the development of local services for primary health care through the inefficiency and duplicated effort of competing personnel and facilities.4 The multiple interacting health problems that are intractable cannot be dealt with without a personfocused population-oriented approach. Vertically oriented and externally funded services interfere with the responsibility of the state to improve its own health services.5 The need for integration of health services by primary health care was emphasised by a workshop in May, 2008, in Geneva.6 The 15by2015 campaign (launched in March, 2008, to strengthen health systems led by primary care) asked donors to invest 15% of their funding in local primary health care.7 A system with a list of patients, mixed capitation, and no co-payments is more cost effective (through less use of secondary care, medical imaging, and laboratory testing, and more cost-effective prescribing) and of better quality (better performance in prevention) than most current approaches.8 The report9 by WHO and the Commission on Social Determinants of Health emphasises the importance of health systems based on primary care principles that take into account the range of social determinants, where prevention and promotion are in balance with investment in curative interventions and where there is an emphasis on the primary level of care with referral to higher levels only when justified by need. At the middle level, the gap between primary health care and public health must be bridged by intersectoral actions for health to address social and health deter-

Published Online October 14, 2008 DOI:10.1016/S01406736(08)61524-X

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