Lawn, Stephen D

Wood, Robin

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Lawn, SD; Wood, R (2012) Timing of Antiretroviral Therapy forHIV-1-Associated Tuberculosis. The New England journal of medicine,366 (5). p. 474. ISSN 0028-4793Downloaded from: http://researchonline.lshtm.ac.uk/39511/Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: Copyright the publishersn engl j med 366;5 nejm.org february 2, 2012474T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n ec o r r e s p o n d e n c eTiming of Antiretroviral Therapy for HIV-1–Associated TuberculosisTo the Editor: Three randomized trials report-ed by Blanc et al.,1 Havlir et al.,2 and Abdool Karim et al.3 (Oct. 20 issue) consolidate the evi-dence base underpinning recommendations on when to start antiretroviral therapy (ART) in pa-tients with human immunodeficiency virus (HIV)–associated tuberculosis. However, more than 80% of the global burden of this disease is in sub-Saharan Africa, where the health care in-frastructure is weak and a lack of integration of the health care pathway represents a major hur-dle to timely initiation of ART.4 Patients typically attend completely separate HIV and tuberculosis clinics in different localities. In a township in South Africa, we found that delays in starting ART were almost three times as high in patients who were referred between nonintegrated tuber-culosis services and ART clinics as in those with tuberculosis that was diagnosed in the ART clin-ic.5 Thus, among patients with CD4 counts of less than 50 cells per cubic millimeter who were referred to tuberculosis clinics, only 11% started ART within 4 weeks after receiving a diagnosis of tuberculosis. This is a prime example of how a lack of integration of tuberculosis and ART ser-vices compromises patient care. Progress toward integration is slow and must be accelerated. The time between tuberculosis diagnosis and initia-tion of ART might be a useful indicator of suc-cessful integration.Stephen D. Lawn, M.D.London School of Hygiene and Tropical Medicine London, United Kingdom stevelawn@yahoo.co.ukRobin Wood, F.C.P.University of Cape Town Cape Town, South AfricaNo potential conflict of interest relevant to this letter was re-ported.1. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculo-sis. N Engl J Med 2011;365:1471-81.2. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365:1482-91.3. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:1492-501.4. Lawn SD, Campbell L, Kaplan R, et al. Time to initiation of antiretroviral therapy among patients with HIV-associated tu-berculosis in Cape Town, South Africa. J Acquir Immune Defic Syndr 2011;57:136-40.5. Lawn SD, Campbell L, Kaplan R, Little F, Morrow C, Wood R. Delays in starting antiretroviral therapy in patients with HIV-associated tuberculosis accessing non-integrated clinical ser-vices in a South African township. BMC Infect Dis 2011;11:258.To the Editor: Török and Farrar1 summarize the findings of three controlled trials of when to start ART in HIV-associated tuberculosis and raise a number of practical issues to consider outside of the research setting. A practical point not considered is the setting of ART initiation. Loss to follow-up is typically the largest contrib-this week’s letters474 Timing of Antiretroviral Therapy for HIV-1–Associated Tuberculosis476 Glucocorticoids plus N-Acetylcysteine in Alcoholic Hepatitis477 Early Liver Transplantation for Severe AlcoholicHepatitis480 Ultraviolet A and Photosensitivity during Vemurafenib Therapy481 Staphylococcus aureus Reactivation Osteomyelitis after 75 YearsThe New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on January 24, 2014. For personal use only. No other uses without permission.  Copyright © 2012 Massachusetts Medical Society. All rights reserved. correspondencen engl j med 366;5 nejm.org february 2, 2012 475utor to attrition from HIV care,2 and initiating ART in patients in the hospital is associated with a doubling of the risk of loss to follow-up as compared with initiating ART in patients who are not in the hospital.3Inpatient ART initiation will be necessary in severely immunocompromised patients or those with long hospital stays, in which case adequate linkage to community programs must be en-sured. Studies show that ART can safely be de-layed in less severely immunocompromised pa-tients with the possible advantages of reduced risks of immune reconstitution inflammatory syndrome (IRIS) and adverse events leading to switches in antiretroviral drugs.Outpatient ART initiation should be the pre-ferred option whenever possible. Adequate link-age to outpatient care allowing prompt ART initiation in the community will also be impor-tant in securing the success of this approach.Tom H. Boyles, B.M., B.Ch.University of Cape Town Cape Town, South Africa tomboyles@yahoo.comNo potential conflict of interest relevant to this letter was re-ported.1. Török ME, Farrar JJ. When to start antiretroviral therapy in HIV-associated tuberculosis. N Engl J Med 2011;365:1538-40.2. Fox MP, Rosen S. Patient retention in antiretroviral therapy programs up to three years on treatment in sub-Saharan Africa, 2007-2009: systematic review. Trop Med Int Health 2010;15: Suppl:1-15.3. Boyles TH, Wilkinson LS, Leisegang R, Maartens G. Factors influencing retention in care after starting antiretroviral therapy in a rural South African programme. PLoS One 2011;6(5):e19201.Dr. Blanc and coauthors Reply: Lawn and Wood point out that a major hurdle to rapidly initiating ART in patients with HIV-associated tuberculosis is the separation between tubercu-losis and HIV services that is typical of most re-source-limited settings. We cannot agree more. On the basis of the results of the Cambodian Early versus Late Introduction of Antiretrovirals trial (CAMELIA; ClinicalTrials.gov number, NCT00226434) and two other recent studies, which show that early initiation of ART in very immunosuppressed patients with tuberculosis decreases mortality, it is no longer acceptable to allow patients to wait for treatment while being referred from tuberculosis services to HIV ser-vices or vice versa. In these patients, tuberculosis treatment and ART should be initiated at the same place to save time and to ultimately save lives. Therefore, to reduce the interval between the start of treatment for each of the two infec-tions, we urge early initiation of ART in tubercu-losis services and an expedited process for pa-tients to receive tuberculosis treatment in HIV services. We anticipate that this strategy, which was successfully accomplished in Cambodia dur-ing the CAMELIA trial, will have a considerable impact on the mortality associated with tubercu-losis and HIV coinfection.François-Xavier Blanc, M.D., Ph.D.Bicêtre Hospital Le Kremlin-Bicêtre, France xavier.blanc@bct.aphp.frDidier Laureillard, M.D.Agence Nationale de Recherche sur le Sida et les Hépatites Virales Ho Chi Minh City, VietnamAnne E. Goldfeld, M.D.Harvard Medical School Boston, MASince publication of their article, the authors report no fur-ther potential conflict of interest.Dr. Havlir and coauthors Reply: Delivering antiretroviral therapy as early as 2 weeks after a tuberculosis diagnosis will require major adapta-tions in health delivery for patients with HIV and tuberculosis. As reported by Lawn and Wood, in-adequate integration of HIV and tuberculosis services leads to delays in antiretroviral initiation and excess mortality.1 Several models to deliver integrated care are emerging and include “partial integration,” in which tuberculosis clinics man-age antiretroviral therapy during tuberculosis treatment and “co-location” of HIV and tubercu-losis clinics. With any model, streamlined HIV counseling, provider education including man-agement of the IRIS, and rigorous infection-con-trol policies to reduce transmission of tuberculo-sis are essential components.2 Integration of some HIV and tuberculosis activities such as HIV testing among tuberculosis patients has in-creased over the past few years.3 New data from our study and others call for acceleration of the integration of HIV and tuberculosis services and early delivery of HIV antiretroviral therapy to re-duce mortality and AIDS among HIV-infected patients who acquire tuberculosis.Diane V. Havlir, M.D.University of California, San Francisco San Francisco, CA dhavlir@php.ucsf.eduThe New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on January 24, 2014. For personal use only. No other uses without permission.  Copyright © 2012 Massachusetts Medical Society. All rights reserved. T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 366;5 nejm.org february 2, 2012476Prudence Ive, M.D. Ian Sanne, M.D.University of Witwatersrand Johannesburg, South AfricaSince publication of their article, the authors report no fur-ther potential conflict of interest.1. Lawn SD, Campbell L, Kaplan R, et al. Time to initiation of antiretroviral therapy among patients with HIV-associated tu-berculosis in Cape Town, South Africa. J Acquir Immune Defic Syndr 2011;57:136-40.2. Howard AA, El-Sadr WM. Integration of tuberculosis and HIV services in sub-Saharan Africa: lessons learned. Clin Infect Dis 2010;50:Suppl:S238-S244.3. Uyei J, Coetzee D, Macinko J, Guttmacher S. Integrated de-livery of HIV and tuberculosis services in sub-Saharan Africa: a systematic review. Lancet Infect Dis 2011;11:855-67.The Editorialists Reply: The health care set-ting in which ART is initiated is one of the fac-tors associated with successful care of patients with HIV-associated tuberculosis. However, such decisions need to take into account the patient, his or her community, the clinical facilities avail-able, and the extent to which tuberculosis and HIV care is integrated. The recent studies sug-gest that early ART initiation is beneficial in pa-tients with opportunistic infections and ad-vanced immunosuppression, with the exception of those with central nervous system infections. In patients with severe or life-threatening HIV-related illnesses, initiation of ART in the inpa-tient setting is clearly prudent. For patients who are not hospitalized, outpatient initiation of ART is preferable. Even in the outpatient setting, how-ever, delays in the initiation of ART1 and loss to follow-up2,3 are common. Loss to follow-up may result from poor coordination of HIV and tuber-culosis services, rather than simply being a con-sequence of where the ART was initiated. The key to improving outcomes for patients with HIV-associated tuberculosis is coordinated and inte-grated HIV and tuberculosis services.4 How that is achieved requires a locally relevant, flexible, and pragmatic approach.M. Estée Török, M.D., Ph.D.University of Cambridge Cambridge, United KingdomJeremy J. Farrar, M.D., Ph.D.Hospital for Tropical Diseases Ho Chi Minh City, VietnamSince publication of their article, the authors report no fur-ther potential conflict of interest.1. Lawn SD, Campbell L, Kaplan R, Little F, Morrow C, Wood R. Delays in starting antiretroviral therapy in patients with HIV-associated tuberculosis accessing non-integrated clinical ser-vices in a South African township. BMC Infect Dis 2011;11:258.2. Fox MP, Rosen S. Patient retention in antiretroviral therapy programs up to three years on treatment in sub-Saharan Africa, 2007-2009: systematic review. Trop Med Int Health 2010;15: Suppl:1-15.3. Bassett IV, Chetty S, Wang B, et al. Loss to follow-up and mortality among HIV-infected people co-infected with TB at ART initiation in Durban, South Africa. J Acquir Immune Defic Syndr 2012;59:25-30.4. Lawn SD, Harries AD, Wood R. Strategies to reduce early mor-bidity and mortality in adults receiving antiretroviral therapy in resource-limited settings. Curr Opin HIV AIDS 2010;5:18-26.Glucocorticoids plus N-Acetylcysteine in Alcoholic HepatitisTo the Editor: The study by Nguyen-Khac et al. (Nov. 10 issue)1 sidesteps old contentious issues regarding the use of glucocorticoid therapy in al-coholic hepatitis. Among the 8 references cited in support of glucocorticoid treatment, 2 in fact concluded that the therapy was of no benefit.2,3 In addition, 8 of 13 clinical trials published since 1971 showed that glucocorticoid therapy had no benefit as compared with placebo, although 5 of these did suggest an association with decreased short-term mortality.The rationale for treating alcoholic hepatitis with antiinflammatory agents is soft. It is illogi-cal to inhibit cytokines instead of targeting the putative pathogens that induce them. Exposing immunocompromised patients with severe alco-holic hepatitis to high-dose steroids exacerbates their already increased risk of infection, and the benefits are far from proven. In a multicenter trial of prednisolone and infliximab in the treat-ment of severe alcoholic hepatitis, increased mortality in the infliximab group caused prema-ture termination of the study.4In the study by Nguyen-Khac et al., N-acetyl-cysteine was associated with fewer infectious complications, but the primary outcome was not improved. The idea of adding one unproven treatment to another has little merit.Gerond Lake-Bakaar, M.D.Harvard Medical School Boston, MA glakebak@bidmc.harvard.eduNo potential conflict of interest relevant to this letter was re-ported.The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on January 24, 2014. For personal use only. No other uses without permission.  Copyright © 2012 Massachusetts Medical Society. All rights reserved. 

Timing of antiretroviral therapy for HIV-1-associated tuberculosis.

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Timing of antiretroviral therapy for HIV-1-associated tuberculosis.

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