Lawn, Stephen D

Wood, Robin

LSHTM Research Online

Lawn, SD; Wood, R (2007) When should antiretroviral treatment bestarted in patients with HIV-associated tuberculosis in South Africa?South African Medical Journal, 97 (6). 412, 414-5. ISSN 0256-9574Downloaded from: http://researchonline.lshtm.ac.uk/9293/DOI: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: Creative Commons Attribution Non-commercialhttp://creativecommons.org/licenses/by-nc/3.0/June 2007, Vol. 97, No. 6  SAMJSAMJ FORUM412Since 1990 the HIV epidemic in South Africa has had a huge impact on the burden of tuberculosis (TB), especially within poor communities where annual notification rates have risen as high as 1 500/100 000 population.1 Not surprisingly, as antiret-roviral treatment (ART) clinics have been established in these communities, TB has emerged as a key clinical problem within these services. A large proportion of patients at programme enrolment have a history of treated TB or active TB, or develop TB during ART. For example, of patients entering a service in Gugulethu, Cape Town, 52% had a history of one or more previously treated episodes of TB, 25% had a diagnosis of active TB, and approximately 10% of patients developed TB in the first year of ART.2 Patients who have TB at entry to ART programmes have a high mortality risk, which is twofold greater than that of patients who do not have TB.2 Several large studies agree that in multivariate analysis this excess mortality risk is not independently associated with TB disease activity or even with the fact that they have a TB diagnosis; instead high mortality risk is associated with these patients’ degree of immunodeficiency, which is typically more advanced than that of patients who are TB free.3-6 The fact that immunodeficiency appears to be the key determinant of mortality in these patients suggests that, in addition to antituberculosis treatment and co-trimoxazole prophylaxis, they should start ART without undue delay. However, for a long time there has been caution regarding early initiation of ART among TB patients in view of the multiple potential complications.Factors favouring delayed ARTThe key factors thought to be important in deciding the best time to start ART in TB patients are shown in Table I. However, data from a number of studies now indicate that several of the issues favouring delayed ART are of less importance than was perhaps once thought. A major concern was that concurrent treatment would undermine ART outcomes owing to high pill burdens, poor tolerability of combined multi-drug regimens, and pharmacokinetic drug interactions. However, in Gugule-thu, despite the fact that over one-third of patients have over-lapping TB treatment during their first year of ART, treatment compliance levels are extremely high and over 90% of patients maintain viral load suppression rates < 400 copies/ml at all follow-up time points.7 More specifically, TB patients receiving standard dose efavirenz-containing ART and rifampicin-con-taining antituberculosis treatment were found to have identical viral load suppression rates to those without TB (both 94% < 400 copies/ml at 48 weeks).2 Data from London also confirm that ART outcomes are not undermined by concurrent antitu-berculosis treatment, irrespective of the timing of ART.8 It is well established that concurrent rifampicin-containing antitu-berculosis treatment reduces plasma levels of non-nucleoside reverse transcriptase inhibitors (NNRTIs) by around 30%.9,10 However, viral load suppression rates were not impaired among patients in Thailand receiving standard dosages of efavirenz-based or nevirapine-based ART at the same time as rifampicin.9,10 All these data indicate that pharmacokinetic inter-actions, high pill burden and potential intolerance of combined multi-drug regimens do not undermine ART outcomes to an appreciable extent. Another important concern is the risk of adverse events during combined treatment, especially hepatotoxicity. Many patients in sub-Saharan Africa receive nevirapine-based ART, which is well recognised to be associated with a significant risk of hepatotoxicity when used concurrently with rifampicin.11 However, the risk of hepatotoxicity is much lower with efavirenz,12 an alternative NNRTI which is available and widely used in South Africa. In the ART clinic in Gugulethu, where monitoring of serum hepatic transaminase concentrations is available, no deaths due to efavirenz and rifampicin co-toxicity have been observed.6,13 ISSUES IN MEDICINEWhen should antiretroviral treatment be started in patients with HIV-associated tuberculosis in South Africa?Stephen D Lawn, Robin WoodCorresponding author: S D Lawn (stevelawn@yahoo.co.uk)Dr Stephen D Lawn is an Honorary Consultant in Infectious Diseases and Tropical Medicine and a Senior Lecturer at the London School of Hygiene and Tropical Medicine. He is based at the Desmond Tutu HIV Centre and the Institute of Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town. His major research interest is HIV-associated tuberculosis.  Professor Robin Wood is Head of the Desmond Tutu HIV Centre at the IIDMM. His research interests are HIV, antiretroviral treatment and tuberculosis. Pg 412-415.indd   412 5/21/07   11:40:56 AMAnd now, anotheroutstanding innovation from SA EagleJust when you thought the insurance industry was plagued by stale,unimaginative thinking, along comes SA Eagle to combine both yourbusiness and personal insurance into one innovative policy. It’s called Flexifliteand it means less administration and a much simpler solution.Flexiflite is the ideal insurance for the small business or sole proprietorship,be it in the trade, retail or professional field. Its strength is its exceptionaladaptability. You are able to choose and define your insurance cover.Category options are wide-ranging, including domestic buildings andcontents, motor, all risks, public liability, accidental damage and goods intransit, to name just a few.Find a comprehensive one policy one payment solution. Isn’t it time yousimplified your life? Step one is to call your broker and choose Flexiflite.Authorised Financial Services ProviderGlobal strength. Local commitmentwww.saeagle.co.zaFlexifliteBUSINESS AND DOMESTIC INSURANCE IN ONE POLICYOPENCOMM 1237June 2007, Vol. 97, No. 6  SAMJSAMJ FORUM414Immune reconstitution disease develops in approximately 30% of patients with TB who initiate ART,14 with the rate being highest for those with low CD4 cell counts initiating ART within the first 1 - 2 months after TB diagnosis.14 Most cases are mild and self-limiting, but the manifestations are severe in a minority of patients and occasional deaths have been documented at the Gugulethu clinic in Cape Town and elsewhere.15,16 Risk of mortality from immune reconstitution disease therefore remains an important variable favouring delayed initiation of ART.Factors favouring early ARTThe key argument favouring early initiation of ART in patients with TB is the risk of further HIV-associated morbidity and mortality. This risk was highlighted by observational stud-ies from London, UK, which documented a high burden of morbidity and mortality among TB patients waiting to start ART.17,18 However, it is important to note that early mortality rates within ART programmes in resource-limited settings are over fourfold higher than rates among patients receiving ART in high-income settings, even after adjusting for the baseline de-gree of immunodeficiency.19 Consistent with this, the mortality rate among South African patients preparing to start ART is ex-ceptionally high, with the result that even short delays in ART initiation may be associated with considerable mortality risk in this setting.13,20 The risk assessment around timing of ART in TB patients may therefore differ between high-income and resource-limited settings and tip the balance further towards earlier ART in the latter.Supporting this suggestion, we have analysed mortality among TB patients (N = 73) in the Gugulethu clinic from the time of programme enrolment until 4 months of ART. With a median delay between TB diagnosis and initiation of ART of 42 days, we found that of 14 deaths, 10 (71%) were among patients waiting to start ART and only 4 (29%) occurred during ART.6 All patients who died awaiting ART had a CD4 cell count  < 100 cells/μl or WHO stage 4 disease. While non-randomised observational data are limited, these data nevertheless suggest that currently in this clinic the number of deaths that might be averted by earlier treatment far exceeds the number of deaths that might in any way have been caused by treatment.Antiretroviral treatment guidelinesWhile international guidelines agree that ART initiation can be delayed in patients with TB who have CD4 cell counts > 200 cells/μl, there is a lack of consensus regarding patients with CD4 cell counts < 200 cells/μl.21-24 Clearly in resource-limited settings, where patients typically access ART services with very advanced immunodeficiency, this must be a mortality-based decision. In the situation where an efavirenz-based (low hepato-toxicity risk) ART regimen is used, we agree with workers else-where25 that the decision analysis in South Africa centres around two key issues: the mortality risk associated with delayed ART versus the mortality risk from immune reconstitution disease with early ART. Currently, pre-ART deaths in the Gugulethu clinic greatly exceed those that occur during treatment, indicat-ing the potential for mortality reduction from earlier treatment. The current South African Antiretroviral Treatment Guidelines (1st edition)26 state that ART should be delayed for 2 months except for patients with a CD4 cell count < 50 cells/μl or a ‘serious HIV illness’. However, the data we have reviewed in this article clearly suggest that these should be revised. The current WHO antiretroviral treatment guidelines (2006) state that for patients with TB and a CD4 cell count < 200 cells/μl ART should be started between 2 and 8 weeks of TB treatment and that for those with severe immunosuppression ART should be started as soon as possible within this time-frame once antituberculosis treatment is tolerated. The data we have reviewed from South Africa strongly support these guidelines and a move towards earlier treatment, especially for patients with CD4 cell counts < 100 cells/μl or stage 4 disease.Integration of TB and HIV clinical servicesIn addition to changes in treatment guidelines, much needs to be done to foster closer working relationships between TB clinics and ART services. Fifteen per cent of patients entering the ART clinic in Gugulethu have had TB diagnosed elsewhere prior to referral for ART.2 These patients arrive at the ART clinic having already completed a median of 3 months of antitubercu-losis treatment despite having a median CD4 cell count of just 66 cells/μl.6 This represents a huge delay and it is very likely that considerable mortality occurs among such patients before Table I. Factors affecting the optimal time to start antiretroviral treatment (ART) in patients with tuberculosis (TB)Factors favouring delayed initiation of ART     Potential factors favouring early initiation of ARTPill burden and reduced adherence      Risk of further HIV-associated morbidityLow tolerability of combined multidrug regimens     Risk of HIV-associated mortality*Pharmacokinetic drug interactions impairing ART outcomes   Reduced risk of TB relapseDrug co-toxicityMorbidity and mortality due to immune reconstitution disease**Factors identified as being the most important. Pg 412-415.indd   414 5/21/07   11:40:56 AMSAMJ FORUM415June 2007, Vol. 97, No. 6  SAMJthey reach the ART programme. HIV status and blood CD4 cell counts should be promptly assessed at TB diagnosis and, where appropriate, patients should be quickly referred to the ART ser-vice. However, in Gugulethu, for example, these separate clinics are over a mile apart and are run separately by provincial and city administrations. This clearly highlights the need for close collaboration or integration of TB treatment and ART services. ConclusionsThe new HIV/AIDS and sexually transmitted infections (STI) Strategic Plan for South Africa 2007 - 2011 offers new hope for the millions of South Africans who are living with HIV and sets important targets to improve joint management of TB and HIV. To enable our clinical services to provide better care for those with both diseases, we also suggest that the South African national antiretroviral treatment guidelines for use of ART in patients with TB should be updated to recommend earlier ini-tiation of treatment. Moreover, stronger efforts should be made towards greater integration of TB and HIV treatment services. SDL is funded by the Wellcome Trust, London, UK. RW is funded in part by the National Institutes of Health, USA, RO1 grant (A1058736-01A1) and CIPRA grant 1U19AI53217-01.  1.  Lawn SD, Bekker LG, Middelkoop K, Myer L, Wood R. Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: The need for age-specific interventions. Clin Infect Dis 2006; 42: 1040-1047.  2.  Lawn SD, Myer L, Bekker LG, Wood R. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS 2006; 20: 1605-1612.  3.  Stringer JS, Zulu I, Levy J, et al. Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes. JAMA 2006; 296: 782-793.  4.  Zachariah R, Fitzgerald M, Massaquoi M, et al. Risk factors for high early mortality in patients on antiretroviral treatment in a rural district of Malawi. AIDS 2006; 20: 2355-2360.  5.  Reid S, Levy J, Jham M, et al. Clinical outcomes among TB/HIV co-infected patients enrolled in antiretroviral therapy (ART) in Lusaka, Zambia. Abstracts of the 16th International AIDS Conference, Toronto, Canada, 13-18 August 2006. Abstract #MOPE0166.  6.  Lawn SD, Myer L, Bekker LG, Wood R. Early mortality in patients with HIV-associated tuberculosis in Africa: implications for time to initiation of treatment. Programme and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections (CROI), Los Angeles, USA, 25-28 February 2007. Abstract #0-126.  7.  Bekker LG, Myer L, Orrell C, Lawn S, Wood R. Rapid scale-up of a community-based HIV treatment service: programme performance over 3 consecutive years in Guguletu, South Africa. S Afr Med J 2006; 96: 315-320.  8.  Breen RA, Miller RF, Gorsuch T, et al. Virological response to highly active antiretroviral therapy is unaffected by antituberculosis therapy. J Infect Dis 2006; 193: 1437-1440.  9.  Manosuthi W, Sungkanuparph S, Thakkinstian A, et al. Efavirenz levels and 24-week efficacy in HIV-infected patients with tuberculosis receiving highly active antiretroviral therapy and rifampicin. AIDS 2005; 19: 1481-1486.10.  Manosuthi W, Sungkanuparph S, Thakkinstian A, et al. Plasma nevirapine levels and 24-week efficacy in HIV-infected patients receiving nevirapine-based highly active antiretroviral therapy with or without rifampicin. Clin Infect Dis 2006; 43: 253-255.11.  Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005; 191: 825-829.12.  Danel C, Moh R, Anzian A, et al. Tolerance and acceptability of an efavirenz-based regimen in 740 adults (predominantly women) in West Africa. J Acquir Immune Defic Syndr 2006; 42: 29-35.13.  Lawn SD, Myer L, Orrell C, Bekker LG, Wood R. Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design. AIDS 2005; 19: 2141-2148.14.  Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5: 361-373.15.  Manosuthi W, Kiertiburanakul S, Phoorisri T, Sungkanuparph S. Immune reconstitution inflammatory syndrome of tuberculosis among HIV-infected patients receiving antituberculous and antiretroviral therapy. J Infect 2006; 53: 357-363.16.  Lawn SD, Myer L, Bekker LG, Wood R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007; 21: 335-341.17.  Dean GL, Williams DI, Churchill DR, Fisher MJ. Transient clinical deterioration in HIV patients with Pneumocystis carinii pneumonia after starting highly active antiretroviral therapy: another case of immune restoration inflammatory syndrome. Am J Respir Crit Care Med 2002; 165: 1670.18.  Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy. J Infect Dis 2004; 190: 1670-1676.19.  Braitstein P, Brinkhof MW, Dabis F, et al. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet 2006; 367: 817-824.20.  Lawn SD, Myer L, Harling G, Orrell C, Bekker LG, Wood R. Determinants of mortality and nondeath losses from an antiretroviral treatment service in South Africa: implications for program evaluation. Clin Infect Dis 2006; 43: 770-776.21.  World Health Organization. Treatment of Tuberculosis. Guidelines for National Programmes. 3rd ed. WHO/CDS/TB 2003.313. Geneva: WHO, 2003.22.  World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach. 2006 rev. Geneva: WHO, 2006.23.  Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167: 603-662.24.  Pozniak AL, Miller RF, Lipman MC, et al. BHIVA treatment guidelines for tuberculosis (TB)/HIV infection 2005. HIV Med 2005; 6 suppl 2, 62-83.  25.  Schiffer JT, Sterling TR. Timing of antiretroviral therapy initiation in tuberculosis patients with AIDS: a decision analysis. J Acquir Immune Defic Syndr 2007; 44: 229-234.26. National Department of Health, South Africa. National Antiretroviral Treatment Guidelines. 1st ed. Pretoria: DOH, 2004.medical schemeauthorised financial services providerPg 412-415.indd   415 5/21/07   11:40:57 AM

When should antiretroviral treatment be started in patients with HIV-associated tuberculosis in South Africa?

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When should antiretroviral treatment be started in patients with HIV-associated tuberculosis in South Africa?

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