Debate Southern African Journal of HIV Medicine Vol. 6 (3) 2005: pp. 49-5

Maartens, G

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THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE                                        SEPTEMBER 2005  49Initiating antiretroviral therapyGary MaartensDivision of Clinical Pharmacology, University of Cape TownThe current South African Department of Health guideline onwhen to initiate highly active antiretroviral therapy (HAART) inadults is based on the 2002 WHO guidelines. It is a veryconservative guideline, with HAART being initiated with AIDS,diagnosed either clinically (World Health Organization (WHO)stage 4) or immunologically (CD4+ lymphocyte count < 200cells/µl). The current Southern African HIV Clinicians Societyguidelines extend these conservative guidelines to includepatients with other evidence of clinical immune suppression(WHO clinical stage 3) and patients with CD4 counts 200 - 350cells/µl. In common with international guidelines, it isrecommended that patients in the CD4 stratum 200 - 350cells/µl be followed up until their CD4 count is close to 200cells/µl, unless their viral load is high. I shall centre myargument on the proposal to use the SA HIV Clinicians Societyguidelines to initiate HAART in the public sector.The evidence that starting HAART at CD4 counts 200 - 350cells/µl leads to a better outcome than at counts < 200 cells/µlis persuasive rather than definitive as it comes fromobservational cohort studies, not randomised controlled trials.These cohort studies show worse short-term (generally 3years) survival in patients commencing HAART at counts< 200 cells/µl. The magnitude of this benefit is less impressivewhen controlled for lead time,1 which is a source of bias incohort studies. Nevertheless, the survival benefit remains evenafter correcting for lead time. The key issue though is that thesurvival benefit is over the short term. As argued by Philips et al.,2 HAART is a long-term intervention.We do not yet know how long HAART will prolong survival, butit is unlikely that the average patient will have normal survival.We know that there is a steady failure rate on HAART, and thatachieving virological success (an undetectable viral load) isprogressively more difficult with successive regimens, largelyowing to resistance. Although there is clinical benefit incontinuing HAART despite resistance, ultimately HIV diseaseprogression does occur.3 Taking a longer time view of HAART,Philips et al. concluded that it is ‘likely that those deferringART [until CD4 counts < 200 cells/µl] ... eventually willexperience somewhat lower long-term risk of AIDS and deaththan if they had started ART immediately’, because mostpatients will eventually fail therapy. Therefore I do not believethere is a compelling case to be made for moving the CD4count criterion for starting HAART in the public sector.Starting at WHO stage 3 is attractive for resource-poorcountries, particularly for those without access to flowcytometry for CD4+ lymphocyte count monitoring. Clinicalstaging is simple to learn for nurse-driven services.Furthermore, it is known that WHO stage 3 confers a relativelypoor survival independently of the CD4 count. However, whenfacilities to monitor CD4 counts exist, these should be used inconjunction with WHO staging. Tuberculosis occurs across awide spectrum of immunity in HIV infection. In our study ofincident cases of tuberculosis, about a third of cases presentedwith CD4 counts > 500 cells/µl.4 I do not believe that thesepatients need HAART. A further problem is that oral thrush, acommon stage 3 condition, can occur with seroconversion orfollowing a course of antibiotics. The 2003 revision of theWHO guidelines of when to initiate HAART in resource-poorsettings has added WHO 3 together with CD4 count < 350cells/µl for those countries, like South Africa, which canmeasure CD4 counts. Although I do believe we should considerWE SHOULD NOT CHANGE GUIDELINES FORINITIATION OF HAART IN ADULTS IN THE SOUTHAFRICAN PUBLIC SECTORSEPTEMBER 2005                                        THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE  50adding this to our public sector guideline in the future, I donot believe we should add it soon.South Africa has a massive burden of HIV infection. AddingWHO stage 3 to the criteria of when to start HAART willapproximately treble the number of eligible patients. Even ifwe only targeted stage 4 patients (without using CD4 criteria)and only managed to treat 50% of these, we would still needto treat approximately 1 400 000 by 2008 (extrapolated fromASSA 2002 model by Andrew Boulle). Until it is clear that wecan achieve this daunting target we should not talk abouteasing the criteria for initiation. We have an obligation to firstdeal with those who are suffering most.REFERENCES1. Cole S, Li R, Anastos K, Detels R, Young M, Chmiel JS, Munoz A. Accounting forleadtime in cohort studies: evaluating when to initiate HIV therapies. Stat Med2004; 23: 3351-3363.2. Philips AN, Lepri AC, Lampe F, Johnson M, Sabin CA. When should antiretroviraltherapy be started for HIV infection? Interpreting the evidence fromobservational studies. AIDS 2003; 17: 1863-1869.3. Deeks SG, Barbour JD, Grant RM, Martin NJ. Uration and predictors of CD4-Tcell gains in patients who continue combination therapy despite detectableplasma viremia. AIDS 2002; 16: 201-207.4. Badri M, Ehrlich R, Wood R, Maartens G. Tuberculosis should not be consideredan AIDS-defining illness in areas with a high tuberculosis prevalence. Int JTuberc Lung Dis 2002; 6: 231-237.SHOULD WE BE INITIATING ANTIRETROVIRALTHERAPY EARLIER?Robin WoodDesmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape TownANTIRETROVIRAL PROGRAMME RATIONALESAntiretroviral therapy (ART) programmes are a part of theresponse to the massive mortality occurring in the countriesmost affected by the HIV epidemic. UNAIDS estimated that 2.3million deaths from AIDS occurred in sub-Saharan Africaduring 2004. South Africa faces the prospect of anaccumulated 6 - 7 million AIDS deaths by 2010, with themajority affecting the age group 20 - 40 years, a stage of lifewhen adults are productive and caring for the nextgeneration. In September 2003 the World Health Organization(WHO) declared the lack of access to HIV treatment a globalhealth emergency. WHO called for ‘unprecedented action’ toensure that by the end of 2005 at least 3 million people inneed of ART will have access to it. To date the nationalevaluations of the status of ART programmes have revolvedaround reporting on numbers on treatment rather thanimpact on AIDS mortality. The primary purpose of the SouthAfrican and other national ARV programmes is to minimiseHIV-associated mortality.  DEBATE FOCUSThe key to the present debate revolves around the thresholdsof ART initiation as set out in various treatment guidelines andhow different programme entry criteria impact on populationHIV-related deaths. The WHO Treatment Guidelines Committeerecognises in the 2003 guidelines preface that they will needto be updated on a regular basis in order to reflect ‘bestcurrent clinical practice’. The SA national rollout programmecurrently uses the older WHO 2000 guidelines, which are notinternationally recognised as the ‘best current clinical practice’and have ceased to be used by many other countries in ourregion such as Botswana, Namibia and Uganda.The current SA guidelines recommend both clinical and CD4criteria for allowing access to the ART programme. APPRAISAL OF PRESENT SA GUIDELINESFirstly the clinical and CD4 count criteria are very mismatched.Patients with AIDS die at a rate of 6% per month whileasymptomatic patients with CD4 counts < 200 µl haveapproximately a 1% monthly mortality. Clinical AIDS istherefore very specific for identifying patients at high risk ofdeath while a CD4 of < 200 is very sensitive measure.Secondly, the majority of patients access health care andantiretroviral (ARV) programmes because they have clinicalsymptoms rather than because they have just passed the CD4threshold of < 200 cells. The median CD4 cell count of patientsaccessing ARVs in Kampala, Uganda, is still 65/µl and inGugulethu, Cape Town, it is less than 100/µl after 3 years ofthe programme. A CD4 count of < 200 cells/µl will gain utilitywhen a large proportion of people living with AIDS (PWAs)have access to sequential CD4 count monitoring. This CD4count threshold would then be a very sensitive but not specificmeasure for identifying patients at high risk of death.However, widespread CD4 count testing is not widely availablein South Africa or elsewhere in sub-Saharan Africa. Thirdly, theclinical threshold of AIDS as an entry criterion for ART resultsin high mortality, as there are inevitable delays in accessingtreatment. In Gugulethu the time between referral andcommencing ARVs is short at 28 days. However, 66% ofprogramme deaths are recorded during this period, occurringalmost exclusively in those patients with AIDS before theycould start ARVs. The reported delay in the Médecins SansFrontières, Khayelitsha, ARV project was 4 months. Waitingtime to access ARVs in other programmes is frequently muchlonger. Waiting lists in Cape Town hospitals have been up to 8months and are in excess of 8 months in Malawi, which resultsin an unrecorded 50% of AIDS patients dying before access toARV programmes. Currently this pre-treatment mortality isnot recorded as part of the treatment programme, althoughreduction of HIV mortality is the primary aim of ARVtreatment. AIDS patients not only have a high in-programmedeath rate, they are also difficult to clinically manage andinvestigate, thereby consuming a disproportionate amount ofprogramme resources. AIDS is therefore too late a thresholdfor entry into an ARV programme. If the guidelines do not represent ‘best current clinicalpractice’ but are being used as a means of rationing access tocare, they should identify those who will benefit most fromtherapy.  Clinical stage is more predictive of HIV mortality thanCD4 count. South African published data have reported thatthe death rate of patients with WHO stage 3 disease is 2 - 2.5times higher than that of asymptomatic patients with < 200CD4 cells/µl. Until CD4 count testing is more widely available,

Initiating antiretroviral therapy

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Initiating antiretroviral therapy

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