Appendix C
Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Treatment Guidelines for a Public Health Approach

2003 REVISION

The creation of the present guidelines would not have been possible without the participation of numerous experts.

The World Health Organization wishes to express special gratitude to the Writing Committee that developed this document. This Committee was chaired by Professor Scott Hammer of Columbia University (New York City, USA) and its other members were Diane Havlir (University of California at San Francisco, USA), Elise Klement (Médecins sans Frontières, France), Fabio Scano (WHO/ HTM/STB, Switzerland), Jean-Ellie Malkin (ESTHER, France), Jean-François Delfraissy (CHU BICETRE, ANRS, Paris, France), Joep Lange (International AIDS Society, Sweden), Lydia Mungherera (GNP+, Uganda), Lynne Mofenson (National Institute of Health, NICHD, USA), Mark Harrington (Treatment Action Group, New York, USA), Mauro Schechter (Universidade Federal do Rio de Janeiro, Brazil), N. Kumarasamy (YRG Centre for AIDS Research and Education, India), Nicolas Durier (Médecins sans Frontières, Thailand), Papa Salif Sow (University of Dakar, Senegal), Shabir Banoo (Medicines Control Council, South Africa) and Thomas Macharia (Nazareth Hospital, Kenya).

This document was developed through an expert consultation process in which account was taken of current scientific evidence and the state of the art in the treatment of HIV infection. The primary focus was the context of resource-limited settings. After the production of draft guide-

Reprinted with permission, World Health Organization. Copyright WHO, 2004.



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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Appendix C Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Treatment Guidelines for a Public Health Approach 2003 REVISION The creation of the present guidelines would not have been possible without the participation of numerous experts. The World Health Organization wishes to express special gratitude to the Writing Committee that developed this document. This Committee was chaired by Professor Scott Hammer of Columbia University (New York City, USA) and its other members were Diane Havlir (University of California at San Francisco, USA), Elise Klement (Médecins sans Frontières, France), Fabio Scano (WHO/ HTM/STB, Switzerland), Jean-Ellie Malkin (ESTHER, France), Jean-François Delfraissy (CHU BICETRE, ANRS, Paris, France), Joep Lange (International AIDS Society, Sweden), Lydia Mungherera (GNP+, Uganda), Lynne Mofenson (National Institute of Health, NICHD, USA), Mark Harrington (Treatment Action Group, New York, USA), Mauro Schechter (Universidade Federal do Rio de Janeiro, Brazil), N. Kumarasamy (YRG Centre for AIDS Research and Education, India), Nicolas Durier (Médecins sans Frontières, Thailand), Papa Salif Sow (University of Dakar, Senegal), Shabir Banoo (Medicines Control Council, South Africa) and Thomas Macharia (Nazareth Hospital, Kenya). This document was developed through an expert consultation process in which account was taken of current scientific evidence and the state of the art in the treatment of HIV infection. The primary focus was the context of resource-limited settings. After the production of draft guide- Reprinted with permission, World Health Organization. Copyright WHO, 2004.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities lines by the Writing Committee in October 2003, the document was sent to more than 200 institutional and organizational partners worldwide and made available for public consultation from 28 October to 14 November 2003 on the WHO and ITAC websites. WHO wishes to acknowledge comments and contributions by Alexandra Calmy (Switzerland), Andrew Hill (USA), Annabel Kanabus (United Kingdom), Anthony Amoroso (USA), Anthony Harries (Malawi), Artur Kalichman (Brazil), Bernard Taverne (Senegal), Beverley Snell (Australia), Bess Miller (USA), Brian Eley (South Africa), Carrie Jeffries (USA), Charles Gilks (WHO, Switzerland), Chris Duncombe (Thailand), Chris Green (Indonesia), Clement Malau (Australia), David Cohn (USA), Diana Gibb (United Kingdom), Emanuele Pontali (Italy), Emilia Rivadeneira (USA), Eric Van Praag (USA), Fionuala Mcculagh (Cameroon), Francis Onyango (WHO, AFRO), François Dabis (France), Gray Sattler (Philippines), Guido Levi (Brazil), Heloisa Marques (Brazil), Herbert Peterson (WHO, Switzerland), Isabelle Girault (United Kingdom), Jaime Uhrig (Myanmar), Jeffrey Sturchio (USA), Joia Mukherjee (Haiti), Jonathan Cohn (USA), Jose Zuniga (USA), Karin Timmermans (Indonesia), Karyaija Barigye (USA), Keith Alcorn (United Kingdom), Kenji Tamura (WHO, Switzerland), Kulkanaya Chokephaibulkit (Thailand), Lali Khotenashvilli (WHO, EURO), Leon Levin (South Africa), Márcia Dal Fabbro (Brazil), Marcia Rachid (Brazil), Marga Vitgnes (South Africa), Maria Vigneau (WHO, Switzerland), Marinella de la Negra (Brazil), Marta Segu (Spain), Monica Beg (WHO, Switzerland), Mukadi Ya-Diul (USA), Olavo Munhoz (Brazil), Paul Jareg (Norway), Paula Fujiwara (IUATLD, France), Peter Anton (South Africa), Peter Godfrey-Faussett (United Kingdom), Pier Angelo Todo (Italy), Praphan Pranuphak (Thailand), Ricardo Marins (Brazil), Richard Laing (WHO, Switzerland), Robin Gray (WHO, Switzerland), Rosana Del Bianco (Brazil), Sailesh Upadhyay (Nepal), Stephen Spector (USA), Sudarshan Kumari (India), Taimor Nawaz (Bangladesh), Thurma Goldman (USA), Vincent Habiyambere (WHO, Switzerland), William Burman (Denver, USA) and Wladimir Queiroz (Brazil) during the public consultation process. Their contributions were discussed by the Writing Committee on 26 October 2003 and, where appropriate, the draft guidelines were amended to take their suggestions into account. WHO also wishes to thank the Agence Nationale de Recherche contre le SIDA, Paris, for hosting the meeting of the Writing Committee on 15–17 October 2003. This work was coordinated by Marco Vitória and Jos Perriëns of WHO/ HTM/HIV, Geneva, Switzerland.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities ABBREVIATIONS ABC abacavir ACTG AIDS Clinical Trials Group AIDS acquired immunodeficiency syndrome ALT alanine aminotransferase ART antiretroviral therapy ARV antiretroviral ATV atazanavir bid twice daily CD4 T-lymphocyte CD4+ CNS central nervous system d4T stavudine DART development of antiretroviral therapy in Africa ddI didanosine DOT directly observed therapy EFV efavirenz ENF (T-20) enfuvirtide FBC full blood count FDC fixed-dose combination FTC emtricitabine GI gastrointestinal HAART highly active antiretroviral therapy Hgb haemoglobin HIV human immunodeficiency virus HIVab human immunodeficiency virus antibody IDU injecting drug user IDV indinavir LPV lopinavir MTCT mother-to-child transmission (of HIV) NAM nucleoside analogue mutation NFV nelfinavir NGO nongovernmental organization NNRTI non-nucleoside reverse transcriptase inhibitor NsRTI nucleoside analogue reverse transcriptase inhibitor NtRTI nucleotide analogue reverse transcriptase inhibitor NVP nevirapine PCR polymerase chain reaction PI protease inhibitor qd once daily RT reverse transcriptase RTI reverse transcriptase inhibitor RTV ritonavir

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities RTV-PI ritonavir-boosted protease inhibitor sgc soft gel capsule SQV saquinavir TB tuberculosis TDF tenofovir disoproxil fumarate TLC total lymphocyte count UN United Nations UNAIDS Joint United Nations Programme on HIV/AIDS WBC white blood cell WHO World Health Organization ZDV zidovudine (also known as AZT) /r low dose ritonavir INTRODUCTION The advent of potent antiretroviral therapy (ART) in 1996 led to a revolution in the care of patients with HIV/AIDS in the developed world. Although the treatments are not a cure and present new challenges with respect to side-effects and drug resistance, they have dramatically reduced rates of mortality and morbidity, have improved the quality of life of people with HIV/ AIDS, and have revitalized communities. Moreover, HIV/AIDS is now perceived as a manageable chronic illness rather than as a plague (Palella et al., 2003). Unfortunately, most of the 40 million people currently living with HIV/ AIDS reside in developing countries and do not share this vastly improved prognosis (Joint United Nations Programme on HIV/AIDS and World Health Organization, 2003). WHO conservatively estimated that, at the end of 2003, some 6 million people in developing countries were in immediate need of life-sustaining ART. However, only about 400 000 persons were being treated, over a third of them in Brazil. At the UN General Assembly High-Level Meeting on HIV/AIDS on 22 September 2003, WHO declared that the lack of access to HIV treatment was a global health emergency. WHO calls for unprecedented action to ensure that by the end of 2005 at least 3 million people in need of ART will have access to it. In order to achieve this target, WHO will develop a strategic framework with the following pillars: global leadership, strong partnership and advocacy; urgent sustained country support; simplified standardized tools for the delivery of ART; an effective and reliable supply of medicines and diagnostics; rapid identification and reapplication of new knowledge and success.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities The present updated and simplified treatment guidelines are a cornerstone of the WHO 3-by-5 Plan and are more directive than its predecessor with respect to first-line and second-line therapies. They take into account not only the evidence generated by clinical trials and observational studies on the efficacy and side-effects of the treatment regimens discussed, but also the experience gained with ART by programmes in resource-limited settings and the cost and availability of drugs in those settings. By taking this approach, WHO seeks to assist countries and regions in providing effective antiretroviral therapy to the millions of individuals in immediate or imminent need of treatment. This document, dealing with recommendations for ARV treatment and monitoring, is intended to be a component of a comprehensive package of care at the country level, including the prevention and treatment of opportunistic infections, nutritional programmes and psychosocial support for infected persons. Treatment for HIV, facilitated by these guidelines, complements the full range of HIV prevention efforts for uninfected people at the country level. The following recent advances in the ART field have been considered in the preparation of this revision: clinical trial data, including those suggesting the inferior virological efficacy of the triple nucleoside combination, ZDV/3TC/abacavir (ABC) in comparison with a three-drug or four-drug efavirenz-based regimen; the availability of the nucleotide analogue, tenofovir disoproxil fumarate (TDF); toxicity concerns regarding the dual nucleoside component of stavudine (d4T)/didanosine (ddI); increasing recognition of the extent of drug class cross-resistance among the nucleoside and nucleotide analogues; the approval of a new nucleoside analogue, emtricitabine (FTC), a protease inhibitor, atazanavir (ATV), the fusion inhibitor, enfuvirtide (ENF, T-20) and increasing availability and clinical experience with generic ARV preparations, particularly in fixed-dose combinations and blister packs (ENF will not be considered further in this document because of the requirement for parenteral administration and the cost of the drug, making it impractical for use in resource-limited settings). These treatment guidelines are part of WHO’s commitment to the treatment of persons living with HIV/AIDS. The first edition of these recommendations, published in April 2002, reflected the best practices at that time on the basis of a review of evidence. In this rapidly evolving field, WHO recognized at the outset that the recommendations would have to be regularly updated. The present revision has been brought forward as a result of new scientific data and the increasing reality of ART scale-up in many countries.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities DOCUMENT OBJECTIVES Currently, fewer than 5% of people in developing countries who need ART can access the medicines in question. WHO believes that at least 3 million people needing care should be able to get the medicines by 2005. This represents almost a tenfold increase. These treatment guidelines are intended to support and facilitate the proper management and scale-up of ART in the years to come by proposing a public health approach to achieve the goals. The key tenets of this approach are as follows. Scaling-up of antiretroviral treatment programmes with a view to universal access, i.e. all persons requiring treatment as indicated by medical criteria should have access to it. Standardization and simplification of ARV regimens so as to support the efficient implementation of treatment programmes in resource-limited settings. Ensuring that ARV treatment programmes are based on scientific evidence in order to avoid the use of substandard protocols that compromise the outcomes of individual patients and create a potential for the emergence of drug-resistant virus. However, it is also important to consider the realities with respect to the availability of human resources, health system infrastructures and socioeconomic contexts so that clear and realistic recommendations can be made. While it is hoped that this document will be useful to clinicians in resource-limited settings, it is primarily intended for use by treatment advisory boards, national AIDS programme managers and other senior policy-makers who are involved in the planning of national and international HIV care strategies in developing countries. The treatment guidelines serve as a framework for selecting the most potent and feasible ARV regimens as components of expanded national responses for the care of HIV-infected individuals. The framework aims to standardize and simplify antiretroviral therapy, as with tuberculosis (TB) treatment in national TB control programmes, while acknowledging the relative complexity of HIV treatment. Accordingly, options for first-line and secondline regimens are presented, bearing in mind the need to strengthen health systems that often lack staffing power and monitoring facilities, with a view to maximizing the quality and outcomes of the treatments offered. The guidelines consider when ART should begin, which ARV regimens should be introduced, the reasons for changing ART and the regimens that should be continued if treatment has to be changed. They also address how treatment should be monitored, with specific reference to the side-effects of ART and drug adherence, and make specific recommendations for certain subgroups of patients.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities WHEN TO START ARV THERAPY IN ADULTS AND ADOLESCENTS WHO recommends that, in resource-limited settings, HIV-infected adults and adolescents should start ARV therapy when the infection has been confirmed and one of the following conditions is present. Clinically advanced HIV disease: WHO Stage IV HIV disease, irrespective of the CD4 cell count; WHO Stage III disease with consideration of using CD4 cell counts <350/mm3 to assist decision-making. WHO Stage I or II HIV disease with CD4 cell counts <200/mm3 (Table A). The rationale for these recommendations is as follows. The treatment of patients with WHO Stage IV disease (clinical AIDS) should not be dependent on a CD4 cell count determination. However, where available, this test can be helpful in categorizing patients with Stage III conditions with respect to their need for immediate therapy. For example, pulmonary TB can occur at any CD4 count level and, if the CD4 cell count level is well maintained (i.e. >350/mm3), it is reasonable to defer therapy and continue to monitor the patient. For Stage III conditions a threshold of 350/mm3 has been chosen as the level below which immune deficiency is clearly present such that patients are eligible for treatment when their clinical condition portends rapid clinical progression. A level of 350/mm3 is also in line with other consensus guideline documents (DHHS; Yeni et al., 2002). For patients with Stage I or Stage II HIV disease the presence of a CD4 cell count <200/mm3 is an indication for treatment. In cases where CD4 cell counts cannot be assessed the presence of a total lymphocyte count of 1200/mm3 or below can be used as a substitute indication for treatment in the presence of symptomatic HIV disease. While the total lymphocyte count correlates relatively poorly with the CD4 cell count in asymptomatic persons, in combination with clinical staging it is a useful marker of prognosis and survival (Badri and Wood, 2003; Beck et al., 1996; Brettle, 1997; Fournier and Sosenko, 1992; Kumarasamy et al., 2002; van der Ryst et al., 1998). An assessment of viral load (e.g. using plasma HIV-1 RNA levels) is not considered necessary before starting therapy. Because of the cost and complexity of viral load testing, WHO does not currently recommend its routine use in order to assist with decisions on when to start therapy in severely resource-constrained settings. It is hoped, however, that increasingly affordable methods of determining viral load will become available so that this adjunct to treatment monitoring can be more widely employed. It should be noted that the current WHO Staging System for HIV Infection and Disease for Adults and Adolescents was developed several years ago

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities TABLE A. Recommendations for Initiating Antiretroviraltherapy in Adults and Adolescents with Docummented HIV Infection If CD4 testing available, it is recommended to document baseline CD4 counts and to offer ART to patients with: • WHO Stage IV disease, irrespective of CD4 cell count • WHO Stage III disease (including but not restricted to HIV wasting, chronic diarrhoea of unknown etiology, prolonged fever of unknown etiology, pulmonary TB, recurrent invasive bacterial infections or recurrent/persistent mucosal candidiasis), with consideration of using CD4 cell counts <350/mm3 to assist decision-makinga • WHO Stage I or II disease with CD4 cell counts 200/mm3b If CD4 testing unavailable, it is recommended to offer ART to patients with: • WHO Stage IV disease, irrespective of total lymphocyte count • WHO Stage III disease (including but not restricted to HIV wasting, chronic diarrhoea of unknown etiology, prolonged fever of unknown etiology, pulmonary TB, recurrent invasive bacterial infections or recurrent/persistent mucosal candidiasis), irrespective of the total lymphocyte countc • WHO Stage II disease with a total lymphocyte count 1200/mm3d aCD4 count advisable to assist with determining need for immediate therapy. For example, pulmonary TB may occur at any CD4 level and other conditions may be mimicked by non-HIV etiologies (e.g. chronic diarrhoea, prolonged fever). bThe precise CD4 level above 200/mm3 at which ARV treatment should start has not been established. cThe recommendation to start ART in all patients with stage III disease, without reference to total lymphocyte counts reflects consensus of expert opinion. It took into account the need of a practical recommendation that allows clinical services and TB programmes in severely resource constrained settings to offer access to ART to their patients. As some adults and adolescents with stage III disease will be presenting with CD4 counts above 200, some of them will receive antiretroviral treatment before the CD4 < 200 threshold is reached. However, if CD4 counts cannot be determined, starting ART earlier in these patients was not considered problematic. dA total lymphocyte count of 1200/mm3 can be substituted for the CD4 count when the latter is unavailable and HIV-related symptoms exist. It is not useful in the asymptomatic patient. Thus, in the absence of CD4 cell testing, asymptomatic HIV-infected patients (WHO Stage I) should not be treated because there is currently no other reliable marker available in severely resourceconstrained settings. and has consequent limitations. Adaptations at the level of national programmes may therefore be appropriate. Nevertheless, it remains a useful tool for assisting in defining parameters for initiating therapy in resource-limited settings and thus has continued to be applied in this revision.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities RECOMMENDED FIRST-LINE ARV REGIMENS IN ADULTS AND ADOLESCENTS Countries are encouraged to use a public health approach to facilitate the scale-up of ARV use in resource-limited settings as delineated in the WHO 3-by-5 Plan. This means that ART programmes should be developed which can reach as many people as possible who are in need of therapy and requires that ARV treatment be standardized. In particular, it is suggested that countries select a first-line regimen and a limited number of second-line regimens, recognizing that individuals who cannot tolerate or fail the first-line and second-line regimens will be referred for individualized care by specialist physicians. The use of standardized regimens is an essential component of the 3-by-5 Plan and will facilitate WHO’s efforts to assist Member States with achieving this goal. This is the approach to ARV regimen selection taken in the present document. Among the factors that should be considered in the selection of ART regimens at both the programme level and the level of the individual patient are: potency; side-effect profile; laboratory monitoring requirements; potential for maintenance of future treatment options; anticipated patient adherence; coexistent conditions (e.g. coinfections, metabolic abnormalities); pregnancy or the risk thereof; use of concomitant medications (i.e. potential drug interactions); potential for infection with a virus strain with diminished susceptibility to one or more ARVs, including that resulting from prior exposure to ARVs given for prophylaxis or treatment; very importantly, availability and cost. The use of quality-assured1 antiretrovirals in fixed-dose combinations (FDCs)2 or as blister packs3 is another important consideration as this pro- 1   Quality-assured medicines assembled in fixed-dose combinations (FDCs), in the context of this document, include individual products which have been deemed to meet or exceed international standards for quality, safety and efficacy. In the case of drug combinations whose components are from different manufacturers the international standards include a requirement for clinical bioequivalence studies to establish therapeutic interchangeability of the components. For WHO’s work on prequalification of ARVs see: http://www.who.int/medicines/organization/qsm/activities/pilotproc/proc.shtml 2   Fixed-dose combinations are based on the principle of inclusion of two or more active pharmacological products in the same pill, capsule, tablet or solution. 3   A blister pack is a plastic or aluminum blister containing two or more pills, capsules or tablets.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities motes better adherence and, in turn, limits the emergence of drug resistance. It also facilitates ARV storage and distribution logistics. Additional considerations relevant to the developing world include access to a limited number of ARV drugs, limited health service infrastructures (including human resources), the need to deliver drugs to rural areas, high incidences of TB and hepatitis B and/or C in populations and the presence of varied HIV types, groups and subtypes. The previous (April 2002) version of these treatment guidelines recommended that countries should select a first-line treatment regimen and identified regimens composed of two nucleosides plus either a non-nucleoside, or abacavir, or a protease inhibitor as possible choices. Since that version was published, many countries have started ARV treatment programmes and have chosen their first-line treatment regimens, taking into account how the above factors would come into play in the different settings. The majority of treatment programmes in developing countries have opted for a regimen composed of two nucleosides and a nonnucleoside RT inhibitor. Triple nucleoside regimens including abacavir were almost never selected because of their cost and concerns over hypersensitivity reactions, and regimens containing a protease inhibitor became secondary options, mainly because of their cost, notwithstanding price decreases. However, high pill counts, their side-effect profile and more difficult logistics (some requiring a cold chain) were probably also considerations. The Writing Committee examined non-nucleoside-based regimens and took account of clinical experience with the efficacy and toxicity of the nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) components, the availability of fixed-dose combinations (Annex D), the lack of a requirement for a cold chain, and drug availability and cost. On this basis the Committee concluded that the four first-line ARV regimens listed in Table B were appropriate for adults and adolescents. These regimens consist of a thymidine analogue NRTI, i.e. stavudine (d4T) or zidovudine (ZDV), a thiacytidine NRTI, i.e. lamivudine (3TC), and an NNRTI, i.e. nevirapine (NVP) or efavirenz (EFV). The choice between d4T and ZDV should be made at the country level on the basis of local considerations but it is recommended that both drugs be available. d4T is initially better tolerated than ZDV and does not require haemoglobin monitoring. However, among the NRTIs, it has been consistently most associated in developed countries with lipoatrophy and other metabolic abnormalities, including lactic acidosis, particularly when combined with didanosine (ddI). It can also cause peripheral neuropathy and pancreatitis. ZDV has also been implicated in metabolic complications of therapy but to a lesser extent than d4T. Initial drug-related side-effects (headache, nausea) are more frequent with ZDV and the drug can cause severe anaemia and neutropenia, which, at the very least, requires that haemoglobin should be monitored before and during treatment with ZDV. d4T can be substituted for ZDV in the event of intolerance to the latter and

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities vice versa (except in cases of suspected lactic acidosis, in which instance neither drug should be prescribed). However, the initial need for less laboratory monitoring might, at present, favour d4T as the nucleoside of choice for the majority of patients in ART programmes in settings with severe resource limitations where rapid scaling-up is intended. 3TC is a potent NRTI with an excellent record of efficacy, safety and tolerability. It can be given once or twice daily and has been incorporated into a number of fixed-dose combinations. Emtricitabine (FTC) is a recently approved nucleoside analogue that is structurally related to 3TC, shares its resistance profile and can be given once daily (Bang and Scott, 2003). It is currently being tested as a coformulated product with tenofovir disoproxil fumarate (TDF). Because of the relatively recent approval of FTC in a limited number of countries it is not included in WHO’s recommended first-line regimens but this may change in the light of future experience with the drug and its availability and cost. The dual nucleoside component of d4T/ddI is no longer recommended as part of first-line regimens because of its toxicity profile, particularly in pregnant women (Boubaker et al., 2001). It is also worth emphasizing that ZDV and d4T should never be used together because of proven antagonism between them (Pollard et al., 2002). TDF has a long intracellular half-life and can therefore be used as part of once-daily triple-drug regimens. It has been shown that TDF is an effective component of first-line regimens in combination with 3TC and efavirenz (EFV) (Gallant and Deresinski, 2003; Staszewski et al., 2003). It is generally well tolerated although there have been reports of renal insufficiency in patients receiving TDF (Karras et al., 2003; Schaaf et al., 2003; Verhelst et al., 2002). However, worldwide experience with the drug is still relatively limited. In addition, its limited availability and relatively high cost in developing countries continue to be significant factors. For the purposes of the present treatment guidelines, therefore, discussion of its use will be restricted to second-line therapy. As experience, availability and cost issues in resource-limited settings become clarified the inclusion of TDF in WHO-recommended first-line regimens should be reconsidered. Globally, NNRTI-based regimens are now the most widely prescribed combinations for initial therapy. They are potent and relatively simple but are inactive in respect of HIV-2 and group O of HIV-1. EFV and NVP are both potent NNRTIs with demonstrated clinical efficacy when administered in appropriate combination regimens. However, differences in toxicity profile, a potential for interaction with other treatments, and cost, allow the formulation of both positive and negative recommendations on their use (Staszewski et al., 2003; Ena et al., 2003; Keiser et al., 2002; Law et al., 2003; Martin-Carbonero et al., 2003; Moyle, 2003; van Leth et al., 2003). NVP has a higher incidence of rash, which may be severe and life-threaten-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Name of drug Formulations Pharmaco-kinetic data available Age (weight), dose and dose frequency Other comments Efavirenz (EFV) Syrup: 30 mg/ ml (note: syrup requires higher doses than capsules; see dosing chart) Capsules: 50 mg, 100 mg, 200 mg Only for children over 3 years of age Capsule (liquid) dose for >3 years: 10 to 15 kg: 200 mg (270 mg = 9 ml) once daily 15 to <20 kg: 250 mg (300 mg = 10 ml) once daily 20 to <25 kg: 300 mg (360 mg = 12 ml) once daily 25 to <33 kg: 350 mg (450 mg = 15 ml) once daily 33 to <40 kg: 400 mg (510 mg = 17 ml) once daily Maximum dose: ≥ 40 kg: 600 mg once daily Capsules may be opened and added to food but have very peppery taste; however, can be mixed with sweet foods or jam to disguise taste Can be given with food (but avoid after high- fat meals, which increase absorption by 50%); best given at bedtime, especially first 2 weeks, to reduce CNS side-effects. Drug interactions Fixed-dose combination of d4T plus 3TC plus NVP No liquid available Tablet: 30 mg d4T/150 mg 3TC/200 mg NVP; 40 mg d4T/150 mg 3TC/ 200 mg NVP Adults and adolescents Maximum dose: 30-60 kg: one 30 mg d4Tbased tablet twice daily ≥ 60 kg: one 40 mg d4Tbased tablet twice daily Preferably, tablet should not be split At weight <30 kg, d4T/3TC/ NVP cannot be dosed accurately in tablet form; if tablets are split, NVP dose requirements will be inadequate for very young children and additional NVP is needed to give total of 200 mg/m2/dose twice daily

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities         Contains NVP, therefore dose escalation required (see NVP dosing recommendations) See comments under individual drug components Protease inhibitors Nelfinavir (NFV) Powder for oral suspension (mix with liquid): 200 mg per level teaspoon (50 mg per 1.25 ml scoop): 5 ml Tablet: 250 mg (tablets can be halved; can be crushed and added to food or dissolved in water) All ages However, extensive pharmacokinetic variability in infants, with requirement for very high doses in infants <1 year <1 year: 50 mg/kg/dose three times daily or 7 5 mg/kg/dose twice daily >1 year to <13 years: 55 to 65 mg/kg/dose twice daily Maximum dose: ≥ 13 years: 1250 mg/dose twice daily Powder is sweet, faintly bitter but gritty and hard to dissolve; must be reconstituted immediately before administration in water, milk, formula, pudding, etc.; do not use acidic food or juice (which increase bitter taste); solution stable for 6 hours Because of difficulties with use of powder, use of crushed tablets preferred (even for infants) if appropriate dose can be given Powder and tablets can be stored at room temperature Take with food Drug interactions (less than ritonavir-containing protease inhibitors)

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Name of drug Formulations Pharmaco-kinetic data available Age (weight), dose and dose frequency Other comments Lopinavir/ritonavir, (LPV/r) Oral solution: 80mg/ml lopinavir plus 20 mg/ml ritonavir Capsules: 133.3 mg lopinavir plus 33.3 mg ritonavir 6 months of age or older >6 months to 13 years: 225 mg/m2 LPV/57.5 mg/m2 ritonavir twice dailya or weight- based dosing: 7-15 kg: 12mg/kg LPV/ 3 mg/ kg ritonavir/ dose twice daily 15-40 kg: 10 mg/ kg lopinavir/2.5 mg/kg ritonavir twice daily Maximum dose: >40 kg: 400 mg LPV/ 100 mg ritonavir (3 capsules or 5 ml) twice daily Preferably, oral solution and capsules should be refrigerated; however, can be stored at room temperature up to 25° C (77° F) for 2 months; at temperature >25° C (77° F) the drug degrades more rapidly Liquid formulation has low volume but bitter taste Capsules large Capsules should not be crushed or opened but must be swallowed whole Should be taken with food Drug interactions aMetre 2 (m2) body surface area calculation: square root of (height in centimetres times weight in kilograms divided by 3600).

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities ANNEX D. Fixed-dose Combinations of ARVS Available on 1 December 2003 Three-drug d4T (40 mg) + 3TC (150 mg) + NVP (200 mg) fixed-dose d4T (30 mg) + 3TC (150 mg) + NVP (200 mg) combinations ZDV (300 mg) + 3TC (150 mg) + ABC (300 mg) ZDV (300 mg) + 3TC (150 mg) + NVP (200 mg) Two-drug d4T (30 mg) + 3TC (150 mg) fixed-dose d4T (40 mg) + 3TC (150 mg) combinations ZDV (300 mg) + 3TC (150 mg) NOTE: WHO encourages the use of fixed-dose combinations when formulations of assured quality and proven bioequivalence are available and offer operational advantages. Not all the FDCs in this table have been evaluated for prequalification by WHO. WHO operates a voluntary prequalification system, in which, as of 1 December 2003, three manufacturers prequalified ZDV/3TC combinations, two prequalified d4T/3TC/NVP combinations, and one prequalified ZDV/3TC/ABC. The list of WHO-prequalified manufacturers is continuously updated and is available at: http://www.who.int/medicines

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities ANNEX E. WHO Staging System for HIV Infection and Disease and Disease in Adults and Adolescents Clinical Stage I: 4. Asymptomatic 5. Generalized lymphadenopathy Performance scale 1: asymptomatic, normal activity Clinical Stage II: 6. Weight loss <10% of body weight 7. Minor mucocutaneous manifestations (seborrhoeic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations, angular cheilitis) 8 Herpes zoster within the last five years 9. Recurrent upper respiratory tract infections (i.e. bacterial sinusitis) And/or performance scale 2: symptomatic, normal activity Clinical Stage III: 10. Weight loss >10% of body weight 11. Unexplained chronic diarrhoea, >1 month 12. Unexplained prolonged fever (intermittent or constant), >1 month 13. Oral candidiasis (thrush) 14. Oral hairy leucoplakia 15. Pulmonary tuberculosis 16. Severe bacterial infections (i.e. pneumonia, pyomyositis) And/or performance scale 3: bedridden <50% of the day during last month Clinical Stage IV: 17. HIV wasting syndromea 18. Pneumocystic carinii pneumonia 19. Toxoplasmosis of the brain 20. Cryptosporidiosis with diarrhoea >1 month 21. Cryptococcosis, extrapulmonary 22. Cytomegalovirus disease of an organ other than liver, spleen or lymph node (e.g. retinitis) 23. Herpes simplex virus infection, mucocutaneous (>1month) or visceral 24. Progressive multifocal leucoencephalopathy 25. Any disseminated endemic mycosis 26. Candidiasis of oesophagus, trachea, bronchi 27. Atypical mycobacteriosis, disseminated or pulmonary 28. Non-typhoid Salmonella septicaemia 29. Extrapulmonary tuberculosis 30. Lymphoma 31. Kaposi’s sarcoma 32. HIV encephalopathyb And/or performance scale 4: bedridden >50% of the day during last month aHIV wasting syndrome: weight loss of >10% of body weight, plus either unexplained chronic diarrhoea (>1 month) or chronic weakness and unexplained prolonged fever (>1 month). bHIV encephalopathy: clinical findings of disabling cognitive and/or motor dysfunction interfering with activities of daily living, progressing over weeks to months, in the absence of a concurrent illness or condition, other than HIV infection, which could explain the findings.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities ANNEX F. WHO Staging System for HIV Infection and Disease in Children Clinical Stage I: 1. Asymptomatic 2. Generalized lymphadenopathy Clinical Stage II: 3. Chronic diarrhoea >30 days duration in absence of known etiology 4. Severe persistent or recurrent candidiasis outside the neonatal period 5. Weight loss or failure to thrive in the absence of known etiology 6. Persistent fever >30 days duration in the absence of known etiology 7. Recurrent severe bacterial infections other than septicaemia or meningitis (e.g. osteomye litis, bacterial (non-TB) pneumonia, abscesses) Clinical Stage III: 8. AIDS-defining opportunistic infections 9. Severe failure to thrive (wasting) in the absence of known etiologya 10. Progressive encephalopathy 11. Malignancy 12. Recurrent septicaemia or meningitis aPersistent weight loss >10% of baseline or less than 5th percentile on weight for height chart on 2 consecutive measurements more than 1 month apart in the absence of another etiology or concurrent illness.

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