Scaling Up Treatment for the Global AIDS Pandemic Challenges and Opportunities (2005) / Chapter Skim
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Appendix C: Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Treatment Guidelines for a Public Health Approach
Appendix C: Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Treatment Guidelines for a Public Health Approach
Pages 220-278
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From page 220... ...
. 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.
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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.
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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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From page 223... ...
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.
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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.
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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)
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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)
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, with consideration of using CD4 cell counts <350/mm3 to assist decision-makinga · WHO Stage I or II disease with CD4 cell counts 200/mm3 b 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/mm3 d aCD4 count advisable to assist with determining need for immediate therapy.
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From page 228... ...
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.
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, 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.
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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)
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EFV should not be given to women of childbearing potential unless effective contraception can be assured. However, it is important to emphasize that EFV and NVP may interact with estrogen-based contraceptive pills.
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d4T/3TC/NVP d4T-related neuropathy, pancreatitis Yes and lipoatrophy; NVP-related hepatotoxicity and severe rash ZDV/3TC/NVP ZDV-related GI intolerance, anaemia, Yes and neutropenia; NVP-related hepatotoxicity and severe rash d4T/3TC/EFV d4T-related neuropathy, pancreatitis Nob and lipoatrophy; EFV-related CNS toxicity and potential for teratogenicity ZDV/3TC/EFV ZDV-related GI intolerance, anaemia Nob and neutropenia; EFV-related CNS toxicity and potential for teratogenicity aPeople with TB disease and HIV coinfection. bWomen of childbearing potential or who are pregnant.
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From page 233... ...
EFV not Yes 611-986 be given to pregnant available as part women or women of of FDC; childbearing potential however, partial unless effective FDC available contraception can be for ZDV/3TC assured significant interactions with other drugs that preclude or complicate their use during TB treatment regimens using rifampicin, metabolic abnormalities and the need for a functioning cold chain for ritonavir-boosted regimens. Consequently, in these treatment guidelines, PI-based regimens are primarily reserved for second-line therapy.
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From page 234... ...
and relatively lower pill burden, but the requirement for a cold chain and the support of frequent laboratory monitoring present problems for many low-resource countries. LPV/r is administered as a twice-daily regimen and is relatively well tolerated, but frequently causes elevations in plasma lipid levels.
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From page 235... ...
Thus, its virological inferiority to EFV-based regimens in a directly comparative trial moves this triple NRTI combination to a lower tier of consideration but does not, and should not, remove it from serious consideration. It may be useful, for example, when NNRTIs cannot be used because of intolerance or drug resistance and when PI-based regimens are not available.
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From page 236... ...
Similarly, drug resistance testing will not become a routine part of clinical care in resource-limited settings in the foreseeable future and so is not considered in these recommendations. However, it should be recognized that, in the developing world, treatment failure will be recognized later solely on the basis of clinical and/or CD4 criteria, thus providing a greater opportunity for drug resistance mutations to evolve before regimen change.
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CLINICAL AND LABORATORY MONITORING WHO recommends that in resource-limited settings the basic clinical assessment before the initiation of ART include documentation of past
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concomitant infection to explain This must be differentiated from the transient CD4 cell decreasec immune reconstitution syndrome · >50% fall from therapy CD4 peak level which can occur in the first three without other concomitant infection months following the initiation of to explain transient CD4 cell decreasec ART.a The latter does not signify treatment failure and the opportunistic infection should be treated as usual, without changes in the antiretroviral regimen. · Recurrence of previous opportunistic infection.b · Onset or recurrence of WHO Stage III conditions (including but not restricted to HIV wasting, chronic diarrhoea of unknown etiology, prolonged fever of unknown etiology, recurrent invasive bacterial infections, or recurrent/persistent mucosal candidiasis)
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From page 239... ...
However, it is hoped that more cost-effective technologies will allow regional referral centres to acquire this capability, given its utility in assessing treatment failure. care centres (level 1)
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Once therapy has begun, clinical assessment should cover · signs/symptoms of potential drug toxicities (Table D) ; · adherence; · response to therapy; · weight; · basic laboratory monitoring considerations as listed in Table F
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Symptom-directed Recommended: Hgb determination of Hgb, Desirable but not required: WBC for toxicity FBC, CD4 CD4 q6-12 months, if available, for efficacy effective methodologies at the country level and ensuring supplies of reagents and the maintenance of equipment. CHOICE OF ARV REGIMENS IN THE EVENT OF TREATMENT FAILURE OF FIRST-LINE COMBINATIONS IN ADULTS AND ADOLESCENTS WHO recommends that the entire regimen be changed from a first-line to a second-line combination in the setting of treatment failure.
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From page 242... ...
When (d4T or ZDV) + 3TC are used as part of the first-line regimen, nucleoside cross-resistance may compromise the potency of alternative dual nucleoside components in the second-line regimen, especially in the presence of long-standing virological failure.
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From page 243... ...
In these situations the options depend on the constraints imposed by the circumstances of individual patients, the capabilities of individual managements to test for resistance to drugs, and the limited ARV formulary that may exist in particular country programmes. Treatment failure on a triple NRTI regimen is more easily managed because two important drug classes (NNRTIs and PIs)
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From page 244... ...
Additionally, the dual NRTI combination of d4T/ ddI should be avoided in pregnancy and only used when no other alternatives exist, because of the potential increased risk of lactic acidosis with this combination in pregnant women. Symptomatic NVP-associated hepatic or serious rash toxicity, although uncommon, is more frequent in women than in men and is more likely to be seen in women with comparatively elevated CD4 cell counts (>250/mm3)
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From page 245... ...
Until definitive data are available on this matter, women who have received single-dose NVP prophylaxis or 3TC prophylaxis for the prevention of MTCT should be considered eligible for NNRTI-based regimens and should not be denied access to life-sustaining therapy. Several country programmes are already considering the use of shortcourse triple combination therapy for the prevention of MTCT in women who are not yet in need of treatment for their own HIV infection, and the cessation of therapy postpartum if the women do not require its continuation for their own health.
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From page 246... ...
In such cases, HIV antibody testing must be repeated at the age of 18 months in order to definitively confirm that the children are HIV-infected; ARV therapy should only be continued in infants with confirmed infection. · For HIV-seropositive children aged 18 months or over, WHO recommends initiation of ARV therapy in the following circumstances: · WHO Paediatric Stage III HIV disease (i.e.
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In cases where the CD4 cell count cannot be assessed, therefore, the total lymphocyte count may be used as a substitute indication for the treatment of infants or children with documented HIV infection in the presence of symptomatic disease (WHO Paediatric Stage II or III)
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248 a,d a,c to (Annex with III AIDS)
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249 3 a If of of In no assay (e.g. with with years.
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Standardization is important so that non-expert personnel can safely dispense correct doses, and consequently it is desirable to provide health care workers with a table of drug doses that can be administered according to weight bands. Such tables may vary between localities in accordance with the availability of ARV drugs and formulations in the country concerned.
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From page 251... ...
The use of ZDV/3TC/ ABC as first-line therapy is now considered a secondary alternative because of the results obtained with ACTG A5095 in adults; further data are awaited. EFV would be the NNRTI of choice for children who require ARV therapy but need or are receiving anti-TB therapy containing rifampicin.
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From page 252... ...
However, until there are data allowing these questions to be definitively answered, children who require ARV therapy and who have previously received single-dose NVP or 3TC as part of MCTC prophylaxis should be considered eligible for NNRTI-based regimens and should not be denied access to life-sustaining therapy. Clinical Assessment of Infants and Children Receiving ARV Therapy Important clinical signs of response to ARV therapy in children include: improvement in growth in children who have been failing to grow; improvement in neurological symptoms and development in children who have been demonstrating delay in the achievement of developmental milestones or encephalopathy; and/or decreased frequency of infections (bacterial infections, oral thrush, and/or other opportunistic infections)
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TABLE I Clinical and CD4 Count Definitions of Treatment Failure in Infants and Children Clinical signs of treatment failure CD4 cell criteria for treatment failurea · Lack of growth among children who · Return of CD4 cell percentage (or for show an initial response to treatment, children > 6 years of age, of absolute or decline in growth among children CD4 cell count)
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From page 254... ...
No data are available on the use of total lymphocyte counts for the evaluation of response to ARV therapy. Recommended Second-line ARV Therapy for Infants and Children Second-line therapy for children in the event of failure of a first-line regimen includes a change in the nucleoside backbone, in accordance with the same principles as are applied for adults (e.g.
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In the absence of CD4 cell counts, ART is recommended for all patients with TB. It is acknowledged that this will result in the treatment of individuals with CD4 cell counts over 350 who otherwise would not receive ART.
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Case-fatality rates in many patients with TB during the first two months of TB treatment are high, particularly when they present with advanced HIV disease, and ART in this setting might be life-saving. On the other hand, pill burden, drug-to-drug interaction, potential toxicity and immune reconstitution syndrome should be kept in mind when deciding on the best time to
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From page 257... ...
However, deferring the start of ART may be reasonable in a variety of clinical scenarios. For example, in patients with higher CD4 cell counts the commencement of ART may be delayed until after the induction phase of TB therapy is completed in order to simplify the management of treatment.
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Viral load testing will not be widely introduced in the developing world in the near future because of cost and technical considerations. Consequently, it is particularly important to focus on maximizing adherence in order to try to avoid drug resistance and ensure the durability of effect of ARV regimens.
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Scale-up programmes in the developing world can take advantage of the lessons learnt in developed countries through proper initiation of potent regimens, incorporation of culturally appropriate adherence training and maintenance programmes, and synchronization with drug resistance surveillance and monitoring initiatives. Drug resistance genotyping is not on the near-term or mid-term hori
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From page 260... ...
This will allow countries to detect potential drug resistance at the population level and to modify recommended treatment regimens accordingly. Initially, treatment-naive persons should be surveyed in order to establish prevalence rates of drug resistance in the infected population, and treatment-experienced persons should be monitored, particularly those diagnosed with their first episode of treatment failure.
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Product-specific information should be consulted for dose adjustments that may be indicated with renal or hepatic dysfunction or for potential drug interactions with other HIV and non-HIV medications. b See TB section for other specific TB dosing.
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262 in infection Age-specific % 25% 15%24% <15% virus on Based 3 years System 612 No./mm 500 immunodeficiency 200499 <200 human for Classification system % 25% 15%24% <15% Category 3 classification years Immune 15 No./mm 1000 revised 500999 <500 1994 Paediatric RR-12)
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From page 263... ...
263 well per at continued not glass and tablet mixed water children in /dose or of food 2 HIV stable syrup is d4T opened of antiretroviral older with mg/m for contents immediately storage light-sensitive be amount in with is dispersed 600 and and given can use comments volume needs and of required small (solution temperature) be food not tolerated jars day encephalopathy contents crushed with or taken room (antagonistic effect)
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From page 264... ...
264 be and in of and not and and opening) and small and small food form of must stored food food or amount room with should ZDV with or dosed solution and opened with at (use crushed taken crushed taken kg, be tablet of refrigerated; days; month water be small be mixed tablet in be 30 water mixed of <30 given one shaken can with comments can can for bottles tolerated be solution cannot volume solution well weight temperature within contents amount immediately split contents amount immediately 3TC accurately stable be glass mixed Other Well Can Store Tablet Preferably, Tablet At Large Keep Capsules if daily daily kg: kg: given twice mg/dose dose mg/dose >60 twice be mg/kg/dose <60 kg)
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From page 265... ...
265 be at kept be continued in if not in individual must stomach, before water, dissolved in hours eating appropriate small (stable AZT should refrigerated; be opened 24 antiretroviral under days; of empty buffering beadlets on be with minutes after food water for tablet 30 on 30 dispersed should can of or use for tablets components suspension shaken hours 2 sprinkled not comments least 2 adequate food solution refrigerated) (antagonistic effect)
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From page 266... ...
266 be and not and small be if WARNED form food food with BE ZDV/3TC/ or stopped hypersensitivity should dosed reaction should with crushed ingested if kg, be tablet PARENTS be in be mixed MUST water occurs tablet <30 permanently given HYPERSENSITIVITY HYPERSENSITIVITY comments can cannot WARN be should weight contents amount immediately permanently reaction split ABC accurately stopped hypersensitivity occurs Other Can Tablet PARENTS ABOUT REACTION ABC Preferably, At MUST ABOUT REACTION. ZDV/3TC/ABC daily kg: daily kg: twice dose 37.5 twice <37.5 or dose: or dose: tablet/dose frequency 1 daily years mg/dose kg: (weight)
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From page 267... ...
267 be a be food rash, parts can with or well can rash has from continued WARNED section) room be if food and equal dose; escalation; water administered rash TB at BE dosing must mg of dose discontinue coadministration, with two combined dose (see scored 100 MUST mild/moderate when of into a and restart rash, use given are RASH.
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From page 268... ...
268 be by be if 200 and very can or to (but not NVP dose of meals, bedtime, have form; young foods food at weeks, d4T/3TC/ be total daily opened but taste should dosed NVP however, absorption 2 very be sweet with high-fat given side-effects. kg, be tablet will additional give in split, for twice food first tablet may taste; <30 to and to with disguise given after increase best CNS are /dose comments to cannot 2 be interactions weight needed added peppery mixed jam avoid which 50%)
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From page 269... ...
Contains See Powder Because Powder Take Drug 7 daily or dose mg/dose twice years: daily mg/kg/dose 1250 <13 mg/kg/ dose: 50 times to 65 daily daily years: to year: mg/kg/dose year three 5 55 twice 13 twice <1 >1 Maximum for year in doses <1 with high ages infants All However, extensive pharmacokinetic variability infants, requirement very in level be to with per ml in per 5 mg (tablets can (mix mg added oral (50 mg 200 scoop) : and dissolved for ml 250 halved; or be suspension liquid)
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From page 270... ...
270 up be and can low crushed 2 be be food drug has taste be solution temperature for rapidly not the must with however, °F) temperature bitter oral but whole should room °F)
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From page 271... ...
APPENDIX C 271 ANNEX D Fixed-dose Combinations of ARVS Available on 1 December 2003 Three-drug d4T (40 mg)
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From page 272... ...
. 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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From page 273... ...
pneumonia, abscesses) Clinical Stage III: 8.
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From page 274... ...
Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: a substudy of Pediatric AIDS Clinical Trials Group protocol 316. J Infect Dis 2002;186:181-188.
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From page 275... ...
Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an Inter national AIDS Society-USA Panel. Clin Infect Dis 2003;37(1)
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From page 276... ...
A randomised trial of monitoring practice and structured treatment interruptions in the management of antiretroviral therapy in adults with HIV infection in Africa: the DART trial. 13th International Conference on AIDS and STIs in Africa (ICASA)
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From page 277... ...
Reduced risk of tuberculosis among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy. Clin Infect Dis 2002;34(4)
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Treatment with highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children is associated with a sustained effect on growth. Pediatrics 2002;109(2)
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