safe and effective use of antiretroviral treatments in...

World Health OrganizationInitiative on HIV/AIDS and Sexually Transmitted Infections

safe and effective

use of antiretroviraltreatments in adultswith particular references to resource limited settings

WHO/HSI/2000.04Original: EnglishDistr.: General

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IASINTERNATIONAL

SOCIETY

World Health OrganizationInitiative on HIV/AIDS and Sexually Transmitted infections

use of antiretroviral treatments in adults

safe and effective

with particular references to resource limited settings


IASINTERNATIONAL

SOCIETY

INTRODUCTION 1

SECTION ONE. PRINCIPLES OF ANTIRETROVIRAL THERAPY (ART) 31.1. BACKGROUND 3

1.2. CHARACTERISTICS OF AVAILABLE ANTIRETROVIRAL DRUGS 4

1.3. INITIATION OF THERAPY 5

1.4. MONITORING 8

1.5. TREATMENT FAILURE 9

1.6. HIV RESISTANCE TO ANTIRETROVIRAL DRUGS 10

1.7. FUTURE APPROACHES TO THERAPY 11

SECTION TWO. SOME EXPERIENCES WITH ART IN RESOURCE LIMITED SETTINGS 132.1. ART COVERAGE 13

2.2. CONTEXT: PUBLIC OR PRIVATE SECTOR, DONOR SUPPORTED AND RESEARCH PROJECTS 13

2.3. QUALITY OF CARE AND OUTCOMES 13

2.4. LABORATORY MONITORING SERVICES 14

2.5. SURVEILLANCE FOR DRUG RESISTANCE 14

2.6. SUPPLY AND DISTRIBUTION OF THE DRUGS 14

2.7. INITIATION OF TREATMENT 14

2.8. CHOICE OF THERAPEUTIC REGIMEN 15

SECTION THREE. GUIDE TO ART IN RESOURCE LIMITED SETTINGS 163.1. WHAT SHOULD BE IN PLACE BEFORE INITIATING ART PROGRAMMES 16

3.2. COUNSELLING FOR ART 16

3.3. CLINICAL EVALUATION BEFORE INITIATION OF ART 19

3.4. INITIATION OF THERAPY 21

3.6. MONITORING ANTIRETROVIRAL THERAPY 23

3.7. CONSIDERATIONS OF DRUG INTERACTIONS 25

3.7. FURTHER RESEARCH NEEDS 27

3.8. INFORMATION AND TRAINING 27

ANNEXESI. LIST OF PARTICIPANTS 29

II. DRUG CHARTS 31

SAFE AND EFFECTIVE USE OF ANTIRETROVIRAL TREATMENTS IN ADULTS

TABLE OF CONTENTS

Copyright © World Health Organization 2000.

This document is not a formal publication of the World Health Organization (WHO) and all rights are reserved by the Organization. This document may, however, be reviewed, abstracted, quoted or translated in part, but not for sale or for use in conjunction with commercial purposes.

No part of this document may be stored in a retrieval system or transmitted in any form or by any means – electronic, mechanical, or other – without the prior written permission of WHO.

Design by RSdeSigns.com.

This document was prepared by:

■ Dr. Paula Munderi;WHO Initiative on HIV/AIDS and STI, Geneva

■ Dr. Eric van Praag;WHO Initiative on HIV/AIDS and STI, Geneva

■ Dr. Stefano Vella; Istituto Superiore di Sanita, Rome, President, International AIDS Society (IAS)

The WHO Initiative on HIV/AIDS and STI acknowledges the following individuals who reviewed the draft text and provided helpful comments and suggestions:

■ Prof. Eba Francois Aoussi, Service des Maladies Infecteuses et Tropicales - CHU Treichville,Abidjan ■ Dr Roberto Badaro,

Hospital Edgard Santos, Salvador ■ Dr Rachel Baggaley, Consultant - WHO, London ■ Dr Hilde Carlier, Medical Department

- G.C.V. Böhringer Ingelheim Coordination Center, Brussels ■ Prof. Robert Colebunders, Department of Clinical Sciences -

Institute of Tropical Medicine,Antwerp ■ Prof. Jean-Pierre Coulaud, Service des Maladies Infectieuses - CHU Bichat Claude

Bernard, Paris ■ Dr Paola de Felici, Communicable Disease Surveillance and Response,WHO, Geneva ■ Dr Alexander

Gromyko,WHO Regional Office for Europe, Copenhagen ■ Dr Vincent Habiyambere,WHO Initiative on HIV/AIDS and

STI, Geneva ■ Dr Scott Hammer, Division of Infectious Diseases - Columbia Presbyterian Medical Center, Columbia

University, New York ■ Dr Elly Katabira,Associate Dean - Makerere University Faculty of Medicine, Kampala ■ Mrs Alison

Katz,WHO Initiative on HIV/AIDS and STI, Geneva ■ Prof. Michel Kazatchkine,Agence Nationale de Rercherche sur le

SIDA, Paris ■ Dr Chaiyos Kunanusont, Department of Communicable Disease Control - Ministry of Public Health,Thailand ■

Dr John Lambert, Glaxo Wellcome Research and Development, Middlesex ■ Dr. Dermot Maher,WHO Stop TB Initiative,

Geneva ■ Dr. David Miller, Department of Policy Strategy and Research, UNAIDS, Geneva ■ Dr. Francis Ndowa,WHO

Initiative on HIV/AIDS and STI, Geneva ■ Dr Jos Perriens, Department of Policy Strategy and Research, UNAIDS, Geneva ■

Dr Gilles Poumerol,WHO Regional Office for the Western Pacific, Manila ■ Prof. Salif Sow, Clinique des Maladies

Infectueuses – CHU de FANN, Dakar ■ Dr Catherine Sozi,The Mildmay Centre, Kampala ■ Dr. Paul Weidle, Division of

HIV/AIDS Prevention, CDC,Atlanta ■ Dr Michael Youle, Royal Free Centre for HIV Medicine, London ■ Mr Winstone

Zulu, Network of Zambian People Living with HIV/AIDS, Lusaka.


ACKNOWLEDGEMENTS

In April 1997,WHO and UNAIDS held anInformal Consultation on the Implications ofAntiretroviral Treatments for HIV/AIDS, with theobjective of providing policy guidance on majorissues relating to the use and provision ofantiretroviral drugs.1 As a follow up activity to thisconsultation, a set of nine Guidance Modules onseveral aspects of antiretroviral treatments wasproduced. 2 Guidance Module number 4, entitledSafe and Effective use of AntiretroviralTherapies, provided guidance primarily toclinicians, counsellors, and managers of clinicalservices. Policy makers, people living withHIV/AIDS (PLHA) and decision-makers innational referral and district hospitals as well astraining institutions have also found this guidancemodule very helpful.The module reflected thepublished standards of care and the consensus ofparticipants at the time of the consultative meetingin 1997.

Treatment guidelines need to be regularly updatedto take into account evolution in knowledge andexperiences from different healthcare settings.There is today a much better understanding of thebiological basis for antiretroviral therapy (ART)and clinical research has provided consistent dataon its effectiveness.The adherence difficulties andadverse effects associated with some of theantiretroviral drug combinations are betterunderstood and regimens that are easier to take are

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1. The Implications of Antiretroviral Treatments.Informal Consultation – April 1997. WHO/ASD/97.2.

2. Guidance Modules on Antiretroviral Treatments. WHO/ASD/98.1; UNAIDS/98.7.

being developed.There is also an increasing bodyof knowledge on the therapeutic implications ofantiretroviral drug resistance.A variety ofinternational treatment guidelines have beendeveloped to keep clinical practice as much aspossible in pace with the data emerging frombasic and clinical research.

Clinical guidance for the use of ART must take intoaccount the profile of patients seeking care as wellas the capacities of the healthcare setting in whichthis care is being delivered. Low and middle-income countries have requestedrecommendations for the provision andmonitoring of ART that are more directly relevantto their resource limited settings than thepublished International Guidelines. In response tothis requirement,WHO in collaboration withUNAIDS and the International Aids Society (IAS)organised a technical consultative meeting, inFebruary 2000.This consultation brought togetherexperts in HIV/AIDS care and HIV clinicalresearch from industrialised countries anddeveloping countries, to analyse available scientificevidence and discuss contextual issues relating tothe safe and effective use of antiretroviral therapiesin resource limited settings.This guide is a resultof the discussions and recommendations of theFebruary 2000 consultation.

In section one, the principles behind current useof antiretroviral drugs for the treatment of HIV-1infection are outlined.This section refers toexisting international recommendations.

INTRODUCTION


Several factors that relate to the profile of patientsseeking HIV care in resource limited countriesmay influence the choice and the outcome ofantiretroviral therapy:

■ the vast majority of patients are currentlytreatment naive because antiretroviral drugs areusually not available through the public sectorand are poorly introduced into private markets.

■ most patients have advanced stage HIV diseaseat the time treatment is initiated because in theabsence of wide spread counselling and testing,diagnosis is often delayed.

■ patients in resource poor countries are morelikely to have co-existing morbidity such asanaemia, malnutrition as well as tuberculosisand other medical conditions, which may act inconcert to affect the choice of therapy and theconsiderations on the potential spectrum ofdrug interactions and drug toxicity.

■ the majority of patients are in a low-incomebracket and because antiretroviral drugs are notusually provided free of charge, financialconstraints are a common cause of treatmentinterruptions and of further delay in initiatingtherapy.


Within many resource limited countries there are“sites of excellence” where small scale ARTprogrammes have been implemented. Nevertheless,inadequacy of healthcare services in terms ofconsistency of supplies and quality assurance oflaboratory support as well as a scarcity of trainedclinicians, are characteristic of most resourcelimited settings. Experiences with the use of ART inthese settings, however, continue to accumulate andthere are important lessons to be drawn from them.

In section two of this guide, some national ARTprogrammes and some pilot initiatives from sixlow and middle income countries are described.

In section three, discussions andrecommendations on the use of antiretroviraldrugs in resource limited settings, for thetreatment of HIV-1 infection, are presented.

The participation of patients in decision-makingprocesses is crucial to the outcome of anytreatment programme. People living withHIV/AIDS (PLHA), from resource limitedcountries participated in this consultation andtheir contributions on adherence issues and on thepsychosocial support needs of patients form animportant element of the contents of this guide.

2

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1.1. BACKGROUNDData published over the last two years in Europe andNorth America, from clinical trials and observationalcohorts, provide convincing evidence of thebeneficial impact of combination antiretroviraltherapy on the morbidity and premature mortalityfrom HIV infection.This benefit is mainly due to areversal of the progressive immune deficiency that ischaracteristic of HIV infection and to effectiverestoration of the immune system’s reactivity to HIVinduced opportunistic infections (OIs).

The course of many OIs has been altered bywidespread use of effective ART. Previouslyuntreatable OIs like cryptosporidiosis and AIDSdefining illnesses like Kaposi’s sarcoma may resolvewithout specific treatment and the clinicalprogression of complicated OIs like cytomegalovirusand atypical mycobacterial infections may be haltedand/or reversed.As an extension of the benefits ofeffective ART, criteria for the discontinuation ofchemoprophylaxis against pneumocystis cariniipneumonia, which in the past was a lifelongintervention, have been introduced into currentpractice guidelines. In time, HIV infection maytherefore be considered as a chronic diseasemanageable over the course many years.

The approach to antiretroviral therapy and thedesign of therapeutic regimens has beeninfluenced by the following key findings fromstudies on the pathogenesis of HIV infection:

■ demonstration that a continuous high-level ofreplication of HIV is present from the earlystages of infection (at least 1010 particles areproduced and destroyed each day)

■ demonstration that a specific immune responseto HIV occurs in HIV infected subjects during“primary” infection but begins to decline afterthe first months of infection.

The strength of this primary immune responsemay be predictive of subsequent concentrations ofHIV in the body as measured by the plasma HIV-RNA or “viral load”.

■ demonstration that the measured concentrationof plasma viral load is predictive of thesubsequent risk of disease progression and death.

■ proof that combination antiretroviral therapy isnot only able to consistently suppress HIVreplication, but also able to induce a significantdelay in progression to AIDS; this survivalbenefit is particularly marked in previouslyuntreated patients.

■ elucidation of the molecular, functional andclinical impact of resistance to antiretroviral drugs.

3

SECTION ONEPRINCIPLES OF ANTIRETROVIRAL THERAPY (ART)*

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* Published guideline documents that are cited in this section:

1. Antiretroviral Therapy in Adults. Updated Recommendations of

the International Aids Society, USA Panel. JAMA, January 19, 2000 –

Vol. 283, N° 3.

2. Guidelines for the use of antiretroviral agents in HIV – infectedadults and adolescents. US Department of Health and Human

Services (DHHS) and Henry J. Kaiser Family Foundation. Issued

January 28 2000 available online at: http://www.hivatis.org/.

3. Guidelines for the prevention of opportunistic infections in personsinfected with HIV. USPHS/IDSA, MMWR 1999; 48 (No. RR-10).

Since ongoing replication of HIV drives the diseaseprocess, causing progressive immunologicaldamage, an ideal target of antiretroviral treatment isto obtain timely and sustained suppression of viralreplication. Many ART regimens that achieve thistarget to some degree have already becomeavailable. Reliable techniques for quantifying HIVin plasma, measured as the amount of HIV-RNA orthe “viral load” are also available and have allowedclinical researchers to compare the relative antiviralpotency of various antiretroviral drug regimens,while providing a rational tool for monitoring theefficacy of ART in clinical practice. Measurement ofthe numbers of CD4+ cells in the blood are areliable indicator of the extent of immunologicaldamage caused by HIV infection and providefurther rationale for clinical decisions onantiretroviral therapy.

While the progress so far has been impressive, thereis a growing appreciation of some of the difficultiesassociated with ART and much work still remains tobe done. Difficulties with adherence to treatment,long-term toxicity and cross-resistance amongantiretroviral drugs have become major drawbacksof current ART strategies. Even with the most potentantiretroviral drug regimens available today, thereexists a proportion of patients who fail to havecomplete and durable virologic responses to therapyfor a myriad of reasons.These shortcomings of thecurrent regimens are particularly evident in patientswhose baseline levels of plasma “viral load” arehigh, who have had extensive prior treatment andin whom the stage of disease is advanced.

1.2. CHARACTERISTICS OF AVAILABLE ANTIRETROVIRAL DRUGS

Currently available antiretroviral drugs belong totwo major classes:

1. Reverse Transcriptase Inhibitors (RTIs)2. Protease Inhibitors (PIs).

followed by multiplication, creating several billionnew copies of HIV per day.The enzyme proteasecontributes to viral reproduction by enabling theassembly and release of viable particles of HIVfrom infected cells.

For optimal efficacy, antiretroviral drugs, usuallyfrom different classes, must be used incombination.A similar approach to therapy isalready established practice in the treatment ofother important long-term diseases such ascancers, tuberculosis and leprosy. Severalcombination regimens with demonstratedeffectiveness in achieving durable suppression ofHIV replication are available.

All available antiretroviral drugs have class-specificadverse effects, which are summarised below. Formore details on drug specific adverse effects, seeAnnex II.

Nucleoside Reverse Transcriptase Inhibitors

(NRTIs) may cause fatty change in the liver, whichis reversible upon stopping the medications, orlactic acidosis, a metabolic complication that ispotentially fatal if unrecognised.These two adverseeffects are due to toxicity of the NRTIs on cellularmitochondria. Changes in body fat distribution aswell as derangements in the metabolism of fats,which are described below, have also beenassociated with the prolonged use of NRTIcontaining regimens.

Protease Inhibitors

(PIs) have been associated with body fatredistribution which manifests physically asthinning of the arms, legs and face and/ordeposition of fat in the abdominal and shoulderregions.A further effect of this class of drugs on themetabolism of fat may result in raised levels ofserum cholesterol and serum triglycerides, in


Reverse Transcriptase Inhibitors are further dividedinto 2 groups:

1.1 Nucleoside Reverse Transcriptase Inhibitors(NRTIs)

1.2 Non-Nucleoside Reverse TranscriptaseInhibitors (NNRTIs).

In most industrialised countries a range ofantiretroviral agents have been approved, licensedand registered for the treatment of HIV.At present,they include:

six NRTIs

zidovudine (AZT, ZDV)didanosine (ddI)zalcitabine (ddC)stavudine (d4T)lamivudine (3TC)abacavir (ABC)

three NNRTIs

nevirapine (NVP)efavirenz (EFV)delavirdine (DLV)

five PIs

saquinavir (SQV)ritonavir (RTV)indinavir (IDV)nelfinavir (NFV)amprenavir (APV)

All these drugs act by blocking the action ofenzymes that are important for replication andfunctioning of HIV. Once HIV invades amacrophage or T-lymphocyte, the enzyme HIVreverse transcriptase initiates copying of the viralgenetic code (RNA) into the genetic code of theinfected host cells (DNA).After this, HIV geneticmaterial is integrated into the host’s DNA.This is

insulin resistance and rarely in increased bloodsugar levels.The overall cumulative incidence ofthese metabolic disturbances may be 30% to 60%after 1 to 2 years of treatment, increasing withduration of therapy.All drugs in this class may causebleeding episodes in patients with hemophilia.

Non-Nucleoside Reverse Transcriptase Inhibitors

All NNRTIs may cause a skin rash.These rashes aregenerally mild and self-limited, though severeforms similar to a Stevens-Johnson syndrome havebeen reported. NNRTIs may also cause elevation ofserum aminotransferases and rare cases of fatalhepatitis have been reported.

1.3. INITIATION OF THERAPY

Earlier hopes that HIV could be eradicated from aninfected individual were based on the erroneousassumption that complete suppression of viralreplication could be achieved using currentlyavailable therapies. It is now known that low-levelreplication of HIV occurs at concentrations ofplasma “viral load” below the limits of detectionby the most sensitive assays in use.The decay half-life of resting memory CD4+ lymphocytes whichharbor latent HIV in ‘sanctuary sites’in the body, isat least 6 months and as long as 44 months. It istherefore estimated that eradication of HIV withART alone would take at least a decade and so thegoal of treatment must now be redirected towardsthe long-term management of a chronic infection.

The ultimate aim of antiretroviral treatment mustbe maximal suppression of HIV replication becausethe major short-term risk of any continuing viralreplication in the presence of antiretroviral drugs,is the emergence of drug resistance.The success ofART is determined more by the patient’scompliance with and adherence to the prescribedregimen than by the specific drug combinationused. Decisions about when to start therapy and

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what regimens to use are crucial because futuretreatment options may be severely compromisedby an initial regimen that is inadequately adheredto or insufficiently potent. Physicians and patientstogether need to weigh the advantages anddisadvantages of starting antiretroviral therapy andmake individualised informed decisions.

Arguments in favour of early initiation ofantiretroviral treatment include:

■ HIV infection almost invariably causesprogressive immune damage

■ disruption of the immune system and thebuilding of viral reservoirs are early events

■ the natural history of untreated HIV infectionincludes selection for more diverse and morevirulent strains of HIV

There is, however, an increasing tendency to deferinitiation of ART until immune deficiencybecomes measurable and the risk of diseaseprogression becomes relevant because:

■ the risk of disease progression is low untilsubstantial CD4+ cell loss has occurred

■ immune recovery is impressive even whentherapy is delayed

■ many patients only achieve incomplete ortransient control of viral replication, resulting inselection for resistant strains of HIV

■ any regimen has toxicity and cost.

According to current published internationalguidelines, the following broad criteria guidethe selection of patients for initiation of therapy:

■ all patients with symptomatic HIV infection,regardless of CD4+ count and “viral load” levels

■ all patients with CD4+ counts below 350/mm3

■ all patients with a high viral load (i.e. above30,000 copies/ml by RT - PCR*)

Combination regimens containing a Protease Inhibitor

PI-containing regimens, (2 NRTIs + 1 PI), havebeen the first choice for initiating ART since 1997and there is sufficient data on their effectivenessover the last two to three years. Protease Inhibitorregimens have proven potency and are effective inpatients at all levels of plasma “viral load.”However, there are important disadvantages thatlimit the acceptability of PI containing regimens:

■ complexity of the regimens makes adherencedifficult

■ cross-resistance between different PIs may limitfuture use if initial therapy fails

■ there is growing concern over the long-termtoxicity of PIs, particularly the fat redistributionand the metabolic abnormalities whose effecton cardiovascular morbidity and mortalityremains uncertain.

Combinations of 2 PIs are increasingly being usedinstead of a single PI because they havepharmacokinetic advantages and possibly increasethe PI regimen’s potency while potentiallyimproving adherence to therapy.Addition of areduced dose of Ritonavir, to Saquinavir, Indinavir orAmprenavir improves the pharmacokinetic profiles,may reduce pill burden, lower the dose frequency,lower cost, and obviate the need foradministration of PIs on an empty stomach.Thelong-term benefit and toxicity of dual PIcombinations remains to be fully characterised.

Combination regimens without a Protease Inhibitor

Combinations between NNRTIs and NRTIs haverecently gained popularity.There is convincingevidence from controlled clinical trials that intreatment-naive patients, NNRTI regimens offer asuitable alternative to PI-containing combinationsin terms of antiviral potency. Besides the advantage


Current guidelines recommend that treatment beconsidered for patients in the intermediate range,i.e. plasma viral load between 10, 000 and 30,000copies/ml (RT-PCR) and CD4+ cell countsbetween 350/mm3 and 500/mm3.

Treatment of asymptomatic patients, with CD4+cell counts above 500 mm3 is generally deferredas long as the probability of significant immunesystem damage and of clinical progression of HIVinfection remains low.

1.3.1. Choice of regimen

Several regimens with acceptable antiviral potencyare available, particularly for patients being treatedfor the first time.These regimens are composed ofthree to four drugs.Two Nucleoside ReverseTranscriptase Inhibitors (NRTIs) generally formthe backbone of most of these combinations.Thechoice of specific NRTI is based on convenience,adverse effects and patient preference.

Possible NRTI combinations (not in preferred order)

■ zidovudine + didanosine,zalcitabine, or lamivudine

■ stavudine + didanosine or lamivudine

Zidovudine and Stavudine should not be used togetherbecause of their antagonistic effect on each other.Similarly, Didanosine and Zalcitabine may lead toadditive neurotoxicity and should not becombined.

of deferring the introduction of PIs, NNRTIcontaining regimens may also allow for a lowerpill burden and for improved adherence.The maindisadvantage of NNRTIs is the ease and rapiditywith which resistance develops to the individualdrugs in this class if they are used in the context ofa regimen that is not maximally suppressive andthe very strong likelihood that cross classresistance will follow. Data on the long-termclinical efficacy of NNRTI containing regimensremains limited.

The use of three NRTIs to “spare” both PIs andNNRTIs has recently been proposed. Most datarefer to the combination of abacavir, zidovudine andlamivudine which has shown durable antiviralactivity (after 48 weeks of treatment), equivalentto that of a “standard” 2NRTI + 1PI regimen(zidovudine/lamivudine/indinavir), in treatment naivepatients.This combination, however, seems to havereduced potency in patients with high baselineplasma viral loads.The main attraction of a 3NRTIregimen is deferral of the use of PIs, while alsosparing the NNRTI and placing only a single classof antiretroviral drugs “at risk” for thedevelopment of resistance. Once again, the long-term efficacy and toxicity of multinucleosideregimens remains unknown and there is concernover the potential possibility of selecting formultinucleoside-resistant variants of HIV.

There is no data at present demonstratingsuperiority of any one of the above acceptablypotent initial regimens over the others andrecommendations for a specific initial regimen orfor a specific combination of individual drugscannot be made.The choice of a particularregimen remains individualised withconsideration given to the strength of supportivedata, the tolerability of the regimen, the potentialfor adverse effects, likely drug-drug interactions,

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* The different techniques used for measuring viral load; reverse

transcriptase polymerase chain reaction (RT-PCR), branched chain

DNA (bDNA) and nucleic- acid sequence based amplification

(NASBA), produce different results that are consistent within the

technique, but different between techniques. The values of viral load

referred to in this document are those of RT-PCR.


Table 2a. HIV-RNA measurements in monitoring antiretroviral therapyHIV-RNA levels that suggest initiation of therapy ■ above 30,000 copies/ml by RT-PCR

Target level of HIV-RNA after initiation of treatment ■ “below the limits of detection”(at present taken as below 50 copies/ml RT-PCR)(< 400 copies/ml may be acceptable in some settings)

Timing of target response ■ “below the limits of detection” within 3 to 4 months of initiating ART(in patients with high baseline HIV-RNA levels, maximal suppression may not be for 6-8 months)

Frequency of HIV-RNA measurements ■ at baseline: 2 measurements 3-4 weeks apart■ within 1 month of starting therapy

to confirm antiviral activity of the regimen■ every 2 months until viral load is below

the limits of detection ■ every 3 to 4 months thereafter together with CD4 count

(shorter intervals before critical decisions on therapy)

Table 1. Summary of currently available initial ART regimens*

Advantages Disadvantages2 NRTIs + 1PISolid clinical data Complexity and high pill burdenLongest experience for viral suppression May compromise future PI regimens

Concerns on long-term toxicity

2 NRTIs + 2PIsHigh potency High pill burden with some regimensLow pill burden Long-term toxicities unknown

2 NRTIs + 1 NNRTILow pill burden Limited long-term dataEqual potency to PI regimens Compromises future NNRTI regimens

3 NRTIsDefers 2 classes (PI, NNRTI) Lower potency in patients with high baseline viral loadLow pill burden Limited long-term data

May compromise future NRTI regimensPotential convergence of mitochondrial toxicity

* Source: Carpenter et al. JAMA, January 19, 2000: 283 (3); 384.

the assays in use, the baseline viral loadmeasurement before initiation of treatment andany measurement thereafter that indicates a viral“rebound” significant enough to warrantconsidering a change in therapy, is routinelyconfirmed by a repeat test.

1.5. TREATMENT FAILURE

The most frequent reasons for changing treatmentare drug toxicity, drug intolerance, difficulties withadherence to theregimen and treatmentfailure i. e. a drugregimen that isproviding insufficientcontrol of viralreplication as indicatedby lack of an adequate and sustained suppression ofplasma HIV-RNA, lack of a satisfactory increase inCD4+ cell count or clinical progression of disease.

In clinical trials, a substantial proportion ofpatients (over 30%) do not achieve viral loadsbelow the limits of detection.This is dependenton many factors such as baseline viral load andCD4+ count, primary acquisition of drugresistant virus, prior antiretroviral treatment,occurrence of adverse events and poor quality ofadherence. In clinical practice, up to one year afterthe initiation of potent combination antiretroviraltherapy, up to 1/3 of patients on ART may have

viral loads above20,000 copies/ml.(RT-PCR)

Failure to reach thevirologic target oftherapy prompts

investigation into probable problems of drugadherence, drug absorption or the presence ofdrug resistant virus.

convenience and likelihood of adherence and thepotential for alternative treatment options shouldan initial combination fail.

1.4. MONITORING

Response to ART is monitored clinically andbiologically.The most important biologicalmeasurements are the concentration of HIV – RNA inplasma (the “viral load”) and CD4+ cell counts.These measurements correlate with clinical outcome.

The desirable “virologic” endpoint is a plasmaviral load that is “below the limits of detection”,by the most sensitive assay being used, within 3 to4 months of starting treatment and theachievement of a minimum decline from thebaseline viral load of 1.5-2.0log by the end of thefirst month of treatment. In patients with higherbaseline plasma viral loads (e.g. above 100,000


copies/ml by RT-PCR) maximal suppression ofviral replication may take a longer time.

When optimal response to therapy is achieved, themedian CD4+ cell rise is 100 – 200 cells withinthe first year.The CD4+ cell response may lagbehind the “virologic” response in timing and attimes the two responses may even be discordant.

The optimal frequency of viral load monitoring isunknown. In general, plasma viral load is checkedwithin 1 month of initiating therapy and two-monthly thereafter until the virologic goal oftherapy, i.e. viral load below the limits ofdetection, is achieved. Following this, plasma viralload may be checked every 3 to 4 months.

Due to possible individual oscillations in theconcentrations of HIV1-RNA and to variability in

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Table 2b. Viral load in treatment failureChanges in HIV-RNA that suggest treatment failure ■ insufficient viral suppression 4-6 months after starting ART■ confirmed return above 400 copies/ml (by RT-PCR)

in a patient with previously undetectable viral load

HIV there is then a continuous selection for the“fittest” virus population.

Sub-optimal ART regimens that allow replicationof HIV to continue in the presence of antiretroviraldrugs, encourage the growth of viral populationsthat are carrying a genetic mutation whichprotects against these drugs. It is likely that manyof these drug resistance mutations already existbefore any antiretroviral drug is introduced andare further encouraged to proliferate under theselective pressure exerted by drug treatment.

Antiretroviral therapy can minimise theemergence of drug resistance in two ways:

■ by maximising and sustaining the suppressionof viral replication

■ by using drugs where multiple mutations arerequired before resistance can occur.

In recent years laboratory testing for antiretroviraldrug resistance has become available raising thepossibility of using resistance testing to guidetherapeutic choices.The testing methods in use,however, are still hampered by technicalcomplexity, poor sensitivity, difficulties ininterpretation and high cost.The place of resistancetesting in every day clinical practice remains to beclearly defined because while it appears useful inpatients experiencing treatment failure, its utility in

The management of treatment failure depends onthe reasons for failure.Where toxicity andintolerance are the main problems, supportivemedication, dosage alteration or substitution ofthe offending drug is reasonable.When adherencedifficulties are responsible for treatment failure,measures aimed at improving the patients’compliance are advised. If poor control of viralreplication has been going on for an extendedperiod of time, the presence of drug resistance islikely and resistance testing may, in this instance,guide the choice of subsequent treatment.

1.6. HIV RESISTANCE TO ANTIRETROVIRAL DRUGS

The high rate of replication that is foundthroughout the course of HIV infection and thevariability of HIV, coupled with the relativeinaccuracy of the enzyme HIV reverse transcriptase, arethe main reasons for the frequent occurrence ofcopying errors in the transcription of viral geneticinformation. HIV replicates at the rate of around108 to 1010 virus particles per day, probably givingrise daily to about 3x10-3 spontaneous changes(mutations) in its genetic sequence.The ultimatesize of a viral population containing a mutation isprobably determined by three concurrent factors:the forward mutation frequency, the replicativecapability of the mutated virus and the “age” ofthe viral population containing the mutation i.e.how long ago this population was generated.Withthe on-going production of genetic variants of

other situations (treatment naive patients, patientswho have failed on multiple regimens or pregnantHIV-positive women) is still under investigation.When performing testing for antiretroviral drugresistance, it is important to ensure that this is donewhile the patient is still on therapy in order tomaximise accuracy.

Cross resistance among the available classes ofantiretroviral drugs is common and is animportant consideration when assessing thepossibility of sequencing (replacing one drugwith another) should it become necessary tochange a therapeutic regimen (Table 3). Cross-resistance implies that a population of virusresistant to one drug in a class is also resistant toother drugs of the same class.This is particularlyliable to occur with the NNRTIs especially if theyare used as part of a regimen that producesincomplete suppression of viral replication.TheNNRTIs in general present a very low “geneticbarrier” to resistance because a single mutation issufficient to produce resistance.

PIs and NRTIs are more robust in this respect sincemultiple mutations are required to conferresistance to drugs in these classes.

1.7. FUTURE APPROACHES TO THERAPY

The seemingly large number of possibleantiretroviral drug combinations is only apparent.Therapeutic options are actually limited by crossreactivity within the currently available classes ofantiretroviral drugs. New drugs with increasedpotency that are safer, easier to take, with morefavourable pharmacologic properties and withactivity against drug-resistant viruses, are needed.Validation of drug resistance testing for use inclinical practice will provide clinicians with ahelpful patient management tool and the choice oftherapy will hopefully be guided by individual

SAFE AND EFFECTIVE USE OF ANTIRETROVIRAL TREATMENTS IN ADULTS SAFE AND EFFECTIVE USE OF ANTIRETROVIRAL TREATMENTS IN ADULTS

resistance profiles, allowing for more effectivetreatment.

It is becoming increasingly evident that the courseand the outcome of HIV infection are mostlydetermined by events that take place during primaryinfection. Future treatment strategies, throughcontrolled studies, will focus on the earlyrecognition and treatment of primary HIV infection.

There is evidence that a specific and effectivecellular immune response to HIV occurs ininfected subjects.This has led to the exploration ofalternative approaches to therapy that would aimat enhancing this host immune response such astherapy with drugs like Interleukin 2 and withcertain HIV-derived immunogens. Studies areongoing to design further strategies of treatmentbased on immunologic intervention.

The example of the “long term non-progressor”(individuals whose HIV infection is effectivelycontrolled by their own specific CD4+ T cellresponse) suggests that enhancing the immuneresponse may lead to a stable equilibrium betweenvirus and host.A similar response is observed inother persistent viral infections such as thosecaused by herpesviruses, where the host’s immunesystem is able to keep a virus silent. One approachto ART that is under investigation is antiretroviraltherapy with structured treatment interruptions.The hope is that intermittent interruptions in ART,by allowing host immunity to be exposed to HIV,may act to augment the duration and the strengthof host immune responses to HIV and thereforeincrease immunologic control of the infection.Additional potential advantages of structuredinterruptions of ART are: reduced toxicity,improved tolerance, greater adherence totreatment and reduced overall cost. Results from afew uncontrolled studies are available which

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Table 3. Cross resistance among available classes of antiretroviral drugs and possibilities of subsequentsequencing of drugs from the same class.

Likelihood of Possibility ofCross-Resistance Sequencing Comments

NNRTIs High No may only have one chancePIs High/Moderate Yes Recommendations about optimal sequencing

cannot be made from ART history aloneNRTIs Moderate/Low Yes Cross resistance may be due to unique

pathways of multi-drug resistance

Experiences with ART in resource limited settingsare a source of important information in terms ofdefining the standards of clinical practice in thosesettings as well as the social and economiccontexts which influence the use of antiretroviraldrugs. National programmes and pilot initiativesfrom six low and middle-income countries aredescribed in the pages that follow.All have invarying ways fulfilled the essential pre-conditions(See section 3.1) for introduction of ARTprogrammes.

2.1. ART COVERAGE

The proportion of people with symptomatic HIVinfection who are receiving ART ranges from smallto insignificant. In Uganda, probably less than 1%of people with HIV related illnesses are receivingART. In Thailand, in 1996, nearly 10% of peopleeligible for treatment were being treated throughthe Ministry of Public Health (MOPH)programme in 58 hospitals, but that proportionhas substantially decreased since then. In Brazil,however, nearly 100,000 out of 530, 000 peoplewith HIV infection are receiving ART following apresidential decree, in November 1996, that accessto antiretroviral drugs be made universallyavailable through the public health system.

2.2. CONTEXT: PUBLIC OR PRIVATE SECTOR, DONOR SUPPORTED AND RESEARCH PROJECTS

With some exceptions such as Brazil, where ART isprovided at no cost within the public healthsector, “ability to pay” is determining access todrugs in many low and middle-income countries.The drugs themselves may be obtained privately

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SECTION TWOSOME EXPERIENCES WITH ART INRESOURCE LIMITED SETTINGS

indicate that the majority of patients seem toexperience a rapid rebound in plasma HIV-RNAduring treatment interruptions as well as a rapiddecline in CD 4+ cell counts.The implications ofthese results and the possibility of boosting HIV-specific immune responses through this approachstill remain controversial and need to be furtherclarified by controlled studies.

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A variety of other approaches to stimulating theimmune system are under investigation.Whileresearch into eradication of HIV also continues, acombination of potent ART with immune-basedtherapies may be the most durable approach toachieving long term containment of HIV replication.

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and medical care as well as related services such aslaboratory monitoring is often provided throughthe private sector.The public/private distinction ishowever blurred by the fact that private patientswho can pay for the drugs are often treated andmonitored in “centres of excellence” (e.g. theteaching hospitals of major cities) whichthemselves are publicly funded.A few patientsreceive drugs at subsidised cost through donorsupported projects such as the UNAIDS DrugAccess Initiative in Ivory Coast. Similarly, inSenegal, less than one hundred patients are beingtreated with antiretroviral drugs, through aninitiative supported by the National Aids ControlProgramme,Agence Nationale de Recherche sur leSIDA – France, Institut de Médecine etd’Epidemiologie Africaine – Paris and Fondationd’Espoir – France.

A minority of PLHA receive free treatmentthrough participation in clinical trials which maybe externally and/or nationally funded.This is thecase in Thailand, where patients are receivingdrugs through the HIV-NAT clinical trialsconducted in 19 hospitals around the country.

2.3. QUALITY OF CARE AND OUTCOMES

Available data suggest that the clinical outcomes oftreatment, in the context of centres of excellence,externally funded projects or clinical trials, arevery similar to those in industrialised countries.From about 1997, HIV care centres in 2 largeBrazilian cities have recorded a significant decreasein the number of AIDS deaths, a reduction in theprevalence of major HIV related opportunistic

infections and an overall decrease in the numberof hospitalisations for HIV related illnesses. In thecontext of unregulated practice, the quality of careand the outcomes of treatment may be differentbut because such situations are difficult toevaluate, there is no information available.

2.4. LABORATORY MONITORING SERVICES

Access to reliable laboratory monitoring is limitedin low and middle-income countries and isconcentrated in the major cities.Within the publichealth system in Brazil, there is a network of 70laboratories with capacity to perform CD4+counts and 56 laboratories with the capacity tomeasure plasma viral load.Elsewhere, the necessity for regular CD4+ cellcounts and estimations of plasma viral load toevaluate the effectiveness of treatment adds to theoverall cost of ART and within the private sector,laboratory monitoring is largely dependent onfinancial resources, so that patients themselves willoften request for less monitoring in order to payfor more drugs.Treatment centres accredited tothe UNAIDS HIV Drug Access Initiative in Uganda,have been able to carry out the required virologicmonitoring of ART through the collaboration andaid of a donor funded research laboratory, whichprovides the tests at no cost to patients, as part ofthe evaluation of that pilot initiative. Similarly,laboratory monitoring has been provided at nocost to patients within the Drug Access Initiative inIvory Coast, while in Thailand, regularimmunologic and virologic monitoring form partof the research protocols for clinical trials.

2.5. SURVEILLANCE FOR DRUG RESISTANCE

Monitoring for resistance is rarely undertaken inany developing country setting but its importanceas a public health responsibility is recognised.Within every ART programme, as for anyantimicrobial treatment, lies a public health


responsibility to protect the future utilisation ofthe drugs by minimising the emergence of drugresistance. Modalities for surveillance of HIV drugresistance are a necessity and though thetechnology is too costly for most resource limitedcountries to afford, there exist innovative ways tostrike a balance between resource constraints andgood clinical/public health practice.To this end,Ivory Coast, Senegal and Uganda have initiatedcollaboration with international laboratories thathave the capacity to carry out monitoring forantiretroviral drug resistance.

2.6. SUPPLY AND DISTRIBUTION OF THE DRUGS

By and large, the entire range of antiretroviraldrugs is available anywhere in the world throughprivate channels.Where resources permit, thesupply may be adequate and consistent.Throughthe public sector, however, and for low-incomepatients, the choice of drugs may be somewhatrestricted.This has implications for decisions suchas when to start therapy, which therapeuticregimens to use, and what to do when treatmentfails. In the context of clinical trials, reliability ofsupply and quality of drugs is relatively wellassured. In the donor-supported projects, despitethe subsidised cost of antiretroviral drugs, it is stillnot unusual for financial constraints to lead tocessation of treatment. In Brazil, a substantial andrapidly increasing proportion of antiretroviraldrugs are being produced in the country withconsiderable cost savings and a positive impact onsustainability of supply.

2.7. INITIATION OF TREATMENT

The majority of patients in low income countriesstart treatment at an advanced stage of HIV diseaseas illustrated by records from some of the treatmentcentres: in one treatment centre in Ivory Coast, 55%of patients were in CDC category 3 (advanceddisease) at the start of treatment, in Senegal this

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proportion was 75%, while 68% of the patients atthe Mildmay centre in Uganda had advanced diseaseat the start of therapy.This is due to a combinationof factors such as late care seeking through fear ordenial, a lack of accessible counselling and testingservices so that many people are unaware of theirHIV infection and the high cost of the drugs whichleads to treatment being deferred.

Initiation of treatment for private patients mayfollow the same criteria as established inindustrialised countries.At the same time, privatesector patients are often advised to save scarceresources and delay initiation of ART until theoccurrence of the first serious HIV related illness.In the context of clinical trials and donor-supported projects, treatment is initiatedaccording to biological criteria determined by in-country technical committees. In Senegal,treatment for symptomatic patients is startedwhen the CD4+ cell count is below 350/mm3 andthe viral load above 10,000 copies/ml, while theeligibility criterion for asymptomatic patients is aviral load above 100, 000 copies/ml. In the publichealth system in Brazil, the recommendation is

that PLHA be treated when CD4+ cell count isbetween 200 and 350 cells/mm3 or if the viralload is over 50,000-copies/ml.

2.8. CHOICE OF THERAPEUTIC REGIMEN

Most of the ART initiatives particularly thoselinked to clinical trials and in the externallyfunded projects have aimed to use the highlypotent three-drug combination therapies i.e.regimens containing a Protease Inhibitor, asrecommended by international guidelines. InBrazil, 55% of patients on ART are on triplecombination therapy as are 43 of 109 patientstreated in one centre in Ivory Coast. Generallyspeaking, however, as the choice and sustainabilityof ART regimens is largely determined by cost,there is widespread use, especially in privatepractice, of dual nucleoside regimens (2 NRTIs)because of simpler monitoring requirements,improved compliance and lower cost.There is alsoa significant amount of use of Hydroxyureacontaining regimens.The implications of thesetherapeutic practices seeking to adapt ARTcombination regimens to the resources of low-income countries are discussed in section 3.4.

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3.1. WHAT SHOULD BE IN PLACE BEFORE INITIATING ART PROGRAMMES*

Due to the high cost of antiretroviral drugs, thecomplexity of the regimens and the need forcareful monitoring, specific services and facilitiesmust be in place before considering theintroduction of ART into any setting.

The following conditions are essential to theintroduction of ART:

■ Assured access to voluntary HIV counsellingand testing (VCT) and institution of follow upcounselling services for ART to ensurecontinued psychosocial support and to enhanceadherence to treatment.

■ Capacity to recognise and appropriately managecommon HIV related illnesses andopportunistic infections.

■ Reliable laboratory monitoring servicesincluding routine haematological andbiochemical tests for the detection of drugtoxicity as well as access to facilities formonitoring the immunologic and virologicparameters of HIV infection.

■ Assurance of an adequate supply of qualitydrugs, including drugs for the treatment ofopportunistic infections and other HIV relatedillnesses.

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SECTION THREEGUIDE TO ART IN RESOURCE LIMITED SETTINGS

Whenever available, the services of a care providerwith counselling skills are invaluable. However, thecounselling and psychosocial support process is anongoing component of ART requiringcontributions from the prescribing physician, thepharmacist, other health workers, family membersand peer support groups of PLHA.An assessmentof psychosocial support needs should be maderight from the start with the intention of assuringthat this will be maintained through out theperiod of therapy.

The issues that need to be addressed duringcounselling may be broadly classified into 5categories: Financial considerations, Druginformation, Emotional support, Issues ofdisclosure and Adherence.

3.2.1. FINANCIAL CONSIDERATIONS

In many developing countries the patient or theirfamily meets the cost of ART.Alternatively, drugs may be obtained as part of aclinical trial; as part of an “expanded access”program; through private sector funding, e.g.employment health insurance; or as a donation. Itis important to discuss how the drugs are going tobe paid for before embarking on treatment sincefinancial constraints are a common reason fordefault from treatment.The importance ofadherence to therapy and the consequences ofintermittent therapy, cessation of therapy or oftaking sub-optimal doses to minimise drug costs,should be candidly discussed with all concerned.

3.2.2. DRUG INFORMATION

Antiretroviral drugs have received a large amountof publicisation in the popular press. Even in low-income countries many people with HIV knowabout antiretroviral drugs and may at times haveunrealistic expectations about the availability andeffects of ART. Counsellors should be equipped to

answer questions on the different ART drugregimens, the requirements for clinical monitoringof ART, the expected results, the possibility oftreatment failure and the criteria for changing orcessation of therapy. Sources of reliable medicalinformation on ART which are patient oriented,should be identified and provided.

The counsellor must inform that ART is not a cure.Elimination of HIV from the body has not beenachieved using the most potent antiretroviralcombination therapies available and even whenHIV viral RNA is not detectable in the plasma,there is still ongoing viral replication.The drugswill therefore need to be taken for an indefiniteperiod of time. It is equally important to conveyan understanding that knowledge on ART is stillevolving and that up to date information about thepositive and the possible negative outcomes oftreatment will constantly be provided.

Some adverse effects such as headache, nausea andminor allergic reactions are common in the firstfew weeks of ART. Counsellors should be aware ofthese and reassure clients that some initial adverseeffects will usually lessen with time while simplesymptomatic remedies can alleviate many of them.The nausea and vomiting that is commonlyexperienced at the onset of treatment withzidovudine, for example should not lead todiscouragement or discontinuation of treatment.Counsellors should at the same time give detailedinformation on the possibility of potentiallyserious adverse effects in the event of which drugtherapy must be discontinued. Examples are thepolyneuritis and hepatitis, which can occur withReverse Transcriptase Inhibitors and the skin rashthat results from a severe hypersensitivity reactionto abacavir. Patients need to know how to recognisethe symptoms of these adverse effects and whereto go for help should they occur.

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SAFE AND EFFECTIVE USE OF ANTIRETROVIRAL TREATMENTS IN ADULTSSAFE AND EFFECTIVE USE OF ANTIRETROVIRAL TREATMENTS IN ADULTS

■ Identification of sufficient resources to pay fortreatments on a long-term basis.

■ Information and training on safe and effectiveuse of antiretroviral drugs for healthprofessionals in a position to prescribe ART.

■ Establishment of reliable regulatorymechanisms against misuse andmisappropriation of antiretroviral drugs.

3.2. COUNSELLING FOR ART

ART may be a lifelong undertaking.A relationshipof confidence needs to be established from theoutset between the patient and the care team. It isimportant that adequate time is set aside forcounselling so that appropriate and informeddecisions on therapy and its implications are madeby the patient, based on information given tothem that is as accurate and as complete aspossible. Many people seeking ART will have hadprior counselling at the time of diagnosis (pre &post-test counselling).The positive messages andfuture plans initiated during pre and post-testcounselling should be reinforced duringcounselling for ART.

ART must not detract from HIV preventionmessages. Even though the aim of treatment is tolower the amount of HIV in the blood, often tolevels below the limits of detection by sensitivelaboratory assays, patients must not concludethat it is no longer necessary to use protectivemeasures to prevent the transmission of HIV.Counsellors should stress that HIV can still betransmitted even while on ART.* ARV Treatments: Planning and Integration into Health Services –

Guidance Module number 3, Guidance Modules on Antiretroviral

Treatments. WHO/ASD/98.1; UNAIDS/98.7

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about their own serostatus? Should their siblingsbe told? Should the school be told?

3.2.5. ADHERENCE TECHNIQUES

Incomplete adherence to the prescribed drugregimen is a major factor that limits theeffectiveness of ART.The drug regimens are complexand the duration of treatment indefinite. In order tomaximise the benefits of treatment immensepersonal discipline and commitment are required ofthe patient. Possible barriers to adherence such asnumber and timing of doses, number and size ofpills, food restrictions and fear of undesirable sideeffects, should be identified and used to designprograms to support adherence.A “drug timetable”is useful and helps patients with their drug-takingschedule. Reassurance concerning the immediateand long-term side effects of the drugs is also veryhelpful and enhances adherence. In addition, thepatient should be given explanations on the varietyof alternatives available in the event that an initialdrug regimen becomes intolerable.

3.3. CLINICAL EVALUATION BEFORE INITIATION OF ART

A detailed clinical evaluation is essential prior toinitiating ART and should aim to:

■ assess the clinical staging of HIV infection■ identify past HIV related illnesses

The presence and types of food in the stomachaffects the absorption of some of the ProteaseInhibitors. Dietary changes will have to be madeand meals will often have to be planned carefullyaround a drug regimen.This can be inconvenientand disrupt family and social life. If family memberscan be involved in discussions about these issues, itwill help them to understand the importance oftiming meals and changing routines.The counsellormay have to take time to work out a “meal and drugtaking time table” that fits in with the client’s andthe family’s life style. Many PLHA may resent theconstraints that taking drugs imposes on their livesand this has to be acknowledged and exploredwhen starting therapy.Asymptomatic PLHA whofeel unable to embark on the strict regime that someregimens will impose on them may do better topostpone treatment and the implications of thisadvice should also be discussed.

3.2.3. EMOTIONAL SUPPORT AND DIFFICULT DECISIONS

Many PLHA commencing ART in developingcountries, experience feelings of guilt, fear,anxiety and isolation because this therapy isextremely costly and not universally available.Many may have partners and/or children who alsorequire treatment and who cannot access it forfinancial reasons and vital family resources may bebeing diverted to buy the medications. Patientsoften know and associate with other PLHA whothemselves are not being treated but who were asource of encouragement and support before thedecision to commence ART.Very often patientsthemselves question the wisdom of commencingantiretroviral therapy at all.Time taken to workthrough these feelings and doubts willsignificantly enhance commitment to therapy.

ART in symptomatic patients often results inremarkable clinical improvement.This


improvement however, is not universal.Furthermore, clinical improvement may beincomplete or short lived particularly in patientswho have had prior antiretroviral treatment orwhen drug resistance or severe adverse effectssupervene.Additionally, in many resource-limitedsettings, treatment is often put off until suchadvanced stages of immune deficiency that theoutcome is less favourable. Counsellors will have tosupport patients through the disappointment oftreatment failure and balance optimism andrealistic caution. Depression and despair arecommon when CD4+ counts do not rise andweight is not gained as had been expected.This isaggravated when the patient is aware of draininghis or her financial resources into a treatment thatmay be viewed as futile.There will also come atime when counsellor and patient will have todiscuss cessation of treatment and end of life issues.

3.2.4. CONFIDENTIALITY AND SHARING HIV STATUS*

The disruption of life style brought about bycomplicated lifelong ART regimens should not beunderestimated. Involving a partner or significantother in treatment counselling will make takingantiretroviral drugs much simpler.The counsellorshould encourage disclosure of HIV status topartners and/or close relatives so that the burdenof the drug-taking schedule can be understoodand shared. Informing sexual partners of thecontinuing risk of HIV transmission, even whileon ART, also ensures that protective action ismaintained. It is however, important to explore thepatient’s own perception of the risks associatedwith disclosure so that reassurance and supportcan be planned against such barriers to disclosureas the fear of rejection, abandonment andviolence; the risk of loosing one’s employment orthe refusal of insurance.Antiretroviral treatment ofchildren presents a special challenge forcounselling on disclosure. Should children be told

■ identify current HIV related illnesses that willrequire treatment

■ identify co-existing medical conditions thatmay influence the choice of therapy

The standard detailed medical history shouldinclude questions on the following:

■ when the diagnosis of HIV infection was first established

■ the current symptoms and concerns of the patient

■ symptoms of all past illnesses and if known thediagnosis and treatment given

■ a history of symptoms of or previous treatmentfor tuberculosis

■ a history of possible contact with tuberculosis■ past symptoms of sexually transmitted

infections■ the possibility of pregnancy in a woman■ social habits and sexual history

The following are important components of thephysical examination:

■ patient’s weight■ skin and lymphnodes:

➔ herpes zoster, Kaposi’s sarcoma, lympadenitis,HIV dermatitis

■ oropharyngeal mucosa➔ candidiasis, Kaposi’s sarcoma, leucoplakia

■ examination of the heart and lungs includingexamination of a Chest x-ray

■ examination of the abdominal systemparticularly for liver and spleen size

■ examination of neurological andmusculoskeletal systems for:➔ mental state,motor or sensory deficits.

■ whenever possible examine the optic fundus➔ retinitis or papilloedema

■ examination of the genital tract

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* Further reading:

1. Counselling for HIV/AIDS A key to caring. WHO/GPA/HCS/95.15.

2. The Implications of Antiretroviral Treatments. Informal

Consultation – April 1997. WHO/ASD/97.2.

3. Safe and Effective Use of Antiretroviral Treatments. Guidance

Module 4; Guidance Modules on Antiretroviral Treatments.

WHO/ASD/98.1; UNAIDS/98.7.

4. Ethical and Societal Issues Relating to AntiretroviralTreatments. Guidance Module 9; Guidance Modules on

Antiretroviral Treatments. WHO/ASD/98.1; UNAIDS/98.7.

5. HIV/AIDS and Human Rights – International guidelines.

OHCHR/UNAIDS; HR/PUB/98/1.

The initial laboratory evaluation should providethe following:

1. confirmation of diagnosis of HIV infection➔ HIV testing should be done or repeated,

particularly where no prior documentation isavailable and especially if the patient isasymptomatic

2. indicators of the patients immune status➔ CD4+ cell counts* are good indicators of

immune function in HIV infection.➔ The total lymphocyte count correlates very

well with CD4 cell counts, particularly inadvanced HIV disease, and can be used as anindicator of immune function.

3. information on the patients baselinehaematological, hepatic and renal function➔ The baseline blood count complete with

examination of a peripheral blood film isnecessary because of the frequent occurrenceof anaemia, neutropenia andthrombocytopenia both as complications ofHIV infection and as adverse effects of ART.

➔ Biochemical tests of liver function are neededto exclude co-existing hepatitis and asbaseline references in case of ART druginduced hepatic toxicity.A complete urineanalysis comprised of a test for glycosuria,proteinuria and careful microscopy of theurine sediment is adequate initial screeningfor baseline renal function.

viral load assay as part of the initial laboratoryevaluation of a patient who is symptomatic.

Some of the first generation viral load assays givefalsely low results of viral load on samples frompatients with subtype A/E infections and do notdetect HIV-1 group O or HIV-2 RNA.The relativeregional prevalence of HIV subtypes shouldtherefore be taken into consideration whenrecommending viral load assays.

3.4. INITIATION OF THERAPY

3.4.1. WHOM TO TREAT

Most countries with ART programmes haveestablished criteria for initiating ART developed bynational technical committees, which balance theneed to extend access to treatment as widely aspossible against the feasibility of ART.

Wherever possible national criteria should bedeveloped by countries themselves.

In resource limited settings, where the conditionsnecessary for the introduction of ART have beenfulfilled, priority for treatment should be given tosymptomatic patients with severe immune damage(i.e. CD 4 count below 200 cells/mm3), because thesepatients are at a high risk for disease progression.

In the event that initial viral load testing isavailable, patients identified to have very highplasma viral loads, (i.e. above 100 000 copies/mlRT-PCR) have a poor prognosis and should also beoffered treatment.

3.4.2. CHOICE OF THE REGIMEN

The use of combinations of antiretroviral agentsaimed at maximal suppression of viral replicationis the standard of care. (see Table 1)


No currently available antiretroviral agent issufficiently potent to provide sustainedsuppression of viral replication on its own.At best,monotherapy yields incomplete viral suppressionfor a very limited duration of time: 0.6 to 0.8log

reduction in the viral load for 6 to 8 months.Thereafter, drug resistance is inevitable and cross-resistance to other antiretroviral agents mayemerge. Monotherapy is therefore notrecommended for the treatment of HIV infection.However, for the specific indication of preventionof mother to child transmission of HIV infection,short course monotherapy is still recommended.

Dual Nucleoside Therapy (2 NRTIs)

Historically, controlled clinical trials comparingdual nucleoside regimens of 2 NRTIs tomonotherapy demonstrated enhanced ‘virologic’efficacy as well as a survival benefit, in patientswith advanced HIV infection (CD4 counts below350 cells/mm3).

Therapy with 2 NRTIs can potentially achieve a1.5log reduction in “viral load”.

Between 1995 and 1997, before the potent three-drug combinations became the standard oftreatment, many PLHA were treated with dualnucleoside regimens.A small proportion ofpatients in industrialised countries are today stillmaintained on 2 NRTIs because this regimen isrelatively well tolerated by the patients and carefulclinical monitoring indicates continuingsuppression of viral replication. It shouldnevertheless be noted that during the ‘era’ of dualnucleoside therapy in industrialised countries,despite some benefits on an individual level, therewas no record of a significant beneficial impact atpopulation level in terms of reduction in HIVrelated mortality.

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* A number of alternative techniques to the convetional cytofluorometry

method of measuring CD4+ cells should be available soon and these

will allow for reduction in the cost of CD4+ cell measurements.

Table 4. Initial laboratory evaluation for ARTEssential lab Desirable Supplementary investigationsinvestigations investigations that may be indicated by symptoms and signsHIV Serology HIV – 1 RNA Histology on skin biopsy/lymph nodesCD4+ counts or

Total lymphocyte count Screening for STIsComplete Blood Count Pregnancy testTests of Liver Function Abdominal ultrasonographyComplete UrinalysisChest X-ray

4. screening for tuberculosis➔ Tuberculosis is the most common OI in HIV

infection in developing countries and must beactively excluded and/or treated. Examinationof a chest X-ray is therefore considered anessential part of initial clinical evaluation.

5. diagnosis of other intercurrent illnesses➔ Several “supplementary” laboratory

investigations, for the diagnosis of HIV relatedor other illnesses that may require treatment,will be indicated by findings from the patient’shistory and physical examination. Examplesare histological examination of skin lesions toconfirm Kaposi’s Sarcoma, aspiration orbiopsy of enlarged lymph nodes and screeningtests for sexually transmitted infections (STIs).This list is by no means exhaustive.

3.3.1. HIV-RNA TESTING

Plasma HIV-1 RNA assays/viral load assays areuseful for indicating the prognosis of HIVinfection, for indicating when asymptomaticpatients should be treated and as a reference forsubsequent monitoring of the virological responseto therapy. In settings where resources are limitedthe availability and the cost of these assays areimportant considerations for the patient.Thoughdesirable, there is no need to routinely perform a

3.5. MONITORING ANTIRETROVIRAL THERAPY*

Patient on ART should be closely followed to assessadherence to therapy as well as tolerance of thetreatment and efficacy of the treatment.At the startof treatment it is advisable for patients to be seenmonthly and once stabilised they can then be seenevery three to four months. More frequent visitsmay certainly be dictated by various intercurrentneeds so follow up plans should be tailored toindividual patient requirements.

3.5.1. Monitoring adherence to ART

PLHA from resource poor countries haveidentified the following as important determinantsof adherence to ART:■ the quality of initial and continuing counselling

resulting in well-informed decisions andcommitment by the patient to start and tomaintain ART.

■ the availability of accessible, knowledgeable andcommitted medical support teams.

■ the assurance of a continued supply ofantiretroviral medications


analogue reverse transcriptase inhibitors (NRTIs)through various possible mechanisms:

■ depletion of host cellular enzymes that areessential for cell replication;

■ repletion of cellular enzymes necessary formetabolising NRTI’s to active form;

■ depletion of numbers of activated lymphocytesvulnerable to HIV infection.

This specific targeting of host rather than viralproteins provides an alternative approach toantiretroviral therapy so that efficacy ofhydroxyurea is not affected by emergence of HIVmutations resistant to NRTIs.The maindisadvantage is that these effects are also exertedon other replicating cells in the host and this is thebasis for the common toxic effects of hydroxyureai.e. reduction in the numbers of circulating bloodcells.The slight increase in antiviral efficacy whenhydroxyurea is added to Didanosine or Stavudine istherefore offset by a significant decrease in theCD4+ cell numbers.This effect can be harmful inpatients with low CD4 counts who also have activeopportunistic infections.There have also beenrecent reports of fatal acute liver insufficiency aswell as pancreatic insufficiency among patientsreceiving a Hydroxyurea + Didanosine regimen.

Much of the evidence for the therapeuticeffectiveness of Hydroxyurea combined withDidanosine and/or Stavudine comes from small studieswith short follow-up periods. Before anyrecommendation can be given, further safety andefficacy data are needed.

At each follow up visit, adherence to the treatmentshould be discussed in depth.

The “drug timetable” which was made at theonset of ART should be revisited to see how this isfunctioning in real life and the patient should beassisted to work through any difficulties they haveencountered. Close co-operation andcommunication between clinicians,pharmacists/dispensers, other counsellors,patients and family are vital. Carers need to remainaware of the issues surrounding individualpatients’ access to ART in order to anticipatedifficulties in adherence and to plan support.

3.5.2. Monitoring tolerance to ART

The causes of any new symptoms or signsdeveloping after the initiation of ART should beidentified whenever possible. New symptoms maybe related to intercurrent illness or due to adverseeffects of antiretroviral drugs. Shortly aftercommencing ART, certain opportunistic infectionsmay become clinically apparent as a result of thesyndrome of immune reactivation, and theseshould be diagnosed and treated.

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Table 5. Advantages and disadvantages of dual nucleoside regimensAdvantages of 2 NRTI Disadvantages of 2 NRTIlow costlower pill burden/better tolerance lower antiviral potencyeasier to monitor emergence of resistance more likely

Experiences from the resource limited countrieswhere dual nucleoside regimens are presentlybeing used indicate that there is some benefitfrom dual nucleoside regimens, but that theseregimens do not achieve or sustain suppression ofHIV replication to the same extent as thethree-drug regimens.

Despite the limitations of dual nucleosideregimens, where a more potent regimen is notavailable: 2NRTIs may be suitable for treatingpatients with advanced HIV disease, who are athigh risk for disease progression (e.g. CD4 countbelow 200 cells/mm3).

Patients with advanced immune suppression oftenhave high levels of HIV activity as measured by theplasma viral load. Because of the limited durationof the clinical and immunological benefits of dualnucleoside therapy and because viral replication isvery likely to continue during dual nucleosidetherapy, every effort should be made to switch thepatient to a maximally suppressive regimen inorder to minimise the progressive accumulation ofdrug resistance mutations.

The place of Hydroxyurea

In many resource limited settings, Hydroxyurea+ Didanosine or Hydroxyurea + Stavudine are occasionallyused in the treatment of HIV because of the lowcost of these combinations. Hydroxyurea has nodirect antiretroviral activity and is not considered asan antiretroviral drug. Hydroxyurea may, however,enhance the antiviral activity of nucleoside

Table 6. Laboratory monitoring for tolerance of ARTAntiretroviral drug class

Protease Laboratory Tests NRTI NNRTI inhibitorEssential to monitor routinely and at baseline: Complete blood count ✓

Urine (glucose, protein, microscopy) ✓ ✓

Necessary when indicated by clinical features:Serum transaminases ✓ ✓ ✓

Serum amylase ✓

Serum creatinine/Urea ✓ ✓

Creatine phosphokinase ✓

Serum triglycerides ✓

Blood glucose ✓

* Further Reading: Laboratory Requirements for the Safe andEffective Use of Antiretrovirals. Guidance Module number 5.

Guidance Modules on Antiretroviral Treatments. WHO/UNAIDS.

WHO/ASD/98.1; UNAIDS/98.7

If new complaints are due to adverse effects ofdrugs, these should be explained to the patient andappropriate measures implemented, be this byadapting the drug regimen, providing symptomatictreatment or giving simple reassurance.

Direct questioning on early symptoms of thedocumented clinically serious adverse effects ofantiretroviral drugs is mandatory, as is systematicphysical and laboratory examination to look forindicative signs. In this way adverse effects likesevere anaemia and neutropenia; polyneuritis;pancreatitis; hepatitis; nephrolithiasis and serioushypersensitivity dermatitis can be detected earlyand remedial actions taken.

Table 6 lists the ancillary laboratory tests thatshould complement patient interview and physicalexamination to monitor for drug toxicity.Thenecessity for these tests will vary according to theantiretroviral drugs being used and to whether ornot tests are indicated by the patient’s symptoms.

3.5.3. Monitoring the efficacy of ART

The efficacy of ART is indicated by clinicalimprovement of the patient and by a favourableresponse of the biological markers of HIV infection,namely CD4+ cell counts and plasma “viral load”.

Some clinical indicators of disease progression andresponse to treatment:

■ a gain in body weight■ increase in total lymphocyte count■ decrease in frequency/severity of opportunistic

infections■ decrease in occurrence/severity of HIV related

malignancies

When interpreting the results of viral load assayscaution is advised for several reasons:

■ viral load levels vary according to the techniquethat has been used, the laboratory where thetest has been done, the time and the way thesample was transferred to the laboratory.

■ viral load levels may be increased after a recentinfection, vaccination or lapse in treatment;

■ certain viral strains that are particularly frequentin developing countries may be difficult todetect with some of the commercially availabletesting methods.

Wherever ART is introduced, a reliable referencelaboratory, where the necessary biologicalmonitoring tests can be assured, should beestablished.

3.6. CONSIDERATIONS OF DRUG INTERACTIONS

The majority of patients presenting for care inresource limited countries have symptomatic HIVinfection and so, in addition to antiretroviralagents, they are likely to be taking othermedications:

■ for the control of HIV/AIDS related symptoms■ for prophylaxis of opportunistic infections■ for treatment of opportunistic infections and

tumours■ for treatment of other coincident infections

Successful ART results in amelioration of manyHIV/AIDS related symptoms and a decreasedlikelihood of opportunistic infections. It may evenbe possible, once immune competence has beenrestored, to discontinue primary prophylaxis forsome of the opportunistic infections.There arenevertheless, numerous possibilities for drug


CD4 lymphocyte counts*

The clinical manifestations of HIV infection aremostly dependent on the levels of CD 4+ cells; theCD4 count.Where viral load assays are not available,a rise in the CD4 count is an acceptable indicationof treatment efficacy. In addition, CD4+ cell levelsare very useful when deciding on the time to startor to stop prophylaxis against certain opportunisticinfections. In patients in whom undetectable viralload levels have been achieved, which indicates thedesired suppression of retroviral activity, a medianincrease in CD4+ cells of about 100-200 cells peryear may be expected.The magnitude of thisincrease in CD4+ cells will depend on the baselineCD4 count as well as other factors which influencethe outcome of ART. It is worth noting thatfollowing initiation of therapy, the “CD4 response”as evidenced by rising CD4+ cell counts, is muchslower than the “viral load response” and may takeseveral months to years to be complete.A reasonablefrequency of CD4 count measurements in patientson ART is every 3-6 months.

Plasma HIV-1 RNA assay or “viral load”*

The plasma viral load is a measure of HIVreplication and the suppression of viral replicationis one of the primary goals of antiretroviraltherapy. Sustained suppression of HIV replicationis not only an indication of the efficacy oftreatment but also may delay or prevent theemergence of drug resistance. It is advisable tomeasure viral load shortly after initiating ART i.e.within 1 to 3 months, as a check on theeffectiveness of the therapy. It also becomesnecessary to measure the viral load when theresponse to therapy, as shown by the otherindicators, is unfavourable and whenever a changein the therapeutic regimen is contemplated.

interactions of which clinicians need to be aware.Drug interactions are of clinical importance if theyincrease the likelihood of drug toxicity or if theydecrease the therapeutic effectiveness of anadministered drug.The longer the duration of anydrug therapy, the more significant this becomes.In the context of ART clinically importantinteractions are likely:

■ between the different antiretroviral drugs thatare prescribed

■ between prescribed drugs and alternative ornon-prescription medications,

■ between drugs and food (see section 3.2.2)■ with certain “recreational” drugs

A detailed synopsis of all possible druginteractions is beyond the scope of thispublication and only a few important examplesare cited on the following pages.There exist several sources of information onpotential drug interactions, particularly whereaccess to the Internet is available and these are wellworth referring to.*

3.6.1. ANTIRETROVIRAL DRUGS ANDTHE TREATMENT OF TUBERCULOSIS

The Rifamycin antibiotics (Rifampin & Rifabutin)stimulate the activity of the enzyme system in theliver (cytochrome P450) that metabolises ProteaseInhibitors (PIs) and Non Nucleoside ReverseTranscriptase Inhibitors (NNRTIs).This can lead toa reduction in the blood levels of the PIs and theNNRTIs. Conversely, PIs and NNRTIs may alsoenhance or inhibit this same enzyme system,although to individually different extents, and can

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* Some sources of comprehensive drug interaction information

available through the Internet:

American Foundation for AIDS Research (AMFAR) Treatment Directory: http://www.amfar.org

Medscape HIV/AIDS Resources: http://www.medscape.com

* Further Reading: Laboratory Requirements for the Safe andEffective Use of Antiretrovirals. Guidance Module number 5.

Guidance Modules on Antiretroviral Treatments. WHO/UNAIDS.

WHO/ASD/98.1; UNAIDS/98.7

lead to altered blood levels of the Rifamycinantibiotics.The potential drug to drug interactionsmay result in ineffectiveness of the antiretroviraldrugs, to innefective treatment of tuberculosis orto an increased risk of drug toxicity.

It is worth noting that:

■ Rifabutin, can be used with all PIs (exceptSaquinavir) and with all NNRTIs(except Delavirdine), although dosage adjustmentsare sometimes necessary.

■ Isoniazid, which is recommended for thepreventive therapy of tuberculosis, is free fromany interactive effect with PIs and NNRTIs.

■ The Nucleoside Reverse Transcriptase Inhibitors(NRTIs) are not metabolised by the cytochromeP450 enzyme system and are free frominteraction with either of the Rifamycinantibiotics.

Tuberculosis is an important public healthproblem in many resource-limited countries andalso a common “opportunistic infection” in HIVinfected individuals.

With time, as the use of antiretroviral drugsincreases, it is likely that the concurrent treatmentof these two infections will become more frequent.

It has been suggested that in resource limitedsettings, patients with active tuberculosis shouldnot commence ART until chemotherapy fortuberculosis has been completed.While thiswould greatly simplify treatment regimens andenhance adherence, the effects of this approach onthe overall outcomes of treatment have not beenfully evaluated and further research is needed.

Zidovudine. In these situations, careful monitoring ofhaematologic indices is necessary.

Dapsone, may lead to additive neurotoxicity whenused together with Stavudine,Zalcitabine,and Didanosine.

The antifungal agents Ketoconazole and Fluconazole mayinhibit the metabolism of Protease Inhibitors andthe resultant increase in the serum levels of PIs,increases the risk of toxicity.

3.7. FURTHER RESEARCH NEEDS

Research is vital to inform future treatment andcare decisions as well as for the advancement ofscientific knowledge.To date there has been apaucity of controlled clinical trials in low andmiddle-income countries. However someprogrammes such as HIV-NAT in Thailand andHIV-NET in South Africa have paved the way forsuccessful needs based research applicable to localrequirements.This has been achieved throughinteraction between local researchers,governments and international funding andresearch agencies. Such partnerships for clinicalresearch not only provide locally applicableevidence for treatment strategies but also buildresearch capacity in low and middle-incomecountries.

It is vital to ask appropriate research questions thatwill have an impact locally but which could alsobe applicable to other settings. Most treatmentadvances will have initially been evaluated duringthe licensing process in industrialised countries.Whilst not aiming at duplicating research, anevidence base for local application of ARTinterventions must be developed for resourcelimited settings.

A vast amount of medical research is underwayworldwide in the field of HIV. Researchers have a


duty to establish that their studies are notunnecessarily repetitive, ask appropriate questionsand do not unduly raise expectations in advance offavourable findings.The establishment of localresearch committees and a Data and SafetyMonitoring Board for individual studies can helpto maintain transparency and probity of theresearch process.

All research conducted must adhere to the ethicalguidelines which exist in individual countries andwhich reflect those established by Internationalregulatory authorities.

Suitable topics for research could be:

■ Research in supportive medication andprocesses related to medication

■ Alternative therapies including traditionalapproaches to care and treatment

■ Assessment of cost-effectiveness of noveltreatment strategies using antiretrovirals,particularly those investigating simplifiedregimens, new induction-maintenanceregimens and pulsed/cycled antiretroviraltherapy.

■ Treatment and monitoring strategies adapted toresource limited settings.

■ Research related to treatments which have notbeen studied in the populations in which theywill be used

■ Research on utility of treatments against localviral strains and HIV-2

3.8. INFORMATION AND TRAINING NEEDS

Quality information is the basis of good decisionmaking in health care provision, and in-servicetraining or continuing medical education forhealth personnel ensures that standards of goodclinical practice are maintained. Even whenantiretroviral drugs are not yet directly available or

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* Clinical experience and pharmacokinetic data on these combinations

are still limited.

1 Treatment of Tuberculosis: Guidelines for National Programmes.World Health Organisation. 2nd Edition 1997.

2 Safe and effective use of antiretrovirals. Module 4, Guidance

Modules on Antiretroviral Treatments. World Health Organisation.

WHO/ASD/98.13 Updated Guidelines for the Use of Rifabutin or Rifampin for the

Treatment and Prevention of Tuberculosis Among HIV-InfectedPatients Taking Protease Inhibitors or Nonnucleoside ReverseTranscriptase Inhibitors. MMWR March 10, 2000/49 (9); 185-9

In general, the treatment of tuberculsosis should bein accordance with the recommendations of theNational Tuberculosis Programme in each country.1

Since Rifabutin is often not available in resourcelimited countries, the following are possibleoptions for the treatment of tuberculosis inpatients receiving ART, which are drawn frompublished guidelines.2,3

Possible options for ART in patients with active Tuberculosis (TB)

■ Defer ART until TB treatment is completed■ Defer ART until ‘the continuation phase’ of

treatment for TB and use Ethambutol + Isoniazid ascontinuation.

■ Treat TB with Rifampin containing regimen anduse Ritonavir + 2 NRTIs*

■ Treat TB with Rifampin containing regimen anduse Ritonavir/Saquinavir + 2 NRTIs*

■ Treat TB with Rifampin containing regimen anduse Efavirenz + 2 NRTIs*

■ Treat TB with Rifampin containing regimen anduse a 2 NRTIs regimen, then change tomaximally suppressive ART once TB treatment iscompleted.

3.6.2. INTERACTIONS WITH DRUGS COMMONLYUSED FOR THE PREVENTION AND TREATMENT OF OIs

Trimethoprim/Sulfamethoxazole, Ganciclovir andHydroxyurea can potentially cause additivehaematologic toxicity when given together with

Dr Eba Francois AoussiService de Maladies infecteuses etTropicales, CHU TreichvilleS/c Projet RETROCI08 B.P. 1737Abidjan 08, Côte d’IvoireTel: 225 25 41 89/225 25 44 67Fax: 00 225 41 32 51

Dr Roberto BadaroChief of Infectious DiseasesHospital Edgard Santos, Rua Joao DasCanela CEP40110-160 Salvador, BrazilTel: 55 71 2354901Fax: 55 71 3396207E-mail: [email protected]

Dr Rachel Baggaley77 Ridgemount GardensLondon WE1E 71Y, United KingdomTel: 44 171 6375778Fax: 44 171 4364230E-mail: [email protected]

Professor Bill CameronThe Wellcome Trust Centre forEpidemiology of Infectious DiseaseUniversity of OxfordSouth Parks RoadOxford, OX1 3FY, United KingdomTel: 44 1865 281 887Fax: 44 1865 281 245E-mail: [email protected]

Dr Hilde CarlierMedical DepartmentG.C.V. Böhrinder IngelheimCoordination Center,Vesalius Science ParkAvenue Ariane 161200 Brussels, BelgiumTel: 32 2 7733446Fax: 32 2 7733446E-mail: [email protected]

Professor Robert ColebundersDepartment of Clinical SciencesInstitute of Tropical MedicineNationalestraat 1552000 Antwerp, BelgiumTel: 32 3 247 64 26Fax: 32 3 247 64 32,E-mail: [email protected]

Professor Jean-Pierre CoulaudService des Maladies Infectieuses,CHU Bichat Claude Bernard46, rue Henri Huchard75018 Paris, FranceTel: 33 1 4025 7806Fax: +33 1 4229 5300,E-mail: [email protected]

Dr Vinodh GathiramUniversity of NatalFaculty of MedicineP. Bag X7Congella 4013, South AfricaTel: 27 31 2604238Fax: 27 31 2604420,E-mail:[email protected]/[email protected]

Dr Elly KatabiraHead, Dept. of MedicineMakerere University,Mulago HospitalP.O. Box 8933Kampala, UgandaTel:256 41 530188/541188Fax: 256 41 530022/540 718E-mail: [email protected]

Dr Chaiyos KunanusontAIDS DivisionDepartment of CommunicableDisease Control,Ministry of Public HealthTiwanond RoadNonthaburi 11000, ThailandTel:66 2 590 3218/590 3201Fax: 66 2 591 841E-mail: [email protected]

Dr John LambertSenior Research PhysicianGlaxo Wellcome Research and DevelopmentGreenford Road, GreenfordMiddlesex UB6 ONN, United KingdomTel: 44 181 966 4511Fax: 44 181 966 2087,E-mail: [email protected]

Dr Jean-Elie MalkinChef de Service des MSTInstitut Alfred Fournier25 Boulevard Saint-Jacques75680 Paris Cédex 14, FranceTel: 33 1 4078 2670Fax: 33 1 4589 7405,E-mail: [email protected]

Dr Papa Salif SowClinique des Maladies Infectueuses,CHU de FANNP.O. 5035Dakar, SenegalTel: 221 825 2547/8247092Fax: 221 825 369E-mail: [email protected]

Dr Catherine SoziDirector of Clinical ServicesThe Mildmay Centre,P.O. Box 24985Kampala, UgandaTel: 256 41 200862/5/7Fax: 256 41 200861,E-mail: [email protected]

Dr Stefano VellaNational HIV/AIDS Clinical Research Program,Istituto Superiore di SanitàViale Regina Elena 29900161 Rome, ItalyTel: 39 06 4938 7214

39 06 4990 3230Fax: 39 06 4990 2012,E-mail: [email protected]

Dr Mark A. WainbergMcGill University AIDS Centre,Jewish General Hospital3755 Chemin Côté-Ste-CatherineMontrealQuebec HST 1E2, CanadaTel: 1 514 340 7536Fax: 1 514 340 7537,E-mail: [email protected]

Dr. Paul WeidleSenior Staff EpidemiologistDivision of HIV/AIDS Prevention,National Center for HIVSTD and TB PreventionCenters for Disease Control1600 Clifton Road MS E-45Atlanta, GA 30333, USATel: +1 404 639 6155Fax: +1 404 639 6127E-mail: [email protected]

Ms Beatrice WereNational Community of Women Living with HIV/AIDS in Uganda (NACWOLA)P.O. Box 4485Kampala, UgandaTel:/Fax: 256 41 269694E-mail: [email protected]

Dr Michael YouleDirector HIV Clinical ResearchRoyal Free Centre for HIV Medicine,Royal Free HospitalPond StreetLondon NW3 2QG, United KingdomTel: 44 171 830 2589Fax: 44 171 830 22 01,E-mail: [email protected]

Mr Winstone ZuluNetwork of Zambian People Livingwith HIV/AIDS,P.O. Box 32717LusakaZambiaTel: 260 1 223152Fax: 260 1 223191/229849,E-mail: [email protected]

29

TECHNICAL CONSULTATIVE MEETING TO REVIEW AND UPDATE GUIDANCE ON SAFE AND EFFECTIVE USE OF ANTIRETROVIRAL TREATMENTS

WHO HEADQUARTERS, GENEVA15-17 FEBRUARY 2000

LIST OF PARTICIPANTS

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affordable by the health systems or patients, theattention generated by these drugs in the media issuch that carers need to be equipped withregularly updated information that is technicallysound and regularly updated.Information needs to be at a level appropriate forthe user and in suitable language.The targeted populations should include:Decision-makers, Health-care professionals inboth public and private sectors, Patients, Familyand carers and the General Public.

The World Health Organisation Initiative on HIV/AIDS and STI20 Avenue AppiaCH-1211 Geneva 27Switzerland.Fax: 41 22 791 4834Web site: http://www.who.int/asd

UNAIDS Documentation Centre20 Avenue AppiaCH-1211 Geneva 27Switzerland.Web site: http://www.unaids.org

SOME SOURCES OF INFORMATION FOR TRAINING:


Every HIV care centre accredited or regulated toprovide and monitor ART should therefore designan information and training plan as an integralpart of the treatment programme.This represents acost-effective intervention in its own right andtraining programmes on comprehensive clinicalcare of HIV, including ART, should be initiated atcountry level and tailored to local needs.

Enhancing Care InitiativeHarvard AIDS Institute651 Huntington AvenueBoston, MA 02115USAWeb site: http://www.eci.harvard.edu

SHARE Educational ProgrammeInternational AIDS Society (IAS)Rome BranchVia dei Sabelli 19500185 RomeItalyFax: 39 06 4461400E-mail: [email protected] site: http://www.ias-share.org

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WHO REGIONAL ADVISORS

Dr J.-Agness Soumahoroc/o Regional Adviser, a.i.HIV/AIDS/STIWHO Regional Office for Africac/o WHO RepresentativeLomé, TogoTel: 228 22 34 62/22 46 52Fax: 228 22 54 12E-mail [email protected]

Dr Jihane TawlahRegional Adviser STD,WHO Regional Office for the Eastern MediterraneanAlexandria, EgyptTel: 203 482 0223/4203 483 0090/6/7/8Fax: 203 483 8916/4824329E-mail: [email protected]

Dr Alexander GromykoConsultantWHO Regional Office for EuropeCopenhagen, DenmarkTel: 45 39 17 17 17Fax: 45 39 17 18 18/45 39 17 18 75,E-mail: [email protected]

Dr Gilles PoumerolRegional Adviser STD,WHO Regional Office for the Western PacificManila, PhilippinesTel: 63 2 528 8001Fax: 64 2 521 1036/526 0279E-mail: [email protected]

or [email protected]

WHO HEADQUARTERS

Dr Paola de FeliciInfective Surveillance and ResponseCommunicable Disease Surveillance and ResponseTel: 41 22 791 34 92Fax: 41 22 791 48 78,E-mail: [email protected]

Mrs Alison KatzInitiative on HIV/AIDS and SexuallyTransmitted InfectionsTel: 41 22 791 12984Fax: 41 22 791 48 34,E-mail: [email protected]

Dr Dan MakutoFamily and Community HealthTel: 41 22 791 2520Fax 41 22 791 48 30E-mail: [email protected]

Dr Paula MunderiInitiative on HIV/AIDS and SexuallyTransmitted InfectionsTel: 41 22 791 42 28Fax 41 22 791 48 34E-mail: [email protected]

Dr Eric van PraagInitiative on HIV/AIDS and SexuallyTransmitted InfectionsTel: 41 22 791 45 64Fax 41 22 791 48 34E-mail: [email protected]

UNAIDS SECRETARIAT

Mrs. Noerine KaleebaCare and Support TeamDepartment of Policy Strategy and ResearchTel: 41 22 791 46 01Fax 41 22 791 47 41E-mail: [email protected]

Mr. Salvatore NiyonzimaCare and Support TeamDepartment of Policy Strategy and ResearchTel: 41 22 791 44 48Fax 41 22 791 47 41/47 46E-mail: [email protected]

Dr Joseph PerriensCare and Support TeamDepartment of Policy Strategy and ResearchTel: 41 22 791 44 56Fax 41 22 791 47 41/47 46E-mail: [email protected]

Dr Badara SambCare and Support TeamDepartment of Policy Strategy and ResearchTel: 41 22 791 44 52Fax 41 22 791 47 41/47 46E-mail: [email protected]

Generic name

Other name Special instructions Adverse effects Adverse effects

(Trade name®) Recommended dosage Precautions minor, frequent serious, dose limiting

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORSZidovudine 300 mg (1 tablet) bid caution in: initial nausea anaemiaZDV; AZT ■ liver or renal insufficiency headache neutropenia(Retrovir®) ■ pre-existing anaemia fatigue lactic acidosis

muscle painsDidanosine* 200 mg (2 tablets) bid ■ to increase oral bioavailabity take neuropathy pancreatitisddI weight below 60 kg: 100mg bid 1 hour before or after food nausea lactic acidosis(Videx®) ■ contains antacid, affects diarrhea

absorption of other drugsZalcitabine* 0.75 mg (1 tablet) tid neuropathy pancreatitisddC weight below 40 kg: 0.375 mg tid oral ulcers lactic acidosis(Hivid®)Stavudine* 40 mg (1 capsule) bid caution in liver insufficiency neuropathy lactic acidosisd4T weight below 60 kg.: 30 mg bid(Zerit®)Lamivudine 150 mg (1 tablet) bid generally well tolerated lactic acidosis(3TC)(Epivir®)Lamivudine 1 tablet bid caution in: initial nausea anaemia+ Zidovudine ■ liver or renal insufficiency headache neutropenia(Combivir®) ■ pre-existing anaemia fatigue lactic acidosis

muscle pains Abacavir 300 mg (1 tablet) bid caution in: nausea hypersensitivity reaction(Ziagen®) ■ liver or renal insufficiency poor appetite lactic acidosis

vomitingdiscontinue use fatigue if symptoms of hypersensitivity occur sleep disturbance

NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORSNevirapine 200 mg (1 tablet) caution in liver disease skin rash hepatitis(Viramune®) once a day, for 14 days; abnormal liver function tests

followed by 200 mg bidDelavirdine 400 mg (4 tablets) tid caution in liver disease skin rash hepatitis(Rescriptor®) headaches

abnormal liver function testsEfavirenz 600 mg (3 capsules), caution in liver disease skin rash hepatitis(Sustiva®) once a day neuropsychiatric disturbances

abonrmal liver function testsPROTEASE INHIBITORSSaquinavir** 600 mg (3 capsules) tid ■ take with high fat meal diarrhoea hypreglycaemiahard gel capsule to aid absorption nausea lypodystrophy(Invirase®) ■ caution in liver disease abnormal liver function tests abnormal bleedingSaquinavir* 1600 mg (8 capsules) bid ■ take with high fat meal diarrhoea hypreglycaemiahard gel capsule or 1200 mg (6 capsules) tid ■ refrigeration for nausea lypodystrophy(Fortovase®) long term storage abnormal liver function tests abnormal bleeding

■ caution in liver diseaseRitonavir 600 mg (6 capsules) bid ■ capsules require refrigeration nausea hyperglycaemia(Norvir®) (begin with 300 mg bid ■ easier tolerated if diarrhoea lypodistrophy

and escalate over 10 days) taken with food weakness abnormal bleedingskin sensitivity perioral tingling and numbness change in taste

Indinavir 800 mg (2 capsules) tid ■ take on an empty stomach nausea kidney stones(Crixivan®) ■ drink 1.5 litres of liquid per day . pain in belly hyperglycaemia

to avoid kidney problems headache lypodistrophy■ report any loin pain or abnormal bleedingblood in urine

Nelfinavir 750 mg (3 tablets) tid ■ to be taken with food diarrhoea hyperglycaemia(Viracept®) or 1250 mg (5 tablets) bid nausea lypodistrophy

flatulence abnormal bleedingskin rash

Amprenavir 1200 mg (8 capsules) bid ■ decreased absorption nausea hypersensitivity rash(Agenerase®) if taken with fatty meal vomiting

diarrhoea perioral numbnessaltered tastemood disorders

* Dosage adjustments necessary for patients with reduced body weight (bwt)**Saquinavir is available in two formulations, a hard-gel capsule (Invirase) and a soft-gel capsule (Fortovase). Saquinavir as the hard-gel capsule is poorly absorbed and is generally recommended for use in

combination with ritonavir that enhances its bioavailablility through a drug-drug interaction. Saquinavir as the soft-gel capsule is better absorbed and may be used with or without ritonavir.

ANNEX II. SAFE AND EFFECTIVE USE OF ANTIRETROVIRAL TREATMENTS IN ADULTS

World Health OrganizationInitiative on HIV/AIDS and Sexually Transmitted Infections

safe and effective

use of antiretroviraltreatments in adultswith particular references to resource limited settings


For orders, contact :

World Health Organization, Distribution and Sales

20 Avenue Appia , CH-1211 Geneva 27, Switzerland

Phone: +41 22 791 2476

Direct fax: +41 22 791 4857


UNAIDS Information centre

20 Avenue Appia, CH-1211 Geneva 27, Switzerland

Tel : + 41 22 791 4651

Fax: + 41 22 791 4187


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