WHO COnsultatiOn On aRt FailuRe in tHe COntext OF PubliC … · 6 WHO COnsultatiOn On aRt FailuRe in tHe COntext OF PubliC HealtH aPPROaCH The meeting also emphasized the need to

WHO COnsultatiOn On aRt FailuRe in tHe COntext

OF PubliC HealtH aPPROaCH

Geneva, 26-27 February, 2008 Montreux, Switzerland

Meeting Report

WHO Library Cataloguing-in-Publication Data

Towards universal access : scaling up priority HIV/AIDS interventions in the health sector : progress report, April 2007.

“World Health Organization, UNAIDS, UNICEF”.

1.Acquired immunodeficiency syndrome - prevention and control. 2.HIV infections - prevention and control. 3.Acquired immunodeficiency syndrome – therapy. 4.HIV infections – therapy. 5.Health services accessibility. 6.Antiretroviral therapy, Highly active. 7.Disease transmission, Vertical - prevention and control. I.World Health Organization. II.UNAIDS. III.UNICEF.

ISBN 978 92 4 159539 1 (NLM classification: WC 503.6)

© World Health Organization 2007

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3

COntents

1. Acronyms and abbreviations .......................................................................................................................... 3

2. Executive summary ......................................................................................................................................... 4

3. Background ...................................................................................................................................................... 6

3.1 Summary of plenary sessions ............................................................................................................... 6

3.1.1 Section 1: ART switching in the context of the public health approach ...................................... 6

3.1.2 Section 2: Defi nitions of ART failure and consequences of switch strategies ............................ 9

3.1.3 Section 3: Real and modelled outcomes of ART switch strategies and cost analysis .............. 14

3.1.4 Section 4: Programme experiences ......................................................................................... 22

3.2 Summary of expert group recommendations ...................................................................................... 25

3.2.1 Programmatic considerations .................................................................................................. 25

3.2.2 Goals of antiretroviral therapy .................................................................................................. 26

3.2.3 Managing determinants of ART failure ..................................................................................... 26

3.2.4 “Early” versus “late” ART switch approaches ........................................................................... 28

3.2.5 Defi nitions of ART failure .......................................................................................................... 29

3.2.6 Clinical criteria for ART failure .................................................................................................. 29

3.2.7 Immunological criteria for ART failure....................................................................................... 30

3.2.8 Virological criteria for ART failure ............................................................................................. 30

3.2.9 Threshold level of viremia .......................................................................................................... 31

4. Appendix .......................................................................................................................................................... 32

4.1 Appendix 1: National guidelines: aims and defi nitions of ART failure .................................................. 32

4.2 Appendix 2: Immunological and clinical consequences of persistent viraemia .................................. 34

4.3 Appendix 3: Drug resistance and viraemia ........................................................................................... 37

4.4 Appendix 4: Discordance of CD4 and virological failure ...................................................................... 39

4.5 Appendix 5: Indications for ART switch ................................................................................................. 41

4.6 Appendix 6: Recommendations for research ........................................................................................ 42

4.7 Appendix 7: Meeting agenda ............................................................................................................... 43

4.8 Appendix 8: List of participants ........................................................................................................... 46

5. References ..................................................................................................................................................... 48

4 WHO COnsultatiOn On aRt FailuRe in tHe COntext OF PubliC HealtH aPPROaCH

ABC abacavir

ACTG American Clinical Trials Group

ART antiretroviral therapy

AZT zidovudine

BHIVA British HIV Association

CHIC Collaborative HIV Cohort Study (UK)

D4T stavudine

DALY disability adjusted life years

DART Development of Antiretroviral Therapy in Africa

DDI didanosine

DHHS Department of Health and Human Services (USA)

DRV/r darunavir and low dose ritonavir

EACS European AIDS Clinical Society

EPTB extra-pulmonary TB

FDO future drug options

FIRST Flexible Initial Retrovirus Suppressive Therapies (study)

GRADE Grading of Recommendations Assessment, Development and Evaluation

HBAC Home –Based AIDS Care Study

ICER incremental cost -effectiveness ratio

IRIS immune reconstitution infl ammatory syndrome

LIC lower income country

LPV/r lopinavir and low dose ritonavir

MDR HIV multi-drug resistant HIV

MTCT mother to child transmission

MSF Médecins sans Frontières

NRTI nucleoside/nucleotide reverse transcriptase inhibitor

NNRTI non-nucleoside reverse transcriptase inhibitor

NVP nevirapine

OI opportunistic infection

PEPFAR President’s Emergency Plan for AIDS Relief

PI protease inhibitor

PMTCT prevention of mother to child transmission

PLATO Pursuing Later Treatment Options (study)

PY person years

QALY quality adjusted life year

RCT randomised controlled trial

SACEP State AIDS Clinical Expert Panel (India)

SAHCS Southern African HIV Clinician’s Society

SCOPE Observational Study of the Consequences of the Protease Inhibitor Era

SMART Strategies for Management of HIV Therapy

STI structured treatment interruption

TAMs thymidine analogue mutations

TDF tenofovir

TB tuberculosis

UNITAID United to Aid International Drug Purchase Facility

VL viral load

VCT voluntary counselling and testing

WHO World Health Organisation

3TC lamivudine

1. aCROnYMs anD abbReViatiOns

WHO COnsultatiOn On aRt FailuRe in tHe COntext OF PubliC HealtH aPPROaCH 5

Introduction

Anti-retroviral therapy rollout has led to an increased number of patients on ART, with more than 3 million people now being treated. Key to this progress has been the public health approach, which is based on standardized simplifi ed protocols that can be provided to the entire affected population and that aims to avoid mortality and morbidity and improve the quality of life for the most people possible. This creates a standard fi rst line regimens, which is “switched” to a standard second line regimens at treatment failure. Universal access to ART includes access second line therapy, and as programmes expand, the need for second line therapy will increase. Guidance on which ARVs to use second line therapy has recently been published by the WHO, and although it is 5-10 times more expensive, it is now becoming accessible. The 2006 WHO treatment guidelines include recommendations for switching to second line therapy. However additional clarifi cation on when to switch ART is requested.

There is a need to ensure that WHO recommendations can be applied in settings where there is a large range of laboratory capacity, formulary availability and healthcare infrastructure and human resources. Common goals that translate across such differing systems and capacities are required but also need to anticipate ART programme development. Countries are investing in laboratory infrastructure, and technological improvements mean of point of care CD4 and viral load testing will become increasingly available in the near future.

Clear defi nitions of fi rst line ART failure are required to support implementation of switch strategies. There are currently 3 different domains for failure recognized: clinical, immunological, and virological. However, it has been challenging to combine these 3 domains for defi nitions of failure in guidelines with simplicity and clarity that apply in all situations. Clinical and immunological failure is not always associated with virological failure, and has low sensitivity and specifi city for viral replication irrespective of described thresholds (eg < 50 copies, < 1000 copies or >10,000 copies). Using clinical and immunological criteria as treatment endpoints also means patients may continue on therapy with viral replication of unknown quantity and unknown duration. Conversely, ART regimen switches based on immunological or clinical failure defi nitions can be made when the patient is still virologically suppressed, losing drug options prematurely. Late treatment switch may however not lead to worse ultimate clinical outcomes and may offer cost benefi ts and effi ciency savings. Evidence to inform decisions of switch to second line ART after fi rst-line failure is mainly derived from studies set in high-income countries. Furthermore, a high methodological variability and differing defi nitions of failure make comparison diffi cult and the long term outcomes associated with clinical, immunological and virological monitoring and failure criteria are still poorly understood .

The real meaning of viral replication is not well understood. In resource rich countries, where an individualized approach to patient management is usually adopted, and a range of initial and subsequent treatment regimens are tailored to the individual by specialist HIV care providers, the new paradigm for HIV management is one of achieving viral load undetectability, i.e. maximal viral suppression. This approach, dependent on regular viral load monitoring, is intolerant of any viral load replication, and requires repeated ARV drug regimen changes based on resistance profi les ( i.e. not a switch to an entirely new regimen based on two new classes) after VL> 50 copies/ml, and characterizes what is termed ‘early’ switch. Risks associated with ongoing viral replication include disease progression, development of mutations, onward transmission of resistant virus and increased non-AIDS but HIV-related morbidity. However, a certain level of viral replication may be acceptable without signifi cant clinical-immunological damage and may provide effi ciency savings for stressed treatment programmes with limited monitoring capacity, and is - defi ned as a ‘late’ switch. Low level viraemia, and the continuation of a failing regimen may sustain maintain therapeutic benefi t at low level viraemia, but ultimately leads to clinical or immunological failure. The use of expensive second line therapy is therefore deferred. The need for laboratory tests and concomitant costs are minimized or avoided. This may allow resources to be channelled to continued programme roll out and expanding access rather than to laboratory infrastructure and commodities and support treating a larger number of patients.

Of concern with this approach is an implied hierarchy of outcomes, whereby those with resources for laboratory tests and monitoring can benefi t from complete viral suppression, while those in areas of more restricted means endure virological failure and the potential hazards and risks that entails. However, it is still unclear if all patient important outcomes, such as mortality and quality of life, are truly improved with these approaches .

2. exeCutiVe suMMaRY


The meeting also emphasized the need to periodically update WHO recommendations to accommodate the rapid rate of new knowledge, programme development and technological improvements that are anticipated with regards to viral load and other monitoring testing.

Objectives of Meeting

The experts group were asked to:

• review current international, national and regional definitions of ART failure.

• review existing evidence and experience of monitoring responses to ART, using different approaches.

• consider how definitions of ART failure in the context of the public health approach can be built into national programmes providing HIV care and treatment.

Expected Outcomes:

• Refined working definitions of ART failure (“early” and “late” failure definitions) in the context of the public health approach.

• Consensus on available evidence on clinical and laboratory approaches to identify ART failure within a public health approach.

• Guidance for national HIV treatment programmes on how to define and identify ART treatment failure and strategies for switching failing first-line ART to second line ART regimen.

Working Methods

The consultation took place over a period of 2 days. Plenary sessions reviewed current guidance on published evidence and programme experience with regards to approaches to treatment failure. Group work was used to review working definitions of failure of second line therapy and assess strategies to improve access to second line therapies in resource limited settings .

Participants were asked to consider the following questions:

• What should the goals of antiretroviral therapy be within a public health approach?

• What are the benefits and risks of ‘early’ switch’ and ‘late switch’ approaches?

• What does the current evidence and experience of use of laboratory markers (viral load, CD4 cell count) and/ or clinical events (OIs/ clinical staging) to monitor ART tell us?

• What CD4 thresholds and clinical events most reliably indicate first and subsequent line treatment failure and the need to switch ART regimens?

• Where the availability of viral load testing is limited, what is the most programmatically efficient use of VL testing in the management of HIV?

• If viral loads are readily accessible, which viral load thresholds are most useful in monitoring and determining need for switching antiretroviral therapy?


Outcomes

The working group considered public health programme goals, monitoring strategies, definitions of failure and recommendations for switching after first line ART failure. Public health goals were supported. However, the level of evidence available to support current or alternative monitoring strategies was considered low, and recommendations for further research in this area were made by the group. Furthermore, the long term outcomes associated with adoption of varied clinical, immunological and virological failure criteria are still unknown. However, it was unanimously agreed that a lack of viral load monitoring should not impede ART roll out, and funds should not be diverted from rollout to establish or augment viral load monitoring. The group also agreed that continuing expansion of CD4 cell count monitoring capacity is a greater priority than building capacity to perform HIV viral load monitoring capacity, particularly in settings with limited infrastructure. The consequences of not having viral load monitoring, and it was agreed that efforts to expand ART use should continue in parallel with efforts to make inexpensive viral load monitoring more accessible as it becomes available in the future.

Adherence interventions were unanimously recognized as essential interventions when treatment failure, irrespective of the criteria used is initially suspected. They are also important in delaying the development of ART failure. A targeted approach to the use of VL was suggested for programmes who have developed capacity to perform VL measurement . Initially, VL could be used to resolve discordant cases of clinical-immunological failure, and potentially in pregnant women to identify those who have viral replication more likely to result in infants infection. However, such approaches need urgent evaluation before they can be recommended for widespread use. .

In conclusion, the decision on when to switch from 1st to 2nd line therapy continues to be a critical aspect of ART management as programmes evolve and more patients continue on ART. Better evidence and more data is required before more specific recommendations can be made, particularly for resource-limited settings where routine viral load monitoring is usually not affordable or feasible. As additional data become available in the future, WHO will actively monitor and assess their significance in order to revise or establish new recommendations at the earliest and most appropriate time.


3. baCKGROunD

In the last years, anti-retroviral therapy (ART) has become more widely available in resource-limited settings. Cohort studies indicate that the implementation of ART roll-out programmes have been successful, with reduction in HIV-associated morbidity and mortality, and with concomitant improvement of imunovirological achieving outcomes similar to those outcomes observed in higher income settings.

However, for reasons of cost, limited infrastructure and high technological requirements, CD4 cell count and viral load monitoring are not adequately available in most resource poor settings. Furthermore, despite the signifi cant global scale up process, antiretroviral therapy is not yet extensively available and second-line therapy is still expensive and limited in use. This lack of access to laboratory monitoring and high cost of second-line drugs means that the defi nition of treatment failure in resource-limited settings, and decisions to switch to second-line therapy are diffi cult in the context of effi cient and effective use of public health resources.

Evidence to inform decisions of switch after fi rst-line failure is mainly available from studies in high-income countries. Methodological variability and differing defi nitions of failure make comparison diffi cult. Furthermore, the long term outcomes associated with clinical, immunological and virologic failure criteria are unknown. In addition, most research has been done in relation to subtype B viruses, and characterization of resistance mutations has been based on subtype B laboratory strains.

This meeting report presents a summary of the discussions and major fi nding of an international expert panel, convened by WHO to consider the available evidence and programme experiences.

3.1 SUMMARY OF PLENARY SESSIONS

During the 1st day of the meeting, the current scientifi c evidence was presented in plenary sections and discussed by the audience. A background document with an overview of the current evidence on ART failure management in the indexed literature was also prepared, and the GRADE system for appraising the rating of evidence was applied. The major aspects of the plenary sessions are reported as follows:

3.1.1 SECTION 1: ART switching in the context of the public health approach

The Public Health Approach

ART rollout, with more than 3 million people now on therapy. This has been achieved in the context of limited infrastructure, and limited access to health care personnel. A public health approach (1), which moves away from the individual management, that uses a virological defi nition for treatment failure, to an approach with goals based on maximising resources for a higher number of individuals, that optimizes population outcomes and uses standardized simplifi ed approaches. The vision is, using an evidence-based process, to have a standardised approach to 1st line treatment, as in the case of TB management..

The ART public health approach comprises 3 major components:

• Reliance on clinical parameters to enable ART coverage without high technology and expensive tests. There are programmes in Africa and Asia that start on clinical grounds alone.

• First line therapy is NNRTI based, with protease inhibitors reserved for second line.

• Population based surveillance and monitoring of HIV drug resistance.

Consolidation around a small number of therapies for 1st line ART has also been supported in order to attain price consolidation around these products, as well as improvement of programme logistics and quality control.


Second-line therapy

Universal access has been critical in these achievements and includes second line therapy. Guidance on second-line therapy has recently been published by the WHO, with boosted atazanavir and lopinavir as the preferred PIs among the recommended options (2). Although it is 5-10x more expensive, it is now becoming progressively accessible. Countries are reviewing policy for its use, and introducing training around second line ART, as for example in India. As successful as 1st line therapy has been, it has created an issue in terms of second line failure: there is still the limited laboratory infrastructure associated with starting therapy. UNITAID, Global Fund and PEPFAR are moving to funding second line, and further consolidation around drug recommendations is expected soon.

Difficulties in defining failure for switch recommendations

There are 3 different domains for recognition of ART failure: clinical, immunological, and virological. For a single definition of ART failure, it is not easy to combine these 3 domains and the current international guidelines are not always consistent in defining criteria to switch to a second line regimen.. The aim of this meeting was to assess current evidence and experience with regards to managing the switching from first lien to second line regimens, trying to integrate the domains of virological, immunological and clinical failure. The challenge is to review existing evidence and come to a consensus on guidance. However, challenges in establishing definitions and include:

• Surrogate markers: CD4 and VL are prognostic markers in HIV infection, but are not good surrogate markers for virological failure, lacking sensitivity and specificity for that aim [75].Viral load definition of failure: what level is failure? There is no evidence to support this outside the individual paradigm. A threshold of 10,000 copies/ml results from previous debates at WHO, based on scientific evidence available at the time.

• Discordant outcomes: the assumption that virological, immunological then clinical failure is a linear progression, with an implied hierarchy , may not be the course in the lower income country context

• Frequency of monitoring: often only a one off CD4 is taken prior to treatment start in lower income countries, not longitudinal as experienced in wealthier countries

• Operational difficulties: delay in requesting, performing and receiving laboratory results means delay in implementing a switch strategy based on a definition of failure

• Evolving technology: technology advances around laboratory testing may mean changes soon in feasibility of laboratory monitoring, especially with point of care (POC) assays.

• Evidence: There is still insufficient evidence from randomised control trials. Most evidence is from retrospective cohort studies from the wealthier countries with good availability of a range of ARV options.

The key area for discussion is around laboratory definitions of 1st line failure. In particular how much and which laboratory testing is needed to switch to second line treatment, bearing in mind that starting ART is done with as little laboratory testing as possible. A conflict of finance arises, whereby Health Ministries may find it unclear as to whether to invest in laboratory infrastructure or make funds available for ART start and second line.

Current WHO guidance on ART switching

The decision on when to switch from first-line to second-line ART is currently made in one of in three ways: clinically, by disease progression and WHO clinical staging; immunologically, using trends in CD4 cell counts over time; and virologically, by measuring plasma HIV RNA levels (viral load). WHO issued recommendations to guide countries in 2006 for management on this topic, but to date adoption and implementation has also varied. Furthermore, these definitions has been used in different settings and frequently represent different endpoints. There is a need for agreement on better defining treatment failure and for standardization across the different ways to identifying it.


Figure 1: Current WHO guidance on second line therapy (4)

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“Early” versus “late” defi nitions of ART failure

A defi nition of ‘early’ failure would mean preventing virological replication and is implicit when national/regional guidelines have “maximal” viral suppression as a goal of ART. A ‘late’ defi nition of failure would mean a defi nition using CD4 and/or clinical criteria, whereby virological failure would most likely have preceded the time at which failure causes switching of treatment.

To defi ne virological failure early has advantages for protecting viral evolution and preserving future drug options where there is no curtailment on ART available. However, a late defi nition of failure i.e., tolerating a detectable viral load, postpones switching, and maintains drug options for the patient if only fi rst- and second-line regimens of ART are available. The viral load is not generally available for monitoring ART in resource-limited settings, so the ‘late’ switch would be the most commonly used option. However, some countries have access to viral load technology, therefore the viral load can be included in recommendations.

Figure 2: current framework for defi nitions for defi nitions of failure

Precedent for Failure Guidance: European Consultation Meeting on ART failure and strategy for ART switching in the European Region: Summary report of WHO expert consultation (5)

A WHO regional consultation in Europe reviewed evidence in order to produce guidance on monitoring fi rst line ART, defi nitions of failure, and recommendations for switching to second line therapy in European countries. Defi nitions of fi rst line ART failure were clarifi ed, including viral load switch thresholds, and optimal timing of ART switch (early versus late). Europe region is described in 3 sub regions (Western, Central and Eastern Europe) and capacities of each sub region were taken into account, including:


• Disease burden

• Number of people living with HIV on ART

• Range of ART, availability and affordability

• Health system infrastructure

• Human and fi nancial resources

• Laboratory capacity to monitor patients on ART

According to a survey performed by WHO EURO, only one country does not currently have access to viral load testing (Tajikistan). All countries have access to the drugs of the WHO ART formulary. In many of the countries which the programme addressed, the approach to HIV treatment is somewhere between the public health approach and management of the individual patient.

Figure 3: from individual to public health HIV programmes (6)

A consensus defi nition on the goals of therapy were achieved in this EURO meeting: to maximize life expectancy and its quality, and to minimize risk of drug resistance and toxicity.

Failure is not necessarily an indication to switch. Adherence and drug interactions should be considered before switch occurs, and all appropriate steps taken to improve adherence. The following parameters for virological, immunological clinical failure were established:

Virological:

• Primary – no response by patient (VL does not decrease to < 50 copies/ml in 2 different occasions when on ART for longer than 6-9 months).

• Secondary – confi rmed viral rebound after suppressing to VL < 50 copies/ml (i.e., VL> 50 copies/ml in 2 different occasions when on ART for longer than 6-9 months )

Immunological:

• 25% drop of CD4 cell count from the maximum peak

• Failure to increase CD4 cell count > 50cells/mm3 during the fi rst year of ART.

Clinical:

• ART failure based solely on clinical grounds is considered as a suboptimal approach, countries are encouraged to at least ensure regular CD4 monitoring


“Early” versus “late” switch parameters:

• Early switch: VL > 400 (50-1000)copies/ml

• Late switch: VL > 1000 copies/ml 25% drop in CD4 cell count

With regards to treatment monitoring, viral load monitoring is considered to be standard of care for the European Region, but frequency of this monitoring depends on local constraints. Recommendations included:

• optimal viral load monitoring at baseline, then at months 1,3,6 and 12.

• a viral load every 6-12 months was acceptable if there were local constraints.

Immunological monitoring was also considered as an alternative strategy and should be performed in 3 phases:

• Initially as a pre therapy parameter (baseline CD4 cell count)

• 2-4 times in the 1st year

• twice yearly subsequently

If HIV drug resistance testing is not available after fi rst-line failure, a blood sample should be taken and stored.

Blood samples after fi rst- and second-line failure should be tested so as to inform decision regarding salvage regimen.

New drugs should be made available wherever possible..

3.1.2 SECTION 2: Defi nitions of failure and consequences of switch strategies

Current status of second line ART in resource limited countries

There is limited availability of second line ART. Switching is often not done, and incomplete formularies limit options. Often there is no CD4 or viral load monitoring. Current 2nd line regimens are complex, and have diffi cult drug interactions, especially with rifampicin, impacting on the management of TB co-infection. Furthermore, cost is an important barrier. The cost for second line in 2006 was 2% of total cost. By 2010 this will have risen to 35%, estimated, based on current costs, as numbers on second line will rise from 40,000 in 2006 to a predicted 500,000-800,000 by 2010 (7).

Figure 4: Projected need and cost estimate of second line therapy (7)


Current definitions of failure in the major international ART guidelines

The goal of therapy from the public health perspective is to reduce morbidity and mortality, so CD4 conservation and maximal virological suppression should be pursued. However, often in resource limited settings, there is limited or no access to viral load testing and CD4 tests, and without a viral load there is a reliance on immunological and clinical definitions of failure. However, there is lack of consensus on these definitions of failure, particularly in the immunological and clinical domains. More on definitions of failure can be seen in appendix 1.

Table 1: definitions of ART failure according major international ART guidelines

ART Guidelines Virological Immunological Clinical

USA Department Health and Human Services (8)

VL>50 after VL 1 month

NA* NA*

European Aids Clinical Society (10)

VL>50 after VL5,000 30% drop from peak, return to pre therapy

level or lower

HIV related OI/malignancy >3 months

after ART

WHO (2) VL>10,000 fall below pre therapy; fall from peak ;


Viral load threshold and disease progression

The WHO decision to choose the level 10,000 copies/ ml was infl uenced by a number of studies, including PLATO (12), CHORUS (13) and ICONA (14). These suggest that clinical progression and CD4 cell decline is likely not signifi cantly affected while on therapy with a viral load of 10,000 (PLATO and ICONA studies) and maybe even 20,000 copies/ml (CHORUS study). However, Lohse et al saw greater risk of death with those with a VL> 400 6-18 months after initiation of ART (15). Kousignian et al showed a hierarchy of outcomes after treatment start: those that maintained VL1000 copies/ml is to risk at 1 year a new mutation in 44% and to lose a drug in 30% (21). The DART study showed us that persistent viraemia results in increasing TAMS between weeks 24 and 48. Only 4% had TAMS at week 24, but this climbs to 39% at week 48 (22). However, triple class resistance takes some time to accumulate, as shown in the UK CHIC study addressing the risk of extensive failure (23,73).

Figure 5: UK CHIC Study risk of extensive class failure


Impact on second line therapy

When using the public health approach, in which clinical or immunological events define failure rather than virologically identified failure, it is unclear how much the NRTIs included in second-line ART contribute to resuppression in second line therapy. Some patients may in effect, be receiving PI monotherapy. In fact, this is a data free zone. Evidence to date is not based on this clinical scenario, i.e., after 1st line failure in a resource poor country using the public health approach. Current trial data is difficult to extrapolate to Africa, where patients start later with a lower CD4 and are likely to fail with more mutations.

Of note there is an ACTG trial (ACTG 5230) about to start recruitment addressing the question of therapy after patients fail a standard NNRTI-based treatment regimen. Those recruited will be randomised to lopinavir/ ritonavir monotherapy versus lopinavir/ ritonavir and 2 NRTIs (24). Data from LADY, DART and other second line trials are also awaited.

Clinical: HIV and non-AIDS morbidity and mortality

Treatment does not only cover reduction in opportunistic disease, but also non-AIDS related illness. The control of viraemia and subsequent increase in CD4 results in a reduction in AIDS defining events. At low CD4 counts, most illnesses are AIDS events, as demonstrated in the FIRST study (25). However, at higher CD4 cells, there is an increase in proportion of non-AIDS related causes of morbidity and mortality, such as cardiovascular disease, renal disease and non-AIDS malignancies and these too are reduced by virological control. This has been further clarified by the SMART study, where patients that stopped ART were seen to be at risk from AIDS defining and non-AIDS illness (26). On restarting therapy, this increased risk in morbidity subsides but is not completely reversed. In a sub study of naive patients in SMART, those who deferred therapy did worse in terms of all events experienced, including cardiovascular disease, renal disease and liver disease (27). However, it is unclear how far SMART data can be extrapolated to LIC settings.

Resistance in LIC: a subtype effect?

Whether there is a subtype effect is unknown. Most evidence with regards to mutations is on subtype B. There appears to be more resistance on failure in lower income countries. This may be related to time spent failing, so whether this is a subtype effect or programme effect is unknown. The genotype emerging after failure may differ between subtypes, though current data suggests that there is not a subtype treatment effect (74).

Significance of regimen

In experienced multiple cohorts in the late 1980’s, a patient with a persistent viraemia on therapy in general did well and had a sustained CD4 benefit. Notably, this was always on PI based regimens. The PLATO study showed a differential CD4 outcome according to whether the patient was on a PI or not (12). A goal at that time was to give a PI if viral suppression couldn’t be attained. This was a working concept that was familiar to physicians when there weren’t many drugs around. However, all cohort studies that addressed sustained viraemia only looked at those on PI therapy. This was because there is considered to be a ‘PI effect’, whereby PI therapy is associated with better CD4 recovery- the type of regimen appeared to matter. Furthermore, those that were on an NNRTI regimen that had delayed switch at failure did worse in the long term, and kept this increased risk (28).

NNRTI failure has significant impact on outcome. Risk of death among patients failing an NNRTI-based ART regimen is increased by any delay in modification, with higher risk persisting even after a switch has occurred. However, if the goal is to prolong life, the best strategy is to start an NNRTI regimen, and switch quickly if there is failure (28).


Figure 6: Risk of death among patients failing an NNRTI based regimen (28)

If therapy cannot be switched quickly, data suggests that it is better to be on a PI based regimen. If there isn’t monitoring of the regimen, there is a better CD4 sustainability if there is sustained viraemia. ACTG 5142 compared NNRTI+2NA with PI+2NA and showed better virological outcomes with the NNRTI. However, there was a better CD4 response on a PI (29).

Figure 7: Risk of death during PI based ART (28)

Why the ‘PI effect’?

Resistance and viral fi tness?

There may be a better reduction in viral fi tness with PI mutations compared to NNRTI mutations as measured in vivo. The compensatory changes in gag have a dramatic effect on the virus’s capacity to replicate. Therefore the PI effect is more important in the case of ongoing viral replication, and less important in the case of suppressed virus (30).

Preserved thymic function?

PI resistance is associated with preserved thymic function. HIV isolates resistant to protease inhibitor treatment have an impaired ability to replicate in thymocytes, allowing T-cell production to continue despite the peripheral T-cell decline (31).

Direct immunomodulatory effect?

PI resistance/exposure has been associated with reduced levels of T cell activation and apoptosis, which in turn has been associated with preserved CD4 counts(32). As immune activation is considered part of the pathological process of HIV infection, this may have a signifi cant effect. This may be of more importance in Africa, where levels of immune activation are likely to be higher due to background level of disease. Immune activation examined in Uganda compared to San Francisco showed increase in T cell activation when controlled for VL and CD4 (33).


Impact of ART switching at lower versus higher switch thresholds: The ACTG A5115 (34)

This trial is the only attempt in a randomized controlled trial to address the question of whether to switch early or late on a regimen with viral replication. A randomised control trial is now not feasible due to new ART and the current therapeutic goal, in industrialized countries at least, of undetectable viral load in drug experienced patients. The trial was developed to investigate the hypothesis that subjects randomised to a delayed ART switch will have comparable levels of immune activation and viral resistance. This trial has strengths but also shortcomings. Recruitment was slow, and the trial closed early due to slow accrual. An informal canvassing of recruitment centres as to why recruitment was slow revealed a 50:50 divide between those believing that early switch was clearly better versus those believing that late switch was the best option. Also, some patients who were referred to the study were subsequently undetectable at recruitment. Whether this reflects adherence or viral load blips is unclear.

In this study, surrogate end points identified for the study included immune activation as measured by CD38+ expression on CD8 cells and a virologic future drug options score (FDO), using a validated score.

Patients were randomised to:

• Arm A: Immediate switch (threshold: VL >200 copies/mL)

• Arm B: Delayed switch (threshold: confirmed VL >10,000 copies/mL or CD4 T-cell decline of >20%)

The switch regimen was selection by site investigator based on genotypic resistance and history. Inclusion criteria included CD4 > 200; current ART regimen >4 months; VL 200-10,000 copies/ml.

Baseline characteristics of patients were balanced across the arms and in particular the drug resistance score and immune activation. The median duration of ART was 136 weeks, and median VL 2512 copies/ml. The median follow-up time was 82 weeks. 41 (87%) completed 48 weeks on study. 71% of immediate switch group had switched within 6 weeks of study entry (96% within 12 w). 10 (43%) of delayed switch subjects met switch criteria and median time to switch was >60 weeks. Reasons for switch were CD4 decline in 7 subjects and HIV RNA >10,000 copies/ml in 3 subjects. Looking at suppression after the switch, whether immediate or delayed, both groups had good rates of suppression. The timing of the switch did not appear to affect the outcome of second line therapy.

Primary endpoints

• Immune activation was not significantly different in both groups as measured by CD38+ expression or CD38+ DR expression.

• The early switch arm had more suppressed, although this wasn’t significantly different.

• The late switch arm had more mutations, although the FDO scores were not significantly different.

Conclusions from ACTG 5115

In this study population with moderate to high levels of genotypic drug resistance and immune activation at baseline, the level of immune activation and the loss of future treatment options were comparable in the delayed and immediate switch groups. Delayed switch did not appear to affect the virologic or immunological response to the subsequent regimen.

These conclusions are limited by the small sample size and the possibility of type II error.


Following ART guidelines: What happens in real life in developed countries?

Starting ART

Despite guidelines for ART in developed countries being considered as gold standard, outcomes are frequently not perfect. In a review of data across countries, Egger et al showed that, contrary to expectation and national guidelines and recommendations, wealthy countries are starting ART late in disease. Since 2000, CD4 cell count at initiation has increased in Sub-Saharan Africa from 50 -100 cells/mm3; in higher income countries it has remained stable at approximately 150–200 cells/mm3 (35).

Figure 8: Starting CD4 Figure 9: Time to switch UK cohort

“Benchmarking” switching therapy

A BHIVA audit of UK practice showed up to 78 week delay in switching therapy after not achieving virological suppression (36).

It is important to note that even when the goal of therapy in the individualised approach is an undetectable viral load, the desired outcome does not match the actual outcome, as seen in the UK audit of switch after fi rst line failure, where a prolonged period on failing therapy was seen often. If we are hoping for 90% undetectable, most of Europe does not achieve that. This is important for the rest of the world to appreciate this fact.

This concept of benchmarking is very important. There are limited data on the outcomes of many roll out programmes. Benchmarking would be an excellent model to measure programme effectiveness. The resistance surveillance is all we have currently.

Conclusion: what do we know about ART switching?

“Zero tolerance” to VL is standard of care in high and some middle-income countries. The negative consequences of ongoing virological replication are disease progression and accumulation of mutations, with limitation of future drug options and risk of transmission of resistant virus. However, there is sustained clinical benefi t of maintaining ART during virological failure that is commonly observed in North American and European cohorts in the presence of extensive HIV resistance. This is consistently associated with PI-based therapy in salvage patients. The exact risk threshold for virological failure remains to be established (between 50 and 20,000 copies/ml). Except for NNRTIs and M184V mutations, the emergence of resistance is relatively slow. Clinical and immunological benefi t may be maintained for up to 5 years on failing therapy.

Switching therapy based on CD4 monitoring maybe too late or too early, due to discordant outcomes, and switching based on clinical monitoring is thought by some experts to be too late. Stopping ART is the worst option and not recommended.


Access to cheap and simple monitoring tools is still an unmet medical need, but nothing can be worse than not providing access to ART to those in need.

3.1.3 SECTION 3: Real and modelled outcomes of switch strategies including cost analysis

Home-Based AIDS Care (HBAC) Study: Major Findings

This trial aimed to investigate treatment effi cacy and monitoring in Uganda. ART and TB treatment are part of a care package for 1,000 people with HIV. Inclusion criteria included a CD4 < 250/mm3 and a WHO clinical stage 3 or 4 (excluding isolated pulmonary TB). WHO guidelines were followed for medications, unless there was TB in which case efavirenz was used. Second line options included lopinavir/ritonavir, zidovudine, didanosine, and tenofovir.

All patients had weekly home visits with a standard symptom questionnaire. If illness occurred, clinic referrals were made on a system of red/ yellow card alerts by the interviewer. Malaria, TB and diarrhoea could be treated at home.

Figure 10: randomisation of HBAC trial

The major outcomes of the study were AIDS events and mortality after 3 years of follow up. Clinical conferences were held on all deaths, hospitalizations, opportunistic illnesses, abnormal labs and changes in ART regimens. Treatment failure defi nitions were established for each study arm as follows:

Arm A

• 2 consecutive viral loads> 500 copies/ml

• First response to failure was adherence intervention. If a VL 50-5000 copies/ml and well, could continue ART, otherwise a switch was performed.

Arm B

• Persistently declining CD4 count measured on two separate occasions

• Clinical failure

Arm C

• Unintentional weight loss of >10%

• CDC category C illness

• Diarrhoea or fever for >1 month without correctable cause

• New or recurrent oral, oesophageal, vaginal candidiasis


Intention-to-treat analysis was performed from the date of randomization and a per protocol analysis from >90 days after initiating ART, as for the fi rst 90 days management was identical. A total of 1116 naïve patients were randomized, with 1094 starting ART. Median follow up was 3 years, at the end of which 28 (2.7%) had changed to 2nd line medications. Median CD4 cell across arms was about 130, and median viral load 200,000 copies/ml. There were 126 (11.2%) deaths, 47% of which occurred in the fi rst 3 months. There were 148 AIDS defi ning illnesses, of which 57% occurred in the fi rst three months. There was 90% complete viral suppression at 1 year.

Arm C showed signifi cantly increased severe morbidity compared to Arms B and A (fi gure 11). There was no statistical difference between Arms A and B, though more events occurred in Arm B. The rate of events was about twice as high in Arm C as the other arms. Specifi cally there were more cases of TB, PCP, cryptococcal disease and KS in Arm C. There was no difference in the rates of these diseases between Arms A and B. Regarding mortality there was no signifi cant difference between the arms, though a non-signifi cant trend to increased mortality in arm C.

Figure 11: mortality and morbidity outcomes of HBAC

Around 90% had complete viral suppression at 1 year (500 copies/ml during the follow-up was associated with severe morbidity or mortality in this study (20% vs. 9%; p=0.0001) and mortality alone (12% vs. 5%, p=0.001).Arm C had a detectable viral load for longer before switch.

Of those changed to second line therapy, all of arm A and B had a detectable viral load, whereas only 2/17 (12%) in Arm C had a detectable viral load at switch. Of those in Arm C who had detectable viral load but didn’t switch, there were 2 deaths and no other AIDS events. 15 people changed to 2nd line therapy with undetectable viral load, all were changed because of AIDS-defi ning events, all of which occurred after 1 year of therapy. Stage 4 events were not preceded by stage 3 diagnoses. All occurred greater than 1 year after starting therapy.

Reported adherence was high across all arms (Arm A 99%; Arm B 98%; Arm C 98%). Targeted adherence interventions were more frequent in arms A and B at detection of virological or immunological failure, thus supporting adherence as a major factor in outcome. 500 copies changed as adherence interventions resulted in subsequent suppression. Of those that switched to second line, outcomes were good

Conclusions of HBAC study

• Virological suppression rates were high, even in Arm C which had 12% detectable virus.

• Clinical monitoring alone was associated with increased rate of new AIDS-defi ning events and trend towards increased mortality. The exact reason for the increase rate of events in Arm C is unclear, though lack of adherence interventions may account for some effect

• Clinical criteria were poorly sensitive and poorly specifi c for detection of virological failure. Most in Arm C who switched had an undetectable viral load.


• CD4 counts do not predict virological outcomes. However, monitoring CD4 count compared to viral load resulted in equivalent outcomes for AIDS events and mortality after 3 years of follow up.

• In comparing Arm A to Arm B, no statistically significant benefits were seen in adding quarterly viral load measurements. There was no efficacy benefit of monitoring viral load in this trial

• Lay workers can effectively deliver drugs, support adherence, and monitor patients without scheduled clinic visits

• Supporting adherence is an important determinant of success of the programme.

Cost-effectiveness of CD4 and viral load monitoring for ART in rural Uganda

Data from the HBAC study was used to ask the research question: what is the incremental cost-effectiveness of quarterly lab monitoring options for ART? The method used was the incremental cost effectiveness ratio: the incremental costs of adding each test, i.e. the cost of adding CD4 to Arm C (clinical monitoring only); and the cost of adding VL to Arm B (CD4 and clinical monitoring), so that each option is compared to the next less expensive alternative.

Health outcomes are measured in terms of DALYS (disability adjusted life years) averted. This includes both reduced mortality and morbidity, thus merging varied morbidity outcomes and mortality onto a single metric. This is a standard outcome metric now in global health analysis. Of note, ART are not very cost effective DALYs in global health.

Costs from the HBAC trial were also used as the model base costs.

• CD4 counts at $19/year/patient ($4.68/test)

• viral load tests at $119/year/patient ($30/test).

• 1st line therapy $182 per person-year of therapy (d4T, 3TC, NVP)

• Second line $1,080 per person-year of therapy (TDF, ddI, LPV/r)

Rating disease in HBAC study

Diseases and conditions were given a disability rate from standard reference lists (table 2).

DALYs per 100 patient years are seen in table 3. Total costs included labs, health outcomes and ART needed due to averted deaths are seen in Table 4.

Table 2: disease ratings and occurrence per arm


Table 3: Disease episodes and DALYs per 100 patient years per arm

Laboratory costs are highest in Arm A. ART costs are higher in Arm C due to increases rates of switching. Hospital costs are higher in Arm C. There is incremental cost to deaths averted in Arms A and then B compared to C. Arm A had the least DALYs. Total costs per arm and DALYs are highlighted in table 4.

Table 4: Costs and DALYs per Arm in HBAC study

Comparing Across HBAC Study Arms

The total difference between Arm A and B is $15,071, mostly viral load monitoring. The difference between Arm B and C is $10,680.

The difference in DALY averted between Arm B and C was larger than that between A and B, but the cost difference per DALY averted was higher. Again, this is because most cost incurred is the viral load.

There is a 3x difference in DALYs averted between Arm B versus C and Arm A versus B per hundred person years i.e., the difference in health benefit from moving from clinical to CD4 is greater than moving from CD4 to viral load. Further, the cost difference between DALY averted is $3,610 for A versus B, and $831 for Arm B vs C.

Table 5: Differential costs per Arm


Sensitivity Analysis: Adding VL versus CD4 cell count

The incremental of cost of adding viral load to programme is proportionally higher each time for the viral load than the CD4.

If the cost of the VL triples, the cost of a DALY increases to $9000. If the cost of the VL is cut by a 3rd, the cost of the DALY reduces to $2000.

The cost of the CD4 count is not that high, and increasing the cost does not have as big an impact.

The impact of the cost of the viral load is high.

Figure 12: incremental cost impact of viral load testing

National programme scenarios: Preliminary cost estimates for a national programme

The data presented was used to model a national programme costs, comparing virological and clinical monitoring in a scenario where $100,000,000 was available to spend. According to this model, DALYs averted for CD4 monitoring strategy was 120,337 and for VL monitoring was 104,707. That means 15,630 more DALY’s averted for CD4 monitoring, which relates to approximately 1,600 deaths. If the cost of same DALYs averted is considered, viral load monitoring strategy costs $15,000,000 more for the same DALYs averted, not including infrastructure costs.

In conclusion, adding CD4 to clinical monitoring ($831 - $838 per DALY averted) is about as cost-effective as putting another person on ART in Tororo, Uganda ($600 per DALY) for example. Adding viral load to CD4/clinical monitoring has a cost per DALY averted ($3,600 - $11,900), that is 4 to 20 times higher. (This used a model of routine VL monitoring, not a targeted viral load).

Immunological response to second line ART: the DART experience (37)

DART, the Development of Antiretroviral Therapy in Africa study, is an ongoing clinical trial of two monitoring strategies conducted in Uganda and Zimbabwe. Patients were randomised to clinical monitoring alone versus CD4 and clinical monitoring. There is no virological monitoring. A structured treatment interruption (STI) arm was stopped in March 2006, as continuous therapy superior was to STI.


Figure 13: Randomisation in DART study

The aim of study is to compare immunological responses to boosted PI-containing 2nd line regimen versus non-PI containing 1st line regimen in adults initiating ART with low CD4 counts. Median CD4 and change in CD4 were compared with these patients before they switched, and those initiating ART who had not yet switched. WHO defi nitions of failure were used to indicate switch of therapy. Of 3316 naive patients with CD4 cells


This trial suggests that even with a comparatively late switch to second line, without virological monitoring, immunological responses are still excellent and better than when patients were naive to ART and started on fi rst-line therapy without bPIs .

Outcomes from monitoring of patients on antiretroviral therapy in resource-limited settings with viral load, CD4 cell count, or clinical observation alone: a computer simulation model (20)

In this modelling study, the objective is to use a model of HIV infection and the effect of ART to predict and compare outcomes from different strategies for monitoring patients on fi rst line ART. The model was used to study the potential consequences of such monitoring strategies, especially in terms of survival and resistance development.

Figure 16: CD4 count/ VL for a single simulated patient

Methods

A stochastic computer simulation model (called HIV Synthesis) was created of the course of infection in HIV positive people, including the effect of treatment. It creates a data set that looks like one from a cohort. Each time the programme runs, it generates a different set of patient experiences and outcomes, and each time greater than 30,000 patients created with WHO stage 4 are followed from the start of ART. Patients are created with fi xed variables at the start, and then other variable are updated over time, every 3 months. Random selections were made to assess the effect of variations in the model run over 10,000 times.

Variables updated over time on a regular basis include age, VL, CD4 count, risk of AIDS / death, use of specifi c ARTs and resistance mutations and different defi nitions of failure were compared (see table 6)

Table 6: defi nitions of ART failure

Viral load

• viral load >500 copies/ml, on ART for past 6 months

• viral load >10,000 copies/ml, on ART for past 6 months

CD4 count

• confi rmed 50% drop from peak level during current

• period of ART, on ART for past year, current CD4< 200

• confi rmed 33% drop over past 6 months, on ART for past year, current CD4 < 200

Clinical

• new WHO 4 event, on ART past 6 months.

• new WHO 3 (x 2) or 4 event, on ART past 6 months

Discordance: The model includes patients who switch on immunological failure, but are virologically suppressed


Figure 17 compares the time to switch for VL>500 copies/ml criterion for failure, compared with the time to switch on other criteria. The fi rst column shows those meeting criteria for switch before VL>500 copies/ml. CD4 cell count and clinical criteria were sometimes met before VL criteria (discordant). The subsequent column shows the time from VL>500 copies/ml failure to clinical and immunological defi nition of failure met. Of those that met VL>500 copies/ml criterion fi rst, median time to immunological failure was 4 years and clinical failure 3-5 years.

Figure 17: Time from meeting VL - 500 criterion to meeting other criteria for switch

Resistance at second line initiation varied according to switch criterion (table 7). Clearly due to the accumulation of TAMS being time dependent, there is more resistance to d4T the longer a patient is failing. Viral load monitoring means earlier switch. As AZT is used in the second line treatment, there will be reduced activity of this drug if viral load monitoring is not used. Suppression on second line therapy was worse the longer there had been a detectable viral load

Table 7: Resistance developed in model

Resistance at start second-line

ARVMonitoring strategy

VL WHO 3x2

NVP 83% 90%

3TC 85% 90%

d4T 26% 55%

No. active drugs 2nd line 2.71 2.37

The risk of transmission of resistance was also considered, assessing the proportion of life years that people harboured resistance and also had a viral load greater than 1000 copies/ml. This demonstrates the most difference between strategies, with a benefi t to viral load monitoring for this. Mean life years lived is predicted to be greatest when using VL monitoring, but differences are relatively modest. (see Figures 18 and 19).


Figure 18: survival outcomes

Figure 19: Death rates according to monitoring strategy

In the cost-effective analysis, costs were assumed to be $20 for CD4 cell and $60 for VL tests. QALYs were used. As demonstrated in Table 8, the incremental cost-effectiveness of monitoring strategies was expressed as incremental cost per life-year gained, and cost per QALY gained over 20 years. The model predicts that there is a long term penalty to waiting for WHO stage 4 in terms of survival and response to 2nd line therapy., which is extensively consistent with HBAC study. There is more resistance accumulation with the risk of transmission of resistance without viral load monitoring at threshold VL>500 copies/ml.


Table 8: costs per monitoring strategy

Life Disc’d Disc’d Disc’d Incr’l Incr’l Incr’l Cost per lifeMonitoring strategy years life QALYs costs life QALYs cost year gained

years years

Viral load 500 13.46 10.56 9.70 $4055 0.07 0.08 $105 $1500

Viral load 10000 13.34 10.49 9.62 $3950 0.27 0.25 $1083 $4011

New WHO 3/4 13.03 10.22 9.37 $2867 0.16 0.17 $75 $469

CD4 decline from peak 12.76 10.06 9.20 $2792 0.05 0.05 $484 $9680

Current CD4 decline 12.73 10.05 9.20 $2824 -------------- dominated -------------

Multiple WHO 3 / 4 12.71 10.01 9.15 $2308 0.26 0.25 $241 $927

New WHO 4 12.27 9.75 8.90 $2067 ----- ----- ----- -----

In conclusion, this modelling study suggests that monitoring viral load and CD4 show only a modest benefit when compared with clinical monitoring in terms of survival outcomes at a population level. This result is surprising, but persists across many variations of the model. Cheaper and better viral load tests are needed, but widening access to ART is the highest priority.

3.1.4 SECTION 4: Programme experiences

Programmatic Perspectives in India

The national programme for ART was started in India 2004, with the ultimate objective to increase life expectancy and ensure 50% of those on ART are engaged in their previous employment. Other aims include provision of long-term therapy for eligible patients, to monitor and report treatment outcomes and attain adherence rates of 95% or more. Further, the programme aims to provide free ART for 300,000 people living with HIV by 2011, and to standardise treatment. Some patient in the national programme had accessed ART privately prior to entering the national programme.

Many regimens are currently being used, but the aim is to consolidate around a recommended few. First line is 2NRTIs+ NNRTI. Second line is a boosted PI based regimen, with appropriate 2NRTIs. Monitoring is clinical every 3 months, is immunological every 6 months, with a recommended VL at 6 months. Definitions of failure follow WHO guidelines. However, clinicians have shown reservations with regards to the definition value of CD4 count 100 cells/mm³, as some patients were well on therapy despite the failure of the CD4 to rise, particularly if they had started at CD4 counts 10,000). A VL 400-10,000 prompts adherence interventions. The aim is to have 30 centres, one in each state.


Figure 20: referral strategy for second line switch decisions

There have been 9 SACEP meetings for 97 patients. 75 have been recommended for a viral load test and 54 have switched to second line.

Switching ART: Experience in South Africa

South Africa is unique in the size of the epidemic in the context of a middle income country with a large ART programme. Excellent statistics enable good programme assessment, and the epidemic is extensively modelled. 20% of all people with HIV are in South Africa’s borders; 6 million out of 48 million South Africans are HIV positive. It has the biggest HIV programme, with suffi cient funds to support the programme. However, coverage is extremely limited. HIV is increasing due to recent immigration from surrounding countries.

There are 418,000 people on treatment (December 2007).The aim is to start 420,000 per year by 2011, with suffi cient funding to do so. There are also aggressive prevention of mother to child transmission and paediatric programmes. Currently about 200,000 per year are starting treatment. 300,000 per year need ART. It is unclear how and who gets access to ART.

In South Africa, ART is initiated in HIV+ patients with CD4 cell count < 200/mm3 or WHO clinical stage 4. Virological failure is defi ned as VL> 5,000 copies/ml. Of note, d4T toxicity drives nearly all drug changes in South Africa, and the issue of failure in the early stages of the ART programme is small compared to toxicity changes. Virological failure in the Jaffer data is responsible only for 12% of treatment switches (38). Toxicity continues to accumulate on therapy. This may undermine adherence work. A study in Botswana suggests that toxicity may not be driving failure, but preventing people starting, and contributing to default.


Figure 21: reasons for 1st line switch in South Africa

Complex guidelines impede access to programmes. South African ART guidelines state that viral load and CD4 need to be done before programme entry, and therefore there is an initial ‘loss to initiation’. Therefore if guidance around switch after failure is complex, this may impede implementation of those guidelines. Most deaths occur prior to initiation of ART therefore any barrier to programme entry is of signifi cance (39).

Figure 22: High death rate while waiting for ART

Operational constraints were identifi ed on VL use. Often in the clinic it may take 8-9 months to act on viral load. This means that all data on speed of accumulation of mutations is irrelevant, as operational issues means it is diffi cult to prevent this. Further, there is delay on acting on a viral load result (40).

Figure 23: Failure and late switch


In terms of adherence, half all those who have detectable viral load can resuppress if adherence care is good (42). Analysis of HIV subtype showed that 97% of patients have HIV 1 subtype C. In nucleoside analogues mutations patterns evaluation, the M184V was seen in 64% of patients failing, several TAMs were seen in the population, and the K65R at 5%. K65R is seen in those on d4T and much less so with AZT. In NNRTI, K103N, V106M, Y181C, G190A were seen frequently. Protease inhibitor failure happens in the research clinic, with M46I, V82A, I84V, L90M and naturally occurring polymorphisms (41).

In summary, there is little patience in the clinics for complex decision making and recommendations should not create barriers to access with complexity. A VL is not just for switching but can be used for other purposes including adherence interventions. Death due to viral resistance is rare in SA, but death due to lack of access or lack of drug alternatives is still common VL without a linked intervention policy is probably a massive waste of money and may cost lives.

Switching ART: MSF experience

Described are some of the challenges based on MSF experiences in trying to balance HIV “zero tolerance” to replication with the reality of clinical monitoring. There is no universal definition of ART failure, but agreement that viral suppression is key to success at the individual level. Viral load is available to MSF, but logistic restraints compromise its use. There is currently a more programmatic use of targeted viral load. However, this raises the question of which groups to target and this has not been studied in a trial. Proposals include: non-naive patients at inclusion in the program; women previously exposed to a single dose of nevirapine for PMTCT; patients with a confirmed history of poor adherence or of treatment interruption during the first months of treatment.

In MSF projects, all immunological or clinical failures have to be confirmed by a VL prior to changing to second line. If the VL10,000 copies/ml switching is recommended. There is some evidence that those who fail ART can resuppress with adherence alone: Orrell et al found that among individuals with a viral load breakthrough of > 1000copies/ml, 53% subsequently resuppressed and remained on first line therapy (42).

In the 26 country clinical cohorts of MSF(43), switch rates are very low, at about 4.4%. Possible reasons include: reluctance to switch from prescribers; few clinical symptoms; very few routine viral loads are done; immunological failure is hard to define as there often is no peak CD4 count.

Table 9: Cumulative switch rates from first to second line ART treatment-naïve patients, MSF HIV cohort 2001-2006, 26 countries

Reasons for switch were: CD4 value 1000 copies/ml (44). The M184V was frequent at 41/83 genotypes. Analysis showed a linear time trend in the accumulation of NRTI mutations, this was not so clear for NNRTI mutations. However, the etravirine score is seen to increase over time. Some data at CROI showed 90% sensitivity to etravirine after 1st line failure in Nigeria, and 75% in Thailand (45) (46).


Frequency of viral load determination was an important issue discussed in the presentation (see Figure 24) Increased frequency means more attendance at clinic and more cost. However, the clinical gain is uncertain as shown by Keiser et al (47).

Figure 24: comparing viral load frequency of monitoring with virological outcome

In conclusion, the MSF presentation stated that viral load is necessary to detect ‘early’ failure. A routine VL is desirable but reality forces MSF to be tolerant to some kind of viral replication. The targeted viral load strategy is currently used in MSF projects. Point of care viral load testing is technically possible, and is undergoing a fi eld validation in June 2008. Perhaps in the near future a point of care test could detect VL threshold 1000 copies/ml and 10,000 copies/ml, and also the M184V mutation to simplify the switching strategies in settings with limited laboratory resources.

3.2 SUMMARY OF EXPERT GROUP RECOMMENDATIONS

The review of the current scientifi c literature showed limited evidence across all domains, not focused on Public Health approach and with a high variability among the studies, which make generalisability of the conclusions diffi cult to be made. There is presently insuffi cient evidence to fully assess which intervention is the most effective and safest for patients if implemented as public health interventions. Some results are emerging from lower income countries, but the large majority of the current data is extrapolated from industrialized countries. There are no randomised control trials to recommend best practice guidelines. Furthermore, the long term outcomes associated with clinical, immunological and virological failure criteria are still unknown. No long term data on survival, particularly in LIC were found. Urgency is needed for establish a research agenda to inform guidelines. However collation of views occurs where consensus was reached, and representation of differing positions has been made where lack of clarity or dissent positions occurred. A summary of the working groups conclusions and suggestions follows.

3.2.1 Programmatic considerations:

• Availability of resources for ART failure management: Efforts should and must be made to make the resources available to improve the ability of clinicians and programs to diagnose treatment failure with high sensitivity and specifi city.Recommendations are temporary, as programme development, new data and technological improvement are expected with regards to viral load testing and defi ning optimal threshold for switching.

• Impact of diversity of programme needs: There is considerable complexity in constructing guidance to cover the diversity of ART programmes. Recommendations need to account for variability in HIV prevalence, laboratory capacity, formulary availability and healthcare infrastructure. Maintaining common goals across


such differing systems and capacities, and presenting the idea that there are several strategies is difficult. Further, programme development is under way, with countries improving laboratory capacities, thereby providing additional testing: programmes are on the move.

• Variability in Monitoring needs in HIV: To complicate the diversity of programme needs, HIV itself requires differing intensity of monitoring and interventions depending on the stage of the disease. Intensity of monitoring is required to be greater during advanced immunosuppression and after starting or switching therapy.

• Pragmatic approach to the inequity of failure: Common goals need to be endorsed (whether for developed and developing settings), given evidence and unknowns, yet diversity of capacity needs acknowledgement. “aspirational” goals of ART may be common, but pragmatically, definitions of failure are dependent on technology available. Current guidelines lack recommendations around definitions of failure given a level of technological capacity. Of concern with this approach is an implied hierarchy of outcomes, whereby those with resources for laboratory tests and monitoring and several lines of ART can aim for complete viral suppression, while those with more restricted means endure virological failure and the hazards and risks that entails. However, recognising this discomforting reality should not detract from provision of ART in the safest way to those in need.

Summary of the evidence and major recommendations

3.2.2 Goals of antiretroviral therapy

The distinction between public health approach and the more biological individual approach was agreed, with broad support for the more inclusive goals of the public health approach, including:

• Maximising survival for people living with HIV

• Improved quality of life

• Access to ART

• Maximal durable virologic suppression using safe potent ART to suppress HIV

• Immune restoration

• Reduced onward transmission

• Avoid drug resistant HIV and its onward transmission

The working group agreed that in a Public Health approach, the major goal of ART is maximize survival with improved quality of life.

A challenge arises in setting a goal of virological suppression without virological monitoring in some programmes. However, the “aspirational” goal of viral load suppression was endorsed at the meeting by all, despite the fact that it may not be monitored in a country programme. That viral suppression is beneficial to the individual is supported by evidence. What extent of viral replication (level and length of time) that can be tolerated with minimal clinical consequences is not however known. At present, using viral load monitoring as a means to support the goal of full viral suppression in the public health context is unsupported by the limited evidence.

3.2.3 Managing determinants of failure

What should be checked prior ART switching

Failure means that what is prescribed is not working, for which there are many reasons. Failure was agreed to occur after a reasonable trial of 1st line therapy of at least 6 months. Conditions to be addressed before 1st line ART failure identified include:

• Adherence assessment

• OI treated and resolved

• IRIS has been excluded


• other illnesses excluded

• Drug-drug interactions

• Sub-optimal dosing

Importance of Adherence

Adherence failure is the most important operational cause of ART failure. Adherence interventions should always be employed at all suspected and confirmed treatment failures.

Time to failure

Opportunistic infections and IRIS can occur within a year of starting therapy despite virological suppression. Current WHO guidelines suggest that any event occurring before 6 months should not be considered as evidence of failure. Whether this should be extended to a year was discussed. It was felt that this would depend on a programmes laboratory capacity and healthcare infrastructure.

Complexity of current ART failure definitions

Concern was expressed that complexity in guidelines and definitions of failure will impede successful public health programmes. Simple and explicit guidelines will facilitate successful implementation, as many of those monitoring patients are not clinically or healthcare trained. However, definitions of failure and recommendation to switch are complex, given the differing domains for definition of failure (VL, CD4, clinical) and the variability in frequency of monitoring. A balance between simplicity for implementation with a representation of the many needs of programmes is the aim.

Surrogate markers for virological failure and uncertainities on virological threshold

Major difficulties of current definitions of failure are the sensitivity and specificity of immunological and clinical monitoring as surrogates for virological failure and vice-versa. They are inadequate to be used in this capacity.

However, undetectable viremia (VL


on the latest CD4 and a bit on latest viral load – so we know that clinical events can happen in people with viral suppression The reasons for this are unclear, but may be related to increased background disease prevalence and higher immune activation.

Use of mathematical modelling to evaluate cost-effectiveness of ART strategies

Adding viral load may not be cost effective. Modelling suggests that viral load monitoring may have survival and morbidity benefits which are less and more costly than expected (20). However, caution should be attached to decision making based on mathematical modelling only, particularly because there is an important lack of evidence surrounding some key aspects as below:

1. Clinical events as marker of virological failure

2. The optimal viral load threshold for switching

3. Subtype influences outcome in terms of treatment and/or mutations

4. Cost effectiveness of various monitoring strategies

5. Effect of resistance patterns on second line therapy in LIC context

6. Effect of resistance patterns on long-term survival

7. How to define clinical failure in a way that is not too advanced (so death rate is too high) but not too early so that there are lots of switches.

ART monitoring phases and strategies

Guidelines are needed to account for a spectrum of monitoring, across the 3 domains of clinical, immunological and virological. Adherence is essential to success and should be monitored at each patient visit, and switch guidelines may differ if the patient is unwell.

HIV treatment was described as an intervention in a chronic disease of two phases: an initial phase of advanced immunosuppression, followed by immune recovery and treatment continuation. The first phase is considered to require more frequent and laboratory monitoring where possible, and probably includes the first year on therapy. The second phase, when safely established on therapy, probably requires less frequent monitoring and less laboratory monitoring thereafter. In cost terms, it is likely to be more efficient to concentrate scarce or expensive monitoring in the first phase.

The ART monitoring strategies currently in use include:

a. monitored only clinically (no laboratory tools available)

b. monitored clinically, with targeted CD4 cell count monitoring

c. monitored clinically with routine CD4 cell count monitoring

d. monitored clinically, with routine CD4 & targeted VL monitoring

e. use of routine VL monitoring

Importance of Training

Health care workers need clear indicators that treatment isn’t working. It is acknowledged that the health care worker undertaking monitoring may not be medically trained, and adequate training is essential to successf

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