British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy British HIV Association Writing Committee HIV Med 2003 4 Suppl 1 1 41 14511246

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DOI: 10.1046/j.1464-2662.2001.00083.x · Source: PubMed

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British HIV Association (BHIVA) Guidelines 1 July 2003
British HIV Association (BHIVA) guidelines for the treatment
of HIV-infected adults with antiretroviral therapy
July 2003
BHIVA Writing Committee on behalf of the BHIVA Executive Committee*
Correspondence: Dr Anton Pozniak and Professor Brian Gazzard, Chelsea and Westminster
Hospital, 369 Fulham Road, London SW10 9NH, UK; E-mail: anton.pozniak@chelwest.nhs.uk;
http://www.bhiva.org
*BHIVA Writing Committee members: A Pozniak, B Gazzard, J Anderson, A Babiker, D Churchill,
S Collins, M Fisher, M Johnson, S Khoo, C Leen, C Loveday, G Moyle, M Nelson, B Peters,
A Phillips, D Pillay, E Wilkins, I Williams, M Youle
Contents
1.0 Synopsis 4
1.1 When to start treatment 4
1.2 Initial therapy 4
1.3 When to switch therapy for virological failure 5
1.3.1 Which drugs to use following failure of initial therapy 5
1.4 When to switch therapy in the absence of virological failure 5
1.5 Resistance testing 5
1.6 Therapeutic drug monitoring (TDM) 5
1.7 New drugs likely to be used in the near future 6
1.7.1 Atazanavir 6
1.7.2 Enfuvirtide (T20) 6
2.0 Introduction 6
2.1 Purpose of guidelines 6
2.2 Basing recommendations on evidence 7
2.3 Use of evidence published as abstracts 7
2.4 Implication for research 7
2.5 Use of surrogate marker data 7
2.6 Issues concerning design and analysis of clinical trials 8
2.6.1 Trial designs 8
2.6.2 Method of analysis 8
2.6.3 Intention to treat and on treatment analysis 9
2.6.4 Equivalence 9
2.6.5 Cross-study comparisons: presentation of data 9
2.7 Adverse event reporting 10
3.0 When to start treatment 10
3.1 Primary HIV infection 10
3.1.1 Treatment of primary HIV infection to alter the natural history 10
3.1.2 Use of structured treatment interruption in acute infection 11
3.1.3 Treatment during PHI for immediate clinical benefit 11
3.1.4 Treatment during PHI to reduce onward transmission 11
3.1.5 Recommendations for starting treatment in PHI [CIII] 11
3.2 Symptomatic HIV infection 11
3.3 Asymptomatic HIV infection 12
3.3.1.1 Individuals with CD4 counts <200 cells/mm
3
12
3.3.1.2 Individuals with CD4 counts >350 12
3.3.1.3 Individuals with CD4 counts 201-350 cells/mm
3
12
3.3.2 Recommendations regarding asymptomatic chronic HIV infection 12
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British HIV Association (BHIVA) Guidelines 2 July 2003
4.0 What to start with 13
4.1 Choices of initial therapy 13
4.2 Which HAART regimen is best? 13
4.2.1 Two NRTIs plus an NNRTI 13
4.2.1.1 Efavirenz (EFV) 14
4.2.1.2 Nevirapine (NVP) 14
4.2.1.3 Delavirdine 14
4.2.2 Two NRTIs plus a PI 14
4.2.2.1 Two NRTIs plus a boosted PI 15
4.2.3 Three NRTIs 15
4.3 Choice of NRTI backbone for initial therapy 16
4.4 Recommendations for initial therapy: conclusions 16
5.0 Issues concerning antiretroviral use 16
5.1 Follow up of the HIV patient 16
5.2 Adherence 16
5.3 Toxicity 17
5.3.1 Lipodystrophy 17
5.3.1.1 Management of lipodystrophy 18
5.3.1.2 Other therapies 19
5.3.1.3 Conclusions 20
5.3.2 Mitochondrial toxicity and lactic acidosis 20
5.3.2.1 Aetiology of NRTI induced mitochondrial toxicity 20
5.3.2.2 Lactic acidosis and hyperlactataemia 20
5.3.2.3 Incidence 21
5.3.2.4 Clinical and laboratory features 21
5.3.2.5 Management of hyperlactataemia and lactic acidosis 21
5.3.2.6 Recommendations for managing lactic acidosis 21
5.4 Resistance testing 22
5.4.1 Recommendations 23
5.5 Therapeutic drug monitoring (TDM) 23
5.5.1 Drug levels and efficacy 24
5.5.2 Drug levels and toxicity 24
5.5.3 Use of TDM 24
5.5.4 Inhibitory quotients 24
5.6 Structured treatment interruption (STI) 25
6.0 Changing or stopping therapy in the absence of virological failure 25
6.1 Patients started on regimens that are not currently recommended for initial
therapy 25
6.1.1 2NRTI plus unboosted PI regimens 25
6.1.2 3NRTIs 25
6.1.3 Regimens containing stavudine 25
6.1.4 Non-HAART regimens 26
6.2 Patients on recommended regimens 26
6.2.1 Switching from PI-based regimens 26
6.2.2 Switching between NNRTIs 26
6.2.3 Stopping NNRTI-based regimens in non-emergency situations 26
6.3 Stopping therapy in individuals with complete viral suppression (structured
treatment interruption) 27
6.3.1 Intermittent on-off therapy cycles of one month or longer 27
6.3.2 Intermittent on-off therapy cycles of one week 27
6.3.3 Discontinuation of therapy with re-start based on CD4 count [CII] 27
7.0 Changing and stopping therapy for virological failure 28
7.1 Virological failure 28
7.1.1 Viral load blips 28
7.1.2 Sustained viral load rebound 28
7.2 Changing therapy [BII] 28
7.2.1 Failure of two nucleoside analogues plus a protease inhibitor [BII] 29
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British HIV Association (BHIVA) Guidelines 3 July 2003
7.2.2 Failure of two nucleoside analogues plus a non-nucleoside reverse
transcriptase inhibitor [BIII] 29
7.2.3 Failure of triple nucleoside analogue therapy [BIV] 29
7.3 Patients whose therapy fails having used at least three classes of drugs
(“salvage therapy”) 30
7.3.1 Criteria for success in patients exposed to multiple drug classes 30
7.3.2 Principle of optimising success in highly treatment experienced
patients 30
7.3.3 Management of patients with multiple class resistance 31
7.3.4 Recommendations for subsequent virological failure (third or more
regimen) [BIII] 32
8.0 New therapies 32
8.1 Enfuvirtide (T20) 32
8.2 Atazanavir 33
8.3 Extended release stavudine (D4T) 33
8.4 Emtricitabine (FTC) 33
8.5 Tenofovir 33
8.6 Fosamprenavir 34
9.0 References 44
10.0 Conflict of interest 54
List of Tables
Table 1 Basic net NHS cost of antiretroviral drugs 35
Table 2 Grading of recommendations and levels of evidence 36
Table 3 Recommendation for starting treatment 36
Table 4 Initial HAART regimens 37
Table 5 Currently available non-nucleoside reverse transcriptase inhibitors (NNRTIs) 38
Table 6 Currently advised protease inhibitors (PIs) for initial therapy 38
Table 7 Routine tests and examinations in the HIV patient 39
Table 8 Meta-analysis of trials of HIV resistance testing 40
Table 9 Proposed indications for therapeutic drug monitoring (TDM) 40
Table 10 Potential objectives of structured treatment interruptions (STI) in different clinical
settings 41
Table 11 Changing therapy on first virological failure [BIII] 42
Table 12 What to change to after first virological failure: summary of
recommendations [BII/IV] 43
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British HIV Association (BHIVA) Guidelines 4 July 2003
1.0 Synopsis
This synopsis represents a consensus from the writing committee based upon the evidence given in
detail in the full guidelines. It aims to offer a pragmatic approach to some difficult questions
concerning HIV therapy. Some aspects of this synopsis are controversial and clinicians are advised
to read the current guidelines in full, alongside those regarding adherence to treatment and hepatitis
B and C co-infection [1,2].
1.1 When to start treatment
In asymptomatic patients this decision should be driven primarily by the CD4 count. A value of 200
cells/mm
3
represents the minimum level at which treatment should be advised. Treatment should be
initiated when the CD4 count is between 200 and 350 cells/mm
3
, and the exact timing should
depend on individual factors such as symptoms, patient preference, likely adherence and potential
toxicity. In this range, the rate of CD4 decline, viral load (VL) level and age provide additional
information to the CD4 count on the short-term risk of progression. Severely symptomatic disease is
unusual at CD4 counts above 350 cells/mm
3
in chronic HIV infection, but provides a rationale for
treatment when it occurs.
For patients with primary HIV infection, treatment is only recommended for the purpose of resolving
severe symptoms. Otherwise the committee feels there is insufficient evidence to recommend
treatment outside clinical controlled trials.
1.2 Initial therapy
When choosing therapy, the committee takes the view that in the present state of knowledge more
weight should be given to ease of adherence and minimisation of toxicity, including development of
lipodystrophy, than to the likely pattern of resistance mutations emerging following treatment failure.
There is more evidence and experience available in support of initial regimens which include two
nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI) or
an non-nucleoside reverse transcriptase inhibitor (NNRTI) than for other combinations, so we
generally support the use of such combinations for starting therapy. Combinations including
stavudine (d4T) are not recommended for initial therapy due to possible risks of more rapid
development of lipodystrophy. Several recent studies have shown excellent surrogate marker
responses for combinations containing lamivudine (3TC) and efavirenz. On current data, the
nucleoside-only combination abacavir (ABC)/3TC/zidovudine (ZDV) should not be considered as a
first line option for initial therapy (but see section 4.2.3 where this is discussed more fully).
NNRTI regimens produce equivalent or superior surrogate marker responses compared with
unboosted PI regimens. There are no studies of sufficient size that directly compare NNRTIs with
boosted PIs, which the committee recommend when a PI containing regimen is used. Therefore, the
choice between these needs to be based on other considerations. The advantages of NNRTIs over
currently licensed PIs include suitability for use in once daily regimens, lower pill burdens, fewer
clinically important lipid abnormalities, and a lower frequency of central fat accumulation. There is no
evidence of a difference in clinical effectiveness between PI and NNRTI regimens in late disease.
PIs may have advantages in that broad cross class resistance is less likely than for the NNRTIs and
have less hepatotoxicity and rash.
Hence at present the writing committee considers that NNRTIs are more suitable as the agents of
first choice for initial regimens. The choice of NNRTI will need to be made by clinicians interpreting a
range of studies, including the 2NN trial. The latter study indicates that there is little difference in
potency between nevirapine (NVP) and efavirenz (EFV). NVP treatment was associated with more
rash and hepato-toxicity, whereas the disadvantages of EFV are a variable rate of psychological
disturbances and the possibility of teratogenesis. A number of options for once a day therapy are
now available and these regimens are likely to become increasingly popular.
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British HIV Association (BHIVA) Guidelines 5 July 2003
1.3 When to switch therapy for virological failure
A number of strategic studies are in progress to address this issue. Until they report, the committee
takes a pragmatic view.
In cases where tolerable treatment options are available that are likely completely to inhibit viral
replication, these should be used as soon as virological rebound has been confirmed by two
consecutive VLs > 400 copies/ml. The committee emphasizes that before therapy is changed,
factors other than resistance, such as poor adherence and pharmacokinetic effects reducing plasma
levels of drugs to below optimum levels, need to be examined carefully in this group.
In cases where it is unlikely that further treatment will produce complete inhibition of viral replication,
continuation of current therapy is reasonable if the imminent risk of death is low, judged by the CD4
count. However, there is a rationale for switching albeit to a less than optimally suppressive
regimen - in those individuals in whom the imminent risk of death is high, in order to try to improve
viral suppression with the aim of raising the CD4 count.
1.3.1 Which drugs to use following failure of initial therapy
Wherever possible one or two different drugs of the NRTI / PI / NNRTI classes should be included in
such a switch regimen. Resistance testing should be used to inform the choice of regimen,
particularly for those with prior experience of NAs and PIs or NNRTIs. Patients whose therapy fails
with adherence problems may benefit from simpler but effective regimens to which their virus is still
sensitive.
1.4 When to switch therapy in the absence of virological failure
When an individual drug as part of a regimen is causing toxicity the choice of agents to switch to is
often self evident and is usually within class, particularly for patients on complex regimes who are
finding complete adherence difficult. Regimen simplification, for example to a triple NRTI pill of ZDV,
3TC and ABC appears to be safe in those whose previous antiretroviral treatment has not failed and
may improve adherence. Switching because of the development of abnormal lipids or the fat
redistribution syndrome is more complex and of less certain benefit. It is dealt with in detail in the
guidelines. Any improvements in fat redistribution that occur as a result of such switching are likely
to be slow.
1.5 Resistance testing
There is variable evidence for a benefit of resistance testing for treatment-experienced patients in
controlled trials. However, the level of resistance to a regimen predicts the response to a new
regimen and the cost of such testing is low compared with that of drug treatment. We recommend
testing at each virological rebound. Although it will be difficult to design trials to establish the value of
resistance testing in drug-naive individuals, such testing prior to therapy may be of crucial value for a
proportion of patients who carry mutations, especially in the context of demonstrable transmitted
drug resistance. In view of this, resistance testing is recommended for all drug-naive patients prior to
commencing treatment using the nearest available sample to seroconversion or presentation.
1.6 Therapeutic drug monitoring (TDM)
Evidence for the clinical value of TDM remains limited although the committee recognises that it may
have a role in reducing toxicity in individual patients and in adjusting doses in those with significant
hepatic or renal impairment or at extremes of body weight, and may help to explain treatment
failures. It may also be of value in individuals with advanced disease who are limited to using
combinations that may have the potential for unknown pharmacokinetic or drug interactions.
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British HIV Association (BHIVA) Guidelines 6 July 2003
1.7 New drugs likely to be used in the near future
1.7.1 Atazanavir
The main interests in this drug lie in its once-daily dosing, its lack of effect on lipid metabolism and,
by implication, low probability of an association with lipodystrophy. Present studies indicate similar
potency to an NNRTI or unboosted PI in treatment-naive patients. If these early results are
confirmed, many clinicians may find this drug an important option when choosing a first PI.
1.7.2 Enfuvirtide (T20)
This drug has recently been licensed for patients with treatment failure. It is the first of a new class
of compounds interfering with HIV cell entry. Its main disadvantage will be mode of administration
(by injection twice a day). Wherever possible it should be reserved for use after second or
subsequent treatment failure, in combination with one or preferably two other new drugs that are
expected to be active on the basis of resistance data, to give a realistic prospect of suppressing viral
replication completely. This may mean keeping some patients on their current regimen while waiting
for other new drugs to become available for use alongside T20.
In individuals at imminent risk of clinical disease and death, T20 might have a limited role as
additional therapy in a failing regimen where there are no other active drugs available.
2.0 Introduction
The BHIVA executive is committed to producing updates on the antiretroviral treatment guidelines for
adults on a regular basis. Over a 1- to 2-year period, much can change in clinical practice as new
scientific evidence is published. To reflect these changes the guidelines have been extensively
revised and some sections removed and new sections added. The sections on co-infection with HIV
and hepatitis B or C now form separate guidelines which can be found at the BHIVA website
(http://www.bhiva.org). New guidelines on tuberculosis co-infection, paediatric HIV care, and
adherence to treatment are also in preparation, while guidelines on the management of HIV and
pregnancy will be updated over the coming year.
The principles of consensus that overarched the previous guidelines [3,4] were upheld in the
production of this, the latest version. We believe it is important that the process by which the
guidelines have been revised is made clear. As in the previous guidelines each section was
designated to two members of BHIVA, and the Executive Committee have taken on the bulk of this
work. The members were asked to revise the guidelines in line with new evidence that had been
published either in peer reviewed journals or as peer reviewed abstracts at international meetings.
The authors were asked to consult widely with colleagues and co-opt other BHIVA members if need
be.
2.1 Purpose of the guidelines
Guidelines for the treatment and management of HIV infection have been produced in a number of
countries in Europe, as well as in Australia and the USA [5-8].
The BHIVA guidelines have a number of important roles which are:
(1) To promote a uniformly high standard of care in all HIV treatment centres in the UK.
(2) To set out the strengths, weaknesses and relevance of recent research findings.
(3) To assist in discussions between purchasers and providers regarding funding for HIV/AIDS
diagnostic testing, care and treatments.
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British HIV Association (BHIVA) Guidelines 7 July 2003
(4) To act as a basis for clinical audit within clinical governance.
(5) To act as a source of reference on antiretroviral treatments for those physicians caring for
patients infected with HIV.
(6) To act as a source of reference for HIV-positive people.
The cost of drugs has not been considered in preparing these guidelines, but basic NHS costs are
shown in [Table 1]. Clinicians will be aware that actual costs may vary especially where bulk
purchases have been arranged.
These guidelines should not be seen as a substitute for research, nor as a manual for managing an
individual. While the guidelines attempt to represent the current state of knowledge it is inevitable
that, as HIV/AIDS is a rapidly evolving medical field, new data will change therapeutic choices and
preferences. Consequently, the guidelines will require modifications as important new data emerge
and the website version (found at www.bhiva.org) will be amended at regular intervals to reflect
these data. Revisions are planned annually.
Recommendations made within these guidelines have been graded according to the level of
evidence on which they are based [Table 2]. Recommendations range from ‘essential’ to ‘optional’
and the quality of evidence from ‘at least one randomized trial with clinical endpoints’ through to
‘expert opinion’. They are to be found in parentheses in the document, for example (AII).
2.2 Basing recommendations on evidence
The committee used an evidence-based medicine approach to produce these guidelines. In reality, if
only the most reliable form of clinical evidence was taken into account (i.e. results of one or more
randomized controlled trials with clinical endpoints), it would be impossible to formulate these
guidelines. Many important aspects of clinical practice remain to be formally evaluated and very few
trials with clinical endpoints are ongoing or planned. Results from clinical trials with viral load and CD4
count changes as endpoints were included as, in many instances, they are the only source of
evidence. However, most such trials have been performed in order to obtain drug approval and are
not ideally suited to addressing questions of clinical usage. The most significant drawbacks of such
trials are their short duration and the lack of follow-up data on patients who switch therapy. In most
cases the only available data on long term outcomes are from routine clinical cohorts. While such
cohorts are representative of routine clinical populations, the lack of randomization to different
regimens means that comparisons between the outcomes of different regimens are highly
susceptible to bias [9,10] opinion forms an important part of all consensus guidelines; however, this
is the least valuable and robust form of evidence.
2.3 Use of evidence published as abstracts
The authors of these guidelines recognize that there is often a considerable time lag between initial
presentation of important data, whether orally or in abstract/poster format, and full publication.
Consequently, there is danger in relying on data that have not been subjected to formal peer review
and published in full. We have therefore avoided citing any research findings that appeared only in
abstract format more than 3 years ago (i.e. before mid 2000).
2.4 Implications for research
Unless guidelines are interpreted and applied cautiously and sensibly, valuable research initiatives
that might improve standards of care will be stifled. It would be wrong to suggest that certain clinical
controlled trials would be unethical if they did not conform to the guidelines, especially when these
guidelines are based mainly upon expert opinion rather than more reliable evidence. The National
Health Service (NHS) executive has stated that clinical guidelines cannot be used to mandate,
authorize or outlaw treatment options [11].
2.5 Use of surrogate marker data
CD4 cell counts and plasma viral load are used as markers of the biological activity of antiretroviral
therapy in Phase I and II trials. Reduction in viral load leads to a rise in peripheral blood CD4 count,
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British HIV Association (BHIVA) Guidelines 8 July 2003
with greater rises being seen in those with greater and more sustained viral suppression [12].
Changes in these markers in response to therapy are strongly associated with clinical response [13-
16]. CD4 counts measured in people on antiretroviral therapy have been associated with a risk of
AIDS defining diseases no higher than that expected in untreated individuals with similar CD4 counts
[17-21]. The CD4 count is a better indicator of the immediate risk of AIDS defining diseases than the
viral load in those on antiretroviral therapy [22].
Favourable responses to therapy, i.e. a decline in plasma HIV-1 RNA and increase in CD4 cell
counts, have led to accelerated licensing of antiretroviral agents since it is impracticable to wait years
for large clinical endpoint trials to be completed before drugs are approved [13, 14, 23]. Drugs are
given full approval on the basis of trials lasting 48 weeks and, in some countries, accelerated
approval based on data to 16 weeks.
Most clinicians would agree that a drug licensing policy based on surrogate markers is reasonable
and humane. However, it should be remembered that CD4 count and viral load responses do not
precisely reflect the expected clinical outcome and are not perfect surrogates of the clinical response
[24-26]. This is because the drugs have other effects with clinical consequences besides those
reflected in viral load and CD4 count changes. The relatively short length of trials designed to obtain
drug approval means that, at the time of licensing, little may be known about the drugs’ long term
consequences.
2.6 Issues concerning design and analysis of clinical trials
2.6.1 Trial designs
Most antiretroviral drug trials are performed by pharmaceutical companies as part of their efforts to
obtain licensing approval and the designs are often not ideally suited to deriving information on
using the drugs in clinical practice. Besides the short duration of follow-up, their key limitation is the
lack of data on outcomes in people who change from the original randomized regimen, along with a
description of what those new regimens are. The results are therefore only clearly interpretable as
long as a high proportion of participants remain on the original allocated regimens. Clinical questions
about which drugs to start with or switch to require longer term trials that continue despite changes
to the original treatment. From a clinical perspective it makes no sense to ignore what happens to
patients after a regimen has been discontinued. Moreover, use of a given drug can affect outcomes
long after it has been stopped. For example, it may select for virus resistant to drugs not yet
encountered or cause toxicities which overlap with those caused by other drugs. However,
interpretation of such trials is not straightforward, and account must be taken of which drugs were
used subsequent to the original regimen in each arm. Planned or ongoing trials adopting such an
approach include Community Programs for Clinical Research on AIDS (CPCRA)’s FIRST and the
Initio trial [which is being run in the UK by the Medical Research Council (MRC)].
Study design may significantly influence the discontinuation rate of trial drugs. An open trial design
may result in higher levels of discontinuation from what is perceived to be the least effective regimen,
while a double blind, placebo controlled study may reduce adherence in all groups because of the
large pill burden. It is also important to recognize that controlled clinical trials provide an optimal
treatment setting but results from the use of regimens in clinical practice are usually not as good.
The committee generally favours entry into well-constructed trials for patients whose clinical
circumstances are complex, with a number of specific instances being mentioned in these guidelines.
NAM maintains a list of trials currently recruiting in the UK at www.aidsmap.com, and treatment units
should work to ensure arrangements are in place to enable eligible patients to enter trials at centres
within or indeed outside their clinical networks.
2.6.2 Methods of analysis
Several methods have been used to analyse viral load and CD4 count responses, including the
change from baseline at a given time and the time-weighted change from baseline or the area under
the curve (AUC). For virological response, however, the most common approach relates to whether
the viral load is below a certain level, usually 50 HIV-1 RNA copies/mL, which is the approximate
lower limit of quantification for most viral load assays in routine use. The proportion of people with
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British HIV Association (BHIVA) Guidelines 9 July 2003
viral load <50 copies/mL at a given time point is assessed. One reason for the choice of this
outcome measure is that some studies have indicated that if this minimum level is not achieved then
subsequent viral load rebound is more likely [27, 28]. However, when comparing treatment regimens,
differences in viral load between treatment groups, provided levels are >50 copies/mL, are highly
predictive of subsequent differences in clinical outcome [29]. Restricting comparison to those with
viral load <50 copies/mL would not utilize other information contained in the viral load measurement.
A related method of assessing response to an initial regimen is calculating time to virological failure.
Virological failure is typically defined by failure to achieve viral suppression or viral load rebound after
achieving <50 copies/mL, but there is no consensus on precise definitions [23, 30].
2.6.3 Intention to treat and on treatment analysis
Randomization in a trial ensures balance in prognosis between the treatment arms at baseline.
Inability to assess outcomes for some patients can disturb this balance and create bias in the
comparison between the treatment arms. In order to avoid risk of such bias, analysis by intention to
treat includes outcomes for all randomized patients. For this purpose, it is necessary to continue
collecting data on all patients even if they have switched from the original regimen. As this is rarely
done, the intention to treat principle is maintained by imputing values for those patients who have
dropped out of the trial. When the outcome is the proportion of people with viral load <50 copies/mL
at a given time point, the approach almost universally adopted is to assign >50 copies/mL to all
patients who have earlier switched therapy or have the viral load value missing for any reason. This
is known as the missing=failure approach [31]. Such an approach implicitly equates failure of a
regimen due to inadequate potency and/or viral drug resistance with inability to tolerate a regimen
due to pill burden, inconvenience and/or adverse effects, even though the implications of these two
outcomes are likely to be substantially different. This approach is often labelled conservative
because it gives a minimum proportion <50 copies/mL for any given treatment group over all possible
approaches. However, the primary purpose of an endpoint is to compare treatment arms and, in this
context, this approach is not conservative in any general sense.
On treatment analyses consider outcomes only in those still receiving the original allocated
treatment. In the context of the proportion of people with viral load <50 copies/mL at a given time
point, this makes little sense because therapy is switched in patients who experience viral load
rebound during a trial. Given this management policy, the proportion of people remaining on the
original regimen who have a viral load >50 copies/mL will reflect the speed with which clinicians
decide to switch therapy in response to the first viral load value(s) >50 copies/mL. It is difficult to see
how it provides a useful means to compare the efficacy of different regimens. Within the context of
time to virological failure, the on treatment analysis may be more revealing.
In situations where there is a high (>25%) proportion of patients who do not have a viral load value
at a given time point (except where this occurs due to staggered entry), interpretation is inherently
difficult and no analytical approach is entirely satisfactory.
2.6.4 Equivalence
Large numbers of patients are usually required to show equivalence between regimens (i.e. to
demonstrate no or a small difference in response between treatments). Many surrogate marker
studies are underpowered to demonstrate this. Stating that studies have shown no significant
difference between the treatment arms is very different from saying that the arms show equivalence.
Graphical representations that show overlapping increased CD4 cell counts or decreased viral loads
in response to therapy may hide differences in efficacy between drugs. The confidence interval (CI)
for the difference in outcome between treatment arms should be examined carefully in such studies.
Lack of adherence to allocated regimens is an even greater issue in equivalence trials because an
intention to treat analysis would tend to dilute the difference in outcome between treatment groups.
Unless discontinuations and treatment changes during the trial reflect what would happen in clinical
practice, the results from intention to treat analysis would be biased towards equivalence.
2.6.5 Cross-study comparisons: presentation of data
It is tempting to compare results of individual drug combinations assessed in different trials. Such
comparisons are, however, difficult to interpret because of differences in entry criteria (particularly
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British HIV Association (BHIVA) Guidelines 10 July 2003
with respect to viral load and CD4 cell counts), methods of analysis (e.g. intention to treat versus on
treatment), degrees of adherence and sensitivities of viral load assays.
2.7 Adverse event reporting
Many previously unsuspected side effects of antiretroviral therapy have been reported only after
drug licensing. It is vital that prescribers report any adverse events as soon as possible so that these
events are swiftly recognized. A blue-card scheme, organized by the Medicines Control Agency, the
Committee for Safety of Medicines (CSM) and the MRC, operates in the UK for reporting adverse
events relating to the treatment of HIV
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3.0 When to start treatment
With currently available antiretroviral agents, eradication of HIV infection is not likely to be possible
[32]. The main aim of treatment is thus to prolong life and improve quality of life by maintaining
suppression of virus replication for as long as possible.
The three groups of treatment naive patients for whom treatment guidelines are required are:
patients with symptomatic HIV disease or AIDS, patients with asymptomatic HIV infection and
patients with primary HIV infection.. The recommendations are summarised in Table 3.
3.1 Primary HIV infection
3.1.1 Treatment of primary HIV infection to alter the natural history
There is one placebo-controlled study of ZDV monotherapy in primary HIV infection (PHI) [33] and it
showed short-term benefit only. As yet, there is no evidence of long term clinical benefit from any
study of treatment of PHI compared with deferring treatment until later, however. If it is recognised
clinically, the diagnosis of PHI may represent a unique opportunity for therapeutic intervention. It is
likely that, at the time of PHI: (1) there is a narrowing of the genetic diversity of the infecting virus
compared with the virus in the index case [34,35]; (2) viral ability to infect different cell types may be
limited; and (3) the capacity to mount an immune response is usually greater than it is later on.
Therefore, the treatment of PHI may preserve HIV specific immune responses and it has been
hypothesized that long term benefit may ensue. A variety of triple drug therapy regimens appear
able to suppress viral replication in the plasma, lymph nodes and gut for the majority of patients
treated within a few months of PHI [35, 36]. Recent studies have demonstrated that shortly after PHI
there is a specific and strong CD4 helper HIV response [37-40]. This is in contrast to chronic
infection where, with the exception of long term non-progressors [39], the HIV specific CD4 helper
response is generally lost [41]. These CD4 helper responses may be important in maintaining an
adequate CD8 response. Such immune responses appear to be maintained in people treated with
potent antiretroviral therapy shortly after PHI and perhaps represent the best biological evidence
that treatment at this time might be beneficial. Recent data suggest that there is more rapid and
complete immune reconstitution in patients starting therapy during PHI than in those starting later
[42]. There is still no answer to the question of whether treatment at such an early stage will
influence the longer term natural history.
Control of viral replication with no return of viraemia after withdrawal of antiretroviral therapy has
apparently occurred in a few patients treated very soon after PHI [43].
The role of drugs that are known to inhibit CD4 activation, such as hydroxyurea [44] and cyclosporin
A [45], in the suppression of viral replication and boosting of CD4 lymphocyte responses in this
setting is unclear and requires further evaluation. Given the present lack of clarity, it remains
reasonable to consider treating PHI, ideally within a clinical trial. These putative benefits of treatment
during PHI should be tempered by the known risks of toxicity, including lipodystrophy [46, 47] and
the potential for developing drug resistance at an early stage. The potential difficulties of long term
adherence to available regimens cannot be overstated. It is possible that short-term antiretroviral
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British HIV Association (BHIVA) Guidelines 11 July 2003
therapy in PHI may be of some immunological benefit [48], but it is not known if this is associated
with improved clinical outcome.
3.1.2 Use of structured treatment interruption in acute infection
Although earlier data proposed a possible role for structured treatment interruptions (STIs) in
stimulating the host immune response and reducing the virological set point in patients treated very
early during PHI [49], longer follow-up of the same cohort suggested that viral rebound subsequently
occurred with no apparent impact on the natural history [50]. This supports data from others
suggesting that discontinuing therapy initiated during PHI had no apparent effect upon the set point
that would have been expected in the absence of any treatment [51]. Treatment cessation has
been used rather than multiple treatment interruptions [52], demonstrating that a significant
percentage of persons are able to control viraemia spontaneously.
In conclusion, although multiple anecdotal reports as well as small clinical trials and data on
macaques [53] suggest that STIs offer transient benefits in PHI, the few data we have suggest this
does not bring any long term immunological benefit. The exact window of opportunity remains to be
defined and will likely require larger clinical trials.
3.1.3 Treatment during PHI for immediate clinical benefit
Individuals who present with severe or prolonged symptoms (such as meningoencephalitis) due to
PHI may improve if treated with antiretrovirals. However the duration of therapy needed is unknown,
and the possibility of further acute retroviral syndrome on withdrawal of therapy must be considered.
3.1.4 Treatment during PHI to reduce onward transmission
One study has suggested that many recently infected patients have acquired the infection from
others who were themselves recently infected with HIV. Identification and treatment of PHI might
thus have some effect on reducing HIV incidence [54]. Even if treatment is not started during PHI,
there are many benefits of recognizing early HIV infection. These include recognition and monitoring
of primary drug resistance, partner notification and contact tracing and the possibility of preventing
HIV transmission. Particular effort should thus be directed to identifying patients with PHI who may
present to a wide range of healthcare providers.
3.1.5 Recommendations for starting treatment in PHI [CIII]
At the time of PHI patients and physicians should make the most appropriate decision based on the
limited data available.
ß The biological plausibility that early treatment may be beneficial for the immune system
should be balanced against considerations of adherence to long term therapy, potential
toxicity and development of resistance. The committee’s first choice would be for patients to
enter a clinical controlled trial, where available.
ß For those who are treated at this time there is no current available data as to the best
therapeutic regimen. Thus a regimen appropriate for treatment of chronic HIV infection
should be used.
ß If treatment is started the decision to stop or continue may be reviewed in the light of
evolving data or poor adherence.
ß Patients who are currently being treated with antiretroviral therapy started during PHI who
may wish to stop treatment should be encouraged to do so in the context of a clinical study.
3.2 Symptomatic HIV infection
All patients with late disease and/or symptomatic HIV infection with a CD4 lymphocyte count
consistently <200 cells/mm
3
, or who have been diagnosed with AIDS or severe/recurrent HIV related
illnesses* or tumour at any CD4 count, should start therapy. This is because of the high risk of
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British HIV Association (BHIVA) Guidelines 12 July 2003
further opportunistic infections which, although treatable, may cause irreversible damage or be life
threatening.
*With the possible exception of pulmonary tuberculosis
3.3 Asymptomatic HIV infection
There are no ongoing controlled studies that address the optimum time to start therapy [55]. Current
guidelines are therefore based upon previous studies of monotherapy and data from large clinical
cohorts. Since the quality of evidence is relatively poor, opinion is divided on this question. The
absolute CD4 count forms the basis of these guidelines, but treatment may also be considered for
patients with a CD4 percentage below 12%.
In the UK, patients are diagnosed with HIV infection at a late stage. Over 30% present with a CD4
count of <200 cells/mm
3
[56] and, consequently, the ‘early versus late’ debate is irrelevant to many.
The decision on when to start treatment will be influenced principally by two considerations: the short
term risk of developing AIDS prior to treatment and the potential efficacy of starting treatment at
various CD4 counts. Although it may be biologically plausible to start treatment early, this has to be
tempered by the known potential for significant drug toxicity, difficulties with long-term adherence,
and the selection of drug-resistant virus.
3.3.1.1 Individuals with CD4 counts <200 cells/mm
3
Patients with CD4 counts <200 cells/mm
3
have a high short-term risk of disease progression and
death [57]. Several cohort studies have suggested that patients who initiate therapy when the CD4
count is <200 cells/mm
3
have an increased mortality [58-60] compared with those starting with CD4
counts above this level. Some prospective studies have suggested that for some antiretroviral
regimens, patients with a low baseline CD4 count have a poorer virological response [61, 62]. All of
these strands of data suggest that it is better to start therapy before the CD4 count has fallen to
<200 cells/mm
3
.
3.3.1.2 Individuals with CD4 counts >350
If the CD4 count is > 350 cells/mm
3
, the risk of clinical progression in the short term is generally low
[57] although individuals with a high viral load have a greater (but still small) short-term risk of
disease progression [Table 3].
One unrandomised retrospective case-control study [63] has suggested that patients who
commenced therapy with a CD4 count >350 cells were less likely than those who commenced later
to experience disease progression or death. However, a large cohort study [64] has suggested no
difference in disease progression in individuals commencing therapy with CD4 counts >350 versus
201-350 cells/mm
3
. For the majority of patients with CD4 counts >350 cells/mm
3
it is reasonable to
defer therapy until the CD4 count is below 350 but above 200 cells/mm
3
.
3.3.1.3 Individuals with CD4 counts 201-350 cells/mm
3
Ideally, most individuals with established HIV infection should start therapy when the CD4 count is in
the range 201-350 cells/mm
3
. It is important not to let the CD4 count fall below this level before
starting treatment for the reasons outlined above. Whilst it may be safe to monitor the CD4 count in
some individuals with counts in this range, in others there will be an unacceptable risk of disease
progression or of CD4 count falling to <200 cells/mm
3
. These individuals may include those with a
high viral load (e.g. > 60,000 copies/ml [65], >100,000 copies/ml [57]. Patients with a rapidly falling
CD4 count (e.g. falling >80 cells/mm
3
per year on repeated testing [66] have an increased risk of
CD4 cell count decline to <200 cells/mm
3
in the next 6 months. People in these groups may thus be
considered for initiation of therapy relatively earlier within the CD4 count range 200–350 cells/mm
3
.
People who wish to take therapy for a limited period of time and subsequently interrupt treatment
may also be advised to start early to ensure a high CD4 nadir. A further group in whom earlier
initiation of therapy may be considered are those with hepatitis C co-infection, since progression of
liver disease occurs more rapidly with lower CD4 counts [67, 68] and antiretroviral treatment is
associated with a reduced rate of progression of liver disease [69]. An alternative strategy may be
to treat the hepatitis C before it becomes necessary to treat the HIV.
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British HIV Association (BHIVA) Guidelines 13 July 2003
3.3.2 Recommendations regarding asymptomatic chronic HIV infection
ß Currently, our recommendation is that patients start therapy before the CD4 count falls to
<200 cells/mm
3
. (AIII)
ß Given the available data and the limitations of currently available treatment, treatment is not
indicated in asymptomatic individuals with a CD4 count >350 cells/mm
3
. (AII)
ß Within the range 200–350 cells/mm
3
, individuals with a rapidly falling CD4 count (AII), a high
viral load (AII) or hepatitis C co-infection (CIII) may be considered for earlier intervention.
If patients to whom these recommendations apply choose not to go on treatment, it is suggested
that their CD4 count and viral load be monitored intensively (e.g. every 2 months) and the decision
to start treatment be reviewed at regular intervals. (AIII)
4.0 What to start with
4.1 Choices of initial therapy
There is overwhelming evidence from cohort studies that the very dramatic fall in AIDS-related
mortality and frequency of AIDS events seen in the developed world over the last 6 years coincides
with the introduction of HAART [18, 70]. Any HAART regimen should be individualized in order to
achieve the best potency, adherence and tolerability; to minimize potential long-term toxicity; and to
avoid any likely drug–drug interactions (www.hiv-druginteractions.org).
A measurement of a regimen’s success is achieving a viral load of <50 HIV-1 RNA copies/ml within 3-
6 months of starting therapy and maintaining this out to 48 weeks. Regardless of the baseline viral
load, a level of 1000 copies/ml has been found to be achievable in the majority of people by 4
weeks from start of therapy. Failure to achieve this is strongly associated with failure to reach viral
load below 50 copies/ml within 24 weeks. Therefore, if the viral load measured 4 weeks after the
initiation of therapy remains above 1000 copies/ml, this should prompt questions over possible poor
adherence or other reasons such as reduced drug levels or primary drug resistance.
4.2 Which HAART regimen is best?
There have been no definitive controlled trials to demonstrate the clinical superiority of a HAART
regimen used as initial therapy containing a boosted protease inhibitor (PI) when compared with a
regimen containing a non-nucleoside reverse transcriptase inhibitor (NNRTI). Patients should
continue to be informed about and encouraged to participate in available clinical trials to further
clinical practice. It is very important to select a regimen, which is best for the individual patient, and
therefore to fully assess baseline risk factors for hepatitis B/hepatitis C co-infection, cardiovascular
disease, diabetes, and psychiatric disease. In addition lifestyle issues such as smoking, obesity and
recreational drug and alcohol use need to be taken into account. Several regimens will be
discussed below and the advantages and disadvantages of each will be assessed. Their relative
merits in terms of potency, adherence, toxicity, salvageability and potential drug–drug interactions
are summarised in (Table 4). Previous guidelines suggested that patients with high viral loads may
need more than three active drugs to achieve a rapid decline in viral load. There has been no new
evidence from any clinical study to date for us to continue to recommend this strategy.
4.2.1 Two NRTIs plus an NNRTI
Efavirenz (EFV) and Nevirapine (NVP) are both recommended for initial therapy. These combinations
have now been evaluated in a controlled, comparative trial using surrogate marker endpoints [71].
The 2NN study [62] yielded data comparing the two drugs in a randomized manner, showing that
EFV and NVP were comparable in potency. However, equivalence was not formally proven, with a
small chance that NVP was superior to EFV and a rather greater chance of the reverse. Two drug
related deaths occurred in the nevirapine arm.
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British HIV Association (BHIVA) Guidelines 14 July 2003
4.2.1.1 Efavirenz (EFV)
Impressive surrogate marker data have been obtained using EFV with two NRTIs (ZDV/3TC) [72-75].
One of the main advantages of an EFV containing regimen is that this can be prescribed once daily,
and with the new formulation is only one pill, both of which may improve adherence. EFV has a long
plasma half life ensuring that drug levels far exceed the concentration determined in vitro required to
inhibit 90% of viral growth. This advantage however, may be a problem on stopping EFV. The long
half life in comparison to some of the NRTIs means that the drug may remain in the plasma for
several days effectively exposing the patient to monotherapy and the associated risk of drug
resistance. To obviate that, many people would add a short acting protease inhibitor, e.g. nelfinavir
(NFV), to the regimen for two weeks, discontinuing EFV under this umbrella and then stopping all
other drugs at the same time. In an early randomized open-label study, ZDV/3TC/EFV was
compared with ZDV/3TC/indinavir (IDV) and showed either no difference or superior surrogate marker
endpoints up to 144 weeks of follow-up when analysed in a variety of ways (including intention to
treat and on treatment analysis) [75]. The major drawback of this study however was the high
discontinuation rate in both arms. By week 48, 35% of the IDV group and 25% of the EFV group
had withdrawn from the study. This, along with the open nature of the study, may have biased the
intention to treat analysis in favour of EFV. It also needs to be noted that the comparison drug,
unboosted IDV, has a high pill burden requiring three times a day dosing, fasting, and therefore
major adherence issues. It is no longer the normal standard of care for patients on a PI based
regimen.
The major side effect of EFV is dysphoria. Manifestations include vivid dreams, depression,
drowsiness and, in some, insomnia. Most are self-limited and it is unusual for patients to discontinue
the drug for this reason within trials [76], though this may be more common in clinical practice.
Rashes do occur, but severe rashes with EFV are unusual (the incidence of Stevens-Johnson
syndrome is 0.1%). Lipid abnormalities, mainly rises in cholesterol above baseline values, have been
observed in patients on EFV containing combinations [77]. EFV appears to be potent when used in
patients with high viral titres, >100 000 copies/ml and low CD4 counts [76]. This drug may be
teratogenic, so women of childbearing potential should be warned about becoming pregnant whilst
on EFV. It should be avoided in women who may contemplate pregnancy.
4.2.1.2 Nevirapine (NVP)
NVP has been compared with EFV in the 2NN Study and has shown to be of comparable potency.
However as mentioned above there was more serious toxicity in the NVP arm with two drug related
deaths, one from liver failure and one from multi-resistant Staphylococcus aureus septicaemia in a
patient with Stevens-Johnson syndrome. The major side effects are rash which occasionally
manifests as Stevens-Johnson (incidence 0.3%) with occasional fatalities. The rash with NVP can
be made worse by the co-administration of steroids [78-80] and these should not be prescribed.
Hepatitis is the other major side effect in patients treated with NVP and reports of fulminant liver
failure and deaths have been described. NVP is currently used twice a day, but the
pharmacokinetics and now clinical trial data indicate that once daily dosing is possible, although
there are more abnormalities of liver function as a result of using it once a day [62]. As with EFV,
caution is needed when stopping NVP due to its long half-life in comparison with NRTIs.
4.2.1.3 Delavirdine
Delavirdine is currently unlicensed in the UK. It is not recommended for initial therapy in view of the
high pill burden (though this is likely to fall shortly when a larger pill is produced). Delavirdine may
have potential uses in boosting PIs since it inhibits the cytochrome P450 pathway.
4.2.2 Two NRTIs plus a PI
The dramatic decline in clinical progression and HIV related deaths followed the introduction of the
PI class of antiretrovirals. These agents have shown clinical and surrogate marker efficacy in clinical
practice. Sustained suppression of plasma HIV-1 RNA levels for more than 6 years has been seen in
most patients within the Merck 035 study taking IDV and two NRTIs [81]. AIDS Clinical Trials Group
(ACTG) protocol 320 was a clinical endpoint study that demonstrated long-term virological
suppression and improved clinical outcome in patients taking ZDV/3TC/IDV [82]. Improvement in
clinical outcome has also been seen in studies with ritonavir (RTV) added to background
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British HIV Association (BHIVA) Guidelines 15 July 2003
antiretroviral therapy (containing NRTIs) in late disease [83]. The hard gel formulation of saquinavir
(SQV) has also shown clinical benefit when used in combination [62].
4.2.2.1 Two NRTIs plus a boosted PI
Most clinicians now use a PI in combination with low dose RTV to provide a pharmacokinetic
boosting effect when they start antiretroviral naive patients on a PI based regimen. The
disadvantage of this approach is a possible risk of greater lipid abnormalities, particularly raised
fasting triglycerides. Recent data from the 863 study [62] showed superior surrogate marker
endpoint for patients using a boosted PI (lopinavir/RTV) when compared to nelfinavir (NFV) with low
numbers discontinuing for side effects. Additionally, patients receiving lopinavir/RTV who developed
virological failure had no evidence of PI resistance, only 3TC resistance, whilst most patients on the
NFV arm had PI mutations in addition to 3TC resistance. The advantage of using RTV as a
pharmacokinetic booster is that it enhances the pharmacokinetic profile of PIs either by extending
the half-life or by increasing absorption. This may improve potency and may be associated with a
reduced risk of the development resistance. It also aids adherence as regimens can often be
simplified.
The committee feels that currently enough data are now available to suggest that a boosted PI
should be the standard of care if a PI is chosen as part of an initial regimen (with the possible
exception of atazanavir).
The two regimens suggested by the committee are lopinavir/RTV (as Kaletra®
1
) and RTV combined
with SQV HGC (Table 4). RTV/SQV HGC and RTV/IDV showed equal efficacy in a randomised open
study [84], but the toxicity of the IDV dose was unacceptably high in this and other RTV-boosted
IDV studies [85]. Lower dose regimes (RTV 100 mg/IDV 400 mg) have been suggested and have
shown good potency [86]. A further randomised study will report shortly when RTV/SQV is
compared to Kaletra [87]. In the meantime, either combination can be recommended, although there
is currently an advantage in pill burden with Kaletra®. Both regimens have pharmacokinetic profiles
which suggest that once daily dosing is possible and surrogate marker data from clinical studies
have confirmed these findings.
4.2.3 Three NRTIs
There is now surrogate marker endpoint data suggesting that ZDV/3TC/ABC (usually combined as
Trizivir is less potent than combining two NRTIs with either a NNRTI or a PI [88]. In ACTG 5095 the
3 NRTI arm has recently been stopped by the DSMB [73], as Trizivir® was less potent than the
other two arms (Trizivir®/EFVor Combivir®/EFV). Fewer patients had suppressed their viral load to
<200 copies/ml by 16 weeks in the Trizivir® arm when compared to the other two arms. This finding
was found both at high and low entry viral loads. Adherence was unlikely to have been a factor in
these results as the pill burden was low in all groups.
Previous studies indicated that the combination of ABC, ZDV and 3TC was capable of producing
long-term suppression of virus, in patients with lower viral loads [89]. A double blind, placebo
controlled study (CNA 3005 study) [89] of ZDV/3TC/ABC compared with ZDV/3TC/IDV showed no
significant difference in viral load suppression between the two arms. In those patients with high viral
loads >100,000 copies/ml, though, there was a better response in the IDV arm than the ABC arm.
This study was again a double blind, placebo controlled trial with a high pill burden. When a similar
study was performed in an open fashion, no significant differences were seen in the high viral load
strata [90], but there was much higher adherence in the ABC arm. The committee now feels that
Trizivir® should only be considered as a starting regimen in special situations, for example informed
patient choice based on likely poor adherence if alternative options are used, or concomitant
medication such as for TB.
D4T/didanosine (DDI) and 3TC is a triple nucleoside analogue combination and has been compared
with the same D4T/DDI backbone with either NFV or NVP. This study had only a small number of
1
Generic drug names are used where possible in these guidelines. However proprietary names are
used where the choice of a combination formulation may be relevant to ease of adherence.
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British HIV Association (BHIVA) Guidelines 16 July 2003
patients with high viral load, and showed a trend for less suppression to fewer than 50 copies by 48
weeks in the triple nucleoside arm [74].
4.3 Choice of NRTI backbone for initial therapy
In the context of HAART, there is no conclusive data to show which NRTI backbone to use, the
choice of which is governed by issues of adherence and toxicity. Primary drug resistance, especially
to ZDV, may affect the choice of initial NRTIs. This may be of particular relevance when considering
a combination of ZDV/3TC or an NNRTI because of the relative ease with which resistant mutants
are acquired, although there is a possible association between ZDV resistance and EFV
hypersusceptibility [73, 74]. Although ABC has been used most often in triple NRTI combinations, it
may also be used as part of an NRTI backbone and studies suggest that ABC/3TC is a potent
combination [91]. For initial therapy, combinations including D4T are not recommended because of
increasing evidence of its role in the development of lipodystrophy and abnormal lipid profiles. Even
in subsequent therapy, toxicity data suggests that combinations of D4T with DDI should be avoided
where possible and are definitively contra-indicated in pregnancy. Tenofovir is now available for initial
use and a good safety profile was seen in a blinded clinical study with 96 week follow up in a group
of patients for whom pre-existing renal damage was an exclusion criterion. In this study in which
D4T/3TC/EFV and tenofovir/3TC/EFV were compared, both regimens were shown to be highly
effective with more than 80% of patients having an undetectable viral load using a 50 copy assay in
an intention-to-treat analysis at 96 weeks. Tenofovir was not associated with a rise in triglycerides
seen in the D4T treated group. Longer term toxicity data is still limited, however. Tenofovir is
recommended for use as first line therapy with lamivudine in patients with hepatitis B co-infection.
Increasingly, regimens that can be administered once daily are being used. DDI, 3TC and TFV are
each licensed for once daily use, and there are ongoing studies for ABC.
4.4 Conclusions
We therefore believe that there remain insufficient data to make definitive recommendations on best
initial treatment. However data now exists on less favourable combinations, which include D4T
(because of toxicity) and triple nucleosides such as Trizivir (because of lack of potency). Initial
therapy must be individualized for each patient and the risks and benefits of the treatment
considered, including toxicity, adherence, resistance, immunological benefit, long term safety, clinical
trial data and stage of disease. Most clinicians in the UK favour an NNRTI based regimen for initial
therapy [92], reserving boosted PIs for later use, based upon the perceived risks of toxicity and ease
of administration. There is no comparative evidence to support this stance, which may change when
low pill burden PI containing regimens are available which do not produce lipid abnormalities.
5.0 Issues concerning antiretroviral use
5.1 Follow up of the HIV patient
Although there is only limited evidence on which to base recommendations relating to the use of
laboratory tests in follow up of the HIV patient, the committee notes that the BHIVA national audit
showed variable recording of routine tests and feels that some guidance would be helpful. A
recommended summary schedule for specific laboratory tests is included in (Table 7), and a wide
variety of additional tests should be used as clinically indicated. Monitoring is not a substitute for
thorough clinical assessment, and it is important also to weigh patients, measure their blood
pressure and do urinalysis on a regular basis as well as ensuring periodic gynaecological
examinations and an annual cervical smear in women. Checks should be offered as well as
vaccination against hepatitis A and B in those at risk.
5.2 Adherence
The committee views supporting adherence as an extremely important aspect of clinical care for
patients receiving antiretroviral therapy, and BHIVA and the Medical Society for the Study of
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British HIV Association (BHIVA) Guidelines 17 July 2003
Venereal Diseases (MSSVD) have produced specific guidelines on this topic [93]. These are
currently available in draft format from the BHIVA website (http://www.bhiva.org/guidelines.htm).
In addition to addressing the role of adherence in HIV disease and the importance of adherence
support from the perspective of health economics, the guidelines recommend a series of measures
for adoption within HIV clinical care settings, based on evaluation of existing data.
Very high levels of adherence to antiretroviral drugs are a prerequisite for a successful and durable
virological and immunological response while low adherence increases the risk of treatment failure
and disease progression and contributes to the development of resistance.
High adherence is a process, not a single event, and therefore adherence support must be
integrated into clinical follow-up. This is difficult to achieve unless a patient has some understanding
of the way their treatment works and the importance of maintaining a minimum concentration of each
of their drugs. This is also dependent on clear and accurate information being provided for each
drug in relation to timing and flexibility of doses and the importance of dietary restrictions if
applicable. For example, when a drug needs to be taken ‘with food’, this includes providing an
indication of whether this is based on minimum calories or fat content.
Adherence support is likely to be different for a patient just starting therapy compared to someone
who has been on treatment for several years.
Every prescribing unit should have a written policy on provision of adherence support, and ensure
staff are appropriately trained to make delivery of such services possible.
5.3 Toxicity
A wide range of toxicities have been associated with individual drugs used in the treatment of HIV
disease, and are beyond the scope of these guidelines. Clinicians are advised to refer to the British
National Formulary, Electronic Medicines Compendium (http://www.emc.vhn.net) and HIV-
Druginteractions.org (http://www.hiv-druginteractions.org/).
5.3.1 Lipodystrophy
The characteristic morphological changes of lipodystrophy [94] are highly stigmatising to individuals
and may lead to consideration of delaying commencement of therapy, modification of established
therapy to alternative regimens or decisions to stop therapy to prevent or attempt to manage the
problems.
Arguments continue as to the linkage of the main components of the syndrome and indeed as to
whether several different, overlapping syndromes may exist. The main components, which may be
observed individually or in combination in persons on antiretroviral therapy, include:
ß Dyslipidaemia with raised total cholesterol, low HDL cholesterol and raised triglycerides with
increased lipid cycling or turnover
ß Insulin resistance with hyperglycaemia, particularly in susceptible individuals
ß Visceral, breast and/or local fat accumulation
ß Generalized diminution of subcutaneous fat mass possibly with fat cell loss.
In addition, other metabolic and physical changes may also be present in individuals on long term
antiretroviral therapy including raised serum lactate, low bone mineral density, hypogonadism (and
possibly other endocrine abnormalities) and hypertension. The linkage of these problems to
metabolic and morphologic changes remains to be elucidated.
A clinical case definition, based on physician and patient agreement regarding significant and
characteristic morphological changes, potentially enabling more homogeneous populations to be
studied and comparisons made across intervention studies has now been developed [95].
Only through understanding the etiology can optimal management of these problems be
established. The etiology specifically of peripheral lipoatrophy and, to some lesser extent other
clinical and metabolic consequences of antiretroviral therapy remains speculative. Evidence from
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British HIV Association (BHIVA) Guidelines 18 July 2003
cross sectional surveys point to an interaction between HIV disease and/or immune recovery and
antiretroviral medication [96]. Both PIs and nucleoside analogues have been associated with the
changes and theories published hypothesizing how they may play a role [97-99]. Evidence to date
suggests these hypotheses to be, at best, incomplete [100, 101]. Patients with the syndrome who
have never received PIs [102, 103] or have never received (or have developed the syndrome whilst
not receiving) nucleoside analogues [104-106] have been reported, indicating that these agents
alone are not sufficient to cause the problem. The highest cumulative prevalence of morphologic
abnormalities in these studies appear to be in persons receiving both PIs and nucleoside analogues
together, relative to dual or triple nucleoside or nucleoside plus non-nucleoside regimens. As
nucleoside analogues remain the backbone drugs of antiretroviral therapy, these data may
encourage consideration of PI-sparing regimens for initial or long term therapy. Additionally, as D4T
appears to have the highest relative risk of the lipoatrophy or is associated with more rapid fat loss,
its use should be reserved for individuals not suitable for alternative agents such as ABC, DDI,
tenofovir and ZDV. Details of other relevant data and debate are included in references [107-130].
5.3.1.1 Management of Lipodystrophy
Broadly, management approaches to lipodystrophy depend on the current assumptions of etiology.
Actions that diminish the chance of lipodystrophy occurring may be key as treatment of established
lipoatrophy is limited. Issues for prevention lie in:
ß Choice of regimens that avoid combining PIs and NRTIs.
ß Choice or regimens that prefer tenofovir or ZDV (and probably ABC and DDI) to D4T
ß Commencing therapy before 200 CD4 cells/mm3 and before AIDS is diagnosed
ß Consideration of early intervention for metabolic changes as these may be harbingers of
lipodystrophy
ß Dietary advice, possibly dietary supplementation (fibre, omega-3 fatty acids) and exercise.
Benefits for these suggestions are not fully established from randomised clinic trials but are
extrapolated from cross-sectional and limited prospective data with their incumbent limitations.
Once established, the management of lipodystrophy falls into four categories:
ß Lifestyle such as diet, possibly dietary supplementation and exercise
ß Additional therapies, generally focussing on managing individual manifestations
ß Modifying the treatment regimen away from D4T (and possibly ZDV) to ABC (and possibly
tenofovir)
ß Corrective procedures.
The risk versus benefit of these approaches has not been comprehensively tested, although the risk
of diet and exercise can be considered minimal. Broadly, dietary advice should include a
Mediterranean diet rich in omega-3 fatty acids, fresh fruit and vegetables. Fibre is known to improve
insulin sensitivity. Evidence of benefit for specific food supplements is not established. Regular
exercise, a mixture of cardio and weight training may also improve some metabolic parameters and
abdominal shape [131].
Individuals switching therapy must consider that they may risk their long-term HIV management in
exchange for an uncertain outcome with regard to their lipodystrophy. Specifically benefits in terms
of clinically evident lipoatrophy have not been consistently observed in trials and, anecdotally, do not
appear evident with even prolonged (>6 months) of treatment interruption. The majority of switch
studies that have reported data have focused on switching away from PIs [107]. As mentioned,
whilst metabolic benefits are achieved by switching away from PIs to NNRTIs or ABC in many
patients, morphological benefits are more limited or absent. Switching away from D4T and possibly
ZDV to ABC is associated with some gain in fat detectable by DEXA scanning over 24-48 weeks. It
is not know if this recovery of fat is complete or durable. Improvements in metabolic parameters with
this switch are not impressive.
Switching away from a PI-NRTI based regimen to a PI-sparing regimen does, however, currently
represent the first step in management of metabolic abnormalities when ever feasible. NVP, EFV
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British HIV Association (BHIVA) Guidelines 19 July 2003
and ABC perform similarly virologically in treatment naive persons but ABC should be avoided in
those with prior NRTI resistance or mono/dual therapy exposure. Additionally, consideration should
be given as to whether ABC should be used as an alternative to an NNRTI or PI or to another NRTI.
Lipids and insulin sensitivity generally improve with all these approaches; cholesterol improvement
may be greatest with ABC although HDL may rise most with NVP.
Switching away from PI-based regimens may be most beneficial with regards to metabolic
parameters but is not particularly effective at managing peripheral lipoatrophy. Switching away from
thymidine analogues, especially d4T, to ABC appears the only successful approach in this regard.
5.3.1.2 Other Therapies
Interest exits in the use of glitazones (for insulin resistance with weight loss), metformin (for insulin
resistance with weight gain) and growth hormone (for lipoaccumulation) [132]. Metformin may benefit
fat accumulations, insulin resistance and may improve some lipid and coaguability factors. Benefits
on peripheral lipoatrophy have not been reported. Studies with glitazones are now underway in the
US, Australia and the UK. Evidence of their efficacy, increasing fat mass in familial lipodystrophy
[133] provides no guarantee of benefit in HIV-associated lipodystrophy. In HIV associated
lipodystrophy a small randomized trial of rosiglitazone showed no benefit during short-term follow up,
although larger studies are now in progress. Additionally, the safety and potential for
pharmacokinetic interactions with these drugs in people with HIV requires clarification before their
use can be considered or recommended in persons with HIV, especially those with a hepatitis co-
infection [134, 135].
Growth hormone may improve fat management [136] and lead to improvements in appearance of
both fat accumulation and lipoatrophy, including facial changes. However its use is likely to be limited
by expense and by the evidence that unfortunately these benefits appear at least partially lost on
stopping growth hormone. Additionally, growth hormone may preferentially increase lean body mass
(hence its use in wasting) and is accompanied by adverse events including the risk of diabetes
mellitus. Nor is the optimal dose of growth hormone for lipodystrophy established but it is likely to be
lower than the 4-6mg/day recommended for wasting. Combining glitazone agents with growth
hormone is an attractive idea that is currently under pilot investigation.
Anabolic steroids may be best avoided, due to concerns regarding worsening lipid profiles, fat loss
and potential for liver function disturbances, although testosterone replacement for repeatedly
hypogonadal and symptomatic men, who are not hypogonadal due to previous anabolic steroid, use
may be considered.
The use of statins and fibrates is appropriate for the management of dyslipidemia but no benefits
have been described with regards to morphologic changes. The benefits of these agents appear
similar to improvements in cholesterol or triglycerides described in endogenous dyslipidemia [137,
138], hence are like to be associated with reduction in cardiovascular disease risk. However,
relatively few individuals in reported studies have achieved response goals as outlined in NCEP
guidelines [139]. Pravastatin is the most well studied agent due to the low likelihood of drug
interactions with protease inhibitors. Lovastatin may also be suitable. Simvastatin is contraindicated
due to substantial risk of drug interactions with PIs and atorvastatin levels may be increased about
2-fold suggesting caution should be used when using this agent. Interactions between statins and
NNRTIs have not been described. Interactions with fibrates and PIs or NNRTIs are not expected to
be clinically important. Advice from a lipidologist should be sought before combining fibrates and
statins.
Corrective surgery remains the mainstay of management of other acquired lipodystrophies such as
Barraquer-Simons syndrome albeit that they do not address the etiology. Only one randomized
study evaluates outcomes of these approaches [140, 141]. The use of Polylactic acid injections
(New-Fill) has attracted considerable interest. Polylactic acid is hypo-allergenic and biodegradable
over the course of about 2 years (hence does not trigger chronic inflammatory reactions which may
accompany silicone injections) and stimulates fibroblasts to produce collagen (hence is not really a
‘filler’ such as transferred fat or collagen which may rapidly disappear). Injections may be given after
a short training session and involve use of local anaesthetic followed by injection of the substance
via several puncture points on each side. Patients are advised to massage the area after use to
spread the substance evenly in the tissue plane. Bruising and rarely local skin infections are the
main adverse effects. Objective improvements in facial appearance and patient well-being were
noted in one study. Other similar products such as hyaluronic acid are also being used. Additionally,
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the other ‘traditional’ approaches, such as fat transfer, collagen, implants carry considerable
expense and fat transfer is only feasible if fat is available to ‘harvest’ from other body areas. Facial
implants may also be used but risk fat loss occurring around the implant leading to a lumpy
appearance. Plastic surgery is largely suitable for facial changes most reports focusing of the naso-
labial folds and buccal fat pad area although the temporal area may also be filled. The limitations of
plastic surgery underline the need for more specific treatments that addresses etiology and whole
body changes.
5.3.1.3 Conclusions
Lipoatrophy is best avoided as it is difficult to treat. Its appearance may be delayed by avoiding D4T
in the initial regimen.
ß Insulin resistance should be treated with metformin.
ß Abnormal lipid profiles should be treated by switching drugs wherever possible and by the use of
both statins and fibrates.
ß Exercise and diet may have a modest effect on both body habitus and lipid abnormalities.
ß Controlled trial evidence exists for the use of New Fill injections in established lipoatrophy.
5.3.2 Mitochondrial toxicity and lactic acidosis
The link between NRTIs and mitochondrial damage was first suggested in 1989 in relation to
myopathy in patients on ZDV. Subsequently, mitochondrial toxicity has been implicated in a wide
range of other NRTI associated toxicities, including neurological disease in infants, peripheral
neuropathy, hepatic steatosis and lactic acidosis. The role of mitochondrial toxicity in causing these
NRTI associated toxicities has yet to be established in most cases. However, the link for which
evidence appears strongest, lactic acidosis, is one with a potentially fatal outcome.
5.3.2.1 Aetiology of NRTI induced mitochondrial toxicity
NRTIs inhibit gamma DNA polymerase, the enzyme responsible for copying mitochondrial DNA [142].
Inhibitory effects of NRTIs on other enzymes key to normal mitochondrial function have also been
described. Evidence to support DNA polyermease inhibition has been shown by studies that
demonstrate reduced mitochondrial respiratory chain enzyme complex activity, reduced mitochondrial
DNA concentrations, as well as electromyographic changes seen previously with mitochondrial
muscle damage [143-145]. Different NRTIs preferentially affect different cell lineages leading to a
variety of clinical syndromes. Hence there appears to be an hierarchy for which NRTIs cause DNA
polymerase gamma inhibition, with D4T, DDC and DDI causing more inhibition of mitochondrial DNA
replication [142, 146] whereas ZDV may inhibit other mitochondrial enzymes [147] and cause more
cytotoxicity in some cell lines [148]. Some evidence for this is suggested by the improvement in
laboratory findings and clinical features when D4T was switched to ZDV or ABC in patients with
symptomatic hyperlactataemia [149]. Mitochondrial toxicity may, however, represent only one
mechanism by which NRTIs cause adverse effects [147].
5.3.2.2 Lactic acidosis and hyperlactataemia
These two terms are not interchangeable. Hyperlactataemia may occur in physiological as well as
pathological circumstances and is not necessarily accompanied by changes in blood pH or anion
gap. The clinical significance of hyperlactataemia is not established and routine screening of
asymptomatic individuals is not currently recommended. Lactic acidosis is always a serious condition
requiring immediate withdrawal of antiretroviral therapy and other supportive therapy. Definitions are
as follows:
Hyperlactataemia: venous lactate > 2.5–5 mmol/L.
Lactic acidosis: arterial pH <7.35, venous lactate >5 mmol/L.
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5.3.2.3 Incidence
Fatal lactic acidosis associated with NRTI use was first reported in 1993 [150]. A review of a
heterogeneous group of patients receiving antiretroviral therapy in the 5-year period beginning 1989
showed that the risk of developing lactic acidosis with hepatomegaly and hepatic steatosis was
approximately 0.1% per patient per year [151]. More recent estimates are higher, at 1% to 2% per
year, particularly if ‘symptomatic hyperlactataemia’ is included [152-154]. The definition of
symptomatic hyperlactatemia is unclear and in general has included a range of symptoms also
present in persons with consistently normal lactates (e.g. fatigue). Asymptomatic hyperlactataemia
may present in up to 16% or more of individuals on therapy and may be intermittent in nature [155,
156]. This compares to a reported incidence of 2% of those not on ART [156] (as would be
expected by normal ranges being set at 2SD from the median). The duration of the ART is important
in some studies, and certainly an exposure of at least several months appears to be the norm for
most reported cases [157]. It also appears that there is a greater risk of developing lactic acidosis
amongst females [158, 159].
5.3.2.4 Clinical and laboratory features
Hyperlactataemia, defined as between 2 or 2.5 and 5 mmol/L, is often asymptomatic. Intervention is
not required but the individual should be carefully monitored with repeat lactate samples taken
uncuffed and at rest. If accompanied by symptoms such as nausea, malaise, weight loss, abdominal
pain, tender hepatomegaly, worsening of hepatic enzyme abnormalities and/or biochemical
changes, therapy should be interrupted.
Clinical features commonly accompany lactate levels of >5 mmol/L. Features of lactic acidosis include
weight loss, fatigue, abdominal pain, tender hepatomegaly, respiratory distress and failure. As well
as a raised lactate and acidosis and an anion gap that is usually widened (>18 mmol/L), other
laboratory features that might be present include raised hepatic aminotransferases, raised creatine
kinase, lactate dehydrogenase and amylase [107]. The anion gap is calculated as [Na+ + K+] [Cl-
+ HCO
3
-] and should be <12 mmol/L.
Lactic acidosis has been reported in infants of mothers receiving ZDV or ZDV+3TC during
pregnancy. Additionally, d4T+ddI has been associated with several reports of lactic acidosis in
women who became pregnant while taking these medications. Consideration should be given to
monitoring lactate in women receiving antiretroviral therapy during pregnancy.
5.3.2.5 Management of hyperlactataemia and lactic acidosis
There is currently no rationale for performing routine serum lactate measurements. The predictive
value of a single lactate measurement for the development of lactic acidosis is not established but
appears limited. Additionally, there is no evidence to support the routine use of anion gap or lactate
: pyruvate ratios. Instead, it is important to maintain a high index of suspicion for lactic acidosis on
the basis of associated symptoms and signs that could justify the measurement of serum lactate.
A clinician’s decision to reintroduce NRTIs in patients who have had previous acidosis would justify
monitoring serum lactate in those patients. However, there is insufficient evidence to establish
whether NRTIs can be safely re-introduced following hyperlactataemia and, if so, for which group of
patients.
The management of lactic acidosis is cessation of antiretrovirals (and any other possible contributory
agents) and exclusion of other causes. Supportive measures such as ensuring adequate perfusion,
providing oxygen or if necessary assisted ventilation, haemodialysis or dichloracetate may also be
useful [160]. Components required by the mitochondrial respiratory pathway, such as thiamine [161],
riboflavin [162] and co-enzyme Q and carnitine, have been administered without apparent toxicity,
but the evidence for their use is limited.
5.3.2.6 Recommendations for managing lactic acidosis
The recommended minimum requirements for managing lactic acidosis are:
ß All patients should be informed of possible signs and symptoms and encouraged to attend
an available clinic.
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British HIV Association (BHIVA) Guidelines 22 July 2003
ß All clinicians should be fully conversant with the clinical presentations of lactic acidosis and
symptomatic hyperlactataemia and have immediate access to means of measuring lactate
levels in specified patients.
ß All clinicians should be familiar with means of managing lactic acidosis. Identifying
symptomatic patients whose current antiretroviral medication should be immediately stopped
is of particular importance.
5.4 Resistance testing
Resistance interpretation is continually updated. Readers are referred to the latest IAS-USA
algorithm [163].
Antiretroviral drug resistance has been described retrospectively, in vitro and in vivo, to be
associated with poor virological and clinical outcomes. Short-term prospective, randomized
controlled trials have, in some studies, demonstrated the short term benefits of resistance testing
over standard of care [164-174]. It is likely that the relatively modest benefits demonstrated are due
to in part to inadequate interpretation of results at the time of the study. Other factors leading to
differences between studies include the proportion of patients who are NNRTI naive at time of
therapy switch, the availability of expert advice (EA), and the overall therapy experience of
participants. A meta-analysis of the VIRADAPT, GART, HAVANA, ARGENTA, NARVAL and
VIRA3001 has been undertaken, (Table 8) [175] and showed a higher proportion of patients had
undetectable viral loads at 3 and 6 months in the genotype testing groups. This particular analysis
supports the use of genotypic but not phenotypic resistance tests and shows that EA can increase
the virological response. Further, the recent MRC ERA Study: a one year RTC of genotypic (n=152)
versus genotypic plus phenotypic (n=159) testing to guide patient therapy, in a relatively
experienced group of patients (average exposure to 7.7 previous drugs) found no clear evidence of
added value (in terms of virological and immunological markers) of phenotypic resistance testing
against a background of genotypic resistance testing [176]. Genotypic assays are cheaper than
phenotypic assays, and can be normally undertaken within specialist clinical virology laboratories. By
contrast, real time phenotypic assays are generally provided by a few commercial laboratories and
currently require dedicated category 3 facilities.
It is unlikely that randomised, controlled studies of resistance assays will be undertaken in the future,
and further insight into the best use of resistance tests may come from large cohort studies and
clinical database analysis.
In recently infected individuals resistant virus prevalence rates in a small number of subjects range
from 2% in Denmark [177] to 21% in the UK [178]. In these individuals the results of a resistance
test are likely to reflect the actual transmitted virus and so may help regimen selection. Further,
recent studies suggest that time to virological suppression in patients infected with a resistant virus is
longer than for patients infected with wild-type virus [179-181]. Therefore, knowledge of such
resistance prior to initiating therapy will allow optimisation of first line therapy. In chronically HIV-
infected patients not on treatment, the prevalence rate for primary mutations associated with
protease or RT inhibitors ranged from 3.7% in the French Nationwide study [182], to 15% in a
Spanish study [183] and >10% in the USA [184]. Overall, the prevalence of resistance appears
less than studies on primary infections, which may be explained by the fact that the time of infection
for these individuals could have occurred some years previously, prior to the upsurge in transmission
of resistance. Alternatively, transmitted resistant virus may subsequently evolve, with reversion to
wild type, although recent studies demonstrate that many such resistant viruses appear to persist in
the absence of therapy [185]. Moreover, cost effectiveness analyses have shown that when
prevalence rates of between 4% and 10% are reached for mutated virus there is an advantage to
test for resistance in antiretroviral-naive patients [186, 187].
Resistance testing has technical limitations. Both genotypic and phenotypic testing depend on
polymerase chain reaction (PCR) amplification of virus from plasma, and therefore do not address
the properties of different virus components (i.e whole virus vs reverse transcriptase/protease genes
alone). The likelihood of generating sufficient genome product to undertake the further analysis
depends on the starting concentration of virus. Therefore, most current assays require in the order of
1000 copies/ml to reliably provide a result. Although some improvements may be possible, ultimately,
greater sensitivity will only be possible with a larger starting quantity of blood. Secondly, the nature
of current gene sequencing techniques limits the detection of minority strains of virus (within the
plasma virus population) to 20%. Smaller proportions of mutant virus may contribute to subsequent
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British HIV Association (BHIVA) Guidelines 23 July 2003
therapy failure; these will not be detected. These tests are technically demanding, and external
quality control is essential. This is addressed by national and international pathology laboratory
accreditation programmes.
HIV-1 genetic diversity within the UK is widening. In 2002, heterosexual infection from Sub-Saharan
Africa represented the majority of new diagnoses. These individuals are infected with viruses with
significant genetic difference from the subtype B virus common within the gay epidemic. The impact
on resistance testing is two-fold. Firstly, PCR-based assays require optimisation of efficiently produce
results from such viruses, and secondly, the presence of “secondary” resistance mutations as normal
variants in such viruses may require modification of resistance interpretation systems.
In drug experienced patients who stop therapy, pre-existing “wild type” virus, archived from prior to
therapy, can rapidly emerge within 1 month [188], and resistance testing subsequent to this time will
only yield this non-resistant strain. It is therefore un-informative. If possible testing should always be
undertaken on virus from a patient while receiving therapy.
A recent study has shown that NNRTI-naive patients with NNRTI-hypersusceptible virus had an
improved virological (and immunological) response after starting an NNRTI-containing regimen [189].
A further study has shown there is a significant association between the presence of NRTI mutations
and NNRTI hypersusceptibility [190], in particular the duration and number of previous NRTI used
and resistance to ZDV and ABC. Such findings may not yet be represented within interpretation
algorithms.
5.4.1 Recommendations
ß Resistance testing should be undertaken at each point of viral rebound on therapy (although, as
stated above, a viral load of at least 1000 copies/ml is required for a reliable assay), unless a
patient is on a treatment interruption (AIII).
ß As transmission of viruses with reduced sensitivity to drugs is well documented, testing should be
undertaken at time of presentation (BIII).
ß There is little evidence for an advantage of phenotypic over genotypic testing. Both require
interpretation of complex data, and the interpretation systems for fold resistance (phenotype,
and phenotypic interpretation of genotype –virtual phenotype) and mutations (genotype) are
subject to change as more clinical outcome data becomes available. Genotypic assays are
currently cheaper than phenotypic.
ß It is essential that interpretation of resistance testing, and choice of new therapy is taken in the
light of all clinical information, including prior therapies and toxicities. Previous resistance test
results must be considered, and resistance apparent at that previous time must be assumed to
be permanently represented within the virus population. Samples taken for viral load should be
stored frozen within the laboratory, in order that retrospective resistance testing can be
undertaken.
ß In drug experienced patients, resistance testing should be undertaken while the patient is
receiving therapy, to avoid misleading results.
ß Laboratories undertaking resistance testing should be equipped to provide clinical support to HIV
clinics, and demonstrate participation in external quality control programmes and accreditation by
national/international agencies. They should store samples and assay data according to
guidelines of the Royal College of Pathologists.
5.5 Therapeutic drug monitoring
This section discusses the role of TDM for PIs and NNRTIs. TDM is likely to be of little value for NRTIs
as these agents require intracellular activation and levels of intracellular drug-triphosphate bear little
relationship to plasma levels of the parent compound. The abbreviations Cmin, Cmax and AUC refer
to the plasma trough (usually at end of the dosing interval), peak plasma levels and area under the
concentration-time curve, respectively.
Europe has seen increasing uptake of TDM and incorporation of TDM into national HIV treatment
guidelines in several countries. This is despite a surprising lack of data to confirm the benefit of TDM
in routine clinical use, and the opportunity to conduct these trials has largely passed. Nevertheless,
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prospective surveys suggest ~20% patients in clinic have sub-therapeutic (below target for wild-type
HIV) plasma concentrations of PIs and NNRTIs [191-193]. Moreover, the inter-individual variability in
plasma concentrations is immense ( 100-fold difference) despite standard dosing [191].
5.5.1 Drug levels and efficacy
A large number of observational studies have confirmed that drug exposure (Cmin or AUC) of PIs
correlate with virological suppression in patients prospectively followed up in Phase II studies (SQV,
IDV, amprenavir (APV)), treatment-naive patients (including phase III studies) commencing therapy
(SQV, NFV, IDV, RTV), dual PI regimens (SQV, NFV, RTV), salvage antiretroviral therapy (SQV, IDV,
RTV) or else a broader population of clinic patients on antiretroviral therapy (SQV, NFV, IDV, RTV)
[191, 194, 195]. In general, the association between drug concentrations and virological response
varies according to patient group, and is less apparent in very heavily pre-treated patients (in whom
resistance is likely).
For NNRTIs the data are less convincing - one group of investigators reported an association
between NVP concentrations and treatment response in treatment-naive patients in the INCAS trial,
but no correlation in clinic patients who may have had a previous therapy failure [196, 197].
Concentration-effect relationships have also been reported for EFV [198].
5.5.2 Drug levels and toxicity
High plasma drug concentrations have been associated with some toxicities, e.g. urological toxicity
including flank pain, haematuria or elevated creatinine (IDV; related to C
max
and AUC),
gastrointestinal (RTV; related to C
max
) [199], elevated lipids (RTV, and possibly LPV) [200-202] and
hepatotoxicity (NVP- although it is unclear if elevated drug concentrations were a consequence or
cause of abnormal LFTs) [203]. An association between CNS toxicity and EFV concentrations has
been reported [198] in a cross-sectional study of 130 patients receiving the drug for an average of
8 months. However, a recent small study reported no association between EFV concentrations and
sleep disturbances [204]. There are also preliminary data reporting an association between NFV
concentrations and lipodystrophy [205].
5.5.3 Use of TDM
Intervention studies where doses are adjusted to therapeutic and non-toxic levels on the basis of
TDM have been sparse and difficult to interpret. An intensive study [206] of 49 adults commencing
ZDV, 3TC and IDV randomised patients to receive conventional therapy vs TDM, where full plasma
profiles for all 3 drugs plus subsequent multiple sampling was performed. Patients in the TDM arm
had significantly more rapid and durable virological responses to therapy. In the ATHENA study
[207], a subset of treatment-naive patients randomised to receive TDM had improved efficacy (NFV)
or reduced toxicity (IDV). However, these analyses were post-hoc, and in the overall study cohort,
analysis was complicated by ‘unblinding’ of controls as well as low compliance to TDM
recommendations by attending clinicians. Two French studies (Genophar and Pharmadapt) have
failed to observe any benefit of TDM [208, 209] in a group of pre-treated patients. Assessment of
TDM was limited by only a short window in which to observe any effect, since any dose modification
was only instituted at 8 weeks for TDM arm, while all patients in the non-TDM arm received TDM from
week 12 onwards. A further Canadian trial is recruiting slowly. No association has been shown
between CD4 cell response and TDM.
Many of the potential problems with TDM have been overcome. A consensus of what efficacy targets
should be for each drug is emerging [194, 195] (although toxicity targets are more problematic). An
international quality assurance programme is now in place. Most centres utilise a trough
measurement (+/- post-dose concentration), although random levels have also been assessed. TDM
should not be performed during acute illness when concentrations of the acute phase protein a1-
acid glycoprotein (to which PIs bind) may be elevated. BHIVA recommendations for TDM are shown
in [Table 9].
5.5.4 Inhibitory quotients
Inhibitory quotients (IQs) comprise the Cmin of drug divided by some measure of resistance
(phenotype, ‘virtual’ phenotype or genotype). Several different formulas for calculating IQ exist.
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Although IQs have yet to be prospectively evaluated as a tool for managing HIV infection, they have
been shown to be better predictors of virological response in moderately or extensively pre-treated
patients than plasma drug concentrations and/or resistance testing alone [210]. It is important to
recognise that the target IQ for optimal response is likely to be different for different drugs- thus
cross comparisons between different agents is probably not valid. At present, there are insufficient
data to recommend the use of IQs in clinical practice.
5.6 Structured treatment interruption (STI)
The role of structured or supervised treatment interruption (STI) in first and subsequent therapy is still
under investigation, even though it has been used in a number of clinical trials. It is important to
define what is meant by STI and in which clinical settings it is being studied, since the aims may be
very different for each setting (Tables 10, 11, 12). The three settings are acute infection, chronic
infection with virological suppression and chronic infection with treatment failure. STI is discussed in
more detail in sections relating to these settings. The three main objectives are immune
enhancement, limiting drug exposure/toxicity and reducing resistant virus by repopulating with wild
type virus.
The potential problems of STIs include disease progression, induction of an acute antiretroviral
syndrome similar to PHI, and induction of resistance mutations if drugs of differing half lives are
stopped simultaneously. As viral load rises with STI, individuals who engage in unsafe sex may
become relatively more infectious to others and there has been a report of an enhanced risk of
sexual transmission of HIV during STI [211].
6.0 Changing or stopping therapy in the absence of
virological failure
6.1 Patients started on regimens that are not currently
recommended for initial therapy
Many patients are currently established on regimens that are no longer recommended for initial
therapy. Such patients should be advised of recent study results and should have explained to them
where changes in therapy may reduce the risk of virological rebound and improve their quality of life.
Those who are stable with evidence of sustained virological suppression (viral load < 50 copies/ml for
6 months or more) and who are not experiencing side effects (including lipoatrophy), may prefer to
remain on their current therapy as the longer the period of complete suppression, the lower the risk
of subsequent virological rebound is likely to be.
6.1.1 2NRTI plus unboosted PI regimens
Patients who are on PIs suitable for boosting (i.e. IDV or SQV) may find a boosted regimen simpler
to take, with fewer daily doses and food restrictions. Although switching to a boosted regimen may
improve quality of life [212], some studies have shown evidence of a significant increase in toxicity
[85]. NFV is not suitable for boosting and can be continued if the patient is stable with undetectable
viral load.
6.1.2 3NRTIs
Patients taking triple NRTI regimens should be advised of recent trial results indicating a higher risk
of virological rebound as compared with currently recommended regimens. A change in therapy
should be considered for those who have not achieved sustained virological suppression (< 50
copies/ml for more than six months) or who have achieved viral suppression but have previously
received mono or dual nucleoside therapy.
6.1.3 Regimens containing stavudine
D4T is no longer recommended for initial therapy largely because of data from several studies
suggesting that it is associated with an increased risk of lipoatrophy [213]. Patients who are on a
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D4T-containing regimen should consider switching if treatment history and resistance data suggest
that an alternative drug is likely to be active. A switch to ZDV may delay but is not likely to prevent