British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy.

Abstract

Accepted: 27 July 2001 Introduction 1 Purpose of the guidelines 2 Basing recommendations on evidence 3 Use of evidence published as abstracts 4 Implications for research 5 Use of surrogate marker data 6 Issues concerning design and analysis of clinical trials 6.1 Trial designs 1.6.2 Methods of analysis 1.6.3 Intention to treat and on treatment analyses 1.6.4 Equivalence 1.6.5 Cross-study comparisons: presentation of data 7 Adverse event reporting 0 When to start treatment 1 Primary HIV infection 2.1.2 Recommendations for starting treatment in PHI 2 Symptomatic HIV infection 3 Asymptomatic HIV infection 2.3.1 Recommendations for starting treatment in established HIV infection 0 What to start with 1 Choices of initial therapy 2 Which HAART regimen is best? 3 Recommended initial HAART regimens 3.3.1 Two NRTIs plus one or two PIs 3.3.2 Two NRTIs plus an NNRTI 3.3.3 Advantages and disadvantages of NNRTIs 3.3.4 Three NRTIs 3.3.5 Advantages and disadvantages of three NRTIs 4 Choice of NRTI backbone for initial therapy 5 Recommendations for initial therapy 0 Issues concerning antiretroviral use 1 Adherence 2 Toxicity 4.2.1 Lipodystrophy 4.2.2 Management of lipodystrophy 4.2.3 Mitochondrial toxicity and lactic acidosis 0 Changing therapy on first virological failure 1 Initial failure 5.1.1 Viral load blips 5.1.2 Sustained viral load rebound 2 Changing therapy 5.2.1 Recommendation for changing therapy 3 Failure of two NRTIs plus a PI 4 Failure of two NRTIs plus an NNRTI 5 Failure of triple NRTI therapy 0 Therapy after more than one previous failure (‘salvage’ therapy) 1 Definition of salvage therapy 2 Measuring the success of salvage regimens 3 Principles of optimizing salvage success 4 Salvage therapy in PI experienced patients 5 Salvage therapy in NNRTI experienced patients 6 Salvage therapy in patients with multiple class resistance 7 Structured treatment interruption 6.7.1 STI to enhance immune responses 6.7.2 STI for reducing drug exposure/toxicity 6.7.3 STI to induce repopulation with wild type virus 6.7.4 Alternative approaches to treatment failure 6.7.5 Conclusions 8 Viral fitness 9 New therapies 10 Stopping therapy long term 11 Recommendations for subsequent virological failure (third or more regimen) 0 Resistance testing 0 Therapeutic drug monitoring 1 Plasma levels 8.1.1 Low plasma drug levels correlate with virological failure 8.1.2 High plasma drug levels may predict toxicity 2 Adherence 3 Drug interactions 4 Special groups 5 Problems with TDM 6 The way ahead 0 Haemophilia 0 Co-infection with HIV and hepatitis 1 Co-infection with HIV and hepatitis B 10.1.1 Background 10.1.2 Assessment of HBV infection in HIV-infected individuals 10.1.3 Management of HBV in HIV-infected individuals 10.1.4 Co-infection and the use of antiretroviral therapy 2 Co-infection with HIV and hepatitis C (HCV) 10.2.1 Background 10.2.2 Assessment of HCV infection in HIV infected individuals 10.2.3 Natural history of HCV in HIV infection 10.2.4 Management of HCV in HIV-infected individuals 10.2.5 Co-infection and the use of antiretroviral therapy 0 Issues not addressed in these guidelines 1 Pregnancy 2 Paediatrics 3 Post-exposure prophylaxis for healthcare workers 4 Age 5 Sex-based differences 0 BHIVA IAS-USA comparisons 0 References 0 Conflict of interest List of tables Table Grading of recommendations and levels of evidence Table When to start treatment: summary of recommendations Table Choices of initial therapy: summary of recommendations Table Currently available protease inhibitors (PIs) for initial treatment Table Currently available non-nucleoside reverse transcriptase inhibitors (NNRTIs) Table Agents to be used in combination with dual NRTI background Table Promoting adherence: issues to consider Table Management of lipids with specialist advice Table Management of glucose intolerance with specialist advice Table Changing therapy on first virological failure: summary of recommendations Table What to change to after first virological failure: summary of recommendations Table Potential objectives of structured treatment interruptions (STI) in different clinical settings Table Recommendations for use of HIV drug resistance tests Table Proposed indications for TDM Table Management of hepatitis C (HCV) infection in co-infected individuals Table Recommendations for starting antiretroviral therapy in adults: 2001 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 expanded and new sections added. The principles of consensus that overarched the previous guidelines [1, 2] 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. Each section of the guidelines 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. 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 [3-6]. The BHIVA guidelines have a number of important roles which are: To promote a uniformly high standard of care in all HIV treatment centres in the UK. To set out the strengths, weaknesses and relevance of recent research findings. To assist in discussions between purchasers and providers regarding funding for HIV/AIDS diagnostic testing, care and treatments. To act as a basis for clinical audit within clinical governance. To act as a source of reference on AIDS treatments for those physicians caring for patients infected with HIV. To act as a source of reference for HIV-positive people. These guidelines should not be seen as a substitute for research, nor as a manual for managing an individual, and should be interpreted and applied sensibly and appropriately. 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 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 1). Recommendations range from ‘essential’ to ‘not recommended’ 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). 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 [7, 8]. Expert opinion forms an important part of all consensus guidelines; however, this is the least valuable and robust form of evidence. 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 1998). 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 [9]. 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, with greater rises being seen in those with greater and more sustained viral suppression [10]. Changes in these markers in response to therapy are strongly associated with clinical response [11-14]. 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 [15-19]. The CD4 count is a better indicator of the immediate risk of AIDS defining diseases than the viral load in those on antiretroviral therapy [20]. 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 [11, 12, 21]. 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 [22-24]. 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. 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 Initio, Community Programs for Clinical Research on AIDS (CPCRA)′s FIRST, ACTG 384 and the three nation OPTIMA 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. 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 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 [25, 26]. 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 [27]. 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 [21, 28]. 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 [29]. 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. 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. 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 with respect to viral load and CD4 cell counts), methods of analysis (e.g. intention to treat vs. on treatment), degrees of adherence and sensitivities of viral load assays. 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 (http://www.mca.gov.uk/aboutagency/regframework/csm/csmhome.htm). With currently available antiretroviral agents, eradication of HIV infection is not likely to be possible [30]. The 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 primary HIV infection, patients with asymptomatic HIV infection and patients with symptomatic HIV disease or AIDS. The recommendations are summarized in Table 2. There is one placebo-controlled study of zidovudine (ZDV) monotherapy in primary HIV infection (PHI) [31] 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 recognized 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 [32, 33]; (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 [33, 34]. Recent studies have demonstrated that shortly after PHI there is a specific and strong CD4 helper HIV response [35-38]. This is in contrast to chronic infection where, with the exception of long term nonprogressors [37], the HIV specific CD4 helper response is generally lost [39]. 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 [40]. 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 [41]. The role of drugs that are known to inhibit CD4 activation, such as hydroxyurea [42] and cyclosporin A [43], in the suppression of viral replication and boosting of CD4 lymphocyte responses in this setting is unclear and requires further evaluation. Furthermore, limited data propose a possible role for strategic treatment interruptions (STIs) in stimulating the host immune response and reducing the virological set point in patients treated very early during PHI [44]. Others have found 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 [45]. 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]. Furthermore, despite suppression of plasma viral load, HIV replication may continue, with an associated risk of development of drug resistance [48] or transmission of drug resistant virus [49]. Given that the optimal duration of therapy is currently unknown, it should be assumed that lifelong treatment may be required even when initiated during PHI. The potential difficulties of long term adherence to available regimens cannot be overstated. 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 [50]. 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. It is very important at the time of PHI that patients and physicians make the most appropriate decision based on the limited data available. • Few data are currently available to establish the best therapeutic option. Thus the committee's first choice is to enter patients into a clinical trial, where available. • 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. • If treatment is not started within a few months of recognized PHI, a potential advantage may be permanently lost. • The decision to stop or continue treatment, once started, may be reviewed in the light of evolving data or poor adherence. • It is appreciated that many patients will choose not to be treated at this time and, because of the inherent uncertainties, this choice should be respected and be supported. • If patients are treated outside a clinical trial setting, a regimen appropriate for treating chronic HIV infection should be used (see section 3). All patients with late disease and/or symptomatic HIV infection with a CD4 lymphocyte count consistently < 200 cells/μL, or who have been diagnosed with AIDS or severe/recurrent HIV related illnesses** With the possible exception of pulmonary tuberculosis. or tumour at any CD4 count, should start therapy. This is because of the high risk of further opportunistic infections which, although treatable, may cause irreversible damage or be life threatening. There are no ongoing or planned controlled studies that sufficiently address the optimum time to start therapy [51]. 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. In the UK, patients are diagnosed with HIV infection at a late stage. Over 30% present with a CD4 count of < 200 cells/μL [52] and, consequently, the ‘early vs. 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. Data from several cohort studies with short term follow-up have suggested that patients who initiate therapy when the CD4 count is < 200 cells/μL have an increased mortality [53-55] compared with those above this level, but were unable to show any difference in those starting at any CD4 level > 200 cells/μL. However, data from other cohort studies [56, 57] suggest that patients who delay therapy until the CD4 lymphocyte count is < 200 cells/μL may have a similar virological and immunological response to those starting earlier. This is in contrast to data from prospective clinical studies [58, 59], although the effect of baseline CD4 response on therapy may not be the same for all drugs [60]. One study [60] has suggested that patients who commenced therapy with a CD4 count > 350 cells/μL were less likely than those who commenced later to experience disease progression or death. Interpretation of such results is not straightforward; although these studies do not directly address the question of when to start, they do help in evaluating the benefits of therapy as measured by falls in CD4 counts. Clinical event rates by baseline CD4 count mainly reflect the status of the patient before starting therapy, not the effect of therapy. This is in contrast to the viral load endpoint, when changes to < 500 or < 50 copies/mL can be almost entirely attributed to the effect of therapy. It is not correct to say that just because the event rate in the 200–350 CD4 cells/μL group is higher than in the > 350 CD4 cells/μL group, the therapy has less effect in the lower CD4 count group. Nor does this provide any evidence suggesting initiation of therapy at CD4 counts > 350 cells/μL. Taken together these data suggest that, ideally, patients should start therapy earlier, before the CD4 count has fallen to < 200 cells/μL. A number of factors need to be considered when making decisions with each individual patient (Table 2). Patients with a rapidly falling CD4 count (e.g. falling > 80 cells/μL per year on repeated testing) have an increased risk of CD4 cell count decline to < 200 cells/μL in the next 6 months. This group many thus be considered for initiation of therapy relatively earlier within the CD4 count range 200–350 cells/μL. Previous guidelines have suggested starting therapy relatively early in patients with a high plasma viral load [1, 4]. There are three reasons why viral load measurement should help guide decisions about when to start antiretroviral therapy. First, a viral load > 55 000 copies/mL [61] predicts a faster rate of decline in CD4 cells. Second, this level of viral load is an independent risk factor for subsequent disease progression and death. However, these data are from an era before the introduction of highly active antiretroviral therapy (HAART), and may not be relevant. Furthermore, recent cohort studies [53, 54] have suggested that baseline viral load does not predict subsequent mortality independently of the baseline CD4 count after starting therapy. Third, some data have suggested that the baseline viral load adversely affects the virological response to treatment in some prospective studies [62, 63]. This is not consistent, however, for all cohorts [57] or all drug regimens [58, 64, 65], and perhaps represents the differential efficacy of various combinations in patients with higher viral loads, being a better indicator of what to start with rather than when to start. It should be the absolute CD4 count that drives decisions about when to start. Individuals with a rapidly dropping CD4 count or high viral load may be considered for earlier therapy (within the range of 200–350 CD4 cells/μL) to ensure that the CD4 count does not fall to < 200 cells/μL. In asymptomatic patients with es