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

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, are highly predictive of subsequent differences in clinical outcome 27. Restricting comparison to those with viral load 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 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 by the the Committee for of and the in the UK for reporting adverse events to the treatment of HIV available antiretroviral of HIV infection is not likely to be possible The of treatment is to and improve quality of by suppression of virus for as long as The three groups of treatment patients for treatment guidelines are required are: patients with primary HIV patients with HIV infection and patients with HIV or The recommendations are in Table is one study of in primary HIV infection and it As yet there is no evidence of clinical from any study of treatment of PHI with treatment it is the of PHI may represent a for therapeutic It is likely that, at the time of there is a of the of the virus with the virus in the viral to different cell may be and the to an immune response is usually greater than it is the treatment of PHI may HIV immune responses and it has been that long term may A of triple drug therapy regimens to viral in the and for the of patients within a few of PHI studies have that after PHI there is a and CD4 HIV response This is in to infection with the of long term the HIV CD4 response is These CD4 responses may be important in an Such immune responses to be maintained in people with antiretroviral therapy after PHI and represent the biological evidence that treatment at this time might be data suggest that there is more and immune in patients starting therapy during PHI than in those starting is still no to the of whether treatment at such an will influence the longer term of viral with no of after of antiretroviral therapy has in a few patients very soon after PHI The of drugs that are known to CD4 such as and A in the suppression of viral and of CD4 responses in this setting is and data a possible for treatment interruptions in the immune response and reducing the virological set point in patients very during PHI have found that therapy during PHI had no upon the set point that would have been expected in the of any treatment Given the lack of it reasonable to consider ideally within a clinical trial. 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This is in to the viral load when changes to CD4 the therapy has in the lower CD4 count this provide any evidence of therapy at CD4 counts > these data suggest that, patients should start therapy before the CD4 count has to on have an increased risk of CD4 cell count decline to copies/mL a rate of decline in CD4 this level of viral load is an risk for subsequent and However, these data are from an before the of highly antiretroviral therapy and may not be recent studies have that baseline viral load not predict subsequent of the baseline CD4 count after starting therapy. some data have that the baseline viral load the virological response to treatment in some studies This is not however, for all cohorts or all drug regimens and the efficacy of combinations in patients with higher viral being a better indicator of what to start with rather than when to It should be the CD4 count that about when to with a rapidly CD4 count or high viral load may be for earlier therapy the range of CD4 to that the CD4 count not to < In patients with