British HIV Association (BHIVA) guidelines for the treatment of HIV‐infected adults with antiretroviral therapy (2005)

Abstract

1.0 Summary 1.1 HIV testing 1.2 Methodolog 1.3 Adherence 1.4 Gender and ethnicity 1.5 When to start treatment 1.5.1 Primary HIV infection 1.5.2 Symptomatic HIV Infection 1.5.3 Asymptomatic HIV Infection 1.5.3.1 Individuals with CD4 counts <200 cells/μL 1.5.3.2 Individuals with CD4 counts >350 cells/μL 1.5.3.3 Individuals with CD4 counts 201–350 cells/μL 1.6 What to start with 1.7 When to switch therapy in the absence of virological failure 1.8 Changing or stopping therapy for virological failure 1.9 Treatment for patients with evidence of resistance to NNRTIs, nucleoside analogues and PIs 1.10 Resistance testing 1.11 Therapeutic drug monitoring (TDM) 1.12 Metabolic complications 1.13 Co-infection with chronic hepatitis B or C and HIV 1.14 Co-infection with tuberculosis (TB) and HIV 2.0 New issues in these guidelines 2.1 HIV testing and diagnosis 2.2 New drugs 2.2.1 Tipranavir 2.2.2 TMC 114 2.2.3 TMC 125 2.3 Cost–benefit analysis 2.3.1 Cost of antiretroviral drugs 2.4 Structured treatment interruption (STI) 2.5 Gender and ethnicity – implications for therapy 3.0 Methodology 3.1 Basing recommendations on evidence 3.2 Implications for research 3.3 Use of surrogate marker data 3.4 Issues concerning design and analysis of clinical trials 3.4.1 Issues concerning design and analysis of clinical trials: trial designs 3.4.2 Issues concerning design and analysis of clinical trials: viral load outcome measures 3.4.3 Issues concerning design and analysis of clinical trials: non-inferiority 3.4.4 Issues concerning design and analysis of clinical trials: cross-study comparisons: presentation of data 3.5 Adverse event reporting 4.0 Adherence 4.1 Adherence and resistance 4.2 Treatment simplification strategies 4.3 Interventions to improve knowledge and skills 4.4 Cognitive-behavioural interventions 4.5 Pagers/alarms etc. 4.6 Pre-HAART practice placebo dosing 4.7 Directly observed therapy (DOT) 4.8 Injectable therapy 4.9 Recommendations 5.0 When to start treatment 5.1 Primary HIV infection 5.1.1 Treatment of primary HIV infection to alter the natural history 5.1.2 Treatment during PHI for immediate clinical benefit 5.1.3 Treatment during PHI to reduce onward transmission 5.1.4 Recommendations for starting treatment in PHI [CIV] 5.2 Symptomatic HIV infection 5.3 Asymptomatic HIV infection 5.3.1 Individuals with CD4 counts <200 cells/μL 5.3.2 Individuals with CD4 counts >350 cells/μL 5.3.3 Individuals with CD4 counts 201–350 cells/μL 5.3.4 Recommendations regarding asymptomatic chronic HIV infection 6.0 What to start with 6.1 Which HAART regimen is best? 6.1.1 Two NRTIs plus an NNRTI 6.1.1.1 EFV – preferred regimen 6.1.1.2 NVP – alternative regimen 6.1.1.3 Delavirdine – not recommended 6.1.2 Two NRTIs plus a boosted PI 6.1.2.1 RTV-boosted lopinavir – preferred regimen 6.1.2.2 RTV-boosted fosamprenavir – alternative regimen 6.1.2.3 RTV-boosted saquinavir – alternative regimen 6.1.2.4 RTV-boosted or unboosted atazanavir 6.1.3 Three NRTIs 6.2 Choice of 2NRTIs (includes nucleoside and nucleotide RTI) [Table 5] 6.2.1 Co-formulated 2NRTIs 6.2.2 Other 2NRTI/NtRTI combinations 6.3 Conclusions 7.0 Changing or stopping therapy in the absence of virological failure 7.1 Patients started on regimens that are not currently recommended for initial therapy 7.1.1 2NRTI plus unboosted PI regimens 7.1.2 3NRTIs 7.1.3 Regimens containing stavudine (d4T) 7.1.4 Regimens containing ZDV 7.1.5 Non-HAART regimens 7.1.6 NNRTI regimens with TDF and ddI 7.2 Patients on recommended regimens 7.2.1 Switching from PI-based regimens 7.2.2 Switching between NNRTIs 7.2.3 Stopping NNRTI-based regimens in non-emergency situations 7.3 Stopping therapy in individuals with complete viral suppression (STI) 7.3.1 Intermittent on–off therapy cycles of 1 month or longer 7.3.2 Intermittent on–off therapy cycles of 1 week 7.3.3 Discontinuation of therapy with re-start based on CD4 count (CII) 8.0 Changing or stopping therapy for virological failure 8.1 Viral load blips 8.2 Sustained viral load rebound 8.3 Changing therapy [BII] 8.3.1 Virological failure with no resistance 8.3.2 Virological failure with PI mutations [BII] 8.3.3 Virological failure with NNRTI mutations [BIII] 8.3.4 Virological failure with NRTI mutations alone [BIV] 8.3.5 Use of enfuvirtide (T20) 9.0 Treatment for patients with evidence of resistance to NNRTIs, nucleoside analogues and PIs 9.1 Patients whose therapy fails after having used at least three classes of drugs ('salvage therapy') 9.2 Criteria for success in patients exposed to multiple drug classes 9.2.1 Principles of optimizing success in highly treatment-experienced patients 9.2.2 Patient assessment 9.3 Management of patients with multiple class resistance 9.3.1 Stopping therapy long term 9.3.2 MEGA HAART 9.3.3 STI 9.3.4 New agents 9.3.4.1 Use of T20 (enfuvirtide) 9.4 Recommendations for subsequent virological failure (third or more regimen) 10.0 Resistance testing 10.1 Drug-naive patients 10.2 Drug-experienced patients 10.3 Interpretation of resistance 10.4 Recommendations 11.0 Therapeutic drug monitoring (TDM) 11.1 Evidence of a concentration–effect relationship 11.1.1 Efficacy 11.1.2 Toxicity 11.2 Controlled trials of TDM 11.3 Other potential problems with TDM 11.4 Utility of TDM 11.5 Inhibitory quotients 11.6 TDM recommendations 12.0 Metabolic complications 12.1 Lipodystrophy 12.1.1 Aetiology 12.1.2 Lipid abnormalities 12.1.3 Management of lipodystrophy 12.1.4 Other therapies 12.1.5 Corrective procedures for HAART-associated lipoatrophy 12.1.6 Conclusions 12.2 Mitochondrial toxicity and lactic acidosis 12.2.1 Aetiology of NRTI-induced mitochondrial toxicity 12.2.2 Lactic acidosis and hyperlactataemia 12.2.2.1 Incidence 12.2.2.2 Clinical and laboratory features 12.2.3 Management of hyperlactataemia and lactic acidosis 12.2.4 Recommendations for managing lactic acidosis 13.0 Treating patients with chronic hepatitis B or C 13.1 Hepatitis B 13.2 Hepatitis C 13.3 Avoiding antiretroviral hepatotoxicity 13.4 Recommendations Conflict of interest References The Committee believes that a potentially important mechanism for limiting the HIV epidemic is the widespread use of HIV testing in a variety of clinical settings. The availability of effective antiretroviral treatment improves outcome and potentially reduces onward transmission. The section on methodology has been extensively updated since the last version. Additional information includes new discussion of the definition of viral load endpoints, including an explanation of the 'time to loss of virologic response' (TLOVR) algorithm, and a section on issues surrounding non-inferiority trials. Current evidence does not support adherence interventions that include intensive, frequent or prolonged contact with specialist staff or structured group interventions. There is more likely to be some benefit from brief individualized interventions. Treatment simplification should not be at the price of reduced clinical efficacy. Medication alarms may impede adherence. It is important that adherence support should be part of the routine clinical care provided by all health professionals in HIV medicine rather than being the exclusive role of specialist staff members. Every prescribing unit should adopt a standardized approach to assessing adherence and have a written policy on provision of adherence support. Staff must be appropriately trained to make delivery of such support possible. Treatment adherence data should be recorded routinely alongside other clinical parameters in order to detect patients in greatest need of additional treatment support. Increasing numbers of women and people of diverse ethnic backgrounds are being diagnosed with HIV in the UK. Much of the evidence underpinning therapy has been gained from observations in men from resource-rich settings. Although some gender differences in surrogate markers have been observed, clinical outcomes to highly active antiretroviral therapy (HAART) are at least as good in women as they are in men. Adverse events may show some differences between men and women and the selection of medications needs to be mindful of women's child bearing capacity. The increasing ethnic diversity of the UK HIV-positive population has particular implications for access to and uptake of care. In addition, a wider range of HIV viral subtypes is being seen in clinical practice. When equal access to care is available, clinical outcomes on HAART are equivalent, although some ethnic differences in adverse event profiles have been observed. Longer-term follow-up of small numbers of patients treated during PHI, with subsequent treatment interruption, have not supported initial hopes that early treatment would alter the natural history of HIV infection. It is, therefore, the view of the panel that we should not change the recommendation that patients diagnosed during PHI should be offered recruitment into a clinical trial that will address the issue of whether treatment is beneficial in this setting [1]. There is no change to the recommendation in the 2003 guidelines – i.e. that initiation of treatment is recommended in individuals with symptomatic disease and/or an AIDS diagnosis (with the possible exception of pulmonary tuberculosis). 1.5.3.1 Individuals with CD4 counts <200 cells/μL. There is no change to the previous recommendations – i.e. that initiation of therapy is recommended before the CD4 count falls below 200 and in any individual with a confirmed CD4 count <200 cells/μL at diagnosis. 1.5.3.2 Individuals with CD4 counts >350 cells/μL. Although some recent studies have added to the data suggesting a benefit, in the short to medium term, on mortality and morbidity with initiation of HAART at a CD4 of >350 cells/μL, these need to be interpreted with consideration to the likelihood that patients with HIV may live for decades after treatment with HAART. In this group of patients, where the short-term risk of disease progression is low, it is still considered that initiation of HAART may result in greater morbidity, and possibly mortality, in the longer term as a result of drug toxicity and earlier exhaustion of treatment options. 1.5.3.3 Individuals with CD4 counts 201–350 cells/μL. It is recommended that the majority of people should initiate therapy with CD4 counts between 200 and 350 cells/μL. Within this range, the time of initiation in a particular individual may be based upon patient preference, the rapidity of CD4 decline, symptoms, viral load, and co-morbidity such as hepatitis C infection. Treatment should be given with a dual nucleoside analogue and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI). The choice between an NNRTI and boosted PI remains largely a matter of opinion, but more data exist for NNRTI-based regimens in terms of efficacy. The fact that the current NNRTIs are generally more susceptible than PIs to marked loss of activity due to resistance can be used as an argument for using them in first-line therapy rather than in patients who have virologically failed previous regimens. This is on the basis that little benefit is likely to be gained from the NNRTIs if they are used with drugs to which some resistance has developed. However, the incidence of transmitted NNRTI resistance in the treatment-naive population is increasing, which may compromise their activity as first-line agents. NNRTIs have long half-lives that allow once-daily dosing and latitude around dose timing (forgiveness) and produced fewer disturbances in lipid metabolism. In favour of a boosted PI is a higher genetic barrier to resistance, which leads to the rarity of both transmitted resistance and development of PI resistance with treatment failure. The Committee believes that efavirenz (EFV) is the NNRTI of choice, except for women who may wish to become pregnant. Nevirapine (NVP) is an alternative in women with a CD4 count of less than 250 cells/μL and men with a CD4 count below 400 cells/μL, in whom the risks of hepatotoxicity are minimized. Lopinavir (LPV) boosted with ritonavir (RTV) is the PI for which the data on long-term vilorogical outcome is strongest in a PI-naive population. Alternatives are saquinavir (SQV) boosted with RTV and fosamprenavir boosted with RTV, but substantive direct comparisons between RTV-boosted PIs in such populations are not available. The Committee believes that there is insufficient data to recommend RTV-boosted atazanavir. However, if in trials that are currently in progress, the efficacy and durability of this regimen can be confirmed, the once-daily dosing and freedom from serum lipid abnormalities would be an advantage of this regimen. Nucleoside analogues that should be considered when constructing a 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone for initial regimens include: zidovudine (ZDV), lamivudine (3TC), abacavir (ABC), tenofovir (TDF), didanosine (ddI) and emtricitabine (FTC). Three 2NRTI combinations are available as co-formulated pills: Kivexa (ABC and 3TC), Truvada (FTC and TDF) and Combivir (ZDV and 3TC). While this adds to the convenience of the regimen, the Committee did not feel that this was sufficient to pay a large premium for a combination pill rather than using the components individually. Data suggests that ZDV/3TC is less well tolerated than TDF/FTC and produces a lower CD4 count rise than ABC/3TC, although the clinical significance of this is unknown. ZDV/3TC is likely to become considerably cheaper in the next 2 years as generic ZDV becomes available. The extent of the continuing use of ZDV/3TC combinations in the future is likely to depend upon the propensity of ZDV to produce lipodystrophy, which is in itself costly to treat and will be associated with poor adherence [2]. The choice between ABC/3TC and TDF/FTC requires a discussion with the patient about the short-term toxicity of ABC and its management vs. the lack of long-term toxicity data for TDF in clinic populations as opposed to selected patients in randomized controlled trials: in this uncertain situation with no clear data, the relative costs of the two combinations will legitimately be an important consideration. 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. Regimen simplification, e.g. 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. Improvements in fat redistribution that occur as a result of such switching are slow. In patients experiencing viral load rebound, a clinical assessment of factors potentially contributing to reduced plasma drug levels such as adherence and drug–drug interactions should be undertaken and managed appropriately. The addition of a single new agent in individuals experiencing low-level viral load rebound is not recommended as the disadvantages of added toxicity and development of resistance to the new drug are probably greater than the likelihood of achieving a sustained undetectable viral load. Patients should be considered for a change of therapy if they show sustained rebound in viral load levels (as defined by two values at least 1 month apart >400 copies/mL), having previously been undetectable, or have never achieved undetectable levels on their current regimen. A resistance test should be undertaken once sustained viral load rebound occurs and while the patient is still on therapy. The decision to change therapy should be guided by the availability of a treatment option that is likely to have the potency to suppress viral load levels to undetectable levels (<50 copies/mL) and which the patient is likely to be able to adhere to and tolerate. The choice of a new regimen should be guided by the results of current and previous resistance testing, antiretroviral treatment history and the ability and likelihood of the patient to tolerate and adhere to individual drugs. The new regimen should contain at least three active drugs, including one from a new drug class. Active is defined as 'where a drug is likely to have significant antiviral activity in vivo based on the antiretroviral treatment history and the results of all current and previous genotypic resistance testing'. In this setting, where it is unlikely that durable undetectable levels of HIV RNA are achievable, the aim of treatment should shift to maintaining or preserving immunological function and preventing clinical progression. Therefore, when treating patients with evidence of resistance to NNRTIs, nucleoside analogues and PIs, it is very important to maintain CD4 cell count rather than attempt to assess the HIV viral load undetectable with single agents. Structured treatment interruption (STI) is NOT recommended in this setting and needs further evaluation. For patients who are not at risk of rapid clinical progression (stable CD4 cell count 50–100 cells/μL and not falling rapidly), it would be sensible to wait for enough new active drugs to be available in order to have a realistic chance of durable viral suppression to <50 copies/mL. In particular, enfuvirtide (T20) should be used judiciously and, where possible, only when there is another fully active drug in the background regimen. However, patients with multidrug-resistant HIV should be referred to or discussed with larger HIV centres where new investigational drugs are likely to be more accessible; this could be done as part of a managed clinical network or on a shared care basis. Testing for transmitted resistance is recommended in all newly diagnosed patients. This includes patients with either acute seroconversion or established infection. The most appropriate sample is the one closest to the time of diagnosis and this should preferably be tested at the time of initial presentation. For existing patients, testing for transmitted resistance is recommended at the time of starting therapy. Minority species of resistant virus may be missed by conventional resistance testing. In patients without evidence of transmitted resistance using such tests, a suboptimal virological response to first-line therapy (<1 log10 copies/mL reduction in viral load by 4–8 weeks) should prompt resistance testing at that time. The reader should refer to the extended guidelines for additional recommendations. Primary resistance. There is now extensive evidence for the transmission of drug-resistant variants [3, 4], and some evidence that transmitted resistance may compromise response to first-line therapy [5-7]. In some cases, the presence of resistance in an apparently drug-naive patient may in fact reflect previous undisclosed therapy. Epidemiology of drug resistance in treatment-experienced cohorts. Antiretroviral treatment failure con–tinues to occur among patients on HAART and is frequently accompanied by the selection of drug resistance. In a study of UK patients who started HAART previous or dual nucleoside between and there was a risk of failure and a or higher risk of resistance years of follow-up of resistance testing in treatment-experienced patients. The routine use of genotypic resistance testing after treatment failure has been to be effective and and and trials provided evidence of the clinical benefit of resistance testing in highly patients. Interpretation of resistance test results resistance not detect resistant at levels of the virus if these resistant previously Although to detect species have been they are not routinely available and research data that resistant may virological In the absence of drug the virus population will to is in transmitted resistance than in resistance selected by therapy of mutations may occur or from of should be interpreted as evidence that fully resistant are as either or resistance. The of resistance test results is The most are based on which are being for a of drugs. Antiretroviral resistance should be interpreted as a For the NRTIs and PIs not for the virological suppression can be observed with levels of resistance, which may reflect direct antiviral activity as well as the beneficial of reduced viral is defined as the of a virus to and produce in a defined The is a available test that one of viral The clinical of the test has not been can be in mutations resistance to some drugs but to The clinical of this is not resistance have been associated with the HIV genetic diversity on resistance which use a B virus Patients should be to have knowledge of their results and the treatment is an for an of the CD4 viral load and resistance test controlled trials a to the of TDM of NNRTIs and TDM has been to be beneficial in particular clinical where drug are to include the management of drug and and in highly treatment-experienced patients when TDM and resistance test results can be in patients with or patients, potential toxicity, and in the use of alternative dosing regimens whose and efficacy have not been Clinical data the use of are these to be in failure to drug or resistance testing alone in extensively patients regimens. the of HIV infection has has need to and long-term morbidity associated with HIV and HAART. of lipid and fat are likely to a role in for antiretroviral therapy This is the result of the of the of and reduction of adherence associated with lipodystrophy, and for the risk associated with studies address the relative risk of regimens causing the features of lipodystrophy, although suggests the risks are greater with PIs than with NNRTIs and greater with stavudine (d4T) than with have a of lipoatrophy when and possibly ZDV, are by other drugs such as ABC and There are data to that PIs as or switching from leads to a lipid and possibly a reduction of resistance. This class on lipids and resistance does not to and with RTV does not to change The of current health to patients should include of risk and their appropriate management to the most recent as it has been that because of its a greater risk for the development of B virus therapy should be in antiretroviral therapy for all hepatitis B who are hepatitis B or who have a or who have and any In patients with levels but should be used either with TDF or not at treating HIV and TDF alone or in combination with 3TC or is recommended as part of HAART. 3TC or should not be used alone or in combination with drugs should be in the of controlled when a switch of is all hepatitis C virus patients for therapy with and to before the CD4 count has to levels where is is in patients, they should be established on a regimen with a CD4 count cells/μL before therapy is possible ZDV, ddI and should be because of their interactions with possible, (NVP) and RTV in all patients with chronic disease due to their potential RTV can be used The guidelines for managing patients with can be on The management of such patients is complex and requires a It is important that treating such patients are not only of the issues around the and treatment of in HIV but the use of HAART. When to start HIV which to drug and their management and other including the are in these guidelines. The issues surrounding HIV testing are in detail in a of the for an patient has been the of previous for testing that include are less in most an important to improve patient outcome and reduce transmission of HIV is the more widespread of HIV testing. It is important that clinical professionals are to the symptoms, and that possible and are in a to testing. that an to an HIV test should be within the of all and is both possible and within the of a clinic or practice There is no need for skills those which all and for their practice. It is that there be when the risk of HIV infection is In these cases, an individual additional before and a test but should with the most recent guidelines from the on and have available numbers of support to with the of patients who have a when a result is there is still a widespread to an HIV-positive diagnosis and therefore, patients need to be of the of that HIV need to that their staff this the test is patients are likely to need and support. Individuals should be to the implications of of an HIV-positive diagnosis to and testing using from which the diagnosis can be in is being used to a This may in a practice setting, and the of a time to a potentially HIV result may be more The most important outcome for those individuals with an HIV-positive result is the prompt to with in the treatment of HIV and It is that this short of updated recommendations for antiretroviral should be in with the more extensive of the existing data about such therapy in the previous guidelines The of this section is to on drugs which are likely to be in the future or are available on This which is likely to be has been because of its ability to that are resistant to all available PIs in This ability has been confirmed in vivo in 2 and In the 1 and 2 studies patients previously exposed to all three classes of drugs and at least two PIs randomized to background plus or by to treat a viral