Summary

1.1 HIV testing

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.

1.2 Methodology

The section on methodology has been extensively updated since the last version. Additional information includes new discussion of 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.

1.3 Adherence

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.

1.4 Gender and ethnicity

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.

1.5 When to start treatment

1.5.1 Primary HIV infection (PHI)

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].

1.5. 2 Symptomatic HIV Infection

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 Asymptomatic HIV Infection

1.5.3.1 Individuals with CD4 counts <200 cells/mm3:

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/mm³ at diagnosis.

1.5.3.2 Individuals with CD4 counts >350 cells/mm3:

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/mm³, 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/mm3:

It is recommended that the majority of people should initiate therapy with CD4 counts between 200 and 350 cells/mm³. 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.

1.5.1 Primary HIV infection (PHI)

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].

1.5. 2 Symptomatic HIV Infection

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 Asymptomatic HIV Infection

1.5.3.1 Individuals with CD4 counts <200 cells/mm3:

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/mm³ at diagnosis.

1.5.3.2 Individuals with CD4 counts >350 cells/mm3:

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/mm³, 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/mm3:

It is recommended that the majority of people should initiate therapy with CD4 counts between 200 and 350 cells/mm³. 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.

1.5.3.1 Individuals with CD4 counts <200 cells/mm3:

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/mm³ at diagnosis.

1.5.3.2 Individuals with CD4 counts >350 cells/mm3:

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/mm³, 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/mm3:

It is recommended that the majority of people should initiate therapy with CD4 counts between 200 and 350 cells/mm³. 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.

1.6 What to start with

Treatment should be given with a dual nucleoside analogue and either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or boosted PI. Choice between an NNRTI and boosted PI remains largely a matter of opinion but more data exists 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-naïve population is increasing which may compromise their activity as first-line agents. NNRTIs have long half-lives which 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/mm³ and men with a CD4 count below 400 cells/mm³ where the risks of hepatotoxicity are minimized. LPV boosted with RTV is the PI for which the data on long-term vilorogical outcome is strongest in a PI-naïve 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 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 two 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 versus 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.

1.7 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. 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. Improvements in fat redistribution that occur as a result of such switching are slow.

1.8 Changing or stopping therapy for virological failure

• 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 2 values at least one 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 which 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’

1.9 Treatment for patients with evidence of resistance to NNRTIs, nucleoside analogues and PIs

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 to attempt to get 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/mm³ 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 where 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.

1.10 Resistance testing

• 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.

1. Primary resistance. There is now extensive evidence for the transmission of drug resistant variants [3,4], and some evidence transmitted resistance may compromise response to first-line therapy [5–7]. In some cases, the presence of resistance in an apparently drug-naïve patient may in fact reflect previous undisclosed therapy.
2. Epidemiology of drug-resistance in treatment-experienced cohorts. Antiretroviral treatment failure continues 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 (without previous mono or dual nucleoside therapy) between 1996 and 2003, there was a 38% risk of failure and a 27% or higher risk of developing resistance over 6 years of follow-up [8].
3. Benefit of resistance testing in treatment-experienced patients. Routine use of genotypic resistance testing after treatment failures has been shown to be cost effective [9]. TORO-1 and TORO-2 [10,11] and RESIST-1 and RESIST-2 [12,13] trials provided indirect evidence of the clinical benefit of resistance testing in highly drug-experienced patients.
4. Interpretation of resistance test results
   1. Routine resistance assays do not detect resistant viruses present at low levels (<20% of the total virus population), even if these resistant viruses were previously dominant. Although assays to detect minority species have been developed, they are not routinely available and remain research tools only. Limited data indicate that minority resistant quasispecies may affect virological responses [14,15].
   2. In the absence of drug pressure, the dominant virus population will revert to wild type [16]. Reversion is slower in transmitted resistance than in resistance selected by therapy [17–22]. Reversion of mutations may occur through intermediates or revertants (e.g. T215D/N/S from T215Y/F). Detection of revertants should be interpreted as evidence that fully-resistant mutants are present as either minority quasispecies or archived resistance.
   3. The interpretation of resistance test results is complex. The most informative interpretation systems are based on ‘clinical cut-off’ values, which are being determined for a growing number of drugs.
   4. Antiretroviral resistance should be interpreted as a continuum. For the NRTIs and PIs (but not for the NNRTIs) [23], residual virological suppression can be observed with intermediate levels of resistance, which may reflect direct antiviral activity as well as the beneficial effects of reduced viral fitness [24].
   5. Virus fitness is defined as the overall capacity of a virus to infect, replicate, and produce mature infectious progeny in a defined host environment. The Replicative Capacity Assay is a clinically available test that provides one measure of viral fitness. The clinical utility of the test has not been demonstrated.
   6. Hypersusceptibility effects can be demonstrated in vitro. Certain drug-resistance mutations confer resistance to some drugs but increase susceptibility to others. The clinical relevance of this is not clear.
   7. Certain resistance pathways have been associated with the HIV-1 subtypes. HIV genetic diversity also impacts on phenotypic resistance assays, which use a B subtype virus backbone.
5. Patients should be encouraged to have knowledge of their results and the i-Base treatment passport is an ideal vehicle for keeping an ongoing record of the CD4 count, viral load and resistance test results.

1.11 Therapeutic drug monitoring (TDM)

Randomized, prospective, controlled trials remain a high priority to evaluate the usefulness of TDM of NNRTIs and PIs. TDM has been shown to be beneficial in particular clinical scenarios where drug concentrations are difficult to predict. These include the management of drug interactions, pregnancy and paediatrics, and in highly treatment-experienced patients when TDM and resistance test results can be integrated, patients with renal or hepatic impairment, transplant patients, potential toxicity, and the use of alternative dosing regimens whose safety and efficacy have not been established.

Clinical data supporting the use of inhibitory quotient are limited; however, these appear to be superior in predicting failure compared to drug concentrations or resistance testing alone in extensively pre-treated patients commencing salvage regimens.

1.12 Metabolic complications

As the prognosis of HIV infection has markedly improved, so has our need to recognize and manage long-term morbidity associated with HIV and HAART.

Abnormalities of lipid homeostasis and fat distribution are likely to assume a central role in guiding choices for antiretroviral therapy (ART). This is the result of the growing awareness of the increase of stigmatization and reduction of adherence associated with lipodystrophy, especially lipoatrophy, and for the increased cardiovascular risk associated with drug-induced metabolic abnormalities. Few prospective studies address the relative risk of different regimens causing the features of lipodystrophy, although ACTG384 suggests the risks are greater with PIs than with NNRTIs and greater with stavudine (d4T) than with ZDV. Studies have shown a slow reversal of lipoatrophy when d4T and possibly ZDV, are substituted by other drugs such as ABC and TDF. There is convincing data to suggest that avoiding PIs as first line, or switching from them, leads to a better lipid profile and possibly a reduction of insulin resistance. This class effect on lipids and insulin resistance does not apply to atazanavir, and boosting with RTV does not appear to change this.

The application of current health promotion approaches to our patients should include assessments of cardiovascular risk and their appropriate management according to the most recent international guidelines, particularly as it has been suggested that HIV, because of its proinflammatory profile, might present a greater risk for the development of cardiovascular disease.

1.13 Co-infection with chronic hepatitis B or C and HIV

• Anti-hepatitis B virus (HBV) therapy should be included in antiretroviral therapy for all HBsAg+ patients who are HBeAg+, or who have a blood HBV-DNA level >104 genome equivalents/ml, or who have cirrhosis and any detectable HBV-DNA. In patients commencing ART with detectable HBV-DNA levels but <104 genome equivalents/ml, 3TC/FTC should be used either with TDF or not at all.
• If treating HIV and HBV, TDF alone or in combination with 3TC or FTC is recommended as part of HAART. 3TC or FTC should not be used alone or in combination with each other.
• Anti-HBV drugs should be continued in the context of controlled HBV replication when a switch of ART is contemplated.
• Consider all hepatitis C virus (HCV)-positive patients for therapy with pegylated interferon and ribavirin, to commence ideally before the CD4 count has fallen to levels where ART is required.
• If ART is required in HCV-positive patients, they should ideally be established on a stable regimen with a CD4 count >200 cells/mm³ before anti-HCV therapy is considered. Ideally avoid ZDV, ddI and d4T should be avoided because of their interactions with ribavirin.
• If possible, avoid nevirapine (NVP) and high-dose (>1000 mg/day) RTV in all patients with chronic liver disease due to their potential hepatotoxicity. Low dose RTV can be used safely.

1.14 Co-infection with tuberculosis (TB) and HIV

The guidelines for managing HIV-infected patients co-infected with TB can be found on http://www.bhiva.org/index.html

The management of such patients is complex and requires a multidisciplinary approach. It is important that physicians treating such patients are not only aware of the issues around the epidemiology, prevention control and treatment of TB in HIV but also the use of HAART.

When to start HIV treatment, which treatments to use, drug interactions, side effects and their management and other complications including the Immune Reconstitution Inflammatory Syndrome (IRIS) are specifically addressed in these comprehensive guidelines.