New issues in these guidelines

2.1 HIV Testing and diagnosis

The issues surrounding HIV testing are covered in detail in a number of publications [25–27]. Since the outlook for an HIV-seropositive patient has been transformed following the introduction of HAART, previous protocols for testing that include detailed pre-test counselling are less relevant in most situations. Thus, an important means to improve patient outcome and reduce transmission of HIV is the more widespread offer of HIV testing. It is important that clinical healthcare professionals are alert to the symptoms signs and histories that denote possible risk, and are then in a position to offer testing. We believe that an offer to undertake an HIV test should be within the competence of all doctors and is both possible and desirable within the context of a general medical clinic or general practice surgery. There is no need for special counselling skills outside those which all clinicians (nurses and doctors) require for their daily practice.

It is recognized that there might be exceptional circumstances, particularly when the risk of HIV infection is high. In these cases an individual might require an additional counselling either before and following a positive test results, but certainly afterwards. Clinicians should familiarize themselves with the most recent guidelines from the ABI [28] on life insurance and have available telephone numbers of support organisation to help with the minority of patients who have a major reaction when a positive result is disclosed.

Unfortunately, there is still widespread stigma attached to an HIV-positive diagnosis and therefore, patients need to be informed of the strict rules of confidentiality that medical practitioners abide by. Clinics performing HIV tests need to ensure that their staff observe this confidentiality.

If the test is positive, patients are likely to need specialised advice and support. Individuals should be advised to think through carefully the implications of disclosure of an HIV-positive diagnosis to relatives and friends. Increasingly, point of care testing using assays from which the diagnosis can be obtained in 15 minutes are being used to provide a ‘one stop’ service. This may prove difficult in a general practice setting, and the booking of a separate time to discuss a potentially positive HIV result may be more satisfactory. The most important outcome for those individuals with an HIV-positive result is the prompt referral to someone with experience in the treatment of HIV and related infections.

2.2 New Drugs

It is intended that this short summary of updated recommendations for antiretroviral treatments should be read in conjunction with the more extensive review of the existing data about such therapy present in the previous BHIVA guidelines [29]. The intention of this section is to update readers on drugs which are likely to be licensed in the near future or are already available on compassionate release.

2.2. 1 Tipranavir

This PI, which is likely to be licensed shortly, has been developed because of its ability to inhibit viruses which are resistant to all presently available PIs in vitro. This ability has been confirmed in vivo in recently completed Phase 2 and 3 studies. In the combined RESIST 1 AND 2 studies [12,13], 1483 patients previously exposed to all three classes of drugs and at least two PIs were randomized to optimized background plus or minus tipranavir. At 24 weeks by intent to treat analysis, a viral load fall of at least 1 log was seen in 42% of tipranavir-treated patients (19% in the comparator arm) and 23% of patients (9.4% in the comparator arm) achieved a viral load of less than 50 copies/mL at this time point. A higher proportion of patients, who were naïve to enfuvirtide (T20) and given this as part of the optimized background, achieved undetectability. The entries criteria for these two studies were narrow. Patients were required to harbour a virus with one or more primary PI mutations present but two or less mutations at specific sites in the genome (33, 82, 84 or 90). A further study which was conducted in patients who had three or more PI mutations at these specific sites also showed that tipranavir was able to reduce the short-term viral load (over two weeks) compared with other boosted PIs. This study also showed unexpected interactions between tipranavir and other PIs making it difficult to use as part of a double-boosted PI regimens without dose adjustment or therapeutic drug monitoring.

The pharmacokinetics of tipranavir require it to be administered with ritonavir (RTV) 200 mg twice daily. The likelihood of the response to tipranavir can be gauged by the resistance profile of the virus and expert advice is helpful in deciding which which boosted PI is most likely to be effective in a particular patient. Abnormalities of lipid, particularly triglyceride and liver function tests are the main laboratory side effects although the incidence of gastrointestinal side effects is not greater than with other boosted PIs.

Like other drugs essentially used as single effective agents in advanced disease, the virological responses are often short lived and the drug is much more likely to find a role in the early stages of disease when it is possible to construct a regimen capable of suppressing viral replication completely.

2.2.2 TMC 114

TMC114 is an investigational twice-daily PI with activity against PI-resistant HIV-1. It is administered with RTV 100 mg twice daily.

At the Conference on Retroviruses and Opportunistic Infection in 2005 [30], a planned 24 week interim analysis of two 96-week dose finding phase two trials in highly treatment-experienced patients were presented. Patients were experienced in three or more classes with a median viral load over 100,000 copies/ml at baseline (baseline median values were HIV RNA 4.6 log10 copies/mL). They all had one or more primary PI mutations. A total of 497 subjects were randomized to either optimised background (OB) with or without T20 or to OB plus TMC114. The primary endpoint was the decrease in viral load at 24 weeks. The 600/100 mg tipranavir/r twice daily dosing appeared to have the best antiviral effect with a change in viral load from baseline of 1.85 log 10 compared with the control group of -0.27 log 10. Overall, 47% of patients who had a viral load of less than 50 copies at 24 weeks (9% in the OB arm) and this figure rose to 67% for those patients who also received T20 having not been exposed to this drug previously. The CD4 count in the tipranavir arm rose by 75 cells/mm³. There was no difference in toxicity or adverse events between the arms.

2. 2.3 TMC125

TMC125 is made by Tibotec/Janssen-Cilag and is a potent NNRTI active against NNRTI resistant HIV-1. It has been tested against single and multiple mutants as well as clinical isolates with NNRTI-resistance associated mutations. It appears that a high number of mutations are required for a significant increase in the EC50. The TMC125-C207 [31] study was performed over an 8-day period in patients who were failing in NNRTI therapy. Median and viral load was 4 to 4.25 log at baseline and after 7 days of TMC125-C207 the viral load had dropped 1 log. TMC125 is currently in phase IIB dose-finding studies.

2.2. 1 Tipranavir

This PI, which is likely to be licensed shortly, has been developed because of its ability to inhibit viruses which are resistant to all presently available PIs in vitro. This ability has been confirmed in vivo in recently completed Phase 2 and 3 studies. In the combined RESIST 1 AND 2 studies [12,13], 1483 patients previously exposed to all three classes of drugs and at least two PIs were randomized to optimized background plus or minus tipranavir. At 24 weeks by intent to treat analysis, a viral load fall of at least 1 log was seen in 42% of tipranavir-treated patients (19% in the comparator arm) and 23% of patients (9.4% in the comparator arm) achieved a viral load of less than 50 copies/mL at this time point. A higher proportion of patients, who were naïve to enfuvirtide (T20) and given this as part of the optimized background, achieved undetectability. The entries criteria for these two studies were narrow. Patients were required to harbour a virus with one or more primary PI mutations present but two or less mutations at specific sites in the genome (33, 82, 84 or 90). A further study which was conducted in patients who had three or more PI mutations at these specific sites also showed that tipranavir was able to reduce the short-term viral load (over two weeks) compared with other boosted PIs. This study also showed unexpected interactions between tipranavir and other PIs making it difficult to use as part of a double-boosted PI regimens without dose adjustment or therapeutic drug monitoring.

The pharmacokinetics of tipranavir require it to be administered with ritonavir (RTV) 200 mg twice daily. The likelihood of the response to tipranavir can be gauged by the resistance profile of the virus and expert advice is helpful in deciding which which boosted PI is most likely to be effective in a particular patient. Abnormalities of lipid, particularly triglyceride and liver function tests are the main laboratory side effects although the incidence of gastrointestinal side effects is not greater than with other boosted PIs.

Like other drugs essentially used as single effective agents in advanced disease, the virological responses are often short lived and the drug is much more likely to find a role in the early stages of disease when it is possible to construct a regimen capable of suppressing viral replication completely.

2.2.2 TMC 114

TMC114 is an investigational twice-daily PI with activity against PI-resistant HIV-1. It is administered with RTV 100 mg twice daily.

At the Conference on Retroviruses and Opportunistic Infection in 2005 [30], a planned 24 week interim analysis of two 96-week dose finding phase two trials in highly treatment-experienced patients were presented. Patients were experienced in three or more classes with a median viral load over 100,000 copies/ml at baseline (baseline median values were HIV RNA 4.6 log10 copies/mL). They all had one or more primary PI mutations. A total of 497 subjects were randomized to either optimised background (OB) with or without T20 or to OB plus TMC114. The primary endpoint was the decrease in viral load at 24 weeks. The 600/100 mg tipranavir/r twice daily dosing appeared to have the best antiviral effect with a change in viral load from baseline of 1.85 log 10 compared with the control group of -0.27 log 10. Overall, 47% of patients who had a viral load of less than 50 copies at 24 weeks (9% in the OB arm) and this figure rose to 67% for those patients who also received T20 having not been exposed to this drug previously. The CD4 count in the tipranavir arm rose by 75 cells/mm³. There was no difference in toxicity or adverse events between the arms.

2. 2.3 TMC125

TMC125 is made by Tibotec/Janssen-Cilag and is a potent NNRTI active against NNRTI resistant HIV-1. It has been tested against single and multiple mutants as well as clinical isolates with NNRTI-resistance associated mutations. It appears that a high number of mutations are required for a significant increase in the EC50. The TMC125-C207 [31] study was performed over an 8-day period in patients who were failing in NNRTI therapy. Median and viral load was 4 to 4.25 log at baseline and after 7 days of TMC125-C207 the viral load had dropped 1 log. TMC125 is currently in phase IIB dose-finding studies.

2.3 Cost benefit analysis

The prognosis of HIV infection has been revolutionized by antiretroviral treatment. The requirement for life-long treatment, however, has meant that the total cost of antiretrovirals place a burden on third party payers. Antiretrovirals remain among the most cost-effective treatments to save a year of life for a chronic disease with the high cost of drugs being partially offset by the reduction in expensive hospital inpatient care and the avoidance of opportunistic infections.

While the BHIVA Writing Committee continues to believe that the primary purpose of the guidelines is to produce a consensus view of optimal treatment based upon potency, durability and freedom from side effects, we are cognisant that it would not be right in the framework of medical ethics to ignore the issues of costs. These issues become more important as more expensive drugs are developed, which have no clear advantages in terms of antiviral efficacy, but may add to the convenience for patients.

2.3.1 Cost of antiretroviral drugs

These two tables display the current prices as set out in the BNF plus VAT at 17.5% for the 2NRTI backbone and the third drug according to the recommendations for preferred regimens in antiretroviral (ARV)-naïve patients. While formulating this list, the Committee are aware that parallel importing, individual unit or regional discounting, and home delivery of drugs (which is zero rated for VAT) may affect overall price to a significant level. Moreover, total drug costs may be misleading without considering the implications of reduced adherence to more complex regimens and the high cost of managing side effects such as lipid abnormalities. However, throughout the guidelines for the first time when the Committee believes that little distinguishes various drugs apart from cost, this will be mentioned.

Table 1: Cost of preferred regimens as per Table 5: monthly (30 day) cost as set out in list price (April 2005) + VAT at 17.5% in £

r¹ or r² indicate number of ritonavir capsules per day
* For experienced patients only
** Not a preferred regimen but recognized potential cost-savings
# Trizivir^® £683
* d4T/3TC is as effective as other regimens but more toxic and not a preferred regimen
^# 150 mg tablets 

2.3.1 Cost of antiretroviral drugs

These two tables display the current prices as set out in the BNF plus VAT at 17.5% for the 2NRTI backbone and the third drug according to the recommendations for preferred regimens in antiretroviral (ARV)-naïve patients. While formulating this list, the Committee are aware that parallel importing, individual unit or regional discounting, and home delivery of drugs (which is zero rated for VAT) may affect overall price to a significant level. Moreover, total drug costs may be misleading without considering the implications of reduced adherence to more complex regimens and the high cost of managing side effects such as lipid abnormalities. However, throughout the guidelines for the first time when the Committee believes that little distinguishes various drugs apart from cost, this will be mentioned.

Table 1: Cost of preferred regimens as per Table 5: monthly (30 day) cost as set out in list price (April 2005) + VAT at 17.5% in £

r¹ or r² indicate number of ritonavir capsules per day
* For experienced patients only
** Not a preferred regimen but recognized potential cost-savings
# Trizivir^® £683
* d4T/3TC is as effective as other regimens but more toxic and not a preferred regimen
^# 150 mg tablets 

2.4 Structured Treatment Interruption (STI)

Supervised interruption of drug therapy may reduce drug costs and overall toxicity. Enthusiasm for this approach was initially increased by the biological plausibility that the reappearance of viral antigens in the circulation might stimulate the immune system to produce more effective control of viral replication. See the following sections:

1. Seroconversion, see section 5.0
2. Chronic disease, see section 7.3
3. STI in three-call experienced patients, see section 9.2.3

STIs of varying length with re-starting of therapy as indicated by CD4 cells has been showed to be a safe strategy in pilot studies with potential cost benefits but less clear reductions in toxicity. This strategy is being examined in a large international randomized controlled trial with clinical endpoints (SMART) [32] over the next several years.

The chief short-term risks of STI are the development of resistant virus because of virtual monotherapy with the component of the regimen with the longest half-life (usually the NNRTI). Particularly long half-lives have been found with some genetic polymorphisms of the Cytochrome P450 system which may be commoner in people of African origin. It is unclear how often resistance to NNRTIs develops but it would seem a reasonable precaution either to cover the withdrawal of the NNRTI with a shorter-acting PI which can subsequently stopped concomitantly with the two nucleoside analogues e.g. Kaletra or by stopping the NNRTI 14 days prior to the NAs. The disadvantage of this approach is the variability in the terminal half life of the NNRTI.

The Committee would only recommend a treatment interruption outside the clinical controlled trials in those patients who started ART with high CD4 counts e.g. above 400 cells/mm³ in accordance with earlier guidelines. Such patients may be able to withdraw treatment for several years before they require treatment according to newer guidelines.

2.5 Gender and ethnicity – implications for therapy

The HIV epidemic in the UK is increasingly diverse. Although the majority of people with HIV in Britain are men, the number of women is rapidly increasing. In 2003, 45% of new diagnoses were in women of whom almost 70% were from African backgrounds [33]. Much of the data available on both natural history and therapy of HIV has been generated from observations of men leading to a relative lack of information about women. Ethnic diversity within the UK HIV- infected population is also rapidly changing. Since 1999, new diagnoses in Africans have overtaken those in other groups. Gender and ethnicity are bound up with social, psychological and environmental factors which impact on both access to and uptake of care [34–36]. Increasing data exist on the responses and resistance patterns of non-subtype B viral strains to antiretrovirals, as described in the Resistance section. The management of HIV in women who are pregnant is given in the BHIVA pregnancy guidelines [37].

Factors that influence access to care may be implicated in the observations that late presenters are more likely to be female [38] and of African background [39]. In the UK, African men are diagnosed at an older age and have lower CD4 counts at diagnosis than African women [40]. A number of studies have shown that women are less likely to be prescribed antiretroviral drugs [43,44] and to initiate therapy later in disease progression than men [43,44].

In HIV-seronegative populations, women have been observed to have higher CD4 counts than men [45]. At seroconversion higher CD4 cell counts have been described in women compared to men [46], which have been shown to persist with time [47]. Such gender differences in CD4 counts may lead to a delay of initiation of therapy in women compared with men, which has been estimated to be of the order of 12 months [48]. However, despite rather later initiation of HAART, at a population level women show at least the same HAART related improvement in survival as men [49].

Viral load values in women have been noted to be lower for the same stage of disease progression and CD4 count in comparison to men. A metanalysis [50] confirms this finding to be consistent and of the order of 41%. This is of importance in situations where when plasma HIV RNA thresholds are used to inform treatment recommendations for initiating ART. A lower threshold is indicated for women compared with men.

The childbearing potential of women with HIV will influence therapeutic decision making. EFV is associated with teratogenicity and is contraindicated in pregnancy. It should not be used in women planning to conceive.

Once established on treatment, women fare at lest as well as men [51–54] and on starting therapy women may achieve virological suppression at a faster rate than men and have a more durable response [55]. In the UK, white ethnicity has been associated with greater increases in CD4 cell counts during the first 3 months of HAART [56] and in the USA with a more rapid and durable fall in viral load [57]. Large studies from the UK, Switzerland and Denmark [58–60] have all confirmed the prognosis of sub-Saharan African patients on triple therapy to be equivalent to that of northern European patients and that race and ethnic origin play no major role in the outcome associated with HAART if access to health care is free.

Differences in tolerability of antiretroviral medications are marked, with higher rates of side effects in women [61,62]. This difference has been observed across all drug classes. Adverse reactions to NVP are more common in women [63,64]. This is particularly marked at CD4 counts greater than 250 cells/mm³ [65] in whom NVP should not be used. A relationship between NVP toxicity and low body mass index (BMI ) in African women has been suggested [66]. High rates of neurological side effects and an associated reduced clearance of EFV have been closely linked with ethnicity but not gender [67,68]. Clearance has been shown to be 32% slower in African American and Hispanic patients in comparison to Caucasians. Abacavir (ABC) hypersensitivity has been described more commonly in white patients [69,70].

Drug interactions exist between PIs and oral contraceptives. Of particular note, nelfinavir (NFV) reduces the effectiveness of the contraceptive pill and women must be advised to use additional methods of contraception [71].

The impact of HAART on lipid and insulin metabolism appears to be more pronounced in women than in men [72,73] which may cancel out the protective cardiovascular profile usually conferred on women. HAART-associated body shape changes have been noted more commonly in women [74]. The pattern of fat accumulation and loss differs between the sexes, with a greater accumulation in women and loss in men [75]. In an Australian study, black patients preserved both total body fat and limb fat when compared to other ethnic groups [76,77].