A draft version of the 2005 British HIV Association (BHIVA) guidelines were formally introduced by BHIVA’s former president, Professor Brian Gazzard, chair of the guidelines’ writing committee, at the Eleventh Annual Conference of the British HIV Association with the British Association for Sexual Health and HIV in Dublin last week.
Once again, the BHIVA guidelines appear to be entering new territory with a recommendation that HIV testing should no longer be afforded special status; an antiretroviral cost-benefit analysis; a discussion of gender and ethnicity issues; and a broad dismissal of adherence intervention therapies. There is little change from 2003, however, in their recommendations for when to initiate or change therapy, although the writing committee now favours efavirenz (Sustiva) over nevirapine (Viramune) and, as evidence accrues that AZT (zidovudine, Retrovir) is associated with lipoatrophy, the guidelines move away from firmly recommending an AZT-containing regimen as part of a nucleoside backbone.
During his presentation Professor Gazzard stressed that the guidelines are written by a committee and have to reflect a broad spectrum of opinions. He added that they are still a work in progress that can be commented on by any individual or group during a review process which ends on May 3rd 2005, by sending an email to him via his secretary: eileen.witney@chelwest.nhs.uk
Here is a brief summary of the most important new recommendations, discussions and changes:
HIV Testing
In March, an editorial in the British Medical Journal argued that the changing epidemiology of HIV in the UK, the large number of late diagnoses, and the improved prognosis of HIV-positive individuals provide grounds for lowering the threshold for HIV testing and reducing the emphasis on pre-test counselling. The latest BHIVA guidelines appear to have taken that editorial to heart and echo its sentiments.
“Since the outlook for an HIV seropositive person has been transformed following the introduction of HAART, previous arguments about the value of HIV testing are no longer relevant,” they say. “We believe that a request to undertake a 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.”
Cost of treatment
“...when the Committee believes that little distinguishes various drugs apart from cost this will be mentioned.”
For the first time the guidelines contain a list of drug prices to allow comparisons to be made between regimens, although the writing committee warn that the prices do not take into account the potential effect of regional or hospital discounts, parallel imports or home delivery of drugs (exempt from VAT).
“We are cognisant that it would not be right in the framework of medical ethics to ignore the issues of costs,” the guidelines say. “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.”
Gender and ethnicity
The guidelines writing committee acknowledges that more women and people of diverse ethnic backgrounds are being diagnosed with HIV in the UK and that the majority of clinical trials have been in men from resource-rich countries. They discuss nevirapine and efavirenz issues for both women and Africans, lipodystrophy differences between genders, and interactions between nelfinavir (Viracept) and the oral contraceptive pill. In addition, they note that “the increasing ethnic diversity of the UK HIV positive population has particular implications for access to and uptake of care.”
Adherence interventions
The writing committee argues that adherence to anti-HIV medicines is one of the most important issues in ensuring successful therapy. “The leading determinant of a successful and durable virological and immunological responses to HAART is adherence sustained without a lapse at extraordinarily high levels for many years,” they write. “Therefore a core component of the clinical care of HIV positive patients must be adherence support. This should commence before HAART is introduced and continue at varying intensity throughout the treatment course.”
However, after reviewing the published evidence they admit that little appears to help with improving adherence. “Current evidence does not support adherence interventions including intensive, frequent or prolonged contact with specialist staff or structured group interventions. There may be some benefit from brief individualised interventions. Treatment simplification should not be at the price of reduced clinical efficacy. Medication alarms may impede adherence.”
These guidelines may cause some confusion with regards to recommended adherence interventions unless they are rewritten after the consultation period.
What to take first-line
The guidelines discuss the benefits and disadvantages - including the cost implications - of whether to start with a non nucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI) alongside dual nucleoside analogue therapy. “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 guidelines say.
However, when it comes to discussing the two approved NNRTIs, the writing committee’s new preferred first-line regimen is efavirenz. “The Committee believes that efavirenz is the NNRTI of choice except for women who may wish to become pregnant,” they write. “Nevirapine 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 serious adverse reactions are minimised.”
Boosted PI options include favouring first line lopinavir/ritonavir (Kaletra) “which has the most robust data for potency in a PI naïve population.” Alternatives offered include ritonavir-boosted saquinavir (Invirase in its new 500mg formulation) and ritonavir-boosted fosamprenavir (Telzir). Ritonavir-boosted atazanavir (Reyataz) cannot currently be recommended due to insufficient data regarding use of the once-daily boosted PI as a first-line therapy.
The guidelines make no explicit recommendation regarding the NRTI backbone, but do suggest that individuals already taking AZT should be offered the option of switching to abacavir (Ziagen) or tenofovir (Viread), given the long-term risk of lipoatrophy (fat loss) in those taking AZT. The guidelines also state that “until the situation becomes clearer, the increased likelihood of lipoatrophy mitigates against the choice of AZT as initial therapy.”
The guidelines discuss the three available coformulated dual NRTI backbones, Combivir (AZT/3TC), Kivexa (abacavir/3TC) and Truvada (tenofovir/FTC). “While [coformulation] 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.”
Still, the guidelines note that “AZT/3TC is likely to become considerably cheaper in the next two years as generic AZT becomes available. The extent of the continuing use of AZT/3TC combinations in the future is likely to depend upon the propensity of AZT to produce lipodystrophy, which is in itself costly to treat.”
“The choice between [Kivexa] and [Truvada] requires a discussion with the patient about the short term toxicity of abacavir and its management versus the lack of long term data in clinic populations, as opposed to selected patients in randomised controlled trials, and about potential long term toxicity of tenofovir and its reversibility if it occurs,” they say. “In this uncertain situation with no clear data, the relative costs of the two combinations will legitimately be an important consideration.”
Other issues in brief
The guidelines only recommend structured treatment interruptions as part of clinical controlled trials, except for those individuals who began anti-HIV therapy with a CD4 count greater than 400 cells/mm3.
There is an extensively updated section on clinical trial methodology, including a new discussion of the definition of viral load end-points, including an explanation of the "time time to loss of virologic response" (TLOVR) algorithm, and a section on issues surrounding non-inferiority trials.
The latest data on resistance testing, therapeutic drug monitoring and the treatment of metabolic complications are also discussed in the guidelines. Resistance testing is recommended on the first available plasma sample and after each treatment failure. Therapeutic drug monitoring is mentioned as being useful when a patient experiences toxicity, is taking a 'salvage' regimen, during pregnancy and for children, and if an individual is taking an unusual regimen.
There is also a small section on co-infection with hepatitis B and/or C, as well as TB, although BHIVA have produced separate guidelines on these complicated issues. New guidelines have also been produced regarding liver transplantation in HIV-positive patients.
The guidelines also discuss second-line therapy and options for those who are very experienced and/or multi-class resistant, including the new and investigational PIs, tipranavir and TMC114, both of which are boosted by ritonavir. They also include mention of the investigational NNRTI, TMC125, which appears to be a “a potent NNRTI active against NNRTI resistant HIV”, currently about to start phase III trials.