Treatment: what really works best?

This article originally appeared in HIV Treatment Update, a newsletter published by NAM between 1992 and 2013.
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The new edition of the HIV treatment guidelines from the British HIV Association (BHIVA) is now out for public consultation. HTU editor Gus Cairns was one of the two patient representatives on the writing panel, and says that this stands to be the most authoritative set of guidelines yet.

Glossary

representative sample

Studies aim to give information that will be applicable to a large group of people (e.g. adults with diagnosed HIV in the UK). Because it is impractical to conduct a study with such a large group, only a sub-group (a sample) takes part in a study. This isn’t a problem as long as the characteristics of the sample are similar to those of the wider group (e.g. in terms of age, gender, CD4 count and years since diagnosis).

first-line therapy

The regimen used when starting treatment for the first time.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

treatment as prevention (TasP)

A public health strategy involving the prompt provision of antiretroviral treatment in people with HIV in order to reduce their risk of transmitting the virus to others through sex.

BHIVA, essentially, is the body that represents the opinions and interests of HIV doctors and allied professionals in the UK. It doesn’t have to represent patients but has gone out of its way to encourage them to take positions of influence within the organisation. There is a patient representative on its ruling Executive Committee (EC), who is an ex officio trustee; I was the predecessor of the current EC representative, Silvia Petretti. BHIVA also has four permanent sub-committees that each have a position for a patient rep, and regularly appoints ad hoc working groups, which include patient representatives, for specific jobs such as writing sets of standards and guidelines. These are usually advertised on the UK-CAB website (www.ukcab.net).

One job I’d avoided until now, though, was anything to do with writing treatment guidelines. I knew from experience that there’s no point in being a patient rep unless you do some hard work. I was worried that I would have to spend hours wading through scientific studies evaluating evidence.

Although the actual work burden was not too bad, I wasn’t wrong about the amount of evidence. This set of treatment guidelines will be the first to be issued for three and a half years. They are normally issued biennially, but this time round the process of gathering and reviewing evidence had to pass an NHS accreditation process adopted in 2009 (see www.evidence.nhs.uk/accreditation). That meant it had to be done in a much more rigorous way.

Sifting the evidence

Globally, there are numerous different sets of HIV treatment guidelines for different countries and different needs.1 But the three most influential sets are probably the Department of Health and Human Services (DHHS)2 guidelines issued in the US; the European AIDS Clinical Society (EACS)3 guidelines; and the BHIVA guidelines.

There’s no set global standard for the evidence upon which guidelines are based. In theory they could simply be the opinion of a group of experts sitting round a table. Expert opinion, however, is often fallible. Doctors tend to base their opinions on their own patients, who may not be typical; negative results and non-results are notoriously less likely to be published; even people of integrity can be swayed by studies hyped by PR firms. What you think you know ain’t always so.

For this reason, most guidelines attempt to ‘grade’ evidence. This means that you look at each piece of scientific evidence and decide how reliable it is, and how crucial in health terms. It can be done by strength of recommendation, and by reliability of scientific evidence. There are three grades of scientific reliability. Grade 1, the best, is results from randomised trials that pit one treatment against another or against placebo. Grade 2 is data from cohort or population studies; these report what happens in large groups of patients, but results may be distorted by causes that aren’t captured by the data. Grade 3 is expert opinion and case reports. There are also, in the case of the US guidelines, three different strengths of recommendation, A, B and C for ‘strong’, ‘moderate’ and ‘optional’.

I'm trying in everything I do to represent the diversity of our community. Roy Trevelion, patient representative

So you could have a strong recommendation based on weak evidence (A3). This might apply, say, where a potentially lethal side-effect has been observed but where it’s difficult to say how common it is. Or you could have an optional recommendation based on strong evidence (C1), as when a rigorous scientific study establishes an outcome difference in something that doesn’t crucially affect health, like a tendency to get headaches.

These grades are still fallible, however, to experts’ knowledge of trials and to their opinion of how important specific outcomes are. So, for instance, one might regard a (statistically significant) 5% superiority for treatment A over treatment B in terms of patients achieving an undetectable viral load as clinching evidence in favour of treatment A. Another expert, however, might regard the fact that, although only a small number of patients drop dead from heart attacks, 20% more do on treatment A than B as an ironclad reason to favour treatment B.

In some cases, billions of pounds may depend on the result of such disputes, so there may be bitter battles over evidence. HIV is no stranger to this, especially when the cost of drugs is involved. BHIVA was well aware, for instance, of the decision by the London Specialist Commissioning Group to recommend Kivexa (abacavir/3TC) over Truvada (tenofovir/FTC) as first-line therapy for patients with a viral load under 100,000 copies/ml.

BHIVA accordingly stepped up the calibre of its evidence grading for the most crucial recommendations, to the point where the new guidelines may be the most rigorously evaluated anywhere. Firstly, doctors writing a particular section voted on how important they thought particular outcomes were (viral undetectability, speed of viral suppression, side-effects, CD4 count, resistance and so on). They then employed a health researcher to comb through every piece of evidence pertaining to the most crucial outcomes and generate what are called ‘forest plots’ – diagrams that show the overall strength of evidence across the range of available studies. In this case, two of the most crucial decisions – firstly, the choice of nucleoside drugs, which involves for most patients the Kivexa/Truvada decision, and secondly, the choice of which third drug to put alongside those – the result was two documents, one of 52 pages and one of 146.

Some crucial recommendations

The results? BHIVA recommends Truvada over Kivexa, not for particular patients, but generally. As for the third drug, it will broaden the choice: those 146 pages found that there was a dead heat between efavirenz (Sustiva, also in the combination pill Atripla), raltegravir (Isentress), ritonavir-boosted atazanavir (Reyataz) and ritonavir-boosted darunavir (Prezista) in terms of efficacy, but demoted lopinavir/ritonavir (Kaletra).

In terms of when to start treatment, BHIVA sticks to a CD4 count of 350 cells/mm3 as the starting threshold – already having decided that the study that persuaded the US guidelines to suggest 500 cells/mm3 was probably influenced by healthcare conditions in the US.4  However, it broadens the range of patients recommended to start earlier. This includes - though is not restricted to - patients with hepatitis B or untreated hepatitis C, and patients with neurocognitive problems. And it suggests that older patients, who are particularly prone to rapid CD4 count falls, should be considered for early therapy.

This article is too short to contain the many other recommendations, but they can all be read in the consultation document.

There are, however two other sections that people living with HIV might be particularly interested in: the section on Supporting the Patient to take Antiretroviral Therapy and the section on Treatment as Prevention. Although the EACS guidelines have a section on patient readiness, the former is BHIVA’s first statement in treatment guidelines of what doctors need to do in order to assist people and evaluate whether they have the right support to benefit from therapy.

The latter, as far as I’m aware, is an innovation in any set of HIV treatment guidelines. The US guidelines mention that antiretroviral therapy lowers patients’ infectiousness, but makes no recommendations on what to do about it, even though the guidelines include safer-sex counselling recommendations. The current draft of the BHIVA guidelines recommends that the fact that treatment with ART lowers the risk of transmission “is discussed with all patients”, and that if, following discussion, people at any CD4 count wish “to start ART to reduce the risk of transmission to partners, this decision is respected and ART is started”.

Being involved

This may all sound like a lot of work, but the individual burden wasn’t so bad. The guidelines writing group included 32 people. Most were doctors skilled in their area, so in some topic areas (how to combine HIV treatment with cancer chemotherapy, to give one example) I was happy to review the documents but take them on trust.

Now, I’m aware that I may be regarded as expert in some areas myself, so people may be thinking “Fine for Gus, but I’d never get involved in something like that myself.” Don’t just take my word for it. The guidelines were regarded as sufficiently important to need the input of more than one patient rep and so Roy Trevelion became the second one. Roy was diagnosed over 20 years ago but until three years ago worked as an art director for the BBC, and is a newcomer to HIV treatment activism.

He says: “I’ve been getting to grips with this and am very impressed with the whole process. I’ve read all the drafts and evidence summaries, with a medical dictionary in hand. But I actually see my lack of experience as an advantage: I think it’s important to have someone who reviews these guidelines from an ‘unpractised’ point of view, even if this means sometimes bringing up issues that aren’t easily placed in a set of clinical guidelines, such as issues of social disadvantage.

“I’m trying in everything I do to represent the diversity of our community and to include the fact that, because we are all living longer, HIV patients will face increasingly complex combinations of chronic illnesses - and resultant complications in treatment and in who treats them.”

There was also a meeting with other members of UK-CAB to get wider community feedback and a larger one is planned with HIV voluntary-sector organisations.

Dr Ian Williams, chair of this writing group, is also pleased with the outcome. He says: “We’ve tried to evaluate outcomes across all trials instead of some, and spend most time evaluating the outcomes of most importance to patients. The fact that they’ve been evaluated with regard to NHS accreditation means that it will be more difficult to criticise particular recommendations.”

There will be arguments, he acknowledges, and the whole point of issuing a draft for consultation is to allow arguments to be made for recommendations to be changed. But he’s confident in the robustness of the process that has led to BHIVA’s new treatment recommendations.

The consultation draft of the new BHIVA HIV treatment guidelines can be read online at www.bhiva.org/TreatmentGuidelinesConsultation.aspx