The guidelines make no fundamental changes to the CD4 count criteria for starting antiretroviral therapy (ART), retaining 350 cells/mm3 as the threshold. But they extend the range of situations in which ART is recommended for people with higher CD4 cell counts and also include a range of situations in which ART should be 'considered'.
They include a wider range of recommended initial regimens than national guidelines such as those issued by the British HIV Association and the US Department of Health and Human Services. They include either of the first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs efavirenz and nevirapine, three boosted protease inhibitors (atazanavir, darunavir and lopinavir) and the integrase inhibitor raltegravir.
Tenofovir/FTC (Truvada, or with efavirenz as Atripla) or abacavir/3TC (Kivexa) are given equal weight as the nucleoside analogue (NRTI) 'backbone' of combination regimens, though the guidelines note that abacavir 'should be used with caution' with a high viral load or cardiovascular disease risk and that patients should always be advised on the possibility of a hypersensitivity reaction to abacavir, even if they are negative for the B*5701 genetic variation that usually causes this. There are new tables of the most common and serious HIV drug side effects, and also of interactions with drugs commonly used for other illnesses.
Professor Nathan Clumeck of St Pierre University Hospital in Brussels, who chaired the group writing the HIV guidelines, said: “We have probably been quite conservative in our approach. We have included a variety of first-line treatments. The risk is that if you are too prescriptive it will create double standards.”
He said that it was not realistic to be too prescriptive “for a region where some countries have good access to treatment while others have poor access. For instance in our host country Serbia, no Truvada or raltegravir are available.”
In addition to the CD4 count threshold, the guidelines recommend HIV treatment at any CD4 count if there is HIV-related disease, including TB (with a recommendation to start within two weeks for patients with CD4 counts below 100 cells/mm3), cancer including Hodgkin's lymphoma and HPV-related cancer, symptomatic hepatitis B infection, neurocognitive impairment and also in pregnancy. For pregnant women natural delivery is now preferred to Caesarean section if the mother has a viral load below 50 copies/ml.
The guidelines advise physicians to consider treatment for all patients with a CD4 count under 500, especially if they have hepatitis C, and at any CD4 count in patients with high cardiovascular disease risk (greater than 20% 10-year risk), other cancers or primary HIV infection (within eight weeks of infection).
Professor Clumeck was asked if the 'consider' categories would give healthcare funders an excuse to rule out these categories. He said the intention was to leave as much room as possible for physician and patient judgement.
He added that the 'consider' category had been the solution to situations where the writing panel could not agree: “Now we have a variety of treatments that work and less toxicity, there is a wider range of situations where there is clinical equipoise, in other words where the evidence does not firmly point to one strategy or other.”
Monitoring and comorbidities
The most distinctive feature of the EACS guidelines, as before, is their format: a small pocket-size booklet containing procedures and algorithms in graphic form, the better for busy doctors to follow.
There is a new section at the start of the book detailing which tests should be applied to patients at the time of HIV diagnosis, when starting therapy and as regular monitoring. Amongst new recommendations are resistance testing at diagnosis, not just at virological failure and, where available, the B*5701 abacavir hypersensitivity test at diagnosis. This is accompanied by an algorithm to help doctor and patient decide whether the time is right to start HIV therapy.
As in previous years the book is divided into three sections: HIV treatment, treatment for non-infectious comorbidities ranging from cancer through high blood pressure to depression, and treatment of hepatitis B and C.
In the co-morbidities section there are new sections on bone mineral density (BMD) and on vitamin D deficiency in patients with low BMD and revised treatment guidelines for diabetes (with the sulfonylurea drugs now recommended for patients with severe type 2 diabetes and no significant weight gain).
The management of cardiovascular disease is relatively conservative, with lipid-lowering drugs and switching HIV therapy (from protease inhibitors to raltegravir, and away from abacavir) only recommended for patients with a greater than 20% 10-year risk of heart attack. In kidney disease, it is now recommended to measure urinary protein as well as creatinine, and atazanavir is now cited as a risk factor for kidney stones.
There are new pages on risks associated with travel, and on the safety and efficacy of commonly-used vaccines for people with HIV at various CD4 counts.
The guidelines already included a page on how to manage depression, including quick screening question to use. To this has now been added a comprehensive chart on the management of sexual dysfunction and on assessing neurocognitive impairment. The guidelines note that the diagnosis and management of neurocognitive impairment is still an area of controversy: Professor Jens Lundgren of the University of Copenhagen, who chaired the comorbidity group, said: “It was difficult to make recommendations in this area as the evidence is weak and it’s very opinion-based. I’m confident this table will look different in two years."
The group writing the section on hepatitis B and C was chaired by Professor Jürgen Rockstroh of the University of Bonn. These involve new, clarified flowcharts for the initiation and management of hepatitis C treatment and also include the management of hepatitis delta (hepatitis D) in patients with hepatitis B.
The writing group of this section had a dilemma: two hepatitis C protease inhibitor drugs (boceprevir and telaprevir) are now licensed for treatment of patients with hepatitis who do not have HIV, and considerably increase the speed and efficacy of treatment, but are not licensed for patients with HIV. The printed version of the guidelines, on the basis of 12 weeks’ interim results of telaprevir in HIV/hepatitis C coinfected patients, recommends that physicians can choose to add telaprevir to standard therapy for twelve weeks. The online version may include a similar recommendation for boceprevir if positive results are received at next week’s Infectionse Diseases Society of America Meeting. They note that atazanavir and efavirenz are so far the only two non-NRTI drugs that have been evaluated for drug interactions with telaprevir.
The inclusion of this page caused some controversy, with a doctor from the audience commenting that physicians could get into trouble if they prescribed unlicensed drugs, but Professor Rockstroh commented that doctors were entitled to use their clinical judgement to prescribe the new drugs to coinfected patients.
Treatment as prevention
The guidelines make the briefest of mentions of the use of HIV treatment as prevention, with a recommendation to 'actively discuss' early initiation in serodiscordant couples and noting that: “Some experts recommend treatment as a tool for the prevention of HIV transmission”. Professor Clumeck said they had not gone further into the prevention benefits of treatment because, “It is not our role to take the public health approach”.
Professor Lundgren expanded on this in a press conference: “In medicine the goal of treatment is to benefit the individual, so to integrate public health is a huge problem. It’s going to be very difficult to recommend treatment as prevention without more accrued knowledge. Using treatment needs to be part of a whole prevention package: in Europe HIV infection in young gay men is still going up even though we are getting them undetectable.”
Sustaining HIV treatment
Finally, the guidelines contain within their recommendations an awareness that finances are tight for HIV treatment everywhere but that drug stockouts and the denial of treatment are regularly encountered in eastern Europe – a situation covered in another conference session. The guidelines include a specific warning against switching to a new drug regimen with a low barrier against resistance and Professor Clumeck said that this was written with switches due to emergency stockouts in mind. Guidelines for emergency switching are covered by a new European AIDS Treatment Group leaflet issued at the EACS conference – see here for their press release.
Professor Lundgren issued a stark warning at the end of his remarks: “With the help of generic drugs becoming available, I think that HIV treatment will be sustainable in western Europe. But in eastern Europe I fear a real public health emergency over the next few years unless doctors and patients combine to advocate for HIV treatment.”
The new European AIDS Society Clinical Guidelines can be accessed here.