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EACS 2015: With EACS Release, All International HIV Treatment Guidelines Agree on When to Start


The new European AIDS Clinical Society (EACS) Guidelines, released last week at the15th European AIDS Conference in Barcelona, bring Europe into line with the rest of the world by recommending HIV treatment upon diagnosis for all patients. This is the first time since 2006 that all international guidelines have agreed on their "when to start" recommendations.

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As a measure of what has changed since then, in that year the guidelines from EACS, the World Health Organization (WHO), the U.S. Department of Health and Human Services (DHHS), the International AIDS Society USA (IAS-USA), and the British HIV Association (BHIVA) all agreed that treatment was only strongly recommended for people with CD4 T-cell counts below 200 cells/mm3. They did not recommend treatment for people with CD4 counts over 350 cells/mm3, and recommended it only with caution for people with CD4 counts between 200 and 350 cells/mm3.

Now, in line with all other guidelines, EACS recommends that treatment should be offered to all people diagnosed with HIV, though they still reserve a category of "strong recommendation" for people diagnosed with CD4 counts below 350 cells/mm3.

"When to start was the easiest part to write," commented José Gatell, the conference co-chair, referring to the START study, which showed that treatment is beneficial at all CD4 counts.

What to Start With

The various guidelines show much less harmony when it comes to what to start with, however. This partly reflects very new information this year about the effectiveness of the integrase inhibitor drugs raltegravir (Isentress) and dolutegravir (Tivicay, also in Triumeq) and also partly reflects whether guidelines are primarily intended to apply to people in low- or high-income countries.

In terms of what is still called the "backbone" of 2 nucleoside/nucleoside reverse-transcriptase inhibitor (NRTI) drugs, the international guidelines are reasonably in agreement, recommending tenofovir and emtricitabine (the drugs in Truvada) unanimously. Abacavir and lamivudine (the drugs in Epzicom or Kivexa) are recommended as an equal first choice by EACS, DHHS, and IAS-USA, but recommended only as an alternative choice by BHIVA (largely due to questions over its potency in people with high viral loads). WHO does not recommend abacavir/lamivudine since many lower-income countries lack the ability to test people beforehand for the B*5701 genetic variation in their immune system that indicates likely hypersensitivity to abacavir.

There is less agreement over the third agent, however. The biggest disparity in views is over the drug efavirenz (Sustiva or Stocrin, also in Atripla). This former mainstay of HIV treatment, which has been in the drug arsenal since 1998, is still recommended by the WHO as their one preferred first regimen for HIV treatment, either as a component of Atripla or alongside tenofovir and emtricitabine, Atripla’s other components. This partly reflects the fact that the WHO decided not to change its recommendations on what to start with when it changed its recommendation on when to start this year.

In contrast, the DHHS guidelines, also revised this year, do not include any of the non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, of which efavirenz is one, among their 5 recommended first-line regimens. Instead, they recommend only regimens based on the integrase inhibitors and on one remaining protease inhibitor, darunavir (Prezista).

As a measure of how fast things have changed, the IAS-USA guidelines, released only last year, were still recommending regimens based on efavirenz and on 2 other NNRTIs, etravirine (Intelence) and rilpivirine (Edurant, also in Complera or Eviplera), in its 11 recommended starting regimens, and also the protease inhibitor atazanavir (Reyataz), which is not even recommended as an alternative by the DHHS (or by the WHO, which recommends no protease inhibitors, partly due to their higher cost).

EACS compromises between the DHHS and IAS-USA positions. They recommend 6 first-line regimens. Of these, 4 use an integrase inhibitors as their third drug: dolutegravir or raltegravir plus tenofovir/emtricitabine, the combination pill Triumeq (dolutegravir plus abacavir/lamivudine), and the combination pill Stribild (cobicistat-boosted elvitegravir plus tenofovir/emtricitabine). They also recommend the NNRTI-based Complera or Eviplera pill (rilpivirine plus tenofovir/emtricitabine), and the PI-based ritonavir-boosted darunavir plus tenofovir/emtricitabine.

In a panel discussion during a session presenting the new EACS guidelines, Marco Vitoria of the WHO writing group defended the retention of efavirenz.

He said: "Even though with efavirenz there is an increased relative risk of side effects, the absolute risk remains small" and dolutegravir (which is the first non-boosted, once-daily integrase inhibitor) "will not be available as a generic drug for at least 2 years."

EACS treasurer Nathan Clumeck questioned WHO’s decision to have, as its only recommended regimen, one that has a low genetic barrier to resistance (resistance to efavirenz arises very quickly under conditions of partial adherence).

Stefano Vella, answering for WHO said: "We did consider a PI-based regimen as first-line therapy but ruled them all out owing to cost, practicality, and side effects. We have been using efavirenz in low-income countries for years with good effects on mortality."

Gatell said that this was the reason EACS has decided to retain 1 NNRTI-based regimen. The integrase inhibitors were still relatively new and dolutegravir had only recently been licensed: in contrast "NNRTIs are used all over the world," he said, and the EACS guidelines are also used in lower-income countries.

PrEP and PEP

Other changes in the new guidelines include a positive recommendation for pre-exposure prophylaxis (PrEP), which brings them into line with the U.S. DHHS and Centers for Disease Control and Prevention (CDC), WHO, and BHIVA. PrEP is "recommended" for "men who have sex with men and transgender individuals, who are inconsistent in their use of condoms with casual partners or with HIV-positive partners who are not on treatment," and "may be considered" for "heterosexual men and women who are inconsistent in their use of condoms and are likely to have HIV-positive partners who are not on treatment."

The guidelines emphasize that PrEP is a medical intervention that may have side effects, does not protect against other sexually transmitted infections, "may not provide full protection against acquiring HIV," and should be prescribed and supervised by a doctor experienced in sexual health.

The guidelines recommend that PrEP can be prescribed as a daily or intermittent regimen, in the latter case taken as it was in the Ipergay study (a double dose during the 24 hours before sex then 1 dose each on the 2 following days after sex).

EACS has also changed its recommendations for post­-exposure prophylaxis (PEP). They no longer recommend PEP if the source partner is HIV-positive with an undetectable viral load, a change that finally brings them into line with BHIVA, and they recommend Truvada plus darunavir/ritonavir or raltegravir as regimens.

Hepatitis C Coinfection

The hepatitis C recommendations now exclude the use of pegylated interferon and ribavirin as a first choice (although, recognizing that some countries are still using them, dosing advice for interferon/ribavirin regimens is included in the appendix pages that are only available online rather than in the printed guidelines).

The recommendations include 6 direct-acting antiviral (DAA) regimens for hepatitis C virus (HCV) genotype 1, 4, and 6; 3 regimens for genotype 3; 2 regimens for genotype 2; and 1 option for genotype 5. This is necessary because some drugs only work for certain genotypes.

Comorbidities and Aging

Another change is not so much in specific recommendations as emphasis. The section on the Prevention and Treatment of Co-morbidities in people with HIV now includes a specific statement: "We recommend multidisciplinary care for aging HIV patients with multiple co-morbidities and chronic immune activation to preserve good quality of life and prevent frailty."

Georg Behrens, who coordinated the co-morbidity section, said that this section -- which includes recommendations for dealing with everything from cancer to depression -- is the one that has most expanded since the last guidelines, necessitating removal of a number of sections of the web-only version of the guidelines. The challenge in writing guidelines for co-morbidities, he said, was deciding what to leave out -- if you tested for every co-morbidity that can be raised in people with HIV, patients would never leave the clinic."

This is because as the HIV-positive population ages, it is becoming clearer that certain conditions that arise with age can be more frequent or more severe in people with HIV. More "aggressive" monitoring of kidney function is recommended in people with an even slightly depressed glomerular filtration rate (GFR) and progressive decline, and much more use of depression screening is recommended.

Practicality and Affordability

Some people in the audiences commented on the practicality of some recommendations -- integrase-inhibitor-based regimens, PrEP, HCV DAAs -- in eastern Europe. Jürgen Rockstroh, who coordinated the coinfection guidelines, commented that huge and illogical disparities in drug prices were also partly to blame, citing the contrast between Germany, which paid high prices for HCV DAAs, and Portugal, which had managed to negotiate much lower ones.

Guidelines chair Jens Lundgren said he always encouraged his students to work at placements in Eastern Europe -- "it reminds me of what things used to be like here, you still see people dying of AIDS." He urged EACS to do more to liaise with Eastern European doctors and support their fight for better treatments for their patients.



European AIDS Clinical Society. European Guidelines for Treatment of HIV-infected A|adults in Europe. Version 8.0, October. 2015.