New directions in the 2015 WHO ART guidelines
Polly Clayden, HIV i-Base
The 2015 World Health Organization (WHO) Consolidated Antiretroviral Guidelines will recommend antiretroviral therapy (ART) at any CD4 count for HIV positive people of ages. The guidelines will also recommend new alternative first- and second-line regimens. 
Meg Doherty from the WHO HIV department presented new directions in the future consolidated guidelines at a WHO satellite preceding IAS 2015. The previous day WHO’s Gottfried Hirnschall had provided a “sneak preview” of the in-the-process-of-being-updated guidelines at the UN 90-90-90 Target workshop: lessons from the field. 
A summary of what to expect in the 2015 guidelines is presented in Table 1.
|Adults||Start ART at any CD4.|
|Prioritise symptomatic and CD4 < 350.|
|Pregnant and breastfeeding women||Start ART at any CD4 and continue lifelong (Option B+).|
|Adolescents (new age band: 10 to 19 years)||Start ART at any CD4.|
|Prioritise symptomatic and CD4 < 350.|
|Children||Start ART at any CD4 if <1 year old.|
|Start ART at any CD4 if 1 to 10 years old.|
|Prioritise starting if <2 years or symptomatic or CD4% < 25% (<5 years) or CD4 < 350 (>5 years old).|
|New ARV options||Integrase inhibitor (DTG) and optimised (EFV 400 mg, DRV/r) options in 1st and 2nd line therapy.|
|PrEP||PrEP as an additional prevention choice for all people at substantial risk of HIV infection (> 3% incidence).|
Answering the question, “why now?” Dr Doherty explained that since the 2013 guidelines, START and TEMPRANO trials of early versus deferred treatment had begun to report results. Results from trials of key antiretrovirals in specific populations had also been reported. New antiretrovirals and new doses and formulations – including dolutegravir (DTG), efavirenz (EFV) 400mg, and co-formulated darunavir (DRV/r) – will begin to become available for adults. A solid pellet form of lopinavir/ritonavir (LPV/r) has finally been approved for children and more optimised regimens and strategies are in the pipeline.
The new guidelines will also reflect the balance of point of care versus standard CD4, viral load and early infant diagnosis (EID) platforms. WHO recommendations will prepare programmes for greater numbers of people on ART with strategies to improve linkage to care, referral and adherence.
Following this preview of the key recommendations, interim guidelines on when to start and pre-exposure prophylaxis (PrEP) will be launched in September/October and the full updated guidelines on 1 December 2015.
The WHO guidelines recommendations development process considers: the assessment of evidence and ranking of its quality (GRADE) using systematic reviews; assessment of feasibility and cost using modelling; and preferences and values from the standpoint of the community and health care workers.
The evidence for when to start in adults used a comparative pair-wise and network meta-analysis to evaluate 76 trials for direct and indirect evidence: 35,270 participants randomised to 171 treatment arms. The systematic review included 18 eligible studies: 17 observational cohorts and one randomised controlled trial (RCT).
The studies reported on eight separate outcomes (mortality, severe HIV disease, HIV disease progression, AIDS events, non-AIDS events, AIDS and non-AIDS malignancy, and tuberculosis) in people with <500 CD4 and >500 CD4 cells/mm3. The review found clinical benefits of ART initiation over 500 CD4 to all HIV positive people compared with <500 CD4 initiation, including the reduction of severe HIV morbidity, HIV disease progression and HIV transmission, and without increased grade 3 to 4 adverse events.
For what to start with, the evidence for comparative efficacy and safety of integrase inhibitors compared to EFV 600 mg was from six RCTs: SINGLE, PROTOCOL 004, GS 102 study, GS 104 study, SPRING-1 and STARTMRK. Combined data from these studies found integrase inhibitors to be more effective than EFV and other regimens for viral suppression at 24, 48 and 96 weeks, and DTG better than raltegravir. The evidence for EFV 400 mg was from ENCORE 1.
For children and adolescents there was a lack of direct evidence to support starting earlier (particularly for horizontally infected adolescents). But indirect evidence suggests a reduction in mortality and improvement in growth (particularly in children 5 to 10 years old with CD4 >500). A growing body of evidence shows the benefit of ART on growth, neurodevelopment, immunological recovery and in preventing pubertal delays. But these gains appear to be limited for vertically infected adolescents.
The rationale for treating all children and adolescents was largely programmatic – Dr Doherty noted that all but 17% would be already eligible under existing criteria. Treating all eliminates the need for CD4 count to start ART and avoids delays in settings without access to CD4 testing; should simplify paediatric treatment and help to facilitate the expansion of ART in this population (through task shifting and decentalisation which has been much more successful in adults); and is likely to improve retention in care compared with that pre-ART.
Various community groups – including the African Community Advisory Board (AFROCAB) and the International Community of Women living with HIV (ICW) – conducted a global consultation across 24 workshops in eight countries. Participants included: adolescents/young people, adults, parents/caregivers, people who use drugs, sex workers, men who have sex with men and transgender people (206 HIV positive people across the sub groups), and 74 health workers. The findings were presented to the guideline group.
The consultation revealed that starting treatment earlier was acceptable among the community. The importance of a collaborative decision driven by the patient’s readiness was stressed. As well as feeling ready, early initiation requires good treatment literacy information to ensure an informed decision. The participants noted that starting ART is easy but maintaining adherence is harder. Stigma and discrimination were highlighted as important concerns by all participants, which they saw as a barrier to treatment access and adherence.
Some countries are already treating all (or treating all in specific populations)
Dr Doherty briefly showed data from two national programmes: one that is treating all and the other treating all children and adolescents less than 15 years of age.
Brazil has been treating everyone with HIV since changing its national guidelines at the end of 2013. This has led to an increased median CD4 at initiation of 419 compared with 265 in 2009. The Brazilian national programme reported similar retention in care and viral load suppression at 12 months in people with higher and lower CD4 counts: 81% for CD4 > 500.
Uganda started to treat all children less than 15 years in 2014. This has led to an increase in the overall number of children receiving ART. Retention at 12 months is also similar in this programme and viral load suppression is 84%.
Considering that START was one of the main drivers of the WHO decision to change to ART for all, the step from publication to policy was pretty nimble.
Introducing DTG as an alternative to EFV 600 mg first-line (with some restrictions) will spur on research to fill the knowledge gaps that will better inform its use in low- and middle-income countries (particularly information about DTG in pregnant women and with concomitant tuberculosis treatment), and the development and manufacture of generic versions.
ViiV Healthcare (the originator manufacturer of DTG), Aurobindo Pharma, and CHAI recently announced that Aurobindo has submitted an Abbreviated New Drug Application (ANDA) for generic DTG 50 mg, to the FDA for tentative approval.  This product is expected to gain tentative approval in the first quarter of 2016.
Several generic manufacturers are working on FDCs of DTG/TDF/3TC. ViiV has also licensed DTG to the Medicines Patent Pool (MPP). 
Planned or ongoing studies to inform recommendations of new drugs and formulations are described in the 2015 Pipeline Report. 
- Doherty M. New directions in the 2015 WHO Consolidated ARV Guidelines. World Health Organization. Testing, new directions in treatment and measuring impact: new WHO guidelines. IAS 2015. 19 July 2015. Vancouver, BC, Canada. Non-commercial satellite SUA06.
- Hirnschall G. WHO Global HIV Guidelines: How innovations in policy and implementation can pave the way to achieving 90-90-90. UN 90-90-90 Target workshop: lessons from the field.18 July 2015. Vancouver, BC, Canada.
- CHAI. Press release. ViiV Healthcare and CHAI collaboration delivers second milestone with first filing with the FDA of generic dolutegravir by Aurobindo Pharma for the treatment of HIV. 26 May 2015.
- Medicines Patent Pool. Press release. Medicines Patent Pool, ViiV Healthcare sign licence for the most recent HIV medicine to have received regulatory approval. 1 April 2014.
- Clayden P. Fit for purpose: antiretroviral treatment optimisation. 2015 Pipeline Report. i-Base/TAG 2015.