Vancouver July 17-18, 2015

As part of our commitment to working towards global HIV treatment optimization, Pangaea facilitated an expert meeting with AIGHD, CHAI and IAS in Vancouver on July 17-18. The aims of the meeting were to identify gaps in current research and the medium-term agenda on drug development for both first- and second-line therapies appropriate for resource limited countries. The report of the meeting was launched on 22 July at the Vancouver IAS conference and is available here.


Chaired by Dr Tsi Tsi Apollo (Zimbabwe) and Dr Andrew Kambugu (Uganda) Pangaea, AIGHD, Clinton Health Access (CHAI) and the International AIDS Society (IAS) convened an expert meeting to review the progress, gaps and future plans for HIV drug optimization since the second Conference on Antiretroviral Drug Optimization held in 2013. In particular, the perspectives of country implementers, researchers from the North and the South, innovator and generic pharmaceutical companies, community and global normative guideline agencies.

The meeting prioritized key actions that participants considered essential to bringing further to people living with HIV in resource limited settings, effective, tolerable new drugs, formulations and timelines, and how to operationalize these as rapidly as possible. Participants also prioritized recommendations to optimize service delivery as part of the whole treatment optimization package.

The recommendations of this meeting were presented at a formal conference session on treatment optimization during the 2015 IAS conference in Vancouver.

As a key outcome of the meeting, Pangaea reiterated its ongoing commitment to continue monitoring and disseminating progress on all aspects of the treatment optimization agenda, including convening relevant experts where appropriate. In the light of the START and TEMPRANO results, growing global advocacy for treatment for all, the need for significantly increased global and national resources to fund treatment will be needed. In this context, treatment optimization is an even more critical contributor to expanding the scope and quality of long-term HIV treatment.


  • The availability of a limited formulary of antiretrovirals (ARVs) will facilitate optimization of first- line therapy
  • There should be two first-line choices: efavirenz (EFV) or dolutegravir (DTG) paired with tenofovir (tenofovir disoproxil fumarate [TDF] of tenofovir alafenamide fumarate [TAF]) plus emtricatibine or lamivudine (FTC or 3TC, referred interchangeably as XTC).


  • CADO2 recommended that second-line therapy should include boosted darunavir (DRV) as the preferred protease inhibitor. There is a need to identify which booster (ritonavir [RTV] or cobicistat [COBI]) should be prioritized for use in a fixed dose combination.
  • There is a need to clarify the optimal doses of DRV and RTV in a FDC.
  • Potential manufacturers and purchasing agencies need to define volume needs to maximize further opportunities for cost reduction in the manufacturing of DRV.
  • Research into fixed dose combination of DTG and boosted DRV as a key second-line option needs prioritization.
  • Sequencing should be from an EFV-based first line to a boosted DRV plus DTG or recycled nucleosides in second line.
  • Sequencing should be from a DTG-based first-line to a boosted DRV plus two nucleosides in second-line.
  • Research is needed to evaluate if it is feasible for normative guideline agencies to recommend that RTV and cobisistat (COBI) are interchangeable.


  • Treatment optimization means optimization of drugs and service delivery to maximize retention in care.
  • There is a need to incorporate research into improvements in delivery implementation and retention in care into the treatment optimization agenda, particularly as it relates to efficiencies and improvements through “differentiated care” models.
  • The meeting participants called on WHO to clearly articulate what research is needed to make guideline recommendations.


    We have efficacious first-line drugs now and better drugs becoming available, which have the potential for improved tolerability and reduced cost. While a single EFV-based fixed dose combination for almost everybody with HIV has been a remarkable public health achievement, it needs to be rethought based on the data that we currently have available. The concept of a limited formulary of first-line drugs with two choices, either DTG or EFV (at whatever dose is finally decided), paired with TDF and either FTC or 3TC was supported by meeting participants. TDF and TAF were considered interchangeable for this formulary exercise. The limited formulary was thought to be programmatically feasible even as we move to more decentralization and task shifting. A simple algorithm could guide providers in the choice of regimen. The appropriateness of switching from EFV to DTG was discussed. The scale down of stavudine (d4T) was driven by side effects and any possible scale down of EFV does not have the same level of urgency, as millions of people around the world are stable on an EFV-containing regimen. How to potentially switch people from ERFV to DTG is therefore an open question. A possible scenario is that all those who are stable on the EFV could remain on that regimen, those with tolerability issues be switched and those initiating antiretroviral therapy (ART) for the first time could start the DTG (especially those with high CD4 counts and no HIV-related symptoms) who may benefit from the benefit from the better tolerability of DTG.

    In terms of first-line drug optimization, there are three bodies of work around DTG, EFV 400 mg and TAF. Studies are ongoing to examine the efficacy and tolerability of DTG in access markets with a particular focus on its use in pregnancy and HIV/TB coinfection. It was predicted that the cost of DTG would be the same or less than currently available regimens. A study is ongoing to examine the use of EFV 400 mg in pregnancy and funding is needed to study it in HIV/TB coinfection. The group decided it would be important to discuss further with Gilead its development plans for TAF in both the commercial and access markets. Boosted versus unboosted TAF, access to PK/PD data and use of TAF in pregnancy and people with HIV/TB co-infection were highlighted by the group as issues relevant to resource limited settings.

    Second line

    While currently only 5% of people in low- and middle-income countries (LMIC) are on second-line, this will increase as more treatment failure is diagnosed especially as viral load monitoring is rolled out. DRV was approved in the US in 2006 but is still not widely available in LMIC. Reasons include that DRV was registered as a third line drug only in some LMICs and the lack of an FDC, which is expected to change at the beginning of 2016. Approximately 17 LMICs have now filed for DRV approval. The group heard that the science of the superior efficacy and tolerability of DRV over lopinavir (LPV) and atazanavir (ATV) was not reflected in 2013 WHO guidelines, which do not list DRV as a preferred protease inhibitor because of cost. The group called on WHO recommend DRV as the preferred protease inhibitor. The use of RTV and COBI for DRV was discussed. RTV is widely used in LMICs but COBI is not. Formulating a DRV/RTV single tablet is difficult. Even though the dose of RTV is 100mg milligrams the addition of excipients brings the total milligrams closer 500-600 mg tablet, which is too large to swallow. The group called for research is to evaluate if it is feasible for normative guideline agencies to recommend that RTV and COBI are interchangeable. COBI can only be used in once daily regimens and RTV needs to be the booster in pediatric formulations of DRV. A new second-line regimen of DTG plus boosted DRV is in development. In addition to improved tolerability, this regimen simplifies sequencing from two ARV classes in first-line to two new classes in second-line with improved efficacy compared to the current standard of care of recycling nucleosides from first line into second line. DTG has a clear role in both first- and second-line regimens.


    Whatever regimens are used, sequencing within the public health approach requires that first- and second- line be considered as sets of treatment. If a DTG-based regimen is used in first-line, a boosted protease inhibitor plus two nucleosides would be used in second-line. If an EFV-based regimen is used in first-line, second-line would be a boosted protease inhibitor plus DTG.

    Randomized Clinical Trials and Implementation Science

    There are two options in the introduction of a new first line regimen; conduct a randomized clinical trial (RCT) of a DTG-containing regimen versus standard of care in LMICs or to monitor the global population rollout in the same settings. The group favoured the latter. There are programs such as MaxART in Swaziland, the programs of MSF, AMPATH and others that may have the capacity to monitor the efficacy of the new regimen and conduct the necessary pharmacovigilance in these settings.


    Treatment optimization needs to go beyond the optimization of drugs and include the optimization of service delivery and the strengthening of health systems and community systems to accommodate the continuing scale up of ART in an environment of treatment for all those who are ready to start lifelong ART irrespective of this CD4 count. Less than 30% of people diagnosed with HIV infection in resource limited settings navigate the full cascade of care. [Rosen, Mugglin] The delivery of HIV care in the initial rapid scale-up of HIV care and treatment was based on existing clinic-based models, which are common in highly resourced settings and largely undifferentiated for individual needs. A new framework for treatment based on the specific needs of different groups of individuals across the cascade of care is needed. Differentiating the service needs of those who are unwell and those who are stable on ART and where and how those services are delivered is key to maximizing treatment outcomes. Based on consultations with countries and experts, UNAIDS estimates that 95% of HIV service delivery is currently facility based. Further, UNAIDS projects that increasing community-based service delivery to at least 30% of total service delivery will not only reduce costs but, by bringing services closer to the people who need them, improve service uptake and retention in care.

    The meeting and this report were funded by Pangaea. We are enormously grateful to all our supporters who provide unrestricted funding, particularly the Chevron Corporation, who enable us to carry out our work.

    Please download a full copy of the report here.

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