Pill A, Pill B: Simplified Second-Line Treatment for Low-Income Countries

A one pill, once-daily fixed dose combination (FDC) second-line regimen might be feasible for low-income countries according to a clinical development programme presented at AIDS2014.

Anton Pozniak from the St Stephens Centre at Chelsea and Westminster Hospital, London showed plans for a simplified second-line regimen at a scientific workshop entitled: Research to measure success of antiretroviral use for prevention and treatment at individual and community levels.1 The workshop was the first public presentation of the proposed second-line development programme.

Currently, the preferred World Health Organisation (WHO) first-line regimen is a once-daily FDC of efavirenz plus tenofovir plus lamivudine or emtricitabine (EFV/TDF/3TC [or FTC]). Low cost, generic versions of this regimen are available and are simple to give in decentralised programmes by nurses and community health workers.

The WHO preferred regimens for second-line antiretroviral treatment (ART) are PI-based (ritonavir-boosted lopinavir [LPV/r] or atazanavir [ATV/r]) with two new NRTIs. These regimens have several shortcomings including overlapping NRTI resistance, comparatively high pill count, twice-daily dosing (LPV/r), NRTI toxicities and high cost compared to first-line treatment.

The new proposal for people who fail first-line treatment with "Pill A" (EFV/TDF/3TC) is to develop "Pill B" -- a once-daily heat-stable FDC of dolutegravir (DTG) plus optimised darunavir/ritonavir (DRV/r). Market forecasts suggest that Pill B might be available at low cost: US$250 per patient per year.

Dr. Pozniak explained that results from the original dose finding trials of DRV/r, as well as a more recent one with 600/100 mg, suggest that a dose reduction to DRV/r 400/100 mg might be feasible.

The dose ranging (phase 2B) study for the proposed development programme would compare three once daily regimens: TDF/FTC + DRV/r 400/100 mg vs DTG + DRV/r 800/100 mg vs DTG + DRV/r 400/100 mg. This phase would be conducted in treatment naïve participants over 48 weeks.

If 24-week phase 2B data justifies progression of the programme (no obvious safety or efficacy concerns), a 96-week phase 3 pivotal trial with 1050 NNRTI-experienced participants will follow.

Phase 3 -- a non-inferiority study conducted in sites in Africa, South East Asia and Eastern Europe -- would compare 2NRTI+PI/r (control arm) vs DTG + DRV/r 800/100 mg vs DTG + DRV/r 400/100 mg.


The success of this programme should make switching people who are on current first-line regimens with virologic failure to second-line considerably simpler and more accessible.

The one criticism is that this would lead to recommending DTG second-line when many experts believe it should be the preferred first-line option in the future. It is critical that work is funded to ensure that we have enough information to use DTG first-line in low-income settings but research into first- and second-line DTG-based regimens should not be mutually exclusive. A better second line option is needed for the 5% of nearly 13 million people on first-line (and more as scaling up continues) that need to switch. Dr. Pozniak noted that if a DTG/TDF/3TC (or even DTG/TAF/3TC) becomes the future Pill A, Pill B might be DRV/r plus rilpivirine -- which also needs to be investigated.

Research into optimising ART for low-income countries -- usually discussed in small closed meetings -stepped out of the shadows at this conference including this presentation and results from a study with reduced dose AZT (see below).2

We also summarise work on treatment optimisation in the 2014 Pipeline Report.3


  1. Pozniak A. How can we evaluate simple sequences of first and second-line treatment in low-income countries? 20th International AIDS Conference. Melbourne. 20-25 July 2014. Workshop presentation TUWS1105.
  2. Rougemont M et al. The MiniZID study: a randomized controlled trial on safety of reduced dose (400 mg) of zidovudine compared with standard dose (600 mg) in HIV-infected patients starting antiretroviral therapy. 20th International AIDS Conference. Melbourne. 20-25 July 2014. Poster abstract LBPE16.
  3. Clayden P. Fit for purpose: treatment optimisation. i-Base/TAG. 19 July 2014.

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