The WHO now recommends dolutegravir (DTG)-based regimens as the preferred option for first-line and second-line antiretroviral therapy (ART) for all persons with HIV [1,2]. For initial ART, this represents a major shift away from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART and widespread efforts to implement options such as tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) as routine first-line ART are ongoing. As a part of first-line ART, DTG has superior virologic efficacy and durability compared with NNRTIs and compared with ritonavir-boosted lopinavir (LPV/RTV), in addition to the TLD combination reducing pill burden while offering significant cost savings [1,3]. As part of second-line therapy, DTG was superior to LPV/RTV in trials and similarly offers reduced pill burden, better tolerability and improved cost effectiveness [4]. For second-line ART, the WHO guidelines recommend DTG ‘in combination with an optimized nucleoside reverse transcriptase inhibitor [NRTI] backbone’ [1]. This is where questions and controversy persist. What constitutes an effective optimized NRTI backbone? Is recycling TDF/3TC (in other words, offering the fixed-dose TLD) effective as second-line ART?
Traditionally, the options for an optimised NRTI backbone have been limited for patients failing a first or second-line drug regimen. The recommended options for a second-line regimen depend on what was used in the first-line regimen. If TDF and 3TC (or FTC) was used, the preferred option becomes AZT and 3TC because the AZT is presumed to be fully active [1]. Clearly, AZT adds pill burden, toxicity risk, laboratory monitoring and cost, and clinicians are wary of it. Recycling TDF/FTC (or 3TC) does not currently qualify as an optimized NRTI backbone for a second-line regimen, is not in line with WHO guidance (which state that insufficient evidence exists for recycling TDF/3TC), and efficacy as an empiric switch along with DTG has not been proven. However, previous studies have examined recycling NRTIs with ritonavir-boosted protease inhibitors and demonstrated efficacy, suggesting that recycling NRTIs with DTG may also be reasonable [5–7]. Furthermore, the DAWNING study made significant impact by demonstrating that DTG and at least one active NRTI was effective and was superior to LPV/RTV and at least one active NRTI following NNRTI-based first-line ART failure [4]. So, can TLD be implemented as routine second-line ART in real world clinical practice? Can it be prescribed as second-line therapy without a viral load or genotype check for clinics without access or with long delays obtaining those test results? What if there is resistance to both TDF and 3TC, which may occur following failure of NNRTI with TDF/3TC (or FTC)? Will TLD remain effective in this situation?
In this issue of AIDS, Keen et al.[8] present an option to recycle TDF/FTC (or 3TC) in second-line regimens, including a proportion of individuals with resistance to both TDF and FTC/3TC. The findings have significant implications for answering the above questions. The researchers evaluated virologic suppression at 24 weeks in a single-arm, prospective, interventional cohort study of patients failing a first-line regimen containing TDF/3TC (or FTC) with EFV (or NVP) at two clinics in Khayelitsha, South Africa. To achieve 82% [95% confidence interval (95% CI) 72–92] viral suppression, the researchers needed a sample size of 57. They successfully enrolled 60 study participants who completed 24 weeks and, notably, 85% remained virologically suppressed on TLD. Most (89%) had resistance to TDF and FTC/3TC, yet high viral suppression rates were achieved. Remarkably, there was no significant difference in virologic suppression between participants with resistance to FTC/3TC alone compared to those with resistance to TDF and FTC/3TC. In addition, the few nonsuppressed participants at 24 weeks mostly had low-level viremia, and the one person with viral loads above 500 copies/ml had no evidence of emergent integrase inhibitor resistance.
Although this was a relatively small, single-arm study with no comparator group, the implications are substantial. The findings corroborate those of other studies while also adding additional insights. For example, the results suggest that TLD remains effective even in the setting of resistance-associated mutations to both the TDF and 3TC components. Ostensibly, this seems like DTG monotherapy, but actually the effectiveness of TLD in this setting is biologically plausible, as noted by the authors, because recycling NRTIs with resistance-associated mutations and maintaining circulating HIV populations with mutations such as M184 V/I or K65R substantially impairs viral fitness [9–11]. Also, NRTI resistance may prevent the emergence of DTG resistance [12]. Other trials and observational studies have also found DTG, or the similar drug bictegravir, combined with fewer than one active NRTI, to be effective, though typically as a switch strategy in the setting of virologic suppression, which makes the current study findings even more notable [13–15].
To demonstrate noninferiority of the recycled TDF and 3TC (or FTC), the researchers could have compared with a AZT and 3TC (or FTC) or ABC and 3TC backbone as standard of care (WHO recommended options). They also could have included cost, tolerability and adverse events comparisons. These will be important outcomes to evaluate in future work. The research protocol also included extra DTG dose in addition to TLD for the initial 2 weeks to overcome lingering induction effects of EFV, but it is unclear whether this is necessary. It will be important to prove whether this is required or not, because avoiding the extra DTG would reduce pill burden and cost further.
We are glad that the investigators will be following participants to 96 weeks and eagerly await follow-up data from this study, as well as larger studies that are examining similar questions. If longer-term data from this study and related controlled trials demonstrate similarly favourable outcomes on the merits of recycling TDF with 3TC (or FTC) in second-line regimens, supporting an empiric switch to TLD for individuals failing first-line NNRTI therapy, the effect on guidelines and clinical practice will be significant.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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