Reply to Achieng and Riedel

To the Editor—We thank Achieng and Riedel for taking interest in our recent characterization of the S230R drug resistance substitution found in patients treated with dolutegravir (DTG) monotherapy [1, 2]. They reported the case of a patient who lived with human immunodeficiency virus (HIV) for more than 20 years and developed multidrug resistance against protease, nucleos(t)idic, and non-nucleosidic reverse transcriptase inhibitors (PI/N(t)RTI/NNRTIs). Treatment initiation with raltegravir (RAL) in combination with a boosted PI plus 2 NRTIs in 2009 was followed by an initial clinical response. However, a switch to a significantly more fragile RAL/ lamivudine (3TC)/ abacavir (ABC) regimen for reasons of renal impairment expectedly led to yet another treatment failure and, likely, to the development of drug resistance mutations in the integrase region of the pol gene (although integrase genotyping was not reported). Further treatment changes included the replacement of azidothymidine + etravirine with the 2 previously prescribed NRTIs, ABC/3TC, in combination with DTG. It should be noted that this combination, in fact, represented a DTG functional monotherapy. Given previous failure with RAL-based therapy, at the time DTG was initiated, the patient resembled participants to the VIKING trials who had also failed previous treatment with RAL and developed documented RAL resistance mutations [3, 4]. Additionally, previous DTG monotherapy trials have demonstrated that prior exposure to other integrase inhibitors (INIs), such as RAL or elvitegravir (EVG), even in the absence of failure with the same, was sufficient to decrease the efficacy of DTG monotherapy and to favor the development of drug resistance mutations [5, 6]. For these reasons, the DOMONO trial excluded previous use of other INIs [2, 7, 8]. The patient reported by Achieng and Riedel unsurprisingly witnessed the development of major INSTI resistance substitutions at G140, Q148, and E138, which are identical to those found in the VIKING participants who experienced treatment failure [3]. Notably, the VIKING trial also examined doubling the daily dose (BID) of DTG and demonstrated that this latter formulation is preferable for INI-experienced individuals [4]. Such DTG BID dosing was not reported for the patient in question. In fact, given the burden of evidence from these trials, it could be appropriate to consider modifying official guidelines to include DTG BID dosing for all individuals previously exposed to RAL/EVG, at least until viral loads are persistently controlled. In addition, we are aware that individuals can tolerate daily dosing of up to 300 mg DTG without any obvious adverse event. In the absence of alternative therapeutic options, the use of such high dose of DTG should be investigated for salvage therapy. Although this case report originated from Kenya, it is important to note that similar patients can be found in high-income countries, including Canada [9]. Historically, some patients who used toxic and suboptimal first-line antiretroviral drug treatments died with multidrug-resistant viremia. The necessity for polypharmacy, together with the development of age-related diseases, including kidney disorders such as observed in Achieng and Riedel’s patient, considerably complicates the management of HIV infection. We note that Achieng and Riedel’s report supports our previous statements that DTG should be used as a first-line INI, rather than using RAL or EVG that display lower genetic barriers against resistance, and can compromise the entire class of INIs [10, 11]. In this regard, it is important to emphasize that the integrase substitutions T97A, E138K, G140S and Q148R are likely to compromise the activity of the newly developed INIs bictegravir and cabotegravir [12, 13]. If circumstances permit, salvage therapy through compassionate access to new compounds such as doravirine, MK-8591, or capsid inhibitors, which have been reported to have high efficacy in the early stage of clinical trials, should be sought [14–16]. This will only be beneficial in concert with adherence support interventions, as mentioned by the authors. Community-based programs supporting drug adherence and HIV care engagement are vital. It is also important to caution that the effective application of DTG in resource-limited settings will be hampered in the absence of strong genotyping programs. As unfortunately exemplified by this case report, special attention and support should be directed at addressing the critical issue of drug resistance management in resource-limited settings, especially at early stages of the intervention. Physicians also need to be alerted to the high prevalence of HIV-2 resistance to multiple drug classes, particularly in most low- and middle-income countries, where treatment with the core NNRTIs has been used as first-line therapy [17]. Furthermore, we need a better understanding of the distribution of HIV-2 multiple drug resistance, as well as more studies on the efficacy of DTG against HIV non-B subtypes harboring major drug resistance mutations. Finally, we also agree with Achieng and Riedel that we need to act swiftly to implement low-cost regimens containing DTG before more patients start using RAL under suboptimal circumstances. This will also preserve the option of employing RAL in the future, when the side effects of polypharmacy and drug-drug interactions might disqualify aging patients from further DTG use. Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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