Individuals living with HIV thrive in the current era, having several potent, well tolerated options for initial combination antiretroviral therapy (cART), including fixed-dose combination (FDC), single-tablet regimens (STRs). Many individuals who were virologically suppressed on complex regimens are switching to these simpler combinations, though a group of patients remain bound to complex regimens that were selected in order to overcome extensive drug-resistance mutations, while avoiding adverse effects and/or drug–drug interactions. Critically, all STRs to date contain emtricitabine and tenofovir disoproxil fumarate (TDF), and an anchor antiretroviral drug. This implies the available STRs have overlapping contraindications and adverse effects such as the bone and renal consequences of TDF. Studies are evaluating whether tenofovir alafenamide fumarate (TAF) will be an effective and safer alternative to TDF , and the pharmaceutical industry has announced plans to co-formulate dolutegravir and abacavir/emtricitabine as the first TDF-sparing STR.
Novel two-drug combinations are being investigated for initial therapy as well, demonstrating various degrees of efficacy. Lopinavir/ritonavir and lamivudine showed encouraging results in the Study of Lopinavir/Ritonavir and Lamivudine Versus Standard Therapy in Naïve HIV-1 Infected Subjects (GARDEL) , whereas the Maraviroc Once-daily with Darunavir Enhanced by Ritonavir in a New regimen trial (MODERN) (NCT01345630) of ritonavir-boosted darunavir 800/100 mg and maraviroc 150 mg daily was prematurely terminated due to inferior efficacy. Results of ritonavir-boosted darunavir and raltegravir (NCT01066962) are on the horizon.
The next wave of progress in HIV-1 therapeutics needs to further address barriers to long-term antiretroviral drug success in the large population of patients who are already virologically suppressed or become suppressed on conventional three-drug cART, including the once-daily STRs. One major barrier to success is long-term toxicities, which may be compounded by comorbidities as the patient population ages. Additional barriers include cumulative costs and treatment fatigue. Accordingly, there is a need for ‘reductive ART strategies’, which we define as ART with fewer than three antiretroviral drugs per day in patients who are virologically suppressed on conventional three-drug cART.
Most efforts towards reductive ART have focused on ritonavir-boosted protease inhibitor (PI/r) monotherapy, and the latest frontier involves exploration of long-acting antiretroviral drug formulations. Long-acting formulations generally evoke excitement for individuals living with HIV and providers because this strategy opens the door to monthly or even less frequent dosing, which would address treatment fatigue for many patients. On the contrary, memories of suboptimal outcomes with monotherapy and dual therapy in the first decade of ART and equivocal results from other trials feed inertia against reductive ART strategies. Therefore, we find ourselves at a crossroads when considering the possibility of reductive ART in the modern era.
The perils of reductive antiretroviral therapy and potential promise
A number of trials, over the past 15 years, have evaluated the effectiveness of mono-ART or dual-ART in different stages of the HIV-1 treatment continuum. These studies were heterogeneous in design and participant population. The results have been mixed and none convincing enough to push the field to broadly agree on the role of reductive approaches. In fact, some studies were outright failures [3,4], thus consolidating aversion towards mono-ART or dual-ART. However, in recent mono-ART or dual-ART trials, approximately three-quarters of the participants maintained viral suppression after reduction to fewer than three antiretroviral drugs (Table 1), suggesting that this approach is appropriate for some patients [5–9]. In general, trials evaluating PI/r monotherapy have shown the best results in patients who were virologically suppressed and without evidence of prior virologic failure. Concerns about PI/r monotherapy, however, include higher rates of virologic failure, low-level viremia and protease inhibitor resistance, and the possibility of limited central nervous system penetration in the case of atazanavir . Yet, the data should quell some of those concerns as protease inhibitor resistance early during failure of PI/r monotherapy is typically less than 5%, which is comparable to the standard therapy groups [5,6,8]. Furthermore, in the patients who failed reduction to PI/r, between 83 and 100% achieved virologic suppression with re-intensification of the regimen [5,6,9].
A careful appraisal of lessons learned within the existing body of literature suggests that ideal patients and antiretroviral drugs for a reductive strategy may be identified if specific questions are rigorously addressed. For instance, would we see more positive results with monotherapy or dual therapy if patients had years rather than months of virologic suppression on three-drug cART prior to switch? Would a better understanding of the viral reservoirs and a selection of those patients with smaller or less active reservoirs on three-drug ART be better suited for a reduction strategy? It is plausible that patients on longer durations of cART and those with smaller reservoirs may coincide since viral reservoirs tend to diminish with increasing duration of effective cART . What is the ideal degree of plasma viremia prior to monotherapy or dual therapy? This question has become more relevant because it appears that virologic failure rates differ among patients who have different degrees of viral suppression below 50 copies/ml . HIV controllers exhibit an innate ability to maintain some viral control, but still experience harmful levels of immune activation . Would such patients be particularly suited for fewer antiretroviral drugs?
Do newer, more potent therapies with improved pharmacokinetic profiles and more robust barrier against resistance such as the integrase strand transfer inhibitors dolutegravir and S/GSK 1265744 (GSK 744) allow success with fewer drugs? The combination of dolutegravir and lamivudine or even dolutegravir monotherapy is an example regimen that may be worth evaluating in carefully designed clinical trials. Finally, optimal application of long-acting formulations of antiretroviral drugs also demands an in-depth understanding of the best patients for mono-ART or dual-ART. Desirable attributes of a long-acting agent include adequate and prolonged systemic exposure after a low-volume administration, a high barrier against resistance, and absence of late-onset severe adverse reaction or toxicity. The first-in-class long-acting antiretroviral drugs, non-nucleoside reverse transcriptase inhibitor, rilpivirine, and GSK 744, are in phase 2 clinical trials. It would be transformative if long-acting-based strategies were discovered that could be administered alone or in combination every 1–3 months. This may be a potential reductive strategy even for selected patients currently on STR daily therapy.
Reductive antiretroviral therapy and healthcare policy
The global cost of antiretroviral drugs is towering at the same time that the indications for cART are being broadened in treatment guidelines [14–16]. As custodians of resource utilization and allocation, policy makers are programmed to select interventions that have the potential to lower costs, provided other outcomes are similar. Cost analyses of the MONotherapy in Europe with TMC114 trial (MONET) trial showed a cost reduction of 52% with darunavir–ritonavir monotherapy compared to standard triple therapy . Similarly, a 38% reduction in cost was shown in a Spanish observational cohort when switching from triple therapy to PI/r monotherapy . These published data are in line with our deduction of potential costs savings in the United States based on the recommended monthly wholesale cost for commonly used regimens . For example, the listed annual cost of Atripla is $27 046.56, whereas for darunavir/ritonavir it is $18 465.60. Annual savings from using darunavir/ritonavir monotherapy instead of Atripla is $8580.96 or 32%. Of note, a comprehensive assessment of the costs of reductive ART must include those associated with excess treatment failure and resistance, if these actually occur. It will be important to also evaluate the costs associated with long-term adverse effects of treatment.
Guidelines from different parts of the globe diverge in their endorsement of reductive ART. Several European guidelines list reduction to PI/r as an option for treatment simplification or because of tolerability issues [15,19,20], whereas the US Department of Health and Human Services (DHHS) does not . Reductive ART may be particularly relevant in resource-limited settings, but there are scarce data and no supportive recommendations . Interestingly, in a Spanish clinical setting where reductive strategies are being used, only nine of 92 patients (9.8%) had virologic rebound to above 50 copies/ml at 48 weeks after initiating darunavir/ritonavir monotherapy [21,22]. Overall, the time is ripe for studies and expert opinion to harmonize approaches to ART reduction globally. All constituencies must be prepared to rethink the unthinkable.
The way forward
A broadly applicable HIV cure remains elusive. Accordingly, the future as seen through today's lens holds lifelong cART as the primary option for patients. Inevitable consequences include cumulative costs for all and toxicities for many patients. With several once-daily STRs and FDCs now available and even more in development, we have arrived at an era when once-daily regimens can be provided for most patients. The core of current HIV treatment paradigm, however, defies the logic that the treatment of a chronic medical condition should be based on the individual's needs. More drugs are not necessarily better, and the cost of any unnecessary antiretroviral drug is an avoidable financial burden. Overall, there is a need to re-evaluate mono-ART and dual-ART regimens for HIV-1 treatment while ensuring the strategy is not associated with potential harm such as repopulation or expansion of viral reservoirs. A better understanding of the ideal patients for reductive ART may pave the road to maximum impact of long-acting agents as a panacea for treatment fatigue. The benefits of reductive ART to HIV-1-infected patients may be considerable if it proves to be well tolerated and effective in selected individuals.
We would like to thank Dr Eric Daar for his involvement in the review process of this manuscript. B.T. proposed the opinion piece. Each of the authors participated fully in the conceptualization and preparation of the manuscript.
Conflicts of interest
The three authors have completed and submitted the ICMJE Form and Disclosure of Potential Conflicts of Interest. J.C. and V.M. report no conflicts of interest. B.T. has served as a consultant for ViiV, Gilead and GSK, and has received research grants from Pfizer.
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