Individualized antiretroviral therapeutic approaches

Introduction Time for antiretroviral therapy individualization Advances in the understanding of HIV pathogenesis have led to a revolutionary improvement in the care of HIV-infected persons. It took over 25 years to definitively conclude that HIV infection is deleterious starting in the very first days following infection, and therefore HIV has to be controlled with antiretroviral therapy (ART) in every single infected individual as early as the virus is detected in the body [1]. It took over 20 years to gather enough evidence to be convinced that maximal viral suppression in HIV-infected individuals leads to almost complete elimination of sexual transmission [2,3]. It took over 20 years since effective ART was found to optimally suppress HIV to realize that there is no current strategy for HIV cure or even remission [4,5] with no other option at the present time than for lifelong ART that translates to many decades of treatment. It took 10 years from the time the first antiretroviral drug was approved in 1987 to identify that a three-drug combination of HAART could suppress HIV replication ‘optimally’ to concentrations so low that they could not be measured by available assays. Since then, ART guidelines still recommend triple therapy for all. ‘Test and Treat’ strategies are currently recommended, which allow for individuals to begin ART earlier in the course of HIV infection. This approach has resulted in patients being treated at much earlier stages as attested by the shift in median CD4+ cell count and plasma HIV RNA quantitation at the time ART is initiated from approximately 200 CD4+ cells/μl and 5 log10 copies/ml of HIV RNA in clinical trials in ART-naïve patients before 2010 to 405 CD4+ cells/μl and 4.58 log10 copies/ml of HIV RNA in large studies reported in 2013. In a recent study enrolling 1744 patients, only 22% of the participants had an HIV viral load above 5 log10 copies/ml [6]. In most chronic diseases, treatment is adjusted on the basis of severity of the disease with a goal to achieve a quantifiable value – for arterial blood pressure, blood glucose concentration, and cancer size – linked to optimal survival and/or reduced comorbidities. This is in striking contrast to HIV infection with a ‘one size fits all’ treatment approach and no alternative strategies based on any disease parameters. Currently, in relatively rare occasions, we do individualize triple ART; however, it is to a limited extent mainly based on not only avoidance of toxicities such as renal insufficiency with tenofovir disoproxil fumarate (TDF) [7], potential teratogenicity with efavirenz [8], and hypersensitivity with abacavir [9] but also according to prior treatment history and known drug resistance mutations. In some cases, HIV disease status has been taken into account such as high CD4+ cell count for nevirapine initiation [10] and high HIV RNA level for rilpivirine-based or abacavir-containing regimens because of a greater risk for virologic treatment failure [11,12]. Even in these instances, triple therapy of some sort is still recommended. A successful lifelong approach requires innovative strategies that can be adapted to the individual lifestyle and ability to tolerate therapy for many decades. This is in keeping with precision medicine, which is, according to the National Institutes of Health of the United States, ‘an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person [13]. The newer available antiretroviral drugs such as darunavir, dolutegravir, and tenofovir alafenamide are considered to be ‘best in class’ by many, offering significant advantages over predecessor ART. Long-acting drugs in development offer potentially new treatment options with weekly or monthly administration [14,15]. There is a need to explore whether less drug exposure with these newer agents is a viable treatment option for individual patients. Fewer drugs in a lifelong regimen offer potential benefits if viral suppression can be maintained. Such benefits include reduced toxicity, better tolerability, less resistance, class-sparing, and lower costs. Rather than triple therapy for all, the new dogma should become ART and lifelong viral suppression for all. In this article, we will review selected trials with promising results supporting an individual or precision medicine approach that involves treating patients with fewer drugs or intermittent therapy strategies. Scientific evidence supporting reduced drug regimens Two-drug antiretroviral therapy regimens Dual nucleoside reverse transcriptase inhibitor regimen The concept of a dual nucleoside reverse transcriptase inhibitor (NRTI) therapy was essentially abandoned when triple-drug HAART became the standard of care; however, a significant subset of patients may benefit from this approach. In 1998, the TRILEGE ANRS study was one of the very first to address the efficacy of a 12-week induction phase with a nonoptimal three-drug regimen (zidovudine/lamivudine/unboosted indinavir) followed by a maintenance phase with a dual combination (zidovudine/lamivudine or zidovudine/unboosted indinavir) in comparison with maintaining the triple drug therapy [16]. Overall, the triple drug therapy did better in terms of viral suppression; however, there was no significant efficacy difference between groups in patients with baseline viral load less than 30 000 copies/ml. In Trilège, as in the similar ACTG 343 study, baseline viral load was found to be the best predictor of virological failure [16,17]. Later, using newer NRTIs with a safer and more robust profile, a proof-of-concept study with the two-drug TDF and emtricitabine (FTC) showed that 20 treatment-naive patients with a high CD4+ cell count and a low viral load (ranging between 1000 and 30 000 copies/ml) were virologically suppressed within 4 weeks [18]. Resistance development to TDF/FTC is rare when used in combination with a third agent in treatment-naive and virologically suppressed patients. Interestingly, the patent on TDF/FTC will soon end, and generics should be available soon in Western countries, with an affordable cost even for patients in low-to-moderate-income countries. This TDF/FTC strategy in early treatment-naïve patients would be a key issue for ‘Test and Treat’ strategies worldwide with the goal of controlling HIV epidemics. Ritonavir-boosted protease inhibitor and lamivudine Reducing antiretroviral drug burden requires antiviral potency, robustness in terms of genetic barrier to resistance, and favorable pharmacological properties with minimal interindividual and intraindividual variability. Thus, pharmacologically ‘boosted’ protease inhibitors are ideal candidates. The international, multicenter GARDEL study [19] has demonstrated surprising results for many clinicians, showing in ART-naive patients that a dual regimen with lopinavir/ritonavir (lopinavir/r) and lamivudine proved to be virologically noninferior to the standard three-drug regimen with lopinavir/r + two NRTIs including lamivudine, even in patients with baseline HIV RNA more than 100 000 copies/ml. There was no increase in resistance in the two-drug regimen, which also was better tolerated. GARDEL is credited with opening the way for new drug burden reduction strategies in ART. The dual combination of lopiniavir/r and lamivudine was also shown to be highly effective in a switch strategy in comparison with a standard two NRTI + lopinavir/r regimen in the OLE study [20]. Similarly, switching to boosted atazanavir and lamivudine has been shown to be noninferior to standard two NRTI + atazanavir/r in the randomized SALT study [21]. These data were confirmed in the ATLAS-M switch study [22]. Protease inhibitor and integrase inhibitor Combining protease and integrase inhibitors offers the advantage of an NRTI-sparing strategy, with no deleterious drug–drug interactions, which may be an appealing option in patients with prolonged exposure to NRTIs including those with lipoatrophy, fatigue, and/or mild renal insufficiency. The NEAT study investigated in a large population of more than 800 ART-naive patients whether dual therapy with two highly potent drugs such as the protease inhibitor darunavir/ritonavir (darunavir/r) and the integrase inhibitor raltegravir could be noninferior to a standard combination of darunavir/r and TDF/emtricitabine. Overall, the NRTI-sparing strategy, requiring twice daily medication intake, was noninferior to the three-drug regimen for the composite primary endpoint based on clinical and/or virological failure at 96 weeks. However, the genetic barrier of the two-drug regimen in this context was lower compared with that of the three-drug regimen, with more frequent emergence of resistance in the case of virologic failure, particularly in patients with high baseline viral load [23,24]. Similarly, the Progress study also showed that a dual combination with lopinavir/r and raltegravir resulted in noninferior efficacy and comparable safety and tolerability compared with a traditional NRTI-containing triple-drug regimen in 206 ART-naive patients [25]. From a switch perspective, only limited data have been reported. The SPARE pilot comparative study suggested that raltegravir and darunavir/r dual therapy was effective in maintaining viral suppression in virtually all patients [26]. Similar results were obtained with lopinavir/r and raltegravir in the KITE study [27]. In contrast, the HARNESS study reported a higher proportion of virologic failure in the atazanavir/r and raltegravir arm compared with the TDF/emtricitabine/atazanavir/r arm [28]. Integrase inhibitors and lamivudine Combining dolutegravir, a highly potent integrase inhibitor with the best genetic barrier to resistance within its class, with lamivudine, a commonly used and well tolerated NRTI available as a generic, is a highly attractive dual combination. However, only limited data from small pilot studies are currently available to support this concept. The PADDLE pilot study showed a high efficacy rate of dolutegravir and lamivudine in 20 antiretroviral-naive patients with a baseline viral load less than 5 log10 copies/ml. From week 8 and onward, all patients had optimal viral suppression [29]. Two larger randomized studies with this combination as initiation therapy [GEMINI-1 (NCT02831673) and GEMINI-2 (NCT02831764)] are ongoing. Recently, the results of a single-arm, switch strategy study, ANRS-167 LAMIDOL, showed that this combination was able to maintain viral suppression in 101 of 104 patients (97%) [30]. Integrase inhibitor + nonnucleoside analog reverse transcriptase inhibitor The NRTI-free and protease inhibitor-free strategies offer the advantage of almost no metabolic adverse events, no mitochondrial toxicity, and minimal impact on bone and kidney, all of which can be of particular interest in aging patients or those with compromising medical conditions. Raltegravir and etravirine may be potentially used in patients with prior exposure and limited resistance to first-generation nonnucleoside analog reverse transcriptase inhibitors (NNRTIs), with no deleterious drug–drug interaction between both compounds. An observational study reported a success rate of over 90% in maintaining viral suppression in 91 patients who switched from protease inhibitor/r-containing regimens. Virologic rebound occurred only in patients with prior NNRTI resistance [31]. The ANRS 163 ETRAL ongoing study is evaluating the switch for this dual therapy in patients aged more than 45 years (NCT02212379). Results are expected in 2017. Dolutegravir and rilpivirine is an attractive option with both drugs highly effective with good safety and tolerability profiles. Two large studies, with an identical design, SWORD-1 and SWORD-2, evaluated a switch to a two-drug regimen with dolutegravir and rilpivirine (n = 513) versus continuing the current three-drug regimen (n = 511) in patients with suppressed HIV RNA for more than 12 months on a standard three-drug regimen. At week 48 after the switch, the percentage of patients who maintained full viral suppression was similar in both arms {95 versus 95%, difference: −0.4% [95% confidence interval (CI): −3.1, 2.3%]}, confirming the noninferiority of the dual therapy arm with dolutegravir + rilpivirine [32]. One-drug regimens Protease inhibitor monotherapy Nearly 10 years ago, the MONARK study addressed the issue of ART individualization by asking the question whether lopinavir/r as a single-drug ART could be sufficient to induce viral suppression in treatment-naïve patients with a baseline viral load less than 5 log10 copies/ml and CD4+ cell count above 100 cells/μl [33]. Results were mixed with a noninferiority of the two strategies by intent-to-treat analysis but with a higher failure rate in the on-treatment analysis. Interestingly, baseline viral load was the best predictive factor for success [34]. Development of resistance was low in failing patients confirming the high genetic barrier to resistance of protease inhibitor/r [35]. From a switch point of view, other protease inhibitor/r monotherapies such as darunavir, even if not widely used, have proven effective [36,37]. Even though one can argue that there is a slight difference in terms of efficacy, the benefits of sparing NRTIs in over 85% of patients [38–40], the absence of resistance emergence in case of viral rebound, and resuppression of viral load upon resumption of the NRTI backbone, thus without jeopardizing future treatment options [38], should be considered in the portfolio of strategies to cover decades of viral suppression. Dolutegravir monotherapy Temptation to explore dolutegravir monotherapy – the favored integrase inhibitor that shares with boosted protease inhibitors a high potency, inhibitory quotient, and genetic barrier to resistance – has been great. Preliminary data from pilot experiences, mainly in switch settings, have been encouraging with rates of sustained viral suppression approaching 90% at week 24 [41–44]. A pilot study of first-line dolutegravir as single-drug regimen reported full viral suppression in nine antiretroviral-naive patients with a baseline viral load below 5 log10 copies/ml over a median follow-up of 7 months [45]. Very recent results from the 2017 Conference on Retroviruses and Opportunistic Infections have tempered enthusiasm about the genetic barrier to resistance of dolutegravir with reports of emergence of resistance mutations. Indeed, there have been reports of different groups in patients failing dolutegravir monotherapy with an emergence of integrase inhibitors resistance-associated mutations, mainly in patients with prior integrase inhibitor exposure but also in those naive to integrase inhibitors [46,47]. Blanco et al.[46] pooling data of 122 patients on dolutegravir monotherapy from Germany, Quebec, and Spain reported the emergence of resistance mutations in nine out of 11 patients experiencing rebounds in viral load. This echoed emergence of resistance in patients enrolled in a small randomized DTG monotherapy study, successfully suppressed up to 24 weeks, with later emergence of integrase inhibitor resistance-associated mutations in three patients out of the eight who experienced viral rebounds [47]. Altogether, this suggests that even though dolutegravir exhibits a high genetic barrier to resistance in vitro and despite excellent results in a context of a three-drug dolutegravir-containing regimens, integrase inhibitors, as a class, are less forgiving than ritonavir-boosted protease inhibitors in terms of emergence of resistance during single-drug therapy. Scientific evidence supporting intermittent therapy One of the options in the search for reduced drug exposure to maintain viral suppression is to decrease the time on ART exposure using intermittent therapy. First proof-of-concept studies suggested the feasibility of a 7 days ON and 7 days OFF ART strategy [48]; however, this approach proved inferior to continuous therapy in one controlled trial using nonoptimal ART strategies in adults [49]. Considering that a week might be too long a period off ART, more recent approaches suggested that shorter periods off therapy such as a week-end (2 days) or 3 days might be a better option [50]. Two recently published studies reported high success rates of these intermittent strategies. The BREATHER study enrolled 199 children with long-term viral suppression on a first-line regimen with two NRTIs and efavirenz in an open-label, randomized noninferiority trial to compare short cycle therapy (5 days on, 2 days off ART) versus continuous therapy. The rate of viral rebound was 6.1% in short cycle therapy versus 7.3% in continuous therapy (difference: –1.2%, 90% CI: –7.3 to 4.9, P = 0.75) allowing to assess noninferiority of the two strategies with a better tolerability of the intermittent regimen, and no difference in terms of maximal plasma viral suppression even to less than one copy HIV RNA/ml and in inflammation markers [51]. The French ANRS 4-D explored an extended period off therapy of 3 days with a regimen 4 days on/3 days off in a pilot open-label noncomparative study that enrolled 100 adult patients, suppressed for a median of 4 years mainly with a three-drug regimen including mostly TDF/emtricitabine and an NNRTI. The strategy success rate was 96% (95% CI: 90–99). Three patients experienced viral rebound; all resuppressed viral replication once resuming 7-day therapy [52]. A large randomized comparative study, ANRS-QUATUOR, should start in 2017 to address this approach further. Discussion One of the biggest challenges for HIV clinicians will be to individualize long-term suppressive ART with minimal drugs to ensure less drug exposure and long-term toxicity while treatment is continued for several decades. The benefits of reducing the ART burden are numerous, including reduced ART sparing ART to ensure viable future and reducing costs. from a perspective, than to the benefits of reduced drug burden ART one could the question of the benefit of more ART to achieve viral suppression. The current standard of care and worldwide are all based on the that the strategy is the treatment however, this has been in comparative trials for data from clinical studies in the that showed that triple regimens or two-drug ART regimens in efficacy or tolerability, or both fewer drugs without compromising efficacy should be one of In this should be considered in patients with early ART initiation and in patients with several years of sustained viral suppression. of these results and the primary goal of treatment has been the optimal suppression of viral and this should The potential risk for resistance should viral rebound has to be taken into in the case of ritonavir-boosted protease inhibitor while there is a reported less viral suppression efficacy there is no emergence of drug resistance [38], the of resuming a three-drug regimen as a well tolerated and effective treatment The studies have demonstrated that a switch to versus on a three-drug regimen was noninferior with an efficacy rate of [32]. the reduced drug regimen is not should it be used in a of have to be adjusted to and virus In patients with low CD4+ and high viral initiation strategies should to standard that is, triple-drug regimens should the standard of in patients with HIV disease as by status and the plasma viral load Similarly, patients with and follow-up are not the for less than three-drug or intermittent strategies. There is a however, for of markers to individuals for a switch strategy to a therapy could be The baseline viral load has been a key predictor of success in all first-line reduced drug regimen studies This was also in maintenance studies with protease inhibitor/r monotherapy In in maintenance studies, of full viral suppression before ART was also a predictor of sustained viral suppression This is particularly when patients are treatment earlier in HIV infection when they have a better status and lower viral and when they have a shorter of suppression. predictive that is only considered is HIV with HIV Results from several clinical trials have suggested that this may offer an optimal there are many advantages and data to that the reduced drug ART regimens offer benefits to selected a potential of the reduced ART regimen approach the risk of emergence of resistance mutations. This will be by maximal viral and most studies were able to achieve or to maintain high rates of full viral suppression. The risk of emergence of resistance mutations was reported in ART-naive patients with high viral on first-line reduced regimens [23,24]. In switch studies, a with on virological failure, would in the best for such reduced drug maintenance regimens. less than three-drug regimens need In the absence of viral load should be as for any ART that is, viral load within weeks after the at week 12 and 24 and to the standard as of week One could also argue that despite maintaining viral suppression in reducing the of drugs to plasma viral replication may to increase in the HIV this the issue was addressed in both first-line monotherapy studies and maintenance trials in which similar were reported in on reduced drug regimens as well as the standard triple drug therapy. have about the risk of higher adverse for protease inhibitor/r monotherapy versus three-drug regimens Similarly, the of potential increase in or markers in reduced drug regimens is however, several studies have reported no such deleterious It however, that a reduced drug strategy is well tolerated in patients with no and with a CD4+ cell count above 200 cells/μl in the of as or one should also question the ability of these reduced ART regimens to decrease viral burden in In this results have been reported with protease inhibitor/r monotherapy There is a interest from patients with HIV to lifelong exposure to drugs used in ART. This may be because of the new of more potent earlier of viral replication in the HIV disease and for many, a very long prior history of virological on standard The evidence from reduced drug strategy clinical trials should more clinical which challenges the dogma in of standard triple therapy. we have from over 20 years of HAART is that the only dogma we should have HIV is that maximal viral suppression and are is need to new and strategies that will this new approach of precision medicine with the goal of chronic to each HIV – with no cure so – a new for such approach. of interest There are no of

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