HIV and AIDS
advantage over existing strategies that use nucleoside analogues and in particular, tenofovir/FTC in combination with either efavirenz, a boosted protease inhibitor, like atazanavir/ritonavir or darunavir/ritonavir, or raltegravir. It is uncertain if a longer follow up might provide more evidence suggesting the advantage of a nucleosides-sparing strategy.
Monotherapy of boosted PI in treatment-naïve patients is a strategy which did not achieve non-inferiority, as shown by the Monark Study. This study, in which AZT/3TC lopinavir/r was compared to lopinavir/r in patients with a viral load <100,000 copies/ml, had demonstrated lower virological efficacy in lopinavir/r arm in per protocol analysis with a higher frequency of emerging resistance.50
Treatment Option for Virologically Controlled Patients
Changing ARV regimens in virologically-controlled patients (<50 copies/ml) is a real challenge. The aim is to reduce the burden of taking numerous pills and associated side-effects, to simplify the regimen, to prevent long-term toxicity (metabolic side effects induced by ritonavir or thymidine-analogues, renal impairment or osteopaenia induced by tenofovir). At the same time, the potential benefits should not jeopardise the regimen’s efficacy. New strategies of treatment simplification have been studied or are currently underway.
Simplification by Switching Protease Inhibitor or Non-nucleoside Reverse Transcriptase Inhibitor to Raltegravir
Due to its efficacy and good overall tolerance, raltegravir is a potential candidate for maintenance therapy. The Switchmrk study compared the substitution of raltegravir for lopinavir-ritonavir versus continuation of lopinavir-ritonavir in patients with stable plasma viral suppression already on lopinavir-ritonavir-based combination therapy. Unexpectedly, the non-inferiority of raltegravir to lopinavir-ritonavir was not established.51
However, half of the patients with virological
failure after switching to raltegravir had previous virological failure and may have had genotypical resistance to one or more associated drugs. Therefore, switching to raltegravir should be considered only when combined with other active drug(s). A more recent study conducted in patients with sustained virological suppression, switching from ritonavir-boosted protease inhibitor to raltegravir have demonstrated noninferior efficacy and resulted in a better lipid profile at 48 weeks than continuing ritonavir-boosted protease inhibitor.52
Further
studies are needed to determine the specific strategies that warrant recommending treatment switches in specific situations.
Unboosted Atazanavir Regimen
The ARIES Study has demonstrated similar efficacy and tolerability of atazanavir compared to atazanavir/ritonavir, each taken with abacavir/lamivudine, among patients controlled by boosted atazanavir regimen with no previous virological failure.53
The Swan
Hence, the strategy of a deboosted atazanavir maintenance regimen is attractive for patients who have not experienced prior virological failure during PI therapy and could be proposed for patients who have experienced side-effects with boosted atazanavir (i.e. icterus, lipid disorders, etc).
78
study, also conducted in patients with virological suppression while receiving other PIs, showed better maintenance of virological suppression, a comparable safety profile and limited improvement of lipid parameters after switching to a once-per-day regimen containing atazanavir compared to continuing prior PI-based regimens for 48 weeks.54
Monotherapy
Several studies have evaluated monotherapy maintenance strategy with twice-daily lopinavir/ritonavir or once-daily darunavir/ritonavir versus continuing current combined ARV treatment in patients with suppressed plasma HIV-1 RNA. The overall idea is simply to avoid toxicities related to nucleoside analogue use and reduce costs. Data concerning other boosted PIs are inconclusive or severely lacking.
In the Kalesolo study, Lopinavir/ritonavir monotherapy did not achieve non-inferiority versus triple ARV regimen for maintaining plasma HIV-1 RNA <50 copies/ml (84 % for the monotherapy group versus 88 % at week 48).55
Nevertheless, the incidence of virological failure was low and easily managed by treatment intensification, since virological failures in lopinavir/ritonavir monotherapy did not show any acquired resistance mutations in the protease gene. The OK4 study showed that lopinavir/ritonavir monotherapy, with reintroduction of NRTI-therapy as needed, was non-inferior to continuous triple therapy at 96 weeks. Incidence of adverse events leading to treatment discontinuation was significantly lower with monotherapy.56
The darunavir/ritonavir monotherapy has been evaluated, with both MONET and MONOI studies. These trials were conducted in virologically suppressed patients on triple therapy who were randomised to either a darunavir/r triple-drug regimen or darunavir/r monotherapy. Darunavir/r monotherapy exhibited an efficacy rate of over 85 %, which was similar with concordant results in the magnitude of difference with darunavir/r triple drug regimen in both intent-to-treat and per protocol analyses, but discordant conclusions with respect to the non-inferiority margin.57
More importantly, patients failing
darunavir/r monotherapy did not have emergence of new darunavir resistance mutations, thereby preserving future treatment options.
Even if the results of such a strategy seem promising, especially in terms of safety and efficacy, controversy about its use remains, considering that monotherapy is associated with a greater percentage of blips (viral load 40–500 copies/ml). European guidelines for the use of ARV therapy in adults do include monotherapy as an alternative for simplification, contrasted to American experts who express the view that this strategy cannot be currently recommended. PI monotherapy could be a good option for those patients with toxicity related to NRTIs, or as a means to avoid such toxicities in virologically controlled patients (viral load <50 copies/ml for at least six months) without previous failure to PI. Nevertheless, more studies focusing on the control of HIV replication in viral reservoirs with monotherapy, as with triple therapy and the potential cost-effectiveness of monotherapy are warranted.
Conclusion
There is a wide-range of ARV drugs available. Current guidelines are based on the results of numerous trials evaluating virological and immunological efficacy, short-term and long-term tolerability of different treatment regimens and the consequences of resistance on virological failure. All these characteristics must be taken into account when selecting a first-line regimen. The first-line treatment could nowadays be modified after a few months of virological success to a treatment with fewer drugs or side effects (induction-maintenance strategies). With the greater life expectancy among HIV-infected patients, the current challenges facing researchers are to develop new treatment strategies and new drugs in order to improve long-term tolerance, adherence and cost. n
EUROPEAN INFECTIOUS DISEASE
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