The success of combination antiretroviral therapy (cART) is unprecedented in medical history. It was laid in 1996 with the publication of first trials showing a remarkable reduction in morbidity and mortality with the combination of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTI) with two nucleoside reverse transcriptase inhibitors (NRTI). In the following years the sustainability of these effects has been shown in numerous cohort studies and clinical trials, and further improvements were achieved with the introduction of boosted protease inhibitors, efavirenz and once daily regimens [1–5]. With the advance of new drug classes we have witnessed an outstanding success in salvage therapy in patients with long-lasting infection and multiple drug failures [6–9]. The basic principle of this extraordinary success of ART is ‘simple’, it is the combination of at least two active, well tolerable drugs from two drug classes and the potency of these drugs in terms of viral suppression, half-life, through levels and resistance barrier. Therefore, triple cART with either an NNRTI or a boosted protease inhibitor based on an NRTI backbone is the preferred regimen for initiation and maintenance as issued in different and the newest guidelines of the European AIDS Clinical Society in November 2009 (http://www.europeanaidsclinicalsociety.org/) [10–12]. With these therapies the long-term virological and immunological outcome is excellent  and recent studies have demonstrated an overall first-year response of around 90% or higher .
In view of these most impressive developments of HIV treatment over the past 2 decades, monotherapy for maintenance for various reasons must be viewed cautiously. Historically, first monotherapies with zidovudine or didanosine proved to be almost ineffective with a short lasting effect, compromised future treatment options, and led to serious resistance problems in many patients from the early period of ART. A serious resistance issue with monotherapy was observed again in vertical transmission prevention programs that provided nevirapine to pregnant women . Simplified treatment strategies with a mono-class triple NRTI therapy resulted in higher treatment failure rates . Thus, there maybe good reasons why clinicians may keep their reservation against monotherapy. A recent systematic review indicated that the overall efficacy of ritonavir-boosted protease inhibitor monotherapy is inferior to conventional cART . Although valuable, this meta-analysis must be scrutinized because it used inconsistent inclusion criteria, by including nonrandomized studies, monotherapy induction and monotherapy maintenance trials, and most important it did not include newer trials.
In the most recent Monotherapy in Treatment Experienced Adults (MONET) trial Arribas et al. (AIDS, 2010; 24:223–230) compare darunavir/ritonavir boosted protease inhibitor maintenance monotherapy compared with darunavir/r based triple cART. The trial proved the noninferiority in the per protocol analysis for the primary endpoint of less than 50 copies/ml at week 48 for the protease inhibitor monotherapy as compared with the cART arm [86.2 versus 87.8%, difference 1.6%; upper bound of the 95% confidence interval (CI) limit 10.1%, with a noninferiority margin of 12%]. Resistance was rarely observed as only one patient per arm showed at least one mutation, that is, one protease inhibitor mutation and one NRTI mutation, respectively. These results are important in different ways. First, it demonstrates the excellent potency of a single boosted protease inhibitor. Second, it indicates that boosted darunavir may be suited for long-term protease inhibitor-monotherapy in particular in light of the consistent finding of a second not yet published trial . Of note, in the MONET trial most treatment failures corresponded to transient viral load elevations, that is, in the range of 50–200 copies/ml. Importantly, reintroduction of intensification led to viral suppression in most patients and no relevant protease inhibitor mutation.
What are the advantages and disadvantages of maintenance protease inhibitor monotherapy. The one class regimen may preserve future treatment options with other drug classes. Also, the resistance potential for boosted lopinavir and darunavir was shown to be very low. After failure, treatment intensification with NRTIs seems feasible according to the MONET study and earlier trials. Patients with lipoatrophy may particularly benefit from maintenance protease inhibitor monotherapy, but also patients with other long-term toxicity from NRTIs. The lower costs could be an important issue but more data from cost-minimization analyses are needed. Exceptionally, boosted protease inhibitor monotherapy maybe used in patients who have major difficulties to adhere to cART such as patients with illicit drug use going on and off cART to possibly prevent multiclass failure and multiclass resistance. However, for the latter strategy no data exist. In addition, too little is known about the durability of protease inhibitor monotherapy, the risk of low level viremia, the effects of suboptimal adherence and whether protease inhibitor monotherapy sufficiently penetrates to important HIV sanctuary such as the central nervous system and the genital tract.
The concept of protease inhibitor maintenance monotherapy is intriguing but it still includes an uncertainty for which patient groups this treatment is a true option. There is a need for long-term follow-up data and for larger trials. The trials conducted so far lack the power in comparison to established treatment concepts and their estimates for treatment effects remain vague. Once these questions have been addressed, there will still be an answer needed as to which protease inhibitor is then best for monotherapy, although darunavir maybe best suitable (pp. 000–000). Taken together, current evidence suggests that protease inhibitor monotherapy may represent an option in patients with intolerance to NRTI or for treatment simplification. Such a strategy only applies to patients without any history of failure on prior protease inhibitor-based therapy and who have had viral load below 50 copies/ml in at least the past 6 months (http://www.europeanaidsclinicalsociety.org/). Also, we advocate that boosted protease inhibitor monotherapy should be used when treatment options are limited or in the context of clinical trials. Other therapeutic concepts await further research such as dual-class NRTI sparing regimens including novel drug classes. For the time being, clinicians should rely on robust triple cART combining available antiretroviral drugs as a first long-term strategy. Although the MONET trial impressively illustrates the potency of protease inhibitor mono-maintenance therapy and the development of cART since first monotherapies were introduced more than 2 decades ago, the time to abandon the principles of successful cART has not yet come.
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