protease inhibitor monotherapy: what is its role?

ANTIRETROVIRAL THERAPIES (A POZNIAK, SECTION EDITOR)

Protease Inhibitor Monotherapy: What Is Its Role?

Miriam Estébanez & Jose R. Arribas

Published online: 24 February 2012# Springer Science+Business Media, LLC 2012

Abstract Protease inhibitor monotherapy has been shownto be effective in maintaining long-term viral suppression ina majority of patients. Withdrawal of nucleoside analoguescan prevent long-term toxicity related to these drugs. Clin-ical trials have recently reported preliminary data on thebeneficial effect of protease inhibitor monotherapy on bodyfat distribution and bone metabolism. Some of the uncer-tainties possibly associated with protease inhibitor mono-therapy such as the increased risk of neurological events anda higher level of subclinical inflammation will be discussedin this review.

Keywords Protease inhibitor . Monotherapy . Lipoatrophy .

Bone mineral density . Antiretroviral therapies

Introduction

The standard treatment of HIV infection is based on tripleantiretroviral regimens that effectively achieve suppressionof viral replication [1–3]. However, the long-term toxicity ofantiretroviral treatment is a matter of concern for patientsand physicians. The main interest of a protease inhibitor (PI)monotherapy strategy is to reduce the risk of long-term

toxicity due to nucleoside analogues, such as lipoatrophyor loss of bone mineral density. In addition, PI monotherapydramatically reduces treatment costs.

The efficacy of PI monotherapy as a maintenance strate-gy in virologically suppressed patients has been reported inseveral trials [4, 5]. A recently published meta-analysisassessed the efficacy and safety of PI monotherapy as sim-plification strategy in 1,189 virologically suppressedpatients (590 patients on PI monotherapy versus 599 ontriple therapy). This meta-analysis reported that the risk oftreatment failure is slightly increased in patients receiving PImonotherapy for maintenance of virological suppression.By intent-to-treat (ITT) analysis, PI monotherapy was asso-ciated with an increased risk of virological rebound between2% and 6% (worst case scenario 13%). However, in patientswho experienced loss of virological suppression, re-induction with nucleoside analogs led to control of viralreplication in 93% of patients [6••].

Despite the high efficacy of PI monotherapy as mainte-nance strategy in clinical trials there is still disagreementabout the generalization of this strategy in real life practice.Several concerns still remain. PI monotherapy is associatedwith a higher risk of intermittent viremia. However, thesevirological rebounds have not been related in general to thedevelopment of PI resistance mutations. There is still con-troversy about a relationship between more frequent epi-sodes of low-level replication and worsening of theproinflammatory state associated with HIV infection. Inaddition, there is still concern about a higher incidence ofneurological impairment in patients treated with PI mono-therapy due to possible escape of viral replication in theCNS [7•].

In this review, we would like to summarize the mainadvances in relation to the PI monotherapy strategy reportedduring the last year.

M. Estébanez : J. R. ArribasServicio de Medicina Interna, Unidad VIH Hospital La Paz,IdiPAZ,Madrid, Spain

J. R. Arribas (*)Consulta Medicina Interna 2, Hospital La Paz,Paseo de la Castellana 261,28046 Madrid, Spaine-mail: jrarribas.hulp@salud.madrid.org

Curr HIV/AIDS Rep (2012) 9:179–185DOI 10.1007/s11904-012-0112-1

Darunavir/Ritonavir Monotherapy

The main updates of boosted darunavir monotherapy are the144 weeks results of MONET [8] and the 96 weeks resultsof MONOI clinical trials [9•].

The Monotherapy in Europe with TMC114 (MONET)trial [10••] was designed to explore the non-inferior efficacyof darunavir/ritonavir (DRV/r) monotherapy versus a tripletherapy arm of two nucleoside analogues and DRV/r.Recruited patients needed to have plasma HIV RNA levelsbelow 50 copies/mL for at least 24 weeks. In this trial, theprimary endpoint, treatment failure, was defined as twoconsecutive HIV RNA levels above 50 copies/mL at week48 or discontinuation of randomized treatment. The ITTpopulation included all randomized patients and the perprotocol population excluded patients with major protocolviolations or patients randomized incorrectly. The non-inferiority margin was defined at −12%.

In the analysis at week 48, non-inferior efficacy wasshown for the monotherapy in all comparisons despite theless favorable baseline characteristics in the monotherapyarm. In the per protocol, switch equals failure analysis,86.2% had HIV RNA less than 50 copies/mL in the mono-therapy arm, versus 87.8% in the triple therapy arm; by ITT,switch-included analysis, efficacy was 93.5% versus 95.1%at week 48. However, in the week 96 analysis [11••], mono-therapy showed non-inferior efficacy to triple therapy in theswitch included and observed failure (including only viro-logical endpoints) analysis, but not in switch equals failureanalysis. At week 144, in the ITT, switch equals failureanalysis, 69% versus 74% in the DRV/r monotherapy andtriple therapy arms respectively had HIV RNA less than 50copies/mL; by a switch-included analysis, efficacy was 90%versus 83%. So, switching to DRV/r monotherapy showednon-inferior efficacy to triple therapy only in the switch-included analysis at week 144 [8].

Why did DRV/r monotherapy not show non-inferiority inthe switch equals failure analysis at week 96 and 144? It isnecessary to consider that hepatitis C virus (HCV) co-infectionwas a significant predictor of treatment failure (P<0.01) atweek 48 in the multivariate analysis. At baseline, HCV co-infection (determined by serology) was overrepresented in themonotherapy group (18% versus 12% in the triple therapygroup). If we analyze separately the group that was onlymonoinfected with HIV the efficacy of the two treatmentstrategies was similar in the per protocol switch equals failureanalysis (85% in the monotherapy arm versus 84.5% in thetriple therapy arm at week 96; 78.8% versus 78.3% respec-tively at week 144) [12••]. However, monotherapy was clearlyless effective (in the per protocol switch equals failure analy-sis) than triple therapy in the subgroup of patients HIV/HCVco-infected. At week 96, proportion of patients with plasmaHIV RNA <50 copies/mL was 42.9% in the monotherapy arm

versus 66.7% in the triple treatment arm. This lower efficacyof DRV/r monotherapy in HIV/HCV co-infected patients per-sisted at week 144 [12••]. It is possible that the imbalance inthe prevalence of hepatitis C co-infection at baseline betweenthe treatment arms may have led to the worse results in themonotherapy arm at week 96 and week 144. It is not clear whythe subgroup of patients co-infected presented a higher risk oftreatment failure. According to the authors, it is likely that theunderlying cause was a poorer adherence to treatment in thissubgroup of co-infected patients.

The higher risk of virological failure in patients receivingDRV/r monotherapy had little apparent negative consequen-ces, since most of the elevations were transient, low level(50–200 copies/mL), easily controlled after the reinductionwith nucleosides, and not associated with an additional riskof developing PI resistance. Forty-one patients on mono-therapy had at least one determination above 50 copies/mLduring the trial in comparison with 35 patients on tripletherapy at week 96. Twenty-one and 13 patients had twoHIV RNA results above 50 copies/mL in the DRV/r mono-therapy arm and triple therapy arm respectively, of whom18/21 (86%) and 10/13 (77%) had HIV RNA <50 copies/mL at week 144 [8]. One patient in each arm developed amajor PI mutation before week 24, but both patientsremained phenotypically sensitive to darunavir. The patienton monotherapy had the L33F mutation when plasma HIVRNAwas 63 copies/mL and the patient on triple therapy hadpre-existing nucleoside reverse transcriptase inhibitor(NRTI) (M184V) and PI (V82I and L90M) mutations aftera short treatment interruption [13•].

In the MONET clinical trial, switching to monotherapywas not associated with an increased risk of nervous systemor psychiatric disorders [14]. Up to 144 weeks, two patientsin monotherapy arm presented with a drug-related psychiat-ric adverse event versus none in triple therapy arm; fivepatients on monotherapy presented with a drug-related ner-vous system adverse event in comparison with four patientsin triple therapy arm. Up to week 144, two patients discon-tinued from the trial for nervous system or psychiatricadverse events: one patient discontinued from the DRV/rmonotherapy arm for headache and another patient from theDRV/r + 2NRTI arm for disturbances in attention span.Despite a much lower mean “CSF penetration score” (CPE-score) [15] of the monotherapy compared to the triple ther-apy arm, the Functional Assessment of HIV Infection(FAHI) questionnaire showed no difference between thearms for memory, attention, or concentration at week 144[16].

In the MONOI trial, two patients presented mild neurolog-ical events on darunavir/r arm before week 48. A 36-year-oldwoman experienced unusual headaches and a 66-year-oldman with known untreated epilepsy presented seizures. Bothcases showed a discordance between cerebrospinal fluid

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(CSF) and plasma HIV replication (CSF viral load: 330 cop-ies/mL and 580 copies/mL respectively). The reinduction withabacavir and lamivudine achieved viral load decrease below200 copies/mL (lower limit of quantification) and improve-ment of neurological symptoms. In the follow-up to week 96no neurological events were reported.

Given its association with more frequent episodes of low-level viremia, another concern about PI monotherapy iswhether this strategy is associated with a higher level ofsubclinical inflammation than triple therapy. Higherinterleukin-6 (IL-6) and high sensitivity C-reactive protein(hsCRP) levels independently predicted development ofopportunistic disease [17] and mortality [18] in the Strate-gies for Management of Antiretroviral Therapy (SMART)trial. In the MONET trial, hs-RCP and IL-6 levels weremeasured in a subgroup of patients at week 144 [12••].There was no difference between the treatment arms in bothbiomarkers (median level of IL-6 was 2.12 pg/mL in tripletherapy arm versus 1.92 pg/mL in monotherapy arm). Thepercentage of patients with hs-RCP >5 mg/L was 10% intriple therapy arm and 12% in monotherapy arm; and thepercentage of patients with IL-6 >3 pg/mL was 31% and23% respectively (Fig. 1). In this analysis, hepatitis C co-infection was significantly associated with an increasedlevel of IL-6. It is possible that chronic infection withhepatitis C itself influences the elevation of IL-6 [19, 20].

The design of Monotherapy Inhibitor Protease (MONOI)trial has some differences compared with the MONET trial[21••]. This study included a lead-in period of 8 weeks withdarunavir 600/100 mg twice daily in combination with twoNRTIs, and after this lead-in period patients were random-ized to DRV/r monotherapy or DRV/r triple therapy. Dar-unavir was used twice daily instead of once daily up to week

48. After week 48, patients with plasma viral load <50copies/mL were switched to 800/100 mg once daily untilweek 96 [22••]. To be included in the trial patients needed tohave a viral load lower than 400 copies/mL for the past18 months, and less than 50 copies/mL at screening. Thedefinition of virologic failure used a viral load cutoff higherin MONOI (>400 HIV RNA copies/mL) than in MONET(>50 HIV RNA copies/mL). Results of MONOI at week 96showed in the ITT analysis that 88% of subjects on mono-therapy and 84% on triple therapy achieved a viral load <50copies/mL. Until week 96, nine patients on monotherapyversus four patients on triple therapy developed virologicalfailure. No patients had HIV isolates with darunavir resis-tance mutations.

In the MONOI trial investigators performed a sensitivityanalysis considering virologic rebound as two consecutivemeasurements of viral load >50 copies/mL. In this sensitiv-ity analysis, 21.4% of patients in DRV/r group versus 8% intriple therapy group presented at least 1 virologic reboundfrom baseline to week 96. Interestingly, MONOI investiga-tors analyzed factors associated with this definition of viro-logic rebound for patients receiving DRV/r monotherapy[9•]. Until week 48, predictive factors were having a singleblip at day 0 (day of randomization) and/or two consecutiveviral load >1 copy/mL measurements at screening and base-line. At week 96, a shorter time receiving prior antiretroviraltherapy, higher HIV-1 DNA at baseline, and poor adherencewere associated with virologic rebound. According to theseresults, the authors suggested that longer duration of anti-retroviral treatment may be associated with lower residualviremia, and consequently with a lower risk of treatmentfailure with DRV/r monotherapy.

Lopinavir/Ritonavir

The KALESOLO trial [23••] evaluated whether switching tolopinavir/r (LPV/r) monotherapy in patients well controlledby various antiretroviral combinations (not only by PI-containing regimens) was not inferior to continuing currenttriple therapy. KALESOLO included 186 patients with HIV-1 RNA <50 copies/mL for at least 6 months before inclu-sion. At week 48, non-inferiority was not demonstrated inthe missing equal failure analysis (non-inferiority margin setat −12%). A total of 84% of patients receiving LPV/r mono-therapy versus 88% of patients on current combined antire-troviral treatment (cART) were virology suppressed to <50copies/mL (difference −4%, lower limit of 90% two sidedconfidence interval for difference, −12.4%). However, iftreatment re-intensification with nucleosides was not con-sidered as treatment failure, LPV/r monotherapy achievednon-inferiority versus cART group (91% versus 88%,respectively; difference, +2.9%, lower limit of 90% two-sided

Fig. 1 Categories of hs-CRP at week 144 by treatment arm in theMONET trial

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confidence interval for difference, −4.5%). Although the num-ber of blips (transitory viral load >50 copies/mL) was higher inthe monotherapy arm (8 patients versus 18 on current cARTarm), the genotypic analysis for patients with viral rebounddemonstrated no LPV/r resistance mutations. According to theauthors, the causes of low-viremia in LPV/r monotherapycould be explained by less forgiveness of the monotherapystrategy and possibly by poor drug penetration into reservoirsites. Interestingly, only older age was a predictor factor oftreatment failure in the multivariate analysis. Treatment adher-ence, assessed using a standardized questionnaire [24], was notassociated with therapy failure.

McKinnon et al. [25•] evaluated whether virologicalrebound on LPV/r monotherapy is related to the emergence oflow-frequency drug-resistant variants. Plasma samples from15 subjects at virological rebound (HIV-1 RNA >500copies/mL) during the OK04 study [26] were analyzed bysingle genome sequencing (SGS) assay of HIV-1 gag andprotease. Standard population genotype identified major PIresistance mutations in one subject on standard therapy (2NRTI plus LPV/r) and in two subjects on LPV/r monotherapy.SGS identified additional major PI resistancemutations in 3 of11 subjects on LPV/r monotherapy and in 3 of 4 subjects onstandard therapy. There were no significant differencesbetween treatment arms in the frequency of mutations in gagand transframe protein (TFP)-p6 pol resistance mutations atcleavage sites and non-cleavage sites. Consequently, com-pared to the triple therapy group, SGS did not show anincrease in the number of mutations in the LPV/r monother-apy group.

Another recently published pilot study [27] found similarresults in terms of safety, efficacy, and tolerability thanprevious studies such as OK04 [27, 28] and KalMO [29].

Delfraissy et al. published the first randomized trialevaluating LPV/r monotherapy in comparison with LPV/r-zidovudine-lamivudine triple therapy in antiretroviral-naivepatients [30]. To be included in the trial, patients needed tohave an HIV-1 RNA below 100,000 copies/mL and CD4above 100 cells/μL. At week 48, by ITT analysis, 53 of 83patients (64%) in the monotherapy group and 40 of 53 patients(75%) in the triple-drug group achieved a viral load <50copies/mL (P00.34). If we considered only patients receivingthe randomized treatment (on-treatment analysis) at week 48,the monotherapy group showed lower efficacy than tripletherapy (80% versus 98% respectively, P00.02). At week96, by ITT analysis, only 39 of 83 (47%) patients randomizedto LPV/r arm achieved a viral load lower than 50 copies/mL[31]. By week 96, five patients included in monotherapy armand none in triple therapy arm (follow up to 48 weeks) devel-oped selected major PI resistance mutations (M46I at W40,L76V at W48, M46I and L76V at W48, L10F and V82A atW72, and L76V at W84) [32]. Viral re-suppression wasachieved in all five patients after intensification, switching,

or continuation on LPV/r. Ghosn et al. [33] found that pre-therapy mutations in gag site sequence were associated withvirological failure in the monotherapy arm. These resultssuggest that LPV/r monotherapy should not be considered asfirst-line treatment.

Fosamprenavir/Ritonavir Monotherapy

The efficacy of fosamprenavir/ritonavir monotherapy tocontrol viral replication in patients virologically suppressedhas been recently assessed through a single-arm pilot study(the FONT STUDY) [34]. Patient recruitment had to beprematurely stopped due to an excess of virological failure(7/20 patients). As in other studies of monotherapy, re-inductionwith nucleosides analogues achieved re-suppression inthe majority of patients. No discordant HIV replication in theCSF or semen was detected if patients had a suppressed viralload.

Protease Inhibitor Monotherapy and Body FatDistribution

Switching to PI monotherapy seems to be associated with amild improvement in body fat distribution [35, 36]. In theMONARCH study [37•], 30 patients with viral suppressiontaking non-nucleoside reverse transcriptase inhibitors or PI-based HAART were randomized to DRV/r monotherapyversus triple therapy including DRV/r. Switching to DRV/rmonotherapy or triple therapy was associated with a decreasein visceral fat (VAT) in the whole group (medianchange of −4 cm2) at week 48, although there wereno differences between treatment arms. This reductionwas accompanied by decreased in the Homeostasis ModelAssessment of Insulin Resistance (HOMA-IR) (medianchange of −0.5, P00.013). Fat mass in legs remained stableduring the follow-up. It should be noted that the majority ofpatients were not taking thymidine analogues at baseline (16patients had a tenofovir-containing regimen) and the lownumber of patients per arm makes it difficult to obtain signif-icant differences.

In the KALESOLO trial [24], a dual-energy X-rayabsorptiometry (DEXA) scan was performed both at base-line and at week 48 in 53 patients (23 patients on currenttriple therapy arm). The percentage of patients on lamivu-dine/emtricitabine (3TC/FTC), zidovudine (ZDV), anddidanosine at inclusion was 78%, 38%, and 25% respective-ly in current cART group; and 80%, 41%, and 29% respec-tively in LPV/r monotherapy group. At week 48, thesubgroup of patients on monotherapy presented a medianincrease of 160 g in leg fat in comparison with the mediandecrease of 50 g in current triple therapy (P00.023). In this

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study, the discontinuation of thymidine analogues resultedin a significant factor of recovery of fat mass in legs. TheMONARK study results supported these findings [38]. Atweek 48, median change in limb fat was −63 g on LPV/rmonotherapy versus −703 g on LPV/r + ZDV/3TCtriple therapy (P00.014) in naïve patients. In conclusion, PImonotherapy appears to be associated with a significantrecovery of limb fat, especially in patients with lipoa-trophy secondary to chronic treatment with thymidineanalogues.

Protease Inhibitor Monotherapy and Bone Metabolism

There is concern about bone toxicity caused by antiretroviraldrugs [39–41]. There are limited data about changes in bonemass after switching to monotherapy. Simplification studiessuggest that the withdrawal of reverse transcriptase inhib-itors may improve bone mass [38] and vitamin D level.However, no published study has specifically evaluatedwhether tenofovir withdrawal and switching to monother-apy is associated with an improvement in bone mass com-pared to continuing tenofovir-containing regimen. In theMONARCH study [38], the DRV/r monotherapy arm hada mild increase in lumbar bone mineral density (BMD)(median change: +0.01 g/cm2 [−0.01; 0.04] in DRV/r mono-therapy versus −0.0 g/cm2 [−0.03; 0.01] in DRV/r +2NRTIs, P00.03) at week 48. After switching, only 8 outof 15 patients on triple therapy continued with tenofovir.This intriguing result, considering the small number ofpatients and short follow-up, should be confirmed in furtherstudies. In the DEXA substudy of KALESOLO trial, therewere no differences between treatment arms in BMD atweek 48 [24].

A number of studies comparing changes in bone mineraldensity (BMD) in patients receiving standard treatment ormonotherapy have found that bone loss is independent ofthe antiretroviral treatment received [42, 43]. In the MON-ARK study [42], DXAwas performed at baseline and week48 in 43 and 25 naïve patients randomized to LPV/r mono-therapy or LPV/r plus zidovudine plus lamivudine armrespectively. After 48 weeks, there was a significantdecrease in lumbar spine BMD in both treatment arms(median change: −4.4% in monotherapy arm versus −4.0%in triple therapy arm), and at the hip (median change: −3.7%and −3.1%, respectively). There were no differences at week48 between the two treatment arms. Brown et al. [43] assessedtotal BMD changes over 96 weeks in naïve patients startingantiretroviral treatment. In this clinical trial, antiretroviral-naïve subjects were randomized to receive efavirenz pluszidovudine/lamivudine or LPV/r plus zidovudine/lamivudine.Between weeks 24 and 48, subjects randomized to LPV/r armand with viral suppression were simplified to LPV/r

monotherapy up to week 96. At 96 weeks, efavirenz groupand LPV/r group presented a similar decrease in total BMD(−2.3% versus −2.5%, respectively). Switching to LPV/rmonotherapy was not associated with a significant change intotal BMD in LPV/r group.

Patients infected with HIV have a high prevalence ofvitamin D level deficiency [44, 45]. It has been suggestedthat efavirenz appears to increase the risk of low vitamin D[45, 46]. In the MONET trial, patients who discontinuedefavirenz or zidovudine and switched to DRV/r with orwithout nucleosides analogues presented a significant increasein vitamin D level at week 96. However, there were no differ-ences between patients in the monotherapy arm versus thetriple therapy arm [47].

Conclusions

Our review of the PI monotherapy literature published duringthe last year shows that PI monotherapy based on DRV/r oncedaily or LPV/r twice daily as simplification strategy is able tomaintain long-term viral suppression in the majority ofpatients with minimal risk of development of PI resis-tance. Selection of patients with good adherence totreatment appears crucial to ensure the success of viralreplication control. In cases of therapeutic failure, there-introduction of nucleoside analogues achieved viralcontrol in most cases.

PI monotherapy seems to be a therapeutic option inpatients with lipoatrophy. Switching to PI monotherapycould increase the fat mass in legs. Further studies areneeded to evaluate the impact of switching to PI monother-apy on bone metabolism.

Studies are required to assess whether monotherapyimplies a further increase of acute phase reactants, butpreliminary results show that there is not a higher level ofsubclinical inflammation.

There are no sufficient data about the role of monother-apy in the development of neurological impairment. Up tonow in the clinical trials, the group of patients receiving PImonotherapy showed no increased risk of neurologicalevents, psychiatric, or cognitive impairment.

In summary the current role of PI monotherapy is notcompletely defined. Our literature review suggests thatthis therapeutic strategy is better suited for maintenanceof virological control in highly adherent patients, avoid-ing the toxicity of the nucleoside analogs and reducingcost.

Acknowledgments This work was supported by a Fondo de Inves-tigaciones Sanitarias (FIS) grant from the Spanish Ministry of HealthPI10/00483.

Dr. Miriam Estebanez is supported by a grant from the FIS RioHortega program (CM10/00152). Dr. Jose R. Arribas is an investigator

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from the Programa de Intensificación de la Actividad Investigadora enel SNS (I3SNS).

IdiPAZ AIDS and infectious diseases investigator group is partiallysupported by “Red de Investigacion en SIDA” (AIDS Research Net-work) (RIS) RD07/0006/2007.

Disclosure M. Estébanez: speakers’ bureaus for BMS and ViiV; J. R.Arribas: board membership, consultancy, speakers’ bureaus, and hon-oraria from Viiv, Tibotec, Janssen, Abbott, BMS, Gilead, and MSD.

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21. •• Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy ofdarunavir/ritonavir maintenance monotherapy in patients withHIV-1 viral suppression: a randomized open-label, noninferioritytrial, MONOI-ANRS 136. AIDS. 2010;24:2365–74. An importantclinical trial evaluating darunavir/ritonavir monotherapy. In thistrial, darunavir/ritonavir was administered at doses higher (600/100 mg twice daily) than in the MONET study until week 48.Results concordant with MONET.

22. •• Valantin MA, Lambert-Niclot S, Flandre P, et al.; on behalf ofthe MONOI ANRS 136 Study Group. Long-term efficacy ofdarunavir/ritonavir monotherapy in patients with HIV-1 viral sup-pression: week 96 results from the MONOI ANRS 136 study. JAntimicrob Chemother. 2011. Dec 7 [Epub ahead of print]. Two-year update of the MONOI trial. Switching to 800/100 mg oncedaily darunavir/ritonavir confirmed the MONET results. Virologi-cal failure was not associated with development of darunavirresistance mutation.

23. •• Meynard JL, Bouteloup V, Landman R, KALESOLO StudyGroup, et al. Lopinavir/ritonavir monotherapy versus current treat-ment continuation for maintenance therapy of HIV-1 infection: theKALESOLO trial. J Antimicrob Chemother. 2010;65:2436–44. Thistrial compared switching to lopinavir/ritonavir monotherapy versuscontinuing with the triple therapy (containing or non-containing PIregimen). Non-inferiority was non-demonstrated, considering treat-ment intensification as failure. The DEXA substudy shows a signif-icant recovery of fat mass in legs in monotherapy arm.

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26. Pulido F, Arribas JR, Delgado R, OK04 StudyGroup, et al.Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and twonucleosides for maintenance therapy of HIV. AIDS. 2008;22:F1–9.

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ritonavir plus zidovudine and lamivudine triple therapy. Antimi-crob Agents Chemother. 2009;53:2934–9.

33. Ghosn J, Delaugerre C, Flandre P, et al. Polymorphism in Gaggene cleavage sites of HIV-1 non-B subtype and virological out-come of a first-line lopinavir/ritonavir single drug regimen. PLoSOne. 2011;6:e24798.

34. Saumoy M, Tiraboschi J, Gutierrez M, et al. Viral response instable patients switching to fosamprenavir/ritonavir monotherapy(the FONT Study). HIV Med. 2011;12:438–41.

35. Cameron DW, da Silva BA, Arribas JR, et al. A 96-week compar-ison of lopinavir-ritonavir combination therapy followed bylopinavir-ritonavir monotherapy versus efavirenz combinationtherapy. J Infect Dis. 2008;198:234–40.

36. Valantin MA, Flandre P, Kolta S, et al. Fat tissue distribution changesin HIV-infected patients with viral suppression treated with DRV/rmonotherapy vs 2 NRTI + DRV/r in the MONOI–ANRS 136 ran-domized trial: results at 48 weeks [Abstract 721]. Program andabstracts of the 17th Conference on Retroviruses and OpportunisticInfections; San Francisco, California, 16–19 February 2010.

37. • Guaraldi G, Zona S, Cossarizza A, et al. Impact of Switching toDarunavir/ritonavir monotherapy vs. triple-therapy on Body FatRedistribution and Bone Mass in Virologically Suppressed HIV-Infected Adults [PE7.5/4.] The MONARCH randomized con-trolled trial. 13th European AIDS Conference EACS, Belgrade,Serbia, October 2011. This clinical trial evaluated the change inlipoatrophy and bone mineral density after switching to monother-apy in comparison with continuing triple therapy. The monother-apy group shows a stabilization of the body fat distribution and amild improvement in bone metabolism. This study is limited by thesmall number of patients included, and the short-term follow-up ofpatients up to 48 weeks.

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43. Brown TT, McComsey GA, King MS, et al. Loss of bone mineraldensity after antiretroviral therapy initiation, independent of antire-troviral regimen. J Acquir Immune DeficSyndr. 2009;51(5):554–61.

44. Mueller NJ, Fux CA, Ledergerber B, Swiss HIV Cohort Study, etal. High prevalence of severe vitamin D deficiency in combinedantiretroviral therapy-naive and successfully treated Swiss HIVpatients. AIDS. 2010;24:1127–34.

45. Welz T, Childs K, Ibrahim F, et al. Efavirenz is associated withsevere vitamin D deficiency and increased alkaline phosphatase.AIDS. 2010;24:1923–8.

46. Fux CA, Baumann S, Furrer H, et al. Is lower serum 25-hydroxyvitamin D associated with efavirenz or the non-nucleoside reversetranscriptase inhibitor class? AIDS. 2011;25:876–8.

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