HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review
Bierman, Wouter FWa; van Agtmael, Michiel Aa; Nijhuis, Moniqueb; Danner, Sven Aa; Boucher, Charles ABb,c
aDepartment of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
bDepartment of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
cDepartment of Virology, Erasmus Medical Center, Rotterdam, The Netherlands.
Received 5 June, 2008
Revised 6 August, 2008
Accepted 8 August, 2008
Correspondence to Dr Wouter Bierman, MD, Department of Internal Medicine, VU University Medical Center, Secretariaat Inwendige Geneeskunde, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel: +31 20 44 44 444; fax: +31 20 44 44 313; e-mail: email@example.com
Objective: To assess the efficacy of ritonavir-boosted protease inhibitor monotherapy.
Design and methods: Systematic review of all protease inhibitor-monotherapy studies published in peer-reviewed journals or presented at conferences to date. Data of randomized controlled trials were pooled to yield common odds ratios.
Results: Twenty-two protease inhibitor-monotherapy studies were identified. In the intent-to-treat analysis, 395 out of 582 (67.9%) patients had undetectable HIV-RNA at the end of follow-up. In the six randomized controlled trials (all lopinavir/ritonavir monotherapy), the risk of therapy failure was greater on monotherapy: 121 out of 364 (33.2%) patients on monotherapy against 64 out of 280 (22.9%) patients on HAART [pooled odds ratio 1.48 (95% confidence interval 1.02–2.13, P = 0.037)]. Regarding patients with successfully resuppressed HIV-RNA upon (re-)introducing nucleoside reverse transcriptase inhibitors (NRTIs) as nonfailures, the risk of therapy failure was comparable: 98 out of 364 (26.9%) against 64 out of 280 (22.9%) patients [odds ratio 1.05 (95% confidence interval 0.72–1.53, P = 0.81)].
Conclusion: The overall efficacy of ritonavir-boosted protease inhibitor monotherapy is inferior to HAART. The efficacy improves in patients started on monotherapy after suppressed HIV-RNA for at least 6 months. Ten percent of patients have viral rebound with HIV-RNA levels between 50 and 500 copies/ml. Possible explanations are lack of HIV suppression in particular cells or compartments, alternative resistance mechanisms, and nonadherence. Once proven that reintroduction of NRTIs, in patients with loss of viral suppression, is safe and effective, a broader use of simplification of HAART to protease inhibitor monotherapy might be justified. This review supports that the majority of patients with prolonged viral suppression on HAART can successfully be treated with protease inhibitor monotherapy. Arguments for this strategy are NRTI/NNRTI side effects, NRTI/NNRTI resistance, and costs.
Strategies to simplify HIV treatment were conceived, when the initial enthusiasm about highly active antiretroviral therapy (HAART) was tempered by concerns on adverse effects, such as lipodystrophy and cardiovascular complications, the challenge of lifelong adherence, and HIV multidrug resistance. Thus, with certain cancer and infection therapies in mind, the so-called induction–maintenance concept was tried in HIV therapy on the assumption that, after a phase of maximal suppressive HAART (induction), the same level of viral suppression could be maintained by fewer drugs (maintenance). The first trials studying this concept were unsuccessful. Maintenance with two nucleoside reverse transcriptase inhibitors (NRTIs), indinavir ± one NRTI, or nelfinavir and saquinavir or stavudine was inferior to continuing triple or quadruple HAART [1–3]. A Cochrane review comparing three-drug or four-drug with two-drug maintenance regimens found a significantly higher risk of virologic failure with an odds ratio (OR) of 5.5 .
An explanation for these disappointing results was the low genetic barrier of the maintenance therapies, being defined as the number of mutations needed for the patient's HIV strain to escape therapy, together with an insufficient bioavailability of the studied protease inhibitors. Subsequently, it was discovered that the bioavailability of protease inhibitors and thereby their efficacy could be significantly increased (‘boosted’) by adding a low dose of ritonavir, which acts as a cytochrome P450 3A4 inhibitor. Indeed, the first ritonavir-boosted protease inhibitor, lopinavir/ritonavir (LPV/r), was superior to unboosted protease inhibitors if combined with two NRTIs . Hence, using ritonavir-boosted protease inhibitor monotherapy as maintenance and even as induction therapy was considered an option and has been studied increasingly in the past 5 years. These studies were meant to evaluate the paradigm that at least three drugs are needed to effectively suppress the HIV virus and to evaluate the concept of genetic barrier.
If ritonavir-boosted protease inhibitor monotherapy would turn out to be equally effective as HAART, several advantages could be expected. First of all, fewer different drugs could lead to fewer long-term adverse events, for example, lipoatrophy, which is now thought to be mainly caused by NRTIs. Second, fewer drugs would lead to fewer drug–drug interactions. Then, fewer pills might improve adherence. Furthermore, costs would be reduced. Last of all, without the risk of accumulating mutations in reverse transcriptase (RT), more treatment options would remain in case of virologic failure. Moreover, in clinical trials, failure of ritonavir-boosted protease inhibitor-based HAART seldom leads to major mutations in protease related to protease inhibitor resistance , which implies that identifying subsequent suppressive regimens should be relatively easy.
The question is how the efficacy of ritonavir-boosted protease inhibitor monotherapy compares to traditional HAART and what the consequences of failure on such regimens are. The purpose of this study is to give an overview of all ritonavir-boosted protease inhibitor-monotherapy studies published in peer-reviewed medical journals or presented at international HIV conferences in order to assess the efficacy of protease inhibitor monotherapy and to discuss its future role.
We conducted systematic reviews to obtain all published data relating ritonavir-boosted protease inhibitor monotherapy as HIV treatment. Three electronic databases were searched for relevant trials and case series using the following search terms: HIV Protease Inhibitors and (HIV or HIV infections) AND (monotherapy OR ‘single agent’ OR ‘single drug’ OR alone OR simplified). No limits were set. By defining the subject of ritonavir-boosted protease inhibitor monotherapy broadly, we expected a high sensitivity of our search.
Three electronic databases searched are listed as follows:
1. MEDLINE for the years 1982–May 2008 through the PubMed search engine.
2. Embase for the years 1982–May 2008.
3. The Cochrane database of Systematic Reviews in the most recent edition of the Cochrane Library.
We aimed to include all recently presented data at relevant international HIV conferences, including the International AIDS Society (IAS) conferences, the European AIDS Conference (EACS), and the Conference on Retroviruses and Opportunistic Infections (CROI), by reviewing the abstracts. Furthermore, we contacted key researchers in the field of protease inhibitor monotherapy to try to receive data from presented studies.
We categorized the studies by the state of suppression of HIV-RNA at start of monotherapy: suppressed HIV-RNA against unsuppressed HIV-RNA. Therapy failure was defined as HIV-RNA more than 50 copies/ml at the end of the study period in the intent-to-treat (ITT) analysis of all patients that had been dosed once. Per trial protocol defined virologic failure and premature termination of assigned study treatment for whichever reasons were considered as failure as well. In the as-treated analysis, patients that discontinued participation due to other reasons than virologic failure were not included. In our metaanalysis, results from the included randomized controlled trials (RCTs) were combined to generate pooled ORs with 95% confidence intervals (CIs) using a fixed effects model, or a random effects model if there was significant heterogeneity between trials (P ≤ 0.10) .
Using our described search strategy in MEDLINE, we found 13 publications presenting data from ritonavir-boosted protease inhibitor-monotherapy studies out of a total of 533 references. In Embase, we found 1186 references but no additional relevant studies. In the Cochrane Library, we found no relevant studies. Among the abstracts of IAS conferences (2001–2007) and EACS (2003–2007) and CROI (1997–2007), we found nine relevant studies that have not been published in a peer-reviewed medical journal yet. All studies are summarized in Table 1 [8–30].
We found one ritonavir-boosted indinavir (IDV/r), one ritonavir-boosted saquinavir (SQV/r), three ritonavir-boosted atazanavir (ATV/r), and 17 LPV/r monotherapy studies. In 14 studies, monotherapy was started in patients with completely suppressed HIV-RNA. In eight studies, monotherapy was predominantly started in patients with unsuppressed HIV-RNA. Six trials had a randomized controlled design.
Indinavir/ritonavir: suppressed HIV-RNA at start of monotherapy
Kahlert et al.  reported the results of an uncontrolled trial with IDV/r monotherapy. Twelve patients with completely suppressed HIV-RNA on IDV/r-based HAART with a median duration of 28.5 months were switched to monotherapy for 48 weeks, during which no virologic failures occurred. Three patients had HIV-RNA between 50 and 100 copies/ml at 48 weeks. One patient developed a central nervous system T-cell lymphoma during the study period and died after several weeks of chemotherapy.
Saquinavir/ritonavir: unsuppressed HIV-RNA at start of monotherapy
SQV/r has been studied as monotherapy once in a South African retrospective study of 28 patients with advanced HIV infection . SQV/r monotherapy was used as an induction strategy for 4–8 weeks to avoid hematological and hepatic toxicity problems of nonnucleoside reverse transcriptase inhibitor (NNRTI)-based HAART in the most critical phase. The investigators observed a virologic and immunologic response comparable to SQV/r-based HAART.
Atazanavir/ritonavir: suppressed HIV-RNA at start of monotherapy
ATV/r has been studied as monotherapy in three uncontrolled trials. Swindells et al.  reported a trial with 36 patients on protease inhibitor-based HAART switched to ATV/r monotherapy. After 24 weeks, three patients experienced virologic failure, and one patient had withdrawn voluntarily. Two patients discontinued HAART before the treatment switch. Genotypic analysis at failure did only identify a minor protease inhibitor mutation in one patient, of whom no pretreatment sample was available. Plasma atazanavir concentrations at failure were low or below detection in two out of three patients.
The second trial studying ATV/r monotherapy was prematurely terminated after virologic failure in five patients, when only 15 patients out of the planned 30 had been included . The definition of virologic failure was stricter than in any other trial: two consecutive plasma HIV-RNA samples above the limit of detection (>20 copies/ml). To be included patients should have never been treated with protease inhibitor and have undetectable HIV-RNA for a minimum of 12 months. Although interacting medication was not permitted, two patients with virologic failure had been taking acid-suppressing therapy (lansoprazole and ranitidine) before failure. ATV plasma concentrations were in the normal therapeutic range, however. Two of the other patients with virologic failures did have a low ATV concentration before failure despite raising the ritonavir dosage from 100 to 200 mg in one and raising the ATV dosage from 300 to 400 mg in the other.
The third trial studied ATV/r monotherapy during 24 weeks in 30 patients , who had suppressed HIV-RNA on HAART (n = 21) or on IDV/r monotherapy from a previous, aforementioned trial (n = 9) . One patient failed monotherapy at week 8. Retrospectively, he had previously failed a protease inhibitor-based HAART and should not have been included. One patient prematurely terminated treatment at week 20. Of the remaining 28 patients, one patient had detectable HIV-RNA (between 50 and 100 copies/ml) at week 24.
Lopinavir/ritonavir: unsuppressed HIV-RNA at start of monotherapy
Delfraissy et al.  conducted the only RCT that studied ritonavir-boosted protease inhibitor monotherapy as induction therapy in antiretroviral therapy (ART)-naive patients. One hundred and thirty-eight patients were randomized to LPV/r monotherapy (n = 84) or LPV/r and zidovudine/lamuvidine (Combivir, GlaxoSmithKline, London, UK (CBV)) (n = 54). Sixteen percent in the monotherapy arm and 23% in the HAART arm discontinued the study for reasons such as suboptimal response, adverse events, and lost to follow-up. In three monotherapy patients with virologic failure (HIV-RNA >400 copies/ml after becoming undetectable), NRTIs were added. 67.5% of monotherapy patients had HIV-RNA less than 50 copies/ml at 48 weeks, compared with 75.5% of HAART patients (ITT), which was a nonsignificant difference. In the as-treated analysis, the percentage of patients with undetectable HIV-RNA was significantly smaller in the monotherapy arm (78.9 against 93.0%), due to nine patients on monotherapy with low-level viremia (HIV-RNA between 50 and 400 copies/ml) and four against two virologic failures. At 96 weeks, genotypic analysis was done in 32 patients on monotherapy . Seventeen patients had changes in protease, of which five had only minor protease inhibitor mutations and five had also major protease inhibitor mutations. One of seven tested HAART patients had one RT mutation (184 V) and no protease inhibitor-mutations.
Gathe et al.  reported an uncontrolled trial that included 30 ART-naive patients, of which 60% had HIV-RNA less than 50 copies/ml after 48 weeks of LPV/r monotherapy (ITT). Two patients had virologic failure. One of them had one minor protease inhibitor-mutation, but a pretherapy sample was not tested.
Next, Gathe et al.  treated 39 ART-naive patients with LPV/r monotherapy. At 48 weeks, 31 out of 39 (79.5%) patients had HIV-RNA less than 75 copies/ml. Six patients had virologic failure in majority due to poor adherence. Two patients developed new minor protease inhibitor mutations, and one patient developed a major protease inhibitor mutation but was not ART-naive in retrospect. The therapy of five patients was subsequently intensified: three out of five patients received dosage adjustment [LPV/r 600/150 mg twice daily (b.i.d.)] and in therapy of two out of five, tenofovir and emtricitabine was added.
Garrett et al.  described a small case series of 10 patients whose treating physicians had preferred LPV/r monotherapy to HAART due to a range of acute severe concurrent medical comorbidities. After 4–8 weeks, median (range) log10 HIV-RNA reduction was 2.15 (1.62–3.1). One of the four patients continuing monotherapy beyond 8 weeks had virologic failure at 48 weeks. Genotypic testing showed three new major protease inhibitor mutations. The patient had received HAART prior to monotherapy, resulting in NRTI and NNRTI resistance, but prior protease inhibitor use is not stated.
Three other case series studied in total 113 patients mainly with unsuppressed HIV-RNA switched to or started on LPV/r monotherapy [or ATV/r monotherapy (n = 3)] [13–15]. Reasons for the treatment choice included NRTI/NNRTI side effects or NRTI/NNRTI resistance, comorbidity (e.g. renal failure) and anxiousness about facial lipoatrophy. Patients (49–67%) had undetectable HIV-RNA after 60 weeks.
Lopinavir/ritonavir: suppressed HIV-RNA at start of monotherapy
Arribas et al.  conducted the first RCT that included 42 patients without a history of protease inhibitor failure and with completely suppressed HIV-RNA on LPV/r and two NRTIs, who were randomized to LPV/r monotherapy or continuation of HAART. After 48 weeks, 81% in the monotherapy arm against 95% in the HAART arm had HIV-RNA less than 50 copies/ml. Three patients in the monotherapy arm had virologic failure. Two patients had minor protease inhibitor mutations, but only one had a minor mutation which was not found in a pretherapy sample. These two patients had suboptimal adherence according to pharmacy drug dispensation databases. The third patient without protease inhibitor mutations upon failure was 100% adherent throughout the trial according to pharmacy data and had an average LPV plasma concentration (4.4 mg/l). The investigators decided to add the former NRTI backbone, which resulted in viral resuppression in all three patients.
Next, the same investigators, Pulido et al. [23,24] included 103 patients on LPV/r monotherapy against 102 patients continuing LPV/r and two NRTIs. In this study protocol, virologic failure without significant protease mutations followed by successful reintroduction of the former NRTI backbone was not considered treatment failure. According to protocol definition, 13% of monotherapy patients had therapy failure compared with 22% of HAART patients. In the ITT analysis, that considers all loss of virologic suppression as failure, 77.0% of monotherapy patients against 77.6% of HAART patients had HIV-RNA less than 50 copies/ml at 96 weeks. In the as-treated analysis, there was a larger difference: 84.6 against 93.8%. At 96 weeks, therapy of seven patients was reintensified with NRTIs because of persistent low-level viremia. Six patients had virologic failure of which two had major protease inhibitor mutations. Pretherapy samples were not available. The patients without protease inhibitor mutations had successful viral resuppression with their former NRTI backbone. One patient with major protease inhibitor mutations received reintensification with abacavir and didanosine but failed again with an additional protease inhibitor mutation. Five HAART patients had virologic failure of which two had multiple RT mutation and protease inhibitor mutation.
Singh et al.  reported an RCT with 54 patients on HAART (74% LPV/r based), who were randomized 1: 1 to LPV/r monotherapy or continuation of HAART. At 24 weeks, an interim analysis showed that 73.1 against 82.1% patients had HIV-RNA less than 50 copies/ml (ITT). Four against three patients had low-level viremia, and one patient on monotherapy failed without protease inhibitor mutations.
Nunes et al.  randomized 60 patients on HAART (63% NNRTI based) 1: 1 to LPV/r monotherapy or continuation of HAART. At 96 weeks, 80.0 against 89.7% had HIV-RNA less than 80 copies/ml (ITT). In both arms, one patient had virologic failure without protease inhibitor mutations in either patient. The patient failing monotherapy had successful viral resuppression after reinduction with NRTIs.
Cameron et al.  studied 155 ART-naive patients, who were randomized 2: 1 to LPV/r and CBV induction (n = 104) followed by LPV/r monotherapy maintenance after negative viral loads for 3 months (n = 92) or efavirenz (EFV) and CBV (n = 51). Patients (25%) in both arms prematurely discontinued the study. After 96 weeks, the percentage of patients with HIV-RNA less than 50 copies/ml in the monotherapy arm (ITT, including patients that discontinued prior to deintensification, never reached deintensification criteria, or had two consecutive samples with detectable HIV-RNA) was 48.1 against 60.8% in the EFV/CBV arm. In the as-treated analysis, there was a larger difference: 63.3 against 91.2%. Two patients on LPV/r monotherapy developed protease inhibitor mutations upon failure; therapy of six patients without protease inhibitor-mutations was reintensified; one patient in the EFV arm developed NNRTI resistance, while being nonadherent .
Furthermore, two uncontrolled trials included 18 and 19 patients on HAART (90% without LPV/r), of which 63–67% had HIV-RNA less than 50 copies/ml after 24–48 weeks (ITT) [28,29]. In these two studies, four patients had virologic failure. Three patients were tested and had one or two minor protease inhibitor mutations. Pretherapy samples of these patients were not tested.
Falci et al.  presented an uncontrolled trial with 15 patients on LPV/r-based HAART switched to LPV/r monotherapy: 12 patients on LPV/r twice per day and three patients on LPV/r once per day. Two out of 12 and three out of three patients had virologic failure during 19 months of follow-up. According to the investigators, no significant resistance-related mutations were detected.
Campo et al.  described a study of six patients on 24 weeks of LPV/r monotherapy following LPV/r-based HAART. Two patients had virologic failure with minor protease inhibitor mutations also found in pretherapy samples. The other four patients had detectable HIV-RNA in 32% of samples, which the investigators partially blame on the intense sampling frequency.
Finally, in a large case series of 51 patients previously treated with HAART (72.5% LPV/r based) that were switched to monotherapy, 38 patients (75%) had maintained viral suppression after 48 weeks . Failure was mainly due to gastro-intestinal side effects and loss to follow-up. Two patients had virologic failure with a new minor protease inhibitor mutation in one of them. Both patients restarted their NRTI backbone resulting in viral suppression.
At first, we combined all data of patients treated with ritonavir-boosted protease inhibitor monotherapy in prospective-controlled or uncontrolled trials (n = 16; see Fig. 1). The percentage of patients that had undetectable HIV-RNA (usually <50 copies/ml), at the end of the follow-up period) ranged from 33.3 to 90.0% (ITT); overall, 395 of 582 (67.9%) patients. Of patients with unsuppressed HIV-RNA and suppressed HIV-RNA at start of monotherapy, 69.1% (105/152) and 67.4% (290/430), respectively, had undetectable HIV-RNA (ITT). In the as-treated analysis, 79.5% (105/132) and 75.9% (290/382), respectively, had undetectable HIV-RNA; 9.8% (13/132) and 8.9% (34/382), respectively, had HIV-RNA between 50 and (usually) 400 copies/ml. Ten patients had virologic failure with major protease inhibitor mutations out of 58 patients failing from a total of 570 patients treated with protease inhibitor monotherapy in these 16 trials.
Figure 2, which is composed of data of all six RCTs with ritonavir-boosted protease inhibitor monotherapy (all with LPV/r), shows the percentage of patients that had HIV-RNA less than 50 and 400 copies/ml at the end of follow-up (ITT: Fig. 2a; as-treated analysis: Fig. 2b). When all RCTs were pooled (see Fig. 3a and b), the risk of therapy failure (ITT) was greater for those on LPV/r monotherapy: 121 out of 364 patients (33.2%) on monotherapy against 64 out of 280 patients (22.9%) on HAART [OR 1.48 (95% CI 1.02–2.13, P = 0.037), no significant heterogeneity between trials (P = 0.76)]. Using the as-treated analysis data, the risk of failure was also greater on monotherapy: 72 out of 315 (22.9%) against 17 out of 233 patients (7.3%) [OR 3.56 (95% CI 2.00–6.32, P < 0.001)]. When performing a metaanalysis only with the studies that included patients on fully suppressive HAART (Arribas, Singh, Nunes and Pulido et al. [20–24]), the difference in efficacy (ITT) was not significant anymore: 40 out of 177 (22.6%) patients on monotherapy against 31 out of 176 patients (17.6%) on HAART [OR 1.37 (95% CI 0.810–2.32), P = 0.24]. When we considered patients with successfully resuppressed HIV-RNA upon (re-)introducing an NRTI backbone as nonfailures, the risk of therapy failure (ITT) on monotherapy was equal to that of HAART: 98 out of 364 patients (26.9%) against 64 out of 280 patients (22.9%) [OR 1.05 (95% CI 0.72–1.53, P = 0.81)]. In the as-treated analysis, the risk of failure on monotherapy was still significantly greater: 49 out of 315 patients (15.6%) against 17 out of 233 patients (7.3%) [OR 2.15 (95% CI 1.17–3.92, P = 0.013)].
Major protease inhibitor-resistance mutations occurred in 10 out of 61 tested patients on LPV/r monotherapy and in one out of 12 patients on HAART. Patients were tested for various reasons, such as suboptimal response, discontinuation, and viral rebound. Mean CD4+ T-cell change ranged from −40 to +289 cells/μl on monotherapy against +8 to +240 cells/μl on HAART.
In this report, we provide an overview of all ritonavir-boosted protease inhibitor-monotherapy studies published in peer-reviewed medical journals or presented at international HIV conferences to date to evaluate the efficacy of ritonavir-boosted protease inhibitor monotherapy. We found 22 studies of which six were RCTs of LPV/r monotherapy against HAART (none of them was blinded, placebo-controlled). Although final reports of the larger trials including complete follow-up and detailed virologic results are partially lacking, several important conclusions can be drawn from the available data.
Overall efficacy of ritonavir-boosted protease inhibitor monotherapy based on the results of all the LPV/r monotherapy RCTs is less than HAART, with a pooled OR of therapy failure on LPV/r monotherapy against HAART of 1.48 and an absolute risk difference of 10.3%. The overall percentage of patients on monotherapy with undetectable HIV-RNA at the end of the follow-up period in all 16 prospective trials is 67.9% (ITT). However, the results of the trials are diverse, which can be attributed to several aspects.
It is important to note that the studies had significant differences in design and in definition of therapy failure. Most studies included patients that were already taking HAART for a longer period of time, and as a result had undetectable HIV-RNA. A minority of studies included patients that had not been treated before, and, consequently, had detectable HIV-RNA levels. In the study by Cameron et al. , ART-naive patients started LPV/r and CBV and simplified to monotherapy after 3 months of undetectable HIV-RNA. The differences in design have potential virologic implications. In case of a suppressed HIV viral load at start of protease inhibitor monotherapy, there is no or little viral replication and a declining proviral population with potentially reduced genetic diversity . Moreover, the amount of target cells represented by the number of activated CD4+ T-cells decreases after HAART initiation . Finally, patients with undetectable HIV-RNA on HAART represent a population that has shown to be adherent to therapy.
Accordingly, the efficacy of LPV/r monotherapy approached HAART (77 against 82%) in the four RCTs that included patients who had suppressed HIV-RNA on HAART for at least 6 months (and generally much longer) and predominantly were already taking LPV/r as part of their HAART (Arribas, Singh, Nunes and Pulido et al.) [20–24]. Nevertheless, in the metaanalysis of all 16 trials, the efficacy of monotherapy started, when HIV-RNA levels were already suppressed, was similar to the efficacy of monotherapy started when HIV-RNA was unsuppressed.
Interestingly, according to protocol definition of the RCT by Pulido et al. [23,24], a nonsignificantly smaller proportion of therapy failure in the monotherapy arm was found. This was achieved by reintroducing the NRTI backbone in case of monotherapy failure without genotypic protease inhibitor resistance. When we considered patients with successful viral resuppression as nonfailures, we found no difference in therapy failure between monotherapy and HAART in our metaanalysis of RCTs (ITT). However, the validity of this analysis is limited due to incomplete data and unclear or lacking protocol definitions of intensification. Therefore, we believe there is yet insufficient evidence and follow-up to regard this intensification strategy as safe. In the future, this evidence might be provided by Protease Inhibitor monotherapy Versus Ongoing Triple-therapy in the long-term management of HIV infection (PIVOT), a large ritonavir-boosted protease inhibitor-monotherapy trial with a planned follow-up of 5 years that studies this strategy and uses virologic failure with significant drug resistance limiting future treatment options as primary end point .
In the only RCT that studied ritonavir-boosted protease inhibitor monotherapy in ART-naive patients by Delfraissy et al. , LPV/r monotherapy was shown to be inferior to HAART. LPV/r monotherapy was also considerably less effective in the study by Cameron et al.  that included ART-naive patients but used LPV/r and CBV as induction before simplification to monotherapy. It was also less effective than HAART in the as-treated analysis, suggesting a real difference in suppressive potency. Comparing this difference in efficacy with the better results in the four RCTs with patients with a longer duration of viral suppression before monotherapy [20–24], we believe that 3 months of viral suppression may not be enough to safely simplify to protease inhibitor monotherapy as maintenance therapy. An explanation could be the recently reported nonlinear decline in plasma HIV-RNA below 50 copies/ml within 1 year after the initiation of suppressive LPV/r-based HAART with a half-life of 9–15 months similar to the half-life of latently infected CD4+ T cells .
Other reasons for the high failure rate in the study by Cameron et al.  can be the strict definition of failure (HIV-RNA > 50 copies/ml in two consecutive samples) (though a definition comparable with the other RCTs would have reduced the number of failures by only three) and the large number of patients discontinuing LPV/r and CBV induction therapy because of various reasons, such as, lost to follow-up, withdrawn consent, adverse events, and site closure. However, the proportion of patients discontinuing the control regimen EFV and CBV was even larger, which resulted in a substantially higher failure rate of EFV-based HAART than in other recent RCTs [37–39].
LPV/r is by far the most extensively studied protease inhibitor in single-agent HIV therapy trials and the only protease inhibitor studied in a controlled design. Investigators of LPV/r monotherapy studies explain their choice by referring to the potency of LPV/r-based HAART in ART-naive patients in trials with a very long follow-up (up to 7 years) and the complete lack of lopinavir resistance in these trials [40,41]. In a recent large trial comparing ritonavir-boosted fosamprenavir and LPV/r, virologic failure occurred in 24 of 444 patients on LPV/r, of which only two had one minor protease inhibitor-resistance mutation . Other arguments to use LPV/r monotherapy are the reported high genetic barrier to resistance of lopinavir, as at least four or five mutations in protease are needed for the virus to become resistant to LPV/r and its high inhibitory quotient (ratio of trough concentration and 50% inhibitory concentration to wild-type HIV) due to the ritonavir-boosted pharmacokinetic profile . Currently, the only other ritonavir-boosted protease inhibitor that has been studied as monotherapy more than once is ATV/r. Therefore, comparing efficacy of different protease inhibitors as single agents is not yet possible. New trials recruiting patients that study LPV/r, SQV/r, and ritonavir-boosted darunavir monotherapy may allow comparisons in the future [44–48].
We would like to point out two distinctive features of ritonavir-boosted protease inhibitor monotherapy. First, virologic failure occurred more often than in the HAART control group or, in case of uncontrolled trials, more often than can be expected from LPV/r-based HAART trials or clinical experience. Moreover, in 10 cases, this led to detectable protease inhibitor resistance. Interestingly, resistant viruses have rarely been reported in ART-naive patients on LPV/r-based HAART.
Second, in around 10% of patients, low HIV-RNA levels between 50 and 500 copies/ml can be measured, for example, in the OK04 study (see Fig. 4) . This low-level viremia neither meets the definition of a blip , nor does it meet the definition most investigators used for therapy failure. The clinical relevance of this phenomenon is not known, but recent reports indicate that protease inhibitor resistance can occur during low-level viremia under LPV/r monotherapy [31,50].
There are several possible explanations for increased virologic failure and low-level viremia in monotherapy. One explanation could be the lack of HIV suppression in particular cells or compartments such as cerebrospinal fluid (CSF) and semen. It is often hypothesized that multidrug resistance transporters like P-glycoprotein could promote insufficient protease inhibitor concentrations due to active efflux of protease inhibitors [19,51]. Interestingly, several monotherapy studies have measured HIV-RNA in compartments. Swindells et al.  could not detect HIV-RNA in seminal fluid of all eight tested patients on ATV/r monotherapy. In the study by Vernazza et al. , however, two out of 15 patients had detectable HIV-RNA in seminal fluid (2.23, 2.24 log10 copies/ml), and three out of 20 patients had detectable HIV-RNA in CSF (2.2, 2.9, 3.8 log10 copies/ml), despite viral suppression in plasma. Mean ratio of CSF/plasma ATV concentration was 0.9%. Protease sequence from two CSF samples was wild type and the third genotypic test failed. As two of the three patients with detectable HIV-RNA in CSF were switched back to HAART, it is unknown whether a raised HIV-RNA in CSF would eventually lead to or be the first sign of virologic failure or resistance or both. In the second LPV/r monotherapy study by Gathe et al., one out of 11 patients with CSF sampling at median week 38 had detectable HIV-RNA (251 and 747 copies/ml) without protease inhibitor mutations in CSF, despite a high LPV CSF concentration (45-fold above the IC50 of wild-type HIV-1) . Furthermore, all seven of the women in this study had undetectable HIV-RNA in a cervicovaginal lavage . In the RCT by Delfraissy et al., five out of five patients on LPV/r monotherapy and five out of five patients on LPV/r and CBV had undetectable HIV-RNA in semen despite undetectable LPV concentrations in these samples .
Another explanation could be an alternative pathway of protease inhibitor resistance facilitated by the absence of an NRTI-backbone. Recently, a new mutational pathway leading to protease inhibitor resistance via mutations at protease codons 76 and 46 was shown in some LPV/r monotherapy failing patients [31,50]. We do not know how often this or another novel pathway occurred in the reviewed studies, because generally only the protease mutations listed by the IAS-USA at that time are reported. Only in the most recent list of spring 2008 is L76V mentioned as a minor lopinavir mutation .
A third explanation could be that certain HIV subtypes with polymorphisms in protease are slightly less susceptible to protease inhibitors, which becomes observable in monotherapy. Information on prevalence of HIV subtypes is rarely reported. Interestingly, in the study by Delfraissy et al., the aforementioned protease mutation at codon 76 was seen only in HIV-1 subtype CRF02 .
Finally, nonadherence is frequently mentioned as an explanation by investigators. In some trials, virologic failure was indeed associated with self-reported nonadherence or low plasma drug concentrations as an indicator of nonadherence. But why would nonadherence to monotherapy lead to virologic failure more often than nonadherence to HAART? It is doubtful that nonadherence itself occurs more frequently in monotherapy than in HAART. Pulido et al.  postulate that because of the short terminal half-life of LPV/r, a missed dose in monotherapy easily leads to viral rebound, which is prevented in HAART by the long intracellular half-life of NRTIs. This hypothesis is plausible, though one would then expect NRTI resistance to occur more frequently in LPV/r-based HAART. On the contrary, the observation that LPV/r monotherapy failed in each of the three patients treated with LPV/r once per day supports this hypothesis .
In summary, in just a few years, experimental monotherapy with a ritonavir-boosted protease inhibitor has increased. Protease inhibitor monotherapy has several potential advantages such as less NRTI-associated mitochondrial toxicity such as lipoatrophy, more treatment options after therapy failure, fewer drug–drug interactions, fewer pills, and lower costs.
A recently published expert opinion on LPV/r monotherapy proposed research of its use as second-line treatment in resource-limited settings . An NNRTI-based regime is recommended first-line treatment in these settings, and, due to the impossibilities of virologic monitoring, therapy failure will be associated with extensive NNRTI and NRTI resistance. Second-line protease inhibitor-containing HAART would resemble protease inhibitor monotherapy in many cases. However, with its extensive resistance and unsuppressed HIV-RNA, this population is quite different from the study populations of the trials reviewed in our article. An RCT with this concept has recently started recruiting patients on LPV/r-based second-line treatment in Uganda and Zimbabwe .
With an overall risk of therapy failure of 33% LPV/r monotherapy against 23% on HAART, our metaanalysis has shown that LPV/r monotherapy is not equal to HAART, and, therefore, it cannot be considered an alternative to standard treatment. However, we found a comparable failure rate (23 against 18%) in patients with suppressed HIV-RNA for at least 6 months. Thus, a proportion of patients with a substantial period of viral suppression on HAART can successfully be treated with monotherapy for reasons such as NRTI/NNRTI side effects or NRTI/NNRTI resistance, comorbidity, costs, and potential lipoatrophy. This way, monotherapy can be considered as tailored treatment. Indeed, trials have started that study the effect of LPV/r monotherapy in HIV/HCV-coinfected patients [44–46]. Eventually, a broader use of simplification of HAART to protease inhibitor monotherapy in patients with suppressed HIV-RNA might be justified, once it has been proven that reintroduction of NRTIs in failing protease inhibitor monotherapy is safe and effective.
Part of these data was presented previously at the 2nd International Workshop on HIV Treatment, Pathogenesis and Prevention Research in Resource-Poor Settings in Dakar, Senegal, 20–23 May 2008; abstract 58.
W.F.W.B. contributed by search of the studies, review of the studies, statistical analysis, and preparation of the manuscript. M.A.v.A. contributed by review of the studies and supervision of manuscript preparation. M.N. contributed by revising the manuscript from a virologic perspective. S.A.D. contributed by overall research supervision and revising the manuscript from a clinical perspective. C.A.B.B. contributed by concept development and revising the manuscript from a virologic perspective.
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