Combined antiretroviral therapy (cART) with triple drugs from two classes is associated with suppressed viral load and immunologic reconstitution. Simplified maintenance therapies are needed, as antiretroviral treatment will be prolonged long term. Results of the Strategies for Management of Antiretroviral Therapy trial with intermittent therapy were deceptive . One alternative option is to limit the number of classes and drugs for adherence facilitation, prevention of long-term toxicity and reduced costs. In virologically suppressed individuals, trials studied efficacy of boosted protease inhibitor monotherapy (BPIMT), usually compared with continuing triple cART. These strategies were evaluated for atazanavir (ATV) [2,3], lopinavir (LPV) [4–9], saquinavir (SQV)  and darunavir (DRV) [11–13]. Current guidelines diverged concerning BPIMT as a maintenance strategy [14,15]. We used the FHDH-ANRS CO4 cohort with prospective recording of clinical information on HIV-infected individuals followed in French hospitals to study the durability of BPIMT and identify predictive failure factor in clinical routine practice.
The FHDH-ANRS CO4 is an ongoing, prospective, observational, nationwide and hospital-based cohort. Among 49662 HIV-infected individuals followed up in the FHDH during the 2006–2010 period and treated by cART for at least 6 months, 585 individuals with plasma HIV RNA less than 50 copies/ml and not included in a randomized controlled trial were switched to BPIMT with either ATV, LPV or DRV boosted with ritonavir (RTV). Individuals were excluded if no viral load measurement was available while on BPIMT, leaving 529 individuals for the analysis of whom 75% were followed for at least 12 months, and 49% for at least 24 months
Sex and transmission group were combined in four categories (as shown in Table 1). Previous virological failure with protease inhibitor was defined as HIV RNA more than 500 copies/ml with protease inhibitor discontinuation. Virological failure was defined as the first of two consecutive HIV RNA more than 50 copies/ml or one HIV RNA more than 50 copies/ml followed by discontinuation of BPIMT; individuals fully suppressed when taken off BPIMT were censored at the time of switch. Treatment failure was defined as virological failure, reintroduction of other antiretroviral drugs or death. Switches to another BPIMT regimen were not considered as treatment failure.
Time to virological failure, or treatment failure, were analysed using Kaplan–Meier estimates. Predictors for failure were identified using a Cox proportional hazards model. Sociodemographic variables (i.e. age, sex and transmission group and migration from sub-Saharan Africa) and each variables associated with at least one type of failure (P < 0.10) in univariable analysis were included in multivariable models.
Table 1 presents the characteristics of individuals at baseline. Nadir of CD4 was 190 (Q5–Q95, 13–443), and 126 (24%) individuals had a past history of AIDS. Individuals have been treated with cART for a median of 84 months (Q5–Q95, 17–145) with a median of seven different antiretroviral drugs, and 61 (11%) were protease inhibitor naive. While receiving a previous protease inhibitor-containing regimen, 46 (9%) individuals had a history of virological failure. At BPIMT initiation, 413 (78%) individuals were treated with triple therapy, 58 (11%) with a combination of two protease inhibitors or one protease inhibitor and one nonnucleoside reverse transcriptase inhibitor and 58 (11%) with another strategy, mainly one nucleoside reverse transcriptase inhibitor (NRTI) and one protease inhibitor. The median duration of the previous regimen was 18 months (Q5–Q95, 2–75); the median duration with a controlled viral load since the last rebound was 38 months (Q5–Q95, 1–120).
Overall, the 12-month and 24-month probability of virological failure were 21% [95% confidence interval (CI), 17–25] and 31% (95% CI, 27–37), respectively. The 12-month and 24-month probability of treatment failure were 38% (95%CI, 34–43) and 52% (95%CI, 47–57), respectively. Both virological failure and treatment failure rates were increased among individuals with a previous history of AIDS, as well as among individuals who have had virological failure while treated with protease inhibitor, whereas the duration of viral suppression before BPIMT was protective. Lower CD4 cell count at baseline was associated with treatment failure. Individuals treated with either LPV–RTV or DRV–RTV showed the same maintenance of virological suppression, whereas those treated with ATV–RTV were more likely to fail. In multivariable analyses, all risk factors remained strongly associated with both virological failure and treatment failure, with the exception of baseline CD4 cell count (Fig. 1). After adjustment on sociodemographic factors, rates of virological failure were higher among individuals with a history of AIDS-defining events (hazard ratio, 1.5; 95% CI, 1.0–2.3) and individuals with previous virological failure while on a protease inhibitor-containing regimen (hazard ratio, 1.6; 95% CI, 0.9–2.9). Compared to individuals with less than 1 year of sustained virological suppression before the switch to BPIMT, those with longer duration were less likely to experience virological failure with hazard ratio of 0.7 (95% CI, 0.4–1.2) and 0.6 (95% CI, 0.4–0.9) for a duration of 12–23 months and 24 months or more, respectively. Rates of failure were similar for BPIMT with LPV–RTV or DRV–RTV, but BPIMT with ATV–RTV was associated with an increased risk of virological failure (hazard ratio, 1.9; 95% CI, 1.1–3.3).
Median CD4 cell counts increased from 541 (Q5–Q95, 210–1116) at baseline to 595 (240–1105) at the last follow-up on BPIMT. Two-thirds of the individuals had always HIV RNA less than 50 copies/ml on BPMIT, 42 (8%) had transient viremia above 50 copies/ml, 51 (10%) had their last viral load on BPIMT above 50 copies/ml, with 37 being immediately switched to another treatment strategy with addition of NRTIs and/or raltegravir to protease inhibitor (n = 29), or a switch towards a regimen of NRTIs only (n = 3) or NRTIs and raltegravir (n = 4), and 73 (14%) presented confirmed virological failure with a median viral load of 188 copies/ml (Q5–Q95, 61–77199). Among these 73 individuals, 35 (48%) had an HIV-1 drug-resistance sequencing of whom 21, 11 and 3 failing BPIMT with LPV–RTV, DRV–RTV and ATV–RTV, respectively. Four individuals treated with LPV–RTV harboured virus with mutations conferring resistance to LPV according to the HIV-1 genotypic drug resistance interpretation's algorithms , of whom one harboured virus with mutations conferring resistance to both LPV and ATV. While treated with BPIMT, five individuals presented a first AIDS-defining clinical event and 52 individuals presented a new clinical event. In addition, eight individuals died, only one died after virological failure.
Overall, 206 (39%) individuals stopped BPIMT; 132 (64%) for triple therapy, 39 (19%) for an association of one protease inhibitor and one antiretroviral drug from another class – mainly NRTI or raltegravir – 18 (9%) for another combination regimen and 17 (8%) interrupted their antiretroviral therapy. Of 521 living individuals at last follow-up, and whatever their current antiretroviral regimen, 465 (89%) individuals had a controlled viral load (HIV RNA < 50 copies/ml), 35 (7%) had an incomplete viral suppression (HIV-RNA 51–500 copies/ml) and 21 (4%) presented a viral load above 500 copies/ml.
In this observational cohort of 529 virologically suppressed HIV-infected individuals switched to BPIMT, both virological and treatment failure rates increased among individuals with a previous history of AIDS and a previous virological failure while treated with protease inhibitor; on the contrary, the duration of viral suppression before BPIMT was protective. Rates of failure were similar for BPIMT with LPV–RTV or DRV–RTV, but BPIMT with ATV–RTV was associated with an increased risk of virological failure. Whatever their current antiretroviral regimen, nearly all individuals presented viral suppression at last follow-up. Failing on BPIMT did not seem to jeopardize future antiretroviral options, even within the protease inhibitor class. Indeed, four patients who failed on LPV–RTV BPIMT harboured viruses that were resistant to LPV, but DRV retained full antiretroviral activity against these viruses.
The strength of the present study is its large-scale size. After BPIMT initiation, the median duration of follow-up was 2 years; 75% were followed for at least 1 year, similar to the duration of controlled trials. Although the only criteria used for selection in this study was to have been treated by cART for at least 6 months with viral suppression at BPIMT initiation, individuals who experimented this strategy were in fact those with long antiretroviral therapy duration (median 7 years) and best immunological reconstitution (median baseline CD4 541 cells/μl). These baseline characteristics were comparable to individuals included in controlled trials [5–9,12,13]. However, 9% of our individuals had prior virological failure to previous protease inhibitor-containing regimens in contrast to the criteria of ‘no failure’ required in clinical trials. An increased risk of both virological failure and treatment failure was observed among these individuals who confirmed the usefulness of this selection criteria. Individuals enrolled in this study had to be fully suppressed (HIV RNA < 50 copies/ml) at baseline without any duration criteria. In fact, the median duration of continuous virological control was 3 years, but 17% had less than 1 year. Our results indicated that the longer the duration since the last rebound, the lower the risk of subsequent failure. The history of viral suppression was previously described as a major risk factor of viral failure after a treatment change for any reason, except for virological failure . The main limitation of our study is related to external validity. Clinicians could have selected individuals with high level of adherence for initiating BPIMT, or the switch for simplification could have been offered to individuals for adherence facilitation; these two opposite motives are not mutually exclusive. Overall, 206 (39%) individuals were switched to a new regimen, 59% of them without virological failure having occurred and 18% after a single viral load above 50 copies/ml. However, the same risk factors were identified in the two analyses of virological and treatment failures. Subjective elements that could have precluded drug switching are more important in observational database studies than in clinical trials with written guidance criteria.
Ability of BPIMT to control viral replication in the central nervous system and preserve cognitive functioning has been discussed [18–20]. Two individuals without virological failure on BPIMT presented a diagnosis of HIV-related encephalopathy: one after 3 years of treatment with LPV–RTV, the other 7 months after taking off BPIMT with DRV–RTV. Eight individuals died during treatment with BPIMT; two with a non-AIDS-defining cancer, two with an opportunistic infection (one pulmonary infection with mycobacterium, one bacterial pneumopathy), no details were available concerning the four other individuals.
In this observational study, some individuals initiated a simplified maintenance monotherapy with ATV–RTV. A few pilot studies have used this regimen with contradictory results. One pilot study was prematurely stopped before complete recruitment because of excessive virological failures , whereas another suggested that viral suppression can be maintained on BPIMT with ATV . Our results indicated that BPIMT with ATV–RTV is associated with a higher risk of both virological and treatment failure than BPIMT with either LPV–RTV or DRV–RTV. No information on dosage, or dosage monitoring, was collected in the database. Difference of concentration is a possible explanation for the different results achieved by the three protease inhibitors.
A systematic review was performed in 2009 , and a meta-analysis recently published . Both reviews concluded that maintenance monotherapy with boosted protease inhibitor seemed less likely to fully maintain suppression of HIV replication than more traditional cART regimens. Our study confirmed these results. Among individuals with no history of virological failure while treated with protease inhibitor and whose viral load was undetectable for more than 24 months when switched to BPIMT with LPV–RTV, or DRV–RTV, the 12-month probability of virological failure was 14%. This high risk of plasma viremia rebound after simplification with one single very potent drug could be explained by the persistance of HIV reservoir [23,24]. In the MONOI-ANRS-136 trial, baseline ultrasensitive HIV-RNA less than 1 copy/ml has been associated with a decreased risk of virological rebound among patients in the DRV–RTV monotherapy arm . Beyond economic considerations, BPIMT was proposed as an option to prevent long-term toxicity related to the use of nucleosides, whereas maintaining viral suppression and measurement of the size of HIV reservoirs could bring new insights to identify individuals who could benefit from this tailored treatment.
F.R. proposed the study; M.G., J.G., C.D., J.L.M., G.G., M.L.P. and O.L. designed the study; M.G. and D.C. analysed and interpreted the data; M.G. wrote the manuscript. All authors revised the manuscript critically. All authors have read and approved the text as submitted.
Members of FHDH-ANRS CO4 are listed at http://www.ccde.fr/main.php?main_file=fl-1171464013-677.html.
FHDH is supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche sur le SIDA (ANRS) and the French Ministry of Health.
English review by Denise Palczewski.
Conflicts of interest
There are no conflicts of interest.
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