A prospective study showed no relevance of the number of antiretrovirals used to preserve neurocognitive function in aviremic human immunodeficiency virus (HIV)–positive patients, with important implications concerning HIV-associated neurocognitive disorders and the use of nucleoside-sparing regimens.
Keywords: HIV-1, protease inhibitor monotherapy, neurocognitive evolution, lopinavir, darunavir
Abstract
Background. The evolution of neurocognitive performance in aviremic human immunodeficiency virus (HIV)–positive patients treated with <3 antiretrovirals is unknown.
Methods. We prospectively included aviremic (≥1 year) HIV-positive patients, without concomitant major neurocognitive confounders, currently receiving boosted lopinavir or darunavir as monotherapy (n = 67) or triple antiretroviral therapy (ART) (n = 67) for ≥1 year. We evaluated neurocognitive function (7 domains) at baseline and after 1 year. We performed analysis of covariance to evaluate if 1 additional year of exposure to monotherapy compared with triple ART had an effect on Global Deficit Score (GDS) changes after adjustment for potential confounders. We also compared the evolution of neurocognitive performance and impairment rates.
Results. Intention-to-treat analysis showed that monotherapy did not influence 1-year GDS change after adjustment for significant confounders (age, ethnicity, duration of therapy, hepatitis C virus status, and HOMA-IR index); the adjusted effect was −0.04 (95% confidence interval, −.14 to .05; P = .38). Neurocognitive stability was observed with monotherapy and triple therapy (GDS crude mean change, −0.09 [95% confidence interval, −.16 to −.01] vs −0.08 [−.14 to −.02]), after 1 year of follow-up, similar proportions of patients changed neurocognitive status from impaired to unimpaired (monotherapy, 4 of 18 [22.2%]; triple therapy, 4 of 19 [21.1%]; P = .91) and vice versa (monotherapy, 5 of 44 [10.2%] and triple therapy, 3 of 45 [6.3%]; P = .48). Similar results were observed in an on-treatment analysis and with use of clinical ratings instead of GDS changes.
Conclusions. The number of antiretrovirals included in the ART regimen does not seem to influence the evolution of neurocognitive function in HIV-infected patients with suppressed plasma viremia.
(See the Editorial Commentary by Letendre on pages 1635–7.)
Antiretroviral therapy (ART) is able to protect against severe cases of HIV-associated neurocognitive disorders (HAND)—such as HIV dementia [1]—but apparently cannot completely protect against the milder forms of HAND [2]. Indeed, a number of studies have demonstrated a high prevalence of milder forms of HAND in patients receiving effective ART [3, 4]. It is unknown why ART may be ineffective protection against mild forms of HAND. Several studies have found higher rates of HAND in patients treated with ART regimens characterized by poor central nervous system penetration effectiveness (CPE) ranks [5, 6]. Based on these findings, it has been postulated that patients receiving ART regimens with poor CPE might have a higher risk of HAND [7–9].
The lack of knowledge about the importance of low CPE ranks in patients receiving nucleoside-sparing regimens is worrisome because an increasing number of patients are being exposed to these ART combinations. Clinical trials are evaluating dual combinations of a boosted protease inhibitor and a second drug (an integrase inhibitor [10–12] or lamivudine [13]), monotherapy with a boosted protease inhibitor [14], or a dual combination of an integrase inhibitor and rilpivirine [15]. It is not known whether these unconventional ART regimens can provide enough protection against HAND.
Three published studies—2 cross-sectional observations and 1 small clinical trial—have compared the neurocognitive function of patients receiving monotherapy or triple therapy for maintenance of viral suppression [16–18]. The results of the 2 cross-sectional studies were inconclusive because of the limitations inherent to their design [16, 17]. The clinical trial had to be stopped prematurely owing to a high rate of virological failure in patients randomized to receive monotherapy [18]. For these reasons, the question about the importance of the number of antiretroviral drugs for the prevention of HAND remains unanswered.
To elucidate whether prolonged exposure to protease inhibitor monotherapy may increase the risk of HAND, we performed what is to our knowledge the first prospective cohort study to compare the neurocognitive evolution between aviremic HIV-infected patients treated with boosted protease inhibitor monotherapy and those receiving triple-drug ART.
PATIENTS AND METHODS
Study Design
We designed a 1-year longitudinal study to compare change in neurocognitive function of HIV-positive aviremic patients (HIV RNA, <50 copies/mL for ≥1 year) treated with darunavir-ritonavir or lopinavir-ritonavir as monotherapy or as triple therapy with tenofovir-emtricitabine or abacavir-lamivudine. We enrolled native Spanish-speaking patients from a parent cross-sectional study focused on the prevalence of neurocognitive impairment in patients receiving triple therapy or monotherapy. Details of this study have been published elsewhere [16]. We offered the longitudinal follow-up study to all the patients included in the cross-sectional study. Patients enrolled in the longitudinal study were managed according to routine clinical practice.
This longitudinal study included 1 visit after 1 year of follow-up. At the follow-up visit patients underwent a second comprehensive neurocognitive evaluation, performed by a psychologist blinded to the ART regimen and using the same methods as in the parent study [16]. Briefly, we followed the 2007 consensus established by the American Association of Neurology for the diagnosis of HAND (Supplementary Table 1) [19]. In the absence of normative standards specific for the HIV-infected population in Madrid or norms for change over time for Spanish populations, test results were assessed with the best normative standards available for the general Spanish population. Follow-up neurocognitive test results were not adjusted by the learning effect.
To estimate overall neurocognitive performance we used 2 methods that are highly concordant, the Global Deficit Score (GDS) [20] and clinical ratings (CRs) [21]. Although the GDS is more specific for detecting variations of neurocognitive performance in patients presenting neurocognitive deficits, CRs are more sensitive in detecting subtle variations in neurocognitive performance in patients with normal performance [21]. In the absence of standardized methods for a Spanish population, we defined neurocognitive decline as a GDS change (follow-up minus baseline result) of >0.5 and a CR change of >1 (to increase detection in patients with normal neurocognitive performance).
At the follow-up visit, we reevaluated adherence to treatment, use of illicit drugs, and presence of comorbid conditions. We also obtained a fasting blood plasma sample, which was processed using standard methods in the sites' certified clinical laboratories. Levels of glucose, insulin, and lipid fractions were measured to calculate the homeostasis model assessment of insulin resistance (HOMA-IR) (insulin [mU/mL] × glucose [mmol/L])/22.5) and the total cholesterol/high-density lipoprotein ratio. Current CD4 cell count and HIV-1 viral load were determined using flow cytometry and automatized RNA extraction with an AmpliPrep instrument (Roche Diagnostics), respectively, followed by quantification with the COBAS Amplicor Monitor HIV-1 test version. Viral load was categorized as not detected, <50 copies/mL, or >50 copies/mL.
All study procedures were conduced according to the principles expressed in the Declaration of Helsinki. The local ethics committees for clinical research and the institutional review board of each participant hospital approved the protocol and all the above-described procedures. All participants provided written informed consent before study inclusion.
Statistical Analysis
Our primary objective was to evaluate the effect of protease inhibitor monotherapy compared with triple therapy on the evolution of neurocognitive performance. Our secondary objectives were to compare patients receiving monotherapy or triple therapy with regard to neurocognitive performance, overall and by ability domains, neurocognitive decline, and the proportion who changed from neurocognitively impaired to unimpaired and vice versa. These objectives were primary analyzed using an “intention-to-treat” approach that included all patients. However, because ART switches were allowed during follow-up, we performed an “on-treatment” analysis, excluding ART switches and virological failures.
To evaluate our primary objective, we used 2 methods. First, we used analysis of covariance to estimate the effect—fitted by linear regression—of receiving monotherapy on GDS at follow-up, adjusted by baseline GDS, using the triple therapy group as reference. This result was then adjusted by the neurocognitive cofounders (Supplementary Table 2) that changed the relation between monotherapy and follow-up GDS by ≥15%. Second, as a sensitivity analysis, we fitted a linear regression directly over the values of GDS change (GDS at follow-up minus baseline GDS). The first method has the advantage of providing more accurate measurements, avoiding the bias known as regression to the mean. We also repeated all the analyses using CRs instead of GDSs, searching for a more subtle effect of monotherapy in the subgroup of patients with normal neurocognitive performance. All analyses were performed using Stata statistical package software (version 11.1; Stata Corp). All tests were 2 sided, and differences were considered significant at P < .05.
RESULTS
Baseline Characteristics
Of the 191 patients included in the parent cross-sectional study, 57 refused to participate in the prospective study because lack of interest or time. Therefore, we included 134 patients in this prospective study, half of them receiving monotherapy and the other half triple therapy. We compared the baseline characteristics of those patients who accepted to participate with those who declined to participate and found no statistically significant differences between groups (Supplementary Table 3).
After 1 year, there were no losses to follow-up, and 129 patients (96.3%) remained aviremic. During follow-up, 1 patient receiving triple therapy experienced transient loss of virological suppression, and another ended the study with a detectable viral load. None of them developed genotypic resistance mutations. Three patients receiving monotherapy lost HIV suppression without developing genotypic resistance mutations and were successfully reintensified with 2 nucleosides.
In 17 patients receiving triple therapy at baseline, a clinical decision was made to switch the ART regimen owing to adverse events associated with the current regimen; 9 patients were switched to a protease inhibitor plus lamivudine, 3 to darunavir-ritonavir monotherapy, 2 to atazanavir-ritonavir, 2 to nonnucleoside reverse-transcriptase inhibitors, and 1 to elvitegravir-cobicistat. No switches in ART regimen were due to neurocognitive impairment.
The 22 patients (16.4%) in whom the ART regimen was switched or who became viremic during follow-up were included in the intention-to-treat analyses and excluded from the on-treatment sensitivity analyses. Compared with the 112 patients included in the on-treatment analyses, patients who changed ART regimens or lost HIV suppression after baseline were more frequently receiving triple therapy (86.4% vs 42.9%; P < .01), had received ART for a longer time (mean, 12.4 ± 5.4 vs 9.3 ± 5.4 years; P = .01), and had a higher rate of neurological comorbid conditions (22.7% vs 8%; P = .04).
Table 1 shows baseline characteristics of the 134 patients included in the study divided by treatment groups. We found the following significant differences between groups: patients who received monotherapy were older, more frequently Spanish, had a longer exposure to ART and a longer time of HIV suppression and had a higher total cholesterol/high-density lipoprotein levels.
Table 1.
Baseline Characteristics by Treatment Group
| Characteristic | Triple Therapy (n = 67) | Monotherapy (n = 67) | P Value |
|---|---|---|---|
| Male sex, No. (%) | 47 (70.2) | 49 (73.1) | .70 |
| Age, mean (SD) | 44.6 (8.6) | 48.2 (8.4) | .02 |
| Geographic origin, No. (%) | |||
| Spain | 51 (76.1) | 64 (95.5) | <.01 |
| Other countries | 16 (23.9) | 3 (4.5) | |
| Means of HIV transmission, No. (%) | |||
| Sexual | 40 (59.7) | 41 (61.2) | .88 |
| Intravenous | 22 (32.8) | 21 (31.3) | |
| Other | 5 (7.5) | 5 (7.5) | |
| Educational level, mean (SD), y | 11.0 (4.1) | 10.5 (4.9) | .51 |
| AIDS diagnosis, No. (%) | 44 (65.7) | 43 (64.2) | .86 |
| Duration of HIV infection, mean (SD), y | 14.5 (6.9) | 16.8 (5.8) | .07 |
| Duration of virological suppression, mean (SD), y | 5.7 (3.7) | 7.6 (3.4) | <.01 |
| HIV RNA not detected, No. (%) | 48 (70.8) | 39 (56.2) | .09 |
| CD4 cell count, mean (SD), cells/mm3 | |||
| Nadir | 157.8 (115.2) | 191.2 (139.5) | .13 |
| Current | 619.2 (277.6) | 629.0 (254.5) | .84 |
| Duration of ART, mean (SD), y | |||
| Total | 10.6 (5.9) | 13.2 (4.8) | .01 |
| Triple therapy | 10.6 (5.9) | 10.1 (5.4) | .48 |
| Monotherapy | … (…) | 3.1 (2.0) | … |
| Adherence level <100%, No. (%) | 18 (28.1) | 15 (22.4) | .45 |
| Hepatitis C, No. (%) | |||
| Never | 34 (50.8) | 38 (56.7) | .35 |
| Cured | 14 (20.9) | 17 (25.4) | |
| Active | 19 (28.4) | 12 (17.9) | |
| Ever received interferon, No. (%) | 9 (13.4) | 16 (23.9) | .12 |
| Prior comorbid conditions, No. (%) | |||
| Neurological | 7 (10.5) | 7 (10.5) | >.99 |
| Psychiatric | 17 (25.4) | 18 (26.9) | .84 |
| Medical | 28 (41.8) | 38 (56.7) | .08 |
| Use of nonprescribed drugs ever, No. (%) | 33 (49.3) | 31 (46.3) | .73 |
| Framingham risk score >20%, No. (%) | 1 (1.5) | 3 (4.5) | .26 |
| HOMA-IR index, median (IQR) | 1.8 (1.0–3.1) | 2.1 (1.4–3.5) | .24 |
| Cholesterol (total/HDL ratio), median (IQR) | 3.9 (3.3–4.7) | 4.3 (3.6–5.6) | .03 |
Abbreviations: ART, antiretroviral therapy; HDL, high-density lipoprotein; HIV, human immunodeficiency virus; HOMA-IR, homeostasis model assessment of insulin resistance; IQR, interquartile range; SD, standard deviation.
Effect of Monotherapy on Neurocognitive Evolution
Table 2 shows the crude and adjusted effects of monotherapy on follow-up GDS (adjusted by baseline GDS) and on GDS change (sensitivity analysis). We found that exposure to 1 additional year of monotherapy did not have a significant effect on GDS at follow-up, adjusted by baseline GDS, nor on change in GDS. This lack of effect for monotherapy was also observed after adjustment for significant cofounders (age, total duration of ART, geographic origin, hepatitis C coinfection, and the HOMA index). Results were similar for intention-to-treat analysis (effect, −0.04; 95% confidence interval, −.14 to .05) and on-treatment analysis (0.02; −.12 to .09). Results were similar results when CRs were used instead of GDSs (Table 2).
Table 2.
Crude and Adjusted Effect of Monotherapy on 1-Year Neurocognitive Changes by Different Estimates
| Measure of Neurocognitive Change | Intention-to-Treat Analysis |
P Value | On-Treatment Analysis |
P Value | ||
|---|---|---|---|---|---|---|
| Triple Therapy (n = 67; 50.0%) | Monotherapy (n = 67; 50.0%) | Triple Therapy (n = 48; 42.8%) | Monotherapy (n = 64; 57.2%) | |||
| GDS | ||||||
| Baseline, mean (SD) | 0.44 (0.57) | 0.37 (0.39) | .38 | 0.51 (0.65) | 0.37 (0.39) | .16 |
| Follow-up mean (SD) | 0.37 (0.51) | 0.28 (0.45) | .31 | 0.40 (0.57) | 0.29 (0.46) | .25 |
| Crude change, mean (95% CI) | −0.08 (−.14 to −.02) | −0.09 (−.16 to −.01) | .82 | −0.11 (−.18 to −.03) | −0.08 (−.15 to −.01) | .61 |
| Effect of monotherapy on change, mean (95% CI) | ||||||
| Crude | 1 | −0.02 (−.11 to .07) | .60 | 1 | −0.01 (−.10 to .11) | .92 |
| Adjusted | 1 | −0.04 (−.14 to .05) | .38 | 1 | −0.02 (−.12 to .09) | .78 |
| CRs | ||||||
| Baseline, mean (SD) | 4.22 (1.92) | 3.76 (2.08) | .40 | 4.29 (2.05) | 3.86 (1.93) | .34 |
| Follow-up, mean (SD) | 3.88 (1.99) | 3.21 (1.99) | .12 | 3.85 (2.13) | 3.22 (2) | .11 |
| Crude change, mean (95% CI) | −0.46 (−.83 to −.1) | −0.7 (−1.13 to −.27) | .32 | −0.67 (−1.1 to −.24) | −0.44 (−.86 to −.01) | .31 |
| Effect of monotherapy on change, mean (95% CI) | ||||||
| Crude | 1 | −0.33 (−.85 to .19) | .22 | 1 | −0.35 (−.92 to .23) | .24 |
| Adjusted | 1 | −0.26 (−.84 to .31) | .36 | 1 | −0.25 (−.87 to .37) | .43 |
Abbreviations: CI, confidence interval; CRs, clinical ratings; GDS, Global Deficit Score; SD, standard deviation.
Change in Neurocognitive Performance
Estimates of global neurocognitive performance are provided in Table 2. We did not find differences in 1-year changes in GDS or CRs between monotherapy and triple therapy patient groups. Results were also similar for intention-to-treat and on-treatment analyses. Neurocognitive stability was observed for all levels of neurocognitive performance with both ART strategies (Figure 1). Neurocognitive performance by individual ability domains at baseline and at follow-up (Figure 2) showed similar results for monotherapy and triple therapy groups (all P > .05).
Figure 1.
Global neurocognitive performance according to treatment group, as measured by clinical ratings at baseline and at 1-year follow-up.
Figure 2.
Neurocognitive performance distributed by ability domains in patients receiving monotherapy or triple therapy, at baseline and at 1-year follow-up.
Neurocognitive Decline
Rates of neurocognitive decline were similar in monotherapy and triple therapy patient groups. Neurocognitive decline by GDS was observed in 1 patient (1.5%) receiving triple therapy and 2 (3%) receiving monotherapy (P = .56). Of these 3 patients with neurocognitive decline by GDS, none had switched ART regimens or lost virological suppression during follow-up.
With CRs used as the measure, 16 patients (23.9%) receiving triple therapy and 12 (18.18%) receiving monotherapy were classified as having neurocognitive decline (P = .42). Of these 28 patients, 7 had switched ART regimens or lost viral suppression during follow-up.
Neurocognitive Impairment Evolution
Table 3 shows the proportion of patients classified as neurocognitively impaired or unimpaired at baseline and at follow-up by therapy groups. After 1 year, 3 patients in the triple therapy and 5 in the monotherapy group had changed from unimpaired to impaired (P = .48). Four patients each in the triple therapy and monotherapy groups had changed from neurocognitively impaired to unimpaired (P = .91).
Table 3.
Prevalence of Neurocognitive Impairment by Treatment Group at Baseline and After 1 Year of Follow-upa
| Impairment Category | Patients, No. (%) |
|||
|---|---|---|---|---|
| Monotherapy (n = 67) |
Triple Therapy (n = 67) |
|||
| Baseline | Follow-up | Baseline | Follow- up | |
| Nonimpaired | 49 (73.1) | 48 (71.6) | 48 (71.6) | 49 (73.1) |
| Impaired | 18 (26.9) | 19 (28.4) | 19 (28.4) | 18 (26.9) |
| Change from impaired to unimpaired | … | 4 (22.2) | … | 4 (21.1) |
| Change from unimpaired to impaired | … | 5 (10.2) | … | 3 (6.3) |
a Neurocognitive impairment as defined by the American Association of Neurology in 2007 [19].
DISCUSSION
To our knowledge, this is the first prospective study to perform a detailed comparison of the neurocognitive evolution in HIV-positive patients treated with 1 or 3 antiretrovirals. In our cohort of aviremic patients with good immunological status, we found that protease inhibitor monotherapy did not have a negative effect on the evolution of neurocognitive performance after 1 year of follow-up.
In our multivariate analysis, the adjusted effect of monotherapy on 1-year change in GDS was very small and not significant in either the intention-to-treat or the on-treatment analysis. The results did not change when we performed the analysis using CRs instead of GDSs. We also found consistent results between therapy groups when we compared the proportions of patients who changed from neurocognitively impaired to unimpaired or vice versa. These events occurred with similar frequencies in patients receiving both types of ART. Finally, longitudinal changes in individual ability domain test scores were also similar in both groups.
Our results are supported by previous cross-sectional studies finding no difference in the prevalence of neurocognitive impairment between aviremic patients receiving monotherapy or triple therapy [16, 17]. Furthermore, 2 prospective studies have evaluated neurocognitive changes in patients receiving protease inhibitor monotherapy. In the setting of virological failure, the STAR clinical trial showed similar rates of neurocognitive impairment after 1 year of follow-up in Thai patients in whom nonnucleoside reverse-transcriptase inhibitor–based regimens failed, before and after switching to lopinavir-ritonavir monotherapy or lopinavir-ritonavir and tenofovir-lamivudine [22]. Recently, the PIVOT clinical trial has shown similar neurocognitive evolution in aviremic patients receiving monotherapy or triple therapy after a median of 44 months of follow-up [23]. In contrast with our comprehensive evaluation, neurocognitive function was evaluated with a more limited battery of neuropsychological tests in the STAR and PIVOT trials.
Few studies have longitudinally followed neurocognitive function in aviremic patients receiving triple ART, as we did. The RASTA clinical trial found cognitive stability, with improvement in some ability domains, after 48 weeks in aviremic patients switched from different ART regimens to raltegravir plus abacavir-lamivudine or tenofovir-emtricitabine [24]. In the ASSURE clinical trial, neurocognitive function measured by CogState remained stable in aviremic patients randomized to continue on tenofovir, emtricitabine, and atazanavir-ritonavir or switch to abacavir-lamivudine and unboosted atazanavir after 24 weeks of follow-up [25].
Antiretroviral therapy regimens with poor CPE ranks have been associated with cerebrospinal fluid viral escape [5, 6] and worse neurocognitive functioning [7–9]. These observations have been used to question the ability of protease inhibitor monotherapy to protect neurocognitive functioning. In our longitudinal study, the risk of neurocognitive decline was similarly low in both therapy groups. This finding strengthens previous cross-sectional observations of similar prevalences of HAND in patients receiving monotherapy or triple therapy [16, 17]. These data also suggest that CPE rank is not applicable to patients receiving monotherapy.
Vassallo and colleagues [26] have reported that lower CPE ranks predicted neurocognitive worsening in a prospective cohort of 96 HIV-infected patients followed up for up to 2 years [26]. In sharp contrast with our study, only 58% of the patients in their study were aviremic at baseline. We believe this is a critical distinction. Indeed, Letendre et al [6] have reported that plasma HIV RNA suppression is a more important predictor of cerebrospinal fluid HIV RNA suppression than CPE rank. We believe that the neuroprotective effect of maintaining plasma HIV suppression—a requirement to continue protease inhibitor monotherapy—prevails over the number of drugs needed to maintain plasma suppression.
Alternative hypotheses may explain the lack of a negative effect of monotherapy on cognitive evolution. A recent meta-analysis of 23 studies found that the beneficial effects of ART on neurocognition seem to result from the capacity of ART to recover immune function [27]. If this hypothesis is true, ART type might have little influence on cognition in our patients with good immunological status. Reduced neurotoxicity is another hypothesis that can explain the favorable neurocognitive profile of monotherapy. Protease inhibitors have reduced Microtubule-associated protein 2 (MAP-2) neurotoxicity [28], and use as monotherapy avoids the possible neurotoxic side effects associated with some nucleoside reverse-transcriptase inhibitors [29–32]. Finally, in the CHARTER cohort [4], neurocognitive decline was associated with ART failure, ART discontinuation, low current CD4 cell count, or presence of severe comorbid conditions. Patients in our study had high CD4 cell counts, seldom experienced virological failure, and did not have severe comorbid conditions. These factors might explain the low rate of neurocognitive events observed in our patients regardless of the number of antiretrovirals received.
Our study had a number of limitations. First, it was not randomized, and we therefore cannot rule out the possibility that a selection bias producing baseline differences between the monotherapy and triple therapy groups influenced our results. We tried to minimize this bias by selecting patients receiving triple therapy who were also potential candidates to receive monotherapy and by adjusting our analysis by known neurocognitive confounders. Second, sample sizes were relatively small, and type II error is a possibility. However, we believe that our results rule out a large difference in the risk of neurocognitive impairment between groups of therapy. Third, we assumed that the effect of monotherapy on neurocognitive performance was constant over time, when it is possible that the effect might be episodic.
Fourth, it is possible that longer follow-up is necessary to find differences in neurocognitive performance evolution. We consider this possibility unlikely, however, because other studies with similar follow-up have already found significant changes in neurocognitive functioning [8, 24, 33]. Furthermore, in our prior cross-sectional study, we did not find a higher prevalence of neurocognitive impairment in patients with prolonged exposure to monotherapy. On the contrary, rates of neurocognitive impairment seemed inversely associated with duration of monotherapy [16]. Fifth, results were not corrected by the learning effect, and the thresholds used to define neurocognitive decline in our study lack definitive validation. These factors might lead to an underestimation of the incidence of neurocognitive impairment or decline, but it is unlikely that they would affect the comparison of GDS change between therapy groups. Sixth, the triple therapy group had more foreigners, but all were native Spanish speakers, and we do not believe that this factor significantly influenced our results after adjustment. Finally, our results apply only to patients without major neurocognitive confounders who were adherent to therapy and good immunological status and a long history of plasma virological suppression.
Our results are important because they indicate that the risk of neurocognitive impairment in patients with prolonged viral suppression, treated with unconventional regimens, do not seem to be substantially increased. Although protease inhibitor monotherapy is not recommended in all guidelines, it is possible that other nuc-sparing combinations, such as a boosted protease inhibitor and lamivudine or raltegravir, will be more frequently used given their good results in antiretroviral-naive or antiretroviral-experienced patients [11–13].
In conclusion, protease inhibitor monotherapy for maintenance of plasma HIV suppression does not seem to be associated with worse neurocognitive evolution or a higher incidence of neurocognitive impairment than triple-drug ART therapy after 1 year of prospective follow-up. Our findings suggest that in patients with durable virological plasma suppression and good immunological status, the number of antiretrovirals included in the regimen does not influence the evolution of neurocognitive function.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online (http://cid.oxfordjournals.org). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.
Notes
Acknowledgments. We thank all the patients who volunteered to participate in the study and the study nurses Juan Miguel Castro, Mario Mayoral, Blanca Arribas, Raquel Martín Jara, and Marta Galvez.
Financial support. This work was supported by Fondo de Investigaciones Sanitarias, Insituto de Salud Carlos III (grant PI10/00483); grant from the Juan Rodes Program to I. P. V.; the Instituto de Investigación Hospital 12 de Octubre (i+12) (fellowship to M. L.); and Red de Investigación en SIDA (AIDS Research Network) (grant RD07/0006/2007 to the IdiPAZ AIDS and Infectious Diseases investigator group).
Potential conflicts of interest. I. P.-V. is a member of the Gilead Speaker Bureau and has received honoraria from Merck Sharp & Dohme (MSD), Gilead Sciences, Janssen-Cilag, ViiV Healthcare, and Bristol-Myers Squibb (BMS) for lectures. M. L. M.-R. has received consulting fees from Abbott Pharmaceuticals, Boehringer Ingelheim, Janssen-Cilag, Gilead Sciences, and ViiV Healthcare and payment for lectures from Abbott Pharmaceuticals, BMS, and Roche. F. P. has received consultancy and lecture fees from AbbVie, BMS, Janssen-Cilag, Gilead Sciences, MSD, and ViiV Healthcare. J. I. B. has received research funding, consultancy fees, or lecture sponsorships from Abbott Pharmaceuticals, Gilead Sciences, BMS, ViiV Healthcare, Janssen-Cilag, and Boehringer Ingelheim. J. J. G.-G. has received advisory and speaker fees from AbbVie, BMS, Gilead, Janssen-Cilag, MSD, Roche, and ViiV Healthcare. M. L. has received lecture sponsorships from AbbVie, BMS, and Janssen-Cilag. F. A. has received research funding from BMS and Sanofi-Aventis. J. R. A. has received advisory fees, speaker fees, and grant support from ViiV Healthcare, Tibotec, Janssen-Cilag, AbbVie, BMS, Gilead Sciences, MSD, and Tobira. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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