Risk of diabetes in HIV-infected patients is associated with cirrhosis but not with chronic HCV coinfection in a French nationwide HIV cohort.

BACKGROUND: Both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections have been reportedly associated with a higher risk of diabetes mellitus (DM) but results are conflicting. AIMS: To determine whether there is an association between chronic HCV and the incidence of DM, and to study the role of factors such as cirrhosis, IFN-based HCV therapy, sustained virologic response (SVR) and chronic HBV infection among patients living with HIV (PLHIV) followed in a large French multicentre cohort in the combination antiretroviral therapy (cART) era. METHODS: All PLHIV followed up in the Dat'AIDS cohort were eligible. Cox models for survival analysis were used to study the time to occurrence of DM. RESULTS: Among 28 699 PLHIV, 4004 patients had chronic HCV infection. The mean duration of HCV follow-up was 12.5 ± 8.1 years. The rate ratio of DM was 2.74 per 1000 person-years. By multivariate analysis, increasing age, body mass index>25, AIDS status, nadir CD4 cell count ≤200/mm3 , detectable HIV viral load and cirrhosis (HR 2.26 95% CI 1.14-1.18; P < 0.0001) were predictors of DM, whereas longer cART duration was associated with a lower risk of DM. Chronic HCV and HBV infection and IFN-based HCV therapy were not associated with DM. In a subanalysis among HCV-infected patients, SVR was not related to DM. CONCLUSIONS: Our study shows that in the HIV population, cirrhosis is associated with an increased occurrence of DM, but not chronic HCV infection or duration of HCV infection.

Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study).

OBJECTIVES: Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis. METHODS: We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes. RESULTS: Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified. CONCLUSIONS: LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.

From antiretroviral originator to generic drugs: bioequivalence and pharmacovigilance.

UNLABELLED: Antiretroviral drugs have been available in generic form in developing countries, which has expanded access to treatment; they have also become available in developed countries more recently. OBJECTIVES: The validation of generic drugs (GD) compared to originator drugs (OD) is mandatory to ensure that using generics will lead to a decreased cost of treatment. RESULTS: The results were obtained by analyzing published data as well as European Medicines Agency recommendations. METHOD: The GD should have the same qualitative and quantitative active principle formula, the same pharmaceutical forms, and the same criteria in terms of quality, effectiveness, and safety. This equivalence is based on bioequivalence rules: comparison of the concentration/time curves (AUC); Cmax and Tmax (90%), for which the confidence intervals in the range of 80-125% should be included. Naturally, that does not mean that the concentrations can vary from 80 to 125%: this would indicate unacceptable deviations. Conforming to these criteria allows substituting an OD by a GD. Adverse effects should not be different from those observed for the OD. Adverse effects observed when the GD is used must be notified, as is the case for the OD. Accountability is established according to 4 essential pieces of information: a prescriber, a patient, a drug, and an adverse effect. It is sometimes difficult to identify the provider of the GD that has been delivered. CONCLUSION: The level of safety concerning effectiveness and tolerance required is identical for OD and GD, in Europe. Analyzing confirmed adverse effects and therapeutic failures is the only way to identify differences that could question a GD's effectiveness.

Pharmacokinetic and dynamic study of levofloxacin and rifampicin in bone and joint infections.

OBJECTIVE: We studied the pharmacokinetic and pharmacodynamic parameters of levofloxacin and rifampicin in bone and joint infections. The optimal dose regimen of these two antibiotics has not been documented yet. PATIENTS AND METHOD: We performed plasma dosage for each antibiotic in patients with a bone and joint infection requiring treatment with a levofloxacin and rifampicin combination. We then computed the 6 hours post dose area under the concentration-time curve (AUC(0-6h)), the peak plasma concentration (Cmax), the area under the inhibitory concentration curve (AUIC), and the peak-to-minimum-inhibitory-concentration ratio (Cmax/MIC). The pharmacodynamic results were then compared to the published thresholds of effectiveness. The doses used were levofloxacin 500 mg bid and rifampicin 20mg/kg per day. RESULTS: The plasma of 17 patients was dosed. The average AUC(0-6h) for levofloxacin was 46.59 mg.h/l, the average Cmax 10.7 mg/l, the average AUIC 932, and the average Cmax/MIC 107.5. The averages for rifampicin were 42.2mg.h/l, 11.8 mg/l, 11,125 and 1514. Given that bone concentration of levofloxacin is 30% that of the plasma concentration, that concentration was divided by three to estimate bone concentration. CONCLUSION: The optimal thresholds of pharmacodynamic effectiveness were obtained for most patients with levofloxacin at 500 mg bid. Additional studies are still required to determine the optimal rifampicin dose.

NNRTIs: pharmacological data.

One of the choice criteria for antiretroviral therapy, once the viral load is controlled, is long-term treatment safety. Safety, despite similarities in each therapeutic class, can differ significantly from one agent to another, according to their respective pharmacokinetic and pharmacodynamic properties. We reviewed data on two very well-known NNRTIs, efavirenz and nevirapine, in this context. The pharmacokinetic properties of both agents are presented along with their impact on residual viremia and viral reservoirs, as well as their clinical consequences. The implications for the penetration of these antiretroviral drugs in the CNS and in female and male genital tracts are also discussed. Pharmacogenetics could become an interesting tool. Finally, the availability of new NNRTIs has recently boosted this therapeutic class, even if their long-term properties remain to be assessed. The consideration of all this data stresses the importance of communication among clinicians, virologists, and pharmacologists before choosing a treatment.

NNRTIs: future prospects.

The contribution of efavirenz and nevirapine remains clinically relevant and is the reason for the frequent prescription of these two agents. Recent clinical data on efavirenz and nevirapine in naive patients confirms their effectiveness compared to protease inhibitors such as lopinavir/r (ACTG 5142) or atazanavir/r (ACTG 5202) for efavirenz, or such as atazanavir/r (ARTEN trial) for nevirapine. Their easy use is another advantage; efavirenz is part of the first triple therapy as a single tablet given once a day, and nevirapine, with its new extended-release formulation, was designed for a single daily intake. However, the two agents exhibit different safety profiles and pharmacological properties. Their penetration rates in the genital tracts are different (70 to 80% for nevirapine versus 0 to 3% for efavirenz in men and 13-80% for nevirapine versus 0 to 4% for efavirenz in women). Finally, the authors of two recent studies reported the differences in the residual VL measured by ultrasensitive assays in successfully treated patients. The VL of patients treated with nevirapine was significantly more frequently below the detection limit of 1 or 2.5 RNA copies/mL than patients treated with efavirenz.

Role of intravenous cloxacillin for inpatient infections.

One of the issues of antibiotic treatment is to warrant its optimal effectiveness while minimizing the risk for emergence of resistance. The time above minimal inhibiting concentration (MIC) (T>MIC) is the best predictive pharmacological parameter of effectiveness for antibiotics with time-dependent activity, such as cloxacillin. Cloxacillin is the first line antibiotic in a great number of clinical situations generated by methicillin sensitive staphylococci, because of its intrinsic properties: bactericidal effect, tissue distribution and safety. The most recent anti-staphylococcal agents do not improve treatment of MSSA infections compared to penicillin M and especially cloxacillin. Cloxacillin has a narrow microbiological spectrum. This ecological feature is in line with the recommendation to use antibiotics with the narrowest spectrum to reduce the pressure of selection. The consensus is to have T>MIC for at least 40% of the dosing interval and is achieved by infusing 2g of cloxacillin per day (T>MIC=50%) or four infusions of 3g per day (T>MIC=42%) in adults.

Effect of tipranavir/ritonavir combination on the pharmacokinetics of tadalafil in healthy volunteers.

This study evaluated the effects of single-dose administration and steady-state concentrations of tipranavir 500 mg and ritonavir 200 mg (TPV/r) combination on the pharmacokinetics of tadalafil 10 mg (TAD) in an open-label study. Seventeen healthy male volunteers received sequential dosing of the studied product: TAD (day 1) alone in a single dose for 7 days followed by TAD (day 8) in a single dose with TPV/r (500/200 mg twice daily, days 8-18). Pharmacokinetic parameters were determined in a noncompartmental analysis. The geometric mean ratio and 90% confidence interval were used to evaluate drug interactions. The effect of a single dose of TAD on the pharmacokinetics of TPV/r resulted in a small decrease in exposure after either first-dose or steady-state TPV/r (geometric mean ratios [90% confidence interval]: area under the concentration-time curve, 0.85 [0.74-0.97]). In contrast, coadministration of TAD exposure was increased significantly (2.33 [2.02-2.69]) when administered with the first dose of TPV/r but not when TPV/r steady state was reached (1.01 [0.83-1.21]). Antiretroviral activity may not be reduced, but the dose of TAD should be reduced at the start of TPV/r therapy and then a full dose can be resumed after steady state is reached.

The suppression of immune activation during enfuvirtide-based salvage therapy is associated with reduced CCR5 expression and decreased concentrations of circulating interleukin-12 and IP-10 during 48 weeks of longitudinal follow-up.

BACKGROUND: It has been suggested that patients who initiate highly active antiretroviral therapy (HAART) late in their course of infection may have suboptimal CD4 T-cell gains, persistent alterations in T-cell subsets and residual inflammation. To address this issue, we carried out a comprehensive 48-week immunological study in HIV-infected patients who had experienced failures of prior therapies, had low CD4 cell counts, and were receiving enfuvirtide-based salvage therapy. METHODS: Immunological monitoring of peripheral lymphocytes from enfuvirtide-responder patients was performed over a 48-week period. A detailed assessment of immune cell subsets, their activation state [CD38 and human leucocyte antigen (HLA)-DR expression] and homeostasis [activation-induced cell death (AICD) and Ki67 expression], and the expression of co-receptors was performed by flow cytometry. Cytokine and chemokine signatures were assessed using multianalyte profiling technology. RESULTS: Enfuvirtide-based salvage therapy induced a progressive restoration of naïve and central memory CD4 T cells, associated with a decrease in their activation state, suppression of premature priming for AICD and increased expression of Ki67. In addition, a significant decrease in C-C chemokine receptor 5 (CCR5) expression was detected on CD4 T cells, which was strongly correlated with the suppression of immune activation. Changes in circulating proinflammatory molecules occurred; i.e. there were decreases in the concentrations of interleukin (IL)-12, macrophage inflammatory protein MIP-1α, MIP-1ß, monokine induced by IFNγ (MIG) and interferon-γ-inducible protein-10 (IP-10). The decline in circulating IL-12 and IP-10 was correlated with both the reduction in the viral load and CD4 T-cell restoration. CONCLUSIONS: This study shows that suppression of HIV-1 replication with enfuvirtide-based salvage therapy in patients with low CD4 cell counts may result in an immunological benefit, characterized by the restoration of CD4 T-cell subsets associated with decreased immune activation and suppression of inflammation.

Tear concentrations of azithromycin following topical administration of a single dose of azithromycin 0.5%, 1.0%, and 1.5% eyedrops (T1225) in healthy volunteers.

PURPOSE: To evaluate azithromycin tear concentrations after one drop of T1225 0.5%, 1.0%, and 1.5% eyedrops. METHODS: In this randomized, double-masked study, 91 healthy volunteers received one drop into each eye of T1225 0.5% (n=23), T1225 1.0% (n=38), or T1225 1.5% (n=38). Azithromycin tear concentrations were measured by HPLC-MS at seven time points for 24 hours. Tolerability was evaluated. RESULTS: T1225 1.0% and 1.5% had similar pharmacokinetic profiles. After a post-instillation peak (167 to 178 mg/L after 10 minutes), mean concentrations remained above 7 mg/L for 24 hours (except for T1225 1% at H24). A delayed increase of the azithromycin mean tear concentration might be explained by the known late azithromycin release from tissues after storage in cells. Areas under inhibitory curve (AUICs) of T1225 1.0% and 1.5% were higher than AUICs of T1225 0.5% and ranged between 47 and 90. The three T1225 concentrations were safe for the ocular surface. CONCLUSIONS: Once daily instillation of T1225 1.0% and 1.5% was shown to reach an AUIC markedly above the required threshold for an antibacterial activity against Gram-positive bacteria (25-35). These results suggest that a BID instillation is more likely to ensure antimicrobial activity against Gram-negative bacteria (threshold >100).

Nécessité d'approches alternatives dans les stratégies d'évaluation des nouveaux antibiotiques antibactériens.

The golden age of antibacterial antibiotics extend from year 1941 to the 1990s decade. At that time, something like an earth quake occurred: from the thirty molecules or so whose development was being achieved or was already marketed, only three were put on the French market, and faced the greatest difficulties to be prescribed by practicians, because: However, while the debate is raging, many of us think "yes we do", as it is a duty to anticipate today the consequences of tomorrow's bacterial resistances. This paper presents three types of propositions to optimise the development of future molecules: The development of new concepts to develop new drugs which would be active against tomorrow's bacteria compels us to manage in a new fashion today's systems, which have reached their own limits.

[Need for alternative approaches in the evaluation of new antibacterial antibiotics]. / Nécessité d'approches alternatives dans les stratégies d'evaluation des nouveaux antibiotiques antibactériens.

The golden age of antibacterial antibiotics extend from year 1941 to the 1990s decade. At that time, something like an earth quake occurred: from the thirty molecules or so whose development was being achieved or was already marketed, only three were put on the French market, and faced the greatest difficulties to be prescribed by practicians, because: the knights of good practice want a strict limitation of their use to precise indications; the pharmaceutical companies find that the return on investment is almost impossible; the prescribers are stunned by the inconsistency between the MAs, the advances in science and the health economic authorities advices which claim that these products are not very interesting; the research for new antibiotics is stalling; thus, for the first time in 60 years, an iconoclastic question arises: do we need new antibiotics? However, while the debate is raging, many of us think "yes we do", as it is a duty to anticipate today the consequences of tomorrow's bacterial resistances. This paper presents three types of propositions to optimise the development of future molecules: sharpening of the data concerning preclinical security for a better predicting of both the activity and the toxicity; improvement in performances and organization of clinical trials, which implicates to reconsider some of the present methodological rules; inclusion in the evaluation data of some relevant and new features measuring the anti-bacterial activity while taking into account the present and future bacterial resistances. The development of new concepts to develop new drugs which would be active against tomorrow's bacteria compels us to manage in a new fashion today's systems, which have reached their own limits.

Intermittent viremia during first-line, protease inhibitors-containing therapy: significance and relationship with drug resistance.

BACKGROUND: In HIV-infected patients on first-line antiretroviral therapy, the significance of intermittent viremia and their relationship with drug resistance remain unclear. OBJECTIVE: To study the virological characteristics of intermittent viremia (IV) and the association between IV and later virological failure (VF) in patients on a first-line, PI-containing therapy. STUDY DESIGN: Antiretroviral-naive patients were enrolled in the APROVIR substudy of the prospective, multicenter APROCO cohort at the time they initiated a PI-containing therapy and were followed-up at month 1 and every 2 months. IV was defined as plasma HIV-1 RNA > 500 copies/ml on a single specimen. VF were defined as: (1) viral rebound on two consecutive plasma specimens with HIV-1 RNA > 500 copies/ml after an initial response below 500 copies/ml, or (2) persistence of plasma HIV-1 RNA> or =500 copies/ml during the first year of follow-up. Genotypic resistance analysis was performed at baseline and at the time of IV. PI plasma concentrations were determined at the time of IV. RESULTS: IV was found in 20/219 patients in a 2 years follow-up. The occurrence of IV in the first year of therapy was associated with a higher risk of virological failure during the second year (p = 0.03). Genotypic resistance at the time of IV was found in only 4/16 patients and was not predictive of a subsequent virological failure. PI plasma levels suggested lack of adherence in 50% of patients with IV. CONCLUSION: The occurrence of IV > 500 copies/ml among patients on first-line, PI-containing ART is suggestive of a lack of adherence rather than the selection of resistant variants and should lead to an intensification of adherence monitoring in order to reduce the risk of subsequent VF.

[The use of fluoroquinolone plasma levels by physicians]. / Utilisation des dosages plasmatiques des fluoroquinolones par les cliniciens.

OBJECTIVE: To assess how physicians use the results of fluoroquinolone plasma concentrations. METHODS: A retrospective study was carried out on all the patients of the Infectiology department of the University Hospital in Nice who had undergone measurement of ofloxacin, ciprofloxacin or pefloxacin plasma levels between the 1st of January 2001 and the 31st of May 2002. RESULTS: Seventy eight patients were included. Median duration of treatment was 90 days. In 43% of cases, the patients had also received an enzyme inducer (rifampin in 90% cases). The minimum inhibitory concentration was requested 12 times. In 26% of cases, a first inadequate concentration was not followed by a second control analysis. We noted that at the start of treatment, 56% of patients exhibited inadequate levels, and the dose of fluoroquinolone was hence increased by the physician in 40% of cases. We noted 4 bacteriological relapses, all within a context of insufficient dose, with selection of a resistant mutant three times. DISCUSSION: Physicians do not appear to use the fluoroquinolone plasma levels to their best advantage.

Impact of various antiretroviral drugs and their plasma concentrations on plasma lipids in heavily pretreated HIV-infected patients.

OBJECTIVE: To evaluate the frequency and the magnitude of lipid abnormalities (LA) in respect to the nature of the antiretroviral drug and its plasma concentrations. PATIENTS/METHOD: Trough concentrations (C(trough)) of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) were assessed at Weeks 4, 8, 24, 28, and 32. Fasting triglycerides (TG) and total cholesterol (CH) were sampled at Weeks 0, 12, 20, and 32. We analyzed the probability of occurrence of grade 3-4 CH (> 7.8 mmol/L) and TG (> 8.4 mmol/L) during a 24-week period according to the drug taken using a Kaplan-Meier analysis and log rank test. Relation between Week 8 PI or NNRTI C(trough) and Week 12 lipid levels was assessed using the Kendall correlation measure. RESULTS: The PharmAdapt study included 252 patients (mean age 41 years, 83% males); the patients received a PI (73%), an NNRTI (50%), and/or a ritonavir (RTV) booster-containing (46%) regimen. Compared to any other regimen, use of lopinavir (LPV)/RTV or efavirenz (EFV) was associated with a higher risk of grade 3-4 CH. Use of LPV/RTV and RTV booster was associated with a higher risk of grade 3-4 TG. Use of any PI-containing regimen was associated with a higher risk for grade 3-4 CH and TG compared to non PI-based regimens. Kendall correlation coefficients for PI or NNRTI C(trough) and blood lipid levels were close to zero for all drugs and CH or TG, showing the absence of relation between drug concentrations and lipid levels. CONCLUSION: Severity of lipid abnormalities is related to the nature of the antiretroviral drug. There is no short-term relation between PI or NNRTI trough concentrations and blood lipid levels in heavily pretreated patients.

Is there a rationale for the continuous infusion of cefepime? A multidisciplinary approach.

This review is the fruit of multidisciplinary discussions concerning the continuous administration of beta-lactams, with a special focus on cefepime. Pooling of the analyses and viewpoints of all members of the group, based on a review of the literature on this subject, has made it possible to test the hypothesis concerning the applicability of this method of administering cefepime. Cefepime is a cephalosporin for injection which exhibits a broader spectrum of activity than that of older, third-generation cephalosporins for injection (cefotaxime, ceftriaxone, ceftazidime). The specific activity of cefepime is based on its more rapid penetration (probably due to its zwitterionic structure, this molecule being both positively and negatively charged) through the outer membrane of Gram-negative bacteria, its greater affinity for penicillin-binding proteins, its weak affinity for beta-lactamases, and its stability versus certain beta-lactamases, particularly derepressed cephalosporinases. The stability of cefepime in various solutions intended for parenteral administration has been studied, and the results obtained demonstrated the good compatibility of cefepime with these different solutions. These results thus permit the administration of cefepime in a continuous infusion over a 24-h period, using two consecutive syringes.

Valaciclovir as a single dose during prodrome of herpes facialis: a pilot randomized double-blind clinical trial.

BACKGROUND: Randomized clinical trials of valaciclovir in recurrent herpes labialis are lacking. OBJECTIVES: To determine whether a single course of valaciclovir, i.e. 500, 1000 or 2000 mg, administered during the prodrome of herpes facialis, could be beneficial. METHODS: Three hundred and forty-five out-patients with herpes labialis were screened and randomized for a multicentre, double-blind clinical trial. Ninety-six patients had no recurrence after 6 months of follow-up; 249 patients were finally included in the intent-to-treat (ITT) population. The main outcome measure was the rate of aborted episodes at day 3. The three treatment groups were similar at baseline. RESULTS: There was no statistically significant difference between the groups in rates of aborted lesions at day 3 in the ITT population, in particular between the 500 mg and 2000 mg treatment groups. CONCLUSIONS: Although a placebo group was not included in this pilot study, a single dose of valaciclovir was not considered beneficial in patients with recurrent herpes facialis.

Intracellular concentration of protease inhibitors in HIV-1-infected patients: correlation with MDR-1 gene expression and low dose of ritonavir.

BACKGROUND: Protease inhibitors (PIs) are substrates for the P-glycoprotein (P-gp/170) encoded by the multi-drug resistance gene (MDR-1). HIV infection is associated with increased expression of P-gp. The role of MDR gene overexpression in clinical pharmacokinetics is not known. METHOD: We determined by HPLC, at trough and peak levels, the current PI concentrations in plasma (P) and in peripheral blood mononuclear cells (PBMCs) (intracellular concentration [IC]) from 49 HIV-infected patients receiving different treatment combinations: nelfinavir ([NFV] n = 12); indinavir ([IDV] n = 10); amprenavir ([APV] n = 5); ritonavir (RTV) 100 bid/IDV 800 mg bid (n = 6); RTV 400 bid/IDV 400 mg bid (n = 3); RTV 100 bid/saquinavir (SQV) 600 mg tid (n = 9); APV 600 bid/RTV 100 mg bid (n = 4). We determined the mean ratio of intracellular/plasma PI concentration for each treatment group. The MDR-1 gene expression was determined by a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). HIV viral load was simultaneously measured. RESULTS: 49 patients (mean age 41 +/- 8.7 years; mean CD4 cell count 418 [57-972]; mean HIV RNA 2.1 +/- 0.8 log(10)) were included in the study. Patients who overexpressed the MDR-1 gene had significantly lower trough intracellular PI levels (p =.02) or lower intracellular accumulation of PI (p =.042). Patients treated with low-dose RTV in combined regimens with detectable RTV intracellular concentration showed lack of MDR-1 gene expression (p =.01). Patients with HIV RNA < 40 copies/mL had significantly higher RTV intracellular accumulation (p =.029). CONCLUSION: In HIV-infected patients, IC of PI is inversely correlated with MDR-1 gene overexpression. Undetectable viral load was associated with the use of low-dose RTV, probably linked to better intracellular accumulation of the drug. Nevertheless, further investigation is needed to confirm these results.