PI-experienced Patients Research Articles

The efficacy of paritaprevir/ritonavir/ombitasvir+dasabuvir and ledipasvir/sofosbuvir is comparable in patients who failed interferon-based treatment with first generation protease inhibitors - a multicenter cohort study

BackgroundAccording to the EASL and AASLD guidelines, the recommended treatment for patients who failed to achieve a sustained virologic response (SVR) on prior interferon-based triple therapy with protease inhibitors (PI), is a combination of sofosbuvir and NS5A inhibitors. Polish national recommendations also allow the use of paritaprevir/ritonavir/ombitasvir+dasasbuvir±ribavirin (PrODR) in this group of patients. The aim of the study was to evaluate the efficacy and safety of PrODR vs. ledipasvir/sofosbuvir±RBV (LSR) in PI-experienced patients in real-life setting.MethodsOur analysis included patients registered in the nationwide, investigators initiated, multicentre EpiTer-2 database.Among 4530 patients registered, 335 with genotype 1 (93% 1b) were previously treated with IFN-based regimens with PIs: 127 with boceprevir (BOC), 208 with telaprevir (TVR).Patients with advanced fibrosis (F3/F4) were significantly predominant (BOC 28.4%/61.4%, TVR 18.8%/64.4%, respectively).Subjects were assigned to IFN-free retreatment as follows: BOC - 64 (50.4%) PrODR and 63 (49.6%) LSR; TVR- 103 (49.5%) PrODR and 105 (50.5%) LSR.ResultsSVR rates were comparable for particular groups: BOC → PrODR- 100%; BOC → LSR - 98%; TVR → PrODR - 97%; TVR → LSR - 96% (intent-to treat analysis-ITT) and BOC → PrODR→100%; BOC → LSR - 99%; TVR → PrODR - 99%; TVR → LSR - 98% (modified intent-to treat analysis-mITT).Both treatment regimens had a favourable safety profile. Adverse events (AEs) were generally mild or moderate in severity. Three deaths were reported. The treatment was stopped due to AEs in five patients (three treated with PrODR and two with LSR).ConclusionEfficacy and safety of treatment with PrODR and LSR is comparable in BOC or TVR-experienced patients.

Exploring resistance pathways for first-generation NS3/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning

Resistance-associated variants (RAVs) have been shown to influence treatment response to direct-acting antivirals (DAAs) and first generation NS3/4A protease inhibitors (PIs) in particular. Interpretation of hepatitis C virus (HCV) genotypic drug resistance remains a challenge, especially in patients who previously failed DAA therapy and need to be retreated with a second DAA based regimen. Bayesian network (BN) learning on HCV sequence data from patients treated with DAAs could provide insight in resistance pathways against PIs for HCV subtypes 1a and 1b, in a similar way as applied before for HIV. The publicly available ‘Rega-BN’ tool chain was developed to study associative analyses for various pathogens. Our first analysis, comparing sequences from PI-naïve and PI-experienced patients, determined that NS3 substitutions R155K and V36M arise with PI-exposure in HCV1a infected patients, and were defined as major and minor resistance-associated variants respectively. NS3 variant 174H was newly identified as potentially related to PI resistance. In a second analysis, NS3 sequences from PI-naïve patients who cleared the virus during PI therapy and from PI-naïve patients who failed PI therapy were compared, showing that NS3 baseline variant 67S predisposes to treatment-failure and variant 72I to treatment success. This approach has the potential to better characterize the role of more RAVs, if sufficient therapy annotated sequence data becomes available in curated public databases. In addition, polymorphisms present in baseline sequences that predispose patients to therapy failure can be identified using this approach.

Optimal efficacy of interferon-free HCV retreatment after protease inhibitor failure in real life

ObjectivesFirst-generation protease-inhibitors (PIs) have suboptimal efficacy in GT-1 patients with advanced liver disease, and patients experiencing treatment failure may require urgent retreatment. Our objective was to analyse the real-life efficacy of interferon (IFN)-free retreatment after PI-failure, and the role of genotypic-resistance-testing (GRT) in guiding retreatment choice. MethodsIn this multi-centre observational study, patients retreated with IFN-free regimens after first-generation PI-failure (telaprevir-boceprevir-simeprevir) were included. Sustained-virological-response (SVR) was evaluated at week 12 of follow-up. GRT was performed by population-sequencing. ResultsAfter PI-failure, 121 patients (cirrhotic=86.8%) were retreated following three different strategies: A) with ‘GRT-guided’ regimens (N=18); B) with ‘AASLD/EASL recommended, not GRT-guided’ regimens (N=72); C) with ‘not recommended, not GRT-guided’ regimens (N=31). Overall SVR rate was 91%, but all 18 patients treated with ‘GRT-guided’ regimens reached SVR (100%), despite heterogeneity in treatment duration, use of PI and ribavirin, versus 68/72 patients (94.4%) receiving ‘AASLD/EASL recommended, not GRT-guided’ regimens. SVR was strongly reduced (77.4%) among the 31 patients who received a ‘not recommended, not GRT-guided regimen’ (p <0.01). Among 37 patients retreated with a PI, SVR rate was 89.2% (33/37). Four GT-1a cirrhotic patients failed an option (C) simeprevir-containing treatment; three out of four had a baseline R155K NS3-RAS. All seven patients treated with paritaprevir-containing regimens reached SVR, regardless of treatment duration and performance of a baseline-GRT. ConclusionRetreatment of PI-experienced patients can induce maximal SVR rates in real life. Baseline-GRT could help to optimize retreatment strategy, allowing PIs to be reconsidered when chosen after a RASs evaluation.

HIV-1 drug resistance mutations emerging on darunavir therapy in PI-naive and -experienced patients in the UK.

BackgroundDarunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings.ObjectivesWe examined darunavir DRMs emerging in clinical practice in the UK.Patients and methodsBaseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PI-naive controls.ResultsOf 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group.ConclusionsOur findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility.

Virological response and resistance profile in HIV-1-infected patients starting darunavir-containing regimens.

We evaluated the virological response in patients starting a regimen based on darunavir/ritonavir (DRV/r), which is currently the most widely used ritonavir-boosted protease inhibitor. Data from 206 drug-naïve and 327 PI-experienced patients starting DRV/r 600/100mg twice daily (DRV600) or 800/100mg once daily (DRV800) were examined. The probabilities of virological success (VS) and virological rebound (VR) were evaluated in survival analyses. Baseline DRV/r resistance and its evolution at failure were also examined. DRV600 was preferentially administered in patients with complex requirements (older age, higher viraemia, lower CD4 cell count and DRV/PI resistance) compared with DRV800. By 12months, the probability of achieving VS was 93.2% and 84.3% in drug-naïve and PI-experienced patients, respectively. The higher the baseline viraemia, the longer was the time required to achieve VS, both in drug-naïve patients [>500000 HIV-1 RNA copies/mL: median [interquartile range (IQR)] 6.1 (5.1-10.3) months; 100000-500000 copies/mL: median (IQR) 4.9 (3.8-6.1) months; <100000 copies/mL: median (IQR) 3.9 (3.5-4.8) months; P<0.001] and in PI-experienced patients [≥100000 copies/mL: median (IQR) 7.2 (5.7-11.6) months; <100000 copies/mL: median (IQR) 2.8 (2.4-3.3) months; P<0.001]. In PI-experienced patients, the probability of VR was higher for higher viraemia levels (22.3% for ≥100000 copies/ml vs. 9.7% for <100000 copies/mL; P=0.007). Baseline resistance did not affect the virological response. At failure, a high percentage of patients maintained virus susceptible to all PIs (drug-naïve: 95%; PI-experienced: 80%). Despite being used more often in patients with more complex requirements, DRV600 performed as well as DRV800. In clinical practice, use of DRV/r (with its flexible dosage) results in high rates of virological response. These data support the use of PI/r in patients whose characteristics require potent drugs with a high genetic barrier.

Protease mutations emerging on darunavir in protease inhibitor-naïve and experienced patients in the UK.

IntroductionDarunavir (DRV) is a preferred agent in treatment guidelines for ART-naïve and experienced patients [1]. It is considered to have a high genetic barrier to resistance and 11 resistance-associated mutations (RAMs) are recognized by IAS-USA [2]. These have largely been identified by analyses examining the correlation between baseline genotype and virological response [3]. However, there is little information on RAMs that are directly selected by DRV, outside of short-term clinical trials. We aimed to identify emerging mutations by comparing the genotypes of individuals before and after DRV exposure.Materials and MethodsThe UK HIV Drug Resistance Database was used to identify patients aged over 16 who had received at least 30 days of a DRV-containing regimen. Patients were included if they had a “baseline” resistance test, prior to DRV exposure, and a “repeat” test, either on DRV or within 30 days of stopping this agent. To avoid attributing the effects of other PIs on emerging RAMs to DRV, patients were excluded if they had received another PI for greater than 90 days between the baseline genotype and the start of DRV. The baseline and repeat tests were compared to determine the nature of mutations stratified by PI history.ResultsA total of 5623 patients had DRV, of whom 306 met the inclusion criteria. A total of 228 (74.5%) were male, median age at the start of DRV was 42 years (IQR 37–47), and half had subtype B infection. The mode of transmission was homosexual contact for 50%, heterosexual for 38%, and 3% were injection drug users. The median CD4 count at the start of DRV was 257 cells/mm3 (IQR 94–453). A total of 149 patients (49%) had a history of PI use prior to DRV, and 157 (51%) were PI-naïve. The most common previous PIs were lopinavir, atazanavir, and saquinavir. Baseline DRV RAMs were present in 1 (0.6%) PI-naïve and 20 (13.4%) PI-experienced patients. Mutations emerged under DRV pressure in a further 3 (1.9%) PI-naïve patients, and in 7 (4.7%) PI-experienced patients, 5 of whom had other DRV RAMs present at baseline (Table 1). The median time from the start of DRV to the repeat test was 196 days for PI-naïve patients and 296 days for PI-experienced.ConclusionsPI-experienced patients had a greater prevalence of DRV RAMs at baseline than PI-naïve individuals, probably due to the fact that some DRV RAMs can be selected by other PIs. This group also accumulated more RAMs during DRV exposure, possibly because previous PIs had caused minority variants which then emerged on DRV therapy. Overall, only 10 patients accumulated 16 RAMs, which supports the perception that DRV has a high genetic barrier to resistance. Repeat genotyping in the case of virological failure on DRV may still be warranted to detect emerging resistance and guide management decisions.

Long-term efficacy and safety of once-daily fosamprenavir 1400 mg boosted by ritonavir 100 mg: the BOLD100 study

In a retrospective database study at two HIV treatment centres, medical records were accessed to evaluate long-term efficacy and safety parameters in all HIV-infected adults who had achieved HIV-1 RNA <50 copies/mL following the initiation of fosamprenavir (FPV)/ritonavir (RTV) 1400 mg/100 mg once-daily (QD)-containing regimens between January 2004 and January 2006. Data were available for 20 antiretroviral (ARV)-naïve patients (baseline median HIV-1 RNA 5.0 log(10) copies/mL; CD4+ cell count 307 cells/mm(3)), 30 protease inhibitor (PI)-naïve, ARV-experienced patients (HIV-1 RNA 3.6 log(10) copies/mL; CD4+ count 348 cells/mm(3)) and 25 PI-experienced patients switching to FPV/RTV100 for reasons other than virological failure (HIV-1 RNA 2.7 log(10) copies/mL; CD4+ count 328 cells/mm(3)). HIV-1 RNA <50 copies/mL was achieved in 100% of the ARV-naïve cohort (median monitoring period, 2.4 years; range, 1.4-3.2 years), 87% of the PI-naïve cohort (2.4 years; range, 1.2-3.4 years) and 88% of the PI-experienced cohort (2.2 years; range, 1.0-3.2 years). Virological failure occurred in 0%, 7% and 8% of the cohorts, respectively, and median CD4+ count increased above baseline by 224, 155 and 115 cells/mm(3), respectively. Change from baseline in median fasting lipids was: total cholesterol +12, -6, -2 mg/dL; low-density lipoprotein-cholesterol 0, -5, +12 mg/dL; high-density lipoprotein-cholesterol +4, +2, +7 mg/dL; triglycerides +9, -21, -65 mg/dL, respectively. In conclusion, FPV/RTV 1400/100 mg QD-containing regimens remained effective long-term in all ARV-naïve and most PI-naïve and PI-experienced HIV-infected patients.

Should We Switch to a 50-mg Boosting Dose of Ritonavir for Selected Protease Inhibitors?

Should We Switch to a 50-mg Boosting Dose of Ritonavir for Selected Protease Inhibitors?

A reduced dose of darunavir/ritonavir is effective in PI-experienced HIV-infected patients

Darunavir (DRV) is an HIV-1 protease inhibitor that is used together with a low boosting dose of ritonavir as part of an antiretroviral therapy (ART) regimen in treatment-experienced and naïve HIVpositive patients. In naïve and experienced patients with no DRV-mutations, DRV is licensed at the dose of 800 mg plus 100 mg of ritonavir once daily. We report our results in seven ART-experienced HIV-infected patients, in whom a reduced dose of darunavir/ritonavir (600/100 mg once daily) successfully controlled viral replication

A Randomized Clinical Trial Evaluating Therapeutic Drug Monitoring (TDM) for Protease Inhibitor–Based Regimens in Antiretroviral-Experienced HIV-Infected Individuals: Week 48 Results of the A5146 Study

Background: We devised an open-label, randomized trial to evaluate whether therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and dose escalation based upon a normalized inhibitory quotient (NIQ), which integrates PI trough concentration and drug resistance, could improve virologic outcome in PI-experienced patients with treatment failure. Secondary analyses through 48 weeks are presented.Methods: Eligible HIV-infected subjects with a screening viral load of ≥1000 copies/mL initiated a new PI-based regimen at entry and had NIQ performed at week 2. Subjects with an NIQ ≤1 were randomized at week 4 to a standard-of-care (SOC) arm or TDM arm featuring PI dose escalation.Results: One hundred and eighty-three subjects were randomized. There was no significant treatment difference in change from randomization to week 48 in HIV-1 RNA [ P = .13, median (25th, 75th percentile log₁₀ copies/mL change): -0.03 (-0.74, 0.62) with TDM and 0.11 (-2.3, 0.82) with SOC]. In subgroup analysis, patients with ≥0.69 active PIs benefited from TDM compared to those with <0.69 active PIs ( P = .05).Conclusions: While the TDM strategy of PI dose escalation did not improve virologic response at week 48 overall, in subgroup analysis, TDM favorably impacted virologic outcome in subjects taking PI-based regimens with moderate antiviral activity.

Impact of Adding Enfuvirtide to the Predictive Value of the Darunavir Genotypic Resistance Score

Impact of Adding Enfuvirtide to the Predictive Value of the Darunavir Genotypic Resistance Score

Comparison of Protease Inhibitor (PI) Resistance-Associated Mutations Between PI-Naive and PI-Experienced HIV-1 Infected Patients in Thailand Where Subtype A/E is Predominant

Protease inhibitor (PI) resistance-associated mutations (RAMs) are commonly observed in PI-naïve patients who infected with HIV-1 subtype A/E. Few data are available on the genetic mechanisms of PI resistance in non-B HIV-1. This study was aimed to compare PI-RAMs between PI-naïve and -experienced patients and determine PI resistance in each group. Genotypic resistance testing was conducted among a cohort of HIV-1-infected patients who were diagnosed with virologic failure. We studied 137 patients of whom 75 patients were in PI-naïve group and 62 patients in PI-experienced group. Median CD4 cell count and HIV-1 RNA at virologic failure were 169 cells/mm³ and 14,100 copies/mL, respectively. The clinical characteristics between 2 groups were similar (p>0.05) except for the duration of antiretroviral therapy (ART) which was shorter in PI-naïve group (31.5 vs. 46.8 months, p=0.028). Proportion of patients with primary PI-RAMs was 2.7% in PI-naïve and 19% in PI-experienced groups (p=0.002). The most common primary PI-RAMs in the latter group were V82A (10%), I54V (7%) and G48V (4.8%). Proportion of patients with secondary PI-RAMs in the corresponding groups was 99% and 98%, respectively (p=1.000). The most common secondary PI-RAMs in both groups were M36I (91%), H69K (34%) and L89M (30%). In conclusion, primary PI-RAMs are observed exclusively among PI-experienced patients whereas secondary PI-RAMs are equally found in both PI-naïve and PI-experienced patients. Further studies to define virologic response of HIV-1 subtype A/E to various PIs and clinical validation of PI-RAMs in HIV-1 subtype A/E are essentially needed.

Long-term follow-up of 11 protease inhibitor (PI)-naïve and PI-treated HIV-infected patients harbouring virus with insertions in the HIV-1 protease gene

Amino acid insertions in the protease gene have been reported rarely, and mainly in patients receiving protease inhibitors (PIs). The aim of the study was to assess the long-term viro-immunological follow-up of HIV-infected patients harbouring virus with protease insertions. Cases of virus exhibiting protease insertions were identified in routine resistance genotyping tests. Therapeutic, immunological and virological data were retrospectively collected. Eleven patients harbouring virus with a protease gene insertion were detected (prevalence 0.24%), including three PI-naïve patients. The insertions were mainly located between codons 33 and 39 and associated with surrounding mutations (M36I/L and R41K). The three PI-naïve patients were infected with an HIV-1 non-B subtype. Follow-up of these PI-naïve patients showed that the insert-containing virus persisted for several years, was archived in HIV DNA, and displayed a reduced viral replicative capacity with no impact on resistance level. Of the eight PI-experienced patients, 63% were infected with HIV-1 subtype B; one had been antiretroviral-free for 5 years and seven were heavily PI-experienced (median duration of follow-up 24 months; range 10-62 months). The protease insertion was selected under lopinavir in four patients and under darunavir in one, in the context of major PI-resistance mutations, and following long-term exposure to PIs. The insert-containing virus persisted for a median of 32 months (range 12-62 months) and displayed no specific impact on phenotypic resistance level or viral replicative capacity. Our data, obtained during long-term follow-up, show that insertions in the protease gene do not seem to have an impact on resistance level. This finding supports the recommendation of PI-based regimens, although further work is required to confirm it.

Susceptibility of HIV-1 to Tipranavir and Other Antiretroviral Agents in Treatment-Experienced Patients: The UTILIZE Study

The primary objective was to assess HIV-1 susceptibility to the protease inhibitor (PI) tipranavir and other antiretroviral (ARV) agents among treatment-experienced patients (TEP). Secondarily, clinicians' use of resistance testing was examined. UTILIZE was an observational study conducted at 40 sites in the United States. Patients currently failing a PI-based regimen were randomized to receive either a genotype (GT) or combined phenotype-genotype test (PGT) and a treatment decision was made at the second study visit. 246 patients enrolled, 236 had resistance test results, and 139 (59%) had evidence of HIV-1 resistance to >or=1 PI. Among these 139 patients, more than 50% had viruses that remained sensitive to tipranavir and darunavir, whereas susceptibility to other PIs was markedly lower (<22%). Increasing prior PI exposure was associated with reduced susceptibility to most ARV agents. After obtaining resistance test results, 83% of patients changed therapy. Newly available or investigational ARVs were used frequently. The reason investigators most often cited for changing therapy was the patient resistance test results (82%) and the most common reason for not changing therapy was the inability to construct an active regimen. The majority of patients who exhibited PI resistance received two or more active agents in the new regimen. Overall, 59% of TEPs failing a PI-based regimen had HIV-1 with PI resistance. The majority of these patients' viruses remained sensitive to either tipranavir or darunavir. Investigators used results from resistance assays to construct a new regimen, frequently with newer agents. In PI-experienced patients, tipranavir and darunavir remain the most likely available active PIs.

Relationship Between Plasma Protease Inhibitor Concentrations and Lipid Elevations in HIV Patients on a Double‐Boosted Protease Inhibitor Regimen (Saquinavir/Lopinavir/Ritonavir)

The relationship between plasma protease inhibitor (PI) trough concentrations and hyperlipidemic effects were evaluated retrospectively using data from 2 pilot clinical trials of a double-boosted PI regimen (saquinavir/lopinavir/ritonavir) in 25 HIV patients. The patients' median age was 39 years (range, 25-60). At baseline, PI-naive patients had a median viral load of 53 500 copies/mL and median CD4 of 296 cells/mm(3), while PI-experienced patients had 37 750 copies/mL and 214 cells/mm(3). Plasma PI trough concentrations of saquinavir, lopinavir, and ritonavir at week 12 were 520, 4482, and 153 ng/mL, respectively. At week 12, median fasting lipids increased significantly from baseline: total cholesterol increased from 165 to 189 mg/dL (P = .0005) and the triglyceride increased from 113 to 159 mg/dL (P = .001). There were no associations between PI trough concentrations at week 12 and the percent total cholesterol change at week 12. No associations were found between PI trough concentrations and lipid changes in HIV patients on a double-boosted PI regimen (saquinavir/lopinavir/ritonavir). Factors other than systemic exposure to PIs (such as host or genetic factors) may modulate the hyperlipidemic effect of PIs.

A population analysis of weight-related differences in lopinavir pharmacokinetics and possible consequences for protease inhibitor-naive and -experienced patients

Lopinavir is a potent protease inhibitor (PI) used for the treatment of HIV infection. Different lopinavir target trough concentrations (C(troughs)) were previously determined according to patient treatment histories: 1 mg/l for PI-naive patients, and 4 and 5.7 mg/l for PI-experienced patients. However, the probability to achieve these target C(troughs) with the current 400 mg twice-daily or 800 mg once-daily doses of the new tablet form, and the influence of body weight on this probability are unknown. A population pharmacokinetic model for lopinavir was developed using data from 424 HIV type-1-infected patients, and the final model was used to estimate the probability to achieve target C(troughs) via Monte Carlo simulations. A one-compartment model adequately described the data. Mean population estimates (percentage interindividual variability) were 4.61 l/h (36%) for apparent clearance (CL/F) and 63.2 l (70%) for apparent distribution volume. Body weight was found to explain the interindividual variability of lopinavir CL/F. Probability to achieve the 1 mg/l target C(trough) was >96% for the twice-daily dose and comprised between 80% and 90% for the once-daily dose. The probability to achieve the 4 and 5.7 mg/l target C(troughs) with the twice-daily dose significantly decreased when body weight increased (from 76% to 61% and from 56% to 37% respectively, for body weights increasing from 50 to 90 kg). These results support lopinavir therapeutic drug monitoring and the use of higher lopinavir doses for PI-pretreated patients.

Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457)

The maturation inhibitor bevirimat [3-O-(3',3'dimethysuccinyl)betulinic acid; BVM; also known as PA-457 or DSB] potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking protease (PR)-mediated cleavage at the junction between capsid (CA) and spacer peptide 1 (SP1) in Gag. We previously isolated a panel of single-amino-acid substitutions that confer resistance to BVM in vitro (C. S. Adamson, S. D. Ablan, I. Boeras, R. Goila-Gaur, F. Soheilian, K. Nagashima, F. Li, K. Salzwedel, M. Sakalian, C. T. Wild, and E. O. Freed, J. Virol. 80:10957-10971, 2006). The BVM resistance mutations cluster at or near the CA-SP1 cleavage site. Because BVM likely will be used clinically in patients harboring viruses resistant to PR inhibitors (PIs), in this study we evaluated the interplay between a PI-resistant (PIR) PR and the BVM resistance mutations in Gag. As expected, the PIR mutations had no effect on inhibition by BVM; however, we observed general processing defects and a slight delay in viral replication in Jurkat T cells associated with the PIR mutations, even in the absence of compound. When combined, most BVM resistance and PIR mutations acted additively to impair viral replication, particularly in the presence of BVM. The BVM-resistant mutant SP1-A1V was an exception, as it supported robust replication in the context of either wild-type (WT) or PIR PR, even at high BVM concentrations. Significantly, the emergence of BVM resistance was delayed in the context of the PIR PR, and the SP1-A1V mutation was acquired most frequently with either WT or PIR PR. These results suggest that resistance to BVM is less likely to emerge in patients who have failed PIs than in patients who are PI naive. We predict that the SP1-A1V substitution is the most likely to emerge in vivo, as this mutant replicates robustly independently of PR mutations or BVM. These findings offer insights into the effect of PIR mutations on the evolution of BVM resistance in PI-experienced patients.

Genotypic Resistance Analysis of the Virological Response to Fosamprenavir-Ritonavir in Protease Inhibitor-Experienced Patients in CONTEXT and TRIAD Clinical Trials

The aim of this study was to identify human immunodeficiency virus (HIV) protease mutations associated with virological response (VR) to fosamprenavir-ritonavir (FPV/r) in 113 protease inhibitor (PI)-experienced patients randomized in both CONTEXT and TRIAD clinical trials and receiving the same dose (700/100 mg twice daily) of FPV/r. The impact of each protease mutation on the VR to FPV/r, defined as the decrease in HIV RNA at week 12, was investigated with nonparametric analyses. A step-by-step procedure was done using a Jonckheere-Terpstra (JT) test that retains the group of mutations most strongly associated with the VR. Mutations at the following 14 codons were associated with a reduced VR to FPV/r: 10, 15, 33, 46, 54, 60, 62, 63, 72, 73, 82, 84, 89, and 90. The JT procedure led to selecting the CONTEXT/TRIAD genotypic set of mutations, I15V, M46I/L, I54L/M/V, D60E, L63P/T, and I84V, as providing the strongest association with the VR (P = 1.45 x 10(-11)). In the nine patients with zero mutations within this set, the median decrease in HIV RNA was -2.63 log copies/ml, and was -2.22 (n = 45), -1.50 (n = 26), -0.58 (n = 23), -0.47 (n = 6), -0.13 (n = 3), and 0.04 (n = 1) log copies/ml in those with one, two, three, four, five, and six mutations, respectively. This study identified six mutations associated with VR to FPV/r. Some of these mutations are shared with the current FPV/r Agence Nationale de Recherches sur le SIDA (ANRS) resistance score, which has been cross-validated in the CONTEXT/TRIAD data set, suggesting that the current ANRS FPV/r score is a useful tool for the prediction of VR to FPV/r in PI-experienced patients.

Metabolic Changes in Protease Inhibitor-Naive Patients Treated for 1 Year With Lopinavir/Ritonavir

To the Editor: Certain metabolic complications are common in HIV-positive patients treated with antiretroviral therapy. These alterations, especially hypercholesterolemia, could increase the cardiovascular risk (CVR), as measured by the Framingham risk score (FRS). Lopinavir coformulated with ritonavir (LPV/r) is an effective and potent protease inhibitor (PI) with a high genetic barrier, which can produce hypercholesterolemia, hypertriglyceridemia, and insulin resistance.1 To assess the CVR, using the FRS in patients treated with LPV/r, we designed a prospective, open-label, 1-arm study lasting 12 months. Seventy-three (71.2% male) consecutive PI-naive patients were included in the study and received treatment with LPV/r combining a nucleoside/nucleotide backbone. Exclusion criteria were PI-experienced, pregnant, or breast-feeding patients; those receiving concomitant treatments with investigational drugs or with agents that might have potential major interactions with LPV/r; and, finally, patients younger than 18 years of age. The inclusion period was from January 2001 to January 2002. The route of HIV transmission among the 73 included patients was heterosexual intercourse in 39.4%, injection drug abuse in 38.0%, homosexual intercourse in 19.7%, vertical transmission in 1.4%, and others (unknown) in 1.4%. The concurrent antiretroviral therapy was lamivudine in 41.8%, zidovudine in 24.3%, stavudine (d4T) in 11.4%, tenofovir in 11.4%, didanosine in 8.1%, and abacavir in 2.7%. Patients were evaluated clinical and analytically at baseline and every 3 months thereafter. Patients had the following baseline characteristics: duration of HIV infection for 62.9 ± 65.7 months, CD4 T-lymphocyte count of 263 ± 263 cells/μL, CD4 T-lymphocyte percentage of 14.2 ± 9.6%, and plasma HIV-1 RNA level of 415,512 ± 960,152 copies/mL. Initially, the average CVR factor was 1.7 ± 0.9. The number of risk factors per patient was 0 CVR in 5 patients (6.8%), 1 in 24 patients (32.9%), 2 in 32 patients (53.8%), 3 in 11 patients (15.1%), 4 in 0 patients, and 5 in 1 patient (1.4%). The salient CVR was smoking (72.6%). Other common CVRs were age (men older than 45 years of age) in 15.1% of patients and hypertension in 11.1% of patients. The family heart disease history showed that 2.7% of the fathers of patients had ischemic heart disease, and the figure was 4.1% in the case of the mothers of patients. None of the patients had diabetes. Taking into account all CVRs, the FRS was initially 4.4 ± 6.9. At baseline, the levels of cholesterol, high-density lipoprotein (HDL) cholesterol (HDLc), low-density lipoprotein (LPL) cholesterol (LDLc), triglycerides (TGs), and glucose were 165.0 ± 49.4 mg/dL, 35.5 ± 13.6 mg/dL, 99.2 ± 41.6 mg/dL, 160.9 ± 89.0 mg/dL, and 93.1 ± 12.7 mg/dL, respectively. The immunologic, virologic, and metabolic data at the end of the study (12 months) are shown in Table 1. We found a significant increase in total cholesterol, HDLc, and LDLc. TGs also showed an increase that was not significant. No cases of diabetes were diagnosed. LPV/r was discontinued in 19 cases: 12 of them because of side effects (diarrhea and/or digestive alterations in 10 cases) and 5 because of loss to follow-up. Twenty-eight patients were treated for dyslipemia, of whom 25 were treated only with diet and 3 were treated with diet and specific lipid-lowering drugs. Statins were used in 3 to achieve the National Cholesterol Education Project (NCEP) Adult Treatment Panel III (ATPIII) goals. We found no significant increase in the CVR, using the FRS. Accordingly at baseline, the CVR was 4.4; however, after 12 months on the LPV/r-based regimen, the CVR stood at 6.3. This increase was not significant (P = 0.059).TABLE 1: Patients' Data at Baseline and 12 Months of Follow-UpWe know that d4T can induce dyslipemia.2 To assess if the lipid profile could change when the backbone included d4T in an LPV/r-based regimen, the patients were divided into 2 groups: a d4T group and a non-d4T group. Twelve and 45 patients, respectively, completed the treatment for 12 months in each group. No significant difference was found between the 2 groups in the lipid profile. In conclusion, correct management of metabolic complications permits the use of LPV/r without a significant increase in CVR. In fact, the use of LPV/r is recommended in a PI-based regimen in different guidelines for treating antiretroviral-naive patients.3-5 Although a PI-based regimen can produce dyslipemia, correct management of modifiable CVR factors, such as a smoking habit, hypertension, or diabetes, is equally essential. In this series, more than 70% of patients were smokers. Maria José Galindo, MD, PhD* José Verdejo, MD† Miguel Gonzalez-Muñoz, PhD‡ Ana Ferrer, MD* Rosa Polo, MD, PhD§ *Infectious Diseases Department Hospital Clinico Universitario Valencia, Spain †Internal Medicine Service Hospital Madrid Torrelodones Madrid, Spain ‡Department of Immunology Hospital Carlos III Madrid, Spain §National Plan of AIDS Madrid, Spain

Letter to the Editor: Successful Rescue Therapy with Raltegravir (MK-0518) and Etravirine (TMC125) in an HIV-Infected Patient Failing All Four Classes of Antiretroviral Drugs

It is mandatory to find antiretroviral therapies that offer increased efficacy in treatmentexperienced patients with HIV-1 infection, a population whose extensive drug resistance restricts treatment options and has a severe effect on infection management.1 The aim in salvage therapy in patients who were highly treatmentexperienced and in whom multiple regimens had failed was so far limited to the new protease inhibitors (PI) and combination with enfuvirtide.2,3 The new antiretrovirals currently in expanded access programs, such as raltegravir and etravirine, show unprecedented level of virologic efficacy. Raltegravir, formerly MK0518, the first integrase inhibitor under clinical development, showed high potency in multidrug-resistant HIV patients including those resistant to currently available antiretroviral drugs.4 Etravirine, formerly TMC-125, a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) appears to be effective against a variety of HIV viruses that are resistant to efavirenz and nevirapine.5 Few data are available regarding the performance of these drugs combinations in heavily PI-experienced patients, including those for whom tipranavir, darunavir, and enfuvirtide have failed. Hereby, we describe the outcome of salvage therapy based on raltegravir and etravirine in a heavily antiretroviral-experienced patient. A 37-year-old Caucasian male, CDC status C3, had experienced multiple failures to all current classes of antiretroviral agents. Specifically, he had failed eight ritonavir-boosted PI combinations, including tenofovir-lamivudine-enfuvirtide-tipranavir/ritonavir, given in May 2004 with replacement of the latest with darunavir/ritonavir in December 2006. Plasma HIV-RNA levels were measured at baseline and during therapy using a commercial assay, the Versant HIV-1 RNA 3.0 Assay (bDNA; Siemens Medical Solutions Diagnostics, Malvern, PA), with a dynamic range of 50–500,000 HIV-1 RNA copies per milliliter. CD4 cell count was determined by direct immunofluorescence in flow cytometry (Beckman Coulter, Fullerton, CA). Genetic analysis of the pol gene including both HIV-1 reverse transcriptase (codons 4-99) and protease (codons 35-247) regions was performed using the Trugene HIV-1 Genotyping Kit (Siemens Medical Solutions Diagnostics).