Previous Virological Failure Research Articles

Randomized trial of DRV/r or LPV/r QD monotherapy vs maintaining a PI/r-based antiretroviral regimen in persons with suppressed HIV replication.

IntroductionPI/r monotherapy has been suggested as an attainable maintenance strategy in patients achieving stable HIV suppression in plasma. The objective of trial was to compare the virological outcome of two different PI/r QD monotherapy strategies (LPV/r or DRV/r) with maintaining a triple PI/r-based ARV regimen.Material and MethodsPhase III, open-label, non-inferiority (−12% margin), randomized trial of HIV adults with HIV-RNA <50 cp/mL for at least 48 weeks while on PI/r-based cART, CD4 nadir >100 cell/mm3, without previous PIs virological failure. Eligible patients were randomized to continue PI/r+2NRTIs (Arm A), to switch to LPV/r 800/200 mg QD monotherapy (Arm B), or to switch to DRV/r 800/100 mg QD monotherapy (Arm C). Primary endpoint was proportion of patients with plasma HIV-1 RNA <50 cp/mL (TLOVR) at 48w by intent to treat (ITT) analysis (missing/re-induction=failure). FDA snapshot and ITT switch-included analysis (ITT-SI) were also used. In ITT-SI, patients who had <50 copies/mL at 96w were counted as successes even if they had confirmed HIV-RNA elevations and had subsequently successfully intensified by NRTI.ResultsDue to slow recruitment, only 103 patients were included. No differences were observed between the three arms with respect to gender, age, HIV transmission, CD4 nadir and at screening. At randomization, 61 patients were receiving TDF/FTC (60%), 19 ZDV/3TC (18%), 8 ABV/3TC (8%), 75 LPV/r (73%), 13 ATV/r (13%), 4 DRV/r (4%). Differences in proportion of virological success by groups using Arm A as comparator according to FDA TLOVR were reported in Figure 1. Similar results were obtained by Snapshot analysis. Of 14 patients with virological failure, 8 patients restarted triple therapy with 2NRTI and 7/8 regained a VL <50 cp/mL over time. According to ITT-SI analysis, 96 week differences [95% CI] were −5.7 [−29.6; +18.2] in Arm B, and +19.6 [−1.6; +40.8] in Arm C. A GRT was performed in 6/14 patients (one not amplifiable; four without mutations; one showed E138A).ConclusionsCompared to maintaining a PI/r-based triple ARV regimen, LPV/r QD monotherapy tended to have higher rate of virological failure and of discontinuation due to adverse event. In contrast, the response rate at week 96 during DRV/r QD mono-therapy was non-inferior to that of triple PI/r-based ARV therapy. A re-induction with 2NRTI was adequate to obtain an undetectable viremia in most of patients with virological failure.

Impact of Prior Virological Failure and Nucleos(t)ide Genotypic Resistance Mutations on the Efficacy of Switching from Ritonavir-Boosted Protease Inhibitors to Raltegravir

The virological efficacy of switching from a ritonavir-boosted protease inhibitor (PI/r)- to a raltegravir (RAL)-containing regimen remains controversial according to the results of SWITCHMRK and SPIRAL studies. The aim of this analysis is to assess the impact of prior resistance mutations to nucleos(t)ides and other potential factors on the virological outcome. This was a substudy of the prospective, open-label, multicentre SPIRAL study. Demographic, virological variables, prior episodes of virological failures (VF) and archived resistance mutations to nucleos(t)ides were identified from databases and its impact measured by genotypic sensitive scores (GSS) according to the genotypic resistance interpretation algorithm from the Stanford HIV Drug Resistance Database on outcome was analysed. Of 250 patients (128 RAL and 122 PI/r) included in the main SPIRAL study, 74 (30%) had previous VF with prior genotypic resistance tests (GRT). Median time of virological suppression prior to inclusion in SPIRAL study was 63.5 months. GSS for backbone nucleos(t)ides was <1 in 15/38 (39%) in the RAL arm and in 9/36 (25%) in the PI/r arm (P=0.13). Among those with nucleos(t)ides GSS <1, 0/15 (0%) in the RAL versus 2/9 (22%) in the PI/r arm developed VF (P=0.13). Moreover 0/11 subjects with null or residual (GSS≤0.5) backbone activity developed VF in the RAL arm. The 48-week virological efficacy of switching from a PI/r to RAL in subjects with long-term virological suppression was not compromised by a reduction of the nucleos(t)ide backbone activity.

Daclatasvir plus sofosbuvir for HCV infection: An oral combination therapy with high antiviral efficacy

BACKGROUND: All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. METHODS: In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy. RESULTS: Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).

Switch strategies in 2014

Despite great advances in antiretroviral therapy (ART) in the last decade, several limitations remain regarding adverse effects, poor adherence, and drug-drug interactions. Switching ART in stable, virologically suppressed patients with the aim of improving tolerability and convenience is a widely used strategy in clinical practice. Several factors need to be considered when switching from a successful antiretroviral regimen, including previous virologic failure and duration of virologic suppression, genetic barriers to resistance of the new regimen and expected level of adherence. Reductions in the number of pills, drugs, or doses are the most common switching strategies. Triple therapy regimens including ritonavir-boosted protease inhibitors (PI/r) are the most frequently switched regimens. Thymidine analogues, which are now uncommon in developed countries, have been successfully replaced with non-thymidine analogues in recent years. The main aim of this switch is to prevent or improve abnormal fat redistribution. Simple one-pill triple regimens such as tenofovir/emtricitabine (TDF/FTC) plus efavirenz (EFV), rilpivirine (RPV) or Elvitegravir/Cobicistat (ELVI/Cobi) may help to improve adherence and reduce some PI/r toxicities. The use of PI/r monotherapy is accepted in EACS Guidelines for selected virologically suppressed patients and may be an option for patients with previous nucleoside analogue toxicities, such as tenofovir-related nephrotoxicity. Raltegravir may be switched to once-daily regimens to improve adherence or it may replace other drugs to avoid interactions in medically complex patients. Unboosted atazanavir is a PI-containing option for patients who do not tolerate ritonavir. Two drug regimens have been assessed in randomized clinical trials and cohort studies with different results because of negative drug interactions leading to unexpected toxicities or low efficacy in some cases. In summary, many switching options are currently available for virologically suppressed patients. However, although switching strategies may be useful for improving ART, not all regimens used in clinical practice are based on data from randomized clinical trials and not all regimens are suitable for everyone. It is therefore important to individualize treatment, taking into consideration not only patient and drug characteristics but also the best evidence available.

Randomised Study to Assess the Efficacy and Safety of Once-Daily Etravirine-Based Regimen as a Switching Strategy in HIV-Infected Patients Receiving a Protease Inhibitor–Containing Regimen. Etraswitch Study

BackgroundEtravirine (ETR) was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naïve patients. However, data on the switching from protease inhibitors (PI) to ETR are lacking.MethodsHIV-1-infected patients with suppressed viral load (VL) during a PI-containing regimen (>12 months) and no previous virological failure were randomized to switch from the PI to ETR (400 mg/day, dissolved in water) (ETR group, n = 22) or to continue with the same regimen (control group, n = 21). Percentage of patients with VL≤50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile.ResultsWe included 43 patients [72.9% male, 46.3 (42.2; 50.6) years]. Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation) and another in the control group (simplification) discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL); treatment was successful in 95.2% of the control group and 90.9% of the ETR group (intention-to-treat analysis, missing = failure) (p = 0.58). CD4+ T-cell counts did not significantly vary [+49 cells/µL in the ETR group (p = 0.25) and −4 cells/µL in the control group (p = 0.71)]. The ETR group showed significant reductions in cholesterol (p<0.001), triglycerides (p = <0.001), and glycemia (p = 0.03) and higher satisfaction (0–10 scale) (p = 0.04). Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily.ConclusionSwitch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly.Trial RegistrationClinicalTrials.gov NCT01034917

Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study.

Management of persistent low-level viraemia (pLLV) in patients on combined antiretroviral therapy (cART) with previously undetectable HIV viral loads (VLs) is challenging. We examined virological outcome and management among patients enrolled in the Swiss HIV Cohort Study (SHCS). In this retrospective study (2000-2011), pLLV was defined as a VL of 21-400 copies/ml on ≥ three consecutive plasma samples with ≥8 weeks between first and last analyses, in patients undetectable for ≥24 weeks on cART. Control patients had ≥ three consecutive undetectable VLs over ≥32 weeks. Virological failure (VF), analysed in the pLLV patient group, was defined as a VL>400 copies/ml. Among 9,972 patients, 179 had pLLV and 5,389 were controls. Compared to controls, pLLV patients were more often on unboosted protease inhibitor (PI)-based (adjusted odds ratio [aOR; 95% CI] 3.2 [1.8, 5.9]) and nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-only combinations (aOR 2.1 [1.1, 4.2]) than on non-nucleoside reverse transcriptase inhibitor and boosted PI-based regimens. At 48 weeks, 102/155 pLLV patients (66%) still had pLLV, 19/155 (12%) developed VF and 34/155 (22%) had undetectable VLs. Predictors of VF were previous VF (aOR 35 [3.8, 315]), unboosted PI-based (aOR 12.8 [1.7, 96]) or NRTI-only combinations (aOR 115 [6.8, 1,952]), and VLs>200 during pLLV (aOR 3.7 [1.1, 12]). No VF occurred in patients with persistent very LLV (21-49 copies/ml; n=26). At 48 weeks, 29/39 patients (74%) who changed cART had undetectable VLs, compared with 19/74 (26%) without change (P<0.001). Among patients with pLLV, VF was predicted by previous VF, cART regimen and VL≥200. Most patients who changed cART had undetectable VLs 48 weeks later. These findings support cART modification for pLLV>200 copies/ml.

Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection

BackgroundAll-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3.MethodsIn this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa–ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy.ResultsOverall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea.ConclusionsOnce-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.)

Dual therapy with etravirine plus raltegravir for virologically suppressed HIV-infected patients: a pilot study

Clinical use of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) may be hampered by toxicity, interactions or resistance issues. Simple and effective antiretroviral regimens avoiding both drug classes may be needed for selected patients. This was a prospective cohort study. Virologically suppressed patients on PI or NRTI regimens, with problems of tolerability, safety concerns due to comorbidities or risk of drug interactions for both PIs and NRTIs, were given the opportunity to switch their regimen to etravirine plus raltegravir. Patients were required not to have prior virological failure to raltegravir and if there was prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure, only patients in whom efficacy of etravirine could be anticipated through the Stanford Drug Resistance Database were included. Follow-up was scheduled for at least 48 weeks, unless the patient was lost to follow-up or discontinued therapy. Twenty-five patients were included. Their median age was 54 years; they had a median of 16 years on antiretroviral therapy and a median of nine previous regimens; 21 (84%) patients had previous virological failure; and 15 (60%) patients had a genotypic test that showed three or more NRTI mutations in 9 (36%), four or more PI mutations in 11 (44%) and at least one NNRTI mutation in 8 (32%) patients. At 48 weeks efficacy was 84% (95% CI 65.3%-93.6%) by intent-to-treat analysis and 91.3% (95% CI 73.2%-97.6%) by per-protocol analysis. One (4%) patient died, two (8%) discontinued due to intolerance and one (4%) experienced virological failure. The CD4/CD8 ratio and plasma lipids improved. Dual therapy with etravirine plus raltegravir was well tolerated and maintained durable viral suppression in selected virologically suppressed patients for whom both PI and NRTI therapy was challenging.

Darunavir Minimum Plasma Concentration and Ritonavir-Boosted Darunavir Monotherapy Outcome in HIV-Infected Patients

This study aimed to evaluate whether low darunavir (DRV) minimum plasma concentration (Cmin) values contribute to virological outcomes during DRV/ritonavir monotherapy (mtDRV/rtv). This was a prospective observational single-arm 96-week efficacy study in virologically suppressed subjects on triple therapy switched to mtDRV/rtv (800/100 mg every 24 h). Previous virological failures (VF) on protease-inhibitor-based regimens were allowed if the historical resistance tests showed no major resistance mutation to DRV/rtv. VF was defined as two consecutive HIV RNA measurements of >200 copies/ml. Efficacy was analysed by per-protocol and by intention-to-treat analyses. Plasma DRV Cmin values were measured by LC-MS/MS. A total of 150 subjects were included. At week 96, the efficacy rate on treatment was 83.6% (95% CI 77.2%, 90.0%) by per-protocol analysis and 67.6% (95% CI 60.0%, 75.2%) by intention-to-treat. In the whole cohort the median (IQR) DRV Cmin was significantly higher during the periods of undetectable than of detectable viraemia (1.82 µg/ml [1.47-2.46] versus 1.56 µg/ml [0.93-2.32]; P=0.006) as well as in the subjects with blips and VF. However, a cutoff point sufficiently sensitive and specific could not be found. The DRV Cmin values are related to viral control during mtDRV/rtv, but therapeutic drug monitoring cannot be recommended routinely as a precise cutoff point is unknown. Adherence is a key success factor on this regimen.

Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

There is significant intra- and intersubject variability in lopinavir (LPV) plasma concentrations after standard dosing; thus, this prospective study was conducted to determine whether low plasma LPV concentrations could be associated with virological outcome throughout lopinavir-ritonavir maintenance monotherapy (mtLPVr) in the clinical practice setting. If this hypothesis would be confirmed, LPV drug monitoring could improve the efficacy of mtLPVr regimens. Patients with previous virological failure (VF) on protease inhibitor-based regimens were also included if the genotypic resistance tests showed no major resistance mutation associated with reduced susceptibility to lopinavir-ritonavir. VF was defined as 2 consecutive determinations of HIV RNA levels of >200 copies/ml. Efficacy was analyzed by per-protocol analysis. Plasma LPV trough concentrations were measured by high-performance liquid chromatography using a UV detector. A total of 127 patients were included (22% with previous failure on protease inhibitors). After 96 weeks, the efficacy rate was 82.3% (95% confidence interval [CI(95)], 75.3 to 89.3%). Virological efficacy was independent of LPV plasma concentrations even when LPVr was given once daily. An adherence of <90% (HR, 4.4 [CI(95), 1.78 to 10.8; P = 0.001]) and the presence of blips in the preceding 12 months (HR, 3.06 [CI(95), 1.17 to 8.01; P = 0.022]) were the only variables independently associated with time to VF. These findings suggest that the LPV concentrations achieved with the standard doses of LPVr are sufficient to maintain virological control during monotherapy and that measurement of LPV concentrations is not useful for predicting virological outcome. Tight control of viral replication in the previous months and strict adherence throughout the mtLPVr regimen could improve the virological efficacy of this maintenance regimen.

Effectiveness and safety of a single‐tablet regimen of emtricitabine/efavirenz/tenofovir in HIV‐1‐infected patients in infectious diseases department

ObjectiveEvaluate the effectiveness and safety of simplification of tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV) in selected treatment‐experienced HIV‐1‐infected patients who have been virologically suppressed for&gt;3 months on their current regimen.MethodsWe selected patients who started the simplified regimen between December 1st 2008 and March 31st 2012. Exclusion criteria: prior therapeutic failure, presence of resistance mutations to any component of TDF/FTC/EFV and patients previously observed in other centers. Efficacy and safety assessments were performed at baseline, 4 weeks after switch and then every 12–24 weeks. Statistical analysis was performed with SPSS version 20.0.Results384 patients were evaluated; 302 (79%) male; mean age 47 (SD=10) years; median CD4 cells count was 504 cells/mm3 (367–710). Baseline median glomerular filtration rate (eGFR; Cockcroft‐Gault equation) was 100 mL/min (86–116) and median ALT was 33 U/L (21–47). Median total cholesterol (TC) was 205 mg/dL (176‐236), high‐density lipoproteins (HDL) 45 mg/dL (38–54); low‐density lipoproteins (LDL) 130 mg/dL (108–151); triglycerides (TG) 125 mg/dL (84–176). Prior NNRTI‐based regimen in 327 (85%) patients (TDF/FTC and EFV in 76%); protease inhibitor in 52 (14%) and integrase inhibitor in 5 (1%). Discontinuation of treatment occurred in 49 patients (13%) after a mean time of 1.1 years (SD=1.1) of follow‐up: nervous system symptoms (n=11), decreased eGFR (n=5), virological failure (n=5), pregnancy (n=5), gastrointestinal symptoms (n=3), rash (n=1), other reasons (n=2); 12 patients dropped out the treatment and 5 died. Occurrence of blips (transient increase in VL ≤200 copies/mL) was documented in 98 (26%) patients; in 70, VL decreased to &lt;20 copies/mL after the blips and in 28 VL is not yet available. 317 patients (83%) achieved≥48 weeks of follow‐up after simplification. Compared with baseline, significantly higher levels of CD4 cells count, HDL and eGFR were found and lower levels of TC, LDL and TG. CD4 AST ALT TC HDL LDL TG eGFR Baseline Median 501 27 32 203 46 130 123 100 Percentiles 25 358 22 22 174 39 108 84 85 Percentiles 75 712 36 45 236 54 151 179 113 Follow‐up Median 541 28 32 196 49 123 115 111 Percentiles 25 397 22 22 174 41 101 80 96 Percentiles 75 734 36 46 223 57 141 155 133 p‐value &lt;0.001 0.395 0.513 &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 ConclusionSimplification to TDF/FTC/EFV was shown to be an efficient and safe option in virologically suppressed patients and without a previous virological failure.

Switching to an etravirine regimen in virologically suppressed patients with previous virological failures and presence of resistance mutations

BackgroundSimplification of antiretroviral therapy (ART) may be an option for virologically suppressed patients for a variety of reasons. Etravirine (ETV) 400 mg qd has a good safety profile and retains activity against viruses resistant to nevirapine or efavirenz. Our objective was to evaluate the efficacy of ETV plus two nucleoside reverse transcriptase inhibitors (NRTIs) as a simplification strategy in treatment‐experienced virologically suppressed individuals with prior episodes of virological failure (VF) and presence of genotypic resistance mutations (GRM).MethodsEligible subjects were followed for ≥6 mo. Primary endpoint was proportion of patients remaining virologically suppressed using an ITT analysis. Genotypic sensitivity score (GSS) to new regimen was calculated according to Stanford resistance database.ResultsFourteen (10%) of 145 subjects switching to ETV+2NRTIs while virologically suppressed had a documented prior VF and presence of GRM and were included in the analysis. Median (range) number of previous episodes of VF to ART, NRTI‐containing regimen, to a NNRTI‐containing regimen and to a PI‐containing regimen were 4 (1–6), 2 (1–5), 1 (0–2) and 1 (0–2) respectively. Median duration of virological suppression before switching therapy was 22.5 months (1‐65). All patients switched from an effective PI‐containing regimen (8 LPV/r, 5 ATV/r and 1 DRV/r) to a qd regimen with ETV 400 mg plus Truvada® (n=12) or Kivexa® (2). 11/14 patients (79%) remained virologically suppressed at ≥6 mo. All of them had a GSS &gt;1.5 to the new regimen and none had resistance to etravirine. Conversely 3/14 (21%) developed a VF at 1, 3 and 6 months respectively. All these 3 patients had a GSS ≤1.5 to the new regimen and 2 of them intermediate resistance to ETV (Y181C). No side effects were reported.ConclusionsOur results suggest that ETV plus 2NRTI could be a good strategy for simplification in virologically suppressed patients despite previous episodes of VF if the GSS to the new regimen is ≥1.5 and ETV remains active.

ARIES 144 Week Results: Durable Virologic Suppression in HIV-Infected Patients Simplified to Unboosted Atazanavir/Abacavir/Lamivudine

Background: The open-label study ARIES (http://ClinicalTrials.gov NCT00440947) utilized a ritonavir (/r)-boosted protease inhibitor treatment simplification strategy. Antiretroviral-naïve subjects received abacavir/lamivudine (ABC/3TC) + atazanavir/ ritonavir (ATV/r) from baseline through randomization at week 36, then maintained or discontinued ritonavir for an additional 108 weeks. Non-inferiority of the unboosted regimen was demonstrated at week 84. In this optional extension phase, virologic suppression and adverse events were assessed through week 144.Methods: Patients were randomized at week 36 if they had confirmed HIV RNA <50 copies/mL by week 30 and no previous virologic failure (VF; defined as failure to achieve HIV RNA <400 copies/mL or confirmed rebound after achieving HIV RNA ≥400 copies/mL). Three hundred sixty-nine subjects who completed 84 weeks in ARIES participated in the extension phase and maintained their randomized regimen for an additional 60 weeks post randomization.Results: At week 144, 146/189 (77%) versus 132/180 (73%) subjects in the unboosted ATV and ATV/r groups, respectively, maintained HIV RNA <50 copies/mL. Post randomization (weeks 36-144), treatment-related grade 2x–4 adverse events were more common in the ATV/r-treated (23%) compared to the ATV-treated (13%) group; the most frequently reported was increased serum bilirubin (6% of ATV-treated subjects vs 14 % of ATV/r-treated subjects). During the extension phase, 3% (11/369) of subjects met protocol-defined VF (5 ATV-treated and 6 ATV/ r-treated subjects); one ATV/r-treated subject had treatment-emergent major viral resistance-associated mutations. The median change in fasting triglycerides from baseline to week 144 was significantly different (P=.001) in the ATV-treated (-8.5 mg/dL) compared to the ATV/r-treated (28.5 mg/dL) groups.Conclusions: These long-term study results demonstrate that ATV in combination with ABC/3TC is a potent, well-tolerated regimen in patients who have achieved initial suppression on a ritonavir-boosted regimen.

Potential for simplification of HIV treatment with boosted protease inhibitor monotherapy

Previous studies have evaluated the simplification of HIV treatment with ritonavir-boosted protease inhibitor monotherapy, demonstrating acceptable efficacy and advantages such as avoidance of the adverse effects of reverse transcriptase inhibitors. To achieve the best results, patients should be appropriately selected for this therapy. The purpose of this study was to estimate the proportion of HIV patients suitable for boosted protease inhibitor monotherapy according to clinical trial criteria. Setting The study was conducted in the outpatient hospital pharmacy service of the Complejo Hospitalario de Navarra in northern Spain. A retrospective analysis was performed on data from 635 adults on antiretroviral therapy. The eligibility criteria were: (1) >18 years of age; (2) prior triple-drug antiretroviral regimen; (3) durability of current treatment >18 months; (4) viral load <400 copies/mL over the 18 months before evaluation and <50 copies/mL over the last 6 months; (5) CD4 count ≥250 cells/μL; (6) CD4 count nadir >100 cells/μL; (7) no previous virological failure under prior protease inhibitor-based regimen; (8) absence of co-infection with hepatitis B virus; (9) absence of HIV-related neurological disease; and (10) adherence >95 %. The average cost of the current treatment was calculated for patients who met all criteria, as well as the potential economic impact of simplification to monotherapy. Number of patients meeting all criteria for simplification to monotherapy according to clinical trial standards. One hundred and three patients (16.5 %) met the clinical trial criteria for protease inhibitor monotherapy. One hundred and fifty patients (24 %) failed to fulfil only one of the conditions. Fifty-four percent of the patients who met all of the criteria had been treated for more than 10 years. The average saving per patient per year was <euro>2,850-<euro>3,400. This treatment strategy represents a realistic, albeit minority, option. Fulfilment of the above conditions should be the basis for simplification to protease inhibitor monotherapy, though the final decision depends on clinical criteria and patient preferences assessed by the attending physician. Further studies are needed to confirm long-term safety and efficacy.

UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients

The nonstructural 3 serine protease inhibitors (PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C (HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment-naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side-effects and costs. To review concisely the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection. These guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed and debated at a national meeting of HCV care providers. We have made recommendations on a number of the key practical issues facing HCV care providers: (i) Which patients to treat?; (ii) Standards for the provision of care; (iii) Pre-treatment considerations; (iv) Which treatment regimens to use?; (v) Stopping rules; and (vi) Management of adverse effects. Finally, we have produced suggested algorithms for the assessment and treatment of these patients. These UK Consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.

HIV-1 Antiretroviral Resistance

The efficacy of an antiretroviral (ARV) treatment regimen depends on the activity of the regimen’s individual ARV drugs and the number of HIV-1 mutations required for the development of resistance to each ARV — the genetic barrier to resistance. ARV resistance impairs the response to therapy in patients with transmitted resistance, unsuccessful initial ARV therapy and multiple virological failures. Genotypic resistance testing is used to identify transmitted drug resistance, provide insight into the reasons for virological failure in treated patients, and help guide second-line and salvage therapies. In patients with transmitted drug resistance, the virological response to a regimen selected on the basis of standard genotypic testing approaches the responses observed in patients with wild-type viruses. However, because such patients are at a higher risk of harbouring minority drug-resistant variants, initial ARV therapy in this population should contain a boosted protease inhibitor (PI) — the drug class with the highest genetic barrier to resistance.In patients receiving an initial ARV regimen with a high genetic barrier to resistance, the most common reasons for virological failure are nonadherence and, potentially, pharmacokinetic factors or minority transmitted drug-resistant variants. Among patients in whom first-line ARVs have failed, the patterns of drug-resistance mutations and cross-resistance are often predictable. However, the extent of drug resistance correlates with the duration of uncontrolled virological replication. Second-line therapy should include the continued use of a dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing backbone, together with a change in the non-NRTI component, most often to an ARV belonging to a new drug class.The number of available fully active ARVs is often diminished with each successive treatment failure. Therefore, a salvage regimen is likely to be more complicated in that it may require multiple ARVs with partial residual activity and compromised genetic barriers of resistance to attain complete virological suppression. A thorough examination of the patient’s ARV history and prior resistance tests should be performed because genotypic and/or phenotypic susceptibility testing is often not sufficient to identify drug-resistant variants that emerged during past therapies and may still pose a threat to a new regimen. Phenotypic testing is also often helpful in this subset of patients. ARVs used for salvage therapy can be placed into the following hierarchy: (i) ARVs belonging to a previously unused drug class; (ii) ARVs belonging to a previously used drug class that maintain significant residual antiviral activity; (iii) NRTI combinations, as these often appear to retain in vivo virological activity, even in the presence of reduced in vitro NRTI susceptibility; and rarely (iv) ARVs associated with previous virological failure and drug resistance that appear to have possibly regained their activity as a result of viral reversion to wild type. Understanding the basic principles of HIV drug resistance is helpful in guiding individual clinical decisions and the development of ARV treatment guidelines.

Unboosted Atazanavir for Treatment of HIV Infection

Atazanavir (Reyataz®) is a protease inhibitor (PI) for the treatment of HIV infection. Several trials have demonstrated the good efficacy and toxicity profile of atazanavir boosted by ritonavir (atazanavir/r). However, several toxicity events and pharmacokinetic issues due to drug-to-drug interactions (partly related to ritonavir) may complicate atazanavir/r therapy. This is why regimens with unboosted atazanavir have been experimented with and are used in clinical practice. The aim of this article is to identify the clinical settings in which unboosted atazanavir may be a safe and effective option for the long-term control of HIV replication. Despite the fact that a favourable lipid profile and good gastrointestinal tolerability have been reported in comparative trials, unboosted atazanavir should not be considered an optimal choice for treatment-naive patients. In fact, boosting with ritonavir produces higher atazanavir plasma levels, which are beneficial in terms of efficacy, especially in untreated patients with high plasma HIV RNA. Clinical data indicate that, in patients with sustained undetectable HIV RNA and without previous virological failure or HIV drug resistance-associated mutations, a switch to unboosted atazanavir-based regimens is a feasible option to control and prevent toxicity events, especially in patients who cannot tolerate ritonavir and in those with severe hyperbilirubinaemia on atazanavir/r. Moreover, while unboosted atazanavir must not be used in pregnant women, it is a recommended option in special populations, such as patients with moderate liver insufficiency. Lastly, unboosted atazanavir in combination with raltegravir may allow the construction of a well tolerated and effective regimen without nucleoside reverse transcriptase inhibitors in patients for whom these drugs are contraindicated. In conclusion, there is a good rationale, significant clinical interest and accumulating clinical experience with unboosted atazanavir-based regimens, although this formulation should be used only in specific situations and as a maintenance strategy. Moreover, therapeutic drug monitoring could be useful in specific circumstances (such as in patients with liver impairment or in case of potential drug-drug interactions).

Optimal Antiviral Switching to Minimize Resistance Risk in HIV Therapy

The development of resistant strains of HIV is the most significant barrier to effective long-term treatment of HIV infection. The most common causes of resistance development are patient noncompliance and pre-existence of resistant strains. In this paper, methods of antiviral regimen switching are developed that minimize the risk of pre-existing resistant virus emerging during therapy switches necessitated by virological failure. Two distinct cases are considered; a single previous virological failure and multiple virological failures. These methods use optimal control approaches on experimentally verified mathematical models of HIV strain competition and statistical models of resistance risk. It is shown that, theoretically, order-of-magnitude reduction in risk can be achieved, and multiple previous virological failures enable greater success of these methods in reducing the risk of subsequent treatment failures.

Added Value of Deep Sequencing Relative to Population Sequencing in Heavily Pre-Treated HIV-1-Infected Subjects

ObjectiveTo explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects.MethodsIn a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%.Results7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir.ConclusionsIn this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects.

Viral response in stable patients switching to fosamprenavir/ritonavir monotherapy (the FONT Study)

The aim of the study was to evaluate the efficacy of fosamprenavir/ritonavir (FPV/r) monotherapy in plasma and reservoirs in virologically suppressed patients. A 48-week, prospective, single-arm pilot trial was carried out (trial registration: ISRCTN78584791). Patients receiving triple therapy [FPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least the previous month], with viral load (VL) <40 HIV-1 RNA copies/mL and no previous virological failure (VF) on protease inhibitors (PIs), were included in the trial and received FPV/r monotherapy (700/100 mg/12 h). VL and FPV/r levels [by liquid chromatography-tandem mass spectrometry (LC/MS/MS); limit of detection (LOD) 0.5 ng/mL] in cerebrospinal fluid (CSF) were determined at week 24. VF was defined as VL >40 copies/mL in three consecutive samples or >500 copies/mL in two samples. Enrolment was prematurely stopped because of a high percentage of VF. Twenty patients (45% men; median age 43.5 years) were included in the trial. Nine patients (45%) presented therapeutic failure [seven (35%) had VF, and two discontinued therapy]. Resistance testing was available in five patients. One patient presented major PI mutations (54L, 32I and 47V) in addition to one minor mutation (13V), whereas two patients had minor PI mutations (10V+36I and 71T, respectively). The patient with major PI mutations switched from FPV/r to darunavir/r and VL was re-suppressed. In the other six patients with VF, VL was re-suppressed after the reintroduction of NRTIs. VL was <40 copies/mL in all CSF samples (n=10). Median amprenavir plasma levels were 2.5 μg/mL (range 0.7-8.6 μg/mL) at week 24 and 2.5 μg/mL (range 0.4-3.8 μg/mL) at VF. The CSF amprenavir concentration was 28.1 ng/mL (range 6.39-83.6 ng/mL), exceeding the reported 50% inhibitory concentration (IC(50) ) range for CSF in nine of 11 patients. The high percentage of patients with VF in our study suggests that the use of FPV/r in a simplification monotherapy strategy should be discouraged. Adequate amprenavir levels and undetectable VL in CSF were documented in all samples evaluated.