Ritonavir-boosted Protease Inhibitor Research Articles

Chronic Kidney Disease and Antiretroviral Therapy in HIV-Positive Individuals: Recent Developments.

Chronic kidney disease (CKD) has emerged as an important health concern in HIV-positive individuals. Preventing long-term kidney toxicity from an antiretroviral therapy is therefore critical. Selected antiretroviral agents, especially tenofovir disoproxil fumarate (TDF) and some ritonavir-boosted protease inhibitors (PI/rs), have been associated with increased risk of CKD. However, the CKD risk attributable to these agents is overall small, especially in those with low baseline risk of CKD and normal renal function. CKD risk in HIV-positive individuals can be further minimized by timely identification of those with worsening renal function and discontinuation of potentially nephrotoxic agents. Clinicians can use several monitoring tools, including the D:A:D risk score and routine measurements of estimated glomerular filtration (eGFR) and proteinuria, to identify high-risk individuals who may require an intervention. Tenofovir alafenamide (TAF), a TDF alternative, promises to be safer in terms of TDF-associated kidney and bone toxicity. While the short-term data on TAF does indicate lower eGFR decline and lower risk of proteinuria (vs. TDF), long-term data on renal safety of TAF are still awaited. Promising results have also emerged from recent trials on alternative dual-therapy antiretroviral regimens which exclude the nucleoside(tide) reverse transcriptase class as well as possibly the PI/rs, thereby reducing the drug burden, and possibly the toxicity. However, long-term safety or benefits of these dual-therapy regimens are still unclear and will need to be studied in future prospective studies. Finally, addressing risk factors such as hypertension and diabetes will continue to be important in this population.

Nonnucleoside Reverse-transcriptase Inhibitor- vs Ritonavir-boosted Protease Inhibitor-based Regimens for Initial Treatment of HIV Infection: A Systematic Review and Metaanalysis of Randomized Trials.

Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. We searched databases to identify randomized trials that compared NNRTI- vs PI/r-based initial therapy. A metaanalysis calculated risk ratios (RRs) or mean differences (MDs), as appropriate. Primary outcome was death or progression to AIDS. Secondary outcomes were death, progression to AIDS, and treatment discontinuation. We calculated RR of virologic suppression and MD for an increase in CD4 cells at week 48. We included 29 trials with 9047 participants. Death or progression to AIDS occurred in 226 participants in the NNRTI arm and in 221 in the PI/r arm (RR, 1.03; 95% confidence interval, .87-1.22; 12 trials; n = 3825), death in 205 participants in the NNRTI arm vs 198 in the PI/r arm (1.04; 0.86-1.25; 22 trials; n = 8311), and progression to AIDS in 140 participants in the NNRTI arm vs 144 in the PI/r arm (1.00; 0.80-1.25; 13 trials; n = 4740). Overall treatment discontinuation (1.12; 0.93-1.35; 24 trials; n = 8249) and from toxicity (1.21; 0.87-1.68; 21 trials; n = 6195) were comparable, but discontinuation due to virologic failure was more common with NNRTI (1.58; 0.91-2.74; 17 trials; n = 5371). At week 48, there was no difference between NNRTI and PI/r in virologic suppression (RR, 1.03; 0.98-1.09) or CD4(+) recovery (MD, -4.7 cells; -14.2 to 4.8). We found no difference in clinical and viro-immunologic outcomes between NNRTI- and PI/r-based therapy.

Maraviroc, as a Switch Option, in HIV-1-infected Individuals With Stable, Well-controlled HIV Replication and R5-tropic Virus on Their First Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Plus Ritonavir-boosted Protease Inhibitor Regimen: Week 48 Results of the Randomized, Multicenter MARCH Study.

Alternative combination antiretroviral therapies in virologically suppressed human immunodeficiency virus (HIV)-infected patients experiencing side effects and/or at ongoing risk of important comorbidities from current therapy are needed. Maraviroc (MVC), a chemokine receptor 5 antagonist, is a potential alternative component of therapy in those with R5-tropic virus. The Maraviroc Switch Study is a randomized, multicenter, 96-week, open-label switch study in HIV type 1-infected adults with R5-tropic virus, virologically suppressed on a ritonavir-boosted protease inhibitor (PI/r) plus double nucleoside/nucleotide reverse transcriptase inhibitor (2 N(t)RTI) backbone. Participants were randomized 1:2:2 to current combination antiretroviral therapy (control), or replacing the protease inhibitor (MVC + 2 N(t)RTI arm) or the nucleoside reverse transcriptase inhibitor backbone (MVC + PI/r arm) with twice-daily MVC. The primary endpoint was the difference (switch minus control) in proportion with plasma viral load (VL) <200 copies/mL at 48 weeks. The switch arms were judged noninferior if the lower limit of the 95% confidence interval (CI) for the difference in the primary endpoint was < -12% in the intention-to-treat (ITT) population. The ITT population comprised 395 participants (control, n = 82; MVC + 2 N(t)RTI, n = 156; MVC + PI/r, n = 157). Baseline characteristics were well matched. At week 48, noninferior rates of virological suppression were observed in those switching away from a PI/r (93.6% [95% CI, -9.0% to 2.2%] and 91.7% [95% CI, -9.6% to 3.8%] with VL <200 and <50 copies/mL, respectively) compared to the control arm (97.6% and 95.1% with VL <200 and <50 copies/mL, respectively). In contrast, MVC + PI/r did not meet noninferiority bounds and was significantly inferior (84.1% [95% CI, -19.8% to -5.8%] and 77.7% [95% CI, -24.9% to -8.4%] with VL <200 and <50 copies/mL, respectively) to the control arm in the ITT analysis. These data support MVC as a switch option for ritonavir-boosted PIs when partnered with a 2-N(t)RTI backbone, but not as part of N(t)RTI-sparing regimens comprising MVC with PI/r. NCT01384682.

Evolution of renal function in African patients initiating second-line antiretroviral treatment: findings from the ANRS 12169 2LADY trial.

To investigate change in renal function in African patients initiating second-line antiretroviral therapy (ART) including ritonavir-boosted protease inhibitor (PI/r) with or without tenofovir disoproxil fumarate (TDF). HIV-1-positive adults, failing standard first-line ART were randomized to either TDF/emtricitabine (FTC)+LPV/r, abacavir + didanosine +LPV/r or TDF/FTC+ darunavir (DRV)/r and followed for 18 months. Patients with an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 at baseline were included in this analysis. Data from 438 out of 454 randomized patients were analysed. Median age was 38 years and 72% were women. Initiation of PI/r-based second-line regimen induced a marked eGFR decline of -10.5 ml/min/1.73 m2 at week 4 in all treatment groups with a greater decrease in TDF/FTC+LPV/r arm (-15.1 ml/min/1.73 m2). At month 18, mean eGFR in the non-TDF containing regimen recovered its baseline level and was significantly greater than eGFR 18-month levels in the TDF-containing regimens that experienced only partial recovery (difference: -10.7; CI -16.8, -4.6; P=0.001 in TDF/FTC+LPV/r and -6.4; CI -12.5, -0.3; P=0.04 in TDF/FTC+DRV/r). At 18 months, prevalence of stage 3 chronic kidney disease was low (<3%) and not associated with treatment. One treatment discontinuation and five TDF dosage reductions for renal toxicities were reported in TDF-containing arms. Overall, these results suggest a reasonable renal tolerance of a regimen associating TDF/FTC+PI/r in African patients with eGFR>60 ml/ml/1.73 m2 at baseline. They also support the recommendation of reassessing renal function 1 month after initiation of treatment including ritonavir to account for the ritonavir-related artefactual decrease of eGFR and determine the new reference baseline value.

HIV-1 p24 and CD4+ T cell count during boosted protease-inhibitor monotherapy in HIV-infected patients

BackgroundPlasma HIV p24 is considered a significant predictor of CD4+ T cell decline and progression to AIDS in HIV-infected patients. We evaluated the p24 levels in patients on triple therapy and after switching to ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv), as well as the relationships with virological and immunological evolution. Materials and methodsPlasma samples from patients participating in two studies of simplification to mtPI/rtv were analysed for presence of p24, using a boosted enzyme-linked immunosorbent assay specific for mature p24. Only patients with available samples at baseline (on triple therapy) and during a follow-up of at least 12 months after switching to mtPI/rtv were included. ResultsA total of 233 samples from 51 patients were analysed. After switching to mtPI/rtv and a median follow-up of 24 months, 14 patients maintained continuous undetectable viraemia, and 37 patients experienced a total of 49 transient viraemic episodes. Unexpectedly, the evolutionary p24 patterns were uniform for most patients, both before and after switching to mtPI/rtv, independently of the virological behaviour, fitting into one of three categories: persistent undetectable p24 levels, positive p24, matching only with the viraemic episodes, and persistent detectable p24 levels. The last group showed lower CD4+ T cell counts and percentages, as well as lower CD4+/CD8+ T cell ratios after 12 and 24 months of follow up. ConclusionTreatment simplification to mtPI/rtv does not influence the behaviour of p24 in plasma. Patients with continuous positive p24, despite undetectable viraemia, showed worse immunological evolution.

Effectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens.

Background and ObjectiveSignificant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens.MethodsThis retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure).ResultsA total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI95, 76.8−81.8) and 91.5% (CI95, 89.6–93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations.ConclusionSwitching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for the administered drug.

Lipid Changes in Virologically Suppressed HIV-Infected Patients Switching from any Antiretroviral Therapy to the Emtricitabine/Rilpivirine/Tenofovir Single Tablet

We carried out a retrospective, multicenter study of a cohort of 298 asymptomatic HIV-infected patients who switched from a regimen based on 2 nucleoside reverse transcriptase inhibitors + protease inhibitor (PI)/nonnucleoside reverse transcriptase inhibitor or ritonavir-boosted PI monotherapy to emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) to analyze lipid changes. At 24 weeks, 284 (95.3%) patients were still taking the same regimen, maintaining similar CD4 counts as at baseline (651 versus 672 cells/mm(3), P = .08), and 98.9% of them with an undetectable viral load. Eight of the other 14 patients were lost to follow up and 6 (2.0%) ceased the new regimen: 3 due to adverse effects, 2 due to virologic failure, and 1 due to abandonment. The mean levels of fasting total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides fell at 12 and 24 weeks, with no changes detected in the TC to HDL-C ratio.

Dual Raltegravir–Darunavir/Ritonavir Combination in Virologically Suppressed HIV-1-Infected Patients on Antiretroviral Therapy Including a Ritonavir-Boosted Protease Inhibitor Plus Two Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Background: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class.Methods: We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks.Results: As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (−85.2 mg/dL), in the prevalence of tubular proteinuria (−56%) and in the mean level of interleukin-6 (−0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events.Conclusion: In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism.

Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in Asian Subjects with Human Immunodeficiency Virus 1 Infection: A Sub-Analysis of Phase 3 Clinical Trials.

The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naïve and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naïve subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively. Studies GS-US-236-115 and GS-US-236-121 were randomized, open-label, 96-week long conducted in ART-experienced subjects, who switched to E/C/F/TDF from ritonavir-boosted protease inhibitors (PI+RTV)+F/TDF, or non-nucleoside reverse transcriptase inhibitors (NNRTI)+F/TDF regimens. The E/C/F/TDF appeared to have sustained efficacy and safety and was well tolerated in the small number of ART-naïve and ART-experienced Asian subjects.

Dual therapy based on raltegravir and boosted protease inhibitors - the experience of Polish centers.

IntroductionThe aim of the study was to present the experience of Polish centers regarding dual therapy based on the integrase inhibitor raltegravir (RAL) and ritonavir-boosted protease inhibitors (PI/r) for treating treatment-naïve and -experienced HIV-infected patients.Material and methodsThe paper concerns a retrospective multicenter study. The medical databases of six main Polish HIV centers from January 2009 to December 2014 were analyzed for the use of combined antiretroviral treatment consisting of RAL + PI/r. This study included 126 HIV-infected patients receiving RAL + PI/r therapy, of whom 17 patients were treatment-naive and 109 patients were treatment-experienced.ResultsIn treatment-experienced patients, the most common reasons for the introduction of a RAL + PI/r regimen were virologic failure and impaired renal function (45 of 109 patients). In the treatment-naïve group kidney disease was the cause of the RAL + PI/r regimen in 3 of 17 participants. In treatment-experienced patients, 80% of individuals still were on RAL + PI/r treatment after 12 months, 65% after 24 months and 53% of subjects after 60 months. In both groups, the simplification of the antiretroviral regimen was the most common reason for discontinuation of RAL + PI/r based therapy.ConclusionsIn antiretroviral-experienced patients the dual therapy based on RAL + PI/s is safe and effective. In antiretroviral-naïve patients the RAL + PI/r regimen is rarely used in Poland.

Late treatment failures in cerebrospinal fluid in patients on long-term maintenance ART with ritonavir-boosted protease PI monotherapy.

Antiretroviral treatment (ART) with ritonavir-boosted protease inhibitor monotherapy (rb-PMT) remains a potentially attractive strategy for treatment simplification in HIV-infected individuals. However, long-term follow-up in particular with respect to HIV-RNA suppression in cerebrospinal fluids (CSF) is still lacking. Patients who participated in one of the three monotherapy trials [indinavir/r, ATARITMO (atazanavir/r), MOST (lopinavir/r)] at our HIV clinic and remained successfully suppressed during the entire trial (plasma<50 copies/mL, CSF<100 copies/mL) were offered to continue their monotherapy under close monitoring. While on rb-PMT, patients were asked to provide CSF samples in yearly or 2-yearly intervals. All patients fully suppressed in plasma and CSF for at least 12months were included in the analysis. Patients demonstrating any failure in plasma or CSF resumed triple combined ART. A total of 27 patients (5 women and 22 men) fulfilled the entry criteria. The median follow-up time was 4.8 (1.1-10.9) years with an overall experience of 139 patient-years on monotherapy. Eleven of 27 (41%) patients (2 women and 9 men) developed virologic failure (1 in plasma only, 4 in CSF only, 4 both in plasma and CSF and 2 in plasma with CSF not available). Plasma failure occurred in 7 patients after a median follow-up of 25 (13-32) months, and CSF failure in 8 patients after a median follow-up of 30 (14-64) months. Seven patients are still on rb-PMT with atazanavir/r. Failure was associated with shorter duration of fully suppressed plasma viral load prior to starting (p<0.022). For selected patients, rb-PMT might be a valid long-term treatment strategy. Nevertheless, even after 12months of full HIV-RNA suppression, more than 1/3 of patients may still develop failure in either plasma or CSF. Given the observation of isolated CSF failure, treatment monitoring with regular lumbar puncture should be recommended in rb-PMT. Only monotherapy with atazanavir/r was successful beyond 39months. Monotherapy failure was significantly associated with a shorter duration of complete HIV-RNA suppression in plasma prior to rb-PMT start. Further investigation is needed to better identify predictors for patients that will qualify for successful long-term rb-PMT.

Nephrotoxicity during tenofovir treatment: a three-year follow-up study in a Brazilian reference clinic

In this study, 275 patients in use of tenofovir were retrospectively followed-up for three years to evaluate risk factors involved in impaired renal function. Analysis of variance (ANOVA) and Tukey's test were used to verify any differences in creatinine levels and estimated clearance at 0, 6, 12, 24 and 36 months, adjusting for the co-variables sex, skin color, age >50 years, arterial hypertension, diabetes and the use of the ritonavir-boosted protease inhibitors (PI/r) lopinavir/r or atazanavir/r. The software package STATISTICA 10® was used for statistical analysis. The patients’ mean age was 43.2±10.7 years. Systemic arterial hypertension (SAH) and diabetes were found in 20.4% and 8.7% of the patients, respectively. Overall, 96.7% were on tenofovir associated with lamivudine (TDF+3TC), 39.3% on lopinavir/r, 29.8% on efavirenz, and 17.6% on atazanavir/r. There was a statistically significant difference in estimated creatinine clearance at 24 months, when the co-variables male (F=3.95; p=0.048), SAH (F=6.964; p=0.009), and age over 50 years (F=45.81; p<0.001) were taken into consideration. Analysis of the co-variable use of atazanavir/r showed a tendency toward an increased risk over time (F=2.437; p=0.063); however, no significant time interaction was seen. At 36-month, a statistically significant difference was found for age over 50 years, (F=32.02; p<0.05) and there was a significant time-by-sex interaction (F=3.117; p=0.0149). TDF was discontinued in 12 patients, one because of a femoral neck fracture (0.7%) and 11 due to nephrotoxicity (4%). Of these latter cases, 9/11 patients were also using protease inhibitors. These data strongly alert that tenofovir use should be individualized with careful attention to renal function especially in male patients, over 50 years, with SAH, and probably those on ATV/r.

Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study

Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration of exposure to antiretrovirals and the development of chronic kidney disease in people with initially normal renal function, as measured by estimated glomerular filtration rate (eGFR). In this prospective international cohort study, HIV-positive adult participants (aged ≥16 years) from the D:A:D study (based in Europe, the USA, and Australia) with first eGFR greater than 90 mL/min per 1·73 m(2) were followed from baseline (first eGFR measurement after Jan 1, 2004) until the occurrence of one of the following: chronic kidney disease; last eGFR measurement; Feb 1, 2014; or final visit plus 6 months (whichever occurred first). Chronic kidney disease was defined as confirmed (>3 months apart) eGFR lower than 60 mL/min per 1·73 m(2). The primary outcome was the occurrence of chronic kidney disease. Poisson regression was used to estimate the incidence rate of chronic kidney disease associated with cumulative exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, ritonavir-boosted lopinavir, other ritonavir-boosted protease inhibitors, or abacavir. Between Jan 1, 2004, and July 26, 2013, 23,905 eligible individuals from the D:A:D study were included. Participants had a median baseline eGFR of 110 mL/min per 1·73 m(2) (IQR 100-125), a median age of 39 years (33-45), and median CD4 cell count of 441 cells per mm(3) (294-628). During a median follow-up of 7·2 years (IQR 5·1-8·9), 285 (1%) of 23,905 people developed chronic kidney disease (incidence 1·76 per 1000 person-years of follow-up [95% CI 1·56-1·97]). After adjustment, we recorded a significant increase in chronic kidney disease associated with each additional year of exposure to tenofovir disoproxil fumarate (adjusted incidence rate ratio 1·14 [95% CI 1·10-1·19], p<0·0001), ritonavir-boosted atazanavir (1·20 [1·13-1·26], p<0·0001), and ritonavir-boosted lopinavir (1·11 [1·06-1·16], p<0·0001), but not other ritonavir-boosted protease inhibitors or abacavir. In people with normal renal function, the annual incidence of chronic kidney disease increased for up to 6 years of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir therapy. Although the absolute number of new cases of chronic kidney disease was modest, treatment with these antiretrovirals might result in an increasing and cumulative risk of chronic kidney disease. Patients on potentially nephrotoxic antiretrovirals or at high risk of chronic kidney disease should be closely monitored. The Highly Active Antiretroviral Therapy Oversight Committee.

Risk of Liver Enzyme Elevation During Treatment With Ritonavir-Boosted Protease Inhibitors Among HIV-Monoinfected and HIV/HCV-Coinfected Patients.

The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection. Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus. A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab-positive and HCV-RNA-positive patients, respectively. Among HCV-Ab-negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab-positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA-positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab-positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis. Occurrence of hepatotoxicity was a rare finding among HCV-Ab-negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus.

Efavirenz-Based Regimens in Antiretroviral-Naive HIV-Infected Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Efavirenz, a non-nucleoside reverse-transcriptase inhibitor (NNRTI) is one of the most commonly prescribed antiretroviral drugs. The present article provides a systematic overview and meta-analysis of clinical trials comparing efavirenz and other active drugs currently recommended for treatment of HIV-infected, antiretroviral-naive patients. Electronic databases (Pubmed, Embase, the Cochrane Library, Trip Database) were searched up till 23 December 2013 for randomized controlled clinical trials published as a peer-reviewed papers, and concerning efavirenz-based regimens used as initial treatment for HIV infection. Thirty-four studies were included in the systematic review, while twenty-six trials were suitable for the meta-analysis. Efavirenz was compared with drugs from four different classes: NNRTIs other than efavirenz (nevirapine or rilpivirine), integrase strand transfer inhibitors (InSTIs), ritonavir-boosted protease inhibitors (bPI) and chemokine (C-C motif) receptor 5 (CCR5) antagonists (maraviroc), all of them were added to the background regimen. Results of the current meta-analysis showed that efavirenz-based regimens were equally effective as other recommended regimens based on NNRTI, ritonavir-boosted PI or CCR5 antagonist in terms of efficacy outcomes (disease progression and/or death, plasma viral HIV RNA <50 copies/ml) while statistically significant more patients treated with InSTI achieved plasma viral load <50 copies/ml at week 48. In comparison with both InSTI-based and CCR5-based therapy, efavirenz-based treatment was associated with a higher risk of therapy discontinuation due to adverse events. However, comparisons of efevirenz-based treatment with InSTI-based and CCR5-based therapy were based on a limited number of trials, therefore, conclusions from these two comparisons must be confirmed in further reliable randomized controlled studies. Results of our meta-analysis support the present clinical guidelines for antiretroviral-naive, HIV-infected patients, in which efavirenz is one of the most preferred regimens in the analyzed population. Beneficial safety profile of InSTI-based and CCR5-based therapy over efavirenz-based treatment needs further studies.

Early Experience with a Boosted PI–Based Single-Tablet Regimen

Despite the need for multiple pills daily, ritonavir-boosted protease inhibitor (PI)–based regimens have been a mainstay for treatment of HIV-infected

Baseline Antiretroviral Resistance Mutations and Treatment-Emergent Resistance in HIV-1 RNA-Suppressed Patients Switching to EVG/COBI/FTC/TDF or Continuing on Their PI-, NNRTI-, or RAL-Based Regimen

Stably suppressed HIV-1-infected patients that switched to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) from regimens containing FTC/TDF plus a ritonavir-boosted protease inhibitor (PI + RTV), nonnucleoside reverse transcriptase inhibitor (NNRTI), or raltegravir in phase 3 studies STRATEGY-PI, STRATEGY-NNRTI, and GS-US-236-0123 maintained high rates of virologic suppression through 48 weeks. In this article, resistance analyses for these studies are described. HIV-1 historical genotypes obtained before therapy initiation were analyzed for preexisting/transmitted resistance (-R) in protease and reverse transcriptase (RT) and subtype. Patients with resistance to FTC/TDF were excluded. Viral isolates with HIV-1 RNA ≥400 copies per milliliter at confirmed virologic failure, discontinuation, or week 48 were analyzed for protease, RT, and integrase genotype and phenotype. Historical genotypes from 626/628 subjects that switched to EVG/COBI/FTC/TDF indicated 25% had ≥1 primary resistance mutation in protease and/or RT. NNRTI-R was identified in 15%, NRTI-R in 8.3%, and PI-R in 3.7% of subjects. Week 48 virologic success rates (HIV-1 RNA <50 copies per milliliter) were 94% for all patients treated with EVG/COBI/FTC/TDF, 94% with preexisting resistance, 93% with subtype B, and 96% with non-B subtypes. Altogether, 2 subjects qualified for postbaseline resistance analyses. Neither had emergent resistance, and both resuppressed to HIV-1 RNA <50 copies per milliliter with no change in therapy. Switching antiretroviral regimens to EVG/COBI/FTC/TDF in HIV-1 RNA-suppressed FTC/TDF-sensitive patients resulted in maintained virologic suppression through 48 weeks. Similar virologic success rates were achieved irrespective of the presence of preexisting resistance mutations or subtype. The lack of emergent resistance through 48 weeks supports utility of EVG/COBI/FTC/TDF for treatment-experienced patients seeking regimen modification or simplification.

Improvement in Renal Function and Bone Mineral Density after a Switch from Tenofovir/Emtricitabine plus Ritonavir-Boosted Protease Inhibitor to Raltegravir plus Nevirapine: A Pilot Study

The antiretroviral regimens including tenofovir and a ritonavir-boosted protease inhibitor (r/PI) have been associated with a reduced bone mineral density (BMD), increased bone turnover markers and renal tubular dysfunction. An observational, prospective study was performed including HIV-1-infected, virologically suppressed patients treated with tenofovir/emtricitabine plus an r/PI for at least 12 months who switched to raltegravir plus nevirapine. The primary end point was changes after 48 weeks in estimated glomerular filtration rate (eGFR), prevalence of tubular dysfunction, BMD and concentration of two serum markers of bone turnover: collagen type-1 cross-linked C-telopeptide (CTX) and bone-specific alkaline phosphatase (BAP). A total of 46 patients were enrolled: 78% were male, 96% were Caucasian, the mean age was 45 years and the mean CD4(+) T-lymphocyte count was 681 cells/mm(3). A renal impairment was present in 72% of patients and was the main reason for the switch. After 48 weeks, prevalence of proximal tubular dysfunction decreased significantly (-72%; P<0.001), whereas the mean value of eGFR did not change significantly. At the same time, after 48 weeks a significant increase in both lumbar spine and total hip BMD, T-score and Z-score was reported (+11.5% in lumbar spine T-score; P<0.001), and there was a significant reduction in both CTX and BAP mean serum concentrations (-15% and -13%, respectively; P<0.001). Two (4.3%) patients had virological failure due to suboptimal adherence and one (2.2%) subject discontinued treatment due to a skin rash. Switching virologically suppressed patients from tenofovir/emtricitabine plus one r/PI to raltegravir plus nevirapine after 48 weeks significantly improved proximal tubular function, increased BMD and reduced serum markers of bone turnover.

Towards interferon-free treatment for all HCV genotypes

It is surely unique in modern medicine that regulatory agencies should approve seven new compounds to treat a specific disease within just 12 months. The European Commission granted marketing authorisation for sofosbuvir, a nucleotide hepatitis C virus (HCV) polymerase inhibitor, in January, 2014. Since then, the HCV protease inhibitor simeprevir (May, 2014), the NS5A inhibitor daclatasvir (August, 2014), and the single-tablet combination of the HCV NS5 inhibitor ledipasvir with sofosbuvir (November, 2014) have reached the market; followed most recently by the three-drug combination of ombitasvir (NS5A inhibitor), the ritonavir-boosted protease inhibitor paritaprevir, and the first non-nucleosidic polymerase inhibitor dasabuvir (January, 2015).

Patient-Reported Outcomes After a Switch to a Single-Tablet Regimen of Rilpivirine, Emtricitabine, and Tenofovir DF in HIV-1-Positive, Virologically Suppressed Individuals: Additional Findings From a Randomized, Open-Label, 48-Week Trial.

BackgroundPatient-reported outcomes (PROs) can provide important information about treatment tolerability in HIV-1-infected patients.ObjectiveThe aim of this study was to evaluate PROs following switching from a boosted protease inhibitor-based regimen to the single-tablet regimen (STR) of rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) in the 48-week open-label Switching Boosted PI to Rilpivirine in Combination with Truvada as a Single-Tablet Regimen (SPIRIT) trial.MethodsIn the open-label SPIRIT trial, patients were randomized to receive an STR of RPV/FTC/TDF (n = 317) for 48 weeks or stay on their baseline regimen of a ritonavir-boosted protease inhibitor and two nucleoside/nucleotide analog reverse transcriptase inhibitors (PI + RTV + 2NRTIs, n = 159) for 24 weeks before switching to RPV/FTC/TDF for another 24 weeks. PRO assessments included the HIV Treatment Satisfaction Questionnaire (TSQ) and the HIV Symptom Index Questionnaire (SIQ).ResultsAt week 24, the mean HIV TSQ improvement from baseline was significantly greater in the RPV/FTC/TDF group than the PI + RTV + 2NRTIs group (p < 0.001). On the HIV SIQ, the percentage of patients reporting a shift from ‘symptom’ to ‘no symptom’ was significantly greater with RPV/FTC/TDF treatment compared with PI + RTV + 2NRTIs for all items (all p ≤ 0.01), with total within-group occurrence of 13/20 symptoms significantly decreasing from baseline for RPV/FTC/TDF patients. In the delayed switch group, significantly fewer patients reported diarrhea and sleep problems at week 48 vs. week 24.ConclusionsThese data suggest that switching to the STR RPV/FTC/TDF from a PI-based multi-pill regimen is associated with greater patient-reported treatment satisfaction and improved tolerability in HIV-1-infected, virologically suppressed individuals.Electronic supplementary materialThe online version of this article (doi:10.1007/s40271-015-0123-2) contains supplementary material, which is available to authorized users.