Antiretrovirals and Weight Change: Weighing the Evidence.

Body weight is influenced by an interplay of individual and environmental factors. In people with HIV (PWH), weight is also influenced by disease status with loss accompanying disease progression that is reversed with effective antiretroviral therapy (ART). Weight changes in comparative ART trials differ by regimen, with greater gains observed with the integrase strand transfer inhibitors (INSTIs) dolutegravir and bictegravir, particularly when co-administered with tenofovir alafenamide fumarate (TAF), compared to regimens that include agents such as tenofovir disoproxil fumarate (TDF) that attenuate weight gain. We review weight changes in major randomized trials of pre-exposure prophylaxis (PrEP) and initial and switch HIV therapy, highlighting the challenges to assessing the role of ART in weight change. This examination forms the basis for a model that questions assumptions regarding an association between INSTI and TAF and excessive weight gain and calls for more careful consideration of these data when making HIV treatment decisions.

Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment.

This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF.

A pseudo-response approach to constructing confidence intervals for the subset of patients expected to benefit from a new treatment.

In precision medicine, there is much interest in estimating the expected-to-benefit (EB) subset, i.e. the subset of patients who are expected to benefit from a new treatment based on a collection of baseline characteristics. There are many statistical methods for estimating the EB subset, most of which produce a 'point estimate' without a confidence statement to address uncertainty. Confidence intervals for the EB subset have been defined only recently, and their construction is a new area for methodological research. This article proposes a pseudo-response approach to EB subset estimation and confidence interval construction. Compared to existing methods, the pseudo-response approach allows us to focus on modelling a conditional treatment effect function (as opposed to the conditional mean outcome given treatment and baseline covariates) and is able to incorporate information from baseline covariates that are not involved in defining the EB subset. Simulation results show that incorporating such covariates can improve estimation efficiency and reduce the size of the confidence interval for the EB subset. The methodology is applied to a randomized clinical trial comparing two drugs for treating HIV infection.

Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks.

BACKGROUND: The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection. METHODS: In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796. FINDINGS: 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI -1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 µmol/L, IQR 5 to 20 vs 1 µmol/L, -6 to 8; p<0·001). INTERPRETATION: If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection. FUNDING: Gilead Sciences.

Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens.

BACKGROUND: Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. OBJECTIVE: This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. METHODS: This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (≥3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. RESULTS: At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. CONCLUSIONS: Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.

Corrigendum: Translating the observed differences in interleukin-6 levels between some antiretroviral regimens into potential long-term risk of serious non-AIDS events: A modeling study.

[This corrects the article DOI: 10.3389/fimmu.2022.976564.].

Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial.

BACKGROUND: The non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (TMC278; Tibotec Pharmaceuticals, County Cork, Ireland), had equivalent sustained efficacy to efavirenz in a phase 2b trial in treatment-naive patients infected with HIV-1, but fewer adverse events. We aimed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). METHODS: We undertook a 96-week, phase 3, randomised, double-blind, double-dummy, non-inferiority trial in 98 hospitals or medical centres in 21 countries. We enrolled adults (≥18 years) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs. We randomly allocated patients (1:1) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily; all patients received an investigator-selected regimen of background N(t)RTIs (tenofovir-disoproxil-fumarate plus emtricitabine, zidovudine plus lamivudine, or abacavir plus lamivudine). The primary outcome was non-inferiority (12% margin on logistic regression analysis) at 48 weeks in terms of confirmed response (viral load <50 copies per mL, defined by the intent-to-treat time to loss of virologic response [TLOVR] algorithm) in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00543725. FINDINGS: From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3.5% [95% CI -1.7 to 8.8]; p(non-inferiority)<0.0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2-4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than they were with efavirenz (31% [104]; p<0.0001), as were rash and dizziness (p<0.0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p<0.0001). INTERPRETATION: Despite a slightly increased incidence of virological failures, a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1. FUNDING: Tibotec.

Impact of Tai Chi exercise on multiple fracture-related risk factors in post-menopausal osteopenic women: a pilot pragmatic, randomized trial.

BACKGROUND: Tai Chi (TC) is a mind-body exercise that shows potential as an effective and safe intervention for preventing fall-related fractures in the elderly. Few randomized trials have simultaneously evaluated TC's potential to reduce bone loss and improve fall-predictive balance parameters in osteopenic women. METHODS: In a pragmatic randomized trial, 86 post-menopausal osteopenic women, aged 45-70, were recruited from community clinics. Women were assigned to either nine months of TC training plus usual care (UC) vs. UC alone. Primary outcomes were changes between baseline and nine months of bone mineral density (BMD) of the proximal femur and lumbar spine (dual-energy X-ray absorptiometry) and serum markers of bone resorption and formation. Secondary outcomes included quality of life. In a subsample (n = 16), quiet standing fall-predictive sway parameters and clinical balance tests were also assessed. Both intent-to-treat and per-protocol analyses were employed. RESULTS: For BMD, no intent-to-treat analyses were statistically significant; however, per protocol analyses (i.e., only including TC participants who completed ≥ 75% training requirements) of femoral neck BMD changes were significantly different between TC and UC (+0.04 vs. -0.98%; P = 0.05). Changes in bone formation markers and physical domains of quality of life were also more favorable in per protocol TC vs. UC (P = 0.05). Changes in sway parameters were significantly improved by TC vs. UC (average sway velocity, P = 0.027; anterior-posterior sway range, P = 0.014). Clinical measures of balance and function showed non-significant trends in favor of TC. CONCLUSIONS: TC training offered through existing community-based programs is a safe, feasible, and promising intervention for reducing multiple fracture risks. Our results affirm the value of a more definitive, longer-term trial of TC for osteopenic women, adequately powered to detect clinically relevant effects of TC on attenuation of BMD loss and reduction of fall risk in this population. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01039012.

Translating the observed differences in interleukin-6 levels between some antiretroviral regimens into potential long-term risk of serious non-AIDS events: A modeling study.

Introduction: Variable levels of systemic inflammation are observed in people with HIV (PWH), but the clinical significance of differences among antiretroviral therapy (ART) regimens on associated levels of inflammatory markers is unclear. Based on data from previous epidemiologic studies that defined the predicted change in risk of serious non-AIDS events (SNAEs)/death by changes in interleukin-6 (IL-6) and D-dimer, we modeled the effects of differences in these markers between specific ART regimens on the long-term risk of clinical outcomes. Methods: We used a Markov model to compare the risk of SNAEs/death with differences in IL-6 and D-dimer levels associated with remaining on specific three-drug regimens versus switching to specific two-drug ART regimens over 5 years of treatment. We used IL-6 and D-dimer data based on trajectories over time from the randomized TANGO and observational AIR studies. Age at model entry was set at 39 years. The primary endpoint was the number needed to treat for one additional SNAE/death. Results: Over 144 weeks, PWH on one of the three-drug regimens studied were predicted to spend 22% more time in the low IL-6 quartile and 13% less time in the high IL-6 quartile compared with those on one of the two-drug regimens. Over 144 weeks, the predicted mean number of SNAEs/deaths per 100 PWH was 5.6 for a three-drug regimen associated with lower IL-6 levels versus 6.8 for a two-drug regimen associated with higher IL-6 levels. The number needed to treat for one additional SNAE/death among PWH receiving a two-drug versus three-drug regimen for 240 weeks was 43. Approximately 2,900 participants would be required for a 240-week clinical study to evaluate the accuracy of the model. Conclusions: Our Markov model suggests that higher IL-6 levels associated with switching from specific three- to two- drug ART regimens may be associated with an increase in the risk of SNAEs/death. Clinical studies are warranted to confirm or refute these results.

Similar efficacy of raltegravir when used with or without a protease inhibitor in treatment-experienced patients.

BACKGROUND: Patients with multiclass-resistant HIV-1 have limited treatment options. Raltegravir, an inhibitor of integrase, has shown excellent efficacy when used with protease inhibitors (Pis) in patients with drug-resistant HIV-1. Limited data are available however about the outcomes when using raltegravir without Pis in this population. METHODS: Medical records of subjects who received raltegravir as part of the Merck EAP study 0518 were reviewed and abstracted at participating sites. Eligibility criteria included HIV positivity, age ≥ 16 years, limited or no treatment options due to resistance or intolerance to multiple antiretroviral regimens, detectable viremia on current treatment regimen, and documented resistance to at least one drug in each antiretroviral class (PI, NNRTI, and nucleoside analogue). Demographic, clinical, and laboratory data were collected locally using a standardized collection form. Genotypic susceptibility scores (GSS) were determined from the most recent genotypic resistance test available prior to the initiation of raltegravir. The main objective was to compare virologic results in patients who received raltegravir with a PI versus those who received raltegravir without a PI. RESULTS: Four hundred forty-two subjects were evaluated from the respective sites in the EAP trial, of whom 340 were evaluable. The baseline mean HIV RNA was 4.6 log copies/ mL, and the mean CD4 cell count was 159 cells/µL. The median number of total and new antiretroviral agents in the background regimen was 4 and 2, respectively. Among the 254 patients who received a PI, the most common PI used was darunavir (89%). Etravirine was commonly used in both groups: 39% of the PI group and 67% of the non-PI group. At week 12, 67% of PI patients and 64% of non-PI patients achieved HIV RNA <75 copies/mL and 85% and 86%, respectively, achieved HIV RNA <400 copies/mL GSS, which was similar in both groups at baseline, predicted achieving an HIV RNA of <400 and 75 copies/mL at week 12 (P < .05). CONCLUSIONS: In treatment-experienced patients, the combination of raltegravir with a regimen not containing a PI (used with etravirine in two-thirds of patients) had similar virologic activity when compared to more standard regimens using raltegravir with a PI. The main determinant of efficacy was the number of active drugs as measured by GSS. These data expand the potential utility of raltegravir in patients with multidrug-resistant HIV.

Cost-effectiveness of nucleoside reverse transcriptase inhibitor pairs in efavirenz-based regimens for treatment-naïve adults with HIV infection in the United States.

OBJECTIVE: To estimate the cost-effectiveness of once-daily tenofovir/emtricitabine compared with twice-daily zidovudine/lamivudine and once-daily abacavir/lamivudine in treatment-naïve adults with HIV-1 infection in the United States. METHODS: A Markov model with four therapy lines and six health states based on CD4(+) cell-count ranges was developed to estimate lifetime costs and health outcomes. Efficacy data (virologic response and CD4(+) cell-count changes) for first-line therapy were from 144-week results of Study 934 comparing tenofovir/emtricitabine with zidovudine/lamivudine and 48-week results of Study CNA30024 comparing abacavir/lamivudine with zidovudine/lamivudine, all in combination with efavirenz. Data from Study CNA30024 for abacavir/lamivudine were adjusted to allow for an indirect comparison with tenofovir/emtricitabine. Subsequent therapy lines were based on likely baskets of antiretroviral therapy recommended by US treatment guidelines. Utility values, mortality rates, and costs (2009 US dollars) were obtained from published sources. Base-case results were tested in sensitivity and variability analyses. RESULTS: Average discounted results showed that individuals using tenofovir/emtricitabine were predicted to remain on first-line therapy for 7.7 years, accrue lifetime costs of $747,327, and experience 15.75 quality-adjusted life-years (QALYs), compared with 6.0 years, $777,090, and 15.68 QALYs for individuals using abacavir/lamivudine and 5.8 years, $778,287, and 15.44 QALYs for individuals using zidovudine/lamivudine. Tenofovir/emtricitabine was cost-effective compared with the other two first-line regimens in more than 75% of all probabilistic sensitivity analysis simulation runs for every willingness-to-pay threshold between $0 and $250,000 per QALY gained. Results were robust in variability and one-way sensitivity analyses. CONCLUSIONS: Tenofovir/emtricitabine was predicted to be more effective and cost-saving compared with abacavir/lamivudine and zidovudine/lamivudine in treatment-naïve adults with HIV-1 infection in the United States.

Similar virologic and immunologic efficacy with fosamprenavir boosted with 100 mg or 200 mg of ritonavir in HIV-infected patients: results of the LESS trial.

PURPOSE: ritonavir (RTV) effectively boosts most protease inhibitors but is associated with significant dose-dependent adverse events (AEs). In an effort to better manage toxicities through a reduced dose of RTV, this study compared fosamprenavir (FPV) boosted with RTV 100 mg (FPV/r100) or with RTV 200 mg (FPV/r200) daily. METHODS: this 24-week, open-label study enrolled patients taking a FPV/r 200-containing regimen who had HIV RNA <400 copies/mL and randomized them 1:2 to continue that regimen or simplify to FPV/r100 once daily. Other medications were not altered. The primary endpoint was the percentage of patients without suspected or confirmed virologic failure (HIV RNA ≥ 400 copies/mL) through week 24 by a missing/discontinuation equals failure (M/D=F) analysis. Noninferiority criteria were demonstrated if the lower bound of the 95% confidence interval (CI) for the difference in the primary endpoint rates between groups was greater than -12. RESULTS: the 2 regimens met prespecified noninferiority criteria (FPV/r100, 92%; FPV/r 200, 94%; 95% CI, -9.36 to 5.12). At week 24, the percentage of patients with HIV RNA <50 copies/mL by M/ D=F was 83% in the FPV/r100 group and 85% in the FPV/r 200 group. Drug-related grade 2-4 AEs were uncommon (FPV/r100, 4%; FPV/r 200, 7%). Median changes in lipids were similar in both groups, with the exception of triglycerides (FPV/r100, -21 mg/dL; FPV/r 200, -2 mg/dL). CONCLUSIONS: this 24-week study demonstrated that among previously suppressed patients, once-daily FPV/r100 was similar to FPV/r 200 in virologic and immunologic effects but was associated with greater decreases from baseline in triglyceride levels.

Tai Chi for osteopenic women: design and rationale of a pragmatic randomized controlled trial.

BACKGROUND: Post-menopausal osteopenic women are at increased risk for skeletal fractures. Current osteopenia treatment guidelines include exercise, however, optimal exercise regimens for attenuating bone mineral density (BMD) loss, or for addressing other fracture-related risk factors (e.g. poor balance, decreased muscle strength) are not well-defined. Tai Chi is an increasingly popular weight bearing mind-body exercise that has been reported to positively impact BMD dynamics and improve postural control, however, current evidence is inconclusive. This study will determine the effectiveness of Tai Chi in reducing rates of bone turnover in post-menopausal osteopenic women, compared with standard care, and will preliminarily explore biomechanical processes that might inform how Tai Chi impacts BMD and associated fracture risks. METHODS/DESIGN: A total of 86 post-menopausal women, aged 45-70y, T-score of the hip and/or spine -1.0 and -2.5, have been recruited from primary care clinics of a large healthcare system based in Boston. They have been randomized to a group-based 9-month Tai Chi program plus standard care or to standard care only. A unique aspect of this trial is its pragmatic design, which allows participants randomized to Tai Chi to choose from a pre-screened list of community-based Tai Chi programs. Interviewers masked to participants' treatment group assess outcomes at baseline and 3 and 9 months after randomization. Primary outcomes are serum markers of bone resorption (C-terminal cross linking telopeptide of type I collagen), bone formation (osteocalcin), and BMD of the lumbar spine and proximal femur (dual-energy X-ray absorptiometry). Secondary outcomes include health-related quality-of-life, exercise behavior, and psychological well-being. In addition, kinetic and kinematic characterization of gait, standing, and rising from a chair are assessed in subset of participants (n = 16) to explore the feasibility of modeling skeletal mechanical loads and postural control as mediators of fracture risk. DISCUSSION: Results of this study will provide preliminary evidence regarding the value of Tai Chi as an intervention for decreasing fracture risk in osteopenic women. They will also inform the feasibility, value and potential limitations related to the use of pragmatic designs for the study of Tai Chi and related mind-body exercise. If the results are positive, this will help focus future, more in-depth, research on the most promising potential mechanisms of action identified by this study. TRIAL REGISTRATION: This trial is registered in ClinicalTrials.gov, with the ID number of NCT01039012.

Low-level viremia in HIV-1 infection: consequences and implications for switching to a new regimen.

Virologic failure, or the inability to maintain or achieve viral suppression below detectable limits (<50 copies/mL), occurs in some patients with human immunodeficiency virus (HIV)-1 infection, despite being on a potent antiretroviral (ARV) regimen. Current guidelines state that the goal of therapy is to achieve and maintain HIV-1 RNA below detectable levels, with recommendations to switch regimens upon virologic failure based on the adverse consequences of higher degrees of viremia. With the introduction of potent, newer agents, the likelihood of achieving this goal in treatment-experienced patients is growing. Not all patients who experience virologic failure while on therapy suffer from immediate virologic and immunologic decline; some experience persistently low, but detectable, levels of HIV-1 RNA in the range of 50-1000 copies/mL. The threshold at which low-level viremia (LLV) becomes predictive of disease progression varies between studies, although evidence shows that incomplete viral suppression leads to the accumulation of resistance mutations with a concomitant increase in viral replication, reduction in CD4 cell counts, increased risk of virologic progression, and clinical deterioration. Furthermore, with increasing resistance, future treatment options are compromised. Although there are clinical consequences when a patient is maintained on a failing regimen, it may be preferable to delay a switch in therapy if the chance for resuppression is low. With the introduction of new ARVs within existing classes that have shown significant activity against resistant virus, as well as the introduction of two new classes of ARV agents, HIV treatment has entered a new era. The options for constructing regimens active against multidrug-resistant virus have expanded.

Prescribing and using self-injectable antiretrovirals: how concordant are physician and patient perspectives?

BACKGROUND: The selection of agents for any treatment regimen is in part influenced by physician and patient attitudes. This study investigated attitudinal motivators and barriers to the use of self-injectable antiretroviral agents among physicians and patients and measured the degree of concordance between physician and patient perspectives. METHODS: Attitudes toward prescribing and usage of self-injectable antiretroviral therapy (SIAT) were assessed by structured interview in 2 cohorts sampled from the European Union and the USA: 499 HIV-treating physicians and 603 treatment-experienced HIV-infected patients. Motivators and barriers to prescribing SIAT were identified from statistical analysis of the associations between physicians' ratings of enfuvirtide-based therapy compared to standard oral-based therapy and 2 indicators of enfuvirtide prescribing behavior. Patients' attitudes were assessed by their responses to a written profile of enfuvirtide and their ratings of the likelihood of accepting a treatment offer. RESULTS: Both indicators of SIAT prescribing behavior were predicted by the same pattern of physician beliefs. Nonprescribing was associated with: (1) the belief that offering enfuvirtide would be perceived negatively by patients, leading to treatment refusal and nonadherence; (2) the belief that prescribing enfuvirtide is harder to justify in terms of time/resources; and (3) a lack of confidence in the efficacy and use of enfuvirtide in practice (all p < 0.05). However, physicians' beliefs were not in concordance with patients' views. After reading a profile of enfuvirtide, 76% patients said that they would be moderately or highly likely to accept a treatment offer, although most (72%) had not discussed enfuvirtide with their doctor. Patients' beliefs predicted the likelihood of accepting enfuvirtide. CONCLUSION: Physician and patient beliefs about SIAT influence prescribing behavior and compliance yet may not be concordant, with patients having more positive attitudes towards SIAT than anticipated by physicians.

Virologic response to lopinavir-ritonavir-based antiretroviral regimens in a multicenter international clinical cohort: comparison of genotypic interpretation scores.

Several genotypic interpretation scores have been proposed for the evaluation of susceptibility to lopinavir/ritonavir (LPV/r) but have not been compared using an independent data set. This study was a retrospective multicenter cohort of patients initiating LPV/r-based therapy. The virologic response (VR) was defined as a viral load of <500 copies/ml at week 24. The genotypic interpretation scores surveyed were the LPV mutation score, the ViroLogic score, the ATU score, the Stanford database score, and the International AIDS Society-USA mutation list. Of the 103 patients included in the analysis, 76% achieved VR at 24 weeks. For scores with clinical breakpoints defined (LPV mutation, ATU, ViroLogic, and Stanford), over 80% of the patients below the breakpoints achieved VR, while 50% or less above the breakpoints responded. Protease mutations at positions 10, 54, and 82 and at positions 54, 84, and 90 were associated with a lack of VR in the univariate and multivariate analyses, respectively. The area under the receiver-operator characteristic curves for the five genotypic interpretation scores studied ranged from 0.73 to 0.76. The study confirms that the currently available genotypic interpretation scores which are widely used by clinicians performed similarly well and can be effectively used to predict the virologic activity of LPV/r in treatment-experienced patients.

Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials.

BACKGROUND: The continuing, randomised, multinational, phase IIB POWER 1 and 2 studies aim to evaluate efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients. We did a pooled subgroup analysis to update results at week 48 for patients receiving the recommended dose of darunavir-ritonavir compared with those receiving other protease inhibitors (PIs). METHODS: After 24-week dose-finding phases and primary efficacy analyses, patients randomised to receive darunavir-ritonavir were given 600/100 mg twice daily, and patients receiving control PIs continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background regimen. We assessed patients who had reached week 48 or discontinued earlier at the time of analysis; for the darunavir-ritonavir group, only patients who received 600/100 mg twice daily from baseline were included. Analyses were intention-to-treat. The POWER 2 study (TMC114-C202) is registered with ClinicalTrials.gov (NCT00071097). FINDINGS: At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%-57%, p<0.0001). Based on a logistic regression model including stratification factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the difference in response was 50% (odds ratio 11.72, 95% CI 5.75-23.89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identified. INTERPRETATION: Efficacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.

Evaluation of efficacy, safety, pharmacokinetics, and adherence in HIV-1-infected, antiretroviral-naïve patients treated with ritonavir-boosted atazanavir plus fixed-dose tenofovir DF/emtricitabine given once daily.

OBJECTIVES: Evaluate efficacy, safety, tolerability, pharmacokinetics, adherence, and treatment satisfaction of atazanavir/ritonavir (ATV/r) 300 mg/100mg and tenofovir DF/emtricitabine (TDF/FTC) 300 mg/200mg once daily in antiretroviral-naïve HIV-infected patients. METHOD: Single-arm, open-label, multicenter 48-week study. RESULTS: 100 patients were evaluated; 17 patients discontinued early including 6 for adverse events. There were 2 deaths (multi-organ failure, lactic acidosis). At 48 weeks, 81% achieved HIV-1 RNA <50 copies/mL (ITT, M=F). No K65R or ATV/r associated mutations emerged; M184V developed in one patient. Median CD4 increase was 217 cells/mm3. The most common adverse events (> or = 10%) were diarrhea, nausea, scleral icterus, fatigue, upper respiratory tract infection, headache, and vomiting. Grade 4 hyperbilirubinemia occurred in 5%. Median increases at 48 weeks in total cholesterol, HDL, LDL, and triglycerides were 11, 3, 2, and 5 mg/dL, respectively. Two patients had confirmed graded increases in serum creatinine (one grade 1, one grade 2). Median (IQR) creatinine clearance change from baseline at 48 weeks was -7 (-19, 2) mL/min. Geometric mean (95% CI) ATV trough concentrations exceeded suggested therapeutic range. At 48 weeks, 92% of patients reported complete adherence by 1-week recall and 90% reported being "very satisfied" with the regimen. CONCLUSION: ATV/r+TDF/FTC was safe, well tolerated, and convenient for patients. Larger comparative trials are ongoing.

Short-term safety and tolerability of a once-daily fixed-dose abacavir-lamivudine combination versus twice-daily dosing of abacavir and lamivudine as separate components: findings from the ALOHA study.

STUDY OBJECTIVE: To evaluate the short-term (12 wks) safety and tolerability of a once-daily, fixed-dose abacavir-lamivudine combination versus twice-daily dosing of the separate components, both with background antiretroviral therapy. DESIGN: Phase IIIB, randomized, open-label, parallel-group, multicenter study. SETTING: One hundred forty-six human immunodeficiency virus (HIV) clinics. PATIENTS: Six hundred eighty antiretroviral therapy-naïve patients with HIV type 1 RNA greater than 1000 copies/ml at baseline. INTERVENTION: Patients were randomly assigned in a 2:1 manner to receive either abacavir 600 mg-lamivudine 300 mg once/day or abacavir 300 mg twice/day and lamivudine 150 mg twice/day. Subjects were stratified based on choice of third or fourth antiretroviral drug (nucleoside reverse transcriptase inhibitor [NRTI], NNRTI, or protease inhibitor), assigned before randomization. MEASUREMENTS AND MAIN RESULTS: The primary end point was occurrence of grades 2-4 adverse events and serious adverse events; abacavir hypersensitivity reactions were considered serious adverse events. Baseline characteristics were similar between the once-daily (455 patients) and twice-daily (225 patients) groups. The rates of all grades 2-4 adverse events were similar: once-daily 33% (150 patients), twice-daily 31% (69). A slightly larger proportion of patients in the twice-daily group experienced drug-related grades 2-4 adverse events: once-daily 10% (47), twice-daily 16% (36). Rates of all serious adverse events (once-daily 11% [49], twice-daily 10% [22]) and drug-related serious adverse events (once-daily 5% [21], twice-daily 8% [17]) were similar. The rate of suspected abacavir hypersensitivity reaction was 5.3% (once-daily 4.4% [20], twice-daily 7.1% [16]), with a higher rate for the NNRTI stratum of the twice-daily group (8.6% [10]) than in any other stratum (once-daily, NNRTI 4.3% [10]; twice-daily, protease inhibitor 5.6% [6]; once-daily, protease inhibitor 4.6% [10]). CONCLUSION: In the short-term, the rates of adverse events in the once-daily and twice-daily groups appeared to be similar. The rate of suspected abacavir hypersensitivity reaction in the once-daily group was lower than the rate in the twice-daily group.

Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis.

OBJECTIVE: TMC125-C223 is an open-label, partially blinded, randomized clinical trial to evaluate the efficacy and safety of two dosages of etravirine (TMC125), a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV-1. DESIGN: A total of 199 patients were randomly assigned 2: 2: 1 to twice-daily etravirine 400 mg, 800 mg and control groups, respectively. The primary endpoint was a change in viral load from baseline at week 24 in the intention-to-treat population. METHODS: Patients had HIV-1 with genotypic resistance to approved NNRTIs and at least three primary protease inhibitor (PI) mutations. Etravirine groups received an optimized background of at least two approved antiretroviral agents [nucleoside reverse transcriptase inhibitors (NRTI) and/or lopinavir/ritonavir and/or enfuvirtide]. Control patients received optimized regimens of at least three antiretroviral agents (NRTIs or PIs and/or enfuvirtide). RESULTS: The mean change from baseline in HIV-1 RNA at week 24 was -1.04, -1.18 and -0.19 log10 copies/ml for etravirine 400 mg twice a day, 800 mg twice a day and the control group, respectively (P < 0.05 for both etravirine groups versus control). Etravirine showed no dose-related effects on safety and tolerability. No consistent pattern of neuropsychiatric symptoms was observed. There were few hepatic adverse events, and rashes were predominantly early onset and mild to moderate in severity. CONCLUSION: Etravirine plus an optimized background significantly reduced HIV-1-RNA levels from baseline after 24 weeks in patients with substantial NNRTI and PI resistance, and demonstrated a favorable safety profile compared with control.