Bioequivalence and Food Effect Assessment of 2 Fixed-Dose Combination Formulations of Dolutegravir and Lamivudine.

This single-dose study evaluated the bioequivalence, food effect, and safety of 2 experimental, 2-drug, fixed-dose formulations of 50 mg dolutegravir and 300 mg lamivudine (formulation AH and formulation AK) as compared with coadministration of single-entity tablets of 50 mg dolutegravir and 300 mg lamivudine (reference). In fasted subjects, formulation AH lamivudine exposure was similar to the reference; however, dolutegravir exposure was consistently higher in formulation AH, with area under the concentration-time curve (AUC) and maximum concentration (Cmax ) approximately 27% to 28% greater than reference. Formulation AK met bioequivalence standards to the reference for dolutegravir (AUC0-∞ and Cmax ) and lamivudine (AUC0-∞ and AUC0-t ) exposure; however, dolutegravir AUC0-t and lamivudine Cmax were approximately 16% and 32% higher than the reference, respectively. A high-fat meal increased dolutegravir AUC and Cmax by up to 33% and 21%, respectively, and decreased lamivudine Cmax by approximately 30%. Both test and reference formulations were well tolerated. The results support further development of formulation AK as a novel, 2-drug, fixed-dose combination tablet treatment for patients with HIV.

Assessment of Drug Interaction Potential Between the Hepatitis C Virus Direct-Acting Antiviral Agents Elbasvir/Grazoprevir and the Nucleotide Analog Reverse-Transcriptase Inhibitor Tenofovir Disoproxil Fumarate.

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.

Real-World Assessment of Renal and Bone Safety among Patients with HIV Infection Exposed to Tenofovir Disoproxil Fumarate-Containing Single-Tablet Regimens.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens have been associated with an increased incidence of renal and bone adverse outcomes. Here, we estimated the real-world incidence of renal and bone adverse outcomes among patients with HIV infection receiving different TDF-containing single-tablet regimens (STRs). METHODS: This cohort study used US health insurance data spanning the years 2008-2014. We identified HIV-infected patients aged ≥18 years (all HIV patients) and those with ≥6 months of continuous enrollment prior to initiating efavirenz/emtricitabine/TDF (EFV/FTC/TDF), rilpivirine/FTC/TDF (RPV/FTC/TDF) or elvitegravir/cobicistat/FTC/TDF (EVG/COBI/FTC/TDF). Renal adverse outcomes were identified using renal International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Bone adverse outcomes were identified using ICD-9-CM diagnosis codes for fracture. Incidence rates (IRs) and associated 95% confidence intervals (CIs) were estimated assuming a Poisson distribution, and outcomes between STRs were compared using IR ratios (IRRs) and IR differences (IRDs). RESULTS: We identified 9876 and 10,383 eligible patients for the renal and fracture analyses, respectively. Observed IRs for renal adverse outcomes were 9.7, 10.5, 13.6, and 18.0 per 1000 person-years among those receiving EFV/FTC/TDF, RPV/FTC/TDF, or EVG/COBI/FTC/TDF, or all HIV patients, respectively. Corresponding values for IRs of fracture were 3.4, 3.6, 7.2, and 4.4 per 1000 person-years, respectively. Renal adverse outcomes with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRD -3.96; 95% CI: -7.31, -1.06). No IRR differences were identified for the renal analysis. Fractures with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRR 0.47; 95% CI: 0.27, 0.81 and IRD -3.85; 95% CI: -5.02, -2.78). CONCLUSIONS: In this large real-world database, observed IRs for renal adverse outcomes with TDF-containing STRs were lower or similar to those for all HIV patients, with the lowest IRs observed among patients receiving EFV/FTC/TDF. Compared with all HIV patients, the observed IR for fracture was higher with EVG/COBI/FTC/TDF, comparable with RPV/FTC/TDF, and lower with EFV/FTC/TDF.

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial.

BACKGROUND: For HIV-1-infected young people facing lifelong antiretroviral therapy (ART), short cycle therapy with long-acting drugs offers potential for drug-free weekends, less toxicity, and better quality-of-life. We aimed to compare short cycle therapy (5 days on, 2 days off ART) versus continuous therapy (continuous ART). METHODS: In this open-label, non-inferiority trial (BREATHER), eligible participants were aged 8-24 years, were stable on first-line efavirenz with two nucleoside reverse transcriptase inhibitors, and had HIV-1 RNA viral load less than 50 copies per mL for 12 months or longer. Patients were randomly assigned (1:1) to remain on continuous therapy or change to short cycle therapy according to a computer-generated randomisation list, with permuted blocks of varying size, stratified by age and African versus non-African sites; the list was prepared by the trial statistician and randomisation was done via a web service accessed by site clinician or one of the three coordinating trials units. The primary outcome was the proportion of participants with confirmed viral load 50 copies per mL or higher at any time up to the 48 week assessment, estimated with the Kaplan-Meier method. The trial was powered to exclude a non-inferiority margin of 12%. Analyses were intention to treat. The trial was registered with EudraCT, number 2009-012947-40, ISRCTN, number 97755073, and CTA, number 27505/0005/001-0001. FINDINGS: Between April 1, 2011, and June 28, 2013, 199 participants from 11 countries worldwide were randomly assigned, 99 to the short cycle therapy and 100 to continuous therapy, and were followed up until the last patient reached 48 weeks. 105 (53%) were men, median age was 14 years (IQR 12-18), and median CD4 cell count was 735 cells per µL (IQR 576-968). Six (6%) patients assigned to the short cycle therapy versus seven (7%) assigned to continuous therapy had confirmed viral load 50 copies per mL or higher (difference -1·2%, 90% CI -7·3 to 4·9, non-inferiority shown). 13 grade 3 or 4 events occurred in the short cycle therapy group and 14 in the continuous therapy group (p=0·89). Two ART-related adverse events (one gynaecomastia and one spontaneous abortion) occurred in the short cycle therapy group compared with 14 (p=0·02) in the continuous therapy group (five lipodystrophy, two gynaecomastia, one suicidal ideation, one dizziness, one headache and syncope, one spontaneous abortion, one neutropenia, and two raised transaminases). INTERPRETATION: Non-inferiority of maintaining virological suppression in children, adolescents, and young adults was shown for short cycle therapy versus continous therapy at 48 weeks, with similar resistance and a better safety profile. This short cycle therapy strategy is a viable option for adherent HIV-infected young people who are stable on efavirenz-based ART. FUNDING: UK National Institute for Health Research Health Technology Assessment; UK Medical Research Council; European Commission; PENTA Foundation; INSERM SC10-US19, France.

Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.

BACKGROUND: For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. METHODS: A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. FINDINGS: Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes. INTERPRETATION: In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity. FUNDING: National Institutes of Health.

Nuke-Sparing Regimens for the Long-Term Care of HIV Infection.

With the efficacy of antiretroviral therapy already guaranteed for all practical purposes, the main objective in the management of HIV-positive patients has moved to reduce and prevent potential long-term toxicities. Nucleos(t)ide-sparing regimens could enable the best to address this issue, with a wide range of current options that may allow adaptation to distinct patient populations. Monotherapy with boosted darunavir and lopinavir has been safely prescribed as maintenance therapy to stable patients on stable antiretroviral therapy without nadir CD4 count < 200/mm³, low-level baseline viremia, prolonged viral suppression, and without prior virologic failure. In the presence of all these requirements, dual therapy with lamivudine plus boosted lopinavir or atazanavir has been shown to be equivalent to standard triple therapy. Other nucleoside-sparing dual therapies, especially using raltegravir combined with boosted darunavir or lopinavir and etravirine or rilpivirine in combination with boosted darunavir, have performed well as simplification strategies or rescue interventions in a wide spectrum of patients as long as drug resistance was absent. With current economical constrains, nuke-sparing regimens have attained a degree of maturity that makes it possible to anticipate that they will play an important role in the optimization of antiretroviral therapy in the near future.

Markov model for characterizing neuropsychologic impairment and Monte Carlo simulation for optimizing efavirenz therapy.

The study was undertaken to develop a pharmacokinetic-pharmacodynamic model to characterize efavirenz-induced neuropsychologic impairment, given preexistent impairment, which can be used for the optimization of efavirenz therapy via Monte Carlo simulations. The modeling was performed with NONMEM 7.2. A 1-compartment pharmacokinetic model was fitted to efavirenz concentration data from 196 Ugandan patients treated with a 600-mg daily efavirenz dose. Pharmacokinetic parameters and area under the curve (AUC) were derived. Neuropsychologic evaluation of the patients was done at baseline and in week 2 of antiretroviral therapy. A discrete-time 2-state first-order Markov model was developed to describe neuropsychologic impairment. Efavirenz AUC, day 3 efavirenz trough concentration, and female sex increased the probability (P01) of neuropsychologic impairment. Efavirenz oral clearance (CL/F) increased the probability (P10) of resolution of preexistent neuropsychologic impairment. The predictive performance of the reduced (final) model, given the data, incorporating AUC on P01and CL /F on P10, showed that the model adequately characterized the neuropsychologic impairment observed with efavirenz therapy. Simulations with the developed model predicted a 7% overall reduction in neuropsychologic impairment probability at 450 mg of efavirenz. We recommend a reduction in efavirenz dose from 600 to 450 mg, because the 450-mg dose has been shown to produce sustained antiretroviral efficacy.

Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: results from the VERITAS study (TMC114HIV4054).

BACKGROUND: Despite the benefit of maintaining inactive Nucleotide/side reverse transcriptase inhibitors (NRTIs) in salvage regimens, they are associated with increased toxicity and treatment costs. Current evidence suggests that NRTI-sparing regimens in patients failing ART are non-inferior to NRTI-including regimens. This study aimed to evaluate the impact of removing at least one inactive NRTI on virologic, safety, and financial outcomes. METHODS: Drug-resistant, virologically suppressed patients with CD4 >250 cells/ml on a stable regimen of four or more antiretrovirals (ARVs) were enrolled in a 48-week prospective, open-label pilot trial. One inactive NRTI was removed at baseline. Patients taking over five ARVs had a second inactive NRTI removed at 24 weeks. Viral load, CD4 count, and adverse events were assessed at baseline, 24, and 48 weeks. RESULTS: Thirty-one male patients participated. Twenty-nine (94%) patients had lamivudine (3TC) or emtricitabine (FTC) removed and four patients had an additional NRTI removed. One patient was excluded at week 26 for discontinuing an active NRTI. All patients maintained undetectable viral loads at weeks 24 (100%) and 48 [PP = 100%; Intent-to-treat (ITT) = 97%]. At 48 weeks, patients had a median gain of 20 CD4 (IQR: - 50, +133; mean +39) compared to baseline. Three patients exhibited Grade III bilirubin elevation (two Grade II and one Grade III at baseline), which returned to baseline levels. No serious adverse events were observed. Removal of one or two ARVs equated to a mean annual savings of $3319 CDN (11%) and $8630 CDN (24%), respectively. CONCLUSION: Removing inactive NRTIs in patients with a controlled viral load appears to be safe, maintains virological suppression, and reduces treatment costs.

Assessment of bone mineral density in tenofovir-treated patients with chronic hepatitis B: can the fracture risk assessment tool identify those at greatest risk?

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is an established nucleotide analogue in the treatment of chronic hepatitis B. Bone mineral density loss has been described in TDF-treated patients with human immunodeficiency virus infection, but limited data exist for patients with chronic hepatitis B. Dual X-ray absorptiometry (DEXA) was used to determine bone mineral density changes in TDF-exposed patients. We evaluated the accuracy of the Fracture Risk Assessment Tool (FRAX) as an alternative to DEXA in clinical practice. METHODS: A total of 170 patients were studied: 122 were exposed to TDF, and 48 were controls. All patients underwent DEXA, and demographic details were recorded. FRAX scores (before and after DEXA) were calculated. RESULTS: TDF was associated with a lower hip T score (P = .02). On univariate and multivariate analysis, advancing age, smoking, lower body mass index, and TDF exposure were independent predictors of low bone mineral density. In addition, the pre-DEXA FRAX score was an accurate predictor of the post-DEXA FRAX treatment recommendation (100% sensitivity and 83% specificity), area under the curve 0.93 (95% CI, .87-.97, P < .001). CONCLUSIONS: TDF-treated patients with chronic hepatitis B have reduced bone mineral density, but the reduction is limited to 1 anatomical site. Age and advanced liver disease are additional contributing factors, underlining the importance of multifactorial fracture risk assessment. FRAX can accurately identify those at greatest risk of osteoporotic fracture.

A farewell to didanosine: harm reduction and cost savings by eliminating use of didanosine.

Didanosine (ddI) is a nucleoside reverse transcriptase inhibitor associated with adverse events and public health concerns which have diminished its place in HIV clinical practice, particularly in resource-rich settings. While international guidelines do not contain ddI-containing regimens in preferred first- or second-line antiretroviral therapy (ART), there is no guidance for management of patients currently on ddI. In 2012 at least 20 countries purchased a total of $1-2 million of ddI. Drug purchase data in that year show 3.2-10.3 times higher costs for ddI compared to lamivudine (3TC). Given issues of multiple toxicities, monitoring, drug interactions, inconvenience, and virologic efficacy, as well as cost and formulary concerns, national (including resource-limited setting) ART programmes should consider complete phase-out of ddI.

[Challenges of lopinavir/ritonavir in the chronicity of human immunodeficiency virus infection]. / Desafíos de lopinavir/ritonavir en la cronicidad de la infección por virus de la inmunodeficiencia humana.

Combination antiretroviral therapy (ART) has increased patient survival, which is currently similar to that of the general population in western countries. However, ART is unable to completely restore normal health, given the persistence of chronic immune activation. Human immunodeficiency virus (HIV) infection has become a chronic disease and 50% of patients will soon be older than 50 years. Currently, there is a debate on the possibility of accelerated aging in the HIV-infected population. An overlap has been observed between chronic inflammation, age-related comorbidities, lifestyle, and the long-term toxicity of ART. ART-related toxicity can encourage the development of comorbidities, especially cardiovascular and renal complications, while toxicity-especially that of thymidine analogs-can also contribute to inflammation and aging. Evidence is available on simplification strategies with boosted protease inhibitor monotherapy aiming to avoid or reduce potential or demonstrated toxicity. Currently, studies are underway of dual therapy strategies with lopinavir/ritonavir (LPV/r) with distinct antiretroviral agents. The studies with the largest samples are those with raltegravir and lamivudine. The GARDEL trial has demonstrated that dual therapy with LPV/r plus a generic drug such as lamivudine is non-inferior to triple therapy in treatment- naïve patients. All of the above indicates the response to the challenge posed to LPV/r by the chronic phase of the disease and by the need to reduce costs.

Assessment of second-line antiretroviral regimens for HIV therapy in Africa.

BACKGROUND: The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit. METHODS: In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%). RESULTS: Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001). CONCLUSIONS: When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.).

Clinical assessment of peripheral neuropathy in HIV-infected children on antiretroviral therapy in rural South Africa.

UNLABELLED: Peripheral neuropathy is a well-known side effect of antiretroviral therapy (ART) in adult patients and is particularly related to the use of nucleoside reverse transcriptase inhibitors. This class of drugs is included in all first-line paediatric ART regimens in Africa, but data on the prevalence of neuropathy in children are scarce. In this cross-sectional study, 182 HIV-infected children on ART in rural South Africa were assessed for peripheral neuropathy using the neuropathy symptom score (NSS) and neuropathy disability score (NDS). Peripheral neuropathy was defined as NSS ≥ 5 or NDS ≥ 3. Neurological assessment was completed for 174 children (96 %). Symptoms of neuropathy were reported in NSS by 48 children (28 %; 95 % confidence interval (CI) 21-34 %), and signs were observed in NDS in 25 children (14 %; 95 % CI 12-16 %). A diagnosis of peripheral neuropathy was established in 42 children (24 %; 95 % CI 18-30 %). Independent risk factors for peripheral neuropathy were co-trimoxazole prophylaxis (adjusted odds ratio 0.45; 95 % CI 0.21-0.95, p = 0.036) and didanosine use (adjusted odds ratio 12; 95 % CI 1.3-116, p = 0.030). CONCLUSION: Peripheral neuropathy as determined by clinical assessment is a common condition in African children on ART.

Costs of adverse events among patients with HIV infection treated with nonnucleoside reverse transcriptase inhibitors.

OBJECTIVES: The aim of the study was to assess the incidence and costs of adverse events (AEs) among patients with HIV infection treated with nonnucleoside reverse transcriptase inhibitors (NNRTIs) from the health care system perspective. METHODS: US medical and pharmacy claims during 2004-2009 were examined to select adult new NNRTI users with HIV infection. The incidence of selected AEs and time to occurrence were assessed during the first year. Episodes of care for each AE were identified using claims associated with AE management. For each AE, a propensity score model was used to match patients with an AE to those without (1:4) based on the propensity of having an AE. Mean total health care costs, AE-associated costs and incremental costs per episode, and annual total health care costs per patient were calculated. RESULTS: Of the 2548 NNRTI-treated patients, 29.3% experienced AEs. The incidence ranged from 0.4 episodes/1000 person-years for suicide/self-injury to 14.9 episodes/1000 person-years for dizziness, 49.8 episodes/1000 person-years for depression and 150.3 episodes/1000 person-years for lipid disorder. The mean AE-associated cost (duration) per episode ranged from $586 (88 days) for lipid disorder to $975 (33 days) for rash, $2760 (73 days) for sleep-related symptoms and $4434 (41 days) for nausea/vomiting. The mean incremental cost per episode ranged from $1580 for rash to $2032 for lipid disorder, $8307 for sleep-related symptoms and $12 833 for nausea/vomiting. During the 12 months following NNRTI initiation, the mean annual total health care cost was $27 299 (efavirenz: $26 185; other NNRTIs: $34 993) and AE-associated costs were $608 (efavirenz: $554; other NNRTIs: $979) among all NNRTI users. CONCLUSIONS: With treatment increasing patient survival, comparisons of therapeutic regimens should consider treatment-associated AEs. Findings from this study could be informative for clinicians and payers in managing HIV infection with NNRTIs.

Rilpivirine: a second-generation nonnucleoside reverse transcriptase inhibitor.

PURPOSE: The pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, dosage and administration, and place in therapy of rilpivirine are reviewed. SUMMARY: Rilpivirine is a human immunodeficiency virus type 1 (HIV-1)-specific nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated for use in combination with other antiretroviral agents in adult patients not previously treated with antiretroviral therapy. Rilpivirine is primarily metabolized by the cytochrome P-450 (CYP)3A isoenzyme system. Therefore, providers should be cautious when administering drugs that are inhibitors or inducers of this pathway. Coadministration with CYP 3A inhibitors may lead to increased concentrations of rilpivirine, thereby increasing the risk of adverse effects. Coadministration with inducers of CYP3A isoenzymes or drugs that increase gastric pH may lead to decreased concentrations of rilpivirine, thus promoting virological failure or resistance to rilpivirine. Two Phase III, randomized, double-blind, double-dummy, active-controlled trials compared rilpivirine with efavirenz in HIV-infected adults not previously treated with an antiretroviral. The investigators concluded that rilpivirine, when combined with two nucleoside or nucleotide reverse transcriptase inhibitors, was noninferior to efavirenz for reaching the endpoint of confirmed virological response (HIV-1 RNA level of <50 copies/mL) in adults with HIV infection not previously treated with antiretroviral therapy. The most commonly reported adverse effects included depression, insomnia, headache, and rash. Rilpivirine is administered as a single 25-mg tablet given once daily in combination with other antiretroviral drugs in order to optimize efficacy and reduce resistance. CONCLUSION: Rilpivirine is a viable NNRTI for HIV-infected patients who have not previously received antiretroviral therapy.

[Evidence-based therapeutic drug monitoring for efavirenz]. / Niveau de preuve du suivi thérapeutique pharmacologique de l'efavirenz.

The efavirenz, a non nucleoside reverse transcriptase inhibitor of HIV-1, presents a marked pharmacokinetics variability related to an intense hepatic metabolism. Efavirenz is also a potent inducer. Central nervous system (CNS) toxicity associated with efavirenz therapy is a major cause of non adherence and therefore treatment failure. The literature has been analyzed to evaluate the level of evidence of the interest of a therapeutic drug monitoring for efavirenz. Several studies have reported that an efavirenz plasma concentration >1 000 ng/mL is a predictive factor of the viral response. Efavirenz plasma concentrations >4 000 ng/mL were associated to an increase frequency of CNS side effects. CNS toxicity was also more frequent in patients carrying the 516G > T mutation (CYP2B6*6 allele), associated with a significantly greater efavirenz plasma exposure. Non-randomized studies have reported the interest of efavirenz therapeutic drug monitoring to optimize viral response and prevent CNS toxicity, allowing to suggest a level of evidence "recommended" for efavirenz.

[Evidence-based therapeutic drug monitoring for nevirapine]. / Niveau de preuve du suivi therapeutique pharmacologique de la névirapine.

Nevirapine, a HIV non nucleosidic reverse transcriptase inhibitor, displays an inter-individual variability in its pharmacokinetics parameters, related to its hepatic metabolism. Based on literature, is the nevirapine therapeutic drug monitoring relevant? In naïve and pre-treated HIV infected patients, the probability of achieving and maintaining an undetectable HIV viral load was significantly associated with a nevirapine plasma trough concentration (C(trough)) > 4 000 ng/mL. The probability of virologic failure was significantly associated with a C(trough) < 3 000 ng/mL. Concerning the exposure-toxicity relationship, the emergence of hepatotoxicity was more frequently associated with high C(trough), especially in case of HCV coinfection. Non-randomized studies have reported the interest of nevirapine therapeutic drug monitoring to optimize the virologic response and, to a lesser extent, to prevent hepatotoxicity. Therefore, the level of evidence of the interest of nevirapine therapeutic drug monitoring is "recommended".

Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of tenofovir disoproxil fumarate for the treatment of chronic hepatitis B, in accordance with the licensed indication, based upon the evidence submission from Gilead to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included two international randomised controlled trials (RCTs) comparing tenofovir with adefovir, and a mixed treatment comparison (MTC) using Bayesian methodology to compare tenofovir with other nucleos(t)ide analogues using direct and indirect RCT evidence. There were no statistically significant differences between tenofovir and adefovir in overall adverse events although, in hepatitis B 'e' antigen (HBeAg)-positive patients, there was a higher incidence of mild nausea in the tenofovir treatment group. The primary outcome, 'complete response', was a composite end point defined as histology response and hepatitis B virus DNA below 400 copies/ml. For both HBeAg-positive and HBeAg-negative patients, a significantly greater proportion had a complete response after 48 weeks with tenofovir than with adefovir. There was no statistically significant difference in histological response in either group of patients compared with adefovir. The MTC could only generate results for HBeAg positive nucleos(t)ide naive patients as there was insufficient evidence for other subgroups. The probability of achieving undetectable HBV DNA with tenofovir was found to be significantly higher than that for all other treatments considered in the analysis at the 0.05 level. The analysis demonstrated that there is a 98% probability that tenofovir is the most potent nucleos(t)ide in terms of this outcome. The manufacturer's submission concluded that tenofovir is a cost-effective option as first-line treatment. For HBeAg-positive patients, tenofovir followed by lamivudine has an incremental cost-effective ratio (ICER) of 9940 pounds per quality-adjusted life-year (QALY) gained, compared with lamivudine followed by tenofovir. A more appropriate treatment strategy of tenofovir followed by tenofovir plus lamivudine has an ICER of 13,619 pounds per QALY gained, compared with lamivudine followed by tenofovir. For HBeAg-negative patients, tenofovir followed by lamivudine has an ICER of 9811 pounds per QALY gained, compared with best supportive care. A more clinically appropriate treatment strategy of tenofovir followed by tenofovir plus lamivudine has an ICER of 13,854 pounds per QALY gained, compared with tenofovir followed by lamivudine. The ERG uncovered a number of errors in the submission and these ICERs approximately doubled when the analysis was corrected and reran. The guidance issued by NICE on 22 July 2009 states that tenofovir disoproxil, within its marketing authorization is recommended as an option for the treatment of people with chronic HBe-Ag-positive or HBe-Ag-negative hepatitis B in whom antiviral treatment is indicated.