The burden of neuropsychiatric disorders in patients living with HIV-1 treated with antiretroviral therapies-A perspective from US Medicaid data.

BACKGROUND: People with human immunodeficiency virus (HIV)-1 face challenges with treatment adherence for various reasons, including consideration of neuropsychiatric disorders and neuropsychiatric adverse reactions associated with antiretroviral therapy (ART). METHODS: A retrospective cohort study was conducted using administrative claims data from the IBM MarketScan® Multi-State Medicaid Database (1/1/2014-12/31/2017). Adults (≥18 years) diagnosed with HIV-1 and newly initiated on antiretroviral therapy with continuous health plan enrollment were included. Primary outcome was the 6-month period prevalence of neuropsychiatric events (NPEs) of interest after ART initiation. RESULTS: Among 1971 newly treated patients included in the study, mean age (standard deviation [SD]) was 38.5 (12.7) years, and 41.4% were female. During the 6 months after ART initiation, 51.4% of patients had a claim for ≥1 NPE versus 30.3% of matched patients without HIV. Among newly treated patients, the most common (≥10%) NPE claims were for depression (42.2%), anxiety (15.8%), headache (11.9%), and bipolar/manic depression (10.1%). Also in this group, the mean (SD) total all-cause healthcare cost during the 6-month post-ART initiation was $16,632 ($33,928), of which $2914 ($18,233) was NPE-related. CONCLUSIONS: In summary, in this Medicaid study of people newly initiated on ART, there was a high prevalence of NPEs, and incremental NPE-associated costs were considerable.

Weight Gain and Related Comorbidities Following Antiretroviral Initiation in the 2000s: A Systematic Literature Review.

Antiretroviral therapies (ARTs) benefit millions with human immunodeficiency virus. However, concerns about subsequent weight gain and related metabolic complications have emerged. Early ARTs are associated with adipose tissue changes. While newer ARTs may have fewer adipose alterations, it is unclear whether they lead to increased weight gain. A systematic literature review was performed to describe current published literature describing the use of newer ARTs, weight gain, and related comorbidities. Titles and abstracts were screened, focusing on studies that examined ART initiation and subsequent weight gain; publications were then ranked based on publication type, methodology, and comorbidities, emphasizing US studies with large patient cohorts. This yielded a comprehensive review of the 50 publications on weight gain and a range of related comorbidities, including diabetes and hypertension. Most of the studies describing weight gain found the most significant gains during the first year after initiating ART. Overall, patients gained ∼5 kg 18-96 months after initiating ART. Many of the studies reported altered weight-related comorbidities, including increased risk of diabetes and hypertension. Despite an expectation that newer ARTs may be safer, a review of the literature suggests that contemporary ART use is associated with pronounced weight gain and related comorbidities. Future studies should define and quantify the direct role of newer ARTs in weight gain and related comorbidities, as well as clarify the role of specific drug classes in metabolic disturbance, to improve intervention strategies.

Rapid initiation of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in acute and early HIV-1 infection: a DIAMOND subgroup analysis.

BACKGROUND: Treatment during acute or early human immunodeficiency virus (HIV)-1 infection is associated with immunologic and virologic benefits. OBJECTIVE: To evaluate darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) efficacy/safety among patients with acute or early HIV-1 infection who rapidly initiate treatment. METHODS: DIAMOND (ClinicalTrials.gov Identifier: NCT03227861), a phase 3 study, evaluated the efficacy/safety of D/C/F/TAF 800/150/200/10 mg in rapid initiation. Adults aged ≥18 years began D/C/F/TAF within 14 days of diagnosis, prior to the availability of screening/baseline laboratory results. In this subgroup analysis, virologic response (HIV-1 RNA <50 copies/mL) was assessed at Week 48 by intent-to-treat FDA snapshot (ITT-FDA snapshot) and observed (excluding patients with missing data) analyses in patients with acute (HIV-1 antibody negative and HIV-1 RNA positive/p24 positive) or early (HIV-1 antibody positive and suspected infection ≤6 months before screening/baseline) infection. RESULTS: Among 109 patients, 13 had acute and 43 had early HIV-1 infection. High rates of virologic response were demonstrated at Week 48 by ITT-FDA snapshot (acute: 10/13 [76.9%]; early: 37/43 [86.0%]) and observed (acute: 10/11 [90.9%]; early: 37/38 [97.4%]) analyses. No patients discontinued or required regimen change due to baseline resistance or lack of efficacy, or developed protocol-defined virologic failure. Through Week 48, 7 (53.8%) acute and 22 (51.2%) early infection patients had a D/C/F/TAF-related adverse event (AE); none had a D/C/F/TAF-related grade 4 or serious AE. CONCLUSIONS: High rates of viral suppression during acute/early infection were achieved with D/C/F/TAF rapid initiation, no treatment-emergent resistant mutations were observed, and D/C/F/TAF was safe and well tolerated.

Treatment Patterns and Predictors of Adherence in HIV Patients Receiving Single- or Multiple-Tablet Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide.

PURPOSE: Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide can be used as a single-tablet regimen (STR, DRV/c/FTC/TAF) or multiple-tablet regimen (MTR, DRV/c+FTC/TAF) to treat patients with human immunodeficiency virus (HIV). This study described treatment patterns and predictors of adherence among patients with HIV initiated on DRV/c/FTC/TAF or DRV/c+FTC/TAF. PATIENTS AND METHODS: A retrospective longitudinal study was conducted using linked claims and electronic medical records from Decision Resources Group's Real World Data Repository (7/17/2017-6/1/2019). Treatment-naïve and treatment-experienced virologically suppressed adults with HIV-1 prescribed DRV/c/FTC/TAF or DRV/c+FTC/TAF (index date) were included. Six-month persistence (no treatment gaps >60 and >90 days) and adherence (proportion of days covered [PDC]) to the index regimen were evaluated among patients with ≥6 months of observation post-index. Predictors of low adherence (PDC<80%) were evaluated using a logistic regression model. RESULTS: Among 2633 eligible patients (49.5 years old, 29% female, 37% African American/Black), 12% were treatment-naïve pre-index and 88% switched from a previous antiretroviral therapy; 84% initiated DRV/c/FTC/TAF and 16% initiated DRV/c+FTC/TAF. Among 822 DRV/c/FTC/TAF patients with ≥6 months of observation post-index, 80% and 86% had no >60- and >90-day gaps in DRV/c/FTC/TAF coverage, respectively, while among 204 DRV/c+FTC/TAF patients with ≥6 months of observation post-index, 69% and 75% had no >60- and >90-day gaps in DRV/c+FTC/TAF coverage, respectively. Mean (median) PDC for the index regimen was 81% (93%) for patients treated with DRV/c/FTC/TAF and 73% (83%) for patients treated with DRV/c+FTC/TAF. Predictors of low adherence included younger age (odds ratio [OR]=2.36, p=0.017), higher Quan-Charlson comorbidity index (OR=1.32, p=0.012), use of MTR regimen at index (OR=1.69, p=0.022), and prior low adherence (OR=2.56, p<0.001). CONCLUSION: Among patients initiating a DRV/c-based regimen, those initiating STR had higher 6-month adherence/persistence than those initiating MTR, highlighting the potential benefits of the STR formulation, particularly among younger patients with multiple comorbidities and prior low adherence.

Real-World Assessment of Weight Change in People with HIV-1 After Initiating Integrase Strand Transfer Inhibitors or Protease Inhibitors.

BACKGROUND: Studies have shown an increase in weight among people living with human immunodeficiency virus (PLWH) who have also initiated integrase strand transfer inhibitors (INSTI). However, limited data are available regarding comparison of these changes with other antiretroviral regimens. OBJECTIVE: To assess differences in weight gain after initiating INSTI- versus protease inhibitor (PI)-based regimens among treatment-naïve PLWH overall, and among a subpopulation of females only. METHODS: This retrospective, observational cohort study included data from the Optum ® deidentified Electronic Health Record (EHR) database. Adult PLWH who initiated INSTI- or PI-based regimens between March 1, 2016 and June 30, 2018 (index date was the first INSTI or PI prescription in this period) with ≥12-month baseline and follow-up periods, ≥1 weight measure during each period, and no prior antiretroviral use were included. The last weight measure between 12 months pre- and 30 days post-index was defined as baseline weight; the last measure between the months 4 and 12 of follow-up was defined as post-weight. Weight change was reported as absolute change and proportion of patients with increased weight. Cohorts were balanced using propensity score (PS) matching. Multivariable models were used to compare outcomes of interest. RESULTS: After matching, 1588 patients were included (794 per cohort). At baseline, 46% were <50 years old, 26% were females, 12% had Type II diabetes and 30% had hypertension (mean baseline weight: INSTI: 83 kg (183 lb), PI: 82 kg (181 lb); P = 0.3). The mean time to follow-up weight measure was 9.3 months; INSTI initiators had a 1.3 kg (2.9 lb) greater mean weight gain (95% CI: 0.5-2.0), and a higher proportion with ≥5% weight gain (30.7% vs 26.1%; [OR=1.3, 95% CI: 1.0-1.6]) than PI initiators. Differences in weight gain between regimens were larger among females; female INSTI initiators had a 2.5 kg (5.3 lb) greater mean weight gain (95% CI: 0.7-4.2) and a higher proportion with ≥5% weight gain (37.5% vs 26.4%; OR=1.7; 95% CI [1.1-2.6]) than PI initiators. CONCLUSION: In a real-world setting, compared to PI-based regimens, INSTI-based regimens are associated with greater weight gain for treatment-naïve PLWH. This study may inform HIV treatment choice for health care providers.

An assessment of weight change associated with the initiation of a protease or integrase strand transfer inhibitor in patients with human immunodeficiency virus.

OBJECTIVE: Evidence suggests that integrase strand transfer inhibitors (INSTIs) are associated with greater weight gain than other antiretrovirals. This real-world study compares weight/body mass index (BMI) change between insured US patients with human immunodeficiency virus (HIV-1) initiating a protease inhibitor (PI) or INSTI. METHODS: A retrospective longitudinal study was conducted using Decision Resources Group's Real World Data Repository (7/17/2017-6/1/2019). Adult patients with HIV-1 who initiated a new PI or INSTI on or after 7/17/2018 (index date) and had ≥12 months of continuous pre-index clinical activity were included. Baseline characteristics were balanced using inverse probability of treatment weighting. The proportion of patients with ≥5% weight/BMI increases and mean weight/BMI change from pre- to post-index were compared using odds ratios (ORs) and mean differences (MDs). RESULTS: 20,367 patients (9993 PI, 10,374 INSTI) were included (mean age = 50 years; ∼30% females). Pre- and post-index weight and BMI measurements were available in 429 and 430 PI patients, and 397 and 383 INSTI patients, respectively (mean time between index and post-index measurements: ∼7 months). The PI cohort was 39%/49% less likely to experience ≥5% weight/BMI increase than the INSTI cohort, respectively (OR [≥5% weight gain] = 0.61; p = .014; OR [≥5% BMI gain] = 0.51; p < .001). Mean weight/BMI gain was significantly lower in the PI cohort than the INSTI cohort (weight MD = -1.90 kg [-4.19 lbs], BMI MD = -0.61kg/m2; both p < .001). CONCLUSIONS: Relative to INSTI, patients initiating a new PI were less likely to experience ≥5% weight/BMI gain post-index. Additionally, mean weight/BMI gain was lower in the PI than in the INSTI cohort.

Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025.

BACKGROUND: Response patterns to nivolumab differ from those seen with other approved targeted therapies. OBJECTIVE: To investigate the efficacy of nivolumab in previously treated patients with advanced renal cell carcinoma who were treated beyond (Response Evaluation Criteria In Solid Tumors) RECIST progression. DESIGN, SETTING, AND PARTICIPANTS: This was a subgroup analysis of patients treated with nivolumab in the phase 3 CheckMate 025 study. Patients continuing to tolerate therapy and exhibiting investigator-assessed clinical benefit were eligible to be treated beyond RECIST progression (TBP) and received therapy for ≥4 wk after first progression; patients not treated beyond RECIST progression (NTBP) received 0 wk to <4 wk of therapy after progression. INTERVENTIONS: Nivolumab 3mg/kg intravenously every 2 wk. RESULTS AND LIMITATIONS: Of 406 nivolumab-treated patients, 316 (78%) progressed by RECIST criteria. Of those who progressed, 48% were TBP, 52% were NTBP. Before being TBP, objective response rate (95% confidence interval) was 20% (14-28) and 14% (9-21) in patients TBP and NTBP, respectively. Differences in clinical characteristics assessed at first progression between patients TBP versus NTBP included better Karnofsky performance status, less deterioration in Karnofsky performance status, shorter time to response, lower incidence of new bone lesions, and improved quality of life. Postprogression, 13% of all patients TBP (20/153) had ≥30% tumor burden reduction including patients with preprogression and postprogression tumor measurements (n=142) and complete/partial response (28%, 8/29), stable disease (6%, 3/47), and progressive disease (14%, 9/66) as their best response before being TBP. Incidence of treatment-related adverse events in patients TBP was lower after (59%) versus before (71%) progression. Limitations included potential bias from the nonrandomized nature of the analysis. CONCLUSIONS: A subset of patients with advanced renal cell carcinoma and RECIST progression experienced tumor reduction postprogression with nivolumab, and had an acceptable safety profile. Clinical judgment remains essential when switching therapy. ClinicalTrials.gov Identifier: NCT01668784. PATIENT SUMMARY: A subset of patients with advanced renal cell carcinoma and disease progression may continue to benefit from nivolumab treatment beyond progression as evidenced by tumor reduction postprogression and an acceptable safety profile.

PRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years.

INTRODUCTION: PRINCE-1 is an ongoing prospective, international, multicentre, nonrandomized, two-stage clinical trial assessing safety and efficacy of once-daily atazanavir (ATV) powder boosted with ritonavir (RTV) liquid plus optimized dual nucleoside reverse-transcriptase inhibitor (NRTI) background therapy in antiretroviral (ARV)-naïve and -experienced children with HIV-1 infection aged ≥3 months to <6 years. METHODS: Children with HIV-1 infection without prior ATV exposure and with a screening HIV-1 RNA ≥1000 copies/mL were enrolled. The dosing of ATV powder, boosted with 80 mg RTV liquid, was based on three baseline weight bands (5 to <10 kg=150 mg, 10 to <15 kg=200 mg and 15 to <25 kg=250 mg). RESULTS: Of the 56 treated patients, 46 completed 48 weeks of therapy, 67.9% were from Africa and 60.7% were ART-naïve. Median ages at baseline were 6, 35 and 55 months, and proportions with HIV-1 RNA >100,000 were 85.7, 52.6 and 25% in the three baseline weight bands, respectively. No unexpected safety events occurred and no deaths were reported. Over 48 weeks, upper respiratory tract infections, diarrhoea, vomiting and Grade 3 to 4 hyperbilirubinaemia occurred in 35.7, 35.7, 28.6, and 9.4% of patients, respectively; five patients (8.9%) discontinued due to adverse events (AEs); and 11 patients (19.6%) experienced serious adverse events. At Week 48, using a modified intent-to-treat analysis (two patients were excluded because they switched to ATV capsules before Week 48), 61.1 and 74.1% of patients overall had an HIV-1 RNA level <50 copies/mL and <400 copies/mL, respectively. Virologic suppression rates increased across the lowest to highest baseline weight bands (47.6, 68.4 and 71.4% had HIV-1 RNA <50 copies/mL, and 66.7, 73.7 and 85.7% had HIV-RNA <400 copies/mL, respectively) but did not differ meaningfully between ARV-naïve and -experienced patients. Overall, the median change from baseline in CD4 cell count was +363 cells/mm(3), and the median change from baseline in CD4 percent was +7.5%. CONCLUSIONS: ATV powder boosted with RTV liquid once daily plus optimized dual NRTI background therapy was effective and well tolerated in this ART-naïve or -experienced paediatric population aged ≥3 months to <6 years. No unexpected safety findings compared with those from previous ATV paediatric and adult studies were identified.

Systematic Literature Review and Meta-Analysis of Renal Function in Human Immunodeficiency Virus (HIV)-Infected Patients Treated with Atazanavir (ATV)-Based Regimens.

Some HIV antiretroviral therapies (ART) have been associated with renal toxicities, which become of increasing concern as HIV-infected patients age and develop comorbidities. The objective of this study was to evaluate the relative impact of atazanavir (ATV)-based regimens on the renal function of adult patients with HIV. We conducted a systematic literature review by searching PubMed, EMBASE, Cochrane library, and the CRD from 2000 until March 2013. Major HIV-related conferences occurring in the past two years were also searched. All randomized clinical trials and large cohort studies assessing renal function in treatment-naïve and/or treatment-experienced HIV patients on ATV-based regimens were included. Fixed-effect mixed-treatment network analyses were carried out on the most frequently reported renal outcomes. 23 studies met the inclusion criteria, and change in estimated glomerular filtration rate (eGFR) from baseline to 48 weeks was identified as the main outcome. Two networks including, respectively, six studies (using the Cockcroft-Gault method) and four studies (using MDRD and CKD-EPI) were analysed. With CG network, ATV/r + TDF/FTC was associated with lower impact on the decline of eGFR than ATV/cobicistat + TDF/FTC but with higher decrease in eGFR than ATV/r + ABC/3TC (difference in mean change from baseline in eGFR respectively +3.67 and -3.89). The use of ATV/cobicistat + TDF/FTC led to a similar decline in eGFR as EVG/cobicistat/TDF/FTC. With respect to third agents combined with TDF/FTC, ATV/r had a lower increase in eGFR in comparison to EFV, and no difference was shown when compared to SQV/r and DRV/r. The effect of ATV-based regimens on renal function at 48 weeks appears similar to other ART regimens and appears to be modest regardless of boosting agent or backbone, although TDF containing backbones consistently leads to greater decline in eGFR.

Changes in bone mineral density after 96 weeks of treatment with atazanavir/ritonavir or lopinavir/ritonavir plus tenofovir DF/emtricitabine in treatment-naive patients with HIV-1 infection: the CASTLE body composition substudy.

: Antiretroviral therapy initiation is associated with declines in bone mineral density (BMD), which seem greatest with tenofovir disoproxil fumarate (DF)-containing regimens. Data comparing protease inhibitors are limited. This CASTLE substudy compared paired baseline with week 96 BMD in patients initiating tenofovir DF/emtricitabine plus atazanavir/ritonavir (n = 106) vs lopinavir/ritonavir (n = 70). In both groups, week 96 BMD declined significantly in arm, leg, trunk, and total body regions. Atazanavir/ritonavir was associated with smaller 96-week trunk and total body BMD declines compared with lopinavir/ritonavir [multivariate-adjusted least squares mean difference +2.00% (95% confidence interval: 0.52 to 3.45; P = 0.008) and +1.24% (95% confidence interval: 0.13 to 2.35; P = 0.029), respectively]. In addition, low baseline CD4 cell count (<50 cells per microliter) and increasing age were associated with larger declines in BMD.

Changes in biomarkers in HIV-1-infected treatment-naive patients treated with tenofovir DF/emtricitabine plus atazanavir/ritonavir or lopinavir/ritonavir for 96 weeks: the CASTLE biomarker substudy.

BACKGROUND: The impact of boosted protease inhibitor therapy on inflammatory and cardiovascular biomarker levels in treatment-naive HIV-infected patients remains unclear and may differ between agents. Unconjugated bilirubin elevation, which favourably affects vascular biomarkers and cardiovascular disease risk in Gilbert's syndrome, occurs with atazanavir. METHODS: CASTLE was a 96-week study comparing efficacy and safety in treatment-naive HIV-1-infected patients randomized to atazanavir/ritonavir (ATV/r) versus lopinavir/ritonavir (LPV/r), each in combination with tenofovir disoproxil fumarate/emtricitabine. In this substudy, fasting plasma tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), high sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen were assessed at baseline, week 12, 24, 48 and 96. Impact of grade 3-4 hyperbilirubinaemia on biomarkers was examined. RESULTS: CASTLE demonstrated similar efficacy in both treatment arms with higher rates of hyperbilirubinaemia on ATV/r and elevated lipids on LPV/r. In this substudy (n=224), patterns of biomarker expression were similar between the ATV/r and LPV/r groups and between-group differences in biomarker percentage change from baseline were not significant at 48 and/or 96 weeks. Hyperbilirubinaemia did not influence fasting biomarker expression. CONCLUSIONS: No significant differences were noted between ATV/r and LPV/r for biomarker percentage changes from baseline. Furthermore, no association was found between total bilirubin levels and biomarker expression.

Comparison of body composition changes between atazanavir/ritonavir and lopinavir/ritonavir each in combination with tenofovir/emtricitabine in antiretroviral-naïve patients with HIV-1 infection.

BACKGROUND AND OBJECTIVE: Antiretroviral drug regimen choice may influence changes in body composition. The objective of this study was to compare changes in body composition between ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted lopinavir (LPV/r) over 96 weeks using data from a substudy of CASTLE, which compared once-daily ATV/r with twice-daily LPV/r, both in combination with tenofovir disoproxil fumarate/emtricitabine in treatment-naïve patients with HIV-1 infection. METHODS: We examined 224 patients (125 on ATV/r; 99 on LPV/r) at baseline, 48 and 96 weeks using dual-energy X-ray absorptiometry and computerised tomography. RESULTS: In the lowest baseline body mass index (BMI) group, there were significantly greater gains at week 96 for ATV/r than for LPV/r in subcutaneous adipose tissue and in visceral adipose tissue (VAT). By week 96, patients with lowest baseline CD4 cell counts on ATV/r had 28 % increases in VAT versus 14 % reductions for patients receiving LPV/r. Those with the lowest baseline BMI on ATV/r had 19 % increases in VAT versus reductions of 5 % for patients on LPV/r. In the highest baseline BMI group, the mean increase in triglycerides was 6 and 70 % in the ATV/r and LPV/r arms, respectively. Compared with baseline, an increase in proportion of patients with high waist circumference (WC)/high triglycerides at 96 weeks was noted in both treatment arms, but this increase was numerically greater with LVP/r (18 %) than with ATV/r (11 %). CONCLUSION: Truncal fat gains on ATV/r primarily led to increases in WC, which may reflect return to health, while on LPV/r increases in WC and triglycerides occurred. Changes in body composition with antiretroviral therapy are influenced by treatment choice and baseline characteristics.

Patient and provider perspectives on cellular phone-based technology to improve HIV treatment adherence.

Innovative techniques, potentially using technology, to improve adherence to antiretroviral therapy (ART) may help patients with HIV who struggle with self-care. This qualitative study compared patient and provider participants' perspectives on ART adherence and text messaging as a tool to promote adherence. Thirteen providers and 14 HIV-infected patients identified four main themes: (1) facilitators, (2) barriers to using text message reminders as a medium for ART medication reminders, (3) framing of text message reminders, and (4) patient responsibility and autonomy in the management of their health and wellness. Ease of use, access, convenience, and confidentiality were cited as benefits of a text message-based adherence intervention; while access, cost, difficulty manipulating cellular phones, lack of knowledge/education, and confidentiality were cited as potential barriers. Providers, but not patients, also identified patient apathy and time burden as potential barriers to a text message-based adherence reminder system. Patients and providers felt that personalization of messages, attention to timing, and confidentiality of messages were key factors for a successful text message-based adherence reminder system. Both providers and patients felt that patient responsibility and autonomy over an individual's own health care is an important issue in adherence to medical care. The majority of patients and providers felt that a text message-based adherence reminder system would be beneficial. While patients and providers had many similar views on factors influencing adherence with ART and the use of text messaging to improve adherence, there were some divergent views between the two groups.

Clinical and pharmacogenetic factors affecting neonatal bilirubinemia following atazanavir treatment of mothers during pregnancy.

A theoretical concern exists that atazanavir (ATV) use during pregnancy may exacerbate physiologic neonatal hyperbilirubinemia. The aim of this substudy was to evaluate patterns of neonatal bilirubin following ATV/ritonavir (RTV) treatment of pregnant mothers and clinical and pharmacogenetic factors that may correlate. The design involved a subanalysis of study AI424182, a multicenter, open-label, prospective, single-arm Phase I study. The study had two treatment arms: (1) ATV/RTV 300/100 mg once daily or (2) ATV/RTV 400/100 mg once daily, both in combination with zidovudine/lamivudine 300/150 mg twice daily. Total bilirubin was assessed at baseline, each visit, and delivery day for mothers and on days 1 (delivery day), 3, 5, and 7 and weeks 2 and 6 for neonates. Blood samples were obtained for UGT1A1 genotyping and ATV cord blood concentration. Bilirubin elevation of any grade occurred in 14/40 neonates (35%). All Grade 3 to 4 bilirubin abnormalities (n=7) occurred after day 14. The pattern of neonatal bilirubin levels reported was consistent with neonatal physiologic elevations of bilirubin. Little correlation was observed between either maternal bilirubin levels over the last 4 weeks of pregnancy (including delivery) or ATV cord concentration and neonatal bilirubin. There was a significant association between UGT1A1 genotype and bilirubin grade in the maternal population (p=0.0006) but not neonates (p=0.49). Neither neonatal UGT1A1 genotype nor cord blood ATV concentration is a good predictor of neonatal hyperbilirubinemia. ATV/RTV treatment of mothers does not appear to exacerbate neonatal physiologic hyperbilirubinemia.

Atazanavir pharmacokinetics, efficacy and safety in pregnancy: a systematic review.

BACKGROUND: For some antiretroviral therapies, drug concentrations are reduced during pregnancy, potentially compromising effective virological suppression. METHODS: Data on atazanavir boosted with ritonavir in pregnancy are reviewed. RESULTS: With standard atazanavir/ritonavir 300/100 mg once-daily dosing: atazanavir area-under-the-concentration-time curves were reduced during pregnancy in most studies, but overall interpretation differed according to the data used for comparison; atazanavir concentration 24 h post-dose was maintained >150 ng/ml in 97.6% of women; no instance of mother-to-child transmission occurred in treatment-adherent mothers; and infant hyperbilirubinaemia was not elevated beyond levels expected in the neonatal period. CONCLUSIONS: With concurrent medications that reduce atazanavir drug concentrations, optimal therapy during pregnancy may require once-daily atazanavir/ritonavir 400/100 mg; however, using this dose during the third trimester doubled maternal grade 3-4 hyperbilirubinaemia rates.

Development and field testing of an HIV medication touch screen computer patient adherence tool with telephone-based, targeted adherence counseling.

BACKGROUND: HIV medication nonadherence is a major problem, yet many providers lack the time and training to carefully ask patients about their adherence. OBJECTIVE: To design and pilot a technology-assisted intervention, for use in clinical settings, to identify nonadherent patients. METHODS: The intervention uses audio computer-assisted self-interview (ACASI) to improve the assessment of adherence and medication-related problems. Patients completed a touch screen computer ACASI which generated graphic clinician and patient reports for discussion during the clinical encounter. RESULTS: 72 patients and 11 providers participated in this study. The patients easily completed the ACASI. Adherence was 63% (3-day) and 47% (30-day). Using the ACASI, 22% of patients identified themselves as nonadherent, when their providers perceived them as adherent. CONCLUSIONS: This ACASI-based intervention is easy to use and helps identify nonadherence. The pilot test engendered enhancements including the addition of phone-based adherence counseling. A larger trial is underway to evaluate whether the intervention leads to improved HIV-related outcomes.

Randomized controlled trial of a personalized cellular phone reminder system to enhance adherence to antiretroviral therapy.

Adherence to antiretroviral therapy (ART) represents one of the strongest predictors of progression to AIDS, yet it is difficult for most patients to sustain high levels of adherence. This study compares the efficacy of a personalized cell phone reminder system (ARemind) in enhancing adherence to ART versus a beeper. Twenty-three HIV-infected subjects on ART with self-reported adherence less than 85% were randomized to a cellular phone (CP) or beeper (BP). CP subjects received personalized text messages daily; in contrast, BP subjects received a reminder beep at the time of dosing. Interviews were scheduled at weeks 3 and 6. Adherence to ART was measured by self-report (SR, 7-day recall), pill count (PC, past 30 days at baseline, then past 3 weeks), Medication Event Monitoring System (MEMS; cumulatively at 3 and 6 weeks), and via a composite adherence score constructed by combining MEMS, pill count, and self report. A mixed effects model adjusting for baseline adherence was used to compare adherence rates between the intervention groups at 3 and 6 weeks. Nineteen subjects completed all visits, 10 men and 9 females. The mean age was 42.7 ± 6.5 years, 37% of subjects were Caucasian and 89% acquired HIV heterosexually. The average adherence to ART was 79% by SR and 65% by PC at baseline in both arms; over 6 weeks adherence increased and remained significantly higher in the ARemind group using multiple measures of adherence. A larger and longer prospective study is needed to confirm these findings and to better understand optimal reminder messages and user fatigue.

A collaborative awareness system for chronic disease medication adherence applied to HIV infection.

Electronic reminder systems have been available for decades, yet medication adherence remains poor. Most systems rely on simple alarms and do not address other determinants of health-related behavior. This paper describes a collaborative awareness system for chronic disease medication adherence that relies on patient self-reflection and clinician support. Visualizations of adherence performance, including estimated plasma concentration graphs and a dynamic, personalized, disease-state simulation, are available to the patient (cell phone and internet media display) and clinician (computer) in real-time. The clinician can send asynchronous video messages of advice and encouragement to the patient regularly. A pilot was conducted with four HIV positive patients for four weeks. Three patients who started with suboptimal adherence improved (93.0% to 99.1%, 83.0% to 96.3%, and 63.9% to 81.3%). One patient who started with optimal medication adherence (>95%) maintained this level. All four patients appreciated the rich feedback and wanted to continue using the system.

Successful bosentan and nonnucleoside reverse transcriptase inhibitor-based therapy in a patient with acquired immunodeficiency syndrome and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH), which can be a complication of human immunodeficiency virus (HIV) infection, is characterized by increased pulmonary arterial pressure and peripheral vascular resistance, subsequently leading to right heart failure. In HIV-infected patients, the management of PAH is challenging given the potential drug interactions between PAH-specific vasodilators and antiretroviral drugs. We describe a 51-year-old female with acquired immunodeficiency syndrome (AIDS) and HIV-associated PAH. She was treated with the oral endothelin receptor antagonist bosentan while taking a nevirapine (a nonnucleoside reverse transcriptase inhibitor)-based antiretroviral regimen. Due to concerns about potential drug interactions with the antiretroviral therapy, her nevirapine plasma concentration, as well as CD4(+) cell count and viral load, were continuously monitored. We observed no interaction between bosentan and nevirapine during a 4-year period. To our knowledge, this report is the first to demonstrate successful, long-term coadministration of bosentan and a nonnucleoside reverse transcriptase inhibitor.

Optimal recall period and response task for self-reported HIV medication adherence.

Self-reported measures of antiretroviral adherence vary greatly in recall time periods and response tasks. To determine which time frame is most accurate, we compared 3-, 7-day, and 1-month self-reports with data from medication event monitoring system (MEMS). To determine which response task is most accurate we compared three different 1-month self-report tasks (frequency, percent, and rating) to MEMS. We analyzed 643 study visits made by 156 participants. Over-reporting (self-report minus MEMS) was significantly less for the 1-month recall period (9%) than for the 3 (17%) or 7-day (14%) periods. Over-reporting was significantly less for the 1-month rating task (3%) than for the 1-month frequency and percent tasks (both 12%). We conclude that 1-month recall periods may be more accurate than 3- or 7-day periods, and that items that ask respondents to rate their adherence may be more accurate than those that ask about frequencies or percents.