Rifabutin pharmacokinetics and safety among TB/HIV-coinfected children receiving lopinavir/ritonavir-containing second-line ART.

BACKGROUND: Treatment options are limited for TB/HIV-coinfected children who require PI-based ART. Rifabutin is the preferred rifamycin for adults on PIs, but the one study evaluating rifabutin with PIs among children was stopped early due to severe neutropenia. METHODS: We evaluated rifabutin safety and plasma pharmacokinetics among coinfected children 3-15 years of age receiving rifabutin 2.5 mg/kg daily with standard doses of lopinavir/ritonavir. The AUC0-24 at 2, 4 and 8 weeks after rifabutin initiation was described using intensive sampling and non-compartmental analysis. Clinical and laboratory toxicities were intensively monitored at 12 visits throughout the study. RESULTS: Among 15 children with median (IQR) age 13.1 (10.9-14.0) years and weight 25.5 (22.3-30.5) kg, the median (IQR) rifabutin AUC0-24 was 5.21 (4.38-6.60) µg·h/mL. Four participants had AUC0-24 below 3.8 µg·h/mL (a target for the population average exposure) at week 2 and all had AUC0-24 higher than 3.8 µg·h/mL at the 4 and 8 week visits. Of 506 laboratory evaluations during rifabutin, grade 3 and grade 4 abnormalities occurred in 16 (3%) and 2 (0.4%) instances, respectively, involving 9 (60%) children. Specifically, grade 3 (n = 4) and grade 4 (n = 1) neutropenia resolved without treatment interruption or clinical sequelae in all patients. One child died at week 4 of HIV-related complications. CONCLUSIONS: In children, rifabutin 2.5 mg/kg daily achieved AUC0-24 comparable to adults and favourable HIV and TB treatment outcomes were observed. Severe neutropenia was relatively uncommon and improved with ongoing rifabutin therapy. These data support the use of rifabutin for TB/HIV-coinfected children who require lopinavir/ritonavir.

Safety and efficacy of rifabutin among HIV/TB-coinfected children on lopinavir/ritonavir-based ART.

BACKGROUND: TB is the leading cause of death among HIV-infected children, yet treatment options for those who require PI-based ART are suboptimal. Rifabutin is the preferred rifamycin for adults on PI-based ART; only one study has evaluated its use among children on PIs and two of six children developed treatment-limiting neutropenia. METHODS: Since 2009, rifabutin has been available for HIV/TB-coinfected children requiring PI-based ART in the Harvard/APIN programme in Nigeria. We retrospectively analysed laboratory and clinical toxicities at baseline and during rifabutin therapy, and examined HIV/TB outcomes. RESULTS: Between 2009 and 2015, 48 children received rifabutin-containing TB therapy with PI (lopinavir/ritonavir)-based ART: 50% were female with a median (IQR) baseline age of 1.7 (0.9-5.0) years and a median (IQR) CD4+ cell percentage of 15% (9%-25%); 52% were ART experienced. Eighty-five percent completed the 6 month rifabutin course with resolution of TB symptoms and 79% were retained in care at 12 months. Adverse events (grade 1-4) were more common at baseline (27%) than during rifabutin treatment (15%) (P = 0.006). Absolute neutrophil count was lower during rifabutin compared with baseline (median = 1762 versus 2976 cells/mm3, respectively), but only one instance (2%) of grade 3 neutropenia occurred during rifabutin treatment. CONCLUSIONS: With clinical and laboratory monitoring, our data suggest that rifabutin is a safe option for TB therapy among children on PI-based ART. By contrast with the only other study of this combination in children, severe neutropenia was rare. Furthermore, outcomes from this cohort suggest that rifabutin is effective, and a novel option for children who require PI-based ART. Additional study of rifabutin plus PIs in children is urgently needed.

Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug-drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART.

Background: HIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low levonorgestrel exposure and unintended pregnancy. Objectives: To investigate clinically applicable dose-adjustment strategies to overcome the known drug-drug interaction (DDI) between levonorgestrel and efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach. Methods: A PBPK model was qualified against clinical data to predict levonorgestrel plasma concentrations when standard-dose (150 mg) levonorgestrel implants were administered alone (control group), as well as when standard-dose or increased-dose (300 mg) levonorgestrel implants were coadministered with either 600 or 400 mg of efavirenz. Results: No difference was seen between in vivo clinical and PBPK-model-simulated levonorgestrel plasma concentrations (P > 0.05). Simulated levonorgestrel plasma concentrations were ∼50% lower at 48 weeks post-implant-placement in virtual individuals receiving standard-dose levonorgestrel with either 600 or 400 mg of efavirenz compared with the control group (efavirenz:control geometric mean ratio = 0.42 and 0.49, respectively). Conversely, increased-dose levonorgestrel in combination with either 600 or 400 mg of efavirenz was sufficient to restore levonorgestrel concentrations to levels similar to those observed in the 150 mg levonorgestrel control group 48 weeks post-implant-placement (efavirenz:control geometric mean ratio = 0.86 and 1.03, respectively). Conclusions: These results suggest that the clinically significant DDI between efavirenz and levonorgestrel is likely to persist despite efavirenz dose reduction, whereas dose escalation of implantable levonorgestrel may represent a successful clinical strategy to circumvent efavirenz-levonorgestrel DDIs and will be of use to inform clinical trial design to assess coadministration of efavirenz and levonorgestrel implants.

Efavirenz decreases etonogestrel exposure: a pharmacokinetic evaluation of implantable contraception with antiretroviral therapy.

OBJECTIVES: The primary objective of this study was to characterize the pharmacokinetics of etonogestrel (ENG) released from a contraceptive implant in Ugandan women living with HIV who were receiving efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART), compared with ART-naive women over 24 weeks. DESIGN: Nonrandomized, parallel-group study with three arms: ART-naive, NVP, or EFV-based ART (N = 20/group). METHODS: Sparse pharmacokinetic sampling of ENG, NVP, or EFV were performed at screening, entry, and then 1, 4, 12, and 24-week postimplant insertion. The primary endpoint was ENG concentrations at week 24, compared between the ART-naive group and each ART group, using geometric mean ratio (GMR) with 90% confidence intervals. RESULTS: Sixty participants competed the 24-week study and data from 58 participants are included; one participant each was excluded from the NVP group and EFV group because of a sample processing error and ART nonadherence, respectively. At week 24, geometric mean ENG was 362, 341, and 66 pg/ml in the ART-naive, NVP, and EFV groups, respectively [GMR: NVP : ART-naive 0.94 (0.90-1.01); EFV : ART-naive 0.18 (0.17-0.20)]. NVP and EFV concentrations were lower at week 24 compared to preimplant [NVP: geometric mean 5.7 versus 6.8 mg/l, respectively, GMR 0.84 (0.83-0.85); EFV: geometric mean 3.6 versus 4.9 mg/l, respectively, GMR 0.73 (0.69-0.80)]. CONCLUSION: After 24 weeks of combined use, ENG exposure was 82% lower in women using EFV-based ART compared with ART-naive women. In contrast, NVP did not significantly impact ENG exposure. These results raise concerns about reduced effectiveness of implantable contraception for women taking EFV-based ART.

Drug-Drug Interactions, Effectiveness, and Safety of Hormonal Contraceptives in Women Living with HIV.

Family planning options, including hormonal contraceptives, are essential for improving reproductive health among the more than 17 million women living with HIV worldwide. For these women, prevention of unintended pregnancy decreases maternal and child mortality, as well as reduces the risk of perinatal HIV transmission. Similarly, treatment of HIV with antiretroviral therapy (ART) is essential for reducing morbidity and mortality among HIV-positive individuals, as well as preventing HIV transmission between sexual partners or from mother to child. Importantly, despite the benefits of hormonal contraceptives, barriers to effective family planning methods exist for HIV-positive women. Specifically, drug-drug interactions can occur between some antiretroviral medications and some hormonal contraceptives, which may influence both contraceptive efficacy and tolerability. In addition, safety concerns have been raised about the impact of hormonal contraceptives on HIV disease progression, tolerability, and the risk of female-to-male HIV transmission. This review article summarizes the potential for drug-drug interactions, tolerability, and contraceptive effectiveness when hormonal contraceptives are combined with ART. In addition, the evidence surrounding the influence of hormonal contraceptives on HIV transmission and HIV disease progression in women living with HIV are summarized.

Superior Effectiveness of Zidovudine Compared With Tenofovir When Combined With Nevirapine-based Antiretroviral Therapy in a Large Nigerian Cohort.

BACKGROUND: Despite sparse efficacy data, tenofovir-emtricitabine or tenofovir-lamivudine plus nevirapine is used in many resource-constrained settings. METHODS: This retrospective cohort study included patients initiating nevirapine-based antiretroviral therapy (ART) with either tenofovir-emtricitabine or lamivudine (tenofovir group) or zidovudine-lamivudine (zidovudine group). Clinical, virologic, and immunologic evaluations were performed at baseline and every 6 months. Virologic failure was defined as 2 consecutive human immunodeficiency virus (HIV)-RNA values >1000 copies/mL. Patients were included from ART initiation until time of failure, regimen switch, discontinuation, or last HIV-RNA measurement. Cox proportional hazards regression was used to model factors influencing time to failure. Bias due to dependent censoring was investigated via inverse probability weighted pooled logistic regression. RESULTS: A total of 5547 patients were evaluated; 1484 (26.8%) were in the tenofovir group and 4063 (73.2%) were in the zidovudine group. In the adjusted model, tenofovir regimen (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.21-1.79) and higher baseline log10 HIV-RNA (HR, 1.15; 95% CI, 1.03-1.28) were associated with virologic failure. Higher baseline log10 CD4+ cell count (HR, 0.50; 95% CI, .40-.63) and increasing age (HR, 0.98; 95% CI, .97-.99) decreased the risk of virologic failure. Inverse probability weighting results were consistent with the primary analysis. CONCLUSIONS: Compared with zidovudine-lamivudine, the use of tenofovir-lamivudine or emtricitabine in combination with nevirapine was a strong predictor of virologic failure in our cohort, which was not explained by other risk factors or criteria for regimen selection.

Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks.

BACKGROUND: Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics. METHODS: This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies. RESULTS: Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43). Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups. CONCLUSIONS: Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy. CLINICAL TRIALS REGISTRATION: NCT01789879.

Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy.

Coadministration of nevirapine-based antiretroviral therapy (ART) and artemether-lumefantrine is reported to result in variable changes in lumefantrine exposure. We conducted an intensive pharmacokinetic study with 11 HIV-infected adults who were receiving artemether-lumefantrine plus nevirapine-based ART, and we compared the results with those for 16 HIV-negative adult historical controls. Exposure to artemether and lumefantrine was significantly lower and dihydroartemisinin exposure was unchanged in subjects receiving nevirapine-based ART, compared with controls. Nevirapine exposure was unchanged before and after artemether-lumefantrine administration.

Antiretroviral Pharmacokinetics in Pregnant Women.

For women infected with the human immunodeficiency virus (HIV) who become pregnant, the use of combination antiretroviral therapy (ART) significantly reduces transmission of HIV from mother to child. Selection of an appropriate ART regimen for use among pregnant women requires consideration of numerous factors including maternal and fetal safety, antiretroviral pharmacokinetics, and regimen efficacy. Optimization of antiretroviral pharmacokinetics during pregnancy requires special consideration because pregnancy-associated changes in drug absorption, distribution, metabolism, and excretion are known to occur throughout pregnancy and postpartum. Understanding antiretroviral placental transfer may offer additional insight into each drug's potential role in preventing HIV transmission in utero and may also have implications regarding viral resistance in cases where transmission does occur. In this review, we summarize key published data describing antiretroviral pharmacokinetics in pregnant women, providing suggestions for clinical application of these data where appropriate.

Patterns and Predictors of First-Line Antiretroviral Therapy Modification in HIV-1-Infected Adults in a Large Urban Outpatient Cohort in Nigeria.

OBJECTIVE: We described the magnitude, type, and factors associated with first-line antiretroviral therapy (ART) modification in HIV-1-infected adults on ART in Jos, Nigeria. METHOD: Data on 6309 patients initiated on first-line ART between January 2004 and December 2006 were analyzed retrospectively. Factors predictive of modification to initial ART were assessed by chi-square and multivariable logistic regression analysis. RESULTS: Overall, 5212 (83%) included patients incurred a modification (73.3% drug substitution and 9.7% drug switch) to their initial first-line ARV regimen during a median (interquartile range) follow-up period of 7 (3-8) years. Drug substitutions of zidovudine (ZDV) were less likely than of tenofovir (TDF; adjusted odd ratio [AOR] 0.6; 95% confidence interval [CI]: 0.51-0.71), and Drug substitutions of efavirenz (EFV) were more likely than of nevirapine (NVP)-containing (AOR 1.82; 95% CI: 1.42-2.33) regimens. Predictors of switch to second-line regimen include older age (AOR 2.05; 95% CI: 1.68-2.51), CD4 count≤100 cells/mm3 (AOR 1.89; 95% CI: 1.49-2.37), EFV compared to NVP (AOR 1.38; 95% CI: 1.02-1.88), and drug toxicity (AOR 1.90; 95% CI: 1.48-2.43). CONCLUSION: Modification to initial ART was common in this study. Further evaluation of the contribution of guideline changes on regimen modification and treatment outcomes is recommended.

Consumer interest in community pharmacy HIV screening services.

OBJECTIVE: To evaluate consumers' interest in pharmacist-provided human immunodeficiency virus (HIV) screening and to evaluate potential barriers and facilitators to HIV screening in the community pharmacy setting. METHODS: Cross-sectional survey of adult patients who presented to one of five community (chain and independent) pharmacies from November 2010 to August 2011. RESULTS: Based on 380 usable surveys, 135 (35.8%) participants were interested in pharmacy-based HIV screening. Independent predictors of interest in HIV screening identified in multivariate analysis (reference groups: ages 30 to 49 years old and white, non-Hispanic race) included younger age (18 to 29 years old) (odds ratio [OR], 2.48; 95% confidence interval [CI], 1.31 to 4.71); black, non-Hispanic race (OR, 2.37; CI, 1.40 to 4.03); and other race (OR, 4.58; CI, 1.63 to 12.87). Lack of perceived risk for HIV was the most commonly cited barrier to HIV screening; and free, rapid, or confidential HIV testing were identified as potential facilitators. CONCLUSION: Interest in pharmacy-based HIV screening was high among participants representing age and race groups disproportionately affected by HIV. Expansion of HIV screening efforts to community pharmacies warrants further consideration.

Pharmacist-provided rapid HIV testing in two community pharmacies.

OBJECTIVE: To evaluate the acceptability and feasibility of pharmacist-provided rapid testing for human immunodeficiency virus (HIV) infection in community pharmacies. PRACTICE DESCRIPTION: A pharmacist-provided HIV testing model-including rapid HIV testing, counseling, and linkage to confirmatory HIV testing services-was developed and implemented. SETTING: Two independent pharmacies located in Michigan cities of different size and with different prevalence of HIV infection. MAIN OUTCOME MEASURES: Number of HIV tests performed, time required for HIV testing services, description of participants who received an HIV test, and pharmacist and participant perception of the HIV testing experience. RESULTS: From October 2011 to March 2013, pharmacists provided HIV tests to 69 participants. One (1.5%) participant had a reactive HIV test and was immediately referred to an appropriate health care provider for confirmatory testing. HIV testing services required a median time of 30 (range, 20-90) minutes. Participants had a median age of 23 (range, 18-61) years and were diverse by gender (59.4% women) and race (46.4% black; 39.1% white). This was the first HIV test for 42% of participants, many of whom reported high-risk behaviors in the prior 6 months. Participants and pharmacists reported favorable perceptions of the HIV testing experience. CONCLUSIONS: This project demonstrates the acceptability and feasibility of pharmacist-provided rapid HIV testing in two community pharmacies with distinct characteristics. Further development of HIV testing services in this practice setting is warranted.

Pharmaceutical care outcomes in an outpatient human immunodeficiency virus treatment center in Jos, Nigeria.

RATIONALE: Pharmacotherapy for patients infected with human immunodeficiency virus (HIV) is complex and increases the potential for drug therapy problems (DTPs). We described the frequency and type of DTPs in a Nigerian cohort of HIV infected patients on antiretroviral therapy (ART), as well as the changes in HIV clinical outcomes after pharmacists' intervention. METHODS: A prospective 1-year descriptive study was conducted from July 2010 to June 2011, at the adult HIV clinic of Jos University Teaching Hospital, Nigeria. DTPs and the associated pharmacist-initiated interventions were documented. Chi-square and Wilcoxon signed ranks test was used as appropriate, to compare the main outcome measures of pre- and post-intervention levels of viral load and CD+ cell count. RESULTS: A total of 64,839 prescriptions were dispensed to 9320 patients. Interventions were documented for 85 unique patients (incidence of 1.31 interventions/1000 prescriptions), of which 62 (73%) and 3 (3.5%) were on first- and second-line ART, respectively, while 20 (23.5%) were yet to commence ART. Reasons for pharmacist intervention included failure to initiate therapy for HIV or hepatitis B infection; therapeutic failure (25.9%); and drug toxicity (24.7%). After intervention, the percentage of patients with HIV ribonucleic acid level <400 copies/mL rose from 29.4% to 67.1% (P < 0.001), while median (interquartile range) CD4+ cell count increased from 200 (123-351) to 361 (221-470) cells/mm(3) (P < 0.001). CONCLUSION: Pharmacist intervention resulted in clinically significant improvements in patients HIV virological and immunological outcomes. This highlights an important role for the pharmacist in the treatment and care of HIV-infected patients, in a multidisciplinary team.

Point-of-care testing for infectious diseases: opportunities, barriers, and considerations in community pharmacy.

OBJECTIVES To identify opportunities to perform point-of-care (POC) testing and/or screening for infectious diseases in community pharmacies, provide an overview of such tests and how they are used in current practice, discuss how the Clinical Laboratory Improvement Amendments of 1988 (CLIA) affect pharmacists performing POC testing, and identify and discuss barriers and provide recommendations for those wanting to establish POC testing for infectious diseases services in community pharmacies. DATA SOURCES PubMed and Google Scholar were searched from November 2012 through May 2013 and encompassed the years 2000 and beyond for the narrative review section of this article using the search terms rapid diagnostic tests, POC testing and infectious diseases, pharmacy services, CLIA waiver, and collaborative drug therapy management. All state boards of pharmacy in the United States were contacted and their regulatory and legislative websites accessed in 2012 and January 2013 to review relevant pharmacy practice laws. DATA SYNTHESIS POC testing for infectious diseases represents a significant opportunity to expand services in community pharmacies. Pharmacist education and training are addressing knowledge deficits in good laboratory practices and test performance and interpretation. Federal regulations do not define the qualifications for those who perform CLIA-waived tests, yet few pharmacists perform such services. Fewer than 20% of states address POC testing in their statutes and regulations governing pharmacy. CONCLUSION POC testing for infectious diseases could benefit patients and society and represents an opportunity to expand pharmacy services in community pharmacies. Existing barriers to the implementation of such services in community pharmacies, including deficits in pharmacist training and education along with state regulatory and legislative variance and vagueness in statutes governing pharmacy, are not insurmountable.

Disposition of amodiaquine and desethylamodiaquine in HIV-infected Nigerian subjects on nevirapine-containing antiretroviral therapy.

OBJECTIVES: Artesunate plus amodiaquine is used for malaria treatment in regions with overlapping HIV endemicity. Co-administration of artesunate/amodiaquine with antiretroviral therapy (ART) may result in drug-drug interactions, but minimal data exist. This study evaluated the impact of nevirapine-based ART, containing a backbone of zidovudine and lamivudine, on the disposition of amodiaquine and its active metabolite, desethylamodiaquine (DEAQ). METHODS: This was an open-label, parallel-group pharmacokinetic comparison between HIV-infected, adult subjects receiving steady-state nevirapine-based ART (n = 10) and ART-naive subjects (control group, n = 11). All subjects received a loose formulation of artesunate/amodiaquine (200/600 mg) daily for 3 days, with serial pharmacokinetic sampling over 96 h following the final dose of artesunate/amodiaquine. Amodiaquine and DEAQ were quantified using a validated HPLC method with UV detection. Pharmacokinetic parameters were determined using standard non-compartmental methods. RESULTS: Exposures to both amodiaquine and DEAQ were significantly lower in the nevirapine-based ART group compared with the control group (amodiaquine AUC0₋24 145 versus 204 ng·h/mL, P = 0.02; DEAQ AUC0₋96 14,571 versus 21,648 ng·h/mL, P < 0.01). The AUCDEAQ/AUC(amodiaquine) ratio was not different between groups (ART group 116 versus control group 102, P = 0.67). CONCLUSIONS: Subjects on nevirapine-based ART had lower exposure to both amodiaquine and DEAQ (28.9% and 32.7%, respectively). Consequently, this may negatively impact the effectiveness of artesunate/amodiaquine in HIV-infected individuals on this ART combination.

Accumulation of protease mutations among patients failing second-line antiretroviral therapy and response to salvage therapy in Nigeria.

BACKGROUND: To date, antiretroviral therapy (ART) guidelines and programs in resource-limited settings (RLS) have focused on 1(st)- and 2(nd)-line (2 L) therapy. As programs approach a decade of implementation, policy regarding access to 3(rd)-line (3 L) ART is needed. We aimed to examine the impact of maintaining patients on failing 2 L ART on the accumulation of protease (PR) mutations. METHODS AND FINDINGS: From 2004-2011, the Harvard/APIN PEPFAR Program provided ART to >100,000 people in Nigeria. Genotypic resistance testing was performed on a subset of patients experiencing 2 L failure, defined as 2 consecutive viral loads (VL)>1000 copies/mL after ≥6 months on 2 L. Of 6714 patients who received protease inhibitor (PI)-based ART, 673 (10.0%) met virologic failure criteria. Genotypes were performed on 61 samples. Patients on non-suppressive 2 L therapy for <12 months prior to genotyping had a median of 2 (IQR: 0-5) International AIDS Society (IAS) PR mutations compared with 5 (IQR: 0-6) among patients failing for >24 months. Patients developed a median of 0.6 (IQR: 0-1.4) IAS PR mutations per 6 months on failing 2 L therapy. In 38% of failing patients no PR mutations were present. For patients failing >24 months, high- or intermediate-level resistance to lopinavir and atazanavir was present in 63%, with 5% to darunavir. CONCLUSIONS: This is the first report assessing the impact of duration of non-suppressive 2 L therapy on the accumulation of PR resistance in a RLS. This information provides insight into the resistance cost of failing to switch non-suppressive 2 L regimens and highlights the issue of 3 L access.

Clinical implications of antiretroviral drug interactions with warfarin: a case-control study.

OBJECTIVES: Warfarin, a frequently prescribed anticoagulant with a narrow therapeutic index, is susceptible to drug-drug interactions with antiretroviral therapy (ART). This study compared the warfarin maintenance dose (WMD) between patients receiving and not receiving ART and evaluated predictors of warfarin dosage among those on ART. METHODS: This was a case-control (1:2) study. Cases were HIV-infected patients receiving warfarin and protease inhibitor (PI)- and/or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Controls were randomly selected HIV-uninfected patients receiving warfarin. The WMD was compared between cases and controls and between cases on varying ART regimens. Bivariate comparisons were performed and a linear regression model was developed to identify predictors of WMD. RESULTS: We identified 18 case and 36 control patients eligible for inclusion. Cases were younger than controls (mean age: 45.8 versus 63.1 years, P < 0.01), more often male (72.2% versus 36.1%, P=0.02) and more likely to be African American (50.0% versus 22.2%, P=0.04). ART was classified as PI-based (n=9), NNRTI-based (n=7) and PI + NNRTI-based (n=2). The WMD (mean ±â€ŠSD) differed between cases and controls (8.6  ±  3.4 mg versus 5.1 ±â€Š1.5 mg, P < 0.01), but not ART regimens (PI: 8.8  ±  4.5 mg; NNRTI: 8.6   ±â€Š1.8 mg; PI + NNRTI: 7.3  ±  3.3 mg; P = 0.86). Race and ritonavir dose were independent predictors of WMD, predicting an increase of 3.9 mg (95% CI: 0.88-6.98, P = 0.02) if a patient was African American or 3.7 mg (95% CI: 0.53-6.89, P = 0.03) if the total daily ritonavir dose was 200 mg. CONCLUSIONS: The required WMD was significantly higher in patients receiving ART. Prompt dose titration to achieve a higher WMD with vigilant monitoring may be required due to these drug-drug interactions.

Optimizing treatment switch for virologic failure during first-line antiretroviral therapy in resource-limited settings.

We evaluated adult Nigerian patients with antiretroviral switch to second-line treatment with ritonavir-boosted protease inhibitor (PI/r)-based regimens due to virologic failure (confirmed HIV-1 RNA viral load [VL] >1000 copies/mL) during first-line antiretroviral therapy. Proportion of patients with VL >400 copies/mL and characteristics associated with nonsuppression during second-line treatment are described. Approximately 15% of patients (34 of 225) had VL >400 copies/mL at 1-year after treatment switch to PI/r-based regimens. In adjusted analyses, VL ≥5 log10 copies/mL at treatment switch (odds ratio [OR] 2.90 [confidence interval (CI) 1.21-6.93]); duration of first-line treatment after virologic failure >180 days (OR 2.56 [CI 1.0-6.54]); and PI/r regimen adherence <90% (OR 3.27 [CI 1.39-7.68]) were associated with VL >400 copies/mL at 1 year of second-line treatment. We therefore recommend that the maximum permissible time between suspicion of virologic failure and completion of antiretroviral treatment switch should not exceed 6 months when patients develop first-line antiretroviral failure in resource-limited settings.

Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults.

In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens. In this article we review atazanavir/r as a treatment for HIV infection and discuss the latest information on its pharmacology, efficacy and toxicity.

Low incidence of renal impairment observed in tenofovir-treated patients.

OBJECTIVES: To compare the incidence of renal impairment in HIV-infected patients exposed versus unexposed to tenofovir and to characterize risk factors associated with renal impairment. METHODS: We undertook a retrospective cohort and nested case-control study of 514 Northwestern University HIV Outpatient Study participants who received antiretroviral therapy (ART) between 1 August 2001 and 31 July 2007. Renal impairment was defined as meeting at least one of two validated criteria based on serum creatinine, calculated glomerular filtration rate and creatinine clearance. Multivariable analysis was performed to identify risk factors for renal impairment. RESULTS: Renal impairment occurred in 14% (n = 72) of the cohort and was not correlated with exposure to tenofovir in univariate analyses. In multivariable analysis, more advanced age [odds ratio (OR) = 1.04, P = 0.02], diabetes (OR = 3.6, P < 0.01), decreased weight (OR = 0.97, P = 0.02) and endpoint CD4 ≤200 cells/mm(3) (OR = 2.5, P = 0.03) were positive predictors of renal impairment; tenofovir exposure (OR = 0.41, P = 0.01) was negatively correlated with renal impairment. CONCLUSIONS: Tenofovir-containing ART was associated with less renal impairment than ART without tenofovir in a patient cohort with a high incidence of renal impairment. Chronic co-morbid conditions known to be associated with renal impairment should be excluded prior to attributing renal impairment to tenofovir.