HIV Clinical Trials[JOURNAL]
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200 papers
Switching from twice-daily raltegravir plus tenofovir disoproxil fumarate/emtricitabine to once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate in virologically suppressed, HIV-1-infected subjects: 48 weeks data.
Mills A, Crofoot G, Ortiz R … +10 more , Rashbaum B, Towner W, Ward D, Brinson C, Kulkarni R, Garner W, Ebrahimi R, Cao H, Cheng A, Szwarcberg J
HIV Clin Trials · 2014 · PMID 24710918 · Publisher ↗
BACKGROUND: Pill burden, dosing frequency, and concerns about safety and tolerability are important obstacles to maintaining adequate medication adherence. Raltegravir (RAL) is indicated for twice-daily dosing and when t...
BACKGROUND: Pill burden, dosing frequency, and concerns about safety and tolerability are important obstacles to maintaining adequate medication adherence. Raltegravir (RAL) is indicated for twice-daily dosing and when taken with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF), it becomes a twice-daily multiple-tablet regimen. Elvitegravir (EVG)/cobicistat (COBI)/FTC/TDF, STB, is the first approved once-a-day integrase strand transfer inhibitor (INSTI) containing single-tablet regimen that combines EVG, an INSTI, and COBI, a novel pharmacoenhancer, with the preferred nucleos(t)ide backbone of FTC/TDF. METHODS: This was a 48-week prospective, single-arm open-label study of the switch to STB in virologically sup-pressed HIV-1-infected adult patients on FTC/TDF and twice-daily RAL for at least 6 months. Objectives were to evaluate the tolerability and safety of a regimen simplification to once-a-day STB, while maintaining viral suppression through 48 weeks. RESULTS: Forty-eight individuals in the United States were enrolled. The median age was 44 years, 96% were male, and 83% were White. The median time on RAL + FTC/TDF treatment prior to enrollment was 34 months. Ninety-six percent of participants cited regimen simplification as the reason to enroll in the switch study. At base-line, the median CD4 count was 714 cell/µL and estimated glomerular filtration rate (eGFR) was 105 mL/min. At week 48, all assessed study participants remained viro-logically suppressed to the lower limit of quantification (HIV-1 RNA<50 copies/mL) and maintained high CD4 cell count (median, 751 cells/mL) and stable eGFR (median, 100.5 mL/min). STB was well tolerated with no discontinuations, no study drug-related serious adverse events, and no study drug-related grade 3/4 adverse events. CONCLUSIONS: All participants switching to 1 tablet once-a-day STB from a twice-daily RAL + FTC/TDF regimen remained virologically suppressed. STB was well tolerated. Switching to STB may be a viable option for virologically suppressed patients wanting to simplify from a twice-daily RAL-containing regimen.
Phase I study demonstrates safety and tolerability of radiofrequency ablation (RFA) of the anal mucosa.
Smulian AG, Moore DM, Robertson JC … +1 more , Kralovic SM
HIV Clin Trials · 2014 · PMID 24525427 · Publisher ↗
BACKGROUND: Anal carcinoma is increasing in high-risk populations. Dysplasia is often distributed throughout the anal mucosa, and focal ablative techniques have high rates of recurrence. METHODS: With the goal of eradica...
BACKGROUND: Anal carcinoma is increasing in high-risk populations. Dysplasia is often distributed throughout the anal mucosa, and focal ablative techniques have high rates of recurrence. METHODS: With the goal of eradicating dysplasia from the entire anal mucosa, we conducted a phase I dose-ranging study to determine the safety and tolerability of radiofrequency ablation (RFA). HIV-infected individuals with high-grade anal intraepithelial neoplasia underwent RFA of the anal mucosa. Patient-reported procedural and postprocedural symptoms were recorded, and mucosal healing was visually assessed. RESULTS: Four groups of 3 subjects each were treated with incrementally increasing numbers of RF pulses (1-3) applied to a single area of anal mucosa. Two or three doses of 12 J/cm2 were found to have acceptable patient tolerance and healing of the mucosa within 4 weeks of ablation. Using these doses, 2 groups underwent ablation of 180° of contiguous mucosa. Subjects experienced a loss of 1 to 3 days of daily activities of living, 7 to 14 days of postprocedure symptoms, and mucosal healing within 4 weeks. One subject in the first treatment group had the procedure aborted due to severe procedural pain. CONCLUSIONS: The study provides evidence of the safety and tolerability of anal RFA of 180° of contiguous mucosa in a single procedure and will allow future RFA efficacy studies in the treatment of anal dysplasia.
Genotypic determination of HIV tropism in a cohort of patients perinatally infected with HIV-1 and exposed to antiretroviral therapy.
Di Biagio A, Parisini A, Bruzzone B … +14 more , Prinapori R, Lauriola M, Paolucci S, Signori A, Barresi R, Icardi G, Calderisi S, Meini G, Dentone C, Cenderello G, Guerra M, Maccabruni A, Rusconi S, Viscoli C
HIV Clin Trials · 2014 · PMID 24518213 · Publisher ↗
The aim of this study was to determine the coreceptor tropism by performing genotypic HIV-1 tropism testing in a cohort of patients perinatally infected with HIV-1 and exposed to antiretroviral therapy. Genotypic corecep...
The aim of this study was to determine the coreceptor tropism by performing genotypic HIV-1 tropism testing in a cohort of patients perinatally infected with HIV-1 and exposed to antiretroviral therapy. Genotypic coreceptor tropism was determined in patients with HIV-1 RNA<100 copies/mL using PBMC samples by gp120 V3 sequencing followed by geno2pheno interpretation (set at a false positive rate [FPR] of 20%) and in patients with ≯100 copies/mL using plasma samples (set at a FPR of 20%), according to European guidelines. Out of 55 patients, 50 had an HIV-1 subtype B strain, and mean (SD) age was 18.2 (4.6) years. The median duration of antiretroviral therapy was 13 years (range, 3-23). Thirty-three (60%) patients harbored the R5 virus. At the time of the testing, the median CD4+ T lymphocyte cell count and percentage were 705 cells/mm3 (474-905) and 32.5% in group R5 and 626 cells/mm3 (450-755) and 31.7% in group X4/D-M, respectively. The nadir of CD4+ T-cell count in groups R5 and X4/D-M were 322 cells/mm3 (230-427) and 340 cells/mm3 (242-356), respectively. These differences were not statistically significant. Fifteen patients had HIV-1 RNA ≯50 copies/mL. The median HIV-1 RNA and HIV-1 DNA were comparable in both groups without a statistical difference. The study provides an overview of the prevalence of coreceptor tropism in a cohort of patients who were vertically infected with HIV-1. The high prevalence of X4/D-M-tropic strains may simply reflect the long-term exposure to HIV.
Durability of the first antiretroviral treatment regimen and reasons for change in patients with HIV infection.
De La Torre-Lima J, Aguilar A, Santos J … +7 more , Jiménez-Oñate F, Marcos M, Núñez V, Olalla J, Del Arco A, Prada JL, Málaga Infectious Disease Group
HIV Clin Trials · 2014 · PMID 24518212 · Publisher ↗
BACKGROUND: To study the durability of the drugs and coformulations currently used in the first treatment regimen of antiretroviral therapy (ART) for HIV patients, and to examine the reasons for changing this medication....
BACKGROUND: To study the durability of the drugs and coformulations currently used in the first treatment regimen of antiretroviral therapy (ART) for HIV patients, and to examine the reasons for changing this medication. METHODS: A retrospective observational multicenter study of patients with HIV infection who started a first-line ART regimen between January 2007 and June 2010. The primary outcome variable was the durability of this first ART regimen until discontinued or amended and the reasons for the change. Survival analysis of durability was performed using Kaplan-Meyer curves analysis, and a Cox multiple regression model was constructed to identify associated factors. RESULTS: A first-line ART regimen was initiated for 600 patients; after 1 year, it had been changed in 172 (28%) cases, with a median duration of 31 months. The main reason for change was toxicity (20.5% of all patients), followed by loss to follow-up (8.3%) and virological failure (5.3%). The most common type of toxicity was gastrointestinal (30%), followed by cutaneous (23%) and neuropsychiatric (18%). The use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) was associated with greater durability than that of protease inhibitors (43 months vs 21 months; P = .001). CONCLUSIONS: The durability of the first-line ART regimen, based on current antiretroviral drugs and coformulations, is about 2.5 years, with toxicity being the main reason for its modification. Gastrointestinal toxicity is the type most commonly reported. NNRTI treatment is associated with greater durability of the first treatment regimen.
Minorities remain underrepresented in HIV/AIDS research despite access to clinical trials.
Castillo-Mancilla JR, Cohn SE, Krishnan S … +7 more , Cespedes M, Floris-Moore M, Schulte G, Pavlov G, Mildvan D, Smith KY, the ACTG Underrepresented Populations Survey Group
HIV Clin Trials · 2014 · PMID 24518211 · Full text
BACKGROUND AND OBJECTIVE: The reasons for minority underrepresentation in HIV/AIDS clinical trials remain unclear. We aimed to evaluate the knowledge, experience, and factors that influence minority participation in HIV/...
BACKGROUND AND OBJECTIVE: The reasons for minority underrepresentation in HIV/AIDS clinical trials remain unclear. We aimed to evaluate the knowledge, experience, and factors that influence minority participation in HIV/AIDS studies in the United States. METHODS: An anonymous, bilingual, self-administered survey on study participation was given to HIV-infected adults attending AIDS Clinical Trials Group-affiliated clinics in the United States and Puerto Rico. Chi-square tests were used to evaluate differences by race, first language, and level of education. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for factors associated with being talked to about participation in a study. RESULTS: We analyzed 2,175 complete surveys (221 in Spanish). Among respondents, 31% were White, 40% were Black/African American (AA), and 21% were Hispanic. The overall rate of previous participation in any HIV/AIDS study was 48%. Hispanics were less likely to know about studies compared to Whites and AAs (67% vs 74% and 76%, respectively; P < .001). Compared to Whites, AAs and Hispanics were less likely to have been talked to about participating in a study (76% vs 67% and 67%, respectively; P < .001). The OR for being talked to about participating in a study was 0.65 (95% CI, 0.52-0.81) for AAs and 0.65 (95% CI, 0.49-0.85) for Hispanics, compared to Whites. AAs and Hispanics were more likely to state that studies were not friendly to their race (17% and 10% vs 4%; P < .001). CONCLUSIONS: Minorities continue to face barriers for HIV/AIDS trial participation, even when clinical research is available. Enrollment strategies should better target minorities to improve recruitment in HIV/AIDS research.
Tenofovir/emtricitabine/efavirenz plus rosuvastatin decrease serum levels of inflammatory markers more than antiretroviral drugs alone in antiretroviral therapy-naive HIV-infected patients.
Calza L, Vanino E, Salvadori C … +6 more , Manfredi R, Colangeli V, Cascavilla A, Di Bari MA, Motta R, Viale P
HIV Clin Trials · 2014 · PMID 24518210 · Publisher ↗
OBJECTIVES: Statins are lipid-lowering drugs that exhibit anti-Inflammatory and immune-modulatory properties, leading to a reduction of serum levels of C-reactive protein (CRP) in the general population. DESIGN: To asses...
OBJECTIVES: Statins are lipid-lowering drugs that exhibit anti-Inflammatory and immune-modulatory properties, leading to a reduction of serum levels of C-reactive protein (CRP) in the general population. DESIGN: To assess the anti-inflammatory effects of statins in HIV-infected patients, because very limited data are available today. METHODS: Longitudinal, observational study of HIV-infected adult patients naive to antiretroviral therapy who started tenofovir/emtricitabine/efavirenz and were followed-up for 48 weeks. Patients with baseline normal cholesterol level and taking only antiretroviral drugs (group A) were compared to those with baseline hypercholesterolemia who received rosuvastatin (10 mg daily) in association with antiretroviral treatment (group B). The primary observation was change in serum markers of inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], interleukin-8 [IL-8]) and tumor necrosis factor-α [TNF- α]) in both groups, whereas secondary observations include variations in CD4 lymphocyte count, HIV viral load, and occurrence of adverse events. RESULTS: Eighty-six patients were enrolled into the study: 46 in group A and 40 in group B. After 48 weeks, patients treated with antiretroviral therapy plus rosuvastatin had significantly greater decreases in serum concentrations of all Inflammatory markers than those taking antiretroviral therapy only. Changes in mean levels of hsCRP and TNF-α were -35.1% and -22.4% in group B and -8.2% and 5.4% in group A, respectively (P < .001, for both parameters). No significant differences in immunovirological parameters and safety profile were reported across the compared groups. CONCLUSIONS: Our findings suggest that tenofovir/emtricitabine/efavirenz plus rosuvastatin has a greater antiInflammatory effect than antiretroviral drugs only.
Lack of effect of doxycycline on trough concentrations of protease inhibitors or non-nucleoside reverse transcriptase inhibitors in HIV-infected patients.
Abgrall S, Le Bel J, Lele N … +6 more , Laouénan C, Eychenne N, Mentré F, Peytavin G, Bouchaud O, Vihvo Study Group
HIV Clin Trials · 2013 · PMID 24334184 · Publisher ↗
BACKGROUND: Many HIV-treated patients travel to malaria-infected zones, but very few data are available on potential interactions between antiretroviral and antimalarial drugs. METHOD: We performed a pharmacokinetic stud...
BACKGROUND: Many HIV-treated patients travel to malaria-infected zones, but very few data are available on potential interactions between antiretroviral and antimalarial drugs. METHOD: We performed a pharmacokinetic study on the interaction of doxycycline (100 mg/d) on 2 protease inhibitors (PIs), atazanavir and lopinavir, and 2 non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz and nevirapine, given at usual daily doses in HIV-infected migrants native from sub-Saharan Africa included in the VIHVO ANRS-study before travelling to a sub-Saharan country. Antiretroviral trough plasma concentrations were measured at enrollment visit during the month preceding the travel before doxycycline introduction and on the week following the patients' return to France when they had been taking doxycycline for at least 15 days. Impact of doxycycline on antiretroviral concentrations was tested either with antiretroviral drugs separately or within the therapeutic classes (PI or NNRTI) in patients with an HIV RNA level <50 copies/mL at both visits and with good declared adherence. The Two One-Sided Test that was adapted to the Wilcoxon test was used to evidence the lack of interaction. Sixty-five patients receiving regimens containing atazanavir (n = 1), ritonavir-boosted atazanavir (n = 14), ritonavir-boosted lopinavir (n = 23), efavirenz (n = 17), nevirapine (n = 10) were included. RESULTS: Lack of pharmacokinetic interaction was statistically significant when tested by therapeutic class (PI, P = .02; NNRTI, P = .005) and was not demonstrated for each antiretroviral when tested separately. CONCLUSION: This study is the first to assess the interaction of doxycycline on PI and NNRTI. This lack of pharmacokinetic interaction supports the choice of doxycycline as the antimalarial drug in patients treated with PI or NNRTI.
Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications.
Cade WT, Reeds DN, Overton ET … +8 more , Herrero P, Waggoner AD, Laciny E, Bopp C, Lassa-Claxton S, Gropler RJ, Peterson LR, Yarasheski KE
HIV Clin Trials · 2013 · PMID 24334183 · Full text
BACKGROUND: Individuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether i...
BACKGROUND: Individuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether interventions shown to be effective in improving peripheral insulin sensitivity can improve basal myocardial insulin sensitivity and diastolic function in people with HIV and peripheral metabolic complications. OBJECTIVE: In a pilot study, we evaluated whether the peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist pioglitazone or combined endurance and resistance exercise training improves basal myocardial insulin sensitivity and diastolic function in HIV+ adults with peripheral metabolic complications. DESIGN: Twenty-four HIV+ adults with metabolic complications including peripheral insulin resistance were randomly assigned to 4 months of pioglitazone (PIO; 30 mg/d) or supervised, progressive endurance and resistance exercise training (EXS; 90-120 min/d, 3 d/wk). Basal myocardial substrate metabolism was quantified by radioisotope tracer methodology and positron emission tomography (PET) imaging, and LV function was measured by echocardiography. RESULTS: Twenty participants completed the study. Neither PIO nor EXS resulted in a detectable improvement in basal myocardial insulin sensitivity or diastolic function. Post hoc analyses revealed sample sizes of more than 100 participants are needed to detect significant effects of these interventions on basal myocardial insulin sensitivity and function. CONCLUSIONS: PIO or EXS alone did not significantly increase basal myocardial insulin sensitivity or LV diastolic function in HIV+ individuals with peripheral metabolic complications.
Genetic predictors of cervical dysplasia in African American HIV-infected women: ACTG DACS 268.
Cespedes MS, Kerns SL, Holzman RS … +3 more , McLaren PJ, Ostrer H, Aberg JA
HIV Clin Trials · 2013 · PMID 24334182 · Full text
OBJECTIVE: To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests. DESIGN: Case-control study...
OBJECTIVE: To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests. DESIGN: Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment-naïve studies in the AIDS Clinical Trials Group (ACTG). METHODS: Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 × 10(-8) for genome-wide associations. RESULTS: No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively). CONCLUSIONS: These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infected women. Given the small sample size, the results need to be validated in a separate cohort.
Early virologic response to abacavir/lamivudine and tenofovir/emtricitabine during ACTG A5202.
Grant PM, Tierney C, Budhathoki C … +7 more , Daar ES, Sax PE, Collier AC, Fischl MA, Zolopa AR, Balamane M, Katzenstein D
HIV Clin Trials · 2013 · PMID 24334181 · Full text
BACKGROUND: ACTG A5202 randomized treatment-naïve individuals to tenofovir-emtricitabine (TDF/FTC) or abacavir-lamivudine (ABC/3TC) combined with efavirenz (EFV) or atazanavir/ritonavir (ATV/r). Individuals in the high s...
BACKGROUND: ACTG A5202 randomized treatment-naïve individuals to tenofovir-emtricitabine (TDF/FTC) or abacavir-lamivudine (ABC/3TC) combined with efavirenz (EFV) or atazanavir/ritonavir (ATV/r). Individuals in the high screening viral load (VL) stratum (≥100,000 copies/mL) had increased rates of virologic failure with ABC/3TC. OBJECTIVE: To compare regimen-specific early virologic response. METHODS: Using Wilcoxon rank-sum tests, we compared regimen-specific VL changes from entry to week 4 in A5202 subjects (N = 1,813) and from entry to week 1, 2, and 4 in substudy subjects (n = 179). We evaluated associations between week 4 VL change and time to virologic failure with Cox proportional hazards models. RESULTS: TDF/FTC and ABC/3TC produced similar week 4 VL declines in the entire study population and in the high VL stratum. EFV produced greater VL declines from baseline at week 4 than ATV/r (median -2.1 vs -1.9 log10 copies/mL; P < .001). In the substudy of subjects with week 1, 2, and 4 VL data, there was no difference in VL decline in individuals randomized to TDF/FTC versus ABC/3TC, but EFV resulted in greater VL decline from entry at each of these timepoints than ATV/r. Smaller week 4 VL decline was associated with increased risk of virologic failure. CONCLUSIONS: Within all treatment arms, a less robust week 4 virologic response was associated with higher risk for subsequent virologic failure. However, between-regimen differences in week 4 VL declines did not parallel the previously reported differences in longer term virologic efficacy in A5202, suggesting that between-regimen differences in responses were not due to intrinsic differences in antiviral activity.
Addition of nitazoxanide to PEG-IFN and ribavirin to improve HCV treatment response in HIV-1 and HCV genotype 1 coinfected persons naïve to HCV therapy: results of the ACTG A5269 trial.
Amorosa VK, Luetkemeyer A, Kang M … +9 more , Johnson VA, Umbleja T, Haas DW, Yesmin S, Bardin MC, Chung RT, Alston-Smith B, Tebas P, Peters MG
HIV Clin Trials · 2013 · PMID 24334180 · Full text
BACKGROUND: We hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/...
BACKGROUND: We hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coinfected persons. METHODS: Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to historical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR). RESULTS: Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%-75.3%), cEVR in 38.8% (28.8%-49.6%). and SVR in 32.8% (23.4%-43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated. CONCLUSION: Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.
Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.
Macarthur RD, Hawkins TN, Brown SJ … +7 more , Lamarca A, Clay PG, Barrett AC, Bortey E, Paterson C, Golden PL, Forbes WP
HIV Clin Trials · 2013 · PMID 24334179 · Publisher ↗
BACKGROUND: HIV-associated diarrhea remains a significant concern with limited treatment options. OBJECTIVE: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea. METHODS: This ran...
BACKGROUND: HIV-associated diarrhea remains a significant concern with limited treatment options. OBJECTIVE: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea. METHODS: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly. RESULTS: Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo. CONCLUSIONS: In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.
Efficacy and tolerability of darunavir/ritonavir in combination with abacavir/lamivudine: an option in selected HIV-infected patients.
de los Santos I, Gómez-Berrocal A, Valencia E … +5 more , Asensi V, Gijón P, Moreno V, Vergas J, Bernardino I
HIV Clin Trials · 2013 · PMID 24144901 · Publisher ↗
OBJECTIVE: To evaluate the safety and efficacy of abacavir/lamivudine (ABC/3TC) plus darunavir/ritonavir (DRV-RTV) in experienced patients. METHODS: The study was conducted in Spain in 6 hospital clinics and involved HIV...
OBJECTIVE: To evaluate the safety and efficacy of abacavir/lamivudine (ABC/3TC) plus darunavir/ritonavir (DRV-RTV) in experienced patients. METHODS: The study was conducted in Spain in 6 hospital clinics and involved HIV-positive patients who needed to change their antiretroviral treatment (ART) for several reasons. They started fixed-dose combination (FDC) ABC/3TC (600 mg/300 mg), DRV (400 mg 2 tablets qd), and RTV (100 mg) from January 2010 to April 2012. The patients were evaluated at baseline and at intervals of 3 to 6 months, and at least once at the end of the follow-up. Adverse events (AEs), concurrent medications, HIV-associated conditions, and adherence were also assessed at each visit. RESULTS: Seventy-six patients were included from 6 sites (60 male). Median CD4 cell count was 479/mm3, and the median time on follow-up was 10.1 months. Thirty-eight patients (50%) have reached 48 weeks of follow-up and 32 (84.2 %) have achieved HIV RNA <50 copies/mL in this period. Immunological recovery was observed with a median CD4 count increase of 119 cells/mm3 by week 48. There were no patients who discontinued the study treatment due to AEs, and all the toxicities that lead to change ART at baseline were resolved or improved substantially. CONCLUSION: This study showed that the study regimen provided consistent antiviral and immunological responses until 48 weeks. The antiretroviral effect of the regimen was observed in subsets of patients evaluated, including those with high baseline HIV-1 RNA levels and virological failure and those with switching, with little or no difference across subgroups.
Site nurse-initiated adherence and symptom support telephone calls for HIV-positive individuals starting antiretroviral therapy, ACTG 5031: substudy of ACTG 384.
Robbins GK, Testa MA, Su M … +6 more , Safren SA, Morse G, Lammert S, Shafer RW, Reynolds NR, Chesney MA
HIV Clin Trials · 2013 · PMID 24144900 · Full text
BACKGROUND: Effective and easy to implement interventions to improve adherence to antiretroviral therapy are needed. OBJECTIVE: To compare site nurse-initiated adherence and symptom support telephone calls for HIV-positi...
BACKGROUND: Effective and easy to implement interventions to improve adherence to antiretroviral therapy are needed. OBJECTIVE: To compare site nurse-initiated adherence and symptom support telephone calls for HIV-positive individuals starting antiretroviral therapy to the study site's standard of care. METHODS: A randomized controlled trial of site nurse-initiated adherence and symptom support telephone calls for HIV-positive individuals starting antiretroviral therapy. Subjects were randomized to receive site nurse-initiated telephone calls (intervention) or no additional calls to the site's standard of care (control). Subjects received calls 1 to 3 days after initiating antiretrovirals, on weeks 1, 2, 3, 6, 10, 14, 18, 22, and 26, and every 8 weeks thereafter. Self-reported adherence was captured during study visits. RESULTS: A total of 333 subjects starting antiretrovirals as part of ACTG 384 were co-enrolled into ACTG 5031. Subjects were followed for up to 160 weeks and were contacted for 74% of scheduled calls. There was no significant difference in proportion of patients with ≯95% mean total adherence (87.9% and 91.2%; P = .34) and mean self-reported total adherence (97.9% and 98.4%) in the intervention and control groups, respectively, or in symptom distress and clinical endpoints. CONCLUSIONS: In the context of a clinical trial where self-reported adherence was exceptionally high, the site nurse-initiated telephone calls did not further improve self-reported adherence, symptom distress, or clinical outcomes.
Bone mineral density effects of randomized regimen and nucleoside reverse transcriptase inhibitor selection from ACTG A5142.
Huang JS, Hughes MD, Riddler SA … +2 more , Haubrich RH, Aids Clinical Trials Group A5142 Study Team
HIV Clin Trials · 2013 · PMID 24144899 · Full text
OBJECTIVE: To compare the longitudinal changes in total bone mineral density (TBMD) across antiretroviral (ARV) regimens. METHODS: A5142 was an open-label study comparing 3 ARV regimens for the initial treatment of HIV-1...
OBJECTIVE: To compare the longitudinal changes in total bone mineral density (TBMD) across antiretroviral (ARV) regimens. METHODS: A5142 was an open-label study comparing 3 ARV regimens for the initial treatment of HIV-1. Subjects were randomized equally to efavirenz (EFV) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs), lopinavir/ritonavir (LPV/r) plus 2 NRTIs, or LPV/r plus EFV without NRTI. The NRTI regimen (lamivudine [3TC] plus zidovudine [ZDV], stavudine [d4T], or tenofovir [TDF]) was selected prior to randomization. TBMD was assessed via whole-body dual-energy X-ray absorptiometry (DXA) at baseline and 48 and 96 weeks. Analysis was modified intent-to-treat (ITT) ignoring regimen changes using all evaluations. RESULTS: Significant mean declines in TBMD at week 48 were observed among subjects. In repeated-measures analysis of changes (including randomized regimen, NRTI used, and time), there was a significant difference in the NRTI-containing arms in mean percentage change in TBMD at week 48 according to NRTI used (P < .001). Subjects taking ZDV had similar changes to those taking d4T (P = .970), whereas those taking TDF had larger declines (P < .001). There was a nonsignificant trend toward greater mean declines among subjects taking LPV/r versus EFV (P = .080). Overall, TDF-containing regimens demonstrated the greatest losses in TBMD, while EFV regimens without TDF had lesser TBMD reductions even compared to the NRTI-sparing arm. From week 48 to 96, all treatment groups continued to lose TBMD at similar rates. CONCLUSIONS: Among NRTI-containing arms, NRTI selection, especially use of TDF, had a greater effect on TBMD change than randomized regimen. The long-term clinical significance remains to be demonstrated.
Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens.
Mills AM, Cohen C, Dejesus E … +8 more , Brinson C, Williams S, Yale KL, Ramanathan S, Wang MH, White K, Chuck SK, Cheng AK
HIV Clin Trials · 2013 · PMID 24144898 · Publisher ↗
BACKGROUND: Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been...
BACKGROUND: Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. OBJECTIVE: This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. METHODS: This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (≥3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. RESULTS: At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. CONCLUSIONS: Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.
Safety, efficacy, and persistence of emtricitabine/tenofovir versus other nucleoside analogues in naive subjects aged 50 years or older in Spain: the TRIP study.
Blanco JR, Caro-Murillo AM, Castaño MA … +12 more , Olalla J, Domingo P, Arazo P, Gómez-Sirvent JL, Riera M, Pulido F, Vera F, Romero-Palacios A, Aguirrebengoa K, Portilla J, Ferrer P, Pedrol E
HIV Clin Trials · 2013 · PMID 24144897 · Publisher ↗
OBJECTIVES: Current antiretroviral guidelines state that being older than 50 to 55 years of age is an indication to start antiretroviral therapy (ART), regardless of CD4 status. However, no references to the preferred co...
OBJECTIVES: Current antiretroviral guidelines state that being older than 50 to 55 years of age is an indication to start antiretroviral therapy (ART), regardless of CD4 status. However, no references to the preferred combination ART (cART) for these patients have been described. Our study compares emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) versus other nucleoside reverse transcriptase inhibitor (NNRTI) regimens in HIV ART-naïve patients who are ≥50 years. DESIGN: National, retrospective cohort analysis of patients who were ≥50 years old when they began the first cART (January 1, 2006 to December 31, 2009). METHODS: We compared safety, effectiveness, and persistence of treatment in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitor (PI) versus NNRTI users and lopinavir/r versus efavirenz users. RESULTS: We included 161 patients: median age was 54.6 years, 83% were men, median CD4 count was 191 cells/µL, median viral load was 4.7 log, and median follow-up was 19 months (maximum, 48 months). Of these participants, 112 started with FTC/TDF and 49 with other nucleotide reverse transcriptase inhibitors (NRTIs). During follow-up, 21.9% of subjects developed at least one laboratory event ≥grade 3, 5.6% interrupted cART due to adverse events,19.3% had virologic failure, and 49.1% modified cART. There were no statistically significant differences between FTC/TDF and non-FTC/TDF users for any output except for persistence: The proportion of subjects who changed cART was 71.4% for non-FTC/TDF users and 38.6% for FTC/TDF users (log rank 0.001; adjusted hazard ratio, 2.10; 95% CI, 1.34-3.29). CONCLUSIONS: In a population of HIV-infected subjects who were ≥50 years old, our study suggests that the use of FTC/TDF is generally safe and effective, with a longer persistence as compared to other regimens.
Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor.
Spreen W, Min S, Ford SL … +6 more , Chen S, Lou Y, Bomar M, St Clair M, Piscitelli S, Fujiwara T
HIV Clin Trials · 2013 · PMID 24144896 · Publisher ↗
BACKGROUND: GSK1265744 is an HIV integrase strand transfer inhibitor selected for clinical development. OBJECTIVE: This first-time-in-human and phase IIa investigation assessed GSK1265744 antiviral activity, pharmacokine...
BACKGROUND: GSK1265744 is an HIV integrase strand transfer inhibitor selected for clinical development. OBJECTIVE: This first-time-in-human and phase IIa investigation assessed GSK1265744 antiviral activity, pharmacokinetics, safety, and tolerability in healthy and HIV-1-infected subjects. METHODS: This double-blind, placebo-controlled study consisted of a dose escalation of single (part A) and multiple (part B) oral doses in 48 healthy subjects and an oral dose (part C) in 11 HIV-1-infected subjects. In part A, 2 cohorts of 9 subjects received either 5 and 25 mg or 10 and 50 mg. In part B, 3 cohorts of 10 subjects received 5, 10, or 25 mg once daily for 14 days. In part C and the phase IIa study, subjects received 5 or 30 mg once daily for 10 days. RESULTS: Dose-proportional increases in drug exposure were observed in healthy and HIV-1-infected subjects. In healthy subjects, pharmacokinetic variability was low following single or repeat dosing (coefficient of variation, 13%-34% and 15%-23%, respectively). Mean plasma half-life was 31.5 hours. GSK1265744 monotherapy significantly reduced plasma HIV-1 RNA from baseline to day 11 in HIV-1-infected subjects receiving 5 or 30 mg versus placebo (P < .001); mean decrease was 2.2 to 2.3 log10 copies/mL, respectively. Study drug was generally well tolerated with no clinically relevant trends in laboratory values, vital signs, or electrocardiograms. CONCLUSIONS: GSK1265744 was well tolerated in healthy and HIV-1-infected subjects. Results demonstrate once-daily doses of 5 or 30 mg exceeded minimum target therapeutic concentrations and produced a significant reduction in plasma HIV-1 RNA viral load.
Long-term safety study of fosamprenavir-containing regimens in HIV-1-infected patients.
Wood R, Gathe JC, Givens N … +3 more , Sedani S, Cheng K, Sievers J
HIV Clin Trials · 2013 · PMID 24144895 · Publisher ↗
BACKGROUND: Safety and efficacy of the protease inhibitor fosamprenavir (FPV) ± ritonavir (r) was evaluated in 3 pivotal 48-week phase III studies. A follow-on study provides long-term data on FPV-based regimens. METHODS...
BACKGROUND: Safety and efficacy of the protease inhibitor fosamprenavir (FPV) ± ritonavir (r) was evaluated in 3 pivotal 48-week phase III studies. A follow-on study provides long-term data on FPV-based regimens. METHODS: International, multicenter, uncontrolled open-label study APV30005 provided FPV as part of combination therapy to HIV-1-infected patients aged ≥13 years who had participated in previous FPV and amprenavir studies. Regimens included FPV/r 1400/200 mg once daily, FPV/r 700/100 mg twice daily, or FPV 1400 mg twice daily. Safety and efficacy were evaluated every 12 weeks, including incidence and frequency of adverse events and laboratory abnormalities, plasma HIV-1 RNA levels, CD4+ cell counts, and frequency of HIV disease progression. Because this was a nonrandomized, observational study, no significance testing was performed. RESULTS: Overall, 753 patients were enrolled. The most common reasons for premature discontinuation were lost to follow-up (88 [12%]) and insufficient viral load response (69 [9%]). The majority of patients had ≯192 weeks exposure to FPV, with 53 patients exposed for more than 8 years. Drug-related grade 2-4 adverse events were reported for 250 patients (33%), with the majority reported in the first 48 weeks of the study. Most commonly reported grade 3/4 laboratory parameters were increased lipase, triglycerides, and elevated liver enzymes. The observed proportions of patients with plasma HIV-1 RNA levels <50 copies/mL remained ≯70% from week 48 onwards. CONCLUSIONS: Extended treatment of up to 8 years with FPV-containing regimens revealed no new safety concerns and was associated with sustained antiviral responses.
Immune response after a single dose of the 2010/11 trivalent, seasonal influenza vaccine in HIV-1-infected patients and healthy controls.
Bickel M, Lassmann C, Wieters I … +7 more , Doerr HW, Herrmann E, Wicker S, Brodt HR, Stephan C, Allwinn R, Jung O
HIV Clin Trials · 2013 · PMID 23924590 · Publisher ↗
BACKGROUND: Immune response rates following influenza vaccination are often lower in HIV-infected individuals. Low vitamin D levels were correlated with weak immune response in cancer patients and are known to be lower i...
BACKGROUND: Immune response rates following influenza vaccination are often lower in HIV-infected individuals. Low vitamin D levels were correlated with weak immune response in cancer patients and are known to be lower in HIV-infected patients. METHODS: Diagnostic study to determine immune response against the H1N1v component after a single, intramuscular dose of the 2010/11 seasonal, trivalent influenza vaccine (TIV) in adult HIV-infected and healthy controls scheduled for influenza vaccination (ClinicalTrials.gov Identifier: NCT01017172). Influenza A/H1N1 antibody titers (AB) were determined before and 21 days after vaccination by hemagglutination inhibition assay. RESULTS: Immune response was not different between HIV-infected patients (n = 36) and healthy controls (n = 42) who were previously naïve to the H1N1v component of the TIV. Comparing HIV-infected patients (n = 55) and healthy controls (n = 63) who had received 1 or 2 doses of an AS03 adjuvanted H1N1 vaccine in the previous winter season (2009/10), seroconversion rate and the geometric mean AB titer after TIV of the HIV-infected patients were more than twice as high compared to healthy controls. This difference was mainly driven by the 2-dose schedule for HIV patients in 2009/10. Vitamin D levels were lower in HIV patients but did not correlate with immune response. CONCLUSION: HIV-infected patients who had received 1 or 2 doses of an adjuvanted H1N1 vaccine in the previous year (2009/10) had a significant higher seroconversion rate following TIV as compared to healthy controls, indicating a stronger memory cell response due to the 2-dose schedule.
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