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Background Gastroparesis causes significant morbidity and treatment options are limited. TZP-102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double-blind, placebo-controlled trial in patients with diabetic gastroparesis. Methods A total of 92 outpatients were randomized to once-daily administrations of 10-mg (n = 22), 20-mg (n = 21), 40-mg (n = 23) TZP-102 or placebo (n = 26). The primary endpoint was the change from baseline in gastric half-emptying time (T½) utilizing 13C-breath test methodology and secondary endpoints included symptom improvement using patient-reported gastroparesis symptom scores (PAGI-SYM questionnaire) and patient and physician overall treatment evaluations (OTE). Key Results Gastric T½ changes were not statistically significant between TZP-102 and placebo after 28 days of treatment at any dose. Clinical improvements (−1.0 to −1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI-SYM, which was significant vs placebo for all TZP-102 doses combined. Improvements became evident after 1 week of treatment. Significantly, more patients given TZP-102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP-102 doses were well-tolerated with no adverse cardiac, weight, or glucose control outcomes. Conclusions & Inferences TZP-102 for 28 days, at doses of 10–40 mg once daily, was well-tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient-defined outcomes in determining therapeutic benefit.

Many trials of antiretroviral therapy in treatment-naïve subjects have investigated the relative efficacy of the third drug in a treatment regimen. However, the nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) components may also affect efficacy.A systematic overview of clinical trials studying initial treatment in naïve subjects receiving efavirenz-containing regimens and providing week 48 time to loss of virologic response (TLOVR) results was undertaken to compare results with different NRTI combinations.Seven trials studying 3,807 subjects were identified that met the inclusion criteria. Baseline characteristics were similar across studies. Using the week 48 TLOVR results as the primary method of comparison, combinations of tenofovir and lamivudine or emtricitabine appeared to provide improved virologic responses. Similar results were obtained when the proportions of subjects with plasma HIV RNA levels50 copies/mL were examined.

Human immunodeficiency virus (HIV)-infected South African patients (n=468) received blinded lamivudine or emtricitabine, stavudine, and either nevirapine or efavirenz (based on screening viral load). Baseline characteristics were analyzed in univariate and multivariate regression, to identify risk factors for hepatotoxicity (grade 3 or greater increase in serum aminotransferase levels). The occurrence of early hepatotoxicity was 17% in the nevirapine group and 0% in the efavirenz group and was balanced between the lamivudine and emtricitabine arms. Two subjects died of hepatic failure. Independent risk factors were body-mass index (BMI)18.5, female sex, serum albumin level35 g/L, mean corpuscular volume85 fL, plasma HIV-1 RNA load20,000 copies/mL, aspartate aminotransferase level75 IU/L, and lactate dehydrogenase level164 IU/L. The use of nevirapine in female patients with a low BMI should be discouraged.

We conducted a randomized, open-label, 10-day study that compared the antiretroviral activity of emtricitabine (FTC) 25, 100, and 200 mg once daily and lamivudine (3TC) 150 mg 2 times/day in 82 human immunodeficiency virus (HIV)-infected patients with virus loads >5000 and

AIM To estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. METHODS A systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. RESULTS Median log(10) baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49,329 copies/ml) and 375 x 10(6) cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA < or = 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA < or = 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 x 10(6) cells/l (95% CI, 111 x 10(6) to 135 x 10(6) cells/l) and +160 x 10(6) cells/l (95% CI, 146 x 10(6) to 175 x 10(6) cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA < or = 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA < or = 50 copies/ml at week 48 (P = 0.0085). CONCLUSIONS The results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

Gastrointestinal recovery is a critical milestone after bowel resection with postoperative ileus resulting in increased risk of complications and prolonged hospitalization.The aim of this study is to evaluate the efficacy and safety of ulimorelin, a ghrelin receptor agonist given postoperatively in 2 identically designed phase 3 studies (ClinicalTrials.gov NCT01285570 and NCT01296620).This investigation is designed as a multicenter, double-blind, randomized, parallel-group study.This study involves hospital inpatients.Adult patients undergoing partial bowel resection were included.Thirty-minute intravenous infusions (160 µg/kg, 480 µg/kg ulimorelin, or placebo) once daily were started within 60 minutes after the end of surgery and ended at the first of the following: primary efficacy end point fulfilled (defined below), hospital discharge, or 7 days treatment.The primary efficacy end point was the time from the end of surgery to the composite end point of the later of first bowel movement and tolerance of solid food. Safety was assessed with the use of standard assessments including adverse events and laboratory tests.Ulimorelin Study of Efficacy and Safety 007, n = 332 patients; Ulimorelin Study of Efficacy and Safety 008, n = 330 patients: in both studies, the primary efficacy end point and the secondary efficacy outcomes, which included postsurgical time to first bowel movement, tolerance of solid food, and discharge eligibility, did not differ significantly among patients treated with either dose of ulimorelin versus placebo. Rates of serious adverse events were comparable across all treatment groups. There was no statistically significant difference from placebo in regard to events of interest, namely nausea, vomiting, ileus as an adverse event, nasogastric tube reinsertion, anastomotic complications, and infections.A possible limitation is the variance inherent in surgery and comorbidities.Although the efficacy of ulimorelin in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous ulimorelin at doses of 160 µg/kg and 480 µg/kg was generally well tolerated in postcolectomy patients. Similar to other promotility agents, ulimorelin may find an application in other indications better suited to its attributes.

Objective: To study the effect of HIV-1 resistance to lamivudine (3TC) and zidovudine (ZDV), and syncytium-inducing (SI) phenotype on virologic response to treatment with ZDV, 3TC, or ZDV plus 3TC in previously untreated individuals with HIV-1 infection. Design: A prospective virologic substudy of GlaxoWellcome protocol NUCA 3001. Methods: HIV-1 isolates obtained at study entry and at week 12 were expanded in peripheral blood mononuclear cell (PBMC) culture, titered, and assayed for phenotypic and genotypic evidence of resistance to ZDV and 3TC, and for syncytium formation on MT-2 cells. Results: Phenotypic and genotypic resistance to 3TC was detected in the majority of HIV-1 isolates from patients who received 3TC alone or in combination with ZDV. Despite showing 3TC resistance, subjects who received 3TC in combination with ZDV had significantly greater decreases in plasma HIV-1 RNA levels compared with those who received ZDV alone. Occurrence of the K70R ZDV resistance mutation was significantly reduced in patients who received the 3TC/ZDV combination as compared with patients on ZDV monotherapy. Plasma HIV-1 RNA returned to near-baseline levels more quickly in patients with SI isolates at study entry. Conclusions: Despite the rapid emergence of 3TC resistance, combination therapy with 3TC plus ZDV resulted in greater reduction in plasma HIV-1 RNA levels over 24 weeks as compared to ZDV monotherapy. Prevention of ZDV resistance may contribute to the sustained activity of the combination therapy.

In a phase I/II trial assessing the toxicity, pharmacokinetics, and activity of the (-)enantiomer of 2'-deoxy-3'-thiacytidine (3TC, lamivudine), 97 patients with AIDS or advanced human immunodeficiency virus (HIV) disease were administered 3TC at 0.5-20.0 mg/kg/day. The cohort's median entry CD4 cell count was 128/mm3 (range, 7-357). A toxic dose was not reached, although some patients reported mild headache, insomnia, and abdominal symptoms, and there was a general downward trend in neutrophil counts at the highest doses. Although subjective and difficult to interpret, increases in energy and appetite were noted, particularly in patients receiving > or = 8.0 mg/kg/day. Immunologic and virologic parameters showed evidence of at least transient anti-HIV activity at those higher doses. Although further studies of 3TC as monotherapy are needed, its favorable toxicity profile, evidence of at least transient clinical activity, and results of in vitro resistance experiments support further clinical testing in combination therapy.

Objective To evaluate the safety and immunogenicity of the H1N1 2009 vaccine in HIV-positive individuals. Design A single-arm study. Setting Clinic at the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. Participants HIV-infected adults with an indication for H1N1 vaccination. Intervention Single intramuscular 15 microg dose of the monovalent, unadjuvanted, inactivated, split virus H1N1 vaccine. Main outcomes Immunogenicity, safety and tolerability. Results A total of 120 participants were enrolled, 71% men, 68% African-American, with median age of 46 years. All of them but one were on antiretroviral treatment, with a median current CD4 cell counts of 502 cells/microl, and a nadir CD4 cell counts of 132 cells/microl. The HIV RNA level was below 400 copies/ml in 92% of participants. All participants completed the 3 weeks of follow-up. Thirty of the 120 (25%) participants had antibody hemagglutination-inhibition assay titers equal or greater than 1: 40 at baseline. Among participants without evidence of previous exposure, only 61% develop protective titers by week 3 of the study. Nonresponders had lower current and nadir CD4 cell counts than responders. Only four of nine participants with detectable HIV viral load at baseline developed protective antibody titers. Age and race were not predictors of the response to the vaccine. The vaccine was well tolerated. Conclusion These results suggest that only 60% of well controlled HIV-infected individuals without preexisting immunity to H1N1 develop protective antibody titers after immunization. Alternative vaccines, dosing, adjuvants or schedule strategies are needed to achieve effective immunization of this vulnerable population.

Background: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. Methods: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of

The presence of drug-associated mutations among ART-naive, HIV-1(+) patients may compromise the response to antiviral therapy. We evaluated the effect of preexisting drug-associated resistance mutations to the response in treatment-naive patients to therapy with emtricitabine (FTC) or stavudine (d4T) in combination with didanosine (ddI) and efavirenz (EFV). Study FTC-301A compared emtricitabine once daily (QD) with stavudine twice daily in combination with didanosine and efavirenz in ART-naive patients. Genotypic analysis was performed on baseline plasma HIV-1 RNA for all available samples and at time of virologic failure (VF). Drug resistance mutations present at baseline were evaluated as predictors of VF using logistic regression. VF rates were compared between subgroups using a two-sided exact test. Baseline drug resistance mutations were observed in 90/546 (16.5%) patients: 56/90 (62.2%) with nonnucleoside analogue (NNRTI) mutations and 42/90 (46.6%) with nucleoside analogue mutations. In a stepwise, multiple regression analysis, the presence of the K103N mutation at initiation of therapy was associated with VF in both arms (p = 0.001), however, there was a higher incidence of VF in the stavudine arm compared to the emtricitabine arm regardless of the presence or absence of mutations at baseline (p = 0.001). In this study, the presence of drug-associated resistance mutations in ART-naive patients was significantly correlated with subsequent development of virologic failure underscoring the utility of testing for resistance in addition to the use of potent and well-tolerated first line regimens in treatment-naive patients.

OBJECTIVE To compare the effectiveness of three drug combination antiretroviral therapy (ART) in treatment-naive HIV-infected persons, and identify the predictors of responses. DESIGN AND METHODS Overview of trials identified by searching public domain publications and conference presentations. The three-drug combination therapy was defined as two nucleoside reverse transcriptase inhibitors (NRTI) or nucleotide and NRTI, and either: (1) a protease inhibitor (PI); (2) a non-nucleoside RTI (NNRTI); (3) a third NRTI; or (4) a ritonavir-boosted PI (BPI). Week 24 and 48 results for the proportions of patients with plasma HIV RNA levels < 400 and < 50 copies/ml, and change in CD4(+) cell counts were recorded. RESULTS Fifty-three trials met the entry criteria, and enrolled 14 264 patients into 90 treatment arms. Overall 55% of patients had plasma HIV RNA levels < 50 copies/ml at week 48 and this percentage increased with later publication dates. In unadjusted pairwise comparisons at week 48, significantly greater percentages of patients receiving NNRTI (64%) and BPI (64%) had RNA < 50 copies/ml than NRTI (54%) or PI (43%), and CD4(+) cell count increases were significantly greater in the BPI group (+200 cells/microl) than the PI (+179), NNRTI (+173), or NRTI (+161) groups. Pill count and percentage of patients with week 48 plasma HIV RNA levels < 50 copies/ml were correlated in the univariate analysis (P = 0.0053; r = -0.323), but pill count was not a significant predictor in the multivariate analyses. Drug class and baseline CD4(+) cell counts were significant predictors, but explained only a modest amount of the treatment effect, (R(2) = 0.355). CONCLUSIONS NNRTI and BPI-containing regimens offer superior virologic suppression over 48 weeks, supporting existing guidelines for the choice of initial ART. Pill count was not a consistent predictor of virologic suppression.

BACKGROUND Once daily (QD) dosing facilitates regimen simplification and adherence to antiretroviral therapy. Emtricitabine (FTC) QD is a newly approved nucleoside reverse transcriptase inhibitor compared in this study to twice daily lamivudine (3TC BID). METHODS Controlled, open label equivalence trial of 440 HIV-1-infected patients with plasma HIV-1 RNA stably suppressed on a regimen of 3TC 150 mg BID, stavudine or zidovudine, and a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Patients were randomized to continue their current regimen or replace 3TC with FTC 200 mg QD. If HIV-1 RNA levels were

Emtricitabine is a new, once-daily nucleoside reverse transcriptase inhibitor (NRTI) with potent activity against human immunodeficiency virus (HIV).To assess the efficacy and safety of emtricitabine as compared with stavudine when used with a background regimen of didanosine and efavirenz.Randomized, double-blind, double-dummy study conducted at 101 research clinics in North America, Latin America, and Europe. The first patient was enrolled on August 21, 2000; no investigator or patient was unblinded until the last patient randomized completed the week 48 visit on October 24, 2002. Analyses were based on data collected in a double-blind setting with a median follow-up of 60 weeks. Patients were 571 antiretroviral-naive, HIV-1-infected adults aged 18 years or older with viral load levels greater than or equal to 5000 copies/mL.Receipt of either 200 mg of emtricitabine once daily (plus stavudine placebo twice daily) (n = 286) or stavudine at standard doses twice daily (plus emtricitabine placebo once daily) (n = 285) plus open-label didanosine and efavirenz, once daily.Persistent virological response, defined as achieving and maintaining viral load at or below the limit of assay quantification (or =400 or 50 copies/mL).At the interim analysis on June 14, 2002, when the last patient randomized completed 24 weeks of double-blind treatment (median follow-up time of 42 weeks), patients in the emtricitabine group had a higher probability of a persistent virological responseor =50 copies/mL vs the stavudine group (85% vs 76%, P =.005). This was associated with a higher mean CD4 cell count change from baseline for the emtricitabine group (156 cells/ microL vs 119 cells/microL, P =.01 [of note, there was no statistical difference at 48 weeks [P =.15], although a sensitivity analysis, using an intent-to-treat population with the last CD4 cell count observation carried forward to week 48 showed a difference [P =.02]]). The independent data and safety monitoring board recommended offering open-label emtricitabine based on the interim analysis. The probability of persistent virological responseor =50 copies/mL through week 60 was 76% for the emtricitabine group vs 54% for the stavudine group (P.001). The probability of virological failure through week 60 was 4% in the emtricitabine group and 12% in the stavudine group (P.001). Patients in the stavudine group had a greater probability of an adverse event that led to study drug discontinuation through week 60 than did those in the emtricitabine group (15% vs 7%, P =.005).Once-daily emtricitabine appeared to demonstrate greater virological efficacy, durability of response, and tolerability compared with twice-daily stavudine when used with once-daily didanosine and efavirenz.

Publisher Summary Three classes of drugs are available to treat patients infected with human immunodeficiency virus (HIV) : the nucleoside reverse transcriptase inhibitors (NRTI), the nonnucleoside reverse transcriptase inhibitors (NNRTI), and the protease inhibitors (PI). Emtricitabine represents one of the most potent anti-HIV agents identified to date, producing two log10 drop in viral load as monotherapy at a 200 mg qd dose as the affected individual became susceptible to opportunistic infections and specific immune deficiency resulting from the depletion of CD4+ lymphocytes. The clinical profile of emtricitabine discussed in this chapter demonstrated (1) a plasma half-life of 8-10 hours with linear kinetics, (2) an intracellular emtricitabine 5’-triphosphate half-life greater than 39 hours that supports daily dosing, (3) no significant drug–drug interactions that limits the use of emtricitabine in combination therapy, (4) comparable safety and efficacy to lamivudine, and (5) low incidence of Ml84V mutations. This important observation suggests that emtricitabine can increase the durability of oxathiolane nucleoside analog-containing drug regimens. Hepatitis B virus (HBV) constitutes a major worldwide health threat, as the clinical development program is just entering the pivotal phase. Emtricitabine can be an extremely important drug for the treatment of patients coinfected with HIV and HBV.

Antiretroviral monotherapy for initial drug characterization risks the selection of resistant virus, yet monotherapy is the only setting where many fundamental properties of a new drug can be reliably determined. Using data on viral replication kinetics and dynamics, we designed an accelerated (14 day) open-label study of single agent emtricitabine (formerly known as FTC)-a nucleoside reverse transcriptase inhibitor-to select a dosing regimen for further therapeutic study. Five regimens (25 mg bd, 100 mg od, 200 mg od, 100 mg bd and 200 mg bd) were evaluated in HIV-1-infected subjects over a 14 day dosing period to determine the optimal dose and pharmacokinetics. Serial blood samples for virological, pharmacokinetic and intracellular FTC-triphosphate measurements were drawn frequently. A dose-response relationship for the antiviral activity of emtricitabine was established, with total daily doses of 200 mg or more producing the greatest median HIV-1 viral load suppression: 1.72-1.92 log 10 . Based on virological outcomes, dose-response analysis and intracellular triphosphate levels, a once-daily dose of 200 mg was selected for further long-term clinical study. Adverse events possibly related to emtricitabine were unremarkable. The antiviral activity of emtricitabine correlated well with intracellular FTC-triphosphate concentrations. This study design is a safe, useful tool for early dose selection for drugs with potent antiretroviral activity and linear pharmacokinetics.

Previous uncontrolled reports have suggested that H2-antagonists may possess immunomodulatory activity in human immunodeficiency virus (HIV)-infected patients. Such trials reported improvements in HIV-related symptoms, increased absolute CD4 cell numbers, and improvements in other measures of host immunity. The present trial was a randomized, placebo-controlled, double-blind trial of ranitidine 300 mg (orally twice daily) in subjects with early HIV infection (absolute CD4 cells, 400-700/mm3). Eighty-one subjects entered the trial and 73 completed 16 weeks on study medications. There were no significant differences in the time-weighted average change from baseline between the 2 treatment groups in absolute CD4 cell number, plasma HIV RNA level, or most other surrogate markers of HIV infection. Serum beta2-microglobulin levels were significantly lower in placebo than ranitidine recipients. Ranitidine should not be recommended for the treatment of HIV-infected patients unless it is used for established indications.

Background. The reverse-transcriptase inhibitor lamivudine has in vitro synergy with zidovudine against the human immunodeficiency virus (HIV). We studied the activity and safety of lamivudine plus zidovudine as compared with either drug alone as treatment for patients with HIV infection, most of whom had not previously received zidovudine. Methods. Three hundred sixty-six patients with 200 to 500 CD4+ cells per cubic millimeter who had received zidovudine for four weeks or less were randomly assigned to treatment with one of four regimens: 300 mg of lamivudine every 12 hours; 200 mg of zidovudine every 8 hours; 150 mg of lamivudine every 12 hours plus zidovudine; or 300 mg of lamivudine every 12 hours plus zidovudine. The study was double-blind and lasted 24 weeks, with an extension phase for another 28 weeks. Results. Over the 24-week period, the low-dose and high-dose regimens combining lamivudine and zidovudine were associated with greater increases in the CD4+ cell count (P=0.002 and P=0.015, respectively) and the percentage of CD4+ cells (P

achieved RVR and of these, 77 (89.5%) had SVR. RVR rates for genotype 1 patients (53.2%) were significantly lower (86.8%) than genotype 2 and 3 (chi(2)=16.563, p=0.000). SVR rates for genotype 1 patients who had achieved RVR (90.4%) were significantly higher than those (9.6%) who had not achieved RVR (chi(2)= 3.232, p=0.000). Of 33 patients with genotype 1 who had achieved RVR, 27 (81.8%) had SVR and of 29 patients who did not achieve RVR, only 4 (13.7%) had SVR. Similarly, of 53 patients with genotypes 2 and 3 who had RVR, 50 (94.3%) had SVR and of 8 patients who did not have RVR, 4 (50%) had SVR. Significant factors associated with SVR were RVR (chi(2)=56.011, p=0.000), genotype (chi(2)=19.319, p=0.000), baseline AST level (p=0.031) and baseline viral load (p=0.049). The positive and negative predictive values of RVR in genotype 1 patients were 82% and 86% respectively and in genotype 2 and 3, 94% and 50% respectively. Conclusion: RVR in patients with chronic hepatitis C, genotype 1 was significantly lower than genotypes 2 and 3. SVR rates were significantly higher in patients who had achieved RVR. RVR predicts SVR in genotypes 1, 2 and 3. RVR, Genotype, baseline viral load and baseline AST level were significant factors for predicting SVR.

ContextEmtricitabine is a new, once-daily nucleoside reverse transcriptase inhibitor (NRTI) with potent activity against human immunodeficiency virus (HIV).ObjectiveTo assess the efficacy and safety of emtricitabine as compared with stavudine when used with a background regimen of didanosine and efavirenz.Design, Setting, and PatientsRandomized, double-blind, double-dummy study conducted at 101 research clinics in North America, Latin America, and Europe. The first patient was enrolled on August 21, 2000; no investigator or patient was unblinded until the last patient randomized completed the week 48 visit on October 24, 2002. Analyses were based on data collected in a double-blind setting with a median follow-up of 60 weeks. Patients were 571 antiretroviral-naive, HIV-1–infected adults aged 18 years or older with viral load levels greater than or equal to 5000 copies/mL.InterventionsReceipt of either 200 mg of emtricitabine once daily (plus stavudine placebo twice daily) (n = 286) or stavudine at standard doses twice daily (plus emtricitabine placebo once daily) (n = 285) plus open-label didanosine and efavirenz, once daily.Main Outcome MeasurePersistent virological response, defined as achieving and maintaining viral load at or below the limit of assay quantification (≤400 or 50 copies/mL).ResultsAt the interim analysis on June 14, 2002, when the last patient randomized completed 24 weeks of double-blind treatment (median follow-up time of 42 weeks), patients in the emtricitabine group had a higher probability of a persistent virological response ≤50 copies/mL vs the stavudine group (85% vs 76%, P = .005). This was associated with a higher mean CD4 cell count change from baseline for the emtricitabine group (156 cells/µL vs 119 cells/µL, P = .01 [of note, there was no statistical difference at 48 weeks {P = .15}, although a sensitivity analysis, using an intent-to-treat population with the last CD4 cell count observation carried forward to week 48 showed a difference {P = .02}]). The independent data and safety monitoring board recommended offering open-label emtricitabine based on the interim analysis. The probability of persistent virological response ≤50 copies/mL through week 60 was 76% for the emtricitabine group vs 54% for the stavudine group (P

Objective : To compare the safety and activity of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine in patients with moderately advanced human immunodeficiency virus (HIV) infection who had received zidovudine. Design : A multicenter, randomized, double-blind, three-arm, 24-week study with a blinded extension through at least 52 weeks. Setting : 21 sites in the United States, Canada, and Puerto Rico. Patients : 254 patients who had received zidovudine (median duration of previous therapy, 20 months) and had absolute CD4+ cell counts of 100 to 300 cells/mm 3 . Interventions : Patients were randomly assigned to receive one of three regimens : 150 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (low-dose lamivudine group) ; 300 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (high-dose lamivudine group) ; or 0.75 mg of zalcitabine plus 200 mg of zidovudine three times daily (zalcitabine group). Measurements : Immunologic activity was assessed primarily by changes in absolute CD4+ cell counts ; virologic activity was assessed by changes in plasma HIV RNA levels as measured by reverse transcriptase polymerase chain reaction. Safety of the treatment regimens was assessed through the reporting of adverse events. Results : 78% of patients completed 24 weeks of study treatment, and 63% of patients completed 52 weeks of study treatment. Changes in absolute CD4 + cell counts were significantly better for the low-dose and the high-dose lamivudine groups than for the zalcitabine group (median changes at 52 weeks were +42.5 cells/mm 3 in the low-dose lamivudine group, +23.33 cells/mm 3 in the high-dose lamivudine group, and -29.58 cells/mm 3 in the zalcitabine group). Suppression of plasma HIV RNA levels was similar for all groups (median changes at 52 weeks were -0.48 log 10 copies/mL in the low-dose lamivudine group, -0.51 log 10 copies/mL in the high-dose lamivudine group, and -0.39 log 10 copies/mL in the zalcitabine group). No significant differences in safety were seen among the three regimens, although the low-dose lamivudine regimen appeared to be better tolerated than the others. Conclusions : In patients with HIV infection who had previously received zidovudine, 150 mg of lamivudine plus zidovudine resulted in greater immunologic evidence of benefit than did 0.75 mg of zalcitabine plus zidovudine and was better tolerated than 300 mg of lamivudine plus zidovudine.