Michael Wulfsohn

A JOINT MODEL FOR SURVIVAL AND LONGITUDINAL DATA MEASURED WITH ERROR

The relationship between a longitudinal covariate and a failure time process can be assessed using the Cox proportional hazards regression model. We consider the problem of estimating the parameters in the Cox model when the longitudinal covariate is measured infrequently and with measurement error. We assume a repeated measures random effects model for the covariate process. Estimates of the parameters are obtained by maximizing the joint likelihood for the covariate process and the failure time process. This approach uses the available information optimally because we use both the covariate and survival data simultaneously. Parameters are estimated using the expectation-maximization algorithm. We argue that such a method is superior to naive methods where one maximizes the partial likelihood of the Cox model using the observed covariate values. It also improves on two-stage methods where, in the first stage, empirical Bayes estimates of the covariate process are computed and then used as time-dependent covariates in a second stage to find the parameters in the Cox model that maximize the partial likelihood.

Modeling the Relationship of Survival to Longitudinal Data Measured with Error. Applications to Survival and CD4 Counts in Patients with AIDS

Abstract A question that has received a great deal of attention in evaluating new treatments in acquired immune deficiency syndrome (AIDS) clinical trials is that of finding a good surrogate marker for clinical progression. The identification of such a marker may be useful in assessing the efficacy of new therapies in a shorter period. The number of CD4-lymphocyte counts has been proposed as such a potential marker for human immune virus (HIV) trials because of its observed correlation with clinical outcome. But to evaluate the role of CD4 counts as a potential surrogate marker, we must better understand the relationship of clinical outcome to an individuals CD4 count history over time. The Cox proportional hazards regression model is used to study the relationship between CD4 counts as a time-dependent covariate and survival. Because the CD4 counts are measured only periodically and with substantial measurement error and biological variation, standard methods for estimating the parameters in the Cox mod...

A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome

Abstract Background. The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity. Methods. To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262). Results. The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the st...

Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection: A Randomized Trial

Context Resistance to antiretroviral drugs is a leading cause of treatment failure in HIV-1infected patients. Contribution In this multicenter, double-blind trial, 552 treatment-experienced patients with detectable RNA levels despite continuing antiretroviral therapy were randomly assigned to receive tenofovir DF (a nucleotide analogue) or placebo. At 6 months, patients given tenofovir DF had greater reductions in HIV-1 RNA levels than those given placebo. Nearly 15% of patients in both groups had clinical adverse events, such as severe diarrhea, pain, or depression. Implications In HIV-infected patients with suboptimal viral suppression, adding tenofovir DF to ongoing antiretroviral therapy reduces viral loads. The Editors Combination antiretroviral therapy has decreased mortality rates for patients with HIV-1 infection (1, 2). Suppression of HIV-1 viral load has been shown to be highly predictive of slower clinical disease progression (3). However, the clinical utility of a combination antiretroviral regimen typically wanes, often because of one or more factors such as drug resistance or poor adherence (4). These factors are even more important for patients who have previously used antiretroviral drugs. This difficult-to-treat population has limited treatment options and often experiences drug-related adverse effects due to previous antiretroviral therapy regimens (5-7). Given these limitations, novel potent agents that combine ease of dosing with favorable safety and resistance profiles are needed to increase the long-term durability of combination antiretroviral therapy (8, 9). Simplifying HIV treatment regimens using once-daily antiretroviral drugs may improve adherence and therapeutic outcomes (10, 11). Tenofovir disoproxil fumarate (tenofovir DF) is an oral prodrug of tenofovir, a novel, acyclic nucleotide analogue with in vitro activity against HIV-1 and HIV-2 (12, 13). Unlike nucleoside analogues, tenofovir is active in both active and resting lymphoid cells and macrophages (13). In rhesus macaques acutely infected with simian immunodeficiency virus, tenofovir administered as monotherapy 24 hours after inoculation eradicated viral DNA from lymph nodes, plasma, and leukocytes (14). Tenofovir has also demonstrated in vitro activity against wild-type and lamivudine-resistant hepatitis B virus (15). In a 186-patient phase II dose-ranging study, Schooley and colleagues (16) demonstrated the potency and favorable safety profile of tenofovir DF, 300 mg, highlighting its potential for further study in larger phase III trials. Tenofovir has a favorable resistance profile with activity against most nucleoside analogueresistant viruses and infrequent (3%) emergence of the K65R resistance mutation through 96 weeks (17-21). Our study was designed to confirm the antiviral efficacy and safety of tenofovir DF compared with placebo in treatment-experienced patients who had detectable HIV-1 RNA levels despite combination antiretroviral therapy. Methods Study Sample Institutional review boards at all study sites approved the study protocol and informed consent statements. Recruitment began in October 1999 and continued until June 2000 at 75 HIV clinics in western Europe, North America, and Australia. All patients gave written informed consent. Patients 18 to 65 years of age were eligible if they had received antiretroviral therapy (four agents or fewer) for at least 8 weeks before randomization and had stable plasma HIV-1 RNA levels of 400 to 10 000 copies/mL on the Roche Amplicor HIV-1 Monitor UltraSensitive test, version 1.0 (Roche Diagnostics, Branchburg, New Jersey). The lower limit of quantification for this test was 50 copies/mL. We placed no entry restrictions on CD4 cell count. Additional inclusion criteria were serum creatinine concentration of 133 mol/L or less ( 1.5 mg/dL), calculated creatinine clearance (using the CockcroftGault formula [22]) of at least 1.00 mL/s ( 60 mL/min), absolute neutrophil count of at least 1.000 109 cells/L, platelet count of at least 50.0 109 cells/L, hemoglobin level of at least 80 g/L, total bilirubin level of 26 mol/L or less ( 1.5 mg/dL), serum phosphorus level of at least 0.71 mmol/L ( 2.2 mg/dL), alanine aminotransferase level less than 108 U/L, aspartate aminotransferase level less than 90 U/L, negative results on a serum pregnancy test for women of childbearing potential, and life expectancy of more than 1 year. We excluded patients who had previously participated in clinical trials with intravenous tenofovir, tenofovir DF, or adefovir dipivoxil; had been immunized within 30 days of baseline; had an active AIDS-defining condition within 30 days of baseline; or were receiving aminoglycoside antibiotics, amphotericin B, cidofovir, cisplatin, foscarnet, intravenous pentamidine, vancomycin, ganciclovir, systemic chemotherapeutic agents, oral corticosteroids, probenecid, or other investigational agents on an ongoing basis. Patients who were receiving their first antiretroviral regimen were not excluded. We assessed 976 patients for eligibility and randomly assigned 552 to study groups (Figure). Four hundred twenty-four patients were excluded. Of the 380 who did not meet inclusion criteria, the most common reason (n = 269) was HIV-1 RNA levels outside the range of 400 to 10 000 copies/mL. Among the remaining 44 patients, 22 elected not to participate in the study and the other 22 were excluded because of investigator decision, concomitant participation in other investigational studies, screening after the cutoff date for enrollment, incomplete laboratory values, lack of follow-up, or family emergency. No statistical analyses were performed for patients who were not randomly assigned to a study group. Figure. Recruitment and disposition flow chart. Design Through an interactive voice response system that centralized patient randomization, Interactive Clinical Technologies, Inc. (San Francisco, California), generated the random allocation sequence, assigned patients to their treatment groups, and blinded kit numbers to conceal the allocation sequence. Patients were stratified according to HIV-1 RNA level (<5000 copies/mL or 5000 copies/mL), CD4 cell count (<0.2 109 cells/L or 0.2 109 cells/L), and number of antiretroviral drugs taken before study entry (fewer than four or at least four). Patients were then randomly assigned in a 2-to-1 ratio to add tenofovir DF, 300 mg, or identical-appearing placebo to their existing antiretroviral regimen. Randomization was not stratified by study center. Changes to the background regimen were discouraged during the first 24 weeks. After week 24, all patients received open-label tenofovir DF for the remainder of the 48-week study. As predefined in both the study protocol and the statistical analysis plan, the single end point for primary efficacy was the time-weighted average change in HIV-1 RNA level from baseline to week 24. Secondary efficacy end points included the proportion of patients with HIV-1 RNA levels of 50 copies/mL or less and 400 copies/mL or less at weeks 24 and 48, the time-weighted average change in HIV-1 RNA level from baseline to week 48, and CD4 cell count at weeks 24 and 48. Adherence to treatment was measured by using pill counts at each study visit, but pill counts were not formally analyzed and drug concentrations were not measured during routine study visits. Approximately half of the patients (n = 274) were randomly assigned to a virologic genotyping substudy at baseline. HIV-1 reverse transcriptase nucleotides 1 to 1200 and all of the HIV-1 protease gene were sequenced by following the reverse transcriptase polymerase chain reaction from plasma HIV-1 RNA (Vircogen, Virco, Mechelen, Belgium). All plasma HIV-1 samples that were obtained at baseline, at week 24 or 48, or at early study termination and had more than 50 copies of HIV-1 RNA per mL were analyzed in a blinded fashion. A polymerase chain reaction product could not be obtained from 21 patients at baseline (14 in the tenofovir DF group, 7 in the placebo group). Plasma HIV-1 RNA was insufficient for genotypic analysis in 58 patients at week 24 (43 patients in the tenofovir DF group, 15 in the placebo group) and 129 patients at week 48. Assessments The incidences of grade 3 or 4 clinical adverse events or laboratory abnormalities were evaluated as safety end points. At each postbaseline study visit (weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), the investigator assessed and recorded all adverse events found during history and physical examination as well as laboratory toxicities found on chemical and hematologic tests and urinalysis, including date of onset and resolution, severity, relationship to study drug, outcome, and action taken with study medication. Severity was recorded and graded according to the modified severity grading for adult adverse experiences outlined by the National Institutes of Allergy and Infectious Diseases, Division of AIDS. Plasma levels of HIV-1 RNA and CD4 cell counts were measured at all study visits except weeks 28, 36, and 44. Statistical Analysis Data were analyzed for the intention-to-treat sample and the as-treated sample. The intention-to-treat sample included all enrolled patients who received at least one dose of study medication and was the primary sample for analyses of efficacy. The as-treated sample included patients who received at least one dose of study medication but excluded all data obtained after permanent discontinuation of assigned study medication or addition of other antiretroviral medication. The safety analysis sample included all patients who received at least one dose of study medication. As the primary efficacy end point, the time-weighted average change in HIV-1 RNA level from baseline to week 24 represents the difference between the time-weighted average postbaseline values and values at baseline. This difference is defined as follows (23, 24). If the area under the curve (AUC) at week 24 (

Genotypic and Phenotypic Predictors of the Magnitude of Response to Tenofovir Disoproxil Fumarate Treatment in Antiretroviral-Experienced Patients

Results from 2 placebo-controlled intensification trials of tenofovir disoproxil fumarate (DF) in treatment-experienced human immunodeficiency type 1 (HIV-1)-infected patients (n=332) were integrated to determine the effects of resistance at baseline on HIV-1 RNA response. In these trials, there was a high prevalence of HIV-1 resistance mutations, with 94% of patients having nucleoside-associated mutations and 71% having thymidine analogue-associated mutations (TAMs). Statistically significant HIV-1 RNA reductions associated with tenofovir DF treatment, relative to placebo (P<.001), were observed for patients without TAMs (n=97) or for patients with 1-2 (n=88) or >or=3 TAMs (n=147). Response to tenofovir DF was reduced among patients with HIV-1 with >or=3 TAMs inclusive of either the M41L or L210W mutation (n=86) or patients who had a preexisting K65R mutation (n=6). Slightly increased treatment responses were observed when the M184V mutation was present. Phenotypic cutoffs were established at 1.4-fold and 4-fold, respectively, for the beginning of reduced response to tenofovir DF and for a strongly reduced response. The results from these controlled clinical trials provide guidance for the use of tenofovir DF for treatment-experienced patients.

A Multicenter Trial of Oral Zidovudine in Children with Advanced Human Immunodeficiency Virus Disease

BACKGROUND AND METHODS Zidovudine has been shown to be an effective antiretroviral treatment in adults with human immunodeficiency virus (HIV) infection. We examined the safety of zidovudine and the tolerance of and therapeutic response to the drug in 88 children with advanced HIV disease. During a 24-week outpatient trial, zidovudine (180 mg per square meter of body-surface area per dose) was given by mouth every six hours and serial measurements were made of clinical, immunologic, and virologic indexes. Children who completed 24 weeks of treatment were permitted to continue receiving zidovudine. RESULTS Of the 88 children (mean age, 3.9 years; range, 4 months to 11 years), 61 completed the initial 24-week trial, and 49 continued to receive zidovudine for up to 90 weeks (median follow-up, 56 weeks). The patients generally tolerated zidovudine well. One or more episodes of hematologic toxicity occurred in 54 children (61 percent)--anemia (hemoglobin level, less than 75 g per liter) in 23 children (26 percent) and neutropenia (neutrophil count, less than 0.75 x 10(9) per liter) in 42 (48 percent). Many of these abnormalities resolved spontaneously, but 30 children required transfusions or a modification of the dose of zidovudine. Only three children had to stop receiving the drug because of hematologic toxicity. Kaplan-Meier analysis demonstrated that the probability of survival was 0.89 after 24 weeks and 0.79 after 52 weeks. There was marked improvement in weight gain, cognitive function (mainly in children less than 3 years old), serum and cerebrospinal fluid concentrations of p24 antigen, and the proportion of cerebrospinal fluid cultures negative for HIV. CD4+ lymphocyte counts (mean at base line, 0.263 x 10(9) per liter) improved during the first 12 weeks, although the improvement was not sustained through the 24th week. CONCLUSIONS Zidovudine in a dose of 180 mg per square meter every six hours can be safely administered to children with advanced HIV disease. The resultant clinical, immunologic, and virologic improvements in children are similar to those reported with zidovudine in adults.

Prevention of Relapse of Histoplasmosis with Itraconazole in Patients with the Acquired Immunodeficiency Syndrome

Amphotericin B is commonly used to treat histoplasmosis in patients with the acquired immunodeficiency syndrome (AIDS). In uncontrolled studies, this drug was highly effective for initial or induction treatment of disseminated histoplasmosis in patients with AIDS [1]. However, the occurrence of relapse within 6 to 18 months necessitated continued maintenance treatment to suppress persistent infection [1]. As many as 50% of patients relapsed while receiving maintenance therapy with ketoconazole, 200 to 400 mg daily [1]. Relapse occurs in as many as 20% of patients who receive 50 to 100 mg of amphotericin B weekly or biweekly as maintenance therapy [1, 2]. The need for intravenous access, the occurrence of catheter-related complications, the inconvenience of intravenous infusion, the gastrointestinal and systemic toxicity, the requirement for laboratory monitoring, and the expense of home intravenous treatment further limit the use of amphotericin B as maintenance therapy in patients who have had histoplasmosis. Itraconazole and fluconazole offer advantages over amphotericin B or ketoconazole as maintenance therapy for fungal disease in patients with AIDS [3]. Both are well absorbed after oral administration and cause few side effects. Although both drugs have been effective in the treatment of murine [4, 5] and human histoplasmosis [6], itraconazole was selected for further study because there is more experience with it in the treatment of histoplasmosis in humans [6]. We carried out an open-label, nonrandomized trial to assess the efficacy and tolerance of itraconazole in the prevention of histoplasmosis relapse in patients with AIDS who had been treated with amphotericin B. Methods Patients Participants were at least 13 years old, had human immunodeficiency virus (HIV) infection, and had received amphotericin B induction therapy at a total dose of at least 15 mg/kg body weight administered for 3 to 12 weeks for proven disseminated histoplasmosis within 6 weeks before enrollment. Successful induction treatment was documented by the absence of clinical findings associated with histoplasmosis and negative fungal blood cultures at the time of enrollment. Patients were excluded from the study if they had a history of allergy to azole antifungal agents; a bilirubin level more than 2.5 times the upper limit of normal; an alanine aminotransferase level more than five times the upper limit of normal; an alkaline phosphatase level more than five times the upper limit of normal; a creatinine level more than three times the upper limit of normal; neutropenia (neutrophil count, <0.75 109/L) or thrombocytopenia (platelet count, <75 109); a Karnofsky score of less than 60; and concurrent treatment with phenytoin, barbiturates, rifampin, corticosteroids in doses exceeding those used in maintenance therapy for adrenal insufficiency, cytotoxic chemotherapy, systemic antifungal agents, or investigational drugs. Patients requiring histamine blockers or antacids were not allowed to receive such therapy within 4 hours of itraconazole administration. Intervention and Evaluation Eligible patients received itraconazole, 200 mg twice daily orally with meals. Patients were evaluated for efficacy and toxicity until the last enrolled patient completed at least 52 weeks of treatment. Patients were evaluated biweekly for 4 weeks, monthly for 12 months, and then bimonthly until the completion of the study. Each evaluation included an assessment of clinical findings to identify evidence of histoplasmosis relapse or side effects of itraconazole therapy, complete blood counts, serum chemistries, and determinations of Histoplasma capsulatum variety capsulatum antigen levels in urine and serum. Plasma itraconazole levels were measured at weeks 2, 4, 12, 24, and 36, and blood was collected for fungal culture at enrollment and at weeks 12, 24, 36, and 52, or as indicated based on clinical findings. Adverse events were graded using the standard AIDS Clinical Trial Group severity scoring system. Selected laboratory criteria are listed in the results section, but complete criteria are available on request. Plasma itraconazole concentrations were measured by bioassay at the Fungus Testing Laboratory, San Antonio, Texas [7]. Histoplasma capsulatum var. capsulatum antigen levels in urine and serum were measured at Indiana University [8, 9]. Antigen levels were measured as specimens were received and in batch after all patients had completed 1 year of treatment or had withdrawn from the study for other reasons. All specimens were stored at 70C. Statistical Analysis The distribution of the times to events was estimated using the method of Kaplan and Meier [10]. In the determinations of duration of follow-up, patients who died were not considered to be lost to follow-up. Mean antigen levels at initiation and completion of 52 weeks of study therapy were compared using a paired t-test. Differences in proportions of patients with positive antigen results at initiation and completion of 52 weeks of study therapy were compared using the McNemar test. Results Forty-two patients were enrolled in the study from 10 AIDS Clinical Trials units and 2 Mycoses Study Group sites. Forty-one of the 42 patients were diagnosed with disseminated histoplasmosis based on demonstration of organisms consistent with H. capsulatum var. capsulatum in extrapulmonary tissues by special stain or culture; the diagnosis in the remaining patient was based on detection of H. capsulatum var. capsulatum antigen in urine and demonstration of granulomas in the bone marrow. Baseline demographic, clinical, and laboratory characteristics, as well as data on induction antifungal therapy, are summarized in Table 1. The median CD4 lymphocyte count at baseline for these patients was 0.047 109/L (range, 0.005 to 0.272). The CD4 count was less than 0.050 109/L in 19 of 37 patients (51%), less than 0.100 109/L in 30 patients (81%), and less than 0.200 109/L in 36 patients (97%); CD4 counts were not available in 5 patients. Disseminated histoplasmosis was the primary AIDS-defining illness in 25 patients (60%). Disseminated histoplasmosis occurred a median of 3 months (range, 0.3 to 12.8 months) after the AIDS-defining illness in the 17 patients in whom histoplasmosis was a second or later AIDS-defining event. Thirty-eight patients had received amphotericin B at a total dose of at least 15 mg/kg given over 4 to 12 weeks, and the remaining 4 patients had received a total dose of at least 10 mg/kg. The median total dosage was 20.9 mg/kg (range, 14.0 to 59.2 mg/kg) given over a median of 36 days (range, 9 to 132 days). Table 1. Baseline Characteristics of 42 Patients at Enrollment Of the 42 patients who enrolled in the study, 15 failed to meet all eligibility criteria but were included in the data analysis. Reasons for failure to meet eligibility criteria included a neutrophil count of less than 0.75 109/L or a platelet count of less than 75 109/L (five patients), induction treatment with less than 15 mg/kg of amphotericin B (four patients), completion of induction therapy more than 6 weeks before enrollment (three patients), and negative cultures at the time of diagnosis of histoplasmosis (three patients). In two of these latter three patients, silver staining of lymph node specimens showed organisms resembling H. capsulatum var. capsulatum; in the third, antigen was detected in the urine. Compliance Compliance with itraconazole treatment was assessed by counts of returned medication and measurement of plasma itraconazole concentrations at specified visits. Less than 25% of medication was returned at 692 of the 720 visits (96%). The 28 visits at which more than 25% of medication was returned were made by 16 patients (38%). Plasma itraconazole concentrations of at least 0.75 g/mL were documented for 233 of 255 determinations (91%) in the 40 patients for whom results were available. Overall, 25 of the 40 patients (63%) had concentrations of at least 0.75 g/mL for every determination. In the remaining 15 patients (37%), concentrations were less than 0.75 g/mL for 31 of 95 determinations (33%). Itraconazole concentrations were determined in specimens obtained at (four occasions) or within 4 weeks (nine occasions) of the visits for which more than 25% of unused medication was returned. Concentrations were at least 0.75 g/mL in 10 of the 13 specimens (77%). Follow-Up The median duration of follow-up was 109 weeks (range, 4 to 134 weeks), and the median survival time was 98 weeks (range, 4 to 134+ weeks) (Figure 1). As of 4 February 1992, when the data were analyzed, 17 patients continued to receive study treatment. Among the 25 patients who were no longer receiving therapy, reasons for discontinuation included death (15 patients), voluntary withdrawal (3 patients), inability to keep scheduled follow-up (3 patients), preterminal HIV-associated disease (2 patients who died within 7 days of discontinuing treatment), toxicity (1 patient), and relapse (1 patient) (Table 2). Of the 10 patients who withdrew or were withdrawn from study, 6 subsequently died. Figure 1. Kaplan-Meier estimates of survival and relapse. Overall, 21 patients had died as of 4 February 1992. Causes of death included progressive HIV infection with wasting (10 patients), opportunistic infections (9 patients), and HIV-related malignancy (2 patients). Of the 9 patients with opportunistic infections, 2 had disseminated Mycobacterium avium-intracellulare complex infection, 2 had pneumonia of uncertain cause, and 1 each had toxoplasmosis, sepsis, disseminated Pneumocystis carinii infection, an undiagnosed central nervous system syndrome with paralysis and coma, and disseminated histoplasmosis. Only 1 patient had an autopsy, and disseminated Pneumocystis carinii infection was found to be the cause of death; cultures for H. capsulatum var. capsulatum were negative. Risk for Relapse One proven and one possible relapse occurred during the study. The prove

Activity of adefovir dipivoxil against all patterns of lamivudine‐resistant hepatitis B viruses in patients

Summary.  One hundred and thirty‐one post‐liver transplantation patients with chronic hepatitis B and failing lamivudine therapy with detectable serum hepatitis B virus (HBV) deoxyribonucleic acid by hybridization assays or ≥1 × 106 copies/mL by polymerase chain reaction, and elevated alanine transaminase levels despite continuous lamivudine, were enrolled in an open‐label study of adefovir dipivoxil. The B and C domains of HBV polymerase were sequenced for baseline samples to determine the presence of lamivudine resistance mutations. The results showed that 98% of the samples had tyrosine‐methionine‐aspartate‐aspartate (YMDD) mutations, indicating a strong correlation between the above clinical definition of lamivudine treatment failure and the presence of YMDD mutations. In addition to the rtM204V/I and the rtL180M mutations, the mutation rtV173L was identified in 19% of patients. Four major patterns of lamivudine‐resistant HBV were identified: rtL180M + rtM204V (60%), rtV173L + rtL180M + rtM204V (19%), rtM204I (9%) and rtL180M + rtM204I (9%). Treatment with adefovir dipivoxil showed similar antiviral efficacy in patients with lamivudine‐resistant virus from all four patterns.

Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults

BACKGROUND Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed tenofovir prodrug, tenofovir disoproxil fumarate, tenofovir alafenamide is stable in plasma and then rapidly converted into tenofovir once inside cells. METHODS The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of tenofovir alafenamide compared with 300 mg of tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied. RESULTS Administration of 40 mg of tenofovir alafenamide for 14 days resulted in lower tenofovir Cmax (13 versus 207 ng/mL) and lower systemic exposures (AUC0-t, 383 versus 1810 ng · h/mL) compared with subjects who received tenofovir disoproxil fumarate. There were higher intracellular tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of tenofovir alafenamide (8.2 μM) and 120 mg of tenofovir alafenamide (16.9 μM) compared with 300 mg of tenofovir disoproxil fumarate (0.9 μM). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were -0.94 log₁₀copies/mL for the tenofovir disoproxil fumarate group, -1.57 log₁₀ copies/mL for the 40 mg of tenofovir alafenamide group and -1.71 log₁₀ copies/mL for the 120 mg of tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were -0.36, -0.63 and -0.64 for the tenofovir disoproxil fumarate group, the 40 mg of tenofovir alafenamide group and the 120 mg of tenofovir alafenamide group, respectively. No resistance mutations to either tenofovir alafenamide or tenofovir disoproxil fumarate were detected. CONCLUSIONS Tenofovir alafenamide, a new once-daily oral prodrug of tenofovir, showed more potent anti-HIV-1 activity and higher intracellular tenofovir levels compared with tenofovir disoproxil fumarate, while maintaining lower plasma tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.

Patterns of resistance emerging in HIV-1 from antiretroviral-experienced patients undergoing intensification therapy with tenofovir disoproxil fumarate.

Study GS-99-907 was a 48-week, phase 3, double-blind, placebo-controlled intensification trial of tenofovir disoproxil fumarate (tenofovir DF). Antiretroviral-experienced patients added tenofovir DF 300 mg once daily to their existing regimen. The patterns of HIV-1 resistance development and the corresponding virologic responses were evaluated in a virology substudy at week 48. Although 94% of these treatment-experienced patients had nucleoside-associated resistance mutations (NAMs) at baseline, addition of tenofovir DF resulted in a mean reduction in viral load of −0.59 log10 copies/mL after 24 weeks that was durable through 48 weeks. Relative to the placebo-controlled arm, patients in the tenofovir DF arm had a reduced frequency of development of resistance mutations to all classes of HIV-1 inhibitors, with reduction in new protease inhibitor (PI)-associated mutations achieving statistical significance. The K65R mutation, which occurred in 8 patients (3%), was the only emergent mutation directly associated with tenofovir DF therapy. New thymidine analogue–associated mutations (TAMs) emerged in 19% of patients by week 48. Other than K65R, the patterns of mutations that developed were not significantly different between the tenofovir DF and placebo control arms, suggesting that the background therapies caused their development. The K65R mutation emerged only in patients with no detectable TAMs at baseline, whereas new TAMs developed similarly between patients with or without TAMs at baseline. Development of K65R was associated with mostly low-level changes in phenotypic susceptibility to tenofovir DF and other nucleoside reverse transcriptase inhibitors and was not associated with viral load rebound. No novel patterns of genotypic or phenotypic resistance to tenofovir were identified. Therefore, intensification with once-daily tenofovir DF therapy resulted in a sustained reduction in HIV-1 viral load and a low risk for development of the K65R mutation in this treatment-experienced patient population.