Paul R. Skolnik

Phase 2 Study of the Safety and Efficacy of Vicriviroc, a CCR5 Inhibitor, in HIV-1-Infected, Treatment-Experienced Patients: AIDS Clinical Trials Group 5211

BACKGROUND Vicriviroc, an investigational CCR5 inhibitor, demonstrated short-term antiretroviral activity in a phase 1 study. METHODS The present study was a double-blind, randomized phase 2 study of vicriviroc in treatment-experienced, human immunodeficiency virus (HIV)-infected subjects experiencing virologic failure while receiving a ritonavir-containing regimen with an HIV-1 RNA level >or=5000 copies/mL and CCR5-using virus. Vicriviroc at 5, 10, or 15 mg or placebo was added to the failing regimen for 14 days, after which the antiretroviral regimen was optimized. The primary end point was the change in plasma HIV-1 RNA levels at day 14; secondary end points included safety/tolerability and HIV-1 RNA changes at week 24. RESULTS One hundred eighteen subjects were randomized with a median HIV-1 RNA level of 36,380 (4.56 log(10)) copies/mL and a median CD4 cell count of 146 cells/mm(3). At 14 days and 24 weeks, mean changes in HIV-1 RNA level (log(10) copies/mL) were greater in the vicriviroc groups (-0.87 and -1.51 [5 mg], -1.15 and -1.86 [10 mg], and -0.92 and -1.68 [15 mg]) than in the placebo group (+0.06 and -0.29) (P<.01). Grade 3/4 adverse events were similar across groups. Malignancies occurred in 6 subjects randomized to vicriviroc and in 2 to placebo. CONCLUSIONS In HIV-1-infected, treatment-experienced patients, vicriviroc demonstrated potent virologic suppression through 24 weeks. The relationship of vicriviroc to malignancy is uncertain. Further development of vicriviroc in treatment-experienced patients is warranted.

Optimal Recall Period and Response Task for Self-Reported HIV Medication Adherence

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

HIV Type 1 Chemokine Coreceptor Use among Antiretroviral-Experienced Patients Screened for a Clinical Trial of a CCR5 Inhibitor: AIDS Clinical Trial Group A5211

BACKGROUND Chemokine coreceptor use impacts both the natural history of human immunodeficiency virus type 1 (HIV-1) disease and the potential use of a new class of antiretroviral agents, the CCR5 inhibitors. METHODS We analyzed HIV-infected patients who were screened for participation in Acquired Immunodeficiency Syndrome (AIDS) Clinical Trial Group protocol A5211, a phase 2b study of the investigational CCR5 inhibitor vicriviroc involving antiretroviral-experienced subjects. Screening CD4(+) cell count, HIV-1 plasma RNA level, HIV-1 genotype, and chemokine coreceptor use phenotype were determined. The univariate and multivariate association of subject characteristics with coreceptor use was assessed by logistic regression. RESULTS Coreceptor use was determined for 391 subjects: 197 (50%) had virus that used the CCR5 coreceptor (the R5 group), 178 [corrected] (46%) had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4 coreceptors (the D/M group), and 16 (4%) had virus that used the CXCR4 coreceptor (the X4 group). The D/M group had a significantly lower median CD4(+) cell count than the R5 virus group (103 cells/ micro L vs. 170 cells/ mu L; P<.001). No other characteristics were independently associated. Among 118 subjects who entered A5211 having R5 virus, 12 (10%) had D/M virus according to the results of a second coreceptor test conducted prior to starting treatment with the study drug. CONCLUSIONS Infection with dual-tropic or mixed HIV-1 populations that use both CCR5 and CXCR4 is common among highly treatment-experienced patients, but infection with virus using CXCR4 alone is uncommon. Subjects in the D/M group had significantly lower CD4(+) cell counts than subjects in the R5 group. Evaluating coreceptor use will be important in the clinical development of CCR5 and CXCR4 inhibitors.

Incomplete Reconstitution of T Cell Subsets on Combination Antiretroviral Therapy in the AIDS Clinical Trials Group Protocol 384

BACKGROUND Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized. METHODS Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4(+), CD4(+) naive and memory, CD4(+) activation, CD8(+), CD8(+) activation, B, and natural killer cells among patients in different baseline CD4(+) strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113. RESULTS Patients in the lower baseline CD4(+) strata did not achieve total CD4(+) cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4(+) cell count increases were similar. Ratios of CD4(+) naive-memory cell counts and CD4(+):CD8(+) cell counts remained significantly reduced in patients with lower baseline CD4(+) cell counts (<or=350 cells/mm(3)). These immune imbalances were most notable for those initiating ART with a baseline CD4(+) cell count <or=200 cells/mm(3), even after adjustment for baseline plasma HIV RNA levels. CONCLUSIONS After nearly 3 years of ART, T cell subsets in patients with baseline CD4(+) cell counts >350 cells/mm(3) achieved or approached the reference range those of control individuals without HIV infection. In contrast, patients who began ART with <or=350 CD4(+) cells/mm(3) generally did not regain normal CD4(+) naive-memory cell ratios. These results support current guidelines to start ART at a threshold of 350 cells/mm(3) and suggest that there may be immunological benefits associated with initiating therapy at even higher CD4(+) cell counts.

The effect of protease inhibitors on weight and body composition in HIV-infected patients

Objectives:To determine the nutritional changes that occur in HIV-infected patients receiving protease inhibitor (PI) therapy and to determine the effects of PI treatment on physical functioning and health perceptions in patients with HIV infection. Design:Longitudinal data analysis of 38 patients from a large Nutrition and HIV cohort. Methods:Patients were included if they had started PI therapy after enrollment in the cohort, if they had taken the drug for at least 4 months without interruption and if data on weight, body composition and viral loads were available. Results:Mean person-months of follow-up was 8.1 months before and 12.2 months after PI treatment. Weight (1.54 kg, P < 0.0001), body mass index (0.50 kg/m2, P < 0.0001), physical functioning (8.52 points, P = 0.0006) and current health perception (6.7 points, P = 0.01) increased significantly, and the daily caloric intake increase was close to significance (915.5 kJ/day, P = 0.06), after treatment with PI. Lean body mass did not change. Patients who responded to PI therapy with decreased viral load (n = 28) had significantly greater weight gain per month than non-responders. Conclusions:PI therapy of HIV infection is associated with weight gain and improvement in quality of life indices. The weight gain is mainly in fat mass, with no change in lean body mass (skeletal muscle). Optimal therapy of HIV-infected patients with weight loss may require highly active antiretroviral therapy combined with an anabolic stimulus such as exercise, anabolic steroids or human growth hormone.

A practical guide to vaccinating the inflammatory bowel disease patient.

The increasing use of corticosteroids, immune modulators, and biologics as a mainstay of therapy in certain Crohns disease and ulcerative colitis patients have placed these inflammatory bowel disease (IBD) patients at increased risk for a variety of infections, many of which are preventable by prior vaccination. This article provides a review of the issues surrounding immunizations in the IBD patient and a practical guide for clinicians regarding the appropriate vaccinations to administer both before and during immunosuppressive therapy.

Randomized Controlled Trial of a Personalized Cellular Phone Reminder System to Enhance Adherence to Antiretroviral Therapy

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

Measuring Retention in HIV Care: The Elusive Gold Standard

Background:Measuring retention in HIV primary care is complex, as care includes multiple visits scheduled at varying intervals over time. We evaluated 6 commonly used retention measures in predicting viral load (VL) suppression and the correlation among measures. Methods:Clinic-wide patient-level data from 6 academic HIV clinics were used for 12 months preceding implementation of the Centers for Disease Control and Prevention/Health Resources and Services Administration (CDC/HRSA) retention in care intervention. Six retention measures were calculated for each patient based on scheduled primary HIV provider visits: count and dichotomous missed visits, visit adherence, 6-month gap, 4-month visit constancy, and the HRSA HIV/AIDS Bureau (HRSA HAB) retention measure. Spearman correlation coefficients and separate unadjusted logistic regression models compared retention measures with one another and with 12-month VL suppression, respectively. The discriminatory capacity of each measure was assessed with the c-statistic. Results:Among 10,053 patients, 8235 (82%) had 12-month VL measures, with 6304 (77%) achieving suppression (VL <400 copies/mL). All 6 retention measures were significantly associated (P < 0.0001) with VL suppression (odds ratio; 95% CI, c-statistic): missed visit count (0.73; 0.71 to 0.75, 0.67), missed visit dichotomous (3.2; 2.8 to 3.6, 0.62), visit adherence (3.9; 3.5 to 4.3,0.69), gap (3.0; 2.6 to 3.3, 0.61), visit constancy (2.8; 2.5 to 3.0, 0.63), and HRSA HAB (3.8; 3.3 to 4.4, 0.59). Measures incorporating “no-show” visits were highly correlated (Spearman coefficient = 0.83–0.85), as were measures based solely on kept visits (Spearman coefficient = 0.72–0.77). Correlation coefficients were lower across these 2 groups of measures (range = 0.16–0.57). Conclusions:Six retention measures displayed a wide range of correlation with one another, yet each measure had significant association and modest discrimination for VL suppression. These data suggest there is no clear gold standard and that selection of a retention measure may be tailored to context.

Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection

Zidovudine (AZT, Retrovir) delays progression of human immunodeficiency virus type 1 (HIV-1) infection and prolongs survival in persons with advanced HIV-1 disease [1-5]. However, with prolonged therapy, clinical disease progresses, CD4+ cell counts decrease, and variants of HIV-1 occur that have decreased in vitro susceptibility to zidovudine [6-12]. Didanosine (Videx), another nucleoside analogue that inhibits the reverse transcriptase of HIV-1, increases CD4+ cell counts and delays progression of HIV-1 disease among patients who previously received zidovudine therapy [13-16]. The combination of zidovudine and didanosine has additive to synergistic inhibitory activity against HIV-1 in vitro [17, 18] and is being used clinically, because both agents are licensed and available. We did a clinical trial to characterize the safety and efficacy of a range of doses using combination zidovudine and didanosine therapy compared with zidovudine therapy alone. We found that this combination therapy is well tolerated and is associated with enhanced in vivo activity as shown by higher and more prolonged increases of CD4+ cell counts, with more frequent decreases in plasma HIV-1 RNA titers, and with more stable hematologic measurements than zidovudine therapy alone. Table 1. Pretreatment Characteristics of Patients in the Six Treatment Groups Methods Patients Between February 1990 and August 1991, 69 patients were enrolled in the study: 30 at University of Washington, 14 at University of Miami, 14 at New England Medical Center and Tufts University, and 11 at University of California, San Francisco. Patients had HIV-1 infection, CD4+ cell counts fewer than 400/mm3, fewer than 121 days of previous zidovudine therapy (Retrovir; Burroughs Wellcome Company, Research Triangle Park, North Carolina), and no previous didanosine therapy (Videx; Bristol Laboratories, Princeton, New Jersey). Patients also had granulocyte counts of 1200 cells/mm3 or more, hemoglobin levels greater than 90 g/L, platelet counts greater than 90 000/mm3, creatinine levels less than 1.5 times the upper limit of normal, and aspartate aminotransferase levels less than 5 times the upper limit of normal. Patients were excluded if they had visceral or progressive Kaposi sarcoma; more than four stools per day for 4 weeks; opportunistic infections requiring maintenance therapy; a history of pancreatitis, seizures, peripheral neuropathy, or zidovudine or didanosine intolerance; were pregnant or nursing; were taking experimental medications; or required chronic acyclovir therapy. Study Design The study was an open-label, partially randomized study of five different combination regimens of zidovudine and didanosine and one dosage regimen of zidovudine alone (Figure 1). Zidovudine was given as capsules three times per day. Didanosine was given twice daily as sachets containing a citrate/phosphate buffer with a neutralizing capacity of 30 to 40 mEq/dose. Because of initial concerns about the safety of this combination, enrollment was required in the lower dose groups (groups 1, 2, and 3) before enrollment in groups 4 and 5. In March 1991, after enrollment was completed in groups 1 to 5, the protocol was modified to enroll consecutively identified eligible patients in the zidovudine-alone regimen (group 6), to permit a comparison with standard therapy. Because standard zidovudine therapy in the United States at the time this trial was done was 500 to 600 mg daily, the groups that included zidovudine at 600 mg daily (groups 3, 5, and 6) were planned to have larger enrollment than the other groups. Treatment duration was 24 weeks. Patients were replaced if they discontinued treatment permanently before week six for reasons other than toxicity. Figure 1. Outline of the study design. Patient Evaluation The study protocol was approved by institutional review boards of participating institutions, and patients gave written informed consent. Patients had a standardized clinical and laboratory evaluation at enrollment and had weekly follow-up visits for 4 weeks and then every 2 weeks. Symptoms and signs were assessed at each visit and were graded as absent or within normal limits, or as mild, moderate, severe, or life-threatening severity. Patients at the University of Washington in groups 3 (n = 9) and 5 (n = 6) had blood samples collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours for pharmacokinetic assays, after a single 200-mg zidovudine dose, 2 days before starting study drugs, and after a single 167- or 250-mg didanosine dose on the day before starting combination therapy. In addition, 26 patients in groups 3 and 5 had plasma collected on a similar schedule during weeks 2 (n = 26) and 12 (n = 23). Doses of study drugs were modified if patients had moderate peripheral neuropathy or certain severe toxicities. Study drugs were permanently discontinued for severe or life-threatening toxicities. Laboratory Measurements CD4+ and CD8+ cells from peripheral blood were enumerated using monoclonal antibodies and flow cytometry [19]. Sera from each patient, frozen at 30C, were assayed simultaneously for HIV-1 p24 antigen by an enzyme-linked immunosorbent assay (Abbott Laboratories, North Chicago, Illinois). A positive result for HIV-1 was defined as 12 pg/mL using an HIV-1 p24 antigen reference standard supplied by the AIDS Clinical Trials Group Virology Reference Laboratory. Sera from patients enrolled at the University of Washington were also assayed for immune-complex dissociated-HIV p24 antigen (Abbott Laboratories). Plasma from patients enrolled at the University of Washington, stored at 70C, was assayed for HIV-1 RNA by a semiquantitative polymerase chain reaction technique, as previously described [20]. All assays were done in duplicate on coded samples, and the semiquantitative assessment of the polymerase chain reaction-signal strength was graded using scanning densitometry without knowledge of any clinical data or treatment group. Zidovudine concentrations in plasma were determined by radioimmunoassay [21]. Plasma didanosine concentrations were analyzed by high-performance liquid chromatography [22]. Data Analysis Comparisons among groups were made using chi-square analysis or the Fisher exact test for discrete variables and using the Wilcoxon Mann-Whitney test and Kruskal-Wallis test among three or more groups for continuous variables. All P values were two-tailed. To evaluate the effect of therapy for sequentially monitored variables, area-under-the-curve (AUC) analyses were done based on absolute change from pretreatment or time-averaged absolute change from pretreatment values. The baseline CD4+ cell count was an average of two pretreatment counts for each patient. The AUC for CD4+ cell counts was calculated by multiplying the average CD4+ cell count between two successive time points by the time elapsed between those time points, summing these areas for the study period, and dividing the result by the duration of the study period. This AUC was strongly related to the pretreatment CD4+ cell count. Analysis of covariance, adjusting for the initial CD4+ cell count, was used to examine the relation between the treatment group and the AUC. Residuals from the model were analyzed, and no pattern was discernible, suggesting the model was appropriate. Area-under-the-curve analysis, based on absolute CD4+ cell changes from pretreatment values, was used to compare these areas across groups using nonparametric statistics. The proportion of patients with an increase in absolute CD4+ cells of 50 and 100 cells/mm3, on two consecutive measurements above the pretreatment value, was evaluated using contingency tables. The duration of response was defined as the time to two consecutive counts at or below baseline and was analyzed using Kaplan-Meier survival techniques. Pharmacokinetic parameter estimates were calculated by standard methods and included the peak concentration (Cmax), the time to peak concentration (Tmax), the elimination half-life (t1/2), the AUC, and the apparent oral clearance. The evaluation of a pharmacokinetic drug interaction between zidovudine and didanosine was done by paired t-test analysis of parameter estimates obtained for those patients in groups 3 and 5 who received single doses of zidovudine alone (day 2) and didanosine alone (day 1) followed by coadministration of both compounds with pharmacokinetic evaluations in weeks 2 and 12. Parameter estimates were considered statistically different for P values less than 0.05. Results Study Patients Sixty-seven (97%) patients were men; 61 (88%) were white, 2 (3%) were black, and 6 (9%) were of other races. The mean age (SD) was 34 6 years. Fifty-four (78%) were homosexual or bisexual men, 8 (12%) were homosexual or bisexual men who also used injection drugs, 2 (3%) were injection drug users, 3 (4%) had heterosexually acquired HIV-1, 1 (1%) had hemophilia, and 1 (1%) had unknown risk behavior for HIV. Thirty-eight (55%) patients were asymptomatic, 22 (32%) had constitutional symptoms, and 9 (13%) had the acquired immunodeficiency syndrome (AIDS). The median pretreatment CD4+ cell count was 259 cells/mm3, and the median Karnofsky performance score was 100. No statistical differences were seen in demographic, clinical, or laboratory characteristics among the six dosing groups, except for the expected difference in frequency of detectable HIV-1 p24 antigen (Table 1). The median HIV-1 p24 antigen level for patients in group 1 was 140 pg/mL (range, 17 to 282 pg/mL). Thirty-one patients had taken previous zidovudine therapy; the mean duration of therapy (SD) was 65 days ( 36 days). Fifty-eight (84%) patients completed 24 weeks of study treatment and 11 (16%) discontinued study treatment, 5 before week 6. Pretreatment characteristics of patients who discontinued treatment were similar to those who completed therapy. The reasons for study medication discontinuation were toxicity (3 patients), administrative reasons (4

Noninvasive Markers of Liver Fibrosis Are Highly Predictive of Liver-Related Death in a Cohort of HCV-Infected Individuals With and Without HIV Infection

OBJECTIVES:Noninvasive markers of liver fibrosis correlate with the stage of liver fibrosis, but have not been widely applied to predict liver-related mortality.METHODS:We assessed the ability of two indices of liver fibrosis, aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and Fib-4, and two markers of extracellular matrix metabolism, hyaluronic acid (HA) and YKL40, to predict liver mortality in a prospective cohort of hepatitis C virus (HCV)-infected individuals with and without HIV coinfection. These were compared with two established prognostic scores, the Child–Pugh–Turcotte (CPT) and model of end-stage liver disease (MELD) scores.RESULTS:A total of 303 subjects, of whom 207 were HIV positive at study entry, were followed up for a mean period of 3.1 years. There were 33 deaths due to liver disease. The ability of each test and score to predict 3-year liver mortality was expressed as the area under the receiver operator curve. The area under the receiver operator curve 95% confidence intervals were: HA 0.92 (0.86–0.96), CPT 0.91 (0.79–0.96), APRI 0.88 (0.80–0.93), Fib-4 0.87 (0.77–0.92), MELD 0.84 (71–0.91). In multivariate analyses HA, APRI, and fib-4 were independent predictors of mortality when included in models with MELD or CPT.CONCLUSION:Noninvasive markers of liver fibrosis are highly predictive of liver outcome in HCV-infected individuals with and without HIV coinfection. These markers seem to have a prognostic value independent of CPT and MELD.