Amy Krambrink

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.

Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort.

Objective: Prior studies have shown improved neurocognition with initiation of antiretroviral treatment (ART) in HIV. We hypothesized that stopping ART would be associated with poorer neurocognitive function. Methods: Neurocognitive function was assessed as part of ACTG 5170, a multicenter, prospective observational study of HIV-infected subjects who elected to discontinue ART. Eligible subjects had CD4 count >350 cells/mm3, had HIV RNA viral load <55,000 cp/mL, and were on ART (≥2 drugs) for ≥6 months. Subjects stopped ART at study entry and were followed for 96 weeks with a neurocognitive examination. Results: A total of 167 subjects enrolled with a median nadir CD4 of 436 cells/mm3 and 4.5 median years on ART. Significant improvements in mean neuropsychological scores of 0.22, 0.39, 0.53, and 0.74 were found at weeks 24, 48, 72, and 96 (all p < 0.001). In the 46 subjects who restarted ART prior to week 96, no significant changes in neurocognitive function were observed. Conclusion: Subjects with preserved immune function found that neurocognition improved significantly following antiretroviral treatment (ART) discontinuation. The balance between the neurocognitive cost of untreated HIV viremia and the possible toxicities of ART require consideration. Classification of evidence: This study provides Class III evidence that discontinuing ART is associated with an improvement in 2 neuropsychological tests (Trail-Making Test A & B and the Wechsler Adult Intelligence Scale–Revised Digit Symbol subtest) for up to 96 weeks. Resuming ART was not associated with a decline in these scores for up to 45 weeks.

Racial differences in virologic failure associated with adherence and quality of life on efavirenz-containing regimens for initial HIV therapy: results of ACTG A5095.

Background:Blacks had higher rates of virologic failure than whites on efavirenz-containing regimens in the AIDS Clinical Trials Group (ACTG) A5095 study; preliminary analyses also suggested an association with adherence. We rigorously examined associations over time among race, virologic failure, 4 self-reported adherence metrics, and quality of life (QOL). Methods:ACTG A5095 was a double-blind placebo-controlled study of treatment-naive HIV-positive patients randomized to zidovudine/lamivudine/abacavir versus zidovudine/lamivudine plus efavirenz versus zidovudine/lamivudine/abacavir plus efavirenz. Virologic failure was defined as confirmed HIV-1 RNA ≥200 copies/mL at ≥16 weeks on study. The zidovudine/lamivudine/abacavir arm was discontinued early because of virologic inferiority. We examined virologic failure differences for efavirenz-containing arms according to missing 0 (adherent) versus at least 1 dose (nonadherent) during the past 4 days, alternative self-reported adherence metrics, and QOL. Analyses used the Fisher exact, log rank tests, and Cox proportional hazards models. Results:The study population included white (n = 299), black (n = 260), and Hispanic (n = 156) patients with ≥1 adherence evaluation. Virologic failure was associated with week 12 nonadherence during the past 4 days for blacks (53% nonadherent failed vs. 25% adherent; P < 0.001) but not for whites (20% nonadherent failed vs. 20% adherent; P = 0.91). After adjustment for baseline covariates and treatment, there was a significant interaction between race and week 12 adherence (P = 0.02). In time-dependent Cox models using self-reports over time to reflect recent adherence, there was a significantly higher failure risk for nonadherent subjects (hazard ratio [HR] = 2.07; P < 0.001). Significant race-adherence interactions were seen in additional models of adherence: missing at least 1 medication dose ever (P = 0.04), past month (P < 0.01), or past weekend (P = 0.05). Lower QOL was significantly associated with virologic failure (P < 0.001); there was no evidence of an interaction between QOL and race (P = 0.39) or adherence (P = 0.51) in predicting virologic failure. Conclusions:There was a greater effect of nonadherence on virologic failure in blacks given efavirenz-containing regimens than in whites. Self-reported adherence and QOL are independent predictors of virologic failure.

Response to Vicriviroc in Treatment-Experienced Subjects, as Determined by an Enhanced-Sensitivity Coreceptor Tropism Assay: Reanalysis of AIDS Clinical Trials Group A5211

The enhanced-sensitivity Trofile assay (Monogram Biosciences) was used to retest coreceptor use at both study screening and study entry for 118 treatment-experienced subjects in AIDS Clinical Trials Group A5211 who had CCR5-tropic (R5) virus detected by the original Trofile assay at study screening. Among 90 recipients of vicriviroc, a significantly (P< .001) greater mean reduction in HIV-1 RNA was observed in 72 subjects with R5 virus versus 15 subjects reclassified as having dual/mixed-tropic viruses at screening: -1.11 versus -0.09 log(10) copies/mL at day 14 and -1.91 versus -0.57 log(10) copies/mL at week 24, respectively. Results suggest that the enhanced-sensitivity assay is a better screening tool for determining patient eligibility for CCR5 antagonist therapy.

Interruption of antiretroviral treatment in HIV-infected patients with preserved immune function is associated with a low rate of clinical progression : A prospective study by AIDS clinical trials group 5170

BACKGROUND We sought to determine the safety of treatment interruption (TI) and to identify parameters that would define patients with human immunodeficiency virus (HIV) for whom TI is safer. METHODS AIDS Clinical Trials Group 5170 was a multicenter, 96-week-long, prospective study of HIV-infected patients receiving antiretroviral therapy (ART) who had CD4(+) cell counts >350 cells/mm(3) and who underwent TI. RESULTS A total of 167 patients were enrolled. The median nadir in CD4(+) cell count was 436 cells/mm(3). The initial decrease (i.e., during the first 8 weeks) in CD4(+) cell count after ART interruption was 20 cells/mm(3)/week; the subsequent decrease was 2.0 cells/mm(3)/week until week 96. Both the CD4(+) cell count before enrollment and the increase in CD4(+) cell count during ART predicted early decrease; later decrease was predicted by the level of interleukin-7 at enrollment. A Centers for Disease Control and Prevention (CDC) diagnosis of a category B or C event was made for 2 and 2 patients, respectively (all had CD4(+) cell counts >350 cells/mm(3)). At week 96, 17 patients had CD4(+) cell counts < or =250 cells/mm(3), and 46 patients had resumed ART; 5 patients died (unrelated to HIV or acquired immunodeficiency syndrome). In a multivariate analysis, a higher nadir in CD4(+) cell count (>400 cells/mm(3)), a lower HIV load (<50 copies/mL) at the time of TI, and an HIV load < or =22,000 copies/mL before ART predicted a longer time to the primary end point (CDC category B or C event, death, CD4(+) cell count < or =250 cells/mm(3), or resumption of ART). CONCLUSION Disease progression after TI was low in this cohort. A higher nadir in CD4(+) cell count, a lower HIV load before ART, and an HIV load < or =50 copies/mL at the time of TI predicted a longer time to the primary end point.

Detection of Nonnucleoside Reverse-Transcriptase Inhibitor-Resistant HIV-1 after Discontinuation of Virologically Suppressive Antiretroviral Therapy

Using standard and ultrasensitive techniques, we detected nonnucleoside reverse-transcriptase inhibitor-associated resistance mutations in 11 (20%) of 54 subjects who discontinued virologically suppressive nonnucleoside reverse-transcriptase inhibitor-containing antiretroviral therapy. Resistance was detected in 45% and 14% of subjects with a baseline human immunodeficiency virus type 1 RNA level of 51-400 copies/mL and <or=50 copies/mL, respectively. Mutations remained detectable for at least 48 weeks in some subjects.

Substitution of nevirapine because of efavirenz toxicity in AIDS Clinical Trials Group A5095.

In AIDS Clinical Trials Group A5095, 9% of participants who experienced an adverse event related to efavirenz substituted nevirapine. Most adverse events resolved; 15 participants ultimately discontinued nevirapine therapy. Grade 3/4 hepatotoxicity was observed in 14% of individuals who substituted nevirapine, compared with 6% who continued efavirenz therapy. Substitution of nevirapine because of efavirenz toxicity was generally safe and efficacious. Clinical trials registration. NCT00013520 .

Three-Year Safety and Efficacy of Vicriviroc, a CCR5 Antagonist, in HIV-1-Infected, Treatment-Experienced Patients

Background:Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity. Methods:Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc. Results:One hundred eighteen subjects were randomized. Virologic failure (<1 log10 decline in HIV-1 RNA ≥16 weeks postrandomization) occurred by week 48 in 24 of 28 (86%), 12 of 30 (40%), 8 of 30 (27%), 10 of 30 (33%) of subjects randomized to placebo, 5, 10, and 15 mg, respectively. Overall, 113 subjects received vicriviroc at randomization or after virologic failure, and 52 (46%) achieved HIV-1 RNA <50 copies per milliliter within 24 weeks. Through 3 years, 49% of those achieving suppression did not experience confirmed viral rebound. Dual or mixed-tropic HIV-1 was detected in 33 (29%). Vicriviroc resistance (progressive decrease in maximal percentage inhibition on phenotypic testing) was detected in 6 subjects. Nine subjects discontinued vicriviroc due to adverse events. Conclusions:Vicriviroc seems safe and demonstrates sustained virologic suppression through 3 years of follow-up. Further trials of vicriviroc will establish its clinical utility for the treatment of HIV-1 infection.

Lymphoma Diagnosis and Plasma Epstein-Barr Virus Load during Vicriviroc Therapy: Results of the AIDS Clinical Trials Group A5211

BACKGROUND Lack of functional CCR5 increases the severity of certain viral infections, including West Nile virus and tickborne encephalitis. In a phase II trial of the investigational CCR5 antagonist vicriviroc (AIDS Clinical Trials Group protocol A5211), 4 lymphomas occurred in study patients who received vicriviroc. Because of the known association between unregulated Epstein-Barr virus (EBV) replication and lymphoma in immunocompromised patients, we evaluated whether vicriviroc exposure was associated with lymphoma EBV antigen positivity and/or had an effect on plasma levels of EBV DNA. METHODS Clinical findings for all 4 patients enrolled in the A5211 study who developed lymphoma (2 Hodgkin and 2 non-Hodgkin) were reviewed, and tumor specimens were assessed for evidence of ongoing EBV replication. Longitudinal plasma samples from 116 patients in the A5211 study were analyzed, and EBV DNA was quantified by real-time polymerase chain reaction. RESULTS Plasma EBV DNA was not detected in the 2 patients with non-Hodgkin lymphoma; both patients with Hodgkin lymphoma who had samples tested had EBV DNA levels <3200 copies/mL. One patient with Hodgkin lymphoma had a lymph node core biopsy specimen that was strongly positive for EBV; the other 3 lymphomas were histochemically EBV negative. None of the 116 patients with available samples experienced sustained increases in plasma EBV levels. CONCLUSIONS CCR5 antagonism by vicriviroc treatment in treatment-experienced patients was not associated with reactivation of EBV infection.

Improved Measures of Quality of Life, Lipid Profile and Lipoatrophy after Treatment Interruption in HIV-Infected Patients with Immune Preservation: results of ACTG 5170

Background:Antiretroviral treatment interruption (TI) occurs frequently in routine clinical practice. The consequences of TI on quality of life (QOL), body habitus, and lipid parameters have not been studied. Methods:We assessed QOL, symptoms, lipid measurements, and body circumference changes in patients who underwent prolonged TI (up to 96 weeks) in AIDS Clinical Trials Group 5170, a multicenter, prospective study. Major entry criteria were pre-antiretroviral therapy (ART) and entry CD4 count >350 cells/mm3, entry HIV RNA <55,000 copies/mL, and on ART for >6 months. QOL was assessed at baseline and subsequent time points (to week 96) by patient self-report (0-100 scale), by patient-reported Symptoms Distress Module, and by the Multidimensional Health Status tool. Fasting total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides were measured at baseline and subsequent time points to week 24. Neck, arm, mid-thigh, waist, and hip circumferences were measured through week 96. Paired t tests, Wilcoxon signed rank tests, and the generalized estimating equation approach were used in the data analysis. Results:A total of 167 subjects enrolled with median baseline and nadir CD4 count of 833 and 436 cells/mm3, respectively, and median time on ART 4.5 years. One hundred forty-nine subjects were receiving a thymidine analog-containing regimen (zidovudine or stavudine before TI). Self-reported QOL score on ART started high (mean 83.4 at baseline) and remained so after TI (83.0 at week 96, P = 0.49). Mean number of symptoms decreased from 8.2 at baseline to 7.0 at week 96, P = 0.016. The overall symptom summary score decreased from baseline to week 96, P = 0.01. The symptoms most frequently reported during TI were fatigue, feeling sad, nervousness, insomnia, myalgias, and changes in body appearance. There were no significant changes from baseline in the Multidimensional Health Status mental or physical domain scores. After TI, lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) decreased at weeks 12 and 24. Lipid changes were similar in patients stopping a nonnucleoside reverse transcriptase inhibitor vs a protease inhibitor regimen, except for HDL, which showed greater decreases in those interrupting an nonnucleoside reverse transcriptase inhibitor. Body circumference measurements of arm, waist, hip, and mid-thigh increased after TI. Conclusions:In a cohort of individuals with high QOL and preserved immune function, QOL did not change during a prolonged TI. Modest decreases in total cholesterol, LDL and HDL cholesterol, and triglycerides and a modest increase in limb fat were observed.