The Setpoint Study (ACTG A5217): Effect of Immediate Versus Deferred Antiretroviral Therapy on Virologic Set Point in Recently HIV-1–Infected Individuals

(See the editorial commentary by Tossonian and Conway, on pages 10–12.

Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings

To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLS)

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial

Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients

No Effect of Raltegravir Intensification on Viral Replication Markers in the Blood of HIV-1–Infected Patients Receiving Antiretroviral Therapy

Controversy continues regarding the extent of ongoing viral replication in HIV-1-infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial

In a double-blind trial, Rajesh Gandhi and colleagues detect no significant reduction in viral load after people with low-level HIV viremia added an integrase inhibitor to their treatment regimen

Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings

OBJECTIVE: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLS). DESIGN: Open-label pilot study of LPV/r monotherapy in participants on first-line non-nucleoside reverse transcriptase inhibitor 3-drug combination ART with plasma HIV-1 RNA 1000–200 000 copies/mL. METHODS: Participants were recruited from 5 sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure (VF) at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r. RESULTS: Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without VF at 24 weeks (87%). Archived samples with HIV-1 RNA levels < 400 at week 24 (n = 102) underwent ultrasensitive assay. Of these subjects, 62 had levels < 40 copies/mL and 30 had levels 40–200. Fifteen subjects experienced VF, among whom 11 had resistance assessed, and 2 had emergent protease inhibitor mutations. The presence of baseline thymidine analogue mutations and K65R predicted a lower VF rate. Thirteen subjects with VF added FTC/TDF, and 1 subject added FTC/ TDF without VF. At study week 48, 11/14 adding FTC/TDF had HIV-1 RNA levels < 400 copies/mL. CONCLUSIONS: In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity

Multiple-Dose Escalation Study of the Safety, Pharmacokinetics, and Biologic Activity of Oral AMD070, a Selective CXCR4 Receptor Inhibitor, in Human Subjects▿ †

AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P ≤ 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an Emax model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070