Replication Capacity

SJ Little and others. High Replication Capacity Is Associated with High Baseline Viral Load in Untreated Subjects with Primary HIV Infection. Abstract 152 (oral session).

Purpose: To evaluate whether drug susceptibility and viral replication capacity (RC, i.e. fitness) are associated with baseline plasma viral load levels in treatment naïve subjects with primary HIV infection.

Authors Conclusions: “Higher baseline viral RC, but not drug resistance, was a significant predictor of higher baseline viral load in subjects presenting with primary HIV infection.  PI HS and phenotypic resistance were associated with a lower baseline RC.  Although the clinical significance of RC requires further study, it may be an important determinant of the rate of disease progression among untreated patients with recent HIV infection.

02/19/03

RO 033-4649

N Cammack and others. RO033-4649:  A New HIV-1 Protease Inhibitor Designed for both Activity against Resistant Virus Isolates and Favorable Pharmacokinetic Properties. Abstract 7 (oral session).

Methods:  RO033-4649 was identified through structure-activity analyses focused particularly on activity against HIV-1 site-directed mutants with 1-5 PI-resistance mutations and showing shifts in phenotypic sensitivity in a replication-competent antiviral assay from 2.5 fold to 10 fold or greater, for one or more marketed protease inhibitors.

Conclusions:  “RO033-4649 is a potent and selective HIV-1 protease inhibitor with promising activity against PI-resistant HIV isolates.  Phase I clinical evaluation has commenced.”

02/19/03

Atazanavir

R Colonno and others. Emergence of Atazanavir Resistance and Maintenance of Susceptibility to Other PIs is Associated with an 150L Substitution in HIV Protease. Abstract 597 (poster).

Authors Conclusions: I50L is the signature amino acid change observed following ATV treatment and results in ATV specific resistance and increased susceptibility to all other PIs. This observation and its implications for the future use of ATV will require further studies.

02/19/03

Tenofovir and HIV Replication Capacity

MD Miller and others. Decreased Replication Capacity of HIV-1 Clinical Isolates Containing K65R or M184V RT Mutations. Abstract 616 (poster).

Authors Conclusions: “In this sample set, TAMs were highly prevalent (49%) and the K65R was infrequent (<1%). Patient isolates with K65R or M184V exhibit decreased RC and these effects on replication appear additive. Conversely, patient isolates with TAMs alone do not have significantly reduced RC. The results with K65R are consistent with the sustained reductions in HIV RNA observed among patients in clinical trials of tenofovir DF who had developed K65R. Although therapeutic strategies should attempt to avoid development of resistance, the clinical consequences of certain resistance mutations may be moderated by the reduced replication capacity of the mutant virus.”

02/19/03

Replication Capacity

JD Barbour and others. Viral pro/pol Replication Capacity Declines Slowly among Untreated, HIV-1 Infected Adults in Early Infection with and without Primary Drug Resistance. Abstract 617 (poster).

Authors Conclusions:  “At baseline, replication capacity (RC) varied widely across patients with and without evidence of drug resistance.  Over the period of observation, RC declined slowly.  Establishing a baseline RC for patients will help interpret changes in RC over time.”

02/19/03

NNRTI and PI

D Linden and others. Discordant CD4/VL Response to NNRTI and Protease Inhibitor (PI)-Based Antiretroviral Therapy (ART) is Associated with CCR-5 Tropism and Differing Levels of Replication Capacity. Abstract 146 (oral session).

Authors Conclusions: HIV from patients with discordant CD4/VL responses is consistently R5-tropic while HIV from patients failing PI-based ART is most often X4-tropic.  PI-based ART appears to impact replication capacity to a greater extent than NNRTI-based ART, perhaps reflecting differing barriers to resistance generation.

02/19/03

Fuzeon (enfuvirtide)

ML Greenberg and others. Baseline (BL) and on-Treatment Susceptibility to Enfuvirtide Seen in TORO 1 and TORO 2 Through 24 Weeks. Abstract 141 (oral session).

Authors Conclusions: “Using GeneSeq and PhenoSense Entry Assays, we characterized susceptibility to ENF at BL and at virological failure. Patients achieved similar virological suppression across the range of BL ENF susceptibility observed. Patients taking ENF who met virological failure criteria had on average a 21-fold loss of ENF susceptibility, associated with concomitant changes in gp41 aa 36-45.”

02/19/03

PhenoSense Assay

NY Parkin and others. Distribution of Phenotypic Drug Susceptibility among >2000 Wild Type Viruses. Abstract 585 (poster).

Results: The average coefficient of variation (CVs) for the reference viruses ranged from 12% to 23% for all drugs except ZDV (36%). The log₁₀-transformed fold change (FC) data from clinical isolates were normally distributed. Results are summarized below:

*ATV=atazanavir

Authors Conclusions: “The mean+2SD FC value for all drugs in wild-type viruses is lower than previously described for “biological” cut-offs using other phenotypic assays. The larger variability in WT drug susceptibility for some drugs (e.g. NFV and the NNRTIs) is not due to differences in assay variation, since the CVs are low and not significantly different between drugs. These observations indicate that the PhenoSense assay can be used to reliably determine clinically relevant breakpoints at low fold-change values (< 2-fold) for stavudine, didanosine, and tenofovir. In addition, greater precision in phenotypic data facilitates the development of more accurate genotype interpretation algorithms.”

02/19/03

Fuzeon (enfuvirtide)

JM Whitcomb and others. Analysis of Baseline Enfuvirtide (T20) Susceptibility and Co-receptor Tropism in Two Phase III Study Populations. Abstract 557 (poster).

Objectives: To describe baseline (BL) ENF susceptibility, co-receptor tropism and genetic variation of entry-inhibitor naïve HIV-1 in patients from TORO 1 & 2.

Authors Conclusions: “At TORO 1&2 study baseline, pure R5 tropic viruses were more prevalent than dual tropic viruses, and pure X4 tropic viruses were rare. BL ENF susceptibility distributions were generally similar for all virus populations, however pure X4 tropic viruses had slightly higher nFC compared to R5 and dual viruses. While polymorphisms in the ENF binding site were uncommon, N42S was associated with lower nFC to ENF.”

02/19/03

Inhibitors

E Paxinos and others. Development and Characterization of a Diverse Panel of Group M Isolates for the Evaluation of HIV-1 Entry Inhibitors. Abstract 630 (poster).

Authors Conclusions:  “We have developed a panel of diverse group M virus envelope expression vectors and a cell-based infectivity assay that permit the evaluation of new agents that target HIV-1 entry.  This panel can also be used to assess antibody neutralization responses elicited by various vaccine candidates.”

02/19/03

Treatment Interruption

S Deeks and others. Continued Reverse Transcriptase Inhibitor Therapy is Sufficient to Maintain Short-Term Partial Suppression of Multi-Drug Resistant Viremia. Abstract 640 (poster).

Methods: This is a prospective non-randomized pilot study of patients interrupting either the protease inhibitor (PI) or reverse transcriptase inhibitor (NRTI) component of a combination regimen. Eligible subjects had persistent viremia (>400 copies/mL) and > 90% adherence to a regimen containing both NRTIs and PIs. The decision to interrupt either PI or NRTI therapy was based on subject-specific toxicity.

Authors Conclusions: “Interrupting PI therapy in patients with multi-drug resistant HIV is associated with stable viremia, reduced toxicity, and halted accumulation of drug resistance (which may preserve future PI options). In contrast, interruption of NRTI therapy was associated with rapid rises in viremia, indicating that NRTIs may have continued antiviral effects against drug resistant HIV. Partial treatment interruptions may be appropriate for maintaining partial virologic responses in persons with limited treatment options.”

02/19/03

Indinavir/Ritonavir

J Szumiloski and others. Determination of an Indinavir Susceptibility Cutoff for Indinavir-Ritonavir-Containing Regimens. Abstract 603 (poster).

Results:  Virologic responses to IDV-RTV treatment were observed across a wide range of IDV phenotypes.  Responses were similar below approximately 10 fold, with reduced responses at greater phenotypic shifts (up to 178 fold).  After correcting for other factors, maximum viral suppression was observed between 1.9 and 5.6 fold, depending on endpoint, with the point of first significant drop from maximum seen between 8.8 and 22 fold. 

Autnors Conclusions: “Baseline IDV resistance predicted viral suppression by IDV‑RTV based regimens.  In these studies, approximately equivalent virologic responses were observed up to approximately 10 fold decreases in IDV susceptibility, with diminishing viral suppression at higher degrees of resistance.  These data are consistent with an IDV clinical cutoff for IDV/RTV 800/200 of approximately 10 fold.”

02/19/03

Predicting NRTI Options

ER Manier. Prediction of NRTI Options by Linking Reverse Transcriptase Genotype to Phenotypic Breakpoints. Abstract 586 (poster).

·          Number of matched GTs and PTs

Conclusions: “Multiple mutational pathways may lead to broad cross-resistance in the NRTI class.  Currently uncommon patterns with low genetic barriers to resistance, such as 184V plus either K65R or L74V (only 2 mutations needed) may increase in prevalence if ABC, ddI and/or TDF use increases, especially if accompanied by a decrease in thymidine analog use.”

02/19/03

Entry Inhibitor PRO 542

WC Olsen and others. Drug Susceptibility and Pharmacologic Analyses of Phase I/II Study Patients Treated with the HIV-1 Entry Inhibitor PRO 542. Abstract 561 (poster).

Results: PRO 542 demonstrated dose-proportional pharmacology. The inter-patient variation in viral sensitivity to PRO 542 was comparable across the reporter- and whole-virus assays. The variation for patient viruses, which represent diverse quasi-species, was consistent with prior in vitro studies performed using cloned or biological isolates.  Within a given dose cohort, significant correlations were observed between viral AUC and viral sensitivity to PRO 542 (r=0.78, p<0.003).

Authors Conclusions: “These studies begin to define an inhibitory quotient for PRO 542 based on drug susceptibility and exposure. Phenotypic drug-resistance testing can reveal inter-patient variations in viral sensitivity to PRO 542 in vitro, and correlations can be drawn between in vitro sensitivity and clinical outcome. Viral resistance testing may have prognostic value for HIV-1 attachment and entry inhibitors.”

02/19/03

Treatment Interruptions in Salvage Pts

R Haubrich and others. Response to LPV/r in Experienced Patients: Effect of a Treatment Interruption. Abstract 565 (poster).

Methods: This is an analysis from CCTG 578, an on-going, randomized, 3x2 factorial study of three adherence interventions crossed with therapeutic drug monitoring. LPV/r levels drawn pre-, 2- and 4-hours post-witnessed dose at week 2, and randomly at weeks 4 and 6 as well as phenotype (ViroLogic) and HIV RNA (week 1, 2, 4 and 6) were assessed. Treatment experienced patients were either on drug (ON) or had interrupted therapy (OFF) for > 4 months when the LPVr regimen was initiated.

Authors Conclusions: “Viral load reduction with LPV/r regimens in experienced patients appeared to be greater after a treatment interruption, but this difference was due to an interaction with baseline viral load.  These data do not support use of interruptions to improve salvage responses.”

02/19/03

Kaletra

B Best and others. Population Pharmacokinetics of Lopinavir/Ritonavir in Experienced Patients. Abstract 527 (poster).

Background: Published lopinavir (LPV) pharmacokinetic data, generated in treatment naïve patients, may not adequately reflect LPV pharmacokinetics and its clinical variability. Our objective was to describe the pharmacokinetics of LPV at steady-state in treatment experienced patients with population methods, and to relate LPV exposure measures to response.

Authors Conclusions: “LPV oral clearance was higher than literature values reported for treatment naïve patients (~ 5 L/hr) despite comparable RTV levels. The C₁₂/IC₅₀ ratio was predictive of RNA changes only for patients who were on therapy when phenotyped.”

02/19/03

Long-Term Non Progressors

B Rodes and others. Immunologic and Virologic Outcome in a Cohort of Long Term Non-Progressors after More than 15 Years of HIV-1 Infection. Abstract 469 (poster).

Methods: Plasma HIV-RNA viral load (pVL) and CD4 counts were measured 2-3 times each year between 1996 and 2002. In recent samples, we also characterized the viruses for gag/pol subtypes, Nef deletions, co-receptor tropism, and replication capacity.  Recent samples were also assayed for CCR5 genotypes and T-cell activation (measured as the expression of CD38 on CD8+ cells).

Conclusions: “The majority of individuals with long-term nonprogressive HIV-1 infection remain with low or undetectable viral load and high and stable CD4 counts over time. Most of them carry viruses exhibiting a low replicative capacity and CCR5 tropism. Progressive immunologic damage seems directly associated with some degree of HIV replication and T cell activation.”

02/19/03

Nevirapine Resistance

SH Eshleman. Evaluation of a Rapid Assay for Evaluation of Nevirapine (NVP) Resistance in Ugandan Women Who Received Single Dose NVP Prophylaxis in HIVNET 012. Abstract 581 (poster).

Authors Conclusions: “Genotyping and the Amp-RT assay gave concordant results for 19 (73%) of 26 samples.  The lack of detection of NVPR in samples with NVPR mutations most likely reflects the low levels of mutant HIV-1 in the samples. The finding of clear NVPR in two post-NVP samples with WT genotypes suggests that mutations other than those defined in subtype B HIV-1 may cause NVPR in other subtypes. Further studies are needed to characterize the genetic correlates of NVPR in non-subtype B HIV-1 and to assess the utility of this rapid assay for evaluation of NVPR in resource-limited settings.”

02/19/03