Continued Slow Decay of the Residual Plasma Viremia Level in HIV-1 – Infected Adults Receiving Long-term Antiretroviral Therapy

We measured plasma human immunodeficiency virus type 1 (HIV-1) RNA levels by means of single-copy assay in 334 participants receiving virologically suppressive antiretroviral therapy (ART). A residual viremia load of ≥1 copy/mL after 4 years of ART was predicted by a higher pre-ART HIV-1 RNA level, higher CD8+ T-cell count during treatment, and a lower ratio of CD4+ T cells to CD8+ T cells during treatment but not by initial ART regimen. In a longitudinal subset of 64 individuals, continued decay of the plasma HIV-1 RNA level was observed, with an average annual decrease of 6% and an estimated half-life of 11.5 years. In contrast to prior reports, the persistent viremia level continues to slowly decline during years 4–12 of suppressive ART

Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262)

To explore darunavir/ritonavir (DRV/r) plus raltegravir (RAL) combination therapy in antiretroviral-naive patients

No Evidence for Decay of the Latent Reservoir in HIV‐1–Infected Patients Receiving Intensive Enfuvirtide‐Containing Antiretroviral Therapy

Human immunodeficiency virus type 1 (HIV-1) persists in a latent reservoir of infected resting memory CD4 cells in patients receiving antiretroviral therapy. We assessed whether multitarget therapy with enfuvirtide, 2 reverse-transcriptase inhibitors, and a ritonavir-boosted protease inhibitor leads to decay of this reservoir. Nineteen treatment-naive patients initiated this regimen; 9 experienced virologic suppression and continued enfuvirtide-containing therapy for at least 48 weeks. In enfuvirtide-treated patients with virological suppression, there was no decay of the latent reservoir (95% confidence interval for half-life, 11 months to infinity). The stability of the latent reservoir despite intensive therapy suggests that new strategies are needed to eradicate HIV-1 from this reservoir

Comparison of Illumina and 454 Deep Sequencing in Participants Failing Raltegravir-Based Antiretroviral Therapy

Background: The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs. Methods: A5262 was a single-arm study of raltegravir and darunavir/ritonavir in treatment-naïve patients. Pre-treatment plasma was obtained from 5 participants with raltegravir resistance at the time of virologic failure. A control library was created by pooling integrase clones at predefined proportions. Multiplexed sequencing was performed with Illumina and 454 platforms at comparable costs. Illumina sequence analysis was performed with the novel snp-assess tool and 454 sequencing was analyzed with V-Phaser. Results: Illumina sequencing resulted in significantly higher sequence coverage and a 0.095% limit of detection. Illumina accurately detected all MVs in the control library at ≥0.5% and 7/10 MVs expected at 0.1%. 454 sequencing failed to detect any MVs at 0.1% with 5 false positive calls. For MVs detected in the patient samples by both 454 and Illumina, the correlation in the detected variant frequencies was high (R2 = 0.92, P<0.001). Illumina sequencing detected 2.4-fold greater nucleotide MVs and 2.9-fold greater amino acid MVs compared to 454. The only raltegravir-resistant MV detected was an E138K mutation in one participant by Illumina sequencing, but not by 454. Conclusions: In participants of A5262 with raltegravir resistance at virologic failure, baseline raltegravir-resistant MVs were rarely detected. At comparable costs to 454 sequencing, Illumina demonstrated greater depth of coverage, increased sensitivity for detecting HIV MVs, and fewer false positive variant calls

Regimen Simplification to Atazanavir‐Ritonavir Alone as Maintenance Antiretroviral Therapy: Final 48‐Week Clinical and Virologic Outcomes

Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/RTV) alone is attractive because of nucleoside reverse-transcriptase inhibitor (NRTI)–sparing benefits, low pill burden, once-daily dosage, and safety

Baseline natural killer and T cell populations correlation with virologic outcome after regimen simplification to atazanavir/ritonavir alone (ACTG 5201)

Objectives: Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. Methods: Thirty-four participants with virologic suppression ≥48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56 +CD16+) cells and cell-associated markers (HLA-DR, CD's 38/69/94/95/158/279). Results: Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) <50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL <50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92-55.3). Simplification was associated with transient increases in naïve and CD25+ CD4+ T-cells, and had no impact on IA levels. Conclusions: Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. Trial Registration: ClinicalTrials.gov NCT00084019

Assembly rules operate only in equilibrium communities: Is it true?

Very little is known of how disturbance affects community assembly rules. We examine this in three disturbance states in each of two ski areas on southern New Zealand mountains. Theory suggests that a community will become progressively more spatially organized during recovery from disturbance. Firstly, different patches of the community should become more similar through time, but this was seen in only one of the two areas and even then only examining species presence/absence. Secondly, it has been suggested that spatial autocorrelation will be stronger in less‐disturbed conditions, that is, there will be a stronger pattern of more distant patches being more dissimilar in species composition. This was generally borne out. However, the method indicated more point randomness in less‐disturbed sites. Assembly rules might be seen in species abundances. Previous work has found maximum evenness of abundances in later successional communities, but the pattern here was the opposite: high evenness in the most disturbed communities. The literature suggests that in undisturbed communities the distribution of species abundances (relative abundance distribution) will be general lognormal, and we further argue that the identity of the species across occupying rank positions in that distribution should be more consistent (rank consistency). Both predictions were borne out in one area, but neither in the other. Many workers suggest that niche‐based assembly rules will be stronger in undisturbed communities. However, there was only weak evidence of constancy in species richness. Local species assemblages tended to contain a relatively constant representation from different morphological/taxonomic guilds (guild proportionality) and this was significant in some tests, but contrary to theory this effect occurred mainly in the most disturbed sites. It is concluded that there is only limited truth in the frequent assumption that community structure is stronger in undisturbed, equilibrium communities

Predictive Value of Pharmacokinetics-Adjusted Phenotypic Susceptibility on Response to Ritonavir-Enhanced Protease Inhibitors (PIs) in Human Immunodeficiency Virus-Infected Subjects Failing Prior PI Therapy

The activities of protease inhibitors in vivo may depend on plasma concentrations and viral susceptibility. This nonrandomized, open-label study evaluated the relationship of the inhibitory quotient (IQ [the ratio of drug exposure to viral phenotypic susceptibility]) to the human immunodeficiency virus type 1 (HIV-1) viral load (VL) change for ritonavir-enhanced protease inhibitors (PIs). Subjects on PI-based regimens replaced their PIs with ritonavir-enhanced indinavir (IDV/r) 800/200 mg, fosamprenavir (FPV/r) 700/100 mg, or lopinavir (LPV/r) 400/200 mg twice daily. Pharmacokinetics were assessed at day 14; follow-up lasted 24 weeks. Associations between IQ and VL changes were examined. Fifty-three subjects enrolled, 12 on IDV/r, 33 on FPV/r, and 8 on LPV/r. Median changes (n-fold) (FC) of 50% inhibitory concentrations (IC(50)s) to the study PI were high. Median 2-week VL changes were −0.7, −0.1, and −1.0 log(10) for IDV/r, FPV/r, and LPV/r. With FPV/r, correlations between the IQ and the 2-week change in VL were significant (Spearman's r range, −0.39 to −0.50; P ≤ 0.029). The strongest correlation with response to FPV/r was the IC(50) FC (r = 0.57; P = 0.001), which improved when only adherent subjects were included (r = 0.68; P = 0.001). In multivariable analyses of the FPV/r arm that included FC, one measure of the drug concentration, corresponding IQ, baseline VL, and CD4, the FC to FPV was the only significant predictor of VL decline (P < 0.001). In exploratory analyses of all arms, the area under the concentration-time curve IQ was correlated with the week 2 VL change (r = −0.72; P < 0.001). In conclusion, in PI-experienced subjects with highly resistant HIV-1, short-term VL responses to RTV-enhanced FPV/r correlated best with baseline susceptibility. The IQ improved correlation in analyses of all arms where a greater range of virologic responses was observed

A test of community reassembly using the exotic communities of New Zealand roadsides in comparison to British roadsides

1 Competing theories of community assembly are very difficult to test. Four main theories exist. The Stochastic theory sees species assembly as being random. The Humpty Dumpty/Alternative Stable States (ASS) theory suggests that a community may be unable to reassemble itself from its constituent species. The Deterministic theory suggests there will be convergence to one stable state. The Pre-adaptation theory is similar to the Deterministic theory but emphasizes that many species fit the stable state because of characters acquired elsewhere. 2 The reassembly of a flora into new communities in a different country, or its assimilation as a major component of such communities, offers a means to test these theories. The invasion of British plant species into New Zealand, and their reassembly into roadside communities there, is a good example of such a natural experiment. 3 Plant communities of NZ roadsides were compared to the communities of the British National Vegetation Classification (NVC). British roadside communities were also compared to the NVC as a control. New Zealand roadside communities provided a fit to the NVC communities of only 54.7% on average. After excluding species that are not present in NZ, and therefore could not possibly reassemble, the fit increased to 61.1%. British roadsides gave a 65.8% fit. The NZ figures are similar to the fit obtained with random data (58.7%), indicating that the NZ communities bear little relation to the ones formed by the same species in Britain. 4 Similarity between roadside communities in NZ and Britain was low, forming two almost distinct sets of communities. 5 Some of the predictions of the Stochastic, Humpty Dumpty/ASS and Deterministic models are borne out, but others are not. It is concluded that British species have reassembled into communities in NZ most of which are new, i.e. distinct from those that occur in the native range of the species in Britain. The evidence points to a process of community assembly by pre-adaptation