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This study offers a framework by which patients can be switched to a maraviroc-containing regimen while maintaining an undetectable viral load. Patients confirmed as having CCR5-tropic HIV according to DNAbased tropism methods had significantly better responses to maraviroc compared to those where CXCR4-using virus was detected in cells.Background. A tropism test is required before administration of the antiretroviral drug maraviroc. However, plasma RNA testing is not possible in patients with undetectable plasma viral loads. Here we assess genotypic testing of cellular human immunodeficiency virus (HIV) DNA from peripheral blood mononuclear cells (PBMCs) to predict virologic responses in treatment-experienced patients beginning maraviroc-containing regimens.Methods. PBMC samples from 181 maraviroc recipients at study entry in MOTIVATE or A4001029 (51% R5 by original Trofile). The V3 loop was amplified in triplicate from cellular HIV DNA, and matching plasma RNA (n = 156). Sequencing was performed using standard population-based methods and next-generation deep sequencing, with tropism assessment as previously defined.Results. Genotypic DNA-based tropism testing from the cellular compartment had 78%–81% sensitivity relative to RNA-based Trofile at the same time point. Cell-based genotypic tropism methods and plasma-based phenotypic and genotypic methods were predictive of virologic response. However, when classifications were discordant, the outcomes favored the plasma predictions over the DNA ones.Conclusions. Genotypic determination of HIV tropism can be performed using cell-derived viral DNA, and is a predictor of virologic success on maraviroc in therapy-experienced patients. However, the PBMC compartment appears to be a suboptimal predictor compared to plasma. [ABSTRACT FROM AUTHOR]

Background. Deep sequencing is a highly sensitive technique that can detect and quantify the proportion of non-R5 human immunodeficiency virus (HIV) variants, including small minorities, that may emerge and cause virologic failure in patients who receive maraviroc-containing regimens. We retrospectively tested the ability of deep sequencing to predict response to a maraviroc-containing regimen in the Maraviroc versus Efavirenz in Treatment- Naive Patients (MERIT) trial. Results were compared with those obtained using the Enhanced Sensitivity Trofile Assay (ESTA), which is widely used in clinical practice. Methods. Screening plasma samples from treatment-naive patients who received maraviroc and efavirenz in the MERIT trial were assessed. Samples were extracted, and the V3 region of HIV type 1 glycoprotein 120 was amplified in triplicate and combined in equal quantities before sequencing on a Roche/454 Genome Sequencer-FLX (n 5859). Tropism was inferred from third variable (V3) sequences, with samples classified as non-R5 if ⩾2% of the viral population scored ⩽3.5 using geno2pheno. Results. Deep sequencing distinguished between responders and nonresponders to maraviroc. Among patients identified as having R5-HIV by deep sequencing, 67% of maraviroc recipients and 69% of efavirenz recipients had a plasma viral load <50 copies/mL at week 48, similar to the ESTA results: 68% and 68%, respectively. Conclusions. Reanalysis of the MERIT trial using deep V3 loop sequencing indicates that, had patients originally been screened using thismethod, themaraviroc arm would have likely been found to be noninferior to the efavirenz arm. [ABSTRACT FROM AUTHOR]

Background. The Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies compared maraviroc versus placebo in treatment-experienced patients with CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1), screened using the original Trofile assay. A subset with non-R5 HIV infection entered the A4001029 trial. We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials. Methods. V3 amplicons were prepared from 1827 screening plasma samples and sequenced on a Roche/454 GS-FLX to a depth of .3000 sequences/sample. Samples were considered non-R5 if ⩾2% of their viral population scored greater than or equal to 24.75 or ⩽3.5 using the PSSMx4/R5 or geno2pheno algorithms, respectively. Results. Deep sequencing identified more than twice as many maraviroc recipients as having non-R5 HIV, compared with the original Trofile. With use of genotyping, we determined that 49% of maraviroc recipients with R5 HIV at screening had a week 48 viral load <50 copies/mL versus 26% of recipients with non-R5. Corresponding percentages were 46% and 23% with screening by Trofile. In cases in which screening assays differed, median week 8 log10 copies/mL viral load decrease favored 454. Other parameters predicted by genotyping included likelihood of changing to non-R5 tropism. Conclusions. This large study establishes deep V3 sequencing as a promising tool for identifying treatment-experienced individuals who could benefit from CCR5-antagonist-containing regimens. [ABSTRACT FROM AUTHOR]

Background: Maraviroc treatment for HIV-1 infected patients results in larger CD4+ T cell rises than are attributable to its antiviral activity alone. We investigated whether this is due to modulation of T cell activation and inflammation. Methods and Findings: Thirty maraviroc-treated patients from the Maraviroc versus Efavirenz Regimens as Initial Therapy (MERIT) study were randomly selected from among those who had CCR5-tropic (R5) HIV on screening and achieved undetectable HIV RNA (<50 copies/mL) by Week 48. Efavirenz-treated controls were matched for baseline characteristics to the maraviroc-treated patients selected for this substudy. Changes in immune activation and inflammation markers were examined for associations with CD4+ T cell changes. Maraviroc treatment tended to result in more rapid decreases in CD38 expression on CD4+ T cells and in plasma D-dimer concentrations than did treatment with efavirenz. The proportion of patients with high-sensitivity C-reactive protein >2 μg/mL increased from 45% to 66% in the efavirenz arm, but remained constant in the maraviroc arm (P = 0.033). Decreases in CD38 expression on CD8+ T cells were correlated with CD4+ T cell rises for maraviroc treatment (r =-0.4, P = 0.048), but not for treatment with efavirenz. Conclusions: Maraviroc-treated patients had earlier, modest decreases in certain markers of immune activation and inflammation, although in this small study, many of the differences were not statistically significant. Levels of highsensitivity C-reactive protein remained constant in the maraviroc arm and increased in the efavirenz arm. Decreases in immune activation correlated with increased CD4+ T cell gains. [ABSTRACT FROM AUTHOR]

Abstract: Immune reconstitution after HAART is incomplete, but no widely accepted method to quantify subclinical immune deficiency is available. We immunized 9 HIV-negative subjects and 29 HIV-infected patients with CD4≥450 cells/µL and undetectable HIV RNA levels with 2 doses of diphtheria/tetanus toxoid (TT) and KLH, a presumed neoantigen. We quantified the response by lymphoproliferative assay, delayed-type hypersensitivity (DTH), and antibody titers up to 59days after enrollment. We assessed T cell proliferative capacity using anti-Vβ3 and anti-Vβ5 antibody stimulation, which we herein show induced predominant proliferation of naïve T cells. Subjects with detectable responses to KLH tended to exhibit greater proliferative responses to anti-Vβ3/Vβ5 stimulation; no such pattern was seen with response to TT. Several measures of in vitro T cell proliferative capacity correlated significantly with DTH and antibody responses to KLH, but not with TT responses; this association was independent of naïve T cell numbers. Our results indicate that naïve T cell proliferation predicts response to neo-, but not recall antigens, and suggest that it may be a meaningful reflection of in vivo immune competence in HIV-infected persons. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration has issued a warning that tipranavir may be associated with increased risk of intracranial hemorrhage. We studied 2 large cohorts to estimate the background rate of intracranial hemorrhage and compared it with rates reported among persons who had been exposed to tipranavir. [ABSTRACT FROM AUTHOR]

To ascertain whether CD4[sup +] lymphocyte increases induced by interleukin (IL)-2 enhanced in vivo immune responses, 38 human immunodeficiency virus (HIV)-infected patients who had received highly active antiretroviral therapy (HAART) or HAART and IL-2 for at least 60 weeks were immunized with tetanus toxoid, inactivated glycoprotein 120-depleted HIV-1, and hepatitis A and B vaccines. Despite dramatic increases in CD4[sup +] lymphocyte counts, IL-2 did not enhance immunization responses. [ABSTRACT FROM AUTHOR]

Compares the rate of Mycobacterium avium complex infection in patients with increased CD4[sup+] cell counts who receive azithromycin and placebo. Involvement of HIV infected patients with low cell count; Measurement of Mycobacterium cultures, CD4[sup+] cell count and clinical evaluations; Localization of the Mycobacterium avium to the vertebral spine; Safety of withdrawal of prophylaxis against M. avium complex.

A correction for the article "Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate‑to‑Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program" by October 13, 2021, which was published in the previous issue of the periodical.

A correction to the article "Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adult with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes" in an issue is presented.