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The enhanced-sensitivity Trofile assay (TF-ES; Monogram Biosciences) was used to retest coreceptor tropism samples from 4 different cohorts of HIV-1-infected patients. Nine percent to 26% of patients with CCR5-tropic virus by the original Trofile assay had CXCR4-using virus by TF-ES. Lower CD4 cell counts were associated with CXCR4-using virus in all cohorts., (© The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.)

Background: The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection., Methods: Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed., Results: The once-daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria. In the primary 48-week analysis (n = 721), maraviroc was noninferior for <400 copies/mL (70.6% for maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%) at a threshold of -10%. More maraviroc patients discontinued for lack of efficacy (11.9% vs 4.2%), but fewer discontinued for adverse events (4.2% vs 13.6%). In a post hoc reanalysis excluding 107 patients (15%) with non-R5 screening virus by the current, more sensitive tropism assay, the lower bound of the 1-sided 97.5% confidence interval for the difference between treatment groups was above -10% for each end point., Conclusions: Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. ClinicalTrials.gov identifier: (NCT00098293) .

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.

When fully suppressive regimens are not available, incompletely suppressive regimens also provide immunologic benefits. In this study, with stable background therapy, human immunodeficiency virus (HIV)-infected patients who were randomized to receive atazanavir or boosted atazanavir, compared with those who continued boosted protease inhibitor therapy, maintained similar virologic and immunologic control, resistance-mutation patterns, and replication capacities with reduced use of lipid-lowering medication.

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.

Background: Rapid progression to AIDS after acute infection with a multidrug-resistant (MDR), dual-tropic strain of human immunodeficiency virus type 1 (HIV-1) was reported in a New York City man (hereafter referred to as "NYC") who has sex with men. The probable source of this HIV-1 (hereafter referred to as "CT01") and the development of a recombinant MDR HIV-1 in the source's partner (hereafter referred to as "CT02") are described., Methods: After identification of the epidemiological link of CT01 and CT02 to NYC, viral sequences and phenotypic analyses were compared. Confirmatory genotypic and phenotypic analyses, replicative capacity, and viral coreceptor use were assessed. Viral recombination was assessed using a sliding window technique and phylogenetic tree analysis., Results: NYC and CT01 were linked historically and epidemiologically and were genetically confirmed from CT01's samples acquired 2 days before and subsequent to the transmission event. Genotypic, recombination, and phylogenetic analyses suggest CT02 became superinfected by CT01 with subsequent production of a recombinant panresistant HIV-1., Conclusion: The probable source of a dual-tropic, MDR HIV-1 that was associated with rapid progression to AIDS is illustrated, suggesting progression was not explained by the HIV-1 variant alone. A probable second finding of a chronically infected host becoming superinfected with MDR HIV-1 with subsequent formation of a panresistant recombinant HIV-1 is described. This case illustrates the public health implications of unsafe sex between serodiscordant and seroconcordant partners.

Background: Chemokine coreceptor use impacts both the natural history of human immunodeficiency virus type 1 (HIV-1) disease and the potential use of a new class of antiretroviral agents, the CCR5 inhibitors., Methods: We analyzed HIV-infected patients who were screened for participation in Acquired Immunodeficiency Syndrome (AIDS) Clinical Trial Group protocol A5211, a phase 2b study of the investigational CCR5 inhibitor vicriviroc involving antiretroviral-experienced subjects. Screening CD4(+) cell count, HIV-1 plasma RNA level, HIV-1 genotype, and chemokine coreceptor use phenotype were determined. The univariate and multivariate association of subject characteristics with coreceptor use was assessed by logistic regression., Results: Coreceptor use was determined for 391 subjects: 197 (50%) had virus that used the CCR5 coreceptor (the R5 group), 178 [corrected] (46%) had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4 coreceptors (the D/M group), and 16 (4%) had virus that used the CXCR4 coreceptor (the X4 group). The D/M group had a significantly lower median CD4(+) cell count than the R5 virus group (103 cells/ micro L vs. 170 cells/ mu L; P<.001). No other characteristics were independently associated. Among 118 subjects who entered A5211 having R5 virus, 12 (10%) had D/M virus according to the results of a second coreceptor test conducted prior to starting treatment with the study drug., Conclusions: Infection with dual-tropic or mixed HIV-1 populations that use both CCR5 and CXCR4 is common among highly treatment-experienced patients, but infection with virus using CXCR4 alone is uncommon. Subjects in the D/M group had significantly lower CD4(+) cell counts than subjects in the R5 group. Evaluating coreceptor use will be important in the clinical development of CCR5 and CXCR4 inhibitors.

Background: Many treatment-experienced, HIV-infected patients who have limited therapeutic options for complete viral suppression continue to receive a partially suppressive treatment regimen pending the availability of at least 2 new antiretroviral drugs. The major risk of this approach is ongoing viral evolution and the loss of future drug options., Methods: Antiretroviral-treated subjects with incomplete viral suppression were sampled from a clinic-based cohort. Inclusion criteria were receipt of a stable treatment regimen for > or = 120 days, a plasma HIV RNA load of > 500 copies/mL, and > or = 1 resistance mutation. Phenotypic and genotypic resistance testing was performed every 4 months., Results: The 106 patients who were eligible for the study had a median of 3 observations during a median of 11.3 months. An estimated 23% and 18% developed at least 1 new nucleoside analogue and 1 new protease inhibitor mutation at 1 year, respectively. An estimated 30% lost the phenotypic equivalent of 1 susceptible drug at 1 year. A lower number of total mutations at baseline was a significant predictor of developing a new nucleoside analogue mutation (P=.01). At 1 year, the probability that an existing mutation would become undetectable using population-based sequencing was 32%. There was a higher rate of change at nonresistance codons than at codons known to be associated with drug resistance., Conclusions: Heavily pretreated patients with HIV infection who remain on a partially suppressive regimen have a measurable risk of losing future drug options, particularly those patients who have few baseline mutations. Resistance mutations vary over time, which suggests that the results of any single resistance test may not be representative of all mutations selected by a given treatment regimen.

We describe five cases of parasitic sinusitis and otitis in patients infected with human immunodeficiency virus (HIV) and review 14 reported cases. The pathogens identified in our group of patients included agents such as Microsporidium, Cryptosporidium, and Acanthamoeba species. The clinical features common to these patients included a long history of HIV seropositivity associated with advanced immunosuppression and multiple opportunistic infections as well as long-standing local symptoms refractory to multiple courses of antibacterial agents. Symptoms often included fever and chills in addition to local tenderness and discharge. Invasive diagnostic procedures were necessary to obtain the final diagnosis and to initiate appropriate therapy. Although most patients responded at least partially to specific therapy, relapses and recurrences were frequent in patients who did not receive long-term suppressive therapy. The general outcome for HIV-infected patients with parasitic sinusitis and otitis was poor; however, deaths were generally associated with other complications of the underlying HIV infection.