Background. Efavirenz (EFV) is metabolized primarily by cytochrome P450 2B6 (CYP2B6), and high plasma concentrations of the drug are associated with a GrT polymorphism at position 516 (516GrT) of CYP2B6 and frequent central nervous system (CNS)-related side effects. Here, we tested the feasibility of genotype-based dose reduction of EFV.Methods. CYP2B6 genotypes were determined in 456 human immunodeficiency virus type 1 (HIV-1)-infected patients who were receiving EFV treatment or were scheduled to receive EFV-containing treatment. EFV dose was reduced in CYP2B6 516GrT carriers who had high plasma EFV concentrations while receiving the standard dosage (600 mg). EFV-naive homozygous CYP2B6 516GrT carriers were treated with low-dose EFV. In both groups, the dose was further reduced when plasma EFV concentration remained high.

This is the first study of our knowledge to identify the association between SNPs in ABCC2 and tenofovir-induced KTD in an Asian population. Close monitoring of renal function is warranted in tenofovir-treated patients with these SNPs.

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LAM- and TDF-containing ART regimens seem to provide prophylaxis against HBV infection, although drug-resistant strains seem to evade these effects.

The IgG-capture BED-enzyme immunoassay (BED-CEIA) is used widely at present to detect recent HIV-1 seroconversion. However, antibody levels and antibody kinetics are impacted by HIV-1 load and antiretroviral treatment, which may have a significant effect on the assay results. In this study, we analyzed serial samples from 11 patients with recent infection, including four patients treated by structured treatment interruption (STI), and compared the results with those of 10 untreated and 7 treated patients with chronic infection. The BED-CEIA missidentified one long-term nonprogressor hemophiliac with an extremely low HIV-1 load and five patients with chronic infection who received antiretroviral treatment. We also found that the ODn values increased slowly in patients with recent infection and low HIV-1 loads and that the ODn values fluctuated in parallel with HIV-1 load during STI. Our data indicate that the results of BED-CEIA are influenced by HIV-1 load and antiretroviral treatment. Care should be taken when interpreting the results of BED-CEIA, especially in individuals with low HIV-1 loads. Those on antiretroviral treatment should be excluded from BED-CEIA testing to improve the predictive value of detecting recent infections.

Background: Acute hepatitis C virus (HCV) infection is increasing among HIV-1–infected individuals in Tokyo. Appropriate clinical management is needed. Setting: To delineate the epidemiological status of HCV transmission, we analyzed stocked plasma samples of HCV/HIV-1–coinfected patients seen at the largest referral center for HIV care in Tokyo. Methods: HCV full-genome sequences were amplified and determined using next-generation sequencing. HCV genotyping and phylogenetic and phylodynamic analyses of thus obtained sequences were performed and combined with the analysis of HIV-1 reverse transcriptase sequences. Results: HCV phylogenetic analysis identified 3 dense clusters containing cases of men who have sex with men (MSM) and injection drug users (IDUs). Most of the confirmed acute infection cases were included within these clusters, indicating that the clustered viruses are currently being actively transmitted among HIV-1–infected MSM and IDU. Phylodynamic analysis indicated population expansion of one of these clusters from 2006 to 2008, during which the largest number of HIV-1–infected MSM was diagnosed in Tokyo. HIV-1 reverse transcriptase sequences of HCV-coinfected patients included in the same clusters did not converge together and did not form clusters, but rather diverged in the area of subtype B in the phylogenetic tree, indicating that they acquired HCV infection from individuals different from those from whom they had acquired HIV-1 infection. It is considered that these MSM changed their sexual partners and that IDU changed their drug use groups. Conclusions: The results warrant careful monitoring of high-risk groups including MSM and IDU and early introduction of HCV treatment to prevent HCV epidemic.

The third variable region (V3) of HIV-1 envelope glycoprotein gp120 plays a key role in determination of viral coreceptor usage (tropism). However, which combinations of mutations in V3 confer a tropism shift is still unclear. A unique pattern of mutations in antiretroviral therapy-naive HIV-1 patient was observed associated with the HIV-1 tropism shift CCR5 to CXCR4. The insertion of arginine at position 11 and the loss of the N-linked glycosylation site were indispensable for acquiring pure CXCR4-tropism, which were confirmed by cell-cell fusion assay and phenotype analysis of recombinant HIV-1 variants. The same pattern of mutations in V3 and the associated tropism shift were identified in two of 53 other patients (3.8%) with CD4+ cell count <200/mm3. The combination of arginine insertion and loss of N-linked glycosylation site usually confers CXCR4-tropism. Awareness of this rule will help to confirm the tropism prediction from V3 sequences by conventional rules.

Etravirine (ETV) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI)introduced recently for salvage antiretroviral treatment after the emergence of NNRTI-resistant human immunodeficiency virus type 1 (HIV-1). Following its introduction, two naturally occurring mutations in HIV-1 RT, V106I and V179D, were listed as ETV resistance-associated mutations. However, the effect of these mutations on the development of NNRTI resistance has not been analyzed yet. To select highly NNRTIresistant HIV-1 in vitro, monoclonal HIV-1 strains harboring V106I and V179D (HIV-1 V106I and HIV-1 V179D ) were propagated in the presence of increasing concentrations of efavirenz (EFV). Interestingly, V179D emerged in one of three selection experiments from HIV-1 V106I and V106I emerged in two of three experiments from HIV-1 V179D . Analysis of recombinant HIV-1 clones showed that the combination of V106I and V179D conferred significant resistance to EFV and nevirapine (NVP) but not to ETV. Structural analysis indicated that ETV can overcome the repulsive interactions caused by the combination of V106I and V179D through fine-tuning of its binding module to RT facilitated by its plastic structure, whereas EFV and NVP cannot because of their rigid structures. Analysis of clinical isolates showed comparable drug susceptibilities, and the same combination of mutations was found in some database patients who experienced virologic NNRTI-based treatment failure. The combination of V106I and V179D is a newly identified NNRTI resistance pattern of mutations. The combination of polymorphic and minor resistance-associated mutations should be interpreted carefully.