Trend of drug-resistant HIV type 1 emergence among therapy-naive patients in Nagoya, Japan: an 8-year surveillance from 1999 to 2006.

We studied the emergence of drug-resistant human immunodeficiency virus type 1 (HIV-1) with major amino acid mutations in 402 therapy-naive patients at Nagoya Medical Center, Japan, between 1999 and 2006. The mean prevalence of drug-resistant HIV-1 was 6.7% (range, 2.3-10.0%; n = 27). HIV-1 variants with protease inhibitor (PI)-resistant mutations alone were most frequently found (3.5%, n = 14), followed by those with nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutations alone (1.7%, n = 7). Variants with nucleoside reverse transcriptase inhibitor (NRTI)-resistant mutations alone were sporadically found (1.0%, n = 4). A variant possessing both NRTI- and PI-resistant mutations was detected in one patient (0.2%) and a variant possessing both NNRTI- and PI-resistant mutations was identified in another patient (0.2%). In addition, another 17 variants (4.2%, n = 17) with only 215-revertant mutations (T215C/D/G/L/S) that can easily reconvert to the nucleoside analogue-associated mutation of T215Y/F were found. The 402 viruses were phylogenetically analyzed, revealing three independent clusters comprising PI-resistant variants with the M46I or L90M mutation, NNRTI-resistant variants with the K103N mutation, and 215-revertant variants. The PI-resistant and 215-revertant strains have been spreading since 2000, and the NNRTI-resistant strain has started spreading since 2003. The nature of the epidemic and information for successfully blocking the spread of drug-resistant HIV-1 were clarified in this study.

[Clinical features and course of 5 cases with HIV encephalopathy].

Clinical features and courses of 5 cases with HIV encephalopathy were reported. The subjects were among the patients registered as HIV patients at the Nagoya Medical Center, between 1996 and 2005. There were 458 patients with HIV infection including 127 cases of AIDS. All patients suffered from severe immunological deficiency when HIV encephalopathy developed. Other opportunistic infections had also occurred in three patients. HIV encephalopathy was one of the presenting manifestations of HIV infection in four patients, and no patients had received antiretroviral therapy. HAART improved motor disturbance and their ADL became independent except for one case. Improvements in neuropsychological examination scores were noted in all cases. Recovery from psychiatric symptoms, however, was incomplete. Four patients could not work, and 3 needed psychological treatment due to behavioral abnormalities. HIV encephalopathy is not a lethal disease but the functional prognosis was very poor. New therapy is needed for HIV encephalopathy.

No observable correlation between central nervous system side effects and EFV plasma concentrations in Japanese HIV type 1-infected patients treated with EFV containing HAART.

The present study assessed the relationship between central nervous system (CNS) side effects and plasma concentrations of efavirenz (EFV) in Japanese HIV-1-infected patients. Subjects consisted of 69 HIV-1-infected patients (57 therapy-naive and 12 therapy-experienced patients) being treated using EFV in combination with other antiretroviral agents at the outpatient HIV clinic. Successful virological treatment was achieved in 61 patients. Eight patients discontinued EFV containing therapy because CNS symptoms did not resolve (four patients), EFV-specific mutations were detected (two patients), or skin rash was observed (two patients). Mean EFV plasma concentration for 61 effectively treated patients, measured at 15 h postdosing, was 2.42 microg/ml (range: 0.78-6.82 microg/ml). This EFV concentration range contributed to suppressed viral load in these Japanese patients. Adverse CNS effects were observed in 19 patients soon after therapy onset. These effects disappeared within 1 month except for four patients who suffered severe CNS side effects. Mean EFV plasma concentrations were not significantly different between subjects with (2.45 +/- 1.08 microg/ml) and without (2.42 +/- 1.40 microg/ml) CNS side effects. We concluded no correlation existed between the plasma EFV concentration and the emergence of CNS side effects in Japanese HIV-1-infected patients. Further investigations, enforced with the drug concentration measurement at earlier time points and more appropriate assessment of CNS symptoms, are required.

HIV-2 CRF01_AB: first circulating recombinant form of HIV-2.

BACKGROUND: Five HIV-2-seropositive cases were recently identified in Japan, outside the HIV-2 endemic area of West Africa. To clarify the molecular epidemiology of HIV-2 in Japan, we analyzed sequences of these cases in detail. METHODS: HIV-2 genetic groups were determined by gag and env sequences. For suspected recombinant isolates, the genetic structure was determined by full-length genomic analyses. To understand the history and evolution of HIV-2 recombinant isolates, we estimated the time of most recent common ancestor by Bayesian Markov chain Monte Carlo method. RESULTS: Three isolates were determined as recombinants of groups A and B, and their mosaic genome structures were identical with that of 7312A, a recombinant isolate reported in 1990 from Côte d'Ivoire. Our 3 isolates and 7312A fulfilled the criteria for determining a circulating recombinant form (CRF). These isolates were verified by the Los Alamos HIV sequence database as the first CRF of HIV-2, HIV-2 CRF01_AB. The mean time of most recent common ancestor of CRF01_AB was estimated as between 1964 and 1973, several decades after the estimated emergence of HIV-2. CONCLUSIONS: We recently identified HIV-2 CRF01_AB cases in Japan. This ectopic observation of the virus outside its original endemic area suggests an ongoing global spread of HIV-2 CRF01_AB.

An 11-Year Surveillance of HIV Type 1 Subtypes in Nagoya, Japan.

Abstract To monitor active HIV-1 transmission in Nagoya, Japan, we have been determining the subtypes of HIV-1 infecting therapy-naive individuals who have newly visited the Nagoya Medical Center since 1997. The subtypes were determined by phylogenetic analyses using the base sequences in three regions of the HIV-1 genes including gag p17, pol protease (PR) and reverse transcriptase (RT), and env C2V3. Almost all HIV-1 subtypes from 1997 to 2007 and 93% of all HIV-1 isolates in 2007 were subtype B. HIV-1 subtypes A, C, D, and F have been detected sporadically since 1997, almost all in Africans and South Americans. The first detected circulating recombinant form (CRF ) was CRF01_AE (11-year average annual detection rate, 7.7%). Only two cases of CRF02_AG were detected in 2006. A unique recombinant form (URF ) was first detected in 1998 and the total number of URFs reached 25 by year 2007 (average annual detection rate, 4.7%). Eleven of these 25 were detected from 2000 to 2005 and had subtypes AE/B/AE as determined by base sequencing of the gag p17, pol PR and RT, and env C2V3 genes (average annual detection rate, 3.7%). Unique subtype B has been detected in six cases since 2006. All 17 of these patients were Japanese. Other recombinant HIV-1s have been detected intermittently in eight cases since 1998. During the 11-year surveillance, most HIV-1s in Nagoya, Japan were of subtype B. We expect that subtype B HIV-1 will continue to predominate for the next several years. Active recombination between subtype B and CRF01_AE HIV-1 and its transmission were also shown.

Analysis of near full-length genomic sequences of drug-resistant HIV-1 spreading among therapy-naïve individuals in Nagoya, Japan: amino acid mutations associated with viral replication activity.

We analyzed a total of 12 near full-length genomes of drug-resistant HIV-1 spreading among therapy-naïve individuals in Nagoya, Japan. Genomes comprised seven protease inhibitor (PI)-resistant viruses possessing an M46I (n = 6) or L90M mutation (n = 1) and five non-nucleoside reverse transcriptase inhibitor-resistant viruses possessing a K103N mutation. All 12 viruses conserved both an H87Q mutation in the cyclophilin A-binding site of Gag p24 (capsid) and a T23N mutation in the cysteine-rich domain of Tat protein. PI-resistant viruses commonly possessed two cleavage site mutations in the p6(Pol)/protease of Pol polyprotein (F48L in p6(Pol)) and the anchor/core domains of Nef protein (L57V). These amino acid mutations represent candidates for enhancing replication activity of drug-resistant viruses and supporting expansion of such viruses in therapy-naïve individuals.

Prevalence of drug-resistant human immunodeficiency virus type 1 in therapy-naive patients and usefulness of genotype testing.

In the present study, we performed genotypic drug-resistance testing in 116 therapy-naive human immunodeficiency virus type 1 (HIV-1)-infected patients between 1999 and 2002 at Nagoya National Hospital, Japan. The prevalence of drug-resistant HIV-1 with one or more major mutations significantly increased from 5.3% (4/75) in 1999-2001 to 17.1% (7/41) in 2002 (P=0.05), suggesting the spread of drug-resistant HIV-1. We identified a patient who possessed a protease (PR) inhibitor-resistant HIV-1 with a major mutation consisting of L90M before the initiation of therapy. The patient was administered zidovudine, lamivudine, and efavirenz as highly active antiretroviral therapy (HAART), as PR inhibitors were excluded based on the result of the drug-resistance testing. The treatment succeeded in strongly suppressing the proliferation of drug-resistant HIV-1 and concomitantly increased CD4 cell counts. Thus, we conclude that drug-resistance testing prior to the initiation of therapy is important for therapy-naive patients to devise the optimum therapy regimen for each individual.

Pharmacokinetics of lopinavir after administration of Kaletra in healthy Japanese volunteers.

The pharmacokinetic parameters of lopinavir (LPV) were examined by administering Kaletra (LPV+ritonavir) to 8 healthy Japanese volunteers both in the fasting and postprandial conditions. LPV showed a biphasic decline, which was slower in the initial phase and became more rapid in the later phase. The behavior of LPV in the initial phase could be modeled using a one-compartment model with first-order absorption. In the fasting study, calculations based on the pharmacokinetic model revealed that the time to reach the maximum concentration (T(max)), maximum concentration (C(max)), half-life (T(1/2)), lag time, apparent volume of distribution (Vd/F) and oral clearance (Cl/F) were 3.2+/-1.0 h, 6.9+/-1.9 microg/ml, 10.0+/-3.7 h, 0.71+/-0.32 h, 51.0+/-12.4 l and 4.2+/-2.6 l/h, respectively. On the other hand, in the postprandial study, the calculated T(max), C(max), T(1/2), lag time, Vd/F and Cl/F were 5.6+/-2.0 h, 7.6+/-1.8 microg/ml, 16.7+/-7.0 h, 2.35+/-0.78 h, 48.0+/-15.9 l and 2.1+/-0.6 l/h, respectively. The values for the area under the curve for data collected over a 24-h period (AUC(24 h)) in the fasting and postprandial studies were 86.0+/-27.7 and 102.1+/-31.0 microg.h/ml, respectively. The T(1/2) had a tendency to be prolonged after food intake, but there were 2 cases with shortened T(1/2). Food intake prolonged the lag time 3-fold and as a result, the postprandial T(max) was 2 times longer.