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1.  AIDS: The Final Chapter? 
doi:10.1089/aid.2013.1503
PMCID: PMC3887424  PMID: 24392796
2.  Designing Preclinical Perceptibility Measures to Evaluate Topical Vaginal Gel Formulations: Relating User Sensory Perceptions and Experiences to Formulation Properties 
Abstract
The effectiveness of any biomedical prevention technology relies on both biological efficacy and behavioral adherence. Microbicide trials have been hampered by low adherence, limiting the ability to draw meaningful conclusions about product effectiveness. Central to this problem may be an inadequate conceptualization of how product properties themselves impact user experience and adherence. Our goal is to expand the current microbicide development framework to include product “perceptibility,” the objective measurement of user sensory perceptions (i.e., sensations) and experiences of formulation performance during use. For vaginal gels, a set of biophysical properties, including rheological properties and measures of spreading and retention, may critically impact user experiences. Project LINK sought to characterize the user experience in this regard, and to validate measures of user sensory perceptions and experiences (USPEs) using four prototype topical vaginal gel formulations designed for pericoital use. Perceptibility scales captured a range of USPEs during the product application process (five scales), ambulation after product insertion (six scales), and during sexual activity (eight scales). Comparative statistical analyses provided empirical support for hypothesized relationships between gel properties, spreading performance, and the user experience. Project LINK provides preliminary evidence for the utility of evaluating USPEs, introducing a paradigm shift in the field of microbicide formulation design. We propose that these user sensory perceptions and experiences initiate cognitive processes in users resulting in product choice and willingness-to-use. By understanding the impact of USPEs on that process, formulation development can optimize both drug delivery and adherence.
doi:10.1089/aid.2013.0099
PMCID: PMC3931431  PMID: 24180360
3.  Use of Principal Components Analysis and Protein Microarray to Explore the Association of HIV-1-Specific IgG Responses with Disease Progression 
Abstract
The role of HIV-1-specific antibody responses in HIV disease progression is complex and would benefit from analysis techniques that examine clusterings of responses. Protein microarray platforms facilitate the simultaneous evaluation of numerous protein-specific antibody responses, though excessive data are cumbersome in analyses. Principal components analysis (PCA) reduces data dimensionality by generating fewer composite variables that maximally account for variance in a dataset. To identify clusters of antibody responses involved in disease control, we investigated the association of HIV-1-specific antibody responses by protein microarray, and assessed their association with disease progression using PCA in a nested cohort design. Associations observed among collections of antibody responses paralleled protein-specific responses. At baseline, greater antibody responses to the transmembrane glycoprotein (TM) and reverse transcriptase (RT) were associated with higher viral loads, while responses to the surface glycoprotein (SU), capsid (CA), matrix (MA), and integrase (IN) proteins were associated with lower viral loads. Over 12 months greater antibody responses were associated with smaller decreases in CD4 count (CA, MA, IN), and reduced likelihood of disease progression (CA, IN). PCA and protein microarray analyses highlighted a collection of HIV-specific antibody responses that together were associated with reduced disease progression, and may not have been identified by examining individual antibody responses. This technique may be useful to explore multifaceted host–disease interactions, such as HIV coinfections.
doi:10.1089/aid.2013.0088
PMCID: PMC3931433  PMID: 24134221
4.  Short Communication: Late Refills During the First Year of Antiretroviral Therapy Predict Mortality and Program Failure Among HIV-Infected Adults in Urban Zambia 
Abstract
We evaluated the association of the number of late antiretroviral therapy (ART) refills with patient outcomes in a large public-sector human immunodeficiency virus treatment program in Lusaka, Zambia. Using pharmacy data routinely collected during 2004–2010, we calculated the number of late refills during the initial year of ART. We used multivariable Cox proportional hazard regression to examine the association between the number of late refills and death or program failure (i.e., death, loss to follow-up, or program withdrawal) >12 months after ART initiation, with and without stratification by the medication possession ratio (MPR) during the initial year of ART. Of 53,015 adults who received ART for ≥12 months (median follow-up duration, 86.1 months; interquartile range, 53.2–128.2 months), 26,847 (50.6%) had 0 late refills, 16,762 (31.6%) had 1, 6,505 (12.3%) had 2, and 2,901 (5.5%) had ≥3. Kaplan–Meier analysis revealed that ≥3 late refills was associated with a greater mortality risk than 1 and 2 late refills (p<0.001, by the log-rank test). The mortality risk was greater for patients with 2 late refills [adjusted hazard ratio (HR), 1.17; 95% confidence interval (CI), 0.99–1.38] or ≥3 late refills (adjusted HR, 1.51; 95% CI, 1.23–1.87), compared with that for patients with 0–1 late refills. Program failure was associated with ≥2 late refills. An MPR of <80% was associated with similar increases in mortality risk across late-refill strata. Monitoring late refills during the initial period of ART may help resource- and time-constrained clinics identify patients at risk for program failure.
doi:10.1089/aid.2013.0167
PMCID: PMC3887398  PMID: 23924188
5.  Inability to Detect Human T Cell Lymphotropic Virus Type 2-Specific Antibodies in a Patient Coinfected with HIV-1, Human T Cell Lymphotropic Virus Type 1, Human T Cell Lymphotropic Virus Type 2, and Hepatitis C Virus 
Abstract
HIV-1, human T cell lymphotropic virus type 1 and type 2 (HTLV-1 and HTLV-2) and hepatitis C virus (HCV) are common among intravenous drug users (IDUs) and can cause chronic infections in the host. Usually, the diagnosis of such viruses employs serological assays; however, some difficulties in confirming HTLV-2 infection have been reported in high-risk populations in Brazil. We present data of an unusual case of coinfection with HIV-1, HTLV-1, HTLV-2, and HCV in a male IDU in which HTLV-2 was detected only by molecular assays. Comparative analysis of retroviruses from 2002 and 2012 showed identical HTLV-1 and HTLV-2 sequences (LTR, env, and tax), and a change in HIV-1 tropism from CXCR4 to CCR5. No mutation was detected in the hot points of the env region of the HTLV-2 isolate that justified the lack of rgp46-II-specific antibodies. These data emphasize the need for molecular assays to diagnose HTLV-2 in high-risk populations in Brazil.
doi:10.1089/aid.2013.0158
PMCID: PMC3887399  PMID: 23875602
6.  Short Communication: A Low-Cost Method for Analyzing Nevirapine Levels in Hair as a Marker of Adherence in Resource-Limited Settings 
Abstract
The measurement of antiretroviral concentrations in hair is emerging as an important technology to objectively quantify adherence to combination antiretroviral therapy. Hair levels of antiretrovirals are the strongest independent predictor of virologic success in large prospective cohorts of HIV-infected patients and surpass self-report in predicting outcomes. Hair is easy to collect and store, but validated methods to analyze antiretroviral levels in hair using liquid chromatography tandem mass spectrometry (LC-MS/MS) are expensive. We report here on the development of a thin-layer chromatography (TLC) assay for the semiquantitative analysis of nevirapine in hair. TLC assay results from 11 samples were consistent with results using LC-MS/MS [Spearman correlation coefficient 0.99 (95% CI 0.95–0.996)]. This simple, low-cost method of analyzing nevirapine concentrations in hair may provide a novel monitoring tool for antiretroviral adherence in resource-limited settings and merits further study in clinical settings.
doi:10.1089/aid.2013.0239
PMCID: PMC3887402  PMID: 24164410
7.  Genotypic and Phenotypic Heterogeneity in the U3R Region of HIV Type 1 Subtype C 
Abstract
Approximately 20% of all HIV-1 mother-to-child transmission (MTCT) occurs in utero (IU). In a chronic HIV infection, HIV-1 exists as a complex swarm of genetic variants, and following IU MTCT, viral genomic diversity is restricted through a mechanism that remains to be described. The 5′ U3R region of the HIV-1 long terminal repeat (LTR) contains multiple transcription factor (TF) binding sites and regulates viral transcription. In this study, we tested the hypothesis that sequence polymorphisms in the U3R region of LTR are associated with IU MTCT. To this end, we used single template amplification to isolate 517 U3R sequences from maternal, placental, and infant plasma derived from 17 HIV-infected Malawian women: eight whose infants remained HIV uninfected (NT) and nine whose infants became HIV infected IU. U3R sequences show pairwise diversities ranging from 0.2% to 2.3%. U3R sequences from one participant contained two, three, or four putative NF-κB binding sites. Phylogenetic reconstructions indicated that U3R sequences from eight of nine IU participants were consistent with placental compartmentalization of HIV-1 while only one of eight NT cases was consistent with such compartmentalization. Specific TF sequence polymorphisms were not significantly associated with IU MTCT. To determine if replication efficiency of the U3R sequences was associated with IU MTCT, we cloned 90 U3R sequences and assayed promoter activity in multiple cell lines. Although we observed significant, yet highly variable promoter activity and TAT induction of promoter activity in the cell lines tested, there was no association between measured promoter activity and MTCT status. Thus, we were unable to detect a promoter genotype or phenotype associated with IU MTCT.
doi:10.1089/aid.2013.0026
PMCID: PMC3887403  PMID: 23826737
8.  Comparison of Antibodies That Mediate HIV Type 1 gp120 Antibody-Dependent Cell-Mediated Cytotoxicity in Asymptomatic HIV Type 1-Positive Men and Women 
Abstract
Recent studies suggest that HIV-specific antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies contribute to protective immunity against HIV. An important characteristic of future HIV vaccines will, therefore, be the ability to stimulate production of these antibodies in both men and women. Early studies suggest that men may have a better ADCC antibody response against HIV than women. Our objective was to determine whether men and women differ with respect to their ADCC response to HIV-1 gp120. HIV-positive, asymptomatic untreated men and women were matched for race, age, CD4+ T cell number, HIV-1 viral load, and treatment and HIV-1 gp120 ADCC antibody titers were compared. A standard 51Cr-release assay was used to determine HIV-1 gp120 ADCC antibody titers in HIV-1-seropositive individuals from the Multicenter AIDS Cohort Study (MACS; n=32) and the Women's Interagency HIV Study (WIHS; n=32). Both sexes had high ADCC titers against HIV-1 gp120: 34.4% (n=11) and 40.6% (n=13) of men and women, respectively, had titers of 10,000; 62.5% (n=20) and 56.3% (n=18) had titers of 100,000. Groups did not differ in percent specific release (% SR), lytic units (LU), correlations of titer to viral load, or titer to CD4+ T cells in men or women. Both groups also had similar cross-clade ADCC antibody responses (p>0.5 for % SR and LU). Comparable groups of asymptomatic HIV-1-infected men and women had comparable HIV-1 gp120 ADCC antibodies. Both sexes had significant cross-clade reactivity. Differences between men and women may become evident as disease progresses; this should be evaluated at later stages of HIV-1 infection.
doi:10.1089/aid.2012.0377
PMCID: PMC3887406  PMID: 23972002
9.  Lentivirus-Activated T Regulatory Cells Suppress T Helper Cell Interleukin-2 Production by Inhibiting Nuclear Factor of Activated T Cells 2 Binding to the Interleukin-2 Promoter 
Abstract
Using the feline immunodeficiency virus (FIV) model for AIDS lentivirus infection, we previously demonstrated that Treg cells from FIV-infected cats up-regulate membrane-associated tumor growth factor beta (mTGF-ß) during the course of infection and that activated T lymphocytes up-regulate TGF-ß receptor II (TGF-ßRII) during the course of infection. Furthermore, we have demonstrated that autologous coculture of Tregs with Th cells from FIV-infected cats leads to suppression of interleukin (IL)-2 production and loss of proliferation in a TGF-ß-dependent fashion. Nuclear factor of activated T cells (NFAT) 2 has been identified as integral to effector Th cell maturation and function by promoting IL-2 transcription. Therefore, we questioned whether NFAT2 expression might be altered by TGF-β signaling. Feline NFAT2 exon sequences were identified based upon sequence homology to human and murine NFAT2. Following stimulation, IL-2 and NFAT2 mRNA levels were similarly increased in both FIV− and FIV+ cats. Activated CD4+CD25− cells from both FIV− and FIV+ cats cocultured with autologous CD4+CD25+ cells or treated with TGF-β demonstrated decreased IL-2 production; however, NFAT2 mRNA levels were unaffected. Although NFAT2 mRNA levels were unaffected, chromatin immunoprecipitation (ChIP) for NFAT2 indicated decreased NFAT2 binding at the IL-2 promoter in suppressed Th cells. These data suggest that TGF-β-mediated Treg cell suppression of IL-2 transcription is modulated through alterations in NFAT2 binding to the IL-2 promoter.
doi:10.1089/aid.2013.0062
PMCID: PMC3887409  PMID: 23924068
10.  Evaluation of the False Recent Classification Rates of Multiassay Algorithms in Estimating HIV Type 1 Subtype C Incidence 
Abstract
Laboratory cross-sectional assays are useful for the estimation of HIV incidence, but are known to misclassify individuals with long-standing infection as recently infected. The false recent rate (FRR) varies widely across geographic areas; therefore, accurate estimates of HIV incidence require a locally defined FRR. We determined FRR for Botswana, where HIV-1 subtype C infection is predominant, using the BED capture enzyme immunoassay (BED), a Bio-Rad Avidity Index (BAI) assay (a modification of the Bio-Rad HIV1/2+O EIA), and two multiassay algorithms (MAA) that included clinical data. To estimate FRR, stored blood samples from 512 antiretroviral (ARV)-naive HIV-1 subtype C-infected individuals from a prospective cohort in Botswana were tested at 18–24 months postenrollment. The following FRR mean (95% CI) values were obtained: BED 6.05% (4.15–8.48), BAI 5.57% (3.70–8.0), BED-BAI 2.25% (1.13–4.0), and a combination of BED-BAI with CD4 (>200) and viral load (>400) threshold 1.43% (0.58–2.93). The interassay agreement between BED and BAI was 92.8% (95% CI, 90.1–94.5) for recent/long-term classification. Misclassification was associated with viral suppression for BED [adjusted OR (aOR) 10.31; p=0.008], BAI [aOR 9.72; p=0.019], and MAA1 [aOR 16.6; p=0.006]. Employing MAA can reduce FRR to <2%. A local FRR can improve cross-sectional HIV incidence estimates.
doi:10.1089/aid.2013.0055
PMCID: PMC3887420  PMID: 23937344
11.  Short Communication: Defining Optimality of a Test for Recent Infection for HIV Incidence Surveillance 
Abstract
The estimation of HIV incidence from cross-sectional surveys using tests for recent infection has attracted much interest. It is increasingly recognized that the lack of high performance recent infection tests is hindering the implementation of this surveillance approach. With growing funding opportunities, test developers are currently trying to fill this gap. However, there is a lack of consensus and clear guidance for developers on the evaluation and optimization of candidate tests. A fundamental shift from conventional thinking about test performance is needed: away from metrics relevant in typical public health settings where the detection of a condition in individuals is of primary interest (sensitivity, specificity, and predictive values) and toward metrics that are appropriate when estimating a population-level parameter such as incidence (accuracy and precision). The inappropriate use of individual-level diagnostics performance measures could lead to spurious assessments and suboptimal designs of tests for incidence estimation. In some contexts, such as population-level application to HIV incidence, bias of estimates is essentially negligible, and all that remains is the maximization of precision. The maximization of the precision of incidence estimates provides a completely general criterion for test developers to assess and optimize test designs. Summarizing the test dynamics into the properties relevant for incidence estimation, high precision estimates are obtained when (1) the mean duration of recent infection is large, and (2) the false-recent rate is small. The optimal trade-off between these two test properties will produce the highest precision, and therefore the most epidemiologically useful incidence estimates.
doi:10.1089/aid.2013.0113
PMCID: PMC3887426  PMID: 24090052
12.  Near Full-Length Genome Identification of a Novel HIV Type 1 B′/C Recombinant Isolate JL100091 in Jilin, China 
AIDS Research and Human Retroviruses  2013;29(12):1609-1612.
Abstract
We report here a novel HIV-1 B′/C recombinant isolate JL100091, identified from an HIV-positive female subject infected through heterosexual transmission in Jilin in 2006. The near full-length genome analyses of the novel recombinant (JL10091) showed that one subtype B′ region (3,085 bp) was inserted into the subtype C backbone, with two breakpoints observed in gag and pol genes. To our knowledge, this is the first detection of a novel HIV-1 B′/C recombinant in Jilin, which indicates ongoing transmission of networks among the heterosexual population in the region. The novel HIV-1 B′/C recombinant (JL10091) in Jilin originated from India subtype C and China subtype B′ may suggest potential transmission routes of HIV-1 in China. Further monitoring of the molecular epidemiology of the HIV-1 epidemic in Jilin will provide critical information for designing effective control and prevention measures against HIV transmission in the region.
doi:10.1089/aid.2013.0134
PMCID: PMC3848441  PMID: 23800314
13.  HIV Antiretroviral Resistance Mutations Among Antiretroviral Treatment-Naive and -Experienced Patients in South Korea 
AIDS Research and Human Retroviruses  2013;29(12):1617-1620.
Abstract
The purpose of this study was to assess the prevalence and characteristics of HIV drug resistance mutations among antiretroviral therapy (ART)-naive and ART-experienced patients in South Korea. A total of 50 ART-naive and 34 ART-experienced Korean HIV-1-infected patients who visited an urban hospital from February 2007 to March 2011 were included. Most patients (86.9%) were infected with clade B HIV-1. Six (12%) ART-naive and 22 (64.7%) ART-experienced patients had HIV strains with resistance mutations. Among ART-naive patients, V179D was the most common mutation, being found in five ART-naive patients. Among ART-experienced patients, M184V was the most common mutation. Eight of 34 ART-experienced patients had thymidine analogue mutations (TAMs). The prevalence of drug-resistant HIV-1 in ART-naive patients was higher than in previous reports, and 50% of patients with virologic failure harbored strains with multiple resistance mutations. HIV drug resistance testing should be recommended to guide therapy of ART-naive patients in South Korea.
doi:10.1089/aid.2013.0184
PMCID: PMC3848436  PMID: 23952717
14.  Acceptance of Male Circumcision Among Male Rural-to-Urban Migrants in Western China 
AIDS Research and Human Retroviruses  2013;29(12):1582-1588.
Abstract
To describe the acceptability of male circumcision (MC) and explore potential factors associated with MC acceptability among male rural-to-urban migrants in western China, a cross-sectional survey of MC acceptability was conducted with 1,904 subjects in three western provinces with high HIV prevalence (Guangxi, Chongqing, and Xinjiang) in China between June 2009 and November 2009. Through face-to-face interviews, the participants completed a self-administered questionnaire about demographics, MC knowledge, willingness and reasons to accept or refuse MC, sexual behaviors, and other psychosocial variables. Factors associated with acceptability of MC were identified by multiple logistic regression analysis. Of the participants (n=1,904), 710 men were willing to accept MC (37.3%); the reasons included promotion of the partners' genital hygiene (54.9%), redundant prepuce or phimosis (43.1%), enhancement of sexual pleasure (40.6%), prevention of penile inflammation or cancer (35.5%), and protection against HIV and sexual transmitted diseases (STDs)(31.1%). A multivariable logistic regression showed that four factors were associated with acceptability of MC, including education level (OR=1.286, 95% CI=1.025∼1.614), redundant prepuce or phimosis (OR=13.751, 95% CI=10.087∼18.745), having one or more circumcised friends (OR=2.468, 95% CI=1.953∼3.119), and having sexual intercourse with a temporary partner in the past year (OR=1.543, 95% CI=1.101∼2.162). Compared with previously published data among the general population in China or worldwide, the acceptability of MC (37.3%) was low among the male rural-to-urban migrants in western China. Nevertheless, appropriate education could greatly improve the acceptability of MC. More public campaigns and health education on MC are needed to increase the rate of MC in China.
doi:10.1089/aid.2013.0156
PMCID: PMC3848437  PMID: 23931654
15.  Effect of Tenofovir With and Without Interferon on Hepatitis D Virus Replication in HIV–Hepatitis B Virus–Hepatitis D Virus-Infected Patients 
AIDS Research and Human Retroviruses  2013;29(12):1535-1540.
Abstract
The effect of tenofovir (TDF) alone or in combination with interferon on hepatitis D virus (HDV) replication is poorly characterized in patients infected with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and HDV. We analyzed triinfected patients undergoing treatment with either TDF alone (n=13) or including interferon (IFN) at some point during TDF therapy (TDF+IFN, n=4). Linear mixed-effect models were used to estimate the mean change from baseline of HDV-RNA and hepatitis surface antigen (HBsAg) levels during treatment. Patients were followed for a median 31.6 (25–75%-tile: 15.0–47.4) months. In the TDF+IFN group, three initiated IFN-based therapy after a median of 21.7 months (range=10.5–24.9) of lamivudine (LAM)+TDF, while the remaining patient had 46.8 months of prior LAM exposure. Significant decreases in HDV-RNA were observed in both groups [TDF alone: –0.380 log10 copies/ml per year (95% CI: −0.557, −0.202) vs. TDF+IFN: −1.325 log10 copies/ml per year (95% CI: −1.931, −0.720)], while the HDV-RNA decline overall was significantly faster in patients with TDF+IFN (p=0.002). Accordingly, two patients achieved HDV-RNA below the limit of quantification (LOQ: <1,000 copies/ml) and one near LOQ (1450 copies/ml), all concomitantly treated with interferon. There were no significant changes in HBsAg levels for either group [TDF alone: −0.008 log10 IU/ml per month (95% CI: −0.019, 0.004), TDF+IFN:−0.011 log10 IU/ml per month (95% CI: −0.037, 0.015)] and no significant difference in slope between treatment groups (p=0.8). Interferon therapy might be more effective after extended previous anti-HBV antiviral exposure among triinfected patients; however, the long-term implications of these findings remain unknown.
doi:10.1089/aid.2013.0008
PMCID: PMC3848444  PMID: 23972039
16.  Influence of CCR5 and CCR2 Genetic Variants in the Resistance/Susceptibility to HIV in Serodiscordant Couples from Colombia 
AIDS Research and Human Retroviruses  2013;29(12):1594-1603.
Abstract
The main genetic factor related to HIV-1 resistance is the CCR5-Δ32 mutation; however, the homozygous genotype is uncommon. The CCR5-Δ32 mutation along with single nucleotide polymorphisms (SNPs) in the CCR5 promoter and the CCR2-V64I mutation have been included in seven human haplogroups (HH) previously associated with resistance/susceptibility to HIV-1 infection and different rates of AIDS progression. Here, we determined the association of the CCR5 promoter SNPs, the CCR5-Δ32 mutation, CCR2-V64I SNP, and HH frequencies with resistance/susceptibility to HIV-1 infection in a cohort of HIV-1-serodiscordant couples from Colombia. Seventy HIV-1-exposed, but seronegative (HESN) individuals, 57 seropositives (SP), and 112 healthy controls (HC) were included. The CCR5-Δ32 mutation and CCR2-V64I SNP were identified by PCR, and the CCR5 promoter SNPs were evaluated by sequencing. None of the individuals exhibited a homozygous Δ32 genotype; the CCR2-I allele was more frequent in HESN (34%) than HC (23%) (p=0.039, OR=1.672). The frequency of the 29G allele was higher in SP than HC (p=0.003, OR=3). HHF2 showed a higher frequency in HC (19%) than SP (9%) (p=0.027), while HHG1 was more frequent in SP (11.1%) than in HC (4.2%) (p=0.019). The AGACCAC-CCR2-I-CCR5 wild-type haplotype showed a higher frequency in SP (14.2%) than in HC (3.7%) (p=0.001). In conclusion, the CCR5-Δ32 allele is not responsible for HIV-1 resistance in this HESN group; however, the CCR2-I allele could be protective, while the 29G allele might increase the likelihood of acquiring HIV-1 infection. HHG1 and the AGACCAC-CCR2-I-CCR5 wild-type haplotype might promote HIV-1 infection while HHF2 might be related to resistance. However, additional studies are required to evaluate the implications of these findings.
doi:10.1089/aid.2012.0299
PMCID: PMC3848445  PMID: 24098976
17.  Short Communication: Aging Not Gender Is Associated with High Atazanavir Plasma Concentrations in Asian HIV-Infected Patients 
AIDS Research and Human Retroviruses  2013;29(12):1541-1546.
Abstract
Physiological effects of aging make the older population more susceptible to adverse drug events and drug–drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged ≥18 years with HIV RNA <50 copies/ml and treated with ATV/r 300/100 mg once daily plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 2 weeks. Atazanavir and ritonavir plasma concentrations were measured by validated high-performance liquid chromatography (HPLC). Plasma PK parameters were calculated using noncompartmental methods. Since 50% of the patients were older than 42 years, age 42 was selected as the cut-off point for the older (>42 years) group. Gender, weight, duration of ATV/r therapy, and proportion treated with tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced creatinine clearance (91 versus 76 ml/min). The older group had a higher atazanavir exposure with median AUC0–24 71.2 vs. 53.1 mg·h/liter, Cmax 8.5 vs. 5.5 mg/liter, and Ctrough 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV Ctrough levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower body weight (BW) (46 versus 63 kg) than the males, but atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher atazanavir concentrations. Parameter estimate for age and atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01–3.33). That is, for every year increase in age, AUC increases by approximately 2 mg·h/liter. Age seems to be an important factor influencing atazanavir pharmacokinetics. Patients from the aging group appeared to have higher atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted.
doi:10.1089/aid.2013.0069
PMCID: PMC3848483  PMID: 24088045
18.  Short Communication: HIV Blips While on Antiretroviral Therapy Can Indicate Consistently Detectable Viral Levels Due to Assay Underreporting 
AIDS Research and Human Retroviruses  2013;29(12):1621-1625.
Abstract
Viral blips, where HIV RNA plasma viral load (pVL) intermittently increases above the lower limit of assay detection, are a cause for concern. We investigated a number of hypotheses for their cause. We assessed HIV RNA, and total and episomal HIV DNA from 16 individuals commencing antiretroviral therapy (ART) consisting of raltegravir and tenofovir/emtricitabine for 3 years, using two assays: a single-copy assay [SCA; lower limit of quantification (LLOQ), <1 copy/ml] and the Amplicor assay (LLOQ of 50 copies/ml). Two individuals exhibited viral blips. From week 20 onward, the period where ART had achieved its final suppressive levels, pVL ranged from <1 to 330 copies/ml, except for one individual at the final time. Both assays were 98% consistent (108/110) in assessing pVL <50 copies/ml, but the Amplicor assay registered 56% of samples (19/34) as below the LLOQ that were in the 50 to 1000 copy/ml range as quantified by SCA. pVL changes between successive time points did not correlate with changes in cellular infection as measured through either total or episomal HIV DNA. Changes in pVL were correlated (negatively) with changes in total CD4+ T cell numbers (p=0.003), naive (CD45RO–CD62L+CD4+), natural regulatory (CD45RO–CD25+CD127–CD4+), activated effector (CD45RO+CD38++CCR5+CD8+), but not activated (CD38+HLA-DR+) CD4+ T cells. Patients receiving stable, seemingly suppressive ART can have pVL near the 50 copy LLOQ at multiple time points. The high Amplicor assay error rate around this level implies that viral blips underrepresent pVL being more consistently above the LLOQ. Activation of latently infected cells is less likely to contribute to this phenomenon.
doi:10.1089/aid.2013.0132
PMCID: PMC3848484  PMID: 23844947
19.  The Potential Role of CD16+ Vγ2Vδ2 T Cell-Mediated Antibody-Dependent Cell-Mediated Cytotoxicity in Control of HIV Type 1 Disease 
AIDS Research and Human Retroviruses  2013;29(12):1562-1570.
Abstract
Increasing evidence has suggested that HIV infection severely damages the Vγ2Vδ2 (Vδ2) T cells that play an important role in the first-line host response to infectious disease. However, little is known about Vδ2 T cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) in HIV disease. We found that although the CD16+ Vδ2 T cell subset hardly participated in phosphoantigen responses dominated by the CD16− Vδ2 T cell subset, the potency of the ADCC function of Vδ2 T cells was correlated with the frequency of the CD16+ subset. Thus, two distinct and complementary Vδ2 T cell subsets discriminated by CD16 were characterized to explore the respective impacts of HIV-1 infection on them. HIV-1 disease progression was not only associated with the phosphoantigen responsiveness of the CD16− Vδ2 subset, but also with the ability of the CD16+ Vδ2 subset to kill antibody-coated target cells. Furthermore, both of the two Vδ2 functional subsets could be partially restored in HIV-infected patients with antiretroviral therapy. Notably, in the context of an overall HIV-mediated Vδ2 T cell depletion, despite the decline of phosphoantigen-responsive CD16− Vδ2 cells, CD16+ Vδ2 cell-mediated ADCC was not compromised but exhibited a functional switch with dramatic promotion of degranulation in the early phase of HIV infection and chronic infection with slower disease progression. Our study reveals functional characterizations of the two Vδ2 T cell subsets with different activation pathways during HIV-1 infection and provides a rational direction for activating the CD16+ Vδ2 T cells capable of mediating ADCC as a means to control HIV-1 disease.
doi:10.1089/aid.2013.0111
PMCID: PMC3848486  PMID: 23957587
20.  Near Full-Length Genome Sequence of a Novel HIV Type 1 Second-Generation Recombinant Form (CRF01_AE/CRF07_BC) Identified Among Men Who Have Sex with Men in Jilin, China 
AIDS Research and Human Retroviruses  2013;29(12):1604-1608.
Abstract
We report here a novel HIV-1 second-generation recombinant form (CRF01_AE/CRF07_BC) composed of CRF01_AE and CRF07_BC, identified among men who have sex with men (MSM) in Jilin, with four breakpoints observed in the pol, vif, and vpr genes. The CRF01_AE regions of the recombinant were clustered with the CRF01_AE lineage, which is mainly circulating among MSM in northern China, with the support of 100% bootstrap value, indicating that the parental origin of the CRF01_AE regions was from MSM, in which recombination events may be more likely to occur. To the best of our knowledge, this is the first detection of a novel HIV-1 second-generation recombinant form (CRF01AE/CRF07_BC) in Jilin, which indicates active transmission networks of HIV-1 infection among MSM in the region. Therefore, it is necessary to continue monitoring the molecular epidemiology of HIV-1 among MSM in Jilin to obtain a better understanding of the transmission and potential public health impact of HIV-1 among MSM in the region.
doi:10.1089/aid.2013.0116
PMCID: PMC3848684  PMID: 23809010
21.  Increasing Extracellular Protein Concentration Reduces Intracellular Antiretroviral Drug Concentration and Antiviral Effect 
AIDS Research and Human Retroviruses  2013;29(11):1434-1442.
Abstract
The objective of this study was to develop an in vitro pharmacodynamic (PD) system to test the impact of protein binding on antiretroviral (ARV) drug effect and intracellular ARV distribution. CD4+ T cells were isolated from peripheral blood mononuclear cells (PBMCs) and exposed to varying and physiologically relevant concentrations of human serum albumin (HSA) and the ARV drugs efavirenz (EFV), raltegravir (RAL), etravirine (ETR), and enfuvirtide (ENF). The effect of varying extracellular protein concentration on the intracellular distribution of EFV, RAL, and ETR was assessed using ultraperformance liquid chromatography tandem mass spectrometry. HIV infectivity was assessed using an HIV-1 reporter virus expressing an Env-green fluorescent protein (GFP) and quantified using flow cytometry. Increasing extracellular HSA concentration was associated with increased relative infectivity for all drugs tested as well as decreased intracellular concentrations for EFV, RAL, and ETR. Median-effect plots indicate linearity between log10 antiviral effect (fraction of virus affected divided by fraction unaffected) and log10 intracellular drug concentration. The median [interquartile range (IQR)] slope (m) of the median-effect plots was 2.97 (2.26–5.85) for EFV, 3.52 (3.11–3.74) for ETR, and 2.39 (2.15–3.74) for RAL. The intracellular ARV concentrations associated with half-maximal antiviral effect (IC50) of EFV, ETR, and RAL were 1.2 (0.51–5.39), 39.06 (30.10–51.76), and 4.67 (3.91–5.02) ng/ml, respectively. This study demonstrates a significant reduction in cell penetration and antiviral effect of highly bound ARVs due to increasing extracellular concentration of HSA. This study is therefore the first to demonstrate experimentally how protein binding impacts intracellular distribution and the efficacy of ARVs.
doi:10.1089/aid.2013.0031
PMCID: PMC3809607  PMID: 23601085
22.  Single Dose Pharmacokinetics of Oral Tenofovir in Plasma, Peripheral Blood Mononuclear Cells, Colonic Tissue, and Vaginal Tissue 
AIDS Research and Human Retroviruses  2013;29(11):1443-1450.
Abstract
HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) 14C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4+ cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58–77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38–76) half-life; Cmax was 20 fmol/million cells (2–63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1–281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials.
doi:10.1089/aid.2013.0044
PMCID: PMC3809387  PMID: 23600365
23.  Short Communication: Expression of Transporters and Metabolizing Enzymes in the Female Lower Genital Tract: Implications for Microbicide Research 
AIDS Research and Human Retroviruses  2013;29(11):1496-1503.
Abstract
Topical vaginal microbicides have been considered a promising option for preventing the male-to-female sexual transmission of HIV; however, clinical trials to date have not clearly demonstrated robust and reproducible effectiveness results. While multiple approaches may help enhance product effectiveness observed in clinical trials, increasing the drug exposure in lower genital tract tissues is a compelling option, given the difficulty in achieving sufficient drug exposure and positive correlation between tissue exposure and microbicide efficacy. Since many microbicide drug candidates are substrates of transporters and/or metabolizing enzymes, there is emerging interest in improving microbicide exposure and efficacy through local modulation of transporters and enzymes in the female lower genital tract. However, no systematic information on transporter/enzyme expression is available for ectocervical and vaginal tissues of premenopausal women, the genital sites most relevant to microbicide drug delivery. The current study utilized reverse transcriptase polymerase chain reaction (RT-PCR) to examine the mRNA expression profile of 22 transporters and 19 metabolizing enzymes in premenopausal normal human ectocervix and vagina. Efflux and uptake transporters important for antiretroviral drugs, such as P-gp, BCRP, OCT2, and ENT1, were found to be moderately or highly expressed in the lower genital tract as compared to liver. Among the metabolizing enzymes examined, most CYP isoforms were not detected while a number of UGTs such as UGT1A1 were highly expressed. Moderate to high expression of select transporters and enzymes was also observed in mouse cervix and vagina. The implications of this information on microbicide research is also discussed, including microbicide pharmacokinetics, the utilization of the mouse model in microbicide screening, as well as the in vivo functional studies of cervicovaginal transporters and enzymes.
doi:10.1089/aid.2013.0032
PMCID: PMC3809391  PMID: 23607746
24.  HIV Vaccine Development: Strategies for Preclinical and Clinical Investigation 
AIDS Research and Human Retroviruses  2013;29(11):1401-1406.
Abstract
This article discusses HIV vaccine discovery and candidate vaccine testing in the context of current realities of funding and clinical trial practice. Lacking perfect animal models for testing candidate HIV vaccines, clinical investigators have proposed a strategy of iterative exploratory clinical trials in the model of cancer chemotherapy development. Problems with the appropriateness of this model to HIV vaccine development are discussed. Also, the future feasibility of this strategy in the context of increasing clinical trial costs and emerging new, efficacious prevention modalities is questioned. Strategies for making better use of animal models are presented as an alternative to iterative exploratory clinical efficacy testing. Some ways in which better data from preclinical studies can refine clinical product development are described. Finally, development of an HIV vaccine under the FDA's “Animal Rule” pathway to licensure when human efficacy studies are not feasible is discussed as a fall-back approach. Not making a preventive vaccine against HIV infection is simply not an option because eradication of AIDS will require a preventive vaccine.
doi:10.1089/aid.2012.0337
PMCID: PMC3809608  PMID: 23379343
25.  In Pursuit of an HIV Vaccine: Designing Efficacy Trials in the Context of Partially Effective Nonvaccine Prevention Modalities 
AIDS Research and Human Retroviruses  2013;29(11):1513-1523.
Abstract
The HIV prevention landscape is evolving rapidly, and future efficacy trials of candidate vaccines, which remain the best long-term option for stemming the HIV epidemic, will be conducted in the context of partially effective nonvaccine prevention modalities. It is essential that these trials provide for valid and efficient evaluation of vaccine efficacy and immune correlates. The availability of partially effective prevention modalities presents opportunities to study their interactions with vaccines to maximally reduce HIV incidence. This article proposes an approach for conducting future vaccine efficacy trials in the context of background use of partially effective nonvaccine prevention modalities, and for conducting future vaccine efficacy trials that provide nonvaccine prevention modalities in one or more of the randomized study groups. Strategies are discussed for responding to emerging evidence on nonvaccine prevention modalities during ongoing vaccine trials. Next-generation HIV vaccine efficacy trials will almost certainly be more complex in their design and implementation but may become more relevant to at-risk populations and better suited to the ultimate goal of reducing HIV incidence at the population level.
doi:10.1089/aid.2012.0385
PMCID: PMC3809388  PMID: 23597282

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