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- Characterization of antiviral activity of a benzamide derivative AH0109 against HIV-1 infection. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2013 May 13.
In the absence of an effective vaccine against HIV-1 infection, anti-HIV-1 strategies play a major role in disease control. However, the rapid emergence of drug-resistance against all currently used anti-HIV-1 molecules necessitates the development of new antiviral molecules and/or strategies against HIV-1 infection. In this study, we have identified a benzamide derivative named AH0109 that exhibits potent anti-HIV-1 activity at an EC50 value of 0.7μM in HIV-1 susceptible CD4+ C8166 T cells. Mechanistic analysis revealed that AH0109 significantly inhibits both HIV-1 reverse transcription and viral cDNA nuclear import. Furthermore, our infection experiments indicated that AH0109 is capable of disrupting the replication of HIV-1 strains that are resistant to the routinely used anti-HIV-1 drugs AZT, 3TC, nevirapine and reltagravir. Together, these findings provide evidence for a newly identified antiviral molecule that can potentially be developed as an anti-HIV-1 agent.
- Simultaneous and sensitive detection of human immunodeficiency virus type 1 (HIV) drug resistant genotypes by multiplex oligonucleotide ligation assay. [JOURNAL ARTICLE]
- J Virol Methods 2013 May 6.
Oligonucleotide ligation assay (OLA) is a highly specific and relatively simple method to detect point mutations encoding HIV-1 drug-resistance, which can detect mutants comprising ≥2-5% of the viral population. Nevirapine (NVP), tenofovir (TDF) and lamivudine (3TC) are antiretroviral (ARV) drugs used worldwide for treatment of HIV infection and prevention of mother-to-child-transmission. Adapting the OLA to detect multiple mutations associated with HIV resistance to these ARV simultaneously would provide an efficient tool to monitor drug resistance in resource-limited settings. Known proportions of mutant and wild-type plasmids were used to optimize a multiplex OLA for detection of K103N, Y181C, K65R, and M184V in HIV subtypes B and C, and V106M and G190A in subtype C. Simultaneous detection of two mutations was impaired if probes annealed to overlapping regions of the viral template, but was sensitive to ≥2-5% when testing codons using non-overlapping probes. PCR products from HIV-subtype B- and C-infected individuals were tested by multiplex-OLA and compared to results of single-codon OLA. Multiplex-OLA detected mutations at codon pairs 103/181, 106/190 and 65/184 reliably when compared to singleplex-OLA in clinical specimens. The multiplex-OLA is sensitive and specific and reduces the cost of screening for NVP, TDF and/or 3TC resistance.
- The NRTIs Lamivudine, Stavudine and Zidovudine Have Reduced HIV-1 Inhibitory Activity in Astrocytes. [Journal Article]
- PLoS One 2013; 8(4):e62196.
HIV-1 establishes infection in astrocytes and macroage-lineage cells of the central nervous system (CNS). Certain antiretroviral drugs (ARVs) can penetrate the CNS, and are therefore often used in neurologically active combined antiretroviral therapy (Neuro-cART) regimens, but their relative activity in the different susceptible CNS cell populations is unknown. Here, we determined the HIV-1 inhibitory activity of CNS-penetrating ARVs in astrocytes and macrophage-lineage cells. Primary human fetal astrocytes (PFA) and the SVG human astrocyte cell line were used as in vitro models for astrocyte infection, and monocyte-derived macrophages (MDM) were used as an in vitro model for infection of macrophage-lineage cells. The CNS-penetrating ARVs tested were the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC), lamivudine (3TC), stavudine (d4T) and zidovudine (ZDV), the non-NRTIs efavirenz (EFV), etravirine (ETR) and nevirapine (NVP), and the integrase inhibitor raltegravir (RAL). Drug inhibition assays were performed using single-round HIV-1 entry assays with luciferase viruses pseudotyped with HIV-1 YU-2 envelope or vesicular stomatitis virus G protein (VSV-G). All the ARVs tested could effectively inhibit HIV-1 infection in macrophages, with EC90s below concentrations known to be achievable in the cerebral spinal fluid (CSF). Most of the ARVs had similar potency in astrocytes, however the NRTIs 3TC, d4T and ZDV had insufficient HIV-1 inhibitory activity in astrocytes, with EC90s 12-, 187- and 110-fold greater than achievable CSF concentrations, respectively. Our data suggest that 3TC, d4T and ZDV may not adequately target astrocyte infection in vivo, which has potential implications for their inclusion in Neuro-cART regimens.
- Abacavir/lamivudine versus tenofovir/emtricitabine with atazanavir/ritonavir for treatment-naive Japanese patients with HIV-1 infection: a randomized multicenter trial. [Journal Article, Research Support, Non-U.S. Gov't]
- Intern Med 2013; 52(7):735-44.
To compare the efficacy and safety of fixed-dose abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) with ritonavir-boosted atazanavir (ATV/r) in treatment-naïve Japanese patients with HIV-1 infection.A 96-week multicenter, randomized, open-label, parallel group pilot study was conducted. The endpoints were times to virologic failure, safety event and regimen modification.109 patients were enrolled and randomly allocated (54 patients received ABC/3TC and 55 patients received TDF/FTC). All randomized subjects were analyzed. The time to virologic failure was not significantly different between the two arms by 96 weeks (HR, 2.09; 95% CI, 0.72-6.13; p=0.178). Both regimens showed favorable viral efficacy, as in the intention-to-treat population, 72.2% (ABC/3TC) and 78.2% (TDF/FTC) of the patients had an HIV-1 viral load <50 copies/mL at 96 weeks. The time to the first grade 3 or 4 adverse event and the time to the first regimen modification were not significantly different between the two arms (adverse event: HR 0.66; 95% CI, 0.25-1.75, p=0.407) (regimen modification: HR 1.03; 95% CI, 0.33-3.19, p=0.964). Both regimens were also well-tolerated, as only 11.1% (ABC/3TC) and 10.9% (TDF/FTC) of the patients discontinued the allocated regimen by 96 weeks. Clinically suspected abacavir-associated hypersensitivity reactions occurred in only one (1.9%) patient in the ABC/3TC arm.Although insufficiently powered to show non-inferiority of viral efficacy of ABC/3TC relative to TDF/FTC, this pilot trial suggested that ABC/3TC with ATV/r is a safe and efficacious initial regimen for HLA-B*5701-negative patients, such as the Japanese population.
- Outcomes of antiretroviral therapy in Vietnam: results from a national evaluation. [Journal Article, Research Support, U.S. Gov't, P.H.S.]
- PLoS One 2013; 8(2):e55750.
Vietnam has significantly scaled up its national antiretroviral therapy (ART) program since 2005. With the aim of improving Vietnam's national ART program, we conducted an outcome evaluation of the first five years of the program in this concentrated HIV epidemic where the majority of persons enrolled in HIV care and treatment services are people who inject drugs (PWID). The results of this evaluation may have relevance for other national ART programs with significant PWID populations.Retrospective cohort analysis of patients at 30 clinics randomly selected with probability proportional to size among 120 clinics with at least 50 patients on ART.Charts of patients whose ART initiation was at least 6 months prior to the study date were abstracted. Depending on clinic size, either all charts or a random sample of 300 charts were selected. Analyses were limited to treatment-naïve patients. Multiple imputations were used for missing data.Of 7,587 patient charts sampled, 6,875 were those of treatment-naïve patients (74.4% male, 95% confidence interval [CI]: 72.4-76.5, median age 30, interquartile range [IQR]: 26-34, 62.0% reported a history of intravenous drug use, CI: 58.6-65.3). Median baseline CD4 cell count was 78 cells/mm(3) (IQR: 30-162) and 30.4% (CI: 25.8-35.1) of patients were at WHO stage IV. The majority of patients started d4T/3TC/NVP (74.3%) or d4T/3TC/EFV (18.6%). Retention rates after 6, 12, 24, and 36 months were 88.4% (CI: 86.8-89.9), 84.0% (CI: 81.8-86.0), 78.8% (CI: 75.7-81.6), and 74.6% (CI: 69.6-79.0). Median CD4 cell count gains after 6, 12, 24, and 36 months were 94 (IQR: 45-153), 142 (IQR: 78-217), 213 (IQR: 120-329), and 254 (IQR: 135-391) cells/mm(3). Patients who were PWID showed significantly poorer retention.The study showed good retention and immunological response to ART among a predominantly PWID group of patients despite advanced HIV infections at baseline.
- A prospective study of highly active antiretroviral therapy in Indian human immunodeficiency virus positive patients. [Journal Article]
- Int J Risk Saf Med 2013 Jan 1; 25(1):53-65.
There are no studies performed in India on the safety of highly active antiretroviral therapy (HAART) combinations which focus on the base-line CD4+ T-cell count. Further, no data on risk factors for Adverse drug reactions (ADRs) to HAART and there is a lack of data on CD4+ T-cell count recovery after HAART.The aim of this study was to assess risk factors for ADRs to HAART. We also compared the efficacy of HAART combinations with respect to base-line CD4+ T-cell count and CD4+ T-cell counts recovery in Indian HIV positive patients.A prospective active surveillance study was adopted at the Antiretroviral Therapy (ART) Centre, District Government Hospital, Udupi, India. HIV-infected patients were intensively monitored to identify risk factors associated with ADRs to HAART from August 2009 to May 2012. The study protocol was approved by the University ethics committee. Baseline CD4+ T-cell count before initiation of HAART and thereafter at every six months of regular follow-up up to 24 months duration was included for comparison. Multivariate logistic regression analysis was used to identify predictors of high risk factors of ADRs. CD4+ T-cell count recovery after HAART from base-line CD4+ T-cell count in different HAART groups was analyzed by test of between-subject effects. P-value <0.05 was considered as statistically significant.A total of 1982 HIV positive patients were enrolled with 1181 (59.6%) males, and 801 (40.4%) females. On multivariate logistic regression analysis, four factors were found to be predictors of high-risk factors for ADRs to HAART: 1) CD4+ T-cell counts, 2) female gender, 3) polypharmacy and 4) opportunistic infections. Between HAART groups, a mean increase of 98 cells/μl of CD4+ T-cell counts recovery was seen in the 3TC + NVP + D4T group (p < 0.001) at 24 months of regular follow-up.In India, Clinician should take into consideration all possible risk factors associated with the use of HAART in order to avoid and minimize ADRs. As initial CD4+ T-cell count and age of patient decides the rise of CD4+ T-cell counts with HAART. HAART should be initiated at the earliest age in order to attain maximum CD4+ T-cell counts recovery.
- Impact of switching from zidovudine to tenofovir disoproxil fumarate on bone mineral density and markers of bone metabolism in virologically suppressed HIV-1 infected patients; a substudy of the PREPARE study. [Journal Article, Research Support, Non-U.S. Gov't]
- J Clin Endocrinol Metab 2013 Apr; 98(4):1659-66.
In virologically suppressed, antiretroviral-treated patients, the effect of switching to tenofovir (TDF) on bone biomarkers compared to patients remaining on stable antiretroviral therapy is unknown.We examined bone biomarkers (osteocalcin [OC], procollagen type 1 amino-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen) and bone mineral density (BMD) over 48 weeks in virologically suppressed patients (HIV RNA < 50 copies/ml) randomized to switch to TDF/emtricitabine (FTC) or remain on first-line zidovudine (AZT)/lamivudine (3TC). PTH was also measured. Between-group differences in bone biomarkers and associations between change in bone biomarkers and BMD measures were assessed by Student's t tests, Pearson correlation, and multivariable linear regression, respectively. All data are expressed as mean (SD), unless otherwise specified.Of 53 subjects (aged 46.0 y; 84.9% male; 75.5% Caucasian), 29 switched to TDF/FTC. There were reductions in total hip and lumbar spine BMD in those switching to TDF/FTC (total hip, TDF/FTC, -1.73 (2.76)% vs AZT/3TC, -0.39 (2.41)%; between-group P = .07; lumbar spine, TDF/FTC, -1.50 (3.49)% vs AZT/3TC, +0.25 (2.82)%; between-group P = .06), but they did not reach statistical significance. Greater declines in lumbar spine BMD correlated with greater increases in OC (r = -0.28; P = .05). The effect of TDF/FTC on bone biomarkers remained significant when adjusted for baseline biomarker levels, gender, and ethnicity. There was no difference in change in PTH levels over 48 weeks between treatment groups (between-group P = .23). All biomarkers increased significantly from weeks 0 to 48 in the switch group, with no significant change in those remaining on AZT/3TC (between-group, all biomarkers, P < .0001).A switch to TDF/FTC compared to remaining on a stable regimen is associated with increases in bone turnover that correlate with reductions in BMD, suggesting that TDF exposure directly affects bone metabolism in vivo.
- Tenofovir based combination therapy for HIV/HBV co-infection: Factors associated with a partial HBV virological response in patients with undetectable HIV viraemia. [JOURNAL ARTICLE]
- AIDS 2013 Feb 21.
OBJECTIVE::The aim of this study was to identify and describe patients with detectable HBV DNA in the presence of undetectable HIV RNA after 48 weeks of TDF/3(F)TC treatment.
DESIGN:: Case-control study. Cases or Delayed Responders (DR) were defined as detectable HBV DNA(>20 IU/ml) with undetectable HIV RNA (<40c/ml) after 48 weeks TDF/3(F)TC combination therapy. Controls or Virological responders (VR) were defined as both undetectable HIV and HBV after 48 weeks TDF/3(F)TC therapy.
RESULTS::23 cases were identified and matched to 24 controls. 87% cases and 46% controls were eAg positive (p = 0.005). 9/23(39%) cases and 7/24(29%) controls had 3TC monotherapy prior to TDF. Similar proportions had 3TC/FTC resistance pre-TDF (30% cases, 24% controls).The cases had significantly higher baseline HBV DNA pre-3TC (median 1.2 × 10IU/ml vs. 3.1 × 10IU/ml p = 0.009) and pre-TDF (1.1 × 10IU/ml vs. 2.6 × 10 IU/ml p = 0.012). 16/23 cases eventually achieved undetectable HBV DNA after 42.2 (27.2, 54.9) months. 6/23 still have detectable HBV DNA after 46.2 (28.2, 65.6) months. Only one DR patient developed a new 3(F)TC mutation and they received intensification with entecavir and achieved undetectable HBV DNA. No patient developed TDF resistance.
CONCLUSION:: We report the largest series of HIV/HBV co-infected patients failing to achieve undetectable HBV after 48 weeks TDF/3(F)TC despite undetectable HIV viraemia. This outcome was associated with positive eAg and higher baseline HBV DNA. Our data suggest that clinicians should not intensify therapy with entecavir unless there is evidence of new 3TC/FTC mutations as the majority of patients go on to suppress HBV. TDF resistance was not seen.
- Vitamin D Attenuates Nucleoside Reverse Transcriptase Inhibitor Induced Human Skeletal Muscle Mitochondria DNA Depletion. [JOURNAL ARTICLE]
- AIDS 2013 Feb 21.
OBJECTIVE::To evaluate the impact of the active metabolite of vitamin D, 1α,25-dihydroxycholecalciferol (1,25D3), on nucleoside reverse transcriptase inhibitor (NRTI) induced mitochondrial DNA (mtDNA) depletion in human skeletal muscle myoblasts and myotubes.
DESIGN:: mtDNA was quantified in human skeletal muscle myoblasts and myotubes following 1,25D3 and NRTI treatment using real-time PCR.
METHODS::Human skeletal muscle myoblasts and myotubes were treated with didanosine (ddI), stavudine (d4T), zidovudine (ZDV), lamivudine (3TC), and abacavir (ABC) alone or in combination either in the presence or absence of 1,25D3 for 5 days. Cells were harvested, DNA extracted and mtDNA quantified.
RESULTS::ddI and ddI-d4T significantly decreased both myoblast and myotube mtDNA in the absence of 1,25D3 compared to untreated controls (P ≤ 0.029). In addition, the ZDV-3TC combination resulted in a 47% decrease in myotube mtDNA (P = 0.005). 1,25D3 increased myotube mtDNA levels in ddI, ZDV, 3TC, ABC, ddI-d4T, d4T-3TC, ZDV-3TC, ZDV-ABC, and ZDV-3TC-ABC containing regimens and myoblast mtDNA levels in ddI, d4T, ZDV, 3TC, ddI-d4T, ZDV-3TC, ZDV-ABC containing regimens. Of note, 1,25D3 protected against myotube mtDNA depletion following ZDV-3TC treatment, rendering them similar to 1,25D3 untreated controls (P = 0.62), and increased both myotube and myoblast mtDNA 2-3-fold in ddI containing regimens (P < 0.05).
CONCLUSIONS::1,25D3 confers a protective effect against NRTI-induced mitochondrial toxicity in skeletal muscle myoblasts and myotubes. These findings support a protective role for vitamin D in preventing mitochondrial toxicity and suggest that supplemental vitamin D may protect against NRTI-associated mitochondrial toxicity.
- High throughput LC-MS/MS method for simultaneous determination of zidovudine, lamivudine and nevirapine in human plasma. [Journal Article, Research Support, Non-U.S. Gov't, Validation Studies]
- J Chromatogr B Analyt Technol Biomed Life Sci 2013 Mar 15.:9-14.
A selective and sensitive high performance liquid chromatography-tandem mass spectrometry method has been developed and validated for simultaneous determination of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) in human plasma. After Solid phase extraction (SPE), analytes and ISTDs were run on Peerless Basic C18 column with an injection volume of 3μL and run time of 3.0min. An isocratic mobile phase of 0.1% formic acid in water:methanol (15:85, v/v) was used with positive mass spectrometric detection. The method was validated over a concentration range of 5-1500ng/mL for ZDV and 3TC and over the concentration range of 10-3000ng/mL for NVP. The intraday and interday precision and accuracy across four validation runs were ranged from 1.6 to 10.1% and 93.8 to 110.8% respectively.