RESUMEN
HIV genotyping is used to assess HIV susceptibility to antiretroviral drugs. The Applied Biosystems HIV-1 Genotyping Kit with Integrase (AB kit, Thermo Fisher Scientific) detects resistance-associated mutations (RAMs) in HIV protease (PR), reverse transcriptase (RT), and integrase (IN). We compared results from the AB kit with results obtained previously with the ViroSeq HIV-1 Genotyping System. DNA amplicons from the AB kit were also analyzed using next-generation sequencing (NGS). HIV RNA was extracted using the MagNA Pure 24 instrument (Roche Diagnostics; 96 plasma samples, HIV subtype B, viral load range: 530-737,741 copies/mL). FASTA files were generated from AB kit data using Exatype (Hyrax Biosciences). DNA amplicons from the AB kit were also analyzed by NGS using the Nextera XT kit (Illumina). Drug resistance was predicted using the Stanford HIV Drug Resistance Database. The mean genetic distance for sequences from ViroSeq and the AB kit was 0.02% for PR/RT and 0.04% for IN; 103 major RAMs were detected by both methods. Four additional major RAMs were detected by the AB kit only. These four major RAMs were also detected by NGS (detected in 18.1%-38.2% of NGS reads). NGS detected 27 major RAMs that were not detected with either of the Sanger sequencing-based kits. All major RAMs detected with ViroSeq were detected with the AB kit; additional RAMs were detected with the AB kit only. DNA amplicons from the AB kit can be used for NGS for more sensitive detection of RAMs.
Asunto(s)
Farmacorresistencia Viral , Técnicas de Genotipaje , Infecciones por VIH , Integrasa de VIH , VIH-1 , Secuenciación de Nucleótidos de Alto Rendimiento , VIH-1/genética , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/aislamiento & purificación , VIH-1/clasificación , Humanos , Infecciones por VIH/virología , Técnicas de Genotipaje/métodos , Farmacorresistencia Viral/genética , Integrasa de VIH/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Genotipo , Juego de Reactivos para Diagnóstico/normas , ARN Viral/genética , Mutación , Transcriptasa Inversa del VIH/genética , Proteasa del VIH/genéticaRESUMEN
Background: High HIV viral load (VL) is associated with increased transmission risk and faster disease progression. HIV controllers achieve viral suppression without antiretroviral (ARV) treatment. We evaluated viremic control in a community-randomized trial with >48,000 participants. Methods: A massively multiplexed antibody profiling system, VirScan, was used to quantify pre- and post-infection antibody reactivity to HIV peptides in 664 samples from 429 participants (13 controllers, 135 viremic non-controllers, 64 other non-controllers, 217 uninfected persons). Controllers had VLs <2,000 copies/mL with no ARV drugs detected at the first HIV-positive visit and one year later. Viremic non-controllers had VLs 2,000 copies/mL with no ARV drugs detected at the first HIV-positive visit. Other non-controllers had either ARV drugs detected at the first HIV-positive visit (n=47) or VLs <2,000 copies/mL with no ARV drugs detected at only one HIV-positive visit (n=17). Results: We identified pre-infection HIV antibody reactivities that correlated with post-infection VL. Pre-infection reactivity to an epitope in the HR2 domain of gp41 was associated with controller status and lower VL. Pre-infection reactivity to an epitope in the C2 domain of gp120 was associated with non-controller status and higher VL. Different patterns of antibody reactivity were observed over time for these two epitopes. Conclusion: These studies suggest that pre-infection HIV antibodies are associated with controller status and modulation of HIV VL. These findings may inform research on antibody-based interventions for HIV treatment.
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Infecciones por VIH , VIH-1 , Humanos , Carga Viral , Anticuerpos Anti-VIH , Antirretrovirales/uso terapéutico , Epítopos , Viremia/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológicoRESUMEN
BACKGROUND: Multi-assay algorithms (MAAs) are used to estimate population-level HIV incidence and identify individuals with recent infection. Many MAAs use low viral load (VL) as a biomarker for long-term infection. This could impact incidence estimates in settings with high rates of early HIV treatment initiation. We evaluated the performance of two MAAs that do not include VL. METHODS: Samples were collected from 219 seroconverters (infected < 1 year) and 4376 non-seroconverters (infected > 1 year) in the HPTN 071 (PopART) trial; 28.8% of seroconverter samples and 73.2% of non-seroconverter samples had VLs ≤ 400 copies/mL. Samples were tested with the Limiting Antigen Avidity assay (LAg) and JHU BioRad-Avidity assays. Antibody reactivity to two HIV peptides was measured using the MSD U-PLEX assay. Two MAAs were evaluated that do not include VL: a MAA that includes the LAg-Avidity assay and BioRad-Avidity assay (LAg + BR) and a MAA that includes the LAg-Avidity assay and two peptide biomarkers (LAg + PepPair). Performance of these MAAs was compared to a widely used MAA that includes LAg and VL (LAg + VL). RESULTS: The incidence estimate for LAg + VL (1.29%, 95% CI: 0.97-1.62) was close to the observed longitudinal incidence (1.34% 95% CI: 1.17-1.53). The incidence estimates for the other two MAAs were higher (LAg + BR: 2.56%, 95% CI 2.01-3.11; LAg + PepPair: 2.84%, 95% CI: 1.36-4.32). LAg + BR and LAg + PepPair also misclassified more individuals infected > 2 years as recently infected than LAg + VL (1.2% [42/3483 and 1.5% [51/3483], respectively, vs. 0.2% [6/3483]). LAg + BR classified more seroconverters as recently infected than LAg + VL or LAg + PepPair (80 vs. 58 and 50, respectively) and identified ~ 25% of virally suppressed seroconverters as recently infected. CONCLUSIONS: The LAg + VL MAA produced a cross-sectional incidence estimate that was closer to the longitudinal estimate than two MAAs that did not include VL. The LAg + BR MAA classified the greatest number of individual seroconverters as recently infected but had a higher false recent rate.
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Infecciones por VIH , Humanos , Estudios Transversales , Incidencia , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Técnicas para Inmunoenzimas , Antirretrovirales/uso terapéutico , Carga Viral , Algoritmos , BiomarcadoresRESUMEN
Introduction: Low HIV viral load is associated with delayed disease progression and reduced HIV transmission. HIV controllers suppress viral load to low levels in the absence of antiretroviral treatment (ART). We used an antibody profiling system, VirScan, to compare antibody reactivity and specificity in HIV controllers, non-controllers with treatment-induced viral suppression, and viremic non-controllers. Methods: The VirScan library contains 3,384 phage-displayed peptides spanning the HIV proteome. Antibody reactivity to these peptides was measured in plasma from a Discovery Cohort that included 13 elite controllers, 27 viremic controllers, 12 viremic non-controllers, and 21 non-controllers who were virally suppressed on ART. Antibody reactivity to selected peptides was also assessed in an independent cohort of 29 elite controllers and 37 non-controllers who were virally suppressed on ART (Validation Cohort) and in a longitudinal cohort of non-controllers. Results: In the Discovery Cohort, 62 peptides were preferentially targeted in HIV controllers compared to non-controllers who were virally suppressed on ART. These specificities were not significantly different when comparing controllers versus viremic non-controllers. Aggregate reactivity to these peptides was also high in elite controllers from the independent Validation Cohort. The 62 peptides formed seven clusters of homologous epitopes in env, gag, integrase, and vpu. Reactivity to one of these clusters located in gag p17 was inversely correlated with viral load set point in an independent cohort of non-controllers. Conclusions: Antibody reactivity was low in non-controllers suppressed on ART, but remained high in viremic controllers despite viral suppression. Antibodies in controllers and viremic non-controllers were directed against epitopes in diverse HIV proteins; higher reactivity against p17 peptides was associated with lower viral load set point. Further studies are needed to determine if these antibodies play a role in regulation of HIV viral load.
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Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH no-Progresivos , VIH-1/fisiología , Adulto , Antirretrovirales/uso terapéutico , Mapeo Epitopo , Epítopos/genética , Epítopos/inmunología , Femenino , Antígenos VIH/genética , Antígenos VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Biblioteca de Péptidos , Carga Viral , Adulto Joven , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
We combined behavioral survey data from the human immunodeficiency virus (HIV) Prevention Trials Network 068 study with phylogenetic information to determine if cluster membership was associated with characteristics of young women and their partners. Clusters were more likely to involve young women from specific villages and schools, indicating some localized transmission.Supplemental digital content is available in the text.
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Infecciones por VIH/transmisión , VIH/genética , Parejas Sexuales , Conducta Social , Adolescente , Factores de Edad , Análisis por Conglomerados , Femenino , Geografía , VIH/fisiología , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Humanos , Masculino , Filogenia , Instituciones Académicas , Sudáfrica/epidemiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: We evaluated use of phylogenetic methods to predict the direction of human immunodeficiency virus (HIV) transmission. METHODS: For 33 pairs of HIV-infected patients (hereafter, "index patients") and their partners who acquired genetically linked HIV infection during the study, samples were collected from partners and index patients close to the time when the partner seroconverted (hereafter, "SC samples"); for 31 pairs, samples collected from the index patient at an earlier time point (hereafter, "early index samples") were also available. Phylogenies were inferred using env next-generation sequences (1 tree per pair/subtype). The direction of transmission (DoT) predicted from each tree was classified as correct or incorrect on the basis of which sequences (those from the index patient or the partner) were closest to the root. DoT was also assessed using maximum parsimony to infer ancestral node states for 100 bootstrap trees. RESULTS: DoT was predicted correctly for both single-pair and subtype-specific trees in 22 pairs (67%) by using SC samples and in 23 pairs (74%) by using early index samples. DoT was predicted incorrectly for 4 pairs (15%) by using SC or early index samples. In the bootstrap analysis, DoT was predicted correctly for 18 pairs (55%) by using SC samples and for 24 pairs (73%) by using early index samples. DoT was predicted incorrectly for 7 pairs (21%) by using SC samples and for 4 pairs (13%) by using early index samples. CONCLUSIONS: Phylogenetic methods based solely on the tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT.
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Transmisión de Enfermedad Infecciosa , Genotipo , Infecciones por VIH/virología , VIH/clasificación , VIH/genética , Epidemiología Molecular/métodos , Filogenia , Estudios de Cohortes , Femenino , VIH/aislamiento & purificación , Infecciones por VIH/transmisión , Heterosexualidad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
BACKGROUND: South Africa has one of the highest rates of HIV-1 (HIV) infection world-wide, with the highest rates among young women. We analyzed the molecular epidemiology and evolutionary history of HIV in young women attending high school in rural South Africa. METHODS: Samples were obtained from the HPTN 068 randomized controlled trial, which evaluated the effect of cash transfers for school attendance on HIV incidence in women aged 13-20 years (Mpumalanga province, 2011-2015). Plasma samples from HIV-infected participants were analyzed using the ViroSeq HIV-1 Genotyping assay. Phylogenetic analysis was performed using 200 pol gene study sequences and 2,294 subtype C reference sequences from South Africa. Transmission clusters were identified using Cluster Picker and HIV-TRACE, and were characterized using demographic and other epidemiological data. Phylodynamic analyses were performed using the BEAST software. RESULTS: The study enrolled 2,533 young women who were followed through their expected high school graduation date (main study); some participants had a post-study assessment (follow-up study). Two-hundred-twelve of 2,533 enrolled young women had HIV infection. HIV pol sequences were obtained for 94% (n = 201/212) of the HIV-infected participants. All but one of the sequences were HIV-1 subtype C; the non-C subtype sequence was excluded from further analysis. Median pairwise genetic distance between the subtype C sequences was 6.4% (IQR: 5.6-7.2). Overall, 26% of study sequences fell into 21 phylogenetic clusters with 2-6 women per cluster. Thirteen (62%) clusters included women who were HIV-infected at enrollment. Clustering was not associated with study arm, demographic or other epidemiological factors. The estimated date of origin of HIV subtype C in the study population was 1958 (95% highest posterior density [HPD]: 1931-1980), and the median estimated substitution rate among study pol sequences was 1.98x10-3 (95% HPD: 1.15x10-3-2.81x10-3) per site per year. CONCLUSIONS: Phylogenetic analysis suggests that multiple HIV subtype C sublineages circulate among school age girls in South Africa. There were no substantive differences in the molecular epidemiology of HIV between control and intervention arms in the HPTN 068 trial.
Asunto(s)
Genes pol/genética , Infecciones por VIH/genética , VIH-1/genética , Filogenia , Adolescente , Adulto , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/epidemiología , VIH-1/patogenicidad , Humanos , Epidemiología Molecular , Sudáfrica/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Antiretroviral (ARV) drugs are used for HIV treatment and prevention. We analyzed ARV drug use and HIV drug resistance in a cohort of young women in rural South Africa enrolled in the HIV Prevention Trials Network (HPTN) 068 study, which evaluated the use of a cash transfer conditional on school attendance to reduce HIV incidence. METHODS: ARV drug testing was performed using plasma samples from 2526 young women. This included 2526 enrollment samples (80 HIV-infected and 2446 HIV-uninfected) and 162 seroconversion samples (first HIV-positive study visit). Testing was performed using a qualitative assay that detects 20 ARV drugs from 5 drug classes. HIV drug resistance testing was performed with the ViroSeq HIV-1 Genotyping System for samples that had HIV viral loads ≥400 copies per milliliter. RESULTS: At enrollment, ARV drugs were detected in 10 (12.5%) of 80 HIV-infected young women. None of 2446 HIV-uninfected young women had ARV drugs detected at enrollment. ARV drugs were also detected in 16 (9.9%) of 162 seroconverters. At enrollment, 9 (13.4%) of 67 young women with genotyping results had HIV drug resistance; resistance was also detected in 9 (6.9%) of 131 seroconverters with genotyping results. CONCLUSIONS: Most of the HIV-infected young women in this cohort from rural South Africa were not taking ARV drugs, suggesting they were unaware of their HIV status or were not in care. HIV drug resistance was detected in young women with both prevalent and new HIV infection.
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Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral , Utilización de Medicamentos/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Adolescente , Fármacos Anti-VIH/sangre , Femenino , Genotipo , Técnicas de Genotipaje , Infecciones por VIH/epidemiología , VIH-1/genética , Humanos , Incidencia , Plasma/química , Plasma/virología , Población Rural , Sudáfrica/epidemiología , Carga Viral , Adulto JovenRESUMEN
INTRODUCTION: We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005-2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm (early ART arm) or <250 cells/mm (delayed ART arm). In May 2011, interim study results showed benefit of early ART, and all participants were offered ART regardless of CD4 cell count; the study ended in 2015. METHODS: Virologic failure was defined as 2 consecutive viral loads >1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure. RESULTS: HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure. CONCLUSIONS: In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.
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Antirretrovirales/farmacología , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH/efectos de los fármacos , Prevención Secundaria , Tiempo de Tratamiento , Adulto , Antirretrovirales/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Ensayos Clínicos como Asunto , Femenino , Genotipo , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Insuficiencia del Tratamiento , Carga ViralRESUMEN
BACKGROUND: HIV Prevention Trials Network (HPTN) 067/ADAPT evaluated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis (PrEP) in women (South Africa) and men who have sex with men (Thailand, US). Participants received once-weekly directly observed therapy (DOT) of TDF/FTC, and were then randomized to daily, time-driven, or event-driven PrEP. This report describes characterization of 12 HIV seroconversion events in this trial. METHODS: HIV rapid testing was performed at study sites. Retrospective testing included fourth generation assays, HIV RNA testing, Western blot, an HIV-1/2 discriminatory assay, resistance testing, and antiretroviral drug testing. RESULTS: Six of the 12 seroconverters received TDF/FTC in the DOT phase, but were not randomized (3 were acutely infected at enrollment; 2 were infected during the DOT phase; 1 was not randomized because of pregnancy). One of the 6 randomized participants had acute infection at randomization but was not diagnosed for 3-4 months because HIV rapid tests were nonreactive; continued daily PrEP use was associated with false-negative antibody tests and low HIV RNA levels. The 5 participants infected after randomization included 4 with low adherence to the PrEP regimen, and one who reported a 7-day period without dosing before infection. Three participants had TDF/FTC resistance (M184I, K65R), including 2 who received only 4 once-weekly TDF/FTC doses; most TDF/FTC mutations were detected by next generation sequencing only. CONCLUSIONS: In HPTN 067/ADAPT, participants who acquired HIV infection had infrequent PrEP dosing or low/suboptimal adherence. Sensitive assays improved detection of HIV infection and drug resistance. Drug resistance was observed with limited PrEP exposure.
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Fármacos Anti-VIH/uso terapéutico , Terapia por Observación Directa , Farmacorresistencia Viral/efectos de los fármacos , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/uso terapéutico , Seropositividad para VIH/tratamiento farmacológico , Profilaxis Pre-Exposición , Adulto , Femenino , Seropositividad para VIH/sangre , Seropositividad para VIH/epidemiología , Humanos , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sudáfrica/epidemiología , Tailandia/epidemiologíaRESUMEN
HIV Prevention Trials Network 052 demonstrated that antiretroviral therapy (ART) prevents HIV transmission in serodiscordant couples. HIV from index-partner pairs was analyzed to determine the genetic linkage status of partner infections. Forty-six infections were classified as linked, indicating that the index was the likely source of the partner's infection. Lack of viral suppression and higher index viral load were associated with linked infection. Eight linked infections were diagnosed after the index started ART: 4 near the time of ART initiation and 4 after ART failure. Linked infections were not observed when the index participant was stably suppressed on ART.
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Fármacos Anti-VIH/administración & dosificación , Quimioprevención/métodos , Transmisión de Enfermedad Infecciosa/prevención & control , Infecciones por VIH/prevención & control , Estudios de Cohortes , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. METHODS: We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis. RESULTS: Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant. CONCLUSIONS: The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581 .).
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Antirretrovirales/uso terapéutico , Transmisión de Enfermedad Infecciosa/prevención & control , Infecciones por VIH/transmisión , VIH-1 , Parejas Sexuales , Adulto , Femenino , Estudios de Seguimiento , Infecciones por VIH/prevención & control , Seropositividad para VIH , VIH-1/genética , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Riesgo , Adulto JovenRESUMEN
Early initiation of antiretroviral treatment (ART) reduces HIV transmission and has health benefits. HIV drug resistance can limit treatment options and compromise use of ART for HIV prevention. We evaluated drug resistance in 85 participants in the HIV Prevention Trials Network 052 trial who started ART at CD4 counts of 350-550 cells per cubic millimeter and failed ART by May 2011; 8.2% had baseline resistance and 35.3% had resistance at ART failure. High baseline viral load and less education were associated with emergence of resistance at ART failure. Resistance at ART failure was observed in 7 of 8 (87.5%) participants who started ART at lower CD4 cell counts.
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Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH/efectos de los fármacos , Adulto , Recuento de Linfocito CD4 , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Infecciones por VIH/inmunología , Humanos , Masculino , Estudios Observacionales como Asunto , Insuficiencia del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. METHODS: Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance-failure association. RESULTS: In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex-treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04-2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22-.98). CONCLUSIONS: In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible. CLINICAL TRIALS REGISTRATION: NCT00084136.
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Farmacorresistencia Viral , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH-1/clasificación , VIH-1/efectos de los fármacos , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Técnicas de Genotipaje , Infecciones por VIH/virología , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia del Tratamiento , Carga Viral , Adulto Joven , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
BACKGROUND: Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking. METHODS: The HIV Prevention Trials Network 057 protocol was a phase 1, open-label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV-infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses on days 0, 3, and 5; maternal 900 mg doses/infant 6 mg/kg doses on days 0, 3, and 5; maternal 600 mg doses/infant 6 mg/kg daily for 7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid, and breast milk tenofovir concentrations were determined by liquid chromatographic-tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing. RESULTS: One hundred twenty-two mother-infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 and 900 mg exceeded that in nonpregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults, and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74%-97% of infants receiving daily dosing. CONCLUSIONS: A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in the studies of TDF efficacy for HIV prevention of mother-to-child transmission and early infant treatment.
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Adenina/análogos & derivados , Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Trabajo de Parto/efectos de los fármacos , Organofosfonatos/farmacocinética , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/farmacocinética , Adenina/uso terapéutico , Adolescente , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Esquema de Medicación , Femenino , Sangre Fetal/química , Infecciones por VIH/complicaciones , Humanos , Recién Nacido , Organofosfonatos/administración & dosificación , Organofosfonatos/efectos adversos , Organofosfonatos/uso terapéutico , Embarazo , Complicaciones Infecciosas del Embarazo/metabolismo , Tenofovir , Adulto JovenRESUMEN
In the HPTN 052 study, transmission between HIV-discordant couples was reduced by 96% when the HIV-infected partner received suppressive antiretroviral therapy (ART). We examined two transmission events where the newly infected partner was diagnosed after the HIV-infected partner (index) initiated therapy. We evaluated the sequence complexity of the viral populations and antibody reactivity in the newly infected partner to estimate the dates of transmission to the newly infected partners. In both cases, transmission most likely occurred significantly before HIV-1 diagnosis of the newly infected partner, and either just before the initiation of therapy or before viral replication was adequately suppressed by therapy of the index. This study further strengthens the conclusion about the efficacy of blocking transmission by treating the infected partner of discordant couples. However, this study does not rule out the potential for HIV-1 transmission to occur shortly after initiation of ART, and this should be recognized when antiretroviral therapy is used for HIV-1 prevention.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/transmisión , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , VIH-1 , HumanosRESUMEN
We analyzed antiretroviral drug susceptibility in HIV-infected adults failing first- and second-line antiretroviral treatment (ART) in Rakai, Uganda. Samples obtained from participants at baseline (pretreatment) and at the time of failure on first-line ART and second-line ART were analyzed using genotypic and phenotypic assays for antiretroviral drug resistance. Test results were obtained from 73 samples from 38 individuals (31 baseline samples, 36 first-line failure samples, and six second-line failure samples). Four (13%) of the 31 baseline samples had mutations associated with resistance to nucleoside or nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). Among the 36 first-line failure samples, 31 (86%) had NNRTI resistance mutations and 29 (81%) had lamivudine resistance mutations; only eight (22%) had other NRTI resistance mutations. None of the six individuals failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Genotypic resistance to drugs included in first-line ART regimens was detected prior to treatment and among participants failing first-line ART. PI resistance was not detected in individuals failing second-line ART. Surveillance for transmitted and acquired drug resistance remains a priority for scale-up of ART.
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Antirretrovirales/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH/efectos de los fármacos , VIH/genética , Adolescente , Adulto , Femenino , Genotipo , VIH/aislamiento & purificación , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mutación Missense , Análisis de Secuencia de ADN , Insuficiencia del Tratamiento , Uganda , Adulto JovenRESUMEN
BACKGROUND: Cross-sectional assessment of HIV incidence relies on laboratory methods to discriminate between recent and non-recent HIV infection. Because HIV diversifies over time in infected individuals, HIV diversity may serve as a biomarker for assessing HIV incidence. We used a high resolution melting (HRM) diversity assay to compare HIV diversity in adults with different stages of HIV infection. This assay provides a single numeric HRM score that reflects the level of genetic diversity of HIV in a sample from an infected individual. METHODS: HIV diversity was measured in 203 adults: 20 with acute HIV infection (RNA positive, antibody negative), 116 with recent HIV infection (tested a median of 189 days after a previous negative HIV test, range 14-540 days), and 67 with non-recent HIV infection (HIV infected >2 years). HRM scores were generated for two regions in gag, one region in pol, and three regions in env. RESULTS: Median HRM scores were higher in non-recent infection than in recent infection for all six regions tested. In multivariate models, higher HRM scores in three of the six regions were independently associated with non-recent HIV infection. CONCLUSIONS: The HRM diversity assay provides a simple, scalable method for measuring HIV diversity. HRM scores, which reflect the genetic diversity in a viral population, may be useful biomarkers for evaluation of HIV incidence, particularly if multiple regions of the HIV genome are examined.