RESUMEN
Human immunodeficiency virus type 1 (HIV-1) infection persists despite years of antiretroviral therapy (ART). To remove the stigma and burden of chronic infection, approaches to eradicate or cure HIV infection are desired. Attempts to augment ART with therapies that reverse viral latency, paired with immunotherapies to clear infection, have advanced into the clinic, but the field is still in its infancy. We review foundational studies and highlight new insights in HIV cure research. Together with advances in ART delivery and HIV prevention strategies, future therapies that clear HIV infection may relieve society of the affliction of the HIV pandemic.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Enfermedad Crónica/terapia , Infecciones por VIH/terapia , VIH-1/efectos de los fármacos , Inmunoterapia/métodos , Latencia del Virus/efectos de los fármacos , Animales , Haplorrinos , HumanosRESUMEN
BACKGROUND: NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America. METHODS: We conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed. RESULTS: Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest - largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose. CONCLUSIONS: NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802.).
Asunto(s)
Vacunas contra la COVID-19 , COVID-19/prevención & control , Eficacia de las Vacunas , Adolescente , Adulto , Anciano , COVID-19/diagnóstico , COVID-19/epidemiología , Prueba de Ácido Nucleico para COVID-19 , Vacunas contra la COVID-19/efectos adversos , Humanos , Incidencia , Masculino , México , Persona de Mediana Edad , SARS-CoV-2 , Método Simple Ciego , Estados UnidosRESUMEN
BACKGROUND: The histone deacetylase inhibitor vorinostat (VOR) can reverse human immunodeficiency virus type 1 (HIV-1) latency in vivo and allow T cells to clear infected cells in vitro. HIV-specific T cells (HXTCs) can be expanded ex vivo and have been safely administered to people with HIV (PWH) on antiretroviral therapy. METHODS: Six PWH received infusions of 2 × 107 HXTCs/m² with VOR 400â mg, and 3 PWH received infusions of 10 × 107 HXTCs/m² with VOR. The frequency of persistent HIV by multiple assays including quantitative viral outgrowth assay (QVOA) of resting CD4+ T cells was measured before and after study therapy. RESULTS: VOR and HXTCs were safe, and biomarkers of serial VOR effect were detected, but enhanced antiviral activity in circulating cells was not evident. After 2 × 107 HXTCs/m² with VOR, 1 of 6 PWH exhibited a decrease in QVOA, and all 3 PWH exhibited such declines after 10 × 107 HXTCs/m² and VOR. However, most declines did not exceed the 6-fold threshold needed to definitively attribute decline to the study intervention. CONCLUSIONS: These modest effects provide support for the strategy of HIV latency reversal and reservoir clearance, but more effective interventions are needed to yield the profound depletion of persistent HIV likely to yield clinical benefit. Clinical Trials Registration. NCT03212989.
Asunto(s)
Infecciones por VIH , VIH-1 , Humanos , Vorinostat/uso terapéutico , Vorinostat/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacología , Linfocitos T CD4-Positivos , Tratamiento Basado en Trasplante de Células y Tejidos , Latencia del VirusRESUMEN
BACKGROUND: Protein-based vaccines for coronavirus disease 2019 (COVID-19) provide a traditional vaccine platform with long-lasting protection for non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogens and may complement messenger RNA vaccines as a booster dose. While NVX-CoV2373 showed substantial early efficacy, the durability of protection has not been delineated. METHODS: The PREVENT-19 vaccine trial used a blinded crossover design; the original placebo arm received NVX-CoV2373 after efficacy was established. Using novel statistical methods that integrate surveillance data of circulating strains with post-crossover cases, we estimated placebo-controlled vaccine efficacy and durability of NVX-CoV2373 against both pre-Delta and Delta strains of SARS-CoV-2. RESULTS: Vaccine efficacy against pre-Delta strains of COVID-19 was 89% (95% CI, 75-95%) and 87% (72-94%) at 0 and 90 days after 2 doses of NVX-CoV2373, respectively, with no evidence of waning (P = .93). Vaccine efficacy against the Delta strain was 88% (71-95%), 82% (56-92%), and 77% (44-90%) at 40, 120, and 180 days, respectively, with evidence of waning (P < .01). In sensitivity analyses, the estimated Delta vaccine efficacy at 120 days ranged from 66% (15-86%) to 89% (74-95%) per various assumptions of the surveillance data. CONCLUSIONS: NVX-CoV2373 has high initial efficacy against pre-Delta and Delta strains of COVID-19 with little evidence of waning for pre-Delta strains through 90 days and moderate waning against Delta strains over 180 days.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Estudios Cruzados , SARS-CoV-2 , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , Persona de Mediana Edad , Masculino , Adulto , Femenino , Eficacia de las Vacunas , Anticuerpos Antivirales/sangre , Anciano , Inmunización Secundaria , Adulto JovenRESUMEN
BACKGROUND: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. METHODS: A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods. RESULTS: A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus. CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Eficacia de las Vacunas , Humanos , COVID-19/prevención & control , COVID-19/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Masculino , Femenino , SARS-CoV-2/inmunología , Persona de Mediana Edad , Adulto , Huésped Inmunocomprometido , Anciano , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. METHODS AND FINDINGS: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). CONCLUSIONS: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. TRIAL REGISTRATION: ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Humanos , Masculino , Femenino , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Anti-VIH/sangre , Persona de Mediana Edad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Adulto Joven , Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos ampliamente neutralizantes/efectos adversos , Adolescente , Inyecciones IntramuscularesRESUMEN
IMPORTANCE: The lack of a reliable method to accurately detect when replication-competent HIV has been cleared is a major challenge in developing a cure. This study introduces a new approach called the HIVepsilon-seq (HIVε-seq) assay, which uses long-read sequencing technology and bioinformatics to scrutinize the HIV genome at the nucleotide level, distinguishing between defective and intact HIV. This study included 30 participants on antiretroviral therapy, including 17 women, and was able to discriminate between defective and genetically intact viruses at the single DNA strand level. The HIVε-seq assay is an improvement over previous methods, as it requires minimal sample, less specialized lab equipment, and offers a shorter turnaround time. The HIVε-seq assay offers a promising new tool for researchers to measure the intact HIV reservoir, advancing efforts towards finding a cure for this devastating disease.
Asunto(s)
Infecciones por VIH , VIH , Provirus , Femenino , Humanos , Linfocitos T CD4-Positivos , ADN Viral/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Nucleótidos , Provirus/genética , Carga Viral , Análisis de Secuencia de ADN , Masculino , Factores Sexuales , VIH/genéticaRESUMEN
We tested the combination of a broadly neutralizing HIV antibody with the latency reversal agent vorinostat (VOR). Eight participants received 2 month-long cycles of VRC07-523LS with VOR. Low-level viremia, resting CD4+ T-cell-associated HIV RNA (rca-RNA) was measured, and intact proviral DNA assay (IPDA) and quantitative viral outgrowth assay (QVOA) were performed at baseline and posttreatment. In 3 participants, IPDA and QVOA declines were accompanied by significant declines of rca-RNA. However, no IPDA or QVOA declines clearly exceeded assay variance or natural decay. Increased resistance to VRC07-523LS was not observed. This combination therapy did not reduce viremia or the HIV reservoir. Clinical Trials Registration. NCT03803605.
Asunto(s)
Infecciones por VIH , VIH-1 , Anticuerpos ampliamente neutralizantes , Linfocitos T CD4-Positivos , VIH-1/genética , Humanos , Viremia/tratamiento farmacológico , Latencia del Virus , Vorinostat/uso terapéuticoRESUMEN
BACKGROUND: The replication-competent human immunodeficiency virus (HIV) reservoir is the major barrier to cure. The quantitative viral outgrowth assay (QVOA), the gold-standard method to quantify replication-competent HIV, is resource intensive, which limits its application in large clinical trials. The intact proviral DNA assay (IPDA) requires minimal cell input relative to QVOA and quantifies both defective and intact proviral HIV DNA, the latter potentially serving as a surrogate marker for replication-competent provirus. However, there are limited cross-sectional and longitudinal data on the relationship between IPDA and QVOA measurements. METHODS: QVOA and IPDA measurements were performed on 156 resting CD4 T-cell (rCD4) samples from 83 antiretroviral therapy-suppressed HIV-positive participants. Longitudinal QVOA and IPDA measurements were performed on rCD4 from 29 of these participants. RESULTS: Frequencies of intact, defective, and total proviruses were positively associated with frequencies of replication-competent HIV. Longitudinally, decreases in intact proviral frequencies were strikingly similar to that of replication-competent virus in most participants. In contrast, defective proviral DNA frequencies appeared relatively stable over time in most individuals. CONCLUSIONS: Changes in frequencies of IPDA-derived intact proviral DNA and replication-competent HIV measured by QVOA are similar. IPDA is a promising high-throughput approach to estimate changes in the frequency of the replication-competent reservoir.
Asunto(s)
Antirretrovirales/uso terapéutico , ADN Viral/análisis , VIH/aislamiento & purificación , Provirus/aislamiento & purificación , Adulto , Estudios Transversales , Femenino , VIH/efectos de los fármacos , VIH/crecimiento & desarrollo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Provirus/crecimiento & desarrollo , Estudios RetrospectivosRESUMEN
Social networks can be leveraged to identify undiagnosed HIV-infected individuals. The NC-LINK clinic-based testing initiative utilized these networks to achieve a 5% (95% CI 1.1-8.9%) positivity rate by providing free HIV testing to anyone who accompanied an HIV-infected patient to their clinic appointment. During 2013-2015, 120 individuals were tested at two clinics (N > 1000 patients each) in North Carolina, with 5 new and 6 total positive results. Of these, three linked to care within 30 days and all within 365 days. If expanded further, this initiative could significantly increase the number of HIV-infected individuals aware of their status.
Asunto(s)
Atención Ambulatoria , Citas y Horarios , Infecciones por VIH/diagnóstico , Red Social , Adolescente , Adulto , Instituciones de Atención Ambulatoria , Femenino , Humanos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , North Carolina , Adulto JovenRESUMEN
Adoptive T cell therapy has had dramatic successes in the treatment of virus-related malignancies and infections following hematopoietic stem cell transplantation. We adapted this method to produce ex vivo expanded HIV-specific T cells (HXTCs), with the long-term goal of using HXTCs as part of strategies to clear persistent HIV infection. In this phase 1 proof-of-concept study (NCT02208167), we administered HXTCs to antiretroviral therapy (ART)-suppressed, HIV-infected participants. Participants received two infusions of 2 × 107 cells/m2 HXTCs at a 2-week interval. Leukapheresis was performed at baseline and 12 weeks post-infusion to measure the frequency of resting cell infection by the quantitative viral outgrowth assay (QVOA). Overall, participants tolerated HXTCs, with only grade 1 adverse events (AEs) related to HXTCs. Two of six participants exhibited a detectable increase in CD8 T cell-mediated antiviral activity following the two infusions in some, but not all, assays. As expected, however, in the absence of a latency reversing agent, no meaningful decline in the frequency of resting CD4 T cell infection was detected. HXTC therapy in ART-suppressed, HIV-infected individuals appears safe and well tolerated, without any clinical signs of immune activation, likely due to the low residual HIV antigen burden present during ART.
Asunto(s)
Terapia Antirretroviral Altamente Activa/métodos , Tratamiento Basado en Trasplante de Células y Tejidos , Infecciones por VIH/terapia , Linfocitos T/trasplante , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Terapia Genética , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T/inmunología , Activación Viral/genética , Activación Viral/inmunología , Replicación Viral/genética , Replicación Viral/inmunologíaRESUMEN
Background: Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)-specific immunity and increase clearance of HIV-1-expressing cells. Methods: We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1-infected adults aged >18 to <70 years on suppressive antiretroviral therapy with CD4+ counts >350 cells/µL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion. Results: Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559. Conclusions: In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1-specific immunity in a subset of participants. Clinical Trials Registration: NCT02028403.
Asunto(s)
Antirretrovirales/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Infecciones por VIH/tratamiento farmacológico , Adulto , Linfocitos T CD8-positivos , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1 , Humanos , Masculino , Persona de Mediana EdadRESUMEN
IMPORTANCE: Although acute HIV infection contributes disproportionately to onward HIV transmission, HIV testing has not routinely included screening for acute HIV infection. OBJECTIVE: To evaluate the performance of an HIV antigen/antibody (Ag/Ab) combination assay to detect acute HIV infection compared with pooled HIV RNA testing. DESIGN, SETTING, AND PARTICIPANTS: Multisite, prospective, within-individual comparison study conducted between September 2011 and October 2013 in 7 sexually transmitted infection clinics and 5 community-based programs in New York, California, and North Carolina. Participants were 12 years or older and seeking HIV testing, without known HIV infection. EXPOSURES: All participants with a negative rapid HIV test result were screened for acute HIV infection with an HIV Ag/Ab combination assay (index test) and pooled human immunodeficiency virus 1 (HIV-1) RNA testing. HIV RNA testing was the reference standard, with positive reference standard result defined as detectable HIV-1 RNA on an individual RNA test. MAIN OUTCOMES AND MEASURES: Number and proportion with acute HIV infections detected. RESULTS: Among 86,836 participants with complete test results (median age, 29 years; 75.0% men; 51.8% men who have sex with men), established HIV infection was diagnosed in 1158 participants (1.33%) and acute HIV infection was diagnosed in 168 participants (0.19%). Acute HIV infection was detected in 134 participants with HIV Ag/Ab combination testing (0.15% [95% CI, 0.13%-0.18%]; sensitivity, 79.8% [95% CI, 72.9%-85.6%]; specificity, 99.9% [95% CI, 99.9%-99.9%]; positive predictive value, 59.0% [95% CI, 52.3%-65.5%]) and in 164 participants with pooled HIV RNA testing (0.19% [95% CI, 0.16%-0.22%]; sensitivity, 97.6% [95% CI, 94.0%-99.4%]; specificity, 100% [95% CI, 100%-100%]; positive predictive value, 96.5% [95% CI, 92.5%-98.7%]; sensitivity comparison, P < .001). Overall HIV Ag/Ab combination testing detected 82% of acute HIV infections detectable by pooled HIV RNA testing. Compared with rapid HIV testing alone, HIV Ag/Ab combination testing increased the relative HIV diagnostic yield (both established and acute HIV infections) by 10.4% (95% CI, 8.8%-12.2%) and pooled HIV RNA testing increased the relative HIV diagnostic yield by 12.4% (95% CI, 10.7%-14.3%). CONCLUSIONS AND RELEVANCE: In a high-prevalence population, HIV screening using an HIV Ag/Ab combination assay following a negative rapid test detected 82% of acute HIV infections detectable by pooled HIV RNA testing, with a positive predictive value of 59%. Further research is needed to evaluate this strategy in lower-prevalence populations and in persons using preexposure prophylaxis for HIV prevention.
Asunto(s)
Anticuerpos Anti-VIH/análisis , Antígenos VIH/análisis , Infecciones por VIH/diagnóstico , VIH-1/genética , ARN Viral/análisis , Enfermedad Aguda , Adulto , California/epidemiología , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Homosexualidad Masculina/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , New York , North Carolina/epidemiología , Prevalencia , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
The quantitative viral outgrowth assay (QVOA) provides a precise minimal estimate of the reservoir of resting CD4(+) T-cell infection (resting cell infection [RCI]). However, the variability of RCI over time during antiretroviral therapy (ART), relevant to assess potential effects of latency-reversing agents or other interventions, has not been fully described. We performed QVOA on resting CD4(+) T cells obtained via leukapheresis from 37 human immunodeficiency virus (HIV)-infected patients receiving stable suppressive ART for a period of 6 years. Patients who started ART during acute (n = 17) or chronic (n = 20) HIV infection were studied once HIV RNA levels were <50 copies/mL for ≥ 6 months. Using random effects analysis of 160 RCI measurements, we found that RCI declined significantly over time (P < .001), with an estimated mean half-life of 3.6 years (95% confidence interval, 2.3-8.1 years), remarkably consistent with findings of prior studies. There was no evidence of more rapid decay in acute versus chronic HIV infection (P = .99) for patients suppressed ≥ 6 months. RCI was reliably estimated with longitudinal measurements generally showing < 2-fold variation from the previous measure. When QVOA is performed in this format, RCI decreases of >6-fold were rare. We suggest that a 6-fold decline is a relevant threshold to reliably identify effects of antilatency interventions on RCI.
Asunto(s)
VIH-1/aislamiento & purificación , VIH-1/fisiología , Latencia del Virus/efectos de los fármacos , Enfermedad Aguda , Adulto , Anciano , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/virología , Enfermedad Crónica , Estudios de Evaluación como Asunto , Infecciones por VIH/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Viremia/tratamiento farmacológico , Adulto JovenRESUMEN
BACKGROUND: Infectious diseases (ID) clinics are locations where members of at risk social networks, including sex partners of HIV-infected patients, make contact with a medical care setting when they accompany HIV-positive patients to appointments. METHODS: We implemented a free point-of-care rapid HIV testing program for anyone accompanying a patient to the University of North Carolina ID clinic. Acceptability of the program among the general clinic population was assessed via an anonymous survey 1 year after program implementation. Basic frequencies of those who underwent and received results of rapid HIV testing, the proportion of positive rapid tests and confirmatory HIV tests performed, and the level of University of North Carolina ID clinic patient satisfaction with the HIV testing program were calculated. RESULTS: Between October 2007 and June 2013, 450 (99.6%) of 452 individuals tested in the program received their results on the same day as testing. Twenty-two individuals (4.9%) tested HIV positive, of which 16 (72.7%) were newly positive, including 3 never previously tested. Excluding previously diagnosed individuals, HIV prevalence was 3.6% (16/446). Among those testing positive by rapid testing, 19 (86.4%) had confirmatory testing and immediately entered into HIV care at the clinic. CONCLUSIONS: The high positivity and confirmatory HIV rates in our program confirm that the provision of rapid HIV testing in an ID clinic capitalizes on missed opportunities among an at-risk population and allows immediate linkage to care.
Asunto(s)
Infecciones por VIH/diagnóstico , Centros Médicos Académicos , Adulto , Instituciones de Atención Ambulatoria , Citas y Horarios , Femenino , Infecciones por VIH/psicología , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Aceptación de la Atención de Salud/psicología , Satisfacción del Paciente , Parejas SexualesRESUMEN
Human immunodeficiency virus (HIV) prevention interventions, such as preexposure prophylaxis (PrEP), are often targeted to men who have sex with men (MSM) who self-report high-risk behaviors. Data from a prospective study evaluating methods to detect acute HIV infection among a primarily young (aged <25 years) and black or African American (African American) population from North Carolina were analyzed. In the study, participants were asked about risk behaviors during pretest counseling (at the time of testing) and then during a partner services interview (at HIV diagnosis). Participants whose disclosure of sexual risk behaviors during pretest counseling was different from their disclosure of sexual risk behaviors during their partner services interview were identified, and factors associated with these discordant responses were examined. Among 113 HIV-infected men, 26 (23.0%) did not disclose male sex partners at pretest counseling, but subsequently did disclose this information during their partner services interview. When compared with men who disclosed having male partners at pretest counseling, these 26 MSM who did not disclose male partners during pretest counseling were found to have a similar number of male partners during contact tracing, but were more likely to have a female partner (30.8% versus 6.9%). In addition, the proportions of MSM found to have at least one HIV-infected partner were similar for both groups (MSM who disclosed having male partners during pretest counseling and those who did not). To better customize HIV prevention interventions for MSM, HIV prevention programs might consider using novel strategies to accurately assess risk in this population.
Asunto(s)
Negro o Afroamericano/psicología , Revelación/estadística & datos numéricos , Infecciones por VIH/diagnóstico , Homosexualidad Masculina/etnología , Asunción de Riesgos , Parejas Sexuales/psicología , Adulto , Negro o Afroamericano/estadística & datos numéricos , Consejo , Infecciones por VIH/prevención & control , Humanos , Masculino , North Carolina , Estudios Prospectivos , Adulto JovenRESUMEN
HIV type 1 (HIV-1) persists within resting CD4(+) T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a mathematical model that accurately predicts (r = 0.65, P = 2.5 × 10(-4)) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4(+) T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4(+) T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4(+) T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Recuento de Linfocito CD4 , Estudios de Cohortes , Infecciones por VIH/inmunología , VIH-1 , HumanosRESUMEN
BACKGROUND: Sexually transmitted infection (STI) diagnosis after diagnosis of acute HIV infection (AHI) indicates ongoing high-risk sexual behavior and possible risk of HIV transmission. We assessed predictors of STI acquisition and the effect of time since care entry on STI incidence in patients with AHI in care and receiving consistent risk-reduction messaging. METHODS: Data on incident gonorrhea, chlamydia, trichomoniasis, primary/secondary syphilis, demographic, and clinical risk factors were abstracted from medical charts for patients diagnosed as having AHI and engaged in care. Poisson regression models using generalized estimating equations were fit to estimate incidence rates (IRs), IR ratios, and robust 95% confidence intervals. RESULTS: Among 185 patients with AHI, 26 (14%) were diagnosed as having at least 1 incident STI over 709.4 person-years; 46 STIs were diagnosed during follow-up (IR, 6.8/100 person-years). The median time from HIV care entry to first STI diagnosis was 609 days (range, 168-1681 days). Men who have sex with men (P = 0.03), a shorter time between presentation to medical care and AHI diagnosis (P = 0.06), and STI diagnosis before AHI diagnosis (P = 0.0003) were predictors of incident STI. Sexually transmitted infection IR greater than 1 year after entering care was double that of patients in care 1 year or less (IR ratio, 2.0; 95% confidence interval, 0.8-4.9). HIV viral load was above the limits of detection within 1 month of 11 STI diagnoses in 6 patients (23.1%) (median, 15,898 copies/mL; range, 244-152,000 copies/mL). CONCLUSIONS: Despite regular HIV care, STI incidence was high among this primarily young, men who have sex with men AHI cohort. Early antiretroviral initiation may decrease HIV transmission given ongoing risk behaviors despite risk-reduction messaging.
Asunto(s)
Seropositividad para VIH/diagnóstico , Hallazgos Incidentales , Enfermedades de Transmisión Sexual/diagnóstico , Sexo Inseguro , Enfermedad Aguda , Adulto , Femenino , Humanos , Incidencia , Masculino , Tamizaje Masivo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Previous studies have revealed that HIV-infected individuals possess circulating CD4(+)CD8(+) double-positive (DP) T cells specific for HIV Ags. In the present study, we analyzed the proliferation and functional profile of circulating DP T cells from 30 acutely HIV-infected individuals and 10 chronically HIV-infected viral controllers. The acutely infected group had DP T cells that showed more proliferative capability and multifunctionality than did both their CD4(+) and CD8(+) T cells. DP T cells were found to exhibit greater proliferation and higher multifunctionality compared with CD4 T cells in the viral controller group. The DP T cell response represented 16% of the total anti-HIV proliferative response and >70% of the anti-HIV multifunctional response in the acutely infected subjects. Proliferating DP T cells of the acutely infected subjects responded to all HIV Ag pools with equal magnitude. Conversely, the multifunctional response was focused on the pool representing Nef, Rev, Tat, VPR, and VPU. Meanwhile, the controllers' DP T cells focused on Gag and the Nef, Rev, Tat, VPR, and VPU pool for both their proliferative and multifunctional responses. Finally, we show that the presence of proliferating DP T cells following all HIV Ag stimulations is well correlated with proliferating CD4 T cells whereas multifunctionality appears to be largely independent of multifunctionality in other T cell compartments. Therefore, DP T cells represent a highly reactive cell population during acute HIV infection, which responds independently from the traditional T cell compartments.
Asunto(s)
Antígenos Virales/inmunología , Antígenos CD4/inmunología , Antígenos CD8/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Linfocitos T/inmunología , Proliferación Celular , Femenino , Infecciones por VIH/patología , Humanos , Masculino , Linfocitos T/patologíaRESUMEN
Background: Persistence of HIV-1 in reservoirs necessitates life-long antiretroviral therapy (ART). There are conflicting data using genetic analysis on whether persistence includes an actively replicating reservoir with strong evidence arguing against replication. Methods: We investigated the possibility of ongoing viral evolution during suppressive therapy by comparing near full-length viral genomic sequences using phylogenetic analysis of viral RNA in plasma before therapy initiation early after infection and from virus induced to grow from the latent reservoir after a period of suppressive ART. We also focused our analysis on evidence of selective pressure by drugs in the treatment regimen and at sites of selective pressure by the adaptive immune response. Results: Viral genomes induced to grow from the latent reservoir from 10 participants with up to 9 years on suppressive ART were highly similar to the nearly homogeneous sequences in plasma taken early after infection at ART initiation. This finding was consistent across the entire genome and when the analysis focused on sites targeted by the drug regimen and by host selective pressure of antibody and cytotoxic T cells. The lack of viral evolution away from pretherapy sequences in spite of demonstrated selective pressure is most consistent with a lack of viral replication during reservoir persistence. Conclusions: These results do not support ongoing viral replication as a mechanism of HIV-1 persistence during suppressive ART.