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Viral frictions : global health and the persistence of HIV stigma in Kenya
\"Viral Frictions takes the reader along a trail of intersecting narratives to uncover how and why it is that HIV-related stigma persists in the age of treatment. Pfeiffer convincingly argues that stigma is a socially constructed process co-produced at the nexus of local, national, and global relationships and storytelling about and practices associated with HIV. Based on a decade of fieldwork in one highway trading center in Kenya, Viral Frictions offers compelling stories of stigma and discrimination as a lens for understanding broader social processes, the complexities of globalization and health, and their profound impact on the everyday social lives and relationships of people living through the ongoing HIV epidemic in sub-Saharan Africa. This highly engaging book is ideal reading for those interested in teaching and learning about intersectionality, as Pfeiffer meticulously demonstrates how HIV stigma interacts with issues of treatment, race, ethnicity, class, gender, sexuality, social change, and international aid systems\"-- Provided by publisher.
BOOK
Combination anti-HIV antibodies provide sustained virological suppression
Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)
1
. However, eradication of the virus in individuals with HIV has not been possible to date
2
. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication
3
. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
Combination therapy of broadly neutralizing monoclonal antibodies can provide long-term virological suppression in individuals infected with HIV without antiretroviral therapy.
Journal Article
Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men
In this study, 2499 HIV-seronegative men or transgender women who were at high risk for HIV acquisition were enrolled in a trial of daily emtricitabine plus tenofovir versus placebo. Those receiving the antiretroviral medication had a 44% reduction in HIV incidence.
A total of 2.7 million new infections with the human immunodeficiency virus (HIV) were diagnosed worldwide in 2008, according to the Joint United Nations Program on HIV/AIDS (UNAIDS). Combination antiretroviral therapy for patients with HIV infection restores health and may decrease the transmission of the virus to uninfected partners.
1
Therapy also decreases mother-to-child transmission.
2
Postexposure chemoprophylaxis is recommended after occupational or nonoccupational exposure to HIV-infected fluids.
3
The use of such chemoprophylaxis requires that people recognize when they might have been exposed to HIV and that they start therapy within 72 hours. Both challenges are substantial limitations to the use of . . .
Journal Article
HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption
A phase IIa clinical trial shows that the administration of the broadly neutralizing antibody 3BNC117 delays viral rebound following the discontinuation of antiretroviral therapy in patients who were chronically infected with HIV-1.
Super anti-HIV antibody tested
A phase IIa clinical trial shows that the administration of the broadly neutralizing antibody 3BNC117, which targets the CD4 binding site of the HIV-1 Env protein, delays viral rebound following the discontinuation of antiretroviral therapy in patients who were chronically infected with HIV-1. The authors conclude that 3BNC117 effectively blocks emergence of antibody-sensitive viruses from HIV-1 reservoirs during analytical treatment interruption, a finding that could have significant implications for HIV-1 treatment initiatives.
Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env
1
, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.
Journal Article
Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study)
The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3).
In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum.
Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy.
clinicaltrials.gov NCT02245022.
Journal Article
Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase
Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. We sequenced pretreatment plasma specimens from the ADVANCE trial (NCT03122262). Our primary outcome was 96-week virologic success, defined as a sustained viral load <1000 copies/mL from 12 weeks onwards, <200 copies/mL from 24 weeks onwards, and <50 copies/mL after 48 weeks. Here we report how this outcome was impacted by PDR, defined by the World Health Organization (WHO) mutation list. Of 1053 trial participants, 874 (83%) have successful sequencing, including 289 (33%) randomized to EFV-based therapy and 585 (67%) randomized to DTG-based therapy. Fourteen percent (122/874) have ≥1 WHO-defined mutation, of which 98% (120/122) are NNRTI mutations. Rates of virologic suppression are lower in the total cohort among those with PDR 65% (73/112) compared to those without PDR (85% [605/713],
P
< 0.001), and for those on EFV-based treatment (60% [12/20] vs 86% [214/248],
P
= 0.002) and for those on DTG-based treatment (61/92 [66%] vs 84% [391/465]
P
< 0.001,
P
for interaction by regimen 0.49). Results are similar in multivariable models adjusted for clinical characteristics and adherence. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of first-line failure in sub Saharan Africa.
Here the authors combine next generation sequencing on plasma from participants of the ADVANCE clinical trial with virological and follow-up data to investigate the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second-generation integrase inhibitors and find an association between NNRTI resistance prior to treatment and long-term treatment.
Journal Article