Safety and Adherence to Intermittent Pre-Exposure Prophylaxis (PrEP) for HIV-1 in African Men Who Have Sex with Men and Female Sex Workers

Background Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). Methods/Principal Findings MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a onemonth recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63–92] for daily dosing and 55% [IQR:28–78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14–50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. Conclusions/Significance Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens</p

Potential Impact of Antiretroviral Chemoprophylaxis on HIV-1 Transmission in Resource-Limited Settings

Background. The potential impact of pre-exposure chemoprophylaxis (PrEP) an heterosexual transmission of HIV-1 infection in resource-limited settings is uncertain. Methodology/Principle Findings. A deterministic mathematical model was used to simulate the effects of antiretroval PreP on an HIV-1 epidemic in sub-Saharan Africa under different scenarios (optimistic neutral and pessimistic) both with and without sexual disinhibition. Sensitivity analyses were used to evaluate the effect of uncertainty in input parameters on model output and included calculation of partial rank correlations and standardized rank regressions. In the scenario without sexual disinhibition after PrEP initiation, key parameters influencing infections prevented were effectiveness of PrEP (partial rank correlation coefficient (PRCC) = 0.94), PrEP discontinuation rate (PRCC=-0.94), level of coverage (PRCC=0.92), and time to achieve target coverage (PRCC=-082). In the scenario with sexual disinhibition, PrEP effectiveness and the extent of sexual disinhibition had the greatest impact on prevention. An optimistic scenario of PrEP with 90% effectiveness and 75% coverage of the general population predicted a 74% decline in cumulative HIV-1 infections after 10 years, and a 28.8% decline with PrEP targeted to the highest risk groups (16% of the population). Even With a 100% increase in at-risk behavior from sexual disinhibition, a beneficial effect (23.4%-62.7% decrease in infections) was seen with 90% effective PrEP across a broad range of coverage (25%-75%). Similar disinhibition led to a rise in infections with lower effectiveness of PrEP (≤50%). Conclusions/Significance. Mathematical modeling supports the potential public health benefit of PrEP. Approximately 2.7 to 3.2 million new HIV-1 infections could be averaged in southern sub-Saharan Africa over 10 years by targeting PrEP (having 90% effectiveness) to those at highest behavioral risk and by preventing sexual disinhibition. This benefit could be lost, however, by sexual disinhibition and by high PrEP discontinuation, especially with lower PrEP effectiveness (≤:50%). © 2007 Abbas et al

Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms

DEB025 (alisporivir) is a synthetic cyclosporine with inhibitory activity against human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV). It binds to cyclophilin A (CypA) and blocks essential functions of CypA in the viral replication cycles of both viruses. DEB025 inhibits clinical HIV-1 isolates in vitro and decreases HIV-1 virus load in the majority of patients. HIV-1 isolates being naturally resistant to DEB025 have been detected in vitro and in nonresponder patients. By sequence analysis of their capsid protein (CA) region, two amino acid polymorphisms that correlated with DEB025 resistance were identified: H87Q and I91N, both located in the CypA-binding loop of the CA protein of HIV-1. The H87Q change was by far more abundant than I91N. Additional polymorphisms in the CypA-binding loop (positions 86, 91 and 96), as well as in the N-terminal loop of CA were detected in resistant isolates and are assumed to contribute to the degree of resistance. These amino acid changes may modulate the conformation of the CypA-binding loop of CA in such a way that binding and/or isomerase function of CypA are no longer necessary for virus replication. The resistant HIV-1 isolates thus are CypA-independent

EPIDEMIOLOGIA MOLECOLARE DEI NOROVIRUS IN FRIULI VENEZIA GIULIA NEGLI ANNI 2005-2011

OBIETTIVI: I Norovirus sono virus a RNA responsabili di epidemie di gastroenteriti di origine alimentare o nosocomiale e sono caratterizzati da una notevole variabilit\ue0 genetica legata a fenomeni di drift e shift antigenico. La variabilit\ue0 genetica \ue8 responsabile di una diversa sensibilit\ue0 dei test diagnostici convenzionali nell\u2019identificazione delle diverse varianti del virus e rende quindi necessario l\u2019impiego combinato di tecniche immunoenzimatiche e molecolari. A partire dal 2005 l\u2019UCO Igiene dell\u2019Universit\ue0 di Trieste collabora con i Dipartimenti di Prevenzione allo studio delle epidemie di gastroenteriti virali (GeV) nel Friuli Venezia Giulia. Inoltre dalla stagione 2010/2011 ha attivato un progetto di sorveglianza virologica delle GeV nella citt\ue0 di Trieste in collaborazione con alcuni pediatri di libera scelta e con il Pronto Soccorso dell\u2019Ospedale Infantile IRCCS \u201cBurlo Garofolo\u201d. METODI: Le indagini di laboratorio comprendono un test immunoenzimatico (R-Biopharm) e tecniche di amplificazione genica (Argene; home made RTPCR). I campioni positivi sono stati tipizzati mediante sequenziamento parziale delle regioni genomiche ORF1 e ORF2. RISULTATI: Tra il 2005 ed il 2011 sono state studiate 7 epidemie da Norovirus: tre nosocomiali e quattro alimentari. Dal 2007 il sottotipo pi\uf9 frequentemente identificato \ue8 stato il GII.; nel 2005/2006 sono stati isolati i genotipi GII.7 e GII.2 mentre il genotipo GII.14 \ue8 stato riscontrato in maniera episodica. Nella stagione 2010/2011 dalla rete della sorveglianza sono stati analizzati 65 campioni. 14 campioni sono risultati positivi mediante real time PCR, di questi soltanto 6 sono risultati positivi al solo test EIA. Il sequenziamento ha permesso di identificare 3 genotipi circolanti: GII.1, che non era stato precedentemente rilevato nella nostra area, GII.3 e GII.4, cui apparteneva la met\ue0 dei virus identificati. CONCLUSIONI: I risultati emersi dallo studio sottolineano l\u2019importanza dell\u2019impiego simultaneo di diverse tecniche diagnostiche nei casi di sospetta infezione da Norovirus per la possibilit\ue0 di ottenere risultati falsi negativi anche con test ad elevata sensibilit\ue0. Inoltre la sorveglianza virologica delle infezioni da Norovirus sia in ambito istituzionale che territoriale \ue8 importante per individuare precocemente le varianti circolanti per conoscere la predittivit\ue0 dei test in uso e per potenziare le misure di prevenzione delle epidemie nelle strutture a rischio

HIV-1 vaccine-induced immune responses which correlate with protection from SHIV infection: compiled preclinical efficacy data from trials with ten different HIV-1 vaccine candidates

The specific immune mechanisms necessary and/or sufficient to elicit HIV-vaccine protection remain undefined. Utilising the SHIV rhesus macaque model the immunogenicity as well as the efficacy of ten different HIV-1 vaccine candidates was evaluated. Comparison of the immune responses induced, with the ability of the vaccine to protect from SHIV infection provided a means to determine which type of immune responses were necessary for protection. Vaccine candidates included VLPs, DNA, subunit protein with novel adjuvant formulations, ISCOMs and pox-virus vectors. Protection from SHIV infection was achieved in approximately half of the animals which received a primary intravenous cell-free challenge. The presence of CTL in the absence of other effector responses did not correlate with protection from this route and type of challenge. Virus neutralising antibodies (Nab) appeared to be necessary but alone were insufficient for protection. If Ag-specific IFN-gamma and/or IL-4 as well as lymphoproliferative (LP) responses were found with the lack of a detectable IL-2 response, then protection was not observed. Immunity correlated with the magnitude of Nab responses, beta-chemokines and as well as balanced, qualitative T-helper responses