Impact of Low-Level-Viremia on HIV-1 Drug-Resistance Evolution among Antiretroviral Treated-Patients

to determine the emergence and evolution of DRAM during LLV in HIV-1-infected patients while receiving antiretroviral therapy (ART).Retrospective analysis of patients presenting a LLV episode defined as pVL between 40 and 500 c/mL on at least 3 occasions during a 6-month period or longer while on the same ART. Resistance genotypic testing was performed at the onset and at the end of LLV period. Emerging DRAM was defined during LLV if never detected on baseline genotype or before.48 patients including 4 naive and 44 pretreated (median 9 years) presented a LLV episode with a median duration of 11 months. Current ART included 2NRTI (94%), ritonavir-boosted PI (94%), NNRTI (23%), and/or raltegravir (19%). Median pVL during LLV was 134 c/mL. Successful resistance testing at both onset and end of the LLV episode were obtained for 37 patients (77%), among who 11 (30%) acquired at least 1 DRAM during the LLV period: for NRTI in 6, for NNRTI in 1, for PI in 4, and for raltegravir in 2. During the LLV period, number of drugs with genotypic resistance increased from a median of 4.5 to 6 drugs. Duration and pVL level of LLV episode, duration of previous ART, current and nadir CD4 count, number of baseline DRAM and GSS were not identified as predictive factors of resistance acquisition during LLV, probably due to limited number of patients.Persistent LLV episodes below 500 c/ml while receiving ART is associated with emerging DRAM for all drug classes and a decreasing in further therapeutic options, suggesting to earlier consider resistance monitoring and ART optimization in this setting

Plasma and Intracellular Antiretroviral Concentrations in HIV-Infected Patients under Short Cycles of Antiretroviral Therapy

Study of plasma and intracellular concentrations of atazanavir, lopinavir, nevirapine, and efavirenz was conducted on 48 patients under short cycles of antiretroviral therapy. Intracellular concentrations (IC) were still measurable for all drugs after 85 h or 110 h drug intake despite the absence of drug in plasma for atazanavir and lopinavir. A linear relationship between plasma and intracellular efavirenz was observed. Further studies to fully understand the impact of IC in the intermittent antiviral treatment are required

Dating the Bushveld Complex: Timing of Crystallization, Duration of Magmatism, and Cooling of the World’s Largest Layered Intrusion and Related Rocks

The Paleoproterozoic Bushveld Complex, including the world’s largest layered intrusion and host to world-class stratiform chromium, platinum group element, and vanadium deposits, is a remarkable natural laboratory for investigating the timescales of magmatic processes in the Earth’s crust. A framework for the emplacement, crystallization, and cooling of the Bushveld Complex based on integrated U–Pb zircon–baddeleyite–titanite–rutile geochronology is presented for samples of different rock types from the Bushveld Complex, including ultramafic and mafic cumulates, mineralized horizons, granitic rocks from the roof, and a carbonatite from the nearby alkaline Phalaborwa Complex. The results indicate that (1) the Bushveld Complex was built incrementally over an ∼5 Myr interval from 2060 to 2055 Ma with a peak in magma flux at c. 2055–2056 Ma, (2) U–Pb zircon crystallization ages do not decrease in an uninterrupted systematic manner from the base to the top of the intrusion, indicating that the Bushveld Complex does not represent the crystallized products of a single progressively filled and cooled magma chamber, and (3) U–Pb rutile dates constrain cooling of the intrusion at the level of the Critical Zone through ∼500 °C by 2053 Ma. The c. 2060 Ma Phalaborwa Complex (pyroxenite, syenite, carbonatite + Cu–Fe-phosphate–vermiculite deposits) represents one of the earliest manifestations of widespread Bushveld-related magmatism in the northern Kaapvaal craton. The extended range and out-of-sequence U–Pb zircon dates determined for a harzburgite from the Lower Zone (c. 2056 Ma), an orthopyroxenite from the Lower Critical Zone (c. 2057 Ma), and orthopyroxenites from the Upper Critical Zone (c. 2057–2060 Ma) are interpreted to indicate that the lower part of the Bushveld Complex developed through successive intrusions and accretion of sheet-like intrusions (sills), some intruded at different stratigraphic levels. Crystallization of the main volume of the Bushveld Complex, as represented by the thick gabbroic sequences of the Main Zone and Upper Zone, is constrained to a relatively narrow interval of time (∼1 Myr) at c. 2055–2056 Ma. Granites and granophyres in the roof, and a diorite in the uppermost Upper Zone, constitute the youngest igneous activity in the Bushveld Complex at c. 2055 Ma. Collectively, these results contribute to an emerging paradigm shift for the assembly of some ultramafic–mafic magmatic systems from the conventional ‘big tank’ model to an ‘amalgamated sill’ model. The volume–duration relationship determined for magmatism in the Bushveld Complex, when compared with timescales established for the assembly of other layered intrusions and more silica-rich plutonic–volcanic systems worldwide, is distinct and equivalent to those determined for Phanerozoic continental and oceanic flood basalts that constitute large igneous provinces. Emplacement of the 2055–2060 Ma Bushveld Complex corresponds to the end of the Lomagundi–Jatuli Event, the largest magnitude positive carbon isotope excursion in Earth history, and this temporal correlation suggests that there may have been a contribution from voluminous Bushveld ultramafic–mafic–silicic magmatism to disruptions in the global paleoenvironment

Resistance-associated mutations to nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and integrase inhibitors (INI) before and after the low-level viremia (LLV) period, according to the 2009 International AIDS Society-USA list.

<p>Resistance-associated mutations to nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and integrase inhibitors (INI) before and after the low-level viremia (LLV) period, according to the 2009 International AIDS Society-USA list.</p