Blunted Response to Combination Antiretroviral Therapy in HIV Elite Controllers: An International HIV Controller Collaboration

Objective: HIV “elite controllers” (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs). Methods: ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models. Results: After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63/month), followed by +0.19/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm3, the estimated mean CD4 T-cell gain during the first 12 months was 139/mm3 in VIRs and 80/mm3 in ECs (p = 0.048). Conclusions: cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients

The at-sea behaviour and ecology of the critically endangered Balearic shearwater

Seabirds are long-lived, diverse and behaviourally complex marine top predators that are capable of traversing large areas of the global oceans. Consequently, this group are at risk from the wide and persistent range of anthropogenic activities working in this environment. Understanding the consistency with which individuals and populations use the marine environment over space and time, and the mechanisms underlying at-sea behaviour is therefore vital for interpreting population dynamics and developing appropriate and long-standing conservation strategies. This thesis utilises a combination of state-of-the-art tracking technologies and biogeochemical analyses to provide a better understanding of the at-sea movements, ecology and behaviour of a critically endangered seabird: the Balearic shearwater Puffinus mauretanicus. This species is the most threatened seabird in Europe and is undergoing continued population declines, believed to be largely associated with at-sea mortality from fisheries bycatch and predation on land. Despite intensive study during the breeding season, knowledge of the at-sea ecology of Balearic shearwaters during key phases of the annual cycle remains poor. Year-round tracking from colonies on the Balearic Islands yielded new insights into migration strategies of individuals and populations. Most individuals remained faithful to non-breeding areas over the course of the five-year study, although some plasticity in migration behaviour was also detected, indicating capacity for change. Patterns of differential migration were persistent in the main study population, and were linked to sex-based (and potential life stage-based) differences in migratory behaviour, which are most likely associated with varying ties to the breeding grounds. Links between reproductive performance and non-breeding behaviour were also detected, demonstrating an importance of carry-over effects in this species, with potential implications for population dynamics. Furthermore, behavioural differentiation was found between island populations. Migration strategies, use of foraging habitat and phenology differed between a potential Balearic/Yelkouan shearwater hybrid population on Menorca and a neighbouring colony of Balearic shearwaters on Mallorca, providing insights into the relatedness of Puffinus species in the Mediterranean, and emphasising the need to identify units for management that are both ecologically and evolutionarily relevant. Combined geolocation, isotope and feather moult data further identified use of a diversity of foraging tactics in northeast Atlantic waters, and spatial differences in non-breeding dietary behaviour. These findings implicate a role of both forage fish and fisheries in shaping patterns of at-sea distribution during the non-breeding season, and may prove useful for future assessment of seabird responses to anthropogenic and environmental change. During the breeding season, persistent use of highly productive coastal habitats was identified, indicating exploitation of predictable resources. Such movements emphasise the vulnerability of the Balearic shearwater to anthropogenic activity, but also highlight the potential of area-based management approaches for species protection, when combined with management of human activities throughout the species’ distribution range. Together, the findings of this research provide urgently needed information on the at-sea behaviour and ecology of the Balearic shearwater, which should contribute to improved management efforts aimed at increasing population viability. In addition, this thesis contributes to a wider understanding of individual behaviours and inter-seasonal interactions in seabirds, and identifies the need to establish the movement behaviour of a wider range of life stages and populations across distinct seasons

Predicted trajectories of mean √CD4 cell counts since HIV diagnosis according to blip status during the period of HIV control (81 HIV controllers, 1668 CD4 measurements).

<p>Predicted trajectories of mean √CD4 cell counts since HIV diagnosis according to blip status during the period of HIV control (81 HIV controllers, 1668 CD4 measurements).</p

Comparison of baseline characteristics between HIV controllers and patients enrolled in the ANRS SEROCO Cohort and still alive in 2007.

<p>Data are median [IQR] or n (%);</p><p>*SSA/C  =  SubSaharan Africans or Caribbeans;</p><p>**Following HIV diagnosis.</p

Predicted trajectories of mean √CD4 cell counts since HIV diagnosis according to blip status in the last five years of control (always ≤50 copies vs. blips within 50–400 and blips >400 copies/mL) (81 HIV controllers, 1668 CD4 measurements).

<p>Predicted trajectories of mean √CD4 cell counts since HIV diagnosis according to blip status in the last five years of control (always ≤50 copies vs. blips within 50–400 and blips >400 copies/mL) (81 HIV controllers, 1668 CD4 measurements).</p

Blunted response to combination antiretroviral therapy in HIV elite controllers: an international HIV controller collaboration.

ObjectiveHIV "elite controllers" (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs).MethodsECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (ResultsAfter cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63√CD4/month), followed by +0.19√CD4/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm(3), the estimated mean CD4 T-cell gain during the first 12 months was 139/mm(3) in VIRs and 80/mm(3) in ECs (p = 0.048).ConclusionscART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients

Characteristics at baseline and at cART initiation in 34 elite Controllers (ECs) and 478 chronically viremic (VIRs) patients from the ANRS COPANA Cohort.

<p>Data are median [IQR] or n (%);</p><p>According to own cohort’s definitions of ECs;</p><p>SSA/Car/BA = Sub-Saharan African, Caribbean or African-American origin.</p

Estimated CD4 cell count dynamics in viremic patients (VIRs: n = 478) and elite controllers (ECs: n = 34) in mixed-effect linear models (mean CD4 T cells gain after 12 months of cART was significantly lower in ECs than in VIRs (p = 0.048)).

<p>Estimated CD4 cell count dynamics in viremic patients (VIRs: n = 478) and elite controllers (ECs: n = 34) in mixed-effect linear models (mean CD4 T cells gain after 12 months of cART was significantly lower in ECs than in VIRs (p = 0.048)).</p