Efficacy, Safety, and Durability of Long-Acting Cabotegravir and Rilpivirine in Adults With Human Immunodeficiency Virus Type 1 Infection: 5-Year Results From the LATTE-2 Study.

BACKGROUND: In the Long-Acting Antiretroviral Treatment Enabling Trial 2 (LATTE-2) phase 2b study, long-acting (LA) injectable cabotegravir + rilpivirine dosed every 8 weeks (Q8W) or every 4 weeks (Q4W) demonstrated comparable efficacy with daily oral antiretroviral therapy (ART) through 96 weeks in ART-naive adults with human immunodeficiency virus type 1 (HIV-1). Here we report efficacy, tolerability, and safety of cabotegravir + rilpivirine LA over approximately 5 years. METHODS: After 20 weeks of oral cabotegravir + abacavir/lamivudine, participants were randomized to cabotegravir + rilpivirine LA Q8W or Q4W or continue oral ART through the 96-week maintenance period. In the extension period through week 256, participants continued their current LA regimen (randomized Q8W/Q4W groups) or switched from oral ART to Q8W or Q4W LA therapy (extension-switch groups). Endpoints assessed included proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot algorithm) and adverse events (AEs). RESULTS: At week 256, 186 of 230 (81%) participants in randomized Q8W/Q4W groups and 41 of 44 (93%) participants in extension-switch groups had HIV-1 RNA <50 copies/mL. No protocol-defined virologic failures occurred after week 48. Injection wsite reactions infrequently resulted in discontinuation (4 [2%] and 1 [2%] participants in randomized Q8W/Q4W and extension-switch groups, respectively). Three participants in randomized Q8W/Q4W groups experienced drug-related serious AEs, including 1 fatal serious AE (Q4W group); none occurred in extension-switch groups. Of 25 participants with AEs leading to withdrawal, 20 were in the randomized Q4W group; no AE leading to withdrawal occurred in >1 participant. CONCLUSIONS: Cabotegravir + rilpivirine LA exhibited long-term efficacy and tolerability, demonstrating its durability as maintenance therapy for HIV-1 infection.Clinical Trials Registration. NCT02120352.

TB contact tracing for young children: an Australian cascade of care review.

OBJECTIVE: To evaluate care cascades for programmatic active case finding and latent TB infection (LTBI) management in young child TB contacts (aged <5 years) in Victoria, Australia. DESIGN: This was a retrospective review of public health surveillance data to identify contacts of all pulmonary TB cases notified from 2016 to 2019. RESULTS: Contact tracing identified 574 young child contacts of 251 pulmonary TB cases. Active TB was found in 28 (4.9%) contacts, none of whom had previously received bacille Calmette-Guérin vaccination, and 529 were tested for TB infection using the tuberculin skin test (TST). The overall TST positivity was 15.3% (95% CI 0.1-0.2). Among the 574 children, 150 (26.1%) were close contacts of sputum smear-positive cases and 25 (16.7%) of these were not referred to TB clinics. Of the 125 referred, 81 were considered to have LTBI, 79 agreed to commence TB preventive treatment (TPT) and 71 (89.9%) completed TPT. Following completion of TPT, no child was subsequently diagnosed with active TB. CONCLUSION: There was a high yield from active case finding and uptake of TPT. Notable losses in the cascade of care occurred around referral to tertiary clinics, but high treatment completion rates and good outcomes were found in those prescribed treatment.

OBJECTIF: Evaluer les cascades de soins pour la recherche active programmatique des cas et la prise en charge de l'infection tuberculeuse latente (ITL) chez les contacts de jeunes patients atteints de TB âgés de <5 ans dans l'état de Victoria, Australie. SCHÉMA: Revue rétrospective de données de surveillance de santé publique afin d'identifier les contacts de tous les cas de TB pulmonaire notifiés de 2016 à 2019. RÉSULTATS: Le traçage des contacts a identifié 574 jeunes enfants tous contacts de 251 cas de TB pulmonaire. Une TB active a été trouvée chez 28 enfants contacts (4,9%), aucun n'ayant reçu le vaccin bacille Calmette-Guérin, et 529 ont été testés à la recherche d'infection TB avec un test cutané à la tuberculine (TCT). La positivité d'ensemble du TCT a été de 15,3% (IC 95% 0,1­0,2). Parmi les 574 enfants, 150 (26,1%) étaient des contacts étroits de cas à frottis de crachats positifs et 25 (16,7%) d'entre eux n'ont pas été référés dans des structures TB. Sur les 125 enfants référés, 81 ont été considérés comme ayant une ITL, 79 ont accepté de débuter un traitement préventif (TPT) et 71 (89,9%) l'ont terminé. Aucun enfant n'a ensuite eu de diagnostic de TB active. CONCLUSION: La recherche active de cas et la couverture TPT ont eu un rendement élevé. Des pertes notables dans la cascade de soins sont survenues lors de référence aux structures tertiaires, mais ceux qui ont reçu un traitement ont eu un taux élevé d'achèvement et de bons résultats.

Oxygen for children and newborns in non-tertiary hospitals in South-west Nigeria: A needs assessment.

BACKGROUND: Oxygen is important for the treatment of hypoxaemia associated with pneumonia, malaria, and other medical, obstetric, and surgical conditions. Access to oxygen therapy is limited in many of the high mortality settings where it would be of most benefit. METHODS: A needs assessment of 12 non-tertiary hospitals in south-west Nigeria, assessing structural, technical and clinical barriers to the provision of safe and effective oxygen therapy. RESULTS: Oxygen supply was reported to be a major challenge by hospital directors. All hospitals had some access to oxygen cylinders, which were expensive and frequently ran out. Nine (75%) hospitals used oxygen concentrators, which were limited by inadequate power supply and lack of maintenance capacity. Appropriate oxygen delivery and monitoring devices (nasal prongs, catheters, pulse oximeters) were poorly available, and no hospitals had clinical guidelines pertaining to the use of -oxygen for children. Oxygen was expensive to patients (median US$20/day) and to hospitals. Estimated oxygen demand is reported using both a constant mean-based estimate and adjustment for seasonal and other variability. CONCLUSIONS: Making oxygen available to sick children and neonates in Nigerian hospitals will require: improving detection of hypoxaemia through routine use of pulse oximetry; improving access to oxygen through equipment, training, and maintenance structures; and commitment to building hospital and state structures that can sustain and expand oxygen initiatives.

Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial.

BACKGROUND: In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. METHODS: In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01641809. FINDINGS: Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 [87%] of 60, 51 [85%] of 60, and 53 [87%] of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77-88) patients in the cabotegravir groups (48 [80%; 70-90], 48 [80%; 70-90], and 53 [87%; 78-95] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60-82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69-82) receiving cabotegravir (41 [68%; 57-80], 45 [75%; 64-86], and 51 [84%; 74-93] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51-75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 [47%], 32 [53%], and 33 [54%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one [2%], one [2%], and four [7%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group. INTERPRETATION: Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection. FUNDING: ViiV Healthcare and Janssen Research and Development.

The enigma of soil animal species diversity revisited: the role of small-scale heterogeneity.

BACKGROUND: "The enigma of soil animal species diversity" was the title of a popular article by J. M. Anderson published in 1975. In that paper, Anderson provided insights on the great richness of species found in soils, but emphasized that the mechanisms contributing to the high species richness belowground were largely unknown. Yet, exploration of the mechanisms driving species richness has focused, almost exclusively, on above-ground plant and animal communities, and nearly 35 years later we have several new hypotheses but are not much closer to revealing why soils are so rich in species. One persistent but untested hypothesis is that species richness is promoted by small-scale environmental heterogeneity. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis we manipulated small-scale heterogeneity in soil properties in a one-year field experiment and investigated the impacts on the richness of soil fauna and evenness of the microbial communities. We found that heterogeneity substantially increased the species richness of oribatid mites, collembolans and nematodes, whereas heterogeneity had no direct influence on the evenness of either the fungal, bacterial or archaeal communities or on species richness of the large and mobile mesostigmatid mites. These results suggest that the heterogeneity-species richness relationship is scale dependent. CONCLUSIONS: Our results provide direct evidence for the hypothesis that small-scale heterogeneity in soils increase species richness of intermediate-sized soil fauna. The concordance of mechanisms between above and belowground communities suggests that the relationship between environmental heterogeneity and species richness may be a general property of ecological communities.

Increasing litter species richness reduces variability in a terrestrial decomposer system.

Debate on the relationship between diversity and stability has been driven by the recognition that species loss may influence ecosystem properties and processes. We conducted a litterbag experiment in the Scottish Highlands, United Kingdom, to examine the effects of altering plant litter diversity on decomposition, microbial biomass, and microfaunal abundance. The design of treatments was fully factorial and included five species from an upland plant community (silver birch, Betula pendula; Scots' pine, Pinus sylvestris; heather, Calluna vulgaris; bilberry, Vaccinium myrtillus; wavy-hair grass, Deschampsia flexuosa); species richness ranged from one to five species. We tested the effects of litter species richness and composition on variable means, whether increasing litter species richness reduced variability in the decomposer system, and whether any richness-variability relationships were maintained over time (196 vs. 564 days). While litter species composition effects controlled variable means, we revealed reductions in variability with increasing litter species richness, even after accounting for differences between litter types. These findings suggest that higher plant species richness per se may result in more stable ecosystem processes (e.g., decomposition) and decomposer communities. Negative richness-variation relationships generally relaxed over time, presumably because properties of litter mixtures became more homogeneous. However, given that plant litter inputs continue to enter the belowground system over time, we conclude that variation in ecosystem properties may be buffered by greater litter species richness.

Toward a complete soil C and N cycle: incorporating the soil fauna.

Increasing pressures on ecosystems through global climate and other land-use changes require predictive models of their consequences for vital processes such as soil carbon and nitrogen cycling. These environmental changes will undoubtedly affect soil fauna. There is sufficient evidence that soil fauna have significant effects on all of the pools and fluxes in these cycles, and soil fauna mineralize more N than microbes in some habitats. It is therefore essential that their role in the C and N cycle be understood. Here we introduce a new framework that attempts to reconcile our current understanding of the role of soil fauna within the C and N cycle with biogeochemical models and soil food web models. Using a simple stoichiometric approach to integrate our understanding of N mineralization and immobilization with the C:N ratio of substrates and faunal life history characteristics, as used in food web studies, we consider two mechanisms through which soil fauna can directly affect N cycling. First, fauna that are efficient assimilators of C and that have prey with similar C:N ratios as themselves, are likely to contribute directly to the mineral N pool. Second, fauna that are inefficient assimilators of C and that have prey with higher C:N ratios than themselves are likely to contribute most to the dissolved organic matter (DOM) pool. Different groups of fauna are likely to contribute to these two pathways. Protists and bacteria-feeding nematodes are more likely to be important for N mineralization through grazing on microbial biomass, while the effects of enchytraeids and fungal-feeding microarthropods are most likely to be important for DOM production. The model is consistent with experimental evidence and, despite its simplicity, provides a new framework in which the effects of soil fauna on pools and fluxes can be understood. Further, the model highlights our gaps in knowledge, not only for effects of soil fauna on processes, but also for understanding of the soil C and N cycle in general.

Virologic and immunologic response to a boosted double-protease inhibitor-based therapy in highly pretreated HIV-1-infected patients.

PURPOSE: To assess the virologic and immunologic response to a boosted double-protease inhibitor (PI) regimen of highly pretreated patients infected with HIV-1 and to examine the role of PI resistance and concentration of serum saquinavir. METHOD: In an open-label prospective study, lopinavir/ritonavir, saquinavir-sgc, lamivudine, and other nucleoside analogues were offered to highly pretreated patients who had advanced HIV-1 infection and who had failed at least 2 previous highly active antiretroviral therapy regimens including at least 1 nonnucleoside reverse transcriptase inhibitor. The relationship between baseline drug resistance and steady-state saquinavir serum levels and early (week 4) and sustained (week 48) virologic response was documented. RESULTS: 35 advanced HIV-1 patients were enrolled. The boosted double-PI regimen was well tolerated. Twenty-two (63%) of the 35 patients had a > 0.8 log(10) decrease in HIV viral load at week 4. After 48 weeks of follow-up, the 22 patients who remained on the study therapy had an average decrease in viral load of 1 log(10) and had a median increase in CD4 cells of 60 cell/microL. Multiple logistic regression analysis indicated that genotypic resistance to both PIs and the week-3 trough concentrations of saquinavir were associated with virologic outcome at week 4. The presence of > or = 6 lopinavir mutations [odds ratio (OR) 0.03; 95% CI 0.01 to 0.79] and the 48V mutation (OR 0.01; 95%CI <0.01 to 0.88) was independently associated with lower odds of achieving an early response, whereas a higher saquinavir concentration at week 3 (OR 8.36; 95% CI 1.28 to 54.70) was associated with greater odds of an early response. CONCLUSION: These findings suggest that baseline PI resistance and saquinavir concentration were associated with virologic response and should be considered when planning salvage therapy.

Toxic shock syndrome in a patient with systemic lupus erythematosus.

A case is presented of toxic shock syndrome in a patient with systemic lupus erythematosus. Toxic shock syndrome is rarely reported in patients who are immunosuppressed, perhaps because such patients are often treated vigorously with antibiotics at the earliest sign of infection. The association in this case may have been coincidental.