Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda

Objectives We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. Methods NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm3) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC50 (FC) relative to wild-type virus. Results HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm. Conclusions Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility

Mapping the medical outcomes study HIV health survey (MOS-HIV) to the EuroQoL 5 Dimension (EQ-5D-3L) utility index

10.1186/s12955-019-1135-8Health and Quality of Life Outcomes1718

Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda.

OBJECTIVES: We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. METHODS: NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm(3)) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC(50) (FC) relative to wild-type virus. RESULTS: HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm. CONCLUSIONS: Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility

Current Status and Future Prospects of Molecular Marker Assisted Selection (MAS) in Millets

Nutritional insecurity has become a major concern for the ever-growing world population. Millets, the small-seeded cereal crops, are predominantly cultivated in Asia and Africa and are an excellent alternative to major staple foods because of minimal water requirement, stress tolerance, adaptation to marginal lands, and nutritional superiority compared to other cereal crops. Marker-assisted breeding with the next-generation sequencing (NGS) approaches can speed up the genomic selection for the germplasm resource analysis, allele mining, QTL mapping, genome-wide marker-trait association, gene tagging, and fine mapping for the millet improvement. There is a need to focus on advanced omics and genomics studies in millets to understand the molecular regulation of important traits and their transfer to other staple cereals for improvement. Efficient transformation and genomic resources will have to gain momentum for successful genome editing in millets. This chapter provides an outlook on the use of marker-assisted selection, genome editing, and omics methods in minor millets for nutrient fortification and the creation of climate-resilient millets with improved nutritional benefits

Status of Sorghum Breeding in Asia

This chapter offers a thorough examination of sorghum breeding in Asia, covering its history, distribution, and domestication. It addresses challenges in breeding, particularly cytoplasmic male sterility, and extensively explores the application of omics approaches such as transcriptomics, genomics, proteomics, metabolomics, and bioinformatics. Emphasis is placed on climate resilience, utilizing genomics to develop sorghum varieties adapted to biotic and abiotic stresses. We summarized biotic and abiotic stresses, along with biotechnological interventions to enhance important agronomic traits. This chapter also delves into modifying flowering, plant height, and the brown midrib structure’s implications for animal feed. Throughout, the significance of these tools and techniques in understanding sorghum genetics and aiding breeding programs is highlighted. In conclusion, we discussed addressing current challenges in sorghum breeding in Asia and advocating ongoing research and collaboration to ensure regional food security and sustainable agriculture. Overall, it provides a comprehensive, up-to-date account of sorghum breeding, showcasing genomics and biotechnology’s pivotal role in enhancing resilience and productivity

Breeding Advancements of Sorghum in Europe

The ability of sorghum to survive in harsh environments makes it an attractive alternative to maize in Europe. Sorghum is tolerant to drought and high temperatures but is susceptible to cold temperatures. The demand for this crop is expected to increase on the continent due to an increase in nutrition-related diseases and changing climate conditions. According to the IPCC report, the northern parts of Europe are expected to experience short-term gains from the changing climate, while the southern parts are expected to experience largely negative effects. Sorghum grows reliably well in marginalized areas. The crop also has a high nutrient density, which has various positive health effects. Broomcorn sorghum is most widely grown in Europe. The production of grain sorghum and high-biomass sorghum is also increasing. Many research projects on sorghum have been undertaken globally and in Europe to improve its adaptation to temperate environments. The collaborative sorghum conversion program that started in the 1980s between the Tropical Agriculture Research Station (TARS), USDA, ARS, S&E and Texas Agricultural Experiment Station (TAES) converted tall photoperiod-sensitive sorghum from tropical regions to dwarf photoperiod-insensitive sorghum. This allowed for desirable characteristics from tropical lines to be transferred to locally adapted sorghum varieties through conventional and modern breeding methods. Many achievements have been made in improving cold tolerance, heat tolerance, drought tolerance, perennial breeding, and nutritional enhancement. This review provides a brief history of sorghum cultivation in Europe, sorghum production and productivity status, sorghum utilization and importance, existing/existed collaborations between Europe and the rest of the continent on sorghum improvement, sorghum germplasm collection, and the extent of genetic diversity among sorghum germplasm utilized. This review provides a thesis of field and screen-house evaluations and “omic” studies conducted on four sorghum varieties (broom-corn, grain, sweet/high biomass, and forage sorghum) against some of the important temperate sorghum production constraints. The body of research included in this review serves as a baseline for further research focused on enhancing sorghum adaptability to European environments

The virological durability of first-line ART among HIV-positive adult patients in resource limited settings without virological monitoring: a retrospective analysis of DART trial data

Few low-income countries have virological monitoring widely available. We estimated the virological durability of first-line antiretroviral therapy (ART) after five years of follow-up among adult Ugandan and Zimbabwean patients in the DART study, in which virological assays were conducted retrospectively

Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial

Background Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV. Methods We did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12–16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039). Findings Baseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral loa

Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial

Background Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings. Methods We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787. Findings Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification. Interpretation Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings. Funding European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO