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1.
Top Antivir Med ; 27(3): 111-121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31634862

RESUMO

The 2019 edition of the IAS-USA drug resistance mutations list updates the Figure last published in January 2017. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The Figure is designed to assist practitioners in identifying key mutations associated with resistance to antiretroviral drugs, and therefore, in making clinical decisions regarding antiretroviral therapy.

2.
Sci Rep ; 9(1): 13351, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527823

RESUMO

Collection of faecal samples for microbiome analysis in acutely sick patients is logistically difficult, particularly if immediate freezing is required (i.e. fresh-frozen, or FF sampling). Previous studies in healthy/non-hospitalized volunteers have shown that chemical stabilization (i.e. stabilized-frozen, or SF sampling) allows room-temperature storage with comparable results to FF samples. To test this in a hospital setting we compared FF and SF approaches across 17 patients undergoing haematopoietic stem cell transplantation (HSCT) using both 16S rRNA gene and shotgun metagenomic sequencing. A paired (same stool specimen) comparison of FF and SF samples was made, with an overall comparable level in relative taxonomic abundances between the two sampling techniques. Though shotgun metagenomic sequencing found significant differences for certain bacterial genera (P < 0.001), these were considered minor methodological effects. Within-sample diversity of either method was not significantly different (Shannon diversity P16SrRNA = 0.68 and Pshotgun = 0.89) and we could not reject the null hypothesis that between-sample variation in FF and SF were equivalent (P16SrRNA = 0.98 and Pshotgun = 1.0). This indicates that SF samples can be used to reliably study the microbiome in acutely sick patient populations, thus creating and enabling further outcomes-based metagenomic studies on similarly valuable cohorts.

3.
Clin Infect Dis ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31504329

RESUMO

BACKGROUND: The efficacy of screening programs to prevent anal cancer in HIV-1-infected subjects is unclear. AIM: To examine the impact of a screening program to detect anal cancer precursors on the incidence of cases of invasive-anal-squamous-cell-carcinoma (IASCC) in HIV-1-infected subjects. PATIENTS AND METHODS: Single-center, retrospective analysis of a prospective cohort of HIV-1-infected outpatients attending a reference HIV Unit from January 2005 onward. All participants were invited to participate in a continued structured screening program for anal cancer prevention. We estimated the incidence of IASCC and performed a comparative analysis between subjects enrolled in the screening program (screening group) and those who declined to participate (non-screening group). To reduce any selection bias, a propensity score analysis was applied. RESULTS: 3111 HIV-1-infected subjects [1596 men-who-have-sex-with-men (MSM), 888 men-who-have-sex-with-women (MSW), 627 women] were included (mean age 41 years), median follow-up 4.7 years (14,595 patient/years of follow-up). Of them, 1691 (54%) participated in the screening program. Ten patients were diagnosed with IASCC: two of them (MSM) in the screening group and eight (4 MSM, 2 MSW and 2 women) in the non-screening one. The incidence rate of IASCC was 21.9 (95%CI:2.7-70.3) and 107.0 (95%CI:46.2-202.0) per 100,000 person-years, respectively. After a propensity score adjustment, the difference was significant in favour to the screening group (HR:0.17, 95%CI:0.03-0.86). CONCLUSIONS: The number of cases of IASCC was significantly lower in HIV-infected subjects engaged in an anal cytology screening program. These results should be validated in a randomized clinical trial.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31507204

RESUMO

In HIV-1-infected patients, virological failure can occur as a consequence of the mutations that accumulate in the viral genome that allow replication to continue in the presence of antiretrovirals (ARVs). The development of treatment-emergent resistance to an ARV can limit a patient's options for future therapy, prompting the need for ARV regimens that are resilient to the emergence of resistance. The genetic barrier to resistance refers to the number of mutations in an ARV's therapeutic target that are required to confer a clinically meaningful loss of susceptibility to the drug. The emergence of resistance can be affected by pharmacological aspects of the ARV, including its structure, inhibitory quotient, therapeutic index, and pharmacokinetic characteristics. Dolutegravir (DTG) has demonstrated a high barrier to resistance, including when used in a two-drug regimen (2DR) with lamivudine (3TC). In the GEMINI-1 and GEMINI-2 studies, DTG +3TC was noninferior to DTG + emtricitabine/tenofovir disoproxil fumarate in treatment-naive participants, with similar proportions achieving HIV-1 RNA <50 copies/mL through 96 weeks. Furthermore, in the TANGO study, virological suppression was maintained at 48 weeks after switching to DTG +3TC from a tenofovir alafenamide (TAF)-based regimen compared with continuing a TAF-based regimen. Most other 2DRs with successful outcomes compared with three-drug regimens have been based on protease inhibitors (PIs); however, this class is associated with adverse metabolic effects and drug-drug interactions. In this review, we discuss the barrier to resistance in the context of a 2DR in which a boosted PI is replaced with DTG +3TC.

5.
Infect Genet Evol ; 74: 104010, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442596

RESUMO

BACKGROUND: Gut parasites exert an important influence on the gut microbiome, with many studies focusing on the human gut microbiome. It has, however, undergone severe richness depletion. Hygienic lifestyle, antimicrobial treatments and altered gut homeostasis (e.g., chronic inflammation) reduce gut microbiome richness and also parasite prevalence; which may confound results. Studying species closely related to humans could help overcome this problem by providing insights into the ancestral relationship between humans, their gut microbiome and their gut parasites. Chimpanzees are a particularly promising model as they have similar gut microbiomes to humans and many parasites infect both species. AIMS: We study the interaction between gut microbiome and enteric parasites in chimpanzees. Investigating what novel insights a closely related species can reveal when compared to studies on humans. METHODS: Using eighty-seven faecal samples from wild western chimpanzees (Pan troglodytes verus) in Senegal, we combine 16S rRNA gene amplicon sequencing for gut microbiome characterization with PCR detection of parasite taxa (Blastocystis sp., Strongyloides spp., Giardia duodenalis, Cryptosporidium spp., Plasmodium spp., Filariae and Trypanosomatidae). We test for differences in gut microbiota ecosystem traits and taxonomical composition between Blastocystis and Strongyloides bearing and non-bearing samples. RESULTS: For Blastocystis, twelve differentially abundant taxa (e.g., Methanobrevibacter), including Prevotella and Ruminococcus-Methanobrevibacter enterotype markers, replicate findings in humans. However, several richness indices are lower in Blastocystis carriers, contradicting human studies. This indicates Blastocystis, unlike Strongyloides, is associated to a "poor health" gut microbiome, as does the fact that Faecalibacterium, a bacterium with gut protective traits, is absent in Blastocystis-positive samples. Strongyloides was associated to Alloprevotella and five other taxonomic groups. Each parasite had its unique impact on the gut microbiota indicating parasite-specific niches. Our results suggest that studying the gut microbiomes of wild chimpanzees could help disentangle biological from artefactual associations between gut microbiomes and parasites.

6.
J Infect Dis ; 220(8): 1325-1334, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31219150

RESUMO

The impact of variation in host genetics on replication of human immunodeficiency virus type 1 (HIV-1) in demographically diverse populations remains uncertain. In the current study, we performed a genome-wide screen for associations of single-nucleotide polymorphisms (SNPs) to viral load (VL) in antiretroviral therapy-naive participants (n = 2440) with varying demographics from the Strategic Timing of AntiRetroviral Treatment (START) trial. Associations were assessed using genotypic data generated by a customized SNP array, imputed HLA alleles, and multiple linear regression. Genome-wide significant associations between SNPs and VL were observed in the major histocompatibility complex class I region (MHC I), with effect sizes ranging between 0.14 and 0.39 log10 VL (copies/mL). Supporting the SNP findings, we identified several HLA alleles significantly associated with VL, extending prior observations that the (MHC I) is a major host determinant of HIV-1 control with shared genetic variants across diverse populations and underscoring the limitations of genome-wide association studies as being merely a screening tool.

7.
Microbiome ; 7(1): 73, 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31078141

RESUMO

BACKGROUND: In rhesus macaques, simian immunodeficiency virus infection is followed by expansion of enteric viruses but has a limited impact on the gut bacteriome. To understand the longitudinal effects of HIV-1 infection on the human gut microbiota, we prospectively followed 49 Mozambican subjects diagnosed with recent HIV-1 infection (RHI) and 54 HIV-1-negative controls for 9-18 months and compared them with 98 chronically HIV-1-infected subjects treated with antiretrovirals (n = 27) or not (n = 71). RESULTS: We show that RHI is followed by increased fecal adenovirus shedding, which persists during chronic HIV-1 infection and does not resolve with ART. Recent HIV-1 infection is also followed by transient non-HIV-specific changes in the gut bacterial richness and composition. Despite early resilience to change, an HIV-1-specific signature in the gut bacteriome-featuring depletion of Akkermansia, Anaerovibrio, Bifidobacterium, and Clostridium-previously associated with chronic inflammation, CD8+ T cell anergy, and metabolic disorders, can be eventually identified in chronically HIV-1-infected subjects. CONCLUSIONS: Recent HIV-1 infection is associated with increased fecal shedding of eukaryotic viruses, transient loss of bacterial taxonomic richness, and long-term reductions in microbial gene richness. An HIV-1-associated microbiome signature only becomes evident in chronically HIV-1-infected subjects.

8.
AIDS Res Hum Retroviruses ; 35(6): 513-518, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909716

RESUMO

Our aim was to evaluate the effectiveness and safety of darunavir/cobicistat (DRV/c) monotherapy as an antiretroviral treatment simplification strategy in HIV-infected patients already on suppressive darunavir/ritonavir (DRV/r) monotherapy in routine clinical practice. We conducted a retrospective multicenter study including all adult patients switched from DRV/r monotherapy to DRV/c monotherapy while HIV-1 RNA was <50 copies/mL and who had at least one follow-up visit. The primary endpoint was the percentage of patients remaining free of treatment failure (TF), defined as discontinuation of monotherapy for any reason, including loss of follow-up. Virological failure (VF) was defined as a confirmed HIV-1 RNA ≥50 copies/mL or any change in the regimen after a single determination with HIV-1 RNA ≥50 copies/mL. Changes in renal function parameters and lipid profile were also evaluated. Factors associated with VF were analyzed using Cox regression. In this study, 173 subjects were included. The median (interquartile range) time of follow-up was 58 (50-67) weeks. Overall, 90% of patients remained free of TF during follow-up. Ten (6%) patients discontinued DRV/c monotherapy for nonvirological reasons and eight (5%) developed VF. No DRV-related mutations were identified in patients with VF. A decrease in triglyceride levels (p = .006) and estimated glomerular filtration rate (p = .005) were observed during follow-up. The presence of blips and CD4+ nadir <100 cells/mm3 were predictors of VF. In conclusion, switching to DRV/c monotherapy seems to be safe and effective in routine clinical practice in HIV-infected patients undergoing suppressive DRV/r monotherapy.

10.
PLoS One ; 13(12): e0208345, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566493

RESUMO

Preventive HIV-1 vaccine strategies rely on the elicitation of broadly neutralizing antibody (bNAb) responses, but their induction in vivo by vaccination remains challenging. Considering that the ability of an epitope to elicit effective humoral immunity depends on its exposure on the virion, we have used a reverse genetics approach to select variants from an HIV-1 AC10_29 randomly mutated envelope library that showed increased affinity for a selected bNAb (4E10 bNAb targeting the HIV-1 MPER region). Isolated envelope sequences were analyzed by deep-sequencing showing a small number of dominant changes, including the loss of four potential N-linked glycosylation sites and disruption of the V1/V2 loop. Accordingly, the dominant variant (LR1-C1), showed not only increased affinity for MPER bNAbs 4E10 and 2F5, but also higher affinity for an additional antibody targeting the V3 loop (447-52D) that could be a consequence of an open conformation tier 1-like Env. Furthermore, the amino acids specific for the selected variant are associated with an increased sensitivity for 4E10 and 2F5 antibodies. In vivo studies showed that sera from mice immunized with LR1-C1 viruses possessed an improved neutralizing activity compared to the wild-type AC10_29 env. While Virus Like Particles (VLPs) carrying this envelope were unable to induce detectable neutralizing activity in immunized rabbits, one animal showed antibody response to the 4E10-proximal region. Our data establish a novel approach that has the potential to yield HIV envelope immunogen sequences that direct antibody responses to specific envelope regions.


Assuntos
HIV-1/imunologia , Imunidade Humoral/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Western Blotting , Microscopia Crioeletrônica , Ensaio de Imunoadsorção Enzimática , Feminino , Células HEK293 , Anticorpos Anti-HIV/imunologia , Humanos , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Testes de Neutralização , Coelhos , Vacinas de Partículas Semelhantes a Vírus/imunologia
11.
J Virol ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487276

RESUMO

Elite and Viremic HIV controllers are able to control their HIV infection and maintain undetectable or low-level viremia in the absence of antiretroviral treatment. Despite extensive studies, the immune factors responsible for such exclusive control remain poorly defined. We identified a cohort of 14 HIV controllers that suffered an abrupt loss of HIV control (LoC) to investigate possible mechanisms and virological and immunological events related to the sudden loss of control. The in-depth analysis of these subjects involved the study of cell-tropism of circulating virus, evidence for HIV super-infection, cellular immune responses to HIV as well as an examination of viral adaptation to host immunity by Gag sequencing. Our data demonstrate that a poor capacity of T cells to mediate in-vitro viral suppression, even in the context of protective HLA alleles, predicts loss of viral control. In addition, the data suggest that inefficient viral control may be explained by an increase of CD8-T-cell activation and exhaustion before LoC. Furthermore, we detected a switch from C5 to X4-tropic viruses in 4 individuals after loss of control, suggesting that tropism shift might also contribute to disease progression in HIV controllers. The significantly reduced inhibition of in vitro viral replication and increased expression of activation and exhaustion markers preceding the abrupt loss of viral control may help to identify untreated HIV controllers that are at risk of losing control and may offer a useful tool for monitoring individuals during treatment interruption phases in therapeutic vaccine trials.IMPORTANCE Few individuals can control HIV infection without the need for antiretroviral treatment and are referred to as "HIV controllers". We have studied such HIV controllers who suddenly loose this ability and present with high in vivo viral replication and decays in their CD4+ T-cell counts, to identify potential immune and virological factors that were responsible for initial virus control. We identify in-vitro determined reductions in the ability of CD8 T cells to suppress viral control and the presence of PD-1 expressing CD8+ T-cells with a naïve immune phenotype as potential predictors of in vivo loss of virus control. The findings could be important for the clinical management of HIV controller individuals and may offer an important tool to anticipate viral rebound in individuals in clinical studies that include cART treatment interruptions and which, if not treated quickly, could pose a significant risk to the trial participants.

12.
J Int AIDS Soc ; 21(10): e25193, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30350345

RESUMO

INTRODUCTION: Next-generation sequencing (NGS) has several advantages over conventional Sanger sequencing for HIV drug resistance (HIVDR) genotyping, including detection and quantitation of low-abundance variants bearing drug resistance mutations (DRMs). However, the high HIV genomic diversity, unprecedented large volume of data, complexity of analysis and potential for error pose significant challenges for data processing. Several NGS analysis pipelines have been developed and used in HIVDR research; however, the absence of uniformity in data processing strategies results in lack of consistency and comparability of outputs from different pipelines. To fill this gap, an international symposium on bioinformatic strategies for NGS-based HIVDR testing was held in February 2018 in Winnipeg, Canada, convening laboratory scientists, bioinformaticians and clinicians involved in four recently developed, publicly available NGS HIVDR pipelines. The goal of this symposium was to establish a consensus on effective bioinformatic strategies for NGS data management and its use for HIVDR reporting. DISCUSSION: Essential functionalities of an NGS HIVDR pipeline were divided into five analytic blocks: (1) NGS read quality control (QC)/quality assurance (QA); (2) NGS read alignment and reference mapping; (3) HIV variant calling and variant QC; (4) NGS HIVDR reporting; and (5) extended data applications and additional considerations for data management. The consensuses reached among the participants on all major aspects of these blocks are summarized here. They encompass not only recommended data management and analysis strategies, but also detailed bioinformatic approaches that help ensure accuracy of the derived HIVDR analysis outputs for both research and potential clinical use. CONCLUSIONS: While NGS is being adopted more broadly in HIVDR testing laboratories, data processing is often a bottleneck hindering its generalized application. The proposed standardization of NGS read QC/QA, read alignment and reference mapping, variant calling and QC, HIVDR reporting and relevant data management strategies in this "Winnipeg Consensus" may serve as a starting guideline for NGS HIVDR data processing that informs the refinement of existing pipelines and those yet to be developed. Moreover, the bioinformatic strategies presented here may apply more broadly to NGS data analysis of microbes harbouring significant genomic diversity.

13.
Lancet HIV ; 5(11): e638-e646, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30282603

RESUMO

BACKGROUND: Implementation of ultrasensitive HIV drug resistance tests for routine clinical use is hampered by uncertainty about the clinical relevance of drug-resistant minority variants. We assessed different detection thresholds for pretreatment drug resistance to predict an increased risk of virological failure. METHODS: We did a case-control study nested within a prospective multicountry cohort. Our study included patients from 12 clinical sites in Kenya, Nigeria, South Africa, Uganda, and Zambia. We defined cases as patients with virological failure (ie, those who had either viral load ≥400 copies per mL at 12 months or had switched to second-line antiretroviral therapy [ART] as a result of virological failure before 12 months) and controls as those with viral suppression (viral load <400 copies per mL at 12 months) on first-line non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. We assessed pretreatment drug resistance with Illumina MiSeq next-generation sequencing, using the International Antiviral Society (IAS)-USA mutation list or the Stanford HIV Drug Resistance Database (HIVDB) genotypic sensitivity score. We calculated diagnostic accuracy measures and assessed the odds of virological failure using conditional logistic regression for 1%, 5%, and 10% pretreatment drug resistance detection thresholds, compared with the conventional 20% or more used in Sanger-based sequencing. FINDINGS: Paired viral load results before ART and at month 12 of follow-up were available from 1896 participants. We identified 178 patients with virological failure and selected 338 matched controls. We excluded 117 patients from pretreatment drug resistance analysis; therefore, 152 cases of virological failure and 247 controls were included in the final analysis. With the IAS-USA mutation list, at a detection threshold of 20% or more in patients with pretreatment drug resistance, the adjusted odds ratio (OR) for virological failure was 9·2 (95% CI 4·2-20·1) compared with those without pretreatment drug resistance. Lowering the threshold resulted in adjusted ORs of virological failure of 6·8 (95% CI 3·3-13·9) at the 10% threshold, 7·6 (3·4-17·1) at the 5% threshold, and 4·5 (2·0-10·2) at the 1% threshold. Lowering the detection threshold from 20% improved the sensitivity (ie, ability to identify cases) from 12% (n=18) to 13% (n=19) at detection threshold 10%, to 15% (n=23) at detection threshold 5%, and to 17% (n=26) at detection threshold 1%, but caused a slight reduction in specificity (ie, ability to identify controls) from 98% (n=241) to 96% (n=238) at the 10% threshold, 96% (n=236) at the 5% threshold, and a larger reduction to 92% (n=227) at the 1% threshold. Diagnostic ORs were 5·4 (95% CI 2·1-13·9) at the 20% threshold, 3·8 (1·7-8·6) at the 10% threshold, 3·8 (1·8-8·1) at the 5% threshold, and 2·3 (1·2-4·2) at the 1% threshold. Use of the Stanford HIVDB genotypic sensitivity scores yielded similar ORs for virological failure, sensitivities, specificities, and diagnostic ORs. INTERPRETATION: Ultrasensitive resistance testing for pretreatment drug resistance improved identification of people at risk of virological failure; however, this came with a reduction in our ability to identify people with viral suppression, especially at very low thresholds. Further modelling is needed to estimate the optimal trade-off for the 5% and 20% thresholds, balancing improved case finding against unnecessary regimen switching. FUNDING: The Netherlands Ministry of Foreign Affairs, IrsiCaixa, and European Union.

14.
Mucosal Immunol ; 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30171206

RESUMO

Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose-effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria. Interestingly, subjects with LGC also showed increased butyrate levels in direct fecal measurements, consistent with enrichment in Roseburia intestinalis despite reductions in other butyrate producers. The microbiomes of subjects with LGC were also enriched in bacterial virulence factors, as well as in genes associated with beta-lactam, lincosamide, tetracycline, and macrolide resistance. Thus, low nadir CD4+ T-cell counts, rather than HIV-1 serostatus per se, predict the presence of gut dysbiosis in HIV-1 infected subjects. Such dysbiosis does not display obvious HIV-specific features; instead, it shares many similarities with other diseases featuring gut inflammation.

15.
AIDS Res Hum Retroviruses ; 34(10): 828-834, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30105916

RESUMO

Our microbial cotravelers have increasingly apparent roles in both maintaining health and causing disease in several organ systems. Investigators gather annually at the National Institutes of Health to present new discoveries regarding the role of the microbiome in human health and a special focus on persons living with HIV. Here, we summarize the discussions from the third annual Virology Education workshop on the microbiome in HIV, which took place in October of 2017.

16.
Clin Infect Dis ; 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-30052811

RESUMO

Background: Contemporary antiretroviral therapies (ART) and management strategies have diminished both human immunodeficiency virus (HIV) treatment failure and the acquired resistance to drugs in resource-rich regions, but transmission of drug-resistant viruses has not similarly decreased. In low- and middle-income regions, ART roll-out has improved outcomes, but has resulted in increasing acquired and transmitted resistances. Our objective was to review resistance to ART drugs and methods to detect it, and to provide updated recommendations for testing and monitoring for drug resistance in HIV-infected individuals. Methods: A volunteer panel of experts appointed by the International Antiviral (formerly AIDS) Society-USA reviewed relevant peer-reviewed data that were published or presented at scientific conferences. Recommendations were rated according to the strength of the recommendation and quality of the evidence, and reached by full panel consensus. Results: Resistance testing remains a cornerstone of ART. It is recommended in newly-diagnosed individuals and in patients in whom ART has failed. Testing for transmitted integrase strand-transfer inhibitor resistance is currently not recommended, but this may change as more resistance emerges with widespread use. Sanger-based and next-generation sequencing approaches are each suited for genotypic testing. Testing for minority variants harboring drug resistance may only be considered if treatments depend on a first-generation nonnucleoside analogue reverse transcriptase inhibitor. Different HIV-1 subtypes do not need special considerations regarding resistance testing. Conclusions: Testing for HIV drug resistance in drug-naive individuals and in patients in whom antiretroviral drugs are failing, and the appreciation of the role of testing, are crucial to the prevention and management of failure of ART.

17.
Clin Infect Dis ; 2018 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-29917039

RESUMO

Background: Treponema pallidum subsp. pertenue and Haemophilus ducreyi are causative agents of cutaneous ulcer (CU) in yaws endemic regions in the tropics. However, a significant proportion of CU patients remain PCR-negative for both bacterial agents. We aimed to identify potential additional aetiological agents of CU in a yaws-endemic region. Methods: This population-based cohort study included children in Lihir Island (Papua New Guinea) examined during a yaws eradication campaign in Oct 2013-Oct 2014. All consenting patients with atraumatic exudative ulcers of more than 1 cm diameter were enrolled. Lesional swabs were collected for Real-Time PCR testing for T. p .pertenue and H. ducreyi. We then performed shotgun whole DNA metagenomics sequencing on extracted DNA and taxonomically assigned shotgun sequences using a human microbiome reference. Findings: Sequence data was available for 122 samples. Shotgun sequencing showed high classification agreement relative to PCR testing: AUC for T. pallidum/H. ducreyi: 0.92/0.85 respectively. Clustering analysis of shotgun data revealed compositional clusters where the dominant species (median relative abundance ranged 32%-66%) was: H. ducreyi (23% of specimens), T. p. pertenue (16%), Streptococcus dysgalactiae (12%), Arcanobacterium haemolyticum (8%) and Corynebacterium diptheriae (8%). Sample clustering derived from ulcer microbial composition did not show geographical patterns. Conclusion: These data suggest a diverse aetiology of skin ulcers in yaws-endemic areas, which may help design more accurate diagnostic tools and more effective antimicrobial treatment approaches to the cutaneous ulcer syndrome.

18.
PLoS One ; 13(5): e0196451, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29742132

RESUMO

BACKGROUND: Few data on HIV resistance in pregnancy are available from Mozambique, one of the countries with the highest HIV toll worldwide. Understanding the patterns of HIV drug resistance in pregnant women might help in tailoring optimal regimens for prevention of mother to child transmission of HIV (pMTCT) and antenatal care. OBJECTIVES: To describe the frequency and characteristics of HIV drug resistance mutations (HIVDRM) in pregnant women with virological failure at delivery, despite pMTCT or antiretroviral therapy (ART). METHODS: Samples from HIV-infected pregnant women from a rural area in southern Mozambique were analysed. Only women with HIV-1 RNA >400c/mL at delivery were included in the analysis. HIVDRM were determined using MiSeq® (detection threshold 1%) at the first antenatal care (ANC) visit and at the time of delivery. RESULTS: Ninety and 60 samples were available at the first ANC visit and delivery, respectively. At first ANC, 97% of the women had HIV-1 RNA>400c/mL, 39% had CD4+ counts <350 c/mm3 and 30% were previously not on ART. Thirteen women (14%) had at least one HIVDRM of whom 70% were not on previous ART. Eight women (13%) had at least one HIVDRM at delivery. Out of 37 women with data available from the two time points, 8 (21%) developed at least one new HIVDRM during pMTCT or ART. Twenty seven per cent (53/191), 32% (44/138) and 100% (5/5) of the mutations that were present at enrolment, delivery and that emerged during pregnancy, respectively, were minority mutations (frequency <20%). CONCLUSIONS: Even with ultrasensitive HIV-1 genotyping, less than 20% of women with detectable viremia at delivery had HIVDRM before initiating pMTCT or ART. This suggests that factors other than pre-existing resistance, such as lack of adherence or interruptions of the ANC chain, are also relevant to explain lack of virological suppression at the time of delivery in women receiving antiretrovirals drugs during pregnancy.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Contagem de Linfócito CD4/métodos , Feminino , HIV-1/efeitos dos fármacos , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Moçambique , Gravidez , Cuidado Pré-Natal/métodos , Adulto Jovem
19.
J Antimicrob Chemother ; 73(7): 1965-1971, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29608685

RESUMO

Background: No controlled comparisons between dolutegravir/lamivudine or dolutegravir maintenance therapy have been done. We hypothesized that these options would have similar efficacy to triple ART. Methods: We used an open-label non-inferiority randomized controlled trial comprising two phases: phase A was established to test that experimental arms did not have an unacceptable (≥5%) failure rate; phase B was intended to include the full number of patients followed for 48 weeks. Treated HIV-1-infected adults with viral load <50 copies/mL for ≥12 months, no prior viral failure or resistance mutations to study drugs, nadir CD4 >200 cells/mm3, and hepatitis B virus surface antigen negative were randomized 1:1:1 to maintain triple therapy (control arm), or to switch to dolutegravir/lamivudine, or to dolutegravir monotherapy stratifying by anchor drug. Premature discontinuation was considered if viral failure or therapy interruption due to adverse events, concurrent illness, protocol deviation or patient's wish occurred. Blips were registered. Planned phase A results at 24 weeks are reported here. The study is registered at EudraCT: 201500027435. Results: Ninety-one (control, n = 31; dual therapy, n = 29; monotherapy, n = 31) patients were randomized. Three patients (none previously exposed to integrase inhibitors) prematurely discontinued treatment due to viral failure: dolutegravir/lamivudine (n = 1), no resistance mutations (subject A); dolutegravir (n = 2), N155H, S147G and Q148R resistance mutations (subject B), and E138K, G140S and N155H resistance mutations (subject C). There were no discontinuations for other reasons. One patient (dolutegravir/lamivudine) experienced a blip in viral load. The Data Safety Monitoring Board recommended stopping the dolutegravir monotherapy arm. Conclusions: In contrast to dolutegravir/lamivudine, a higher than expected risk of viral failure with development of cross-resistance integrase mutations occurred with dolutegravir maintenance monotherapy.

20.
J Antimicrob Chemother ; 73(5): 1167-1172, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29462322

RESUMO

Objectives: To investigate the prevalence and patterns of major and accessory resistance mutations associated with integrase strand transfer inhibitors (INSTIs), across diverse HIV-1 subtypes in sub-Saharan Africa. Methods: pol gene sequences were obtained using Illumina next-generation sequencing from 425 INSTI-naive HIV-infected adults from Kenya (21.2%), Nigeria (7.3%), South Africa (22.8%), Uganda (25.2%) and Zambia (23.5%). Drug resistance interpretation was based on the IAS 2017 mutation list and accessory mutations from Stanford HIVdb with resistance penalty scores of ≥10 to at least 1 INSTI. Resistance was further classified based on sensitivity thresholds of ≥20% (Sanger sequencing) and 1%-20% for low-frequency variants (next-generation sequencing). Results: Of 425 genotypes, 48.7% were subtype C, 28.5% A, 10.1% D, 2.8% G and 9.9% were recombinants. Major INSTI resistance mutations were detected only at <20% threshold, at a prevalence of 2.4% (2.5% in subtype A, 2.4% C, 0% D, 8.3% G and 2.4% in recombinants) and included T66A/I (0.7%), E92G (0.5%), Y143C/S (0.7%), S147G (0.2%) and Q148R (0.5%). Accessory mutations occurred at a prevalence of 15.1% at the ≥20% threshold (23.1% in subtype A, 8.7% C, 11.6% D, 25% G and 23.8% in recombinants), and included L74I/M (10.4%), Q95K (0.5%), T97A (4%), E157Q (0.7%) and G163R/K (0.7%). Conclusions: Major INSTI resistance mutations were rare and only occurred at low-level resistance detection thresholds. INSTI-based regimens are expected to be effective across the different major HIV-1 subtypes in the region.

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