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1.
BMJ Open ; 9(8): e029066, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383704

RESUMO

OBJECTIVE: To evaluate the impact of treatment with new direct-acting antivirals (DAAs) on the prevalent hepatitis C virus (HCV) population in England. DESIGN: A repeated cross-sectional analysis. SETTING: Four secondary care hospitals in England. PARTICIPANTS: Patients who, in 2015 and/or 2016, had chronic HCV infection and were alive were eligible, regardless of the type of HCV intervention received. OUTCOME MEASURES: Data including intravenous drug use (IVDU) status, HCV genotype, cirrhosis status, HCV treatment history, vital status and treatment outcomes were collected at two time points in 2015 and 2016 using electronic case report forms. RESULTS: There were 1605 and 1355 patients with active chronic HCV in 2015 and 2016, respectively. Between 2015 and 2016, the proportion of patients with current IVDU increased (10.3% vs 14.5%, respectively), while that of patients with cirrhosis (28.2% vs 22.4%) and treatment-experienced patients (31.2% vs 27.1%) decreased. Among patients whose treatment outcome was known by 2016, high cure rates were observed, with an overall sustained virological response rate of 93.2%. From 2015 to 2016, there was a progressive increase in the proportion of treated patients who were non-cirrhotic, with current IVDU and non-liver transplant recipients. CONCLUSIONS: The characteristics of patients with HCV remaining in contact with specialised care evolved with a changing landscape of treatment and related health policy. With increasing access to DAAs in UK, high cure rates were achieved in the study cohort.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31299067

RESUMO

BACKGROUND: In sub-Saharan Africa, detecting resistance-associated mutations (RAMs) at failure of first-line ART with two NRTIs plus an NNRTI predicts improved virological responses to second-line therapy with two NRTIs plus a ritonavir-boosted PI (PI/r). This indicates residual NRTI activity in the presence of RAMs, although additional factors may contribute to the effect. OBJECTIVES: The aim of this study was to investigate the influence of pre-existing RAMs on the outcomes of maintenance monotherapy with ritonavir-boosted darunavir within a randomized trial in Cameroon. METHODS: RAMs were detected in HIV-1 DNA using PBMCs collected at initiation of darunavir/ritonavir monotherapy. Adherence was assessed by pill count and visual analogue scale (VAS). Predictors of virological failure (confirmed or last available viral load >400 copies/mL) were explored by logistic regression analysis. Trial name = MANET (NCT02155101). RESULTS: After NNRTI-based therapy, participants (n = 81) had received PI/r-based therapy for a median of 3.2 years and had a confirmed viral load <60 copies/mL and a median CD4 count of 466 cells/mm3. NRTI and NNRTI RAMs were detected in 39/60 (65.0%) and 41/60 (68.3%) HIV-1 DNA sequences, respectively. Over 48 weeks of monotherapy, 16/81 (19.8%) patients experienced virological failure. After adjusting for age, HIV-1 DNA load, adherence by VAS and RAM status, virological failure was less likely with higher VAS-measured adherence (adjusted OR 0.04, 95% CI 0.01-0.37; P = 0.004) and detectable HIV-1 DNA RAMs (adjusted OR 0.15, 95% CI 0.03-0.82; P = 0.028). CONCLUSIONS: Pre-existing NRTI and NNRTI RAMs are associated with improved virological responses to NRTI-sparing ART in sub-Saharan Africa, indicating a predictive effect that is independent of residual NRTI activity.

3.
Lancet ; 393(10189): 2428-2438, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31056293

RESUMO

BACKGROUND: The level of evidence for HIV transmission risk through condomless sex in serodifferent gay couples with the HIV-positive partner taking virally suppressive antiretroviral therapy (ART) is limited compared with the evidence available for transmission risk in heterosexual couples. The aim of the second phase of the PARTNER study (PARTNER2) was to provide precise estimates of transmission risk in gay serodifferent partnerships. METHODS: The PARTNER study was a prospective observational study done at 75 sites in 14 European countries. The first phase of the study (PARTNER1; Sept 15, 2010, to May 31, 2014) recruited and followed up both heterosexual and gay serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex, whereas the PARTNER2 extension (to April 30, 2018) recruited and followed up gay couples only. At study visits, data collection included sexual behaviour questionnaires, HIV testing (HIV-negative partner), and HIV-1 viral load testing (HIV-positive partner). If a seroconversion occurred in the HIV-negative partner, anonymised phylogenetic analysis was done to compare HIV-1 pol and env sequences in both partners to identify linked transmissions. Couple-years of follow-up were eligible for inclusion if condomless sex was reported, use of pre-exposure prophylaxis or post-exposure prophylaxis was not reported by the HIV-negative partner, and the HIV-positive partner was virally suppressed (plasma HIV-1 RNA <200 copies per mL) at the most recent visit (within the past year). Incidence rate of HIV transmission was calculated as the number of phylogenetically linked HIV infections that occurred during eligible couple-years of follow-up divided by eligible couple-years of follow-up. Two-sided 95% CIs for the incidence rate of transmission were calculated using exact Poisson methods. FINDINGS: Between Sept 15, 2010, and July 31, 2017, 972 gay couples were enrolled, of which 782 provided 1593 eligible couple-years of follow-up with a median follow-up of 2·0 years (IQR 1·1-3·5). At baseline, median age for HIV-positive partners was 40 years (IQR 33-46) and couples reported condomless sex for a median of 1·0 years (IQR 0·4-2·9). During eligible couple-years of follow-up, couples reported condomless anal sex a total of 76 088 times. 288 (37%) of 777 HIV-negative men reported condomless sex with other partners. 15 new HIV infections occurred during eligible couple-years of follow-up, but none were phylogenetically linked within-couple transmissions, resulting in an HIV transmission rate of zero (upper 95% CI 0·23 per 100 couple-years of follow-up). INTERPRETATION: Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV. FUNDING: National Institute for Health Research.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Soropositividade para HIV/transmissão , Homossexualidade Masculina , Sexo sem Proteção , Adulto , Terapia Antirretroviral de Alta Atividade , Preservativos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Parceiros Sexuais , Carga Viral
6.
J Antimicrob Chemother ; 74(3): 746-753, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544247

RESUMO

OBJECTIVES: In subjects with transmitted thymidine analogue mutations (TAMs), boosted PIs (PI/b) are often chosen to overcome possible resistance to the NRTI backbone. However, data to guide treatment selection are limited. Our aim was to obtain firmer guidance for clinical practice using real-world cohort data. METHODS: We analysed 1710 subjects who started a PI/b in combination with tenofovir or abacavir plus emtricitabine or lamivudine, and compared their virological outcomes with those of 4889 patients who started an NNRTI (predominantly efavirenz), according to the presence of ≥1 TAM as the sole form of transmitted drug resistance. RESULTS: Participants with ≥1 TAM comprised predominantly MSM (213 of 269, 79.2%), subjects of white ethnicity (206 of 269, 76.6%) and HIV-1 subtype B infections (234 of 269, 87.0%). Most (203 of 269, 75.5%) had singleton TAMs, commonly a revertant of T215Y or T215F (112 of 269, 41.6%). Over a median of 2.5 years of follow-up, 834 of 6599 (12.6%) subjects experienced viraemia (HIV-1 RNA >50 copies/mL). The adjusted HR for viraemia was 2.17 with PI/b versus NNRTI-based therapy (95% CI 1.88-2.51; P < 0.001). Other independent predictors of viraemia included injecting drug use, black ethnicity, higher viral load and lower CD4 cell count at baseline, and receiving abacavir instead of tenofovir. Resistance showed no overall impact (adjusted HR 0.77 with ≥1 TAM versus no resistance; 95% CI 0.54-1.10; P = 0.15). CONCLUSIONS: In this cohort, patients harbouring ≥1 TAM as the sole form of transmitted drug resistance gained no apparent virological advantage from starting first-line ART with a PI/b.

8.
Open Forum Infect Dis ; 5(10): ofy251, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30377627

RESUMO

Background: We monitored the evolution of markers of hepatitis B virus (HBV) infection in virologically suppressed HIV-positive patients switching to nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapy within a randomized trial in Cameroon. Methods: HBV surface antigen (HBsAg), HBV DNA, and antibodies against surface (anti-HBs), core (total anti-HBc), and e-antigen (anti-HBe) were measured retrospectively in samples collected at study entry and over 48 weeks after NRTI discontinuation. Results: Participants (n = 80, 75% females) had a plasma HIV-1 RNA <60 copies/mL, a median CD4 count of 466 cells/mm3, and undetectable HBsAg and HBV DNA at study entry. After NRTI discontinuation, 3/20 (15.0%) anti-HBc-negative patients showed evidence indicative or suggestive of incident HBV infection (163 cases/1000 person-years); 6/60 (10.0%) anti-HBc-positive patients showed evidence indicative or suggestive of HBV reactivation (109 cases/1000 person-years). In one case of reactivation, anti-HBs increased from 14 to >1000 IU/L; sequencing showed HBV genotype A3 and 3 escape mutations in surface (Y100C, K122R, Y161FY). Alongside new-onset detection of HBsAg or HBV DNA, 1 patient experienced acute hepatitis and 6 patients experienced mild or marginal increases in serum transaminase levels. Conclusions: Evolving treatment strategies for sub-Saharan Africa must be accompanied by the formulation and implementation of policy to guide appropriate assessment and management of HBV status.

9.
Sci Rep ; 8(1): 15297, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30333568

RESUMO

Eliminating hepatitis C as a public health threat requires an improved understanding of how to increase testing uptake. We piloted point-of-care testing (POCT) for a current HCV infection in an inner-city Emergency Department (ED) and assessed the influence on uptake of offering concomitant screening for HIV. Over four months, all adults attending ED with minor injuries were first invited to complete an anonymous questionnaire then invited to test in alternating cycles offering HCV POCT or HCV+HIV POCT. Viral RNA was detected in finger-prick blood by GeneXpert. 814/859 (94.8%) questionnaires were returned and 324/814 (39.8%) tests were accepted, comprising 211 HCV tests and 113 HCV+HIV tests. Offering concomitant HIV screening reduced uptake after adjusting for age and previous HCV testing (odds ratio 0.51; 95% confidence interval [CI] 0.38-0.68; p < 0.001). HCV prevalence was 1/324 (0.31%; 95% CI 0.05-1.73); no participant tested positive for HIV. 167/297 (56.2%) POCT participants lived in the most deprived neighbourhoods in England. HCV RNA testing using finger-prick blood was technically feasible. Uptake was moderate and the offer of concomitant HIV screening showed a detrimental impact on acceptability in this low prevalence population. The findings should be confirmed in a variety of other community settings.

10.
BMC Infect Dis ; 18(1): 516, 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30314448

RESUMO

BACKGROUND: Viral hepatitis is an important public health issue in sub-Saharan Africa. Due to rising mortality from cirrhosis and hepatocellular carcinoma and limited implementation of screening and treatment programmes, it has been characterised as a neglected tropical disease. Synthesis of the existing evidence on the epidemiology of viral hepatitis B, C and D in Malawi is required to inform policy and identify research gaps. METHODS: We searched Pubmed, EMBASE and Scopus for studies reporting the epidemiology of viral hepatitis B, C and D in Malawi from 1990 to 2018. Articles reporting prevalence estimates were included provided they described details of participant selection, inclusion criteria and laboratory methods (detection of HBsAg, anti-HCV or anti-HDV antibody, HCV antigen or HCV RNA or HDV RNA). We assessed study quality using a prevalence assessment tool. Where appropriate, a pooled prevalence was calculated using a DerSimonian Laird random effects model. RESULTS: Searches identified 199 studies, 95 full text articles were reviewed and 19 articles were included. Hepatitis B surface antigen (HBsAg) seroprevalence was assessed in 14 general population cohorts. The pooled prevalence among adults was 8.1% (95% CI 6.1, 10.3). In 3 studies where HBsAg was stratified by HIV status, no effect of HIV on HBsAg prevalence was observed (OR 1.2 (95% CI: 0.8, 1.6, p = 0.80)). In a single study of HIV/HBV infected individuals, anti-hepatitis D antibody (anti-HDV) prevalence was low (1.5%). HCV antibody prevalence (anti-HCV) ranged from 0.7 to 18.0% among 12 cohorts in general populations. Among three studies which used PCR to confirm current infection, the pooled rate of HCV RNA confirmation among anti-HCV positive individuals was only 7.3% (95% CI: 0.0, 24.3). CONCLUSIONS: Hepatitis B is highly prevalent in Malawi. There is a paucity of epidemiological data from rural areas where 85% of the population reside, and the Northern region. Priority research needs include large-scale representative community studies of HBV, HDV and HCV seroprevalence, assessment of children following introduction of the HBV vaccine in 2002, prevalence estimates of viral hepatitis among individuals with cirrhosis and HCC and data on HCV prevalence using PCR confirmation, to support a viral hepatitis strategy for Malawi.


Assuntos
Hepatite B/epidemiologia , Hepatite C/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Anticorpos Anti-Hepatite/sangue , Hepatite B/complicações , Hepatite B/diagnóstico , Antígenos de Superfície da Hepatite B/sangue , Hepatite C/complicações , Hepatite C/diagnóstico , Hepatite D/complicações , Hepatite D/diagnóstico , Hepatite D/epidemiologia , Humanos , Malaui/epidemiologia , Prevalência , RNA Viral/sangue , RNA Viral/metabolismo
11.
AIDS ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30325769

RESUMO

OBJECTIVE: To evaluate the effect of primary resistance and selected polymorphic amino-acid substitutions in HIV reverse transcriptase (RT) and protease (PR) on the CD4 count and viral load (VL) set point before the start of ART. DESIGN: Prospective cohort study. METHODS: 6,180 individuals with a resistance test prior to starting ART accessing care in HIV clinics across Europe who had at least 1 VL and 1 CD4 test available were included in the analysis. The impact of amino-acid substitutions variants on VL and CD4 trends was investigated using linear mixed models. Clusters of mutations were studied using principal component analysis. RESULTS: Overall, the detection of any primary resistance was not associated with either the speed of CD4 decline or the viral load set point. However, transmitted nucleoside RT inhibitor and PR inhibitor resistance appeared to be weakly associated with lower VL set points, as were the polymorphic G16E or Q92K PR mutations. There was some evidence suggesting that these effects varied according to HIV subtype, with the effects of transmitted NRTI and PR resistance being particularly marked among individuals with a subtype B virus. A cluster of five polymorphic PR substitutions at position 20, 13, 36, 69 and 89 was associated with less steep CD4 declines and lower VL set points. CONCLUSIONS: Although we found little evidence for an association between primary resistance and CD4 speed of decline and VL set point, the potential role of polymorphic PR (alone or in clusters) and their interplay with HIV subtype needs to be further evaluated.

12.
PLoS Negl Trop Dis ; 12(8): e0006629, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30080852

RESUMO

International sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the pressing need to optimize strategies for prevention, diagnosis and treatment. Selected or transmitted resistance associated mutations (RAMs) and vaccine escape mutations (VEMs) in hepatitis B virus (HBV) may reduce the success of existing treatment and prevention strategies. These issues are particularly pertinent for many settings in Africa where there is high HBV prevalence and co-endemic HIV infection, but lack of robust epidemiological data and limited education, diagnostics and clinical care. The prevalence, distribution and impact of RAMs and VEMs in these populations are neglected in the current literature. We therefore set out to assimilate data for sub-Saharan Africa through a systematic literature review and analysis of published sequence data, and present these in an on-line database (https://livedataoxford.shinyapps.io/1510659619-3Xkoe2NKkKJ7Drg/). The majority of the data were from HIV/HBV coinfected cohorts. The commonest RAM was rtM204I/V, either alone or in combination with associated mutations, and identified in both reportedly treatment-naïve and treatment-experienced adults. We also identified the suite of mutations rtM204V/I + rtL180M + rtV173L, that has been associated with vaccine escape, in over 1/3 of cohorts. Although tenofovir has a high genetic barrier to resistance, it is of concern that emerging data suggest polymorphisms that may be associated with resistance, although the precise clinical impact of these is unknown. Overall, there is an urgent need for improved diagnostic screening, enhanced laboratory assessment of HBV before and during therapy, and sustained roll out of tenofovir in preference to lamivudine alone. Further data are needed in order to inform population and individual approaches to HBV diagnosis, monitoring and therapy in these highly vulnerable settings.

13.
Lancet Infect Dis ; 18(9): 992-1003, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30153934

RESUMO

BACKGROUND: Viral meningitis is increasingly recognised, but little is known about the frequency with which it occurs, or the causes and outcomes in the UK. We aimed to determine the incidence, causes, and sequelae in UK adults to improve the management of patients and assist in health service planning. METHODS: We did a multicentre prospective observational cohort study of adults with suspected meningitis at 42 hospitals across England. Nested within this study, in the National Health Service (NHS) northwest region (now part of NHS England North), was an epidemiological study. Patients were eligible if they were aged 16 years or older, had clinically suspected meningitis, and either underwent a lumbar puncture or, if lumbar puncture was contraindicated, had clinically suspected meningitis and an appropriate pathogen identified either in blood culture or on blood PCR. Individuals with ventricular devices were excluded. We calculated the incidence of viral meningitis using data from patients from the northwest region only and used these data to estimate the population-standardised number of cases in the UK. Patients self-reported quality-of-life and neuropsychological outcomes, using the EuroQol EQ-5D-3L, the 36-Item Short Form Health Survey (SF-36), and the Aldenkamp and Baker neuropsychological assessment schedule, for 1 year after admission. FINDINGS: 1126 patients were enrolled between Sept 30, 2011, and Sept 30, 2014. 638 (57%) patients had meningitis: 231 (36%) cases were viral, 99 (16%) were bacterial, and 267 (42%) had an unknown cause. 41 (6%) cases had other causes. The estimated annual incidence of viral meningitis was 2·73 per 100 000 and that of bacterial meningitis was 1·24 per 100 000. The median length of hospital stay for patients with viral meningitis was 4 days (IQR 3-7), increasing to 9 days (6-12) in those treated with antivirals. Earlier lumbar puncture resulted in more patients having a specific cause identified than did those who had a delayed lumbar puncture. Compared with the age-matched UK population, patients with viral meningitis had a mean loss of 0·2 quality-adjusted life-years (SD 0·04) in that first year. INTERPRETATION: Viruses are the most commonly identified cause of meningitis in UK adults, and lead to substantial long-term morbidity. Delays in getting a lumbar puncture and unnecessary treatment with antivirals were associated with longer hospital stays. Rapid diagnostics and rationalising treatments might reduce the burden of meningitis on health services. FUNDING: Meningitis Research Foundation and UK National Institute for Health Research.

14.
J Antimicrob Chemother ; 73(11): 3148-3157, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30032305

RESUMO

Objectives: The resistance profiles of patients receiving long-term ART in sub-Saharan Africa have been poorly described. This study obtained a sensitive assessment of the resistance patterns associated with long-term tenofovir-based ART in a programmatic setting where virological monitoring is yet to become part of routine care. Methods: We studied subjects who, after a median of 4.2 years of ART, replaced zidovudine or stavudine with tenofovir disoproxil fumarate while continuing lamivudine and an NNRTI. Using deep sequencing, resistance-associated mutations (RAMs) were detected in stored samples collected at tenofovir introduction (T0) and after a median of 4.0 years (T1). Results: At T0, 19/87 (21.8%) subjects showed a detectable viral load and 8/87 (9.2%) had one or more major NNRTI RAMs, whereas 82/87 (94.3%) retained full tenofovir susceptibility. At T1, 79/87 (90.8%) subjects remained on NNRTI-based ART, 5/87 (5.7%) had introduced lopinavir/ritonavir due to immunological failure, and 3/87 (3.4%) had interrupted ART. Whilst 68/87 (78.2%) subjects maintained or achieved virological suppression between T0 and T1, a detectable viral load with NNRTI RAMs at T0 predicted lack of virological suppression at T1. Each treatment interruption, usually reflecting unavailability of the dispensary, doubled the risk of T1 viraemia. Tenofovir, lamivudine and efavirenz selected for K65R, K70E/T, L74I/V and Y115F, alongside M184V and multiple NNRTI RAMs; this resistance profile was accompanied by high viral loads and low CD4 cell counts. Conclusions: Viraemia on tenofovir, lamivudine and efavirenz led to complex resistance patterns with implications for continued drug activity and risk of onward transmission.

15.
AIDS Rev ; 20(1): 27-42, 2018 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29628515

RESUMO

Resistance to antiretroviral therapy (ART) threatens the efficacy of human immunodeficiency virus type 1 (HIV-1) treatment. We present a review of knowledge gaps in the science and technologies of acquired HIV-1 drug resistance (HIVDR) in an effort to facilitate research, scientific exchange, and progress in clinical management. The expert authorship of this review convened to identify data gaps that exist in the field of HIVDR and discuss their clinical implications. A subsequent literature review of trials and current practices was carried out to provide supporting evidence. Several gaps were identified across HIVDR science and technology. A summary of the major gaps is presented, with an expert discussion of their implications within the context of the wider field. Crucial to optimizing the use of ART will be improved understanding of protease inhibitors and, in particular, integrase strand transfer inhibitors (INSTI) in the context of HIVDR. Limited experience with INSTI represents an important knowledge gap in HIV resistance science. Utilizing such knowledge in a clinical setting relies on accurate testing and analysis of resistance-associated mutations. As next-generation sequencing becomes more widely available, a gap in the interpretation of data is the lack of a defined, clinically relevant threshold of minority variants. Further research will provide evidence on where such thresholds lie and how they can be most effectively applied. Expert discussion identified a series of gaps in our knowledge of HIVDR. Addressing prefsuch gaps through further research and characterization will facilitate the optimal use of ART therapies and technologies.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Farmacorresistência Viral/genética , Infecções por HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Mutação/genética
16.
Open Forum Infect Dis ; 5(2): ofy032, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29507867

RESUMO

Background: Persistence of plasma HIV-1 RNA during seemingly effective antiretroviral thereapy (ART) is incompletely understood. Using an ultrasensitive assay, this cross-sectional study investigated residual plasma HIV-1 RNA in subjects maintained on firstline ART with continuous viral load suppression <50 copies/mL for ≤15 years without recognized viral load blips or treatment interruptions and explored its relationship with the duration of suppressive ART, efavirenz concentrations in plasma, 2-LTR circular HIV-1 DNA (2-LTRc DNA) in peripheral blood mononuclear cells, and cellular (CD4 plus CD26/CD38/CD69; CD8 plus CD38/HLA-DR/DP/DQ) and soluble (sCD14, sCD27, sCD30, IL-6) markers of immune activation in peripheral blood. Methods: Residual plasma HIV-1 RNA, total HIV-1 DNA and 2-LTRc DNA were quantified by real-time and digital droplet PCR. Cellular (CD4 plus CD26/CD38/CD69; CD8 plus CD38/HLA-DR/DP/DQ) and soluble (sCD14, sCD27, sCD30, IL-6) markers of immune activation were measured by flow cytometry and ELISA. Results: Residual plasma HIV-1 RNA and 2-LTRc DNA were detected in 52/104 (50%) and 24/104 (23%) subjects, respectively. Among subjects with detectable HIV-1 RNA, 50/52 showed levels ≤11 copies/mL. In adjusted analyses, HIV-1 RNA levels were 0.37 log10 copies/mL higher with each log10 U/mL increase in sCD27 (95% confidence interval, 0.01-0.73; P = .02). No significant association was found between residual plasma HIV-1 RNA and other explored parameters. Conclusions: These findings point to an ongoing relationship between plasma HIV-1 RNA and selected markers of immune activation during continuously suppressive ART. The novel direct association with levels of sCD27 warrants further investigation.

17.
Thorax ; 73(6): 557-564, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29378859

RESUMO

INTRODUCTION: Urban homeless populations in the UK have been shown to have high rates of active tuberculosis, but less is known about the prevalence of latent tuberculosis infection (LTBI). This study aimed to estimate the prevalence of LTBI among individuals using homeless hostels in London. METHODS: We performed a cross-sectional survey with outcome follow-up in homeless hostels in London. Our primary outcome was prevalence of LTBI. Recruitment for the study took place between May 2011 and June 2013. To estimate an LTBI prevalence of 10% with 95% CIs between 8% and 13%, we required 500 participants. RESULTS: 491/804 (61.1%) individuals agreed to be screened. The prevalence of LTBI was 16.5% (81/491; 95% CI 13.2 to 19.8). In UK-born individuals, a history of incarceration was associated with increased risk of LTBI (OR 3.49; 95% CI 1.10 to 11.04; P=0.018) after adjusting for age, length of time spent homeless and illicit drug use. Of the three subjects who met English treatment guidelines for LTBI at the time of the study, none engaged with services after referral for treatment. Prevalence of past hepatitis B infection was 10.4% (51/489; 95% CI 7.7 to 13.1), and 59.5% (291/489; 95% CI 55.1 to 63.9) of individuals were non-immune. Prevalence of current hepatitis C infection was 10.4% (51/489; 95% CI 7.8 to 13.1). CONCLUSIONS: This study demonstrates the high prevalence of LTBI in homeless people in London and the associated poor engagement with care. There is a large unmet need for LTBI and hepatitis C infection treatment, and hepatitis B vaccination, in this group.

18.
Am J Respir Crit Care Med ; 197(12): 1604-1615, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29365279

RESUMO

RATIONALE: People living with HIV are at significantly increased risk of invasive pneumococcal disease, despite long-term antiretroviral therapy (ART). The mechanism explaining this observation remains undefined. OBJECTIVES: To determine if apoptosis-associated microbicidal mechanisms, required to clear intracellular pneumococci that survive initial phagolysosomal killing, are perturbed. METHODS: Alveolar macrophages (AM) were obtained by BAL from healthy donors or HIV-1-seropositive donors on long-term ART with undetectable plasma viral load. Monocyte-derived macrophages (MDM) were obtained from healthy donors and infected with HIV-1BaL or treated with gp120. Macrophages were challenged with opsonized serotype 2 Streptococcus pneumoniae and assessed for apoptosis, bactericidal activity, protein expression, and mitochondrial reactive oxygen species (mROS). AM phenotyping, ultrasensitive HIV-1 RNA quantification, and gp120 measurement were also performed in BAL. MEASUREMENTS AND MAIN RESULTS: HIV-1BaL infection impaired apoptosis, induction of mROS, and pneumococcal killing by MDM. Apoptosis-associated pneumococcal killing was also reduced in AM from ART-treated HIV-1-seropositive donors. BAL fluid from these individuals demonstrated persistent lung CD8+ T lymphocytosis, and gp120 or HIV-1 RNA was also detected. Despite this, transcriptional activity in AM freshly isolated from people living with HIV was broadly similar to healthy volunteers. Instead, gp120 phenocopied the defect in pneumococcal killing in healthy MDM through post-translational modification of Mcl-1, preventing apoptosis induction, caspase activation, and increased mROS generation. Moreover, gp120 also inhibited mROS-dependent pneumococcal killing in MDM. CONCLUSIONS: Despite ART, HIV-1, via gp120, drives persisting innate immune defects in AM microbicidal mechanisms, enhancing susceptibility to pneumococcal disease.

19.
Clin Infect Dis ; 66(12): 1846-1857, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29272346

RESUMO

Background: In sub-Saharan Africa, 25.5 million people are living with human immunodeficiency virus (HIV), representing 70% of the global total. The need for second-line antiretroviral therapy (ART) is projected to increase in the next decade in keeping with the expansion of treatment provision. Outcome data are required to inform policy. Methods: We performed a systematic review and meta-analysis of studies reporting the virological outcomes of protease inhibitor (PI)-based second-line ART in sub-Saharan Africa. The primary outcome was virological suppression (HIV-1 RNA <400 copies/mL) after 48 and 96 weeks of treatment. The secondary outcome was the proportion of patients with PI resistance. Pooled aggregate data were analyzed using a DerSimonian-Laird random effects model. Results: By intention-to-treat analysis, virological suppression occurred in 69.3% (95% confidence interval [CI], 58.2%-79.3%) of patients at week 48 (4558 participants, 14 studies), and in 61.5% (95% CI, 47.2%-74.9%) at week 96 (2145 participants, 8 studies). Preexisting resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) increased the likelihood of virological suppression. Major protease resistance mutations occurred in a median of 17% (interquartile range, 0-25%) of the virological failure population and increased with duration of second-line ART. Conclusions: One-third of patients receiving PI-based second-line ART with continued NRTI use in sub-Saharan Africa did not achieve virological suppression, although among viremic patients, protease resistance was infrequent. Significant challenges remain in implementation of viral load monitoring. Optimizing definitions and strategies for management of second-line ART failure is a research priority. Prospero Registration: CRD42016048985.

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