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1.
Clin Infect Dis ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31606734

RESUMO

BACKGROUND: Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation. METHODS: We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naïve people with HIV (PWH) initiating ART between 2003-2015, comprising over 5,000 participants and 10,000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation. FINDINGS: Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4, higher HIV-1 RNA, no injection drug use, female sex and black race. Integrase strand transfer inhibitors (INSTIs) were associated with more weight gain than protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTI), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine. INTERPRETATION: Weight gain is ubiquitous in clinical trials of ART initiation, and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens contributing. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

2.
AIDS ; 33(10): 1583-1593, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31305329

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of switching from an abacavir/lamivudine (ABC/3TC)-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen in virologically suppressed, HIV-1-infected adults. DESIGN: Randomized, open-label, noninferiority study. METHODS: Participants with HIV-1 RNA levels less than 50 copies/ml receiving ABC/3TC plus a third agent for at least 6 months were randomized 2 : 1 to switch immediately to E/C/F/TAF (immediate-switch group) for 48 weeks or to continue receiving ABC/3TC plus a third agent for 24 weeks followed by E/C/F/TAF for 24 weeks (delayed-switch group). The primary endpoint was HIV-1 RNA less than 50 copies/ml at Week 24 by Food and Drug Administration Snapshot algorithm (-12% noninferiority margin). RESULTS: Baseline characteristics of 274 participants (183 in immediate-switch group and 91 in delayed-switch group) were similar. Virologic response was maintained at Week 24 by 93.4 and 97.8% of participants in the immediate-switch and delayed-switch groups, respectively, with a treatment difference of -4.4% (95% confidence interval: -9.4 to 1.9%), confirming noninferiority. Adverse events of any grade were similar between groups through Week 24 (66% E/C/F/TAF, 64% ABC/3TC); adverse event-related drug discontinuations occurred in 4% of participants switching to E/C/F/TAF (no discontinuations because of renal events) and no participants continuing ABC/3TC. Renal biomarkers of urine albumin:creatinine and beta-2-microglobulin:creatinine ratios significantly improved on E/C/F/TAF. Self-reported treatment satisfaction was significantly higher with E/C/F/TAF. CONCLUSION: Switching to E/C/F/TAF was noninferior to continuing ABC/3TC plus a third agent for maintenance of HIV RNA suppression at Week 24. This study supports E/C/F/TAF as an efficacious and well tolerated option for participants switching from ABC/3TC-based regimens.

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
4.
Lancet HIV ; 6(6): e364-e372, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31068272

RESUMO

BACKGROUND: The single-tablet regimen consisting of bictegravir, emtricitabine, and tenofovir alafenamide is recommended for treatment of HIV-1 infection on the basis of data from 48 weeks of treatment. Here, we examine the longer-term efficacy, safety, and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with dolutegravir plus co-formulated emtricitabine and tenofovir alafenamide at week 96. METHODS: This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 126 outpatient centres in ten countries. We enrolled treatment-naive adults (aged ≥18 years) with HIV-1 infection who had an estimated glomerular filtration rate of at least 30 mL/min and sensitivity to emtricitabine and tenofovir. People with chronic hepatitis B or C infection, or both, and those who had used antivirals previously for prophylaxis were allowed. We randomly assigned participants (1:1) to receive treatment with either co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or dolutegravir 50 mg with co-formulated emtricitabine 200 mg and tenofovir alafenamide 25 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607956. FINDINGS: Between Nov 13, 2015, and July 14, 2016, we screened 742 individuals, of whom 657 were enrolled. 327 participants were assigned to the bictegravir group and 330 to the dolutegravir group. Of these, 320 in the bictegravir group and 325 in the dolutegravir group received at least one dose of study drug. At week 96, HIV-1 RNA less than 50 copies per mL was achieved by 269 (84%) of 320 participants in the bictegravir group and 281 (86%) of 325 in the dolutegravir group (difference -2·3%, 95% CI -7·9 to 3·2), demonstrating non-inferiority of the bictegravir regimen compared with the dolutegravir regimen. Both treatments continued to be well tolerated through 96 weeks; 283 (88%) of 320 participants in the bictegravir group and 288 (89%) of 325 in the dolutegravir group had any adverse event and 55 (17%), and 33 (10%) had any serious adverse event. The most common adverse events were diarrhoea (57 [18%] of 320 in the bictegravir group vs 51 [16%] of 325 in the dolutegravir group) and headache (51 [16%] of 320 vs 48 [15%] of 325). Deaths were reported for three (1%) individuals in each group (one cardiac arrest, one gastric adenocarcinoma, and one hypertensive heart disease and congestive cardiac failure in the bictegravir group and one unknown causes, one pulmonary embolism, and one lymphoma in the dolutegravir group); none were considered to be treatment related. Adverse events led to discontinuation in six (2%) participants in the bictegravir group and five (2%) in the dolutegravir group; one of these events in the bictegravir group versus four in the dolutegravir group occurred between weeks 48 and 96. Study drug-related adverse events were reported for 64 (20%) participants in the bictegravir group and 92 (28%) in the dolutegravir group. INTERPRETATION: These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with chronic HIV. FUNDING: Gilead Sciences, Inc.

5.
AIDS ; 33(9): 1455-1465, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30932951

RESUMO

OBJECTIVE: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, the comparative incidence of clinically significant renal events remains unclear. DESIGN: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes. METHODS: We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios). RESULTS: Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy. CONCLUSION: These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.

7.
Clin Infect Dis ; 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29912307

RESUMO

Background: Both immediate or deferred switching from a PI/r to DTG may improve lipid profile. Methods: NEAT022 is a European, open label, randomized, trial. HIV-infected adults ≥ 50 years or with a Framingham score ≥10% were eligible if HIV RNA < 50 copies/mL. Patients were randomized to switch the PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D) . Week 96 end-points were: proportion of patients with HIV RNA < 50 copies/ml, percentage change of lipid fractions and adverse events. Results: 415 patients were randomized: 205 to DTG-I and 210 to continue PI/r plus a deferred switch (DTG-D) at week 48 . The primary objective of non-inferiority at week 48 was met. At week 96, treatment success rate was 92.2 % in DTG-I arm and 87% in DTG-D arm (difference 5.2%, 95% CI -0.6 to 11). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AE´s or treatment modifying AE´s. Total cholesterol and other lipid fractions (except HDL) significantly (p<0.001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions: Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV patients ≥ 50 years old or with a Framingham score ≥10% was highly efficacious, well tolerated and improved lipid profile.

8.
Lancet HIV ; 5(7): e357-e365, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29925489

RESUMO

BACKGROUND: Bictegravir, co-formulated with emtricitabine and tenofovir alafenamide, has shown good efficacy and tolerability, and similar bone, renal, and lipid profiles to dolutegravir, abacavir, and lamivudine, in treatment-naive adults with HIV-1 infection, without development of treatment-emergent resistance. Here, we report 48-week results of a phase 3 study investigating switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection. METHODS: In this multicentre, randomised, double-blind, active-controlled, non-inferiority, phase 3 trial, HIV-1-infected adults were enrolled at 96 outpatient centres in nine countries. Eligible participants were aged 18 years or older and on a regimen of 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (fixed-dose combination or multi-tablet regimen); had an estimated glomerular filtration rate of 50 mL/min or higher; and had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 3 months or more before screening. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg; herein known as the bictegravir group), or to remain on dolutegravir, abacavir, and lamivudine (herein known as the dolutegravir group), once daily for 48 weeks. The investigators, participants, study staff, and individuals assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (according to the US Food and Drug Administration snapshot algorithm); the prespecified non-inferiority margin was 4%. The primary efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting participants and is in the open-label extension phase, wherein participants are given the option to receive bictegravir, emtricitabine, and tenofovir alafenamide for an additional 96 weeks. This trial is registered with ClinicalTrials.gov, number NCT02603120. FINDINGS: Between Nov 11, 2015, and July 6, 2016, 567 participants were randomly assigned and 563 were treated (282 received bictegravir, emtricitabine, and tenofovir alafenamide, and 281 received dolutegravir, abacavir, and lamivudine). Switching to the bictegravir regimen was non-inferior to remaining on dolutegravir, abacavir, and lamivudine for the primary outcome: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one (<1%) of 281 participants in the dolutegravir group (difference 0·7%, 95·002% CI -1·0 to 2·8; p=0·62). Treatment-related adverse events were recorded in 23 (8%) participants in the bictegravir group and 44 (16%) in the dolutegravir group. Treatment was discontinued because of adverse events in six (2%) participants in the bictegravir group and in two (1%) participants in the dolutegravir group. INTERPRETATION: The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection. FUNDING: Gilead Sciences.

9.
Curr Opin HIV AIDS ; 13(4): 334-340, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29746267

RESUMO

PURPOSE OF REVIEW: Analyzing the evidence for the strand transfer integrase inhibitor cabotegravir (CAB; GSK744, GSK1265744), its properties and differences from other compounds in the class, as well as reviewing the preclinical and clinical evidence for its potential in antretroviral therapy and medical HIV prevention. RECENT FINDINGS: CAB has been investigated both as an oral and an injectable compound. Recent results show that it has promising properties with regards to its potential for parenteral maintenance therapy in combination with other compounds in HIV-infected patients currently suppressed on oral agents, as well as in preexposure prophylaxis. SUMMARY: The strand transfer integrase inhibitor CAB is currently being investigated as an intramuscular preparation with a long half-life allowing for four to eight-weekly injection intervals, and as an oral preparation. The latter is currently only used in trials for achieving an undetectable viral load in antiretroviral-naive patients, assessing tolerability, and covering phases of suboptimal exposure to the parenteral preparation. Phase 2 trials of a dual regimen of CAB and rilpivirine have demonstrated promising virological activity in oral as well as in parenteral therapy, which are currently investigated in phase three trials. Moreover, CAB protected macaques from experimental simian/human immunodeficiency virus infection and showed promising tolerability in the first trial in humans for preexposure prophylaxis of HIV infection. CAB might, therefore, provide the basis of the new treatment paradigm of parenteral treatment and prevention of HIV infection.

10.
AIDS ; 31(18): 2503-2514, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29112070

RESUMO

OBJECTIVE: To compare the efficacy, safety, and impact on lipid fractions of switching from a ritonavir-boosted protease inhibitor (PI/r) to a dolutegravir (DTG) regimen. METHODS: HIV type 1-infected adults more than 50 years or with a Framingham score more than 10% were eligible if plasma HIV RNA less than 50 copies per ml for at least 24 weeks while on a PI/r regimen. Patients were randomized to switch to DTG or to remain on PI/r. Primary endpoints were: proportion maintaining HIV RNA less than 50 copies per ml and percentage change from baseline of total cholesterol at week 48. RESULTS: In total, 415 patients (32 sites in six European countries) were randomized: 205 to DTG and 210 to continue PI/r. About 89% were men, 87% more than 50 years, 74% had a Framingham score more than 10%, with a median CD4 cell count of 617 cells per µl and suppressed viremia for a median of 5 years. At week 48, in the intent-to-treat analysis, treatment success rate was 93.1% in DTG group and 95.2% in PI/r group (difference -2.1%, 95% confidence interval -6.6 to 2.4, noninferiority demonstrated). There were four virological failures with DTG and one with PI/r with no emergent resistance mutations. There was no significant difference in severe adverse events or grade 3 or 4 adverse events or treatment modifying adverse events. Total cholesterol and other lipid fractions (except high-density lipoprotein cholesterol) improved significantly (P < 0.001) in the DTG group regardless of PI/r at baseline. CONCLUSION: Switching to a DTG regimen in virologically suppressed HIV type 1 patients with high cardiovascular disease risk was noninferior, and significantly improved lipid profiles.


Assuntos
Substituição de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores da Protease de HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Quimioterapia de Manutenção/métodos , Ritonavir/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Feminino , Inibidores de Integrase de HIV/efeitos adversos , Inibidores da Protease de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Ritonavir/efeitos adversos , Resposta Viral Sustentada , Resultado do Tratamento
11.
Lancet ; 390(10107): 2073-2082, 2017 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-28867499

RESUMO

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) coadministered with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) are recommended as first-line treatment for HIV, and coformulated fixed-dose combinations are preferred to facilitate adherence. We report 48-week results from a study comparing initial HIV-1 treatment with bictegravir-a novel INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug interactions-coformulated with the NRTI combination emtricitabine and tenofovir alafenamide as a fixed-dose combination to dolutegravir administered with coformulated emtricitabine and tenofovir alafenamide. METHODS: In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-infected adults were screened and enrolled at 126 outpatient centres in 10 countries in Australia, Europe, Latin America, and North America. Participants were previously untreated adults (HIV-1 RNA ≥500 copies per mL) with estimated glomerular filtration rate of at least 30 mL/min. Chronic hepatitis B virus or hepatitis C co-infection was allowed. We randomly assigned participants (1:1) to receive oral fixed-dose combination bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or dolutegravir 50 mg with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg, with matching placebo, once a day for 144 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of -12%. This study is registered with ClinicalTrials.gov, number NCT02607956. FINDINGS: Between Nov 11, 2015, and July 15, 2016, 742 participants were screened for eligibility, of whom 657 were randomly assigned to treatment (327 with bictegravir, emtricitabine, and tenofovir alafenamide fixed-dose combination [bictegravir group] and 330 with dolutegravir plus emtricitabine and tenofovir alafenamide [dolutegravir group]). 320 participants who received the bictegravir regimen and 325 participants who received the dolutegravir regimen were included in the primary efficacy analyses. At week 48, HIV-1 RNA <50 copies per mL was achieved in 286 (89%) of 320 participants in the bictegravir group and 302 (93%) of 325 in the dolutegravir group (difference -3·5%, 95·002% CI -7·9 to 1·0, p=0·12), showing non-inferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of adverse events were similar between groups, and few participants discontinued treatment due to adverse events (5 [2%] of 320 in the bictegravir group and 1 [<1%] 325 in the dolutegravir group). Study drug-related adverse events were less common in the bictegravir group than in the dolutegravir group (57 [18%] of 320 vs 83 [26%] of 325, p=0·022). INTERPRETATION: At 48 weeks, virological suppression with the bictegravir regimen was achieved and was non-inferior to the dolutegravir regimen in previously untreated adults. There was no emergent resistance to either regimen. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated compared with the dolutegravir regimen. FUNDING: Gilead Sciences Inc.


Assuntos
Adenina/análogos & derivados , Antirretrovirais/uso terapêutico , Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Adenina/administração & dosagem , Adulto , Antirretrovirais/farmacologia , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
12.
Lancet ; 390(10101): 1499-1510, 2017 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-28750935

RESUMO

BACKGROUND: Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks. METHODS: In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir-lamivudine 600-300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir-lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir-lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir-lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352. FINDINGS: Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI -5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [-4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related. INTERPRETATION: The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated. FUNDING: ViiV Healthcare and Janssen R&D.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piridonas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Rilpivirina/uso terapêutico , Adulto , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Feminino , Saúde Global , Humanos , Injeções Intramusculares , Lamivudina/uso terapêutico , Masculino , Carga Viral
14.
Infection ; 45(3): 263-268, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28290130

RESUMO

OBJECTIVE: "Choosing Wisely" is a growing international campaign aiming at practice changes to improve patient health and safety by both, conduct of essential and avoidance of unnecessary diagnostic, preventive and therapeutic procedures. The goal is to create an easily recognizable and distributable list ("Choosing Wisely items") that addresses common over- and underuse in the management of infectious diseases. METHODS: The German Society of Infectious Diseases (DGI) participates in the campaign "Klug Entscheiden" by the German Society of Internal Medicine. Committee members of the (DGI) listed potential 'Choosing Wisely items'. Topics were subjected to systematic evidence review and top ten items were selected for appropriateness. Five positive and negative recommendations were approved via individual member vote. RESULTS: The final recommendations are: (1) Imperatively start antimicrobial treatment and remove the focus in Staphylococcus aureus bloodstream infection. (2) Critically ill patients with signs of infection need early appropriate antibiotic therapy. (3) Annual influenza vaccination should be given to individuals with age >60 years, patients with specific co-morbidities and to contact persons who may spread influenza to others. (4) All children should receive measles vaccine. (5) Prefer oral formulations of highly bioavailable antimicrobials whenever possible. (6) Avoid prescribing antibiotics for uncomplicated upper respiratory tract infections. (7) Do not treat asymptomatic bacteriuria with antibiotics. (8) Do not treat Candida detected in respiratory or gastrointestinal tract specimens. (9) Do not prolong prophylactic administration of antibiotics in patients after they have left the operating room. (10) Do not treat an elevated C-reactive protein (CRP) or procalcitonin with antibiotics for patients without signs of infection. CONCLUSIONS: Physicians will reduce potential harm to patients and increase the value of health care when implementing these recommendations.


Assuntos
Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/terapia , Saúde Global , Promoção da Saúde , Procedimentos Desnecessários/estatística & dados numéricos , Assistência à Saúde , Alemanha , Humanos , Saúde Pública
15.
Lancet HIV ; 4(5): e205-e213, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28259776

RESUMO

BACKGROUND: Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine, and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate. METHODS: In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on efavirenz, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to continue a single-tablet regimen of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (assessed by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT02345226. FINDINGS: Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and tenofovir alafenamide and 437 with efavirenz, emtricitabine, tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the tenofovir disoproxil fumarate regimen (difference -2·0%, 95·001% CI -5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. INTERPRETATION: Switching to rilpivirine, emtricitabine, and tenofovir alafenamide from efavirenz, emtricitabine, and tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. FUNDING: Gilead Sciences.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Rilpivirina/uso terapêutico , Tenofovir/uso terapêutico , Adenina/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Pessoa de Meia-Idade
16.
Clin Infect Dis ; 64(10): 1413-1421, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28329090

RESUMO

Background: Antiretrovirals (ARVs) affect bone density and turnover, but their effect on risk of fractures and osteonecrosis of the femoral head is less understood. We investigated if exposure to ARVs increases the risk of both bone outcomes. Methods: EuroSIDA participants were followed to assess fractures and osteonecrosis. Poisson regression identified clinical, laboratory and demographic predictors of either bone outcome. Ever, current, and cumulative exposures to ARVs were assessed. Results: During 86118 PYFU among 11820 included persons (median age 41y, 75% male, median baseline CD4 440/mm3, 70.4% virologically suppressed), there were 619 fractures (incidence/1000 PYFU 7.2; 95% CI 6.6-7.7) and 89 osteonecrosis (1.0; 0.8-1.3). Older age, white race, lower BMI, IV drug use, lower baseline CD4, HCV coinfection, prior osteonecrosis, prior fracture, cardiovascular disease, and recent non-AIDS cancer (last 12 months) were associated with fractures. After adjustment, persons who had ever used tenofovir disoproxil fumarate (TDF) (1.40; 1.15-1.70) or who were currently on TDF (1.25; 1.05-1.49) had higher incidence of fractures. There was no association between cumulative exposure to TDF and fractures (1.08/5 y exposure; 0.94-1.25). No other ARV was associated with fractures (all P > .1). Risk of osteonecrosis was associated with white race, lower nadir CD4, prior osteonecrosis, prior fracture, and prior AIDS. After mutual adjustment, no ARV was associated with osteonecrosis. Conclusions: In human immunodeficiency virus (HIV) infection, host factors, HIV-specific variables, and comorbidities contribute to risk of fractures and osteonecrosis. Exposure to TDF, but not other ARVs, was an independent risk factor for fractures.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Fraturas Ósseas/etiologia , Infecções por HIV/complicações , Osteonecrose/etiologia , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Contagem de Linfócito CD4 , Estudos de Coortes , Coinfecção/epidemiologia , Coleta de Dados , Europa (Continente)/epidemiologia , Feminino , Fraturas do Fêmur/epidemiologia , Fraturas do Fêmur/etiologia , Fraturas do Fêmur/virologia , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etnologia , Fraturas Ósseas/virologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteonecrose/epidemiologia , Osteonecrose/virologia , Análise de Regressão , Fatores de Risco , Tenofovir/efeitos adversos , Tenofovir/uso terapêutico
17.
J Hepatol ; 66(2): 282-287, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27650285

RESUMO

BACKGROUND & AIMS: Moderate cure rates of acute hepatitis C virus (HCV) infections with pegylated interferon and ribavirin have been described in the last decade in men who have sex with men (MSM), who are also coinfected with the human immunodeficiency virus (HIV). However, a subsequent high incidence of HCV reinfections has been reported regionally in men who both clear the infection spontaneously or who respond to treatment. METHODS: Retrospective analysis of reinfections in HIV infected MSM in eight centers from Austria, France, Germany, and the UK within the NEAT network between May 2002 and June 2014. RESULTS: Of 606 individuals who cleared HCV spontaneously or were successfully treated, 149 (24.6%) presented with a subsequent HCV reinfection. Thirty out of 70 (43%) who cleared again or were successfully treated, presented with a second reinfection, 5 with a third, and one with a fourth reinfection. The reinfection incidence was 7.3/100 person-years (95% CI 6.2-8.6). We found a trend for lower incidence among individuals who had spontaneously cleared their incident infection than among individuals who were treated (Hazard ratio 0.62, 95% CI 0.38-1.02, p=0.06). Spontaneous clearance of reinfection was associated with ALT levels >1000IU/ml and spontaneous clearance of a prior infection. CONCLUSIONS: HCV reinfection is an issue of major concern in HIV-positive MSM. Prevention strategies are needed for high risk groups to reduce morbidity and treatment costs. HIV-positive MSM with a prior HCV infection should be tested every 3 to 6months for reinfection. Those who had achieved a reinfection should be tested every 3months. LAY SUMMARY: We evaluated the occurrence of HCV reinfection in HIV-positive men who have sex with men. We found an alarming incidence of 7.3/100 person-years. Prevention measures need to address this specific subgroup of patients at high risk for HCV.


Assuntos
Infecções por HIV , Hepatite C , Adulto , Antivirais/uso terapêutico , Coinfecção/epidemiologia , Controle de Doenças Transmissíveis/estatística & dados numéricos , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Soropositividade para HIV/epidemiologia , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C/virologia , Homossexualidade Masculina , Humanos , Incidência , Masculino , Pessoa de Meia-Idade
18.
Medicine (Baltimore) ; 95(40): e5020, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27749561

RESUMO

Effectiveness data of an unboosted atazanavir (ATV) with abacavir/lamivudine (ABC/3TC) switch strategy in clinical routine are scant.We evaluated treatment outcomes of ATV + ABC/3TC in pretreated subjects in the EuroSIDA cohort when started with undetectable plasma HIV-1 viral load (pVL), performing a time to loss of virological response (TLOVR <50 copies/mL) and a snapshot analysis at 48, 96, and 144 weeks. Virological failure (VF) was defined as confirmed pVL >50 copies/mL.We included 285 subjects, 67% male, with median baseline CD4 530 cells, and 44 months with pVL ≤50 copies/mL. The third drug in the previous regimen was ritonavir-boosted atazanavir (ATV/r) in 79 (28%), and another ritonavir-boosted protease inhibitor (PI/r) in 29 (10%). Ninety (32%) had previously failed with a PI. Proportions of people with virological success at 48/96/144 weeks were 90%/87%/88% (TLOVR) and 74%/67%/59% (snapshot analysis), respectively. The rates of VF were 8%/8%/6%. Rates of adverse events leading to study discontinuation were 0.4%/1%/2%. The multivariable adjusted analysis showed an association between VF and nadir CD4+ (hazard ratio [HR] 0.63 [95% confidence interval [CI]: 0.42-0.93] per 100 cells higher), time with pVL ≤50 copies/mL (HR 0.87 [95% CI: 0.79-0.96] per 6 months longer), and previous failure with a PI (HR 2.78 [95% CI: 1.28-6.04]). Resistance selection at failure was uncommon.A switch to ATV + ABC/3TC in selected subjects with suppressed viremia was associated with low rates of VF and discontinuation due to adverse events, even in subjects not receiving ATV/r. The strategy might be considered in those with long-term suppression and no prior PI failure.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Sulfato de Atazanavir/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Lamivudina/uso terapêutico , Adulto , Fatores Etários , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Sulfato de Atazanavir/administração & dosagem , Sulfato de Atazanavir/efeitos adversos , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/efeitos adversos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ritonavir/uso terapêutico , Fatores Sexuais , Carga Viral/efeitos dos fármacos
19.
Medicine (Baltimore) ; 95(26): e3961, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27367993

RESUMO

To analyze contemporary costs of HIV health care and the cost distribution across lines of combination antiretroviral therapy (cART). To identify variations in expenditures with patient characteristics and to identify main cost determinants. To compute cost ratios between patients with varying characteristics.Empirical data on costs are collected in Germany within a 2-year prospective observational noninterventional multicenter study. The database contains information for 1154 HIV-infected patients from 8 medical centers.Means and standard deviations of the total costs are estimated for each cost fraction and across cART lines and regimens. The costs are regressed against various patient characteristics using a generalized linear model. Relative costs are calculated using the resultant coefficients.The average annual total costs (SD) per patient are &OV0556;22,231.03 (8786.13) with a maximum of &OV0556;83,970. cART medication is the major cost fraction (83.8%) with a mean of &OV0556;18,688.62 (5289.48). The major cost-driving factors are cART regimen, CD4-T cell count, cART drug resistance, and concomitant diseases. Viral load, pathology tests, and demographics have no significant impact. Standard non-nucleoside reverse transcriptase inhibitor-based regimens induce 28% lower total costs compared with standard PI/r regimens. Resistance to 3 or more antiretroviral classes induces a significant increase in costs.HIV treatment in Germany continues to be expensive. Majority of costs are attributable to cART. Main cost determinants are CD4-T cells count, comorbidity, genotypic antiviral resistance, and therapy regimen. Combinations of characteristics associated with higher expenditures enhance the increasing effect on the costs and induce high cost cases.


Assuntos
Síndrome de Imunodeficiência Adquirida/economia , Síndrome de Imunodeficiência Adquirida/terapia , Antirretrovirais/economia , Antirretrovirais/uso terapêutico , Custos de Cuidados de Saúde , Adulto , Feminino , Alemanha , Infecções por HIV/economia , Infecções por HIV/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
20.
Curr Opin HIV AIDS ; 11(3): 268-76, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26895510

RESUMO

PURPOSE OF REVIEW: This review provides international insights into the real-world clinical approach to screening for bone mineral density (BMD) and osteoporosis in people living with HIV (PLWH) using opinions from HIV physicians from key regions around the world. RECENT FINDINGS: Although a significant proportion of PLWH are aged over 50, the relative importance of low BMD to clinical care differs significantly between countries and regions, based on factors such as the population at risk, access to adequate screening resources, and physicians' knowledge. Generally, management of osteoporosis in PLWH follows similar principals as for the general population, with risk factors for fracture combined with measurement of BMD by dual energy X-ray absorptiometry in algorithms such as Fracture Risk Assessment Tool, designed to provide an overall risk estimation. Although in most regions age is considered among the most important factors contributing to low BMD and fractures, considerable country and region-specific factors become apparent, such as malnutrition, inactivity and impact of comorbidities, substance abuse, and increasing use of tenofovir disoproxil fumarate. SUMMARY: These opinions highlight the diversity that still exists in the approach to the long-term management of PLWH and highlight challenges facing development of consensus guidelines that can be effectively implemented worldwide.


Assuntos
Infecções por HIV/complicações , Programas de Rastreamento/métodos , Osteoporose/diagnóstico , Absorciometria de Fóton , Humanos , Internacionalidade , Medição de Risco
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