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1.
Artigo em Inglês | MEDLINE | ID: mdl-33800269

RESUMO

The HIV-1 integrase viral protein is responsible for incorporating the viral DNA into the genomic DNA. The inhibition of viral integration into host cell DNA is part of recent therapeutic procedures. Combination therapy with protease and reverse transcriptase inhibitors has demonstrated good synergistic results in reducing viral replication. The purpose of this study is to assess the occurrence of integrase drug resistance mutations from the period comprising 2013 through 2018 in Puerto Rico (PR). We analyzed 131 nucleotide sequences available in our HIV genotyping database, and we performed drug resistance mutation analyses using the Stanford HIV Drug Resistance Database. Twenty-one sequences (16.03%) harbored major or resistance-associated mutations. We identified the Q148HKR, G140S, Y143R, N155H, S147G, and E138EA major drug resistance mutations and the D232DN, T97TA, E157Q, G163GART accessory mutations. We detected high-level drug resistance to Elvitegravir and Raltegravir (76.19% and 85.71%). Moreover, we identified sequences harboring drug resistance mutations that could provide resistance to Dolutegravir. The transmission of strains with integrase antiretroviral resistance has been previously documented in treatment naïve patients. Given the increase of patients treated with integrase inhibitors, surveillance of drug resistance mutations is an essential aspect of PR's clinical management of HIV infection.


Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , HIV-1 , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , Humanos , Mutação , Porto Rico/epidemiologia , Piridonas
2.
BMC Infect Dis ; 21(1): 379, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892628

RESUMO

BACKGROUND: The Integrase (IN) strand transfer inhibitor (INSTI), Dolutegravir (DTG), has been given the green light to form part of first-line combination antiretroviral therapy (cART) by the World Health Organization (WHO). DTG containing regimens have shown a high genetic barrier against HIV-1 isolates carrying specific resistance mutations when compared with other class of regimens. METHODS: We evaluated the HIV-1 CRF02_AG IN gene sequences from Cameroon for the presence of resistance-associated mutations (RAMs) against INSTIs and naturally occurring polymorphisms (NOPs), using study sequences (n = 20) and (n = 287) sequences data derived from HIV Los Alamos National Laboratory database. The possible impact of NOPs on protein structure caused by HIV-1 CRF02_AG variations was addressed within the context of a 3D model of the HIV-1 IN complex and interaction analysis was performed using PyMol to validate DTG binding to the Wild type and seven mutant structures. RESULTS: We observed 12.8% (37/287) sequences to contain RAMs, with only 1.0% (3/287) of the sequences having major INSTI RAMs: T66A, Q148H, R263K and N155H. Of these,11.8% (34/287) of the sequences contained five different IN accessory mutations; namely Q95K, T97A, G149A, E157Q and D232N. NOPs occurred at a frequency of 66% on the central core domain (CCD) position, 44% on the C-terminal domain (CTD) position and 35% of the N-terminal domain (NTD) position. The interaction analysis revealed that DTG bound to DNA, 2MG ions and DDE motif residues for T66A, T97A, Q148H, N155H and R263K comparable to the WT structure. Except for accessory mutant structure E157Q, only one MG contact was made with DTG, while DTG had no MG ion contacts and no DDE motif residue contacts for structure D232N. CONCLUSIONS: Our analysis indicated that all RAM's that resulted in a change in the number of interactions with encompassing residues does not affect DTG binding, while accessory mutations E157Q and D232N could affect DTG binding leading to possible DTG resistance. However, further experimental validation is required to validate the in silico findings of our study.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Integrase de HIV/genética , HIV-1/enzimologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Modelos Moleculares , Mutação , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Camarões/epidemiologia , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Integrase de HIV/química , Inibidores de Integrase de HIV/química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Oxazinas/química , Filogenia , Piperazinas/química , Polimorfismo Genético , Piridonas/química
3.
Viruses ; 13(2)2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572956

RESUMO

Integrase strand transfer inhibitors (INSTIs) are currently recommended for the first line treatment of human immunodeficiency virus type one (HIV-1) infection. The first-generation INSTIs are effective but can select for resistant viruses. Recent advances have led to several potent second-generation INSTIs that are effective against both wild-type (WT) HIV-1 integrase and many of the first-generation INSTI-resistant mutants. The emergence of resistance to these new second-generation INSTIs has been minimal, which has resulted in alternative treatment strategies for HIV-1 patients. Moreover, because of their high antiviral potencies and, in some cases, their bioavailability profiles, INSTIs will probably have prominent roles in pre-exposure prophylaxis (PrEP). Herein, we review the current state of the clinically relevant INSTIs and discuss the future outlook for this class of antiretrovirals.


Assuntos
Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , DNA Viral/metabolismo , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Integrase de HIV/química , Integrase de HIV/genética , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/enzimologia , HIV-1/genética , Humanos , Mutação , Profilaxia Pré-Exposição , Replicação Viral
4.
AIDS ; 35(6): 939-945, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33635844

RESUMO

OBJECTIVE: The aim of this study was to explore weight gain in people with HIV (PWH) at least 65 years of age who switch to a DTG based regimen (DTG-s) vs. remaining INSTI-naive (INSTI-n) on stable ART. METHODS: This was a longitudinal prospective study of PWH from the GEPPO cohort. At the beginning of the observational period, participants were INSTI-naives (INSTI-n). During follow-up, they were divided in two groups: INSTI-n vs. dolutegravir-switchers (DTG-s) with no further change in ART. Body weight was assessed at baseline and at last follow-up visit. Significant weight gain was defined as an increase at least 5% of baseline weight from the first to the last visit. ART regimens were collected at each patients' visit. Kaplan--Meier curves were drawn to assess time to reach a weight gain more than 5%. RESULTS: Out of 568 PWH (83.1% men, median age 69.5 years), 427 (75%) were INSTI-n and 141 (25%) DTG-s. After an average follow-up of 2.6 (±0.8) years, no significant change in body weight was observed both among INSTI-n [delta weight = 0.02 (±7.5), P = 0.633] and DTG-s [delta weight = -0.04 (±5.2), P = 0.755]. Weight gain was also not significantly different between study groups (9.3% in INSTI-n and 15.1% in DTG-S: P = 0.175). No significant differences in time to achieve a weight gain greater or equal than 5% of baseline weight emerged in INSTI-n vs. DTG-s (P = 0.93), two-drug regimens (2DR) vs. three-drug regimens (3DR) (P = 0.56) or TAF vs. TDF (P = 0.56). CONCLUSION: Results from a large Italian cohort did not show a significant weight gain associated with switch to DTG in PWH 65 years of age or older. This finding emerged also when comparing 3DR vs. 2DR and TAF exposed and unexposed geriatric PWH.


Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , Idoso , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Itália , Masculino , Oxazinas/uso terapêutico , Piperazinas , Estudos Prospectivos , Piridonas , Ganho de Peso
5.
BMC Infect Dis ; 21(1): 222, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637050

RESUMO

BACKGROUND: The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96). METHODS: A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/µL at baseline were analysed separately. RESULTS: The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(- 2.8,12.5)], raltegravir [RAL:2.9%(- 1.6,7.7)] and bictegravir [BIC:2.7%(- 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ ≤ 200 cells/µL at baseline. DTG also achieved greater increase in CD4+ cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)]. CONCLUSION: Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4+ cells/µL, who can be difficult to treat.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Adulto , Fármacos Anti-HIV/uso terapêutico , Feminino , HIV-1/efeitos dos fármacos , Humanos , Masculino , Metanálise em Rede , Resultado do Tratamento
6.
Lancet HIV ; 8(1): e33-e41, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387477

RESUMO

BACKGROUND: Dolutegravir has been widely available in Brazil since 2017. Following the signal that infants born to women with dolutegravir exposure at conception in Botswana had a higher risk of neural tube defects (NTDs), public health leaders initiated a national investigation to evaluate periconception dolutegravir exposure among all pregnant Brazilian women with HIV and its potential association with risk of NTDs, stillbirth, or miscarriage before 22 weeks (also called spontaneous abortion). METHODS: In this retrospective, observational, national, cohort study, we identified all women with pregnancies and possible dolutegravir exposure within 8 weeks of estimated date of conception between Jan 1, 2017, and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz between Jan 1, 2015, and May 31, 2018, using the Brazilian antiretroviral therapy database. We did detailed chart reviews for identified women. The primary outcomes were NTD and a composite measure of NTD, stillbirth, or miscarriage. NTD incidences were calculated with 95% CI. The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1427 included women, 382 were exposed to dolutegravir within 8 weeks of estimated date of conception. During pregnancy, 183 (48%) of 382 dolutegravir-exposed and 465 (44%) of 1045 efavirenz-exposed women received folic acid supplementation. There were 1452 birth outcomes. There were no NTDs in either dolutegravir-exposed (0, 95% CI 0-0·0010) or efavirenz-exposed groups (0, 95% CI 0-0·0036). There were 23 (6%) stillbirths or miscarriages in 384 dolutegravir-exposed fetuses and 28 (3%) in the 1068 efavirenz-exposed fetuses (p=0·0037). Logistic regression models did not consistently indicate an association between dolutegravir exposure and risk of stillbirths or miscarriages. After study closure, two confirmed NTD outcomes in fetuses with periconception dolutegravir exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional dolutegravir-exposed pregnancies between Jan 1, 2015 and Feb 28, 2019, is 0·0018 (95% CI 0·0005-0·0067). INTERPRETATION: Neither dolutegravir nor efavirenz exposure was associated with NTDs in our national cohort; incidence of NTDs is probably well under 1% in dolutegravir-exposed HIV-positive women but still slightly above HIV-uninfected women (0·06%) in Brazil. FUNDING: The Brazilian Ministry of Health and the United States' National Institutes of Health.


Assuntos
Infecções por HIV/complicações , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Defeitos do Tubo Neural/etiologia , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Brasil/epidemiologia , Comorbidade , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/epidemiologia , Oxazinas/administração & dosagem , Oxazinas/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Gravidez , Resultado da Gravidez , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Estudos Retrospectivos , Natimorto , Adulto Jovem
7.
PLoS One ; 15(12): e0243625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382756

RESUMO

OBJECTIVES: To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting. METHODS: Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) <200 copies/mL and failure as at least one of: VL ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/µL. RESULTS: Between January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67-0.82], p <0.001), but similar for NNRTIs (1.07 [CI 0.97-1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71-0.91], p<0.001) and PI/b (0.87 [CI 0.76-0.99], p = 0.04). CONCLUSION: In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , HIV/efeitos dos fármacos , HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia
8.
PLoS Med ; 17(12): e1003397, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33315863

RESUMO

BACKGROUND: Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). The switch to WHO-recommended dolutegravir (DTG)-based regimens could reduce this threat due to DTG's high genetic barrier to resistance. We used mathematical modeling to predict the impact of the scale-up of DTG-based ART on NNRTI pretreatment drug resistance (PDR) in South Africa, 2020 to 2040. METHODS AND FINDINGS: We adapted the Modeling Antiretroviral drug Resistance In South Africa (MARISA) model, an epidemiological model of the transmission of NNRTI resistance in South Africa. We modeled the introduction of DTG in 2020 under 2 scenarios: DTG as first-line regimen for ART initiators, or DTG for all patients, including patients on suppressive NNRTI-based ART. Given the safety concerns related to DTG during pregnancy, we assessed the impact of prescribing DTG to all men and in addition to (1) women beyond reproductive age; (2) women beyond reproductive age or using contraception; and (3) all women. The model projections show that, compared to the continuation of NNRTI-based ART, introducing DTG would lead to a reduction in NNRTI PDR in all scenarios if ART initiators are started on a DTG-based regimen, and those on NNRTI-based regimens are rapidly switched to DTG. NNRTI PDR would continue to increase if DTG-based ART was restricted to men. When given to all men and women, DTG-based ART could reduce the level of NNRTI PDR from 52.4% (without DTG) to 10.4% (with universal DTG) in 2040. If only men and women beyond reproductive age or on contraception are started on or switched to DTG-based ART, NNRTI PDR would reach 25.9% in 2040. Limitations include substantial uncertainty due to the long-term predictions and the current scarcity of knowledge about DTG efficacy in South Africa. CONCLUSIONS: Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance. Starting or switching all men and women to DTG would lead to a sustained decline in resistance levels, whereas using DTG-based ART in all men, or in men and women beyond childbearing age, would only slow down the increase in levels of NNRTI PDR.


Assuntos
Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Modelos Teóricos , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Substituição de Medicamentos , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/provisão & distribução , HIV-1/patogenicidade , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/provisão & distribução , Humanos , Masculino , Oxazinas/efeitos adversos , Oxazinas/provisão & distribução , Piperazinas/efeitos adversos , Piperazinas/provisão & distribução , Piridonas/efeitos adversos , Piridonas/provisão & distribução , África do Sul/epidemiologia , Fatores de Tempo , Resultado do Tratamento
12.
Lancet HIV ; 7(8): e533-e544, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32763217

RESUMO

BACKGROUND: Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. METHODS: We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. FINDINGS: Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir. INTERPRETATION: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Adolescente , Peso Corporal , Criança , Relação Dose-Resposta a Droga , Feminino , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Masculino , Oxazinas , Piperazinas , Piridonas , Comprimidos , Uganda , Zimbábue
13.
BMC Infect Dis ; 20(1): 574, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758161

RESUMO

BACKGROUND: Despite widespread use of combination antiretroviral therapy (cART), HIV-associated neurocognitive disorder (HAND) and HIV-associated myelopathy (HAM) are not showing significant reduction in there occurrence. The HAM is a progressive myelopathy that often occur synchronously with severe form of the HAND in patients' having advanced immunosuppression. However, co-existence of less severe form of the HAND and HAM in patient with relatively preserved CD4 cells is rarely reported clinical entity in post cART era. CASE PRESENTATION: We report a 16-year old male, acquired HIV infection vertically, was on second line regimen because of virological failure since 3 years. His current CD4 lymphocyte count is 835 cells/uL with viral RNA level of 33,008 copies/mL. Currently presented with progressive forgetfulness, gait imbalance, and a frequent staring episodes without loss of postural tone. Neurological examination was pertinent for cognitive dysfunction with score of 6 on International HIV Dementia Scale (motor speed = 3, psychomotor speed = 2, and memory recall = 1). Lower limbs power is 4-/5, increased deep tendon reflexes, and unsteady gait. Brain MRI revealed diffuse both cortical and white matter T2 and FLAIR hyperintense lesions. Thoracic MRI showed abnormal T2 signal prolongation spanning from mid thoracic cord to conus. Electroencephalography study showed severe generalized slowing with evidence of focal dysrhythmia in bilateral frontotemporal regions. Unremarkable serum vitamin B 12 level (286 ng/mL). Virological failure with the HAND, HAM and seizure was considered. Dolutegravir +3TC + ATV/r regimen and valproate for seizure disorder was started. On 6 months follow up evaluation, he is clinically stable with significant improvement of his symptoms related to seizure disorders and modest improvement of his cognitive dysfunction, as he is now attending his school regularly. However, less improvement was observed reading his gait abnormality. CONCLUSION: This case supports the current understanding regarding the persistent occurrence of HIV-associated neurocognitive disorder and HIV-associated myelopathy even decades after introduction of cART. Therefore, it's important to screen HIV+ patients for the HAND and HAM even if they have relatively preserved immunity. Because patient can be easily shifted to ART drugs with better CNS penetrating potential to achieve acceptable virological suppression level, to observe sound clinical improvement.


Assuntos
Complexo AIDS Demência/complicações , Complexo AIDS Demência/diagnóstico , Linfócitos T CD4-Positivos , Convulsões/complicações , Convulsões/diagnóstico , Doenças da Medula Espinal/complicações , Doenças da Medula Espinal/diagnóstico , Carga Viral , Complexo AIDS Demência/tratamento farmacológico , Complexo AIDS Demência/imunologia , Adolescente , Contagem de Linfócito CD4 , Disfunção Cognitiva/diagnóstico , Seguimentos , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Masculino , Oxazinas , Piperazinas , Piridonas , RNA Viral/sangue , Convulsões/tratamento farmacológico , Doenças da Medula Espinal/tratamento farmacológico , Resultado do Tratamento
14.
BMC Infect Dis ; 20(1): 524, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32689975

RESUMO

BACKGROUND: Currently recommended boosted protease-inhibitor (bPI) regimens may be associated with increased risk of cardiovascular or chronic kidney diseases; in addition, boosted regimens are particularly associated with drug-drug interactions. Since both cardiovascular and renal disease, and polypharmacy, are common in ageing people with HIV, there is a need for alternative efficacious regimens. bPI-based regimens are often the treatment of choice for individuals with pre-treatment or treatment-acquired resistance but it is plausible that carefully selected HIV-positive individuals with drug resistance, who are virologically suppressed on their current bPI regimen, could maintain virological efficacy when switched to bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) fixed dose combination (FDC). METHODS/DESIGN: A phase IV, investigator-initiated, multicentre, open label pilot, randomised two-arm study to assess the safety and efficacy of switching from bPI regimen to B/F/TAF single tablet regimen in integrase inhibitor-naïve, virologically suppressed adults with HIV-1 infection harbouring drug resistance mutations. Eligible individuals will either continue on their bPI regimen or switch to B/F/TAF FDC. After 24 weeks, all participants in the bPI arm will be switched to B/F/TAF and followed for a further 24 weeks and all participants will be followed for 48 weeks. The primary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24 using pure virologic response whilst the secondary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 48. Other secondary outcome measures include between arm comparisons of drug resistance at virological failure, safety and tolerability and patient-reported outcome measures. DISCUSSION: We aim to provide preliminary evidence of the efficacy of switching to B/F/TAF in patients with virological suppression on a bPI-based regimen who harbour select drug resistance mutations. TRIAL REGISTRATION: ISRCTN 44453201 , registered 19 June 2019 and EudraCT 2018-004732-30.


Assuntos
Adenina/análogos & derivados , Farmacorresistência Viral/genética , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inibidores de Proteases/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adenina/uso terapêutico , Adulto , Combinação de Medicamentos , Emtricitabina/efeitos adversos , Feminino , Infecções por HIV/genética , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Masculino , Mutação , Projetos Piloto , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento
15.
PLoS One ; 15(5): e0223464, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379830

RESUMO

Resistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. A homology model of HIV-1 subtype C IN was successfully constructed and validated. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Also, interaction analysis was performed between neighbouring residues. Three mutations known to be associated with Raltegravir, Elvitegravir and Dolutegravir resistance were selected; E92Q, G140S and Y143R, for molecular dynamics simulations. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the three mutants indicated different effects, while simulation analysis showed G140S to have the largest affect on protein stability and flexibility. This was further supported by weaker non-bonded pairwise interaction energy and binding free energy values between the drug DTG and E92Q, Y143R and G140S mutants suggesting reduced binding affinity, as indicated by interaction analysis in comparison to the WT. Our findings suggest the G140S mutant has the strongest effect on the HIV-1C IN protein structure and Dolutegravir binding. To the best of our knowledge, this is the first study that uses the consensus wild type HIV-1C IN sequence to build an accurate 3D model to understand the effect of three known mutations on DTG drug binding in a South Africa context.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/metabolismo , Integrase de HIV/genética , Integrase de HIV/metabolismo , HIV-1/enzimologia , Compostos Heterocíclicos com 3 Anéis/metabolismo , Mutação , Sequência de Aminoácidos , Domínio Catalítico/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/química , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Simulação de Dinâmica Molecular , Oxazinas , Piperazinas , Ligação Proteica/genética , Estabilidade Proteica , Piridonas , Quinolonas/metabolismo , Quinolonas/uso terapêutico , Raltegravir Potássico/metabolismo , Raltegravir Potássico/uso terapêutico , África do Sul , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
16.
Lancet HIV ; 7(5): e322-e331, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32386720

RESUMO

BACKGROUND: Although antiretroviral regimens containing integrase inhibitors rapidly suppress HIV viral load in non-pregnant adults, few published data from randomised controlled trials have compared the safety and efficacy of any integrase inhibitor to efavirenz when initiated during pregnancy. We compared safety and efficacy of antiretroviral therapy with either raltegravir or efavirenz in late pregnancy. METHODS: An open-label, randomised controlled trial was done at 19 hospitals and clinics in Argentina, Brazil, South Africa, Tanzania, Thailand, and the USA. Antiretroviral-naive pregnant women (20-<37 weeks gestation) living with HIV were assigned to antiretroviral regimens containing either raltegravir (400 mg twice daily) or efavirenz (600 mg each night) plus lamivudine 150 mg and zidovudine 300 mg twice daily (or approved alternative backbone regimen), using a web-based, permuted-block randomisation stratified by gestational age and backbone regimen. The primary efficacy outcome was plasma HIV viral load below 200 copies per mL at (or near) delivery. The primary efficacy analysis included all women with a viral load measurement at (or near) delivery who had viral load of at least 200 copies per mL before treatment and no genotypic resistance to any study drugs; secondary analyses eliminated these exclusion criteria. The primary safety analyses included all women who received study drug, and their infants. This trial is registered with Clinicaltrials.gov, number NCT01618305. FINDINGS: From Sep 5, 2013, to Dec 11, 2018, 408 women were enrolled (206 raltegravir, 202 efavirenz) and 394 delivered on-study (200 raltegravir, 194 efavirenz); 307 were included in the primary efficacy analysis (153 raltegravir, 154 efavirenz). 144 (94%) women in the raltegravir group and 129 (84%) in the efavirenz group met the primary efficacy outcome (absolute difference 10%, 95% CI 3-18; p=0·0015); the difference primarily occurred among women enrolling later in pregnancy (interaction p=0·040). Frequencies of severe or life-threatening adverse events were similar among mothers (30% in each group; 61 raltegravir, 59 efavirenz) and infants (25% in each group; 50 raltegravir, 48 efavirenz), with no treatment-related deaths. INTERPRETATION: Our findings support major guidelines. The integrase inhibitor dolutegravir is currently a preferred regimen for the prevention of perinatal HIV transmission with raltegravir recommended as a preferred or alternative integrase inhibitor for pregnant women living with HIV. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Allergy and Infectious Diseases.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Raltegravir Potássico/uso terapêutico , Adulto , Alquinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Ciclopropanos , Quimioterapia Combinada , Feminino , Infecções por HIV/prevenção & controle , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Lamivudina/uso terapêutico , Avaliação de Resultados em Cuidados de Saúde , Gravidez , Raltegravir Potássico/efeitos adversos , Carga Viral/efeitos dos fármacos , Adulto Jovem , Zidovudina/uso terapêutico
17.
Lancet HIV ; 7(5): e332-e339, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32386721

RESUMO

BACKGROUND: Late initiation of HIV antiretroviral therapy (ART) in pregnancy is associated with not achieving viral suppression before giving birth and increased mother-to-child transmission of HIV. We aimed to investigate virological suppression before giving birth with dolutegravir compared with efavirenz, when initiated during the third trimester. METHODS: In this randomised, open-label trial, DolPHIN-2, we recruited pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating ART in third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based therapy. HIV viral load was measured 7 days and 28 days after antiretroviral initiation, at 36 weeks' gestation, and at the post-partum visit (0-14 days post partum). The primary efficacy outcome was a viral load of less than 50 copies per mL at the first post-partum visit, and the primary safety outcome was the occurrence of drug-related adverse events in mothers and infants until the post-partum visit. Longer-term follow-up of mothers and infants continues. This study is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23, and Aug 15, 2018, we randomly assigned 268 mothers to dolutegravir (135) or efavirenz (133). All mothers and their infants were included in the safety analysis, and 250 mothers (125 in the dolutegravir group, 125 in the efavirenz group) and their infants in efficacy analyses, by intention-to-treat analyses. The median duration of maternal therapy at birth was 55 days (IQR 33-77). 89 (74%) of 120 in the dolutegravir group had viral loads less than 50 copies per mL, compared with 50 (43%) of 117 in the efavirenz group (risk ratio 1·64, 95% CI 1·31-2·06). 30 (22%) of 137 mothers in the dolutegravir group reported serious adverse events compared with 14 (11%) of 131 in the efavirenz group (p=0·013), particularly surrounding pregnancy and puerperium. We found no differences in births less than 37 weeks and less than 34 weeks gestation (16·4% vs 3·3%, across both groups). Three stillbirths in the dolutegravir group and one in the efavirenz group were considered unrelated to treatment. Three infant HIV infections were detected, all in the dolutegravir group, and were considered likely to be in-utero transmissions. INTERPRETATION: Our data support the revision to WHO guidelines recommending the transition to dolutegravir in first-line ART for all adults, regardless of pregnancy or child-bearing potential. FUNDING: Unitaid.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Adulto , Alquinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Ciclopropanos , Feminino , Infecções por HIV/mortalidade , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Avaliação de Resultados em Cuidados de Saúde , Oxazinas , Piperazinas , Gravidez , Resultado da Gravidez , Terceiro Trimestre da Gravidez , Piridonas , Carga Viral/efeitos dos fármacos
18.
PLoS One ; 15(5): e0232419, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32459822

RESUMO

Uganda adopted the integrase inhibitor dolutegravir (DTG) as part its preferred first-line HIV treatment regimen in 2018. Prior to the national rollout, the Uganda Ministry of Health and Clinton Health Access Initiative (CHAI) launched a pilot study in July 2017 aimed at better understanding patients' and prescribers' experience and acceptability of DTG. Patients were enrolled in the study if they were newly initiating treatment or switched from an NNRTI regimen due to intolerance. Patients were followed up for 6 months after initiation onto DTG and acceptability and experiences were assessed through questionnaires at one-month and six-month follow-up visits. In addition to acceptability side effects of patients on DTG regimens were assessed. Analysis was conducted using MS Excel and SAS 9.4 and confidence intervals were adjusted for facility level clustering. A total of 365 patients from 6 study sites were enrolled in the study, of whom 50% were treatment-experienced and 50% treatment naïve. 325 patients completed the 6 months of follow-up. Survey results showed a high level of acceptability (more than 90%) of DTG-containing regimens for both categories of patients during the from one-month and six-months interviews. The rate of self-reported side effects amongst patients was 33% overall and higher for experienced (37%) than naïve (29%) patients at 6 months. Although frequencies declined between month-1 and month-6, the changes were not statistically significant. Almost all patients (94%) were virally suppressed at 6 months. Overall, the study findings showed a very high level of acceptability of Dolutegravir-based regimens across both experienced and naïve patients. The overall viral suppression rate in this cohort was 94% at six months of taking DTG-based regimen.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Estudos de Coortes , Feminino , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Aceitação pelo Paciente de Cuidados de Saúde , Projetos Piloto , Piperazinas , Estudos Prospectivos , Piridonas , Uganda , Carga Viral/efeitos dos fármacos , Adulto Jovem
19.
J Int AIDS Soc ; 23(4): e25484, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32294337

RESUMO

INTRODUCTION: Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). METHODS: Adult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years. RESULTS: Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI). CONCLUSIONS: PWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Inibidores da Protease de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Ganho de Peso/efeitos dos fármacos , Adulto , Contagem de Linfócito CD4 , Canadá , Estudos de Coortes , Feminino , Infecções por HIV/complicações , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , Inibidores da Transcriptase Reversa/uso terapêutico , Estados Unidos
20.
Sex Transm Infect ; 96(5): 337-341, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32245779

RESUMO

OBJECTIVE: To provide insight on viral kinetics and genetic diversity of HIV in seminal plasma at baseline and 1 month after initiating antiretroviral therapy (ART). PATIENTS AND METHODS: Blood and seminal samples from patients with newly diagnosed HIV were obtained before ART initiation (T0) and 1 month after ART initiation (T1). HIV env genetic diversity was studied using deep sequencing Nextera and V3 chemistry in a MiSeq Illumina platform. The number of viral quasispecies (5% cut-off) and Shannon Index were used to analyse diversity. RESULTS: Forty-seven ART-naive patients were recruited between September 2016 and November 2018. At enrolment, the number of quasispecies in blood (median 4 (IQR 2-5)) was lower than in the seminal compartment (median 6, (IQR 4-8)) (p<0.01); the Shannon Index was also higher (p<0.001) in the seminal compartment than in blood (1.77 vs 0.64). At T1, for the 13 patients with detectable HIV in both blood/seminal plasma, viral diversity remained higher (p=0.139) in seminal plasma (median 2 (IQR 1-4.5)) than in blood (median 1 (IQR 1-1.5)) Integrase inhibitors (INI)-based regimens achieved higher levels of undetectability and led more frequently to lower variability (p<0.001) than protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). CONCLUSION: We provide here further evidence of a larger genetic diversity in seminal plasma, both at diagnosis and short term after ART initiation. Our results strengthen previous findings on HIV diversity in seminal plasma. In addition, INIs decrease variability more rapidly than PI and NNRTI in both blood and seminal plasma.


Assuntos
Antirretrovirais/uso terapêutico , Sangue/virologia , Variação Genética , Infecções por HIV/tratamento farmacológico , HIV/genética , Sêmen/virologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Adulto , Infecções por HIV/sangue , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Inibidores da Transcriptase Reversa/uso terapêutico
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