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1.
Clin Transl Sci ; 13(1): 189-194, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31536156

RESUMO

Adherence with antiretroviral therapy is important for preventing disease progression and HIV transmission. The co-encapsulated pill sensor system sends a signal through a cutaneous patch and allows real-time monitoring of pill ingestion. A 16-week pilot study used a sensor system in 15 HIV-infected individuals with real-time monitoring of pill-taking with a personalized short message system text. System acceptability was assessed by survey at weeks 4, 8, 12, and 16. Follow-up occurred in 80% of subjects through 8 weeks. The system effectively collected measures of pill ingestion, which triggered text message reminders. Only 2 of 14 participants stated that co-encapsulated pills were "unable to take" or "poorly tolerated." At least 75% of respondents stated at each visit that the patch was very or somewhat comfortable. With regard to text message reminders, only 10-15% of the participants at any visit did not find the messages to be helpful. Larger studies will define the utility of this system to assess antiretroviral adherence relative to standard measures.

2.
Medicine (Baltimore) ; 98(50): e18232, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852085

RESUMO

Transgender people continue to be at high-risk for HIV acquisition, but little is known about the characteristics of their sexual partners. To address this gap, we examined sociodemographic and sexual characteristics of cisgender men who have sex with men (MSM) on pre-exposure prophylaxis (PrEP) reporting transgender sexual partners.A cohort of 392 MSM in southern California in a randomized clinical trial for PrEP adherence were followed from 2013 to 2016. Multivariable generalized estimating equation and logistic models identified characteristics of MSM reporting transgender sexual partners and PrEP adherence.Only 14 (4%) MSM reported having transgender sexual partners. MSM were more likely to report transgender partners if they were African American, had incident chlamydia, reported injection drug-using sexual partners, or received items for sex. Most associations remained significant in the multivariable model: African American (adjusted odds ratio [AOR] 11.20, P = .01), incident chlamydia (AOR 3.71, P = .04), and receiving items for sex (AOR 5.29, P = .04). There were no significant differences in PrEP adherence between MSM reporting transgender partners and their counterpart.MSM who report transgender sexual partners share characteristics associated with individuals with high HIV prevalence. Identifying this group distinct from larger cohorts of MSM could offer new HIV prevention opportunities for this group of MSM and the transgender community.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Homossexualidade Masculina/psicologia , Prevenção Primária/métodos , Comportamento Sexual , Parceiros Sexuais , Pessoas Transgênero , Adulto , Seguimentos , Infecções por HIV/epidemiologia , Humanos , Incidência , Masculino , Adesão à Medicação , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia
3.
AIDS Patient Care STDS ; 33(5): 220-226, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31067122

RESUMO

Men who have sex with men (MSM) reporting higher HIV risk behavior over time are often more adherent to pre-exposure prophylaxis (PrEP), but it is unclear if recent risk behavior and partnership type affect long-term PrEP adherence. HIV-negative MSM and transgender women completing the 48-week randomized study TAPIR (Daily Text Messages to Support Adherence to PrEP in At-Risk for HIV Individuals) were included. At baseline and weeks 24 and 48, a modified Calculated Risk (mCalcR) Score estimated the likelihood of HIV seroconversion over 1 year based on reported condomless anal sex acts in the last month and current sexually transmitted infection. mCalcR scores were categorized as low, moderate, and high/very high risk. Partnership type was classified as no partner/single HIV-negative partner (no/single-), single HIV-positive partner (single+), or multiple partners of any serostatus (multi) in the past 3 months. PrEP adherence was measured by intracellular tenofovir-diphosphate (TFV-DP) levels. Among 313 individuals, there was no difference in mCalcR category from baseline to week 48. There was a significant change in partnership type, with no/single partnerships increasing from 0.5% to 9%. Participants with moderate and high/very risk had higher TFV-DP levels than the low-risk group. No/single participants had lower TFV-DP levels than those reporting single+ or multi. Although there was a shift toward lower-risk partnerships, HIV risk category remained stable over time. Individuals with riskier behaviors and partnerships had higher PrEP drug levels, suggesting continued motivation for and adherence to PrEP.

4.
AIDS Res Hum Retroviruses ; 35(7): 608-614, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30907095

RESUMO

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) reduces bone mineral density in HIV-uninfected men who have sex with men (MSM). We hypothesized that PrEP with TDF-FTC would increase bone turnover markers (BTMs) at week 24 and that vitamin D supplementation from weeks 24 to 48 would blunt this increase. Participants were from a cohort of 398 MSM and transgender women who received daily TDF-FTC for PrEP. At week 24, a prospective intervention group initiated vitamin D3 4,000 IU daily. Concurrent controls were selected from the cohort who took ≤400 IU/day of vitamin D3 matched by age, race, and body mass index. The primary endpoint was the change in procollagen-I N-terminal propeptide (P1NP) from weeks 24 to 48. Paired t-tests were used to compare changes in BTMs between intervention and controls. Among 48 intervention-control pairs, median age was 33 years. At baseline, 68.9% of the intervention group and 77.3% of controls were vitamin D sufficient (≥20 ng/mL, p = .94). P1NP, C-telopeptide, parathyroid hormone (PTH), and 25-OH vitamin D3 did not increase significantly at week 24. P1NP fell by a mean ± SD of -27.6 ± 49.9 pg/mL from weeks 24 to 48 with vitamin D and -2.5 ± 40.2 pg/mL in controls (p = .01). There were no significant between-group differences in the weeks 24-48 change in C-telopeptide, PTH, or 25-OH vitamin D3. Vitamin D3 supplementation with 4,000 IU/day resulted in a significant reduction in the BTM P1NP compared with controls, suggesting that this intervention has potential to improve bone health during PrEP.

5.
J Acquir Immune Defic Syndr ; 81(2): 166-174, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30865175

RESUMO

BACKGROUND: Efficacy of HIV pre-exposure prophylaxis (PrEP) among men who have sex with men is well documented in randomized trials. After trial completion, participants are challenged with acquiring PrEP on their own and remaining adherent. METHODS: This was a follow-up study of the TAPIR randomized controlled multicenter PrEP trial. Participants were contacted after their last TAPIR visit (ie, after study-provided PrEP was discontinued) to attend observational posttrial visits 24 and 48 weeks later. Adherence during TAPIR and posttrial visits was estimated by dried blood spot intracellular tenofovir diphosphate levels (adequate adherence defined as tenofovir diphosphate levels >719 fmol/punch). Binary logistic regression analysis assessed predictors of completing posttrial visits and PrEP adherence among participants completing ≥1 visit. RESULTS: Of 395 TAPIR participants who were on PrEP as part of the TAPIR trial for a median of 597 days (range 3-757 days), 122 (31%) completed ≥1 posttrial visit (57% of University of California San Diego participants completed posttrial visits, whereas this was 13% or lower for other study sites). Among participants who completed ≥1 posttrial visit, 57% had adequate adherence posttrial. Significant predictors of adequate adherence posttrial were less problematic substance use, higher risk behavior, and adequate adherence in year 1 of TAPIR. CONCLUSION: More than half of PrEP users followed after trial completion had successfully acquired PrEP and showed adequate adherence. Additional adherence monitoring and intervention measures may be needed for those with low PrEP adherence and problematic substance use during the first year of trial.

6.
J Acquir Immune Defic Syndr ; 80(1): e9-e13, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30334877

RESUMO

BACKGROUND: A public health concern regarding HIV pre-exposure prophylaxis (PrEP) is sexual risk compensation (ie, increased unsafe sex among PrEP users that may undermine prevention efforts). METHODS: This demonstration study (NCT#01761643; initiated in 2013) included 398 men who have sex with men who initiated PrEP and were followed over 48 weeks at 4 sites in Southern California. Wilcoxon signed-rank tests compared previous 30-day number of sex partners and condomless insertive anal sex and receptive anal sex (CIAS and CRAS, respectively) acts at weeks 4, 12, 24, 36, and 48 to baseline. At 2 sites, PrEP users were also compared with a lagged, comparison group of 99 men who have sex with men who did not receive PrEP over 24 weeks using linear regression models, adjusting for age, race/ethnicity, education, and respective baseline scores. Logistic regression compared week 24 sexually transmitted infection (STI) rates. RESULTS: Over 48 weeks in the PrEP group, there were significant decreases in the number of unknown HIV status sex partners and increases in CRAS at all study visits; there was no consistent change in number of HIV+ sex partners or CIAS. Among participants at 2 sites, there were no significant differences between PrEP and non-PrEP users in change in number of partners, CIAS, CRAS, or STI rates at week 24. CONCLUSIONS: Among early adopters of PrEP, there is some evidence for sexual risk compensation. Results support current guidelines of regular STI screening and behavioral risk reduction and adherence counseling with the provision of PrEP.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Profilaxia Pré-Exposição , Tenofovir/uso terapêutico , Sexo sem Proteção/estatística & dados numéricos , Adulto , Aconselhamento Diretivo , Feminino , Infecções por HIV/psicologia , Inquéritos Epidemiológicos , Homossexualidade Masculina , Humanos , Masculino , Modelos Teóricos , Pessoas Transgênero , Sexo sem Proteção/psicologia
7.
Drug Des Devel Ther ; 12: 3731-3740, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464404

RESUMO

As people live longer with HIV infection, there has been a resurgence of interest in challenging the use of three-drug therapy, including two nucleoside reverse transcriptase inhibitors plus a third drug, as initial treatment of HIV infection or for maintenance therapy in virologically suppressed individuals. Although initial studies showed poor efficacy and/or substantial toxicity, more recent regimens have held greater promise. The SWORD-1 and -2 studies were pivotal trials of dolutegravir plus rilpivirine as maintenance therapy in virologically suppressed patients with no history of drug resistance, leading to the US Food and Drug Administration's approval of the regimen as a small, single tablet. More recently, the GEMINI-1 and -2 studies demonstrated that dolutegravir plus lamivudine is as safe and effective as the same regimen when combined with tenofovir disoproxil fumarate in treatment-naïve individuals. Together, these and other studies of novel two-drug regimens offer the potential for improved tolerability and simplicity, as well as a reduction in cost. We will review historical and recent trials of two-drug therapy for the treatment of HIV-1 infection.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Rilpivirina/farmacologia , Comprimidos/farmacologia , Fármacos Anti-HIV/administração & dosagem , Quimioterapia Combinada , Tolerância a Medicamentos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Rilpivirina/administração & dosagem , Comprimidos/administração & dosagem
8.
Emerg Infect Dis ; 24(12)2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30457536

RESUMO

The effectiveness of oral HIV preexposure prophylaxis (PrEP) strongly depends on maintaining adherence. We investigated the association between substance use and PrEP adherence, as well as incident sexually transmitted infections (STIs) in a high-risk cohort of 394 participants (391 men who have sex with men and 3 transgender women) who were enrolled in a PrEP demonstration project. We assessed baseline and ongoing substance use over a 48-week period for stimulants and nonstimulant substances and for each substance separately. We measured PrEP adherence by using dried blood spots to obtain levels of tenofovir diphosphate. No differences in these levels were found between substance users and nonsubstance users. Baseline stimulant use was strongly associated (odds ratio 3.4; p<0.001) with incident STIs during the study. Thus, PrEP adherence was not decreased by substance use. Because substance users had increased rates of STIs, indicating higher-risk behavior, they might be excellent candidates for PrEP.


Assuntos
Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Profilaxia Pré-Exposição , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Consumo de Bebidas Alcoólicas , California/epidemiologia , Feminino , Humanos , Masculino , Modelos de Riscos Proporcionais , Vigilância em Saúde Pública , Ensaios Clínicos Controlados Aleatórios como Assunto , Minorias Sexuais e de Gênero , Doenças Sexualmente Transmissíveis/epidemiologia , Doenças Sexualmente Transmissíveis/prevenção & controle
9.
J Infect Dis ; 218(10): 1551-1559, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30295803

RESUMO

Background: Adherence is necessary for efficacy of preexposure prophylaxis (PrEP), and text-messaging methods are promising tools for both adherence assessment and support. Although PrEP adherence is variable, little research has examined patterns of variability or factors associated with longitudinal use. Methods: In the context of a randomized controlled trial of text-messaging versus standard of care for PrEP adherence, 181 men who have sex with men received once-daily tenofovir disoproxil fumarate/emtricitabine and daily adherence texts for 48 weeks. Growth mixture modeling (GMM) was used to identify subgroups of individuals with similar trajectories of text-reported adherence. Between-group differences in pharmacologic measures of adherence (ie, tenofovir diphosphate and emtricitabine triphosphate levels), as well as predictors and study-end attitudes associated with group membership, were examined. Results: GMM identified 4 trajectories of text-reported adherence. Classes with higher text-reported adherence had higher drug concentrations. Younger age and minority race were associated with lower adherence, and individuals in classes with lower adherence had greater baseline levels of depression, substance use concerns, and sexual risk. Differences in study satisfaction were also associated with adherence. Conclusions: This study supports the use of text-reported PrEP adherence. Identifying factors associated with less-than-optimal adherence may aid clinicians in anticipating at-risk patients requiring augmented intervention. Clinical trials registration: NCT01761643.


Assuntos
Infecções por HIV , Homossexualidade Masculina , Adesão à Medicação/estatística & dados numéricos , Profilaxia Pré-Exposição/métodos , Adulto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Masculino , Mensagem de Texto , Adulto Jovem
10.
Sex Transm Infect ; 94(7): 508-514, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29907624

RESUMO

OBJECTIVES: Rectal douching/enema (RD) is a common practice among men who have sex with men (MSM) in preparation for sex. RD can break down the rectal mucosal barrier and potentially affect the rectal microbiome. The objective of this study was to understand if RD is associated with acquiring rectal infections (RI) with rectal gonorrhoea (NG) and/or chlamydia (CT). METHODS: From 2013 to 2015, 395 adult HIV-uninfected MSM were enrolled in a randomised controlled study for pre-exposure prophylaxis (PrEP) adherence with routine sexual risk survey and testing. Using data from this cohort, baseline differences by RI were assessed using Pearson's χ² and Wilcoxon-Mann-Whitney test. Association between RD and RI was modelled using multivariable logistic regression adjusted for potential confounders (sexual behaviour, substance use and age) selected a priori. Effect modification by number of male partners and sensitivity analysis to rule out reverse causality were also conducted. RESULTS: Of 395 participants, 261 (66%) performed RD and 133 (33%) had at least one NG/CT RI over 48 weeks. Number of condomless anal receptive sex (med: 4, p<0.001), male partners (med:6, p<0.001) and substance use (any of methamphetamine/hallucinogens/dissociative/poppers) (p<0.001) were associated with increased odds of RI. Controlling for potential confounders, odds of prevalent RI were 3.59 (p<0.001, 95% CI 1.90 to 6.78) and incident RI 3.87 (p=0.001, 95% CI 1.78 to 8.39) when douching weekly or more compared with not douching. MSM with more than six male partners had 5.34 (p=0.002, 95% CI 1.87 to 15.31) increased odds of RI when douching weekly or more compared with not douching. CONCLUSION: Rectal hygiene with RD is a common practice (66%) among HIV-uninfected MSM on PrEP in this study, which increases the odds of acquiring rectal NG and/or CT independent of sexual risk behaviour, substance use and other factors. This suggests interventional approaches targeting rectal hygiene products and practices could reduce sexually transmitted infections.


Assuntos
Infecções por Chlamydia/epidemiologia , Enema/estatística & dados numéricos , Gonorreia/epidemiologia , Profilaxia Pré-Exposição/estatística & dados numéricos , Reto/microbiologia , Irrigação Terapêutica/estatística & dados numéricos , Adulto , Chlamydia/isolamento & purificação , Infecções por Chlamydia/prevenção & controle , Estudos de Coortes , Enema/efeitos adversos , Gonorreia/prevenção & controle , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Retais/epidemiologia , Doenças Retais/microbiologia , Doenças Retais/prevenção & controle , Reto/efeitos dos fármacos , Assunção de Riscos , Comportamento Sexual , Parceiros Sexuais , Irrigação Terapêutica/efeitos adversos , Adulto Jovem
11.
AIDS Behav ; 22(8): 2698-2710, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29725790

RESUMO

Poor linkage, engagement and retention remain significant barriers in achieving HIV treatment goals in the US. HIV-infected persons entering or re-entering care across three Southern California academic HIV clinics, were randomized (1:1) to an Active, Linkage, Engagement, Retention and Treatment (ALERT) specialist for outreach and health coaching, or standard of care (SOC). The primary outcome of time to loss to follow up (LTFU) was compared using Cox proportional hazards regression modeling. No differences in the median time to LTFU (81.7 for ALERT versus 93.6 weeks for SOC; HR 1.27; p = 0.40), or time to ART initiation was observed (N = 116). Although, ALERT participants demonstrated worsening depressive symptomatology from baseline to week 48 compared to SOC (p = 0.02). The ALERT intervention did not improve engagement and retention in HIV care over SOC. Further studies are needed to determine how best to apply resources to improve retention and engagement.


Assuntos
Infecções por HIV/terapia , Tutoria , Participação do Paciente , Retenção nos Cuidados , Adulto , California , Depressão/psicologia , Feminino , Infecções por HIV/psicologia , Pessoal de Saúde , Humanos , Perda de Seguimento , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Padrão de Cuidado
12.
Expert Opin Pharmacother ; 19(6): 589-596, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29557204

RESUMO

INTRODUCTION: Treatment options for patients with HIV-1 infection have grown over the past two decades to include multiple fixed-dose combination pharmacotherapies that have greatly simplified administration of antiretroviral therapy (ART) for both patients and providers. Effective virologic control can often be achieved with once-daily use of a single-tablet regimen. Over the past three years, ART drug development has focused on the next generation of fixed-dose combinations for initial and maintenance therapy with improved efficacy, safety and tolerability. AREAS COVERED: This review covers pre-clinical and clinical data searched through PubMed and presented at major conferences through November 2017. EXPERT OPINION: Currently available single-tablet regimens have clinical limitations related to adverse event profiles, drug-drug and drug-food interactions and variable barriers to resistance. Anticipated advances in ART fixed-dose combinations promise combinations of current multiple tablet regimens into single tablets, as well as combinations with novel drugs with improved safety and tolerability. The traditional dogma of effective ART containing at least three active antiretroviral drugs is being challenged by promising data to support efficacy of certain regimens containing two drugs. Implementation of next generation ART will bring to light issues of clinical preference and cost-effectiveness as patents of existing drugs expire and more generic formulations become available.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Quimioterapia Combinada/métodos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Humanos
13.
Clin Infect Dis ; 66(10): 1566-1572, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29228144

RESUMO

Background: Adherence is critical for efficacy of tenofovir disoproxil fumarate/emtricitabine (FTC) as preexposure prophylaxis (PrEP). Methods: Between February 2013 and February 2016, 398 men who have sex with men and transgender women were randomized 1:1 to receive individualized texting for adherence building (iTAB) or standard care (SoC) for 48 weeks. The primary endpoint was dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations at both week 12 and the last on-drug visit of >719 fmol/punch (ie, adequate adherence). Secondary outcomes included DBS TFV-DP concentrations of >1246 fmol/punch (ie, near-perfect adherence) and plasma FTC >350 ng/mL (consistent with dosing within the past 24 hours). Results: Concentrations >719 fmol/punch of TFV-DP were found in 88.6% of participants at week 12 and 82.5% at week 48. For the primary endpoint, the study arms did not differ (72.0% in iTAB and 69.2% in SoC; P > .05). For the secondary composite endpoint of >1246 fmol/punch the iTAB arm was superior to SoC (33.5% vs 24.8%; P = .06), reaching statistical significance when adjusting for age (odds ratio, 1.56 [95% confidence interval, 1.00-2.42]; P < .05). At week 48, iTAB was superior to SoC for near-perfect adherence (51.0% vs 37.4%; P = .02). At week 12, iTAB was superior to SoC for dosing in past 24 hours by plasma FTC (47.5% vs 33.3%; P = .007), but not at weeks 24, 36, and 48 (all P > .05). Conclusions: Automated text messaging is a low-burden tool that improves durability of near-perfect PrEP adherence. Clinical Trials Registration: NCT01761643.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Adesão à Medicação , Organofosfatos/uso terapêutico , Profilaxia Pré-Exposição , Adenina/administração & dosagem , Adenina/sangue , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Humanos , Masculino , Organofosfatos/administração & dosagem , Organofosfatos/sangue , Mensagem de Texto , Pessoas Transgênero
14.
Expert Opin Pharmacother ; 18(4): 427-432, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28151023

RESUMO

INTRODUCTION: Tenofovir alafenamide is a new oral prodrug of tenofovir resulting in relatively low plasma levels and rapid uptake into peripheral blood mononuclear cells in its active form. The United States Food and Drug Administration has now approved this drug coformulated with elvitegravir/cobicistat/emtricitabine, rilpivirine/emtricitabine and emtricitabine. United States guidelines now list this formulation as one of the preferred components of a variety of antiretroviral regimens, and is included as an alternative in other international guidelines, with the notable exception of the World Health Organization, mostly due to limited availability. Areas covered: This review covers pre-clinical and clinical data searched through PubMed​ up to August 2016. Expert opinion: Tenofovir alafenamide is effective as part of an antiretroviral regimen. There is also compelling data that it has less adverse effects on bone mineral density and possibly kidneys than tenofovir disoproxil fumarate. Although approved for use in those with estimated glomerular filtration rates as low as 30 mL/min, data is somewhat limited in this group. While there are few reasons to not use tenofovir alafenamide as a substitute for tenofovir disoproxil fumarate, the former should not be used with rifamycins, is not yet recommended in pregnancy and needs to be studied further before it can be considered as part of a pre-exposure prophylaxis regimen.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Tenofovir/uso terapêutico , Adenina/uso terapêutico , Densidade Óssea/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pró-Fármacos
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