Principles of Applied Clinical Pharmacokinetics and Pharmacodynamics in Antiretroviral Therapy

2017 ◽  
Author(s):  
Neha Sheth Pandit ◽  
Emily L. Heil
Keyword(s):  
Antiretroviral Therapy ◽  
Drug Exposure ◽  
Virologic Failure ◽  
Treatment Success ◽  
Antiretroviral Drugs ◽  
Therapeutic Drug ◽  
Virologic Suppression ◽  
Hiv Replication ◽  
Clinical Pharmacokinetics ◽  
Suboptimal Adherence

Systemic concentrations of antiretroviral drugs (ARVs) are influenced by the pharmacokinetic properties of absorption, distribution, metabolism, and excretion. Pharmacokinetics and local drug exposure can differ significantly within anatomical sanctuary sites compared with the systemic compartment. High variability in interpatient ARV concentrations is common, which makes population pharmacokinetics for ARVs very difficult to interpret. HIV replication is dynamic and requires combination antiretroviral therapy with multiple active agents in order to achieve durable virologic suppression. Direct and indirect relationships between drug exposure, efficacy, and/or toxicity are common for most ARVs, which can be used to improve overall treatment success. Suboptimal adherence can result in inadequate concentrations, drug resistance, and virologic failure. Therapeutic drug monitoring can be considered in certain scenarios that should be evaluated on a case-by-case basis.

scholarly journals Racial Disparities in Virologic Failure and Tolerability During Firstline HIV Antiretroviral Therapy

2019 ◽  
Vol 6 (2) ◽  
Author(s):  
Priya Bhagwat ◽  
Shashi N Kapadia ◽  
Heather J Ribaudo ◽  
Roy M Gulick ◽  
Judith S Currier
Keyword(s):  
Antiretroviral Therapy ◽  
Adverse Events ◽  
Socioeconomic Factors ◽  
Ethnic Groups ◽  
Virologic Failure ◽  
Virologic Suppression ◽  
Factors Associated ◽  
Race Ethnicity ◽  
The Impact ◽  
Racial Ethnic

Abstract Background Racial/ethnic disparities in HIV outcomes have persisted despite effective antiretroviral therapy. In a study of initial regimens, we found viral suppression varied by race/ethnicity. In this exploratory analysis, we use clinical and socioeconomic data to assess factors associated with virologic failure and adverse events within racial/ethnic groups. Methods Data were from AIDS Clinical Trial Group A5257, a randomized trial of initial regimens with either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (each combined with tenofovir DF and emtricitabine). We grouped participants by race/ethnicity and then used Cox-proportional hazards regression to examine the impact of demographic, clinical, and socioeconomic factors on the time to virologic suppression and time to adverse event reporting within each racial/ethnic group. Results We analyzed data from 1762 participants: 757 self-reported as non-Hispanic black (NHB), 615 as non-Hispanic white (NHW), and 390 as Hispanic. The proportion with virologic failure was higher for NHB (22%) and Hispanic (17%) participants compared with NHWs (9%). Factors associated with virologic failure were poor adherence and higher baseline HIV RNA level. Prior clinical AIDS diagnosis was associated with virologic failure for NHBs only, and unstable housing and illicit drug use for NHWs only. Factors associated with adverse events were female sex in all groups and concurrent use of medications for comorbidities in NHB and Hispanic participants only. Conclusions Clinical and socioeconomic factors that are associated with virologic failure and tolerability of antiretroviral therapy vary between and within racial and ethnic groups. Further research may shed light into mechanisms leading to disparities and targeted strategies to eliminate those disparities.

scholarly journals Long-acting antiretrovirals: a new era for the management and prevention of HIV infection

2021 ◽  
Author(s):  
Paul Thoueille ◽  
Eva Choong ◽  
Matthias Cavassini ◽  
Thierry Buclin ◽  
Laurent A Decosterd
Keyword(s):  
Hiv Infection ◽  
Drug Exposure ◽  
Real Life ◽  
Effective Vaccine ◽  
Therapeutic Drug ◽  
People Living With Hiv ◽  
Medical Procedure ◽  
Clinical Pharmacokinetics ◽  
Long Acting ◽  
Prevention Of Hiv

Abstract The long-acting antiretroviral cabotegravir and rilpivirine combination has just received FDA, EMA and Health Canada approval. This novel drug delivery approach is about to revolutionize the therapy of people living with HIV, decreasing the 365 daily pill burden to only six intramuscular injections per year. In addition, islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor, is intended to be formulated as an implant with a dosing interval of 1 year or more. At present, long-acting antiretroviral therapies (LA-ARTs) are given at fixed standard doses, irrespectively of the patient’s weight and BMI, and without consideration for host genetic and non-genetic factors likely influencing their systemic disposition. Despite a few remaining challenges related to administration (e.g. pain, dedicated medical procedure), the development and implementation of LA-ARTs can overcome long-term adherence issues by improving patients’ privacy and reducing social stigma associated with the daily oral intake of anti-HIV treatments. Yet, the current ‘one-size-fits-all’ approach does not account for the recognized significant inter-individual variability in LA-ART pharmacokinetics. Therapeutic drug monitoring (TDM), an important tool for precision medicine, may provide physicians with valuable information on actual drug exposure in patients, contributing to improve their management in real life. The present review aims to update the current state of knowledge on these novel promising LA-ARTs and discusses their implications, particularly from a clinical pharmacokinetics perspective, for the future management and prevention of HIV infection, issues of ongoing importance in the absence of curative treatment or an effective vaccine.

scholarly journals Non-uptake of viral load testing among people receiving HIV treatment in Gomba district, rural Uganda

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Rita Nakalega ◽  
Nelson Mukiza ◽  
George Kiwanuka ◽  
Ronald Makanga-Kakumba ◽  
Robert Menge ◽  
...  
Keyword(s):  
Viral Load ◽  
Virologic Failure ◽  
Treatment Success ◽  
Cross Sectional Study ◽  
Hiv Treatment ◽  
Virologic Suppression ◽  
Load Testing ◽  
Duration Of Treatment ◽  
Cross Sectional ◽  
Art Initiation

Abstract Background Viral load (VL) testing is the gold-standard approach for monitoring human immunodeficiency virus (HIV) treatment success and virologic failure, but uptake is suboptimal in resource-limited and rural settings. We conducted a cross-sectional study of risk factors for non-uptake of VL testing in rural Uganda. Methods We conducted a cross-sectional analysis of uptake of VL testing among randomly selected people with HIV (PWH) receiving anti-retroviral treatment (ART) for at least 6 months at all eight primary health centers in Gomba district, rural Uganda. Socio-demographic and clinical data were extracted from medical records for the period January to December 2017. VL testing was routinely performed 6 months after ART initiation and 12 months thereafter for PWH stable on ART. We used descriptive statistics and multivariable logistic regression to evaluate factors associated with non-uptake of VL testing (the primary outcome). Results Of 414 PWH, 60% were female, and the median age was 40 years (interquartile range [IQR] 31–48). Most (62.3%) had been on ART > 2 years, and the median duration of treatment was 34 months (IQR 14–55). Thirty three percent did not receive VL testing: 36% of women and 30% of men. Shorter duration of ART (≤2 years) (adjusted odds ratio [AOR] 2.38; 95% CI:1.37–4.12; p = 0.002), younger age 16–30 years (AOR 2.74; 95% CI:1.44–5.24; p = 0.002) and 31–45 years (AOR 1.92; 95% CI 1.12–3.27; p = 0.017), and receipt of ART at Health Center IV (AOR 2.85; 95% CI: 1.78–4.56; p < 0.001) were significantly associated with non-uptake of VL testing. Conclusions One-in-three PWH on ART missed VL testing in rural Uganda. Strategies to improve coverage of VL testing, such as VL focal persons to flag missed tests, patient education and demand creation for VL testing are needed, particularly for recent ART initiates and younger persons on treatment, in order to attain the third Joint United Nations Program on HIV/AIDS (UNAIDS) 95–95-95 target – virologic suppression for 95% of PWH on ART.

scholarly journals Laboratory surrogate markers of residual HIV replication among distinct groups of individuals under antiretroviral therapy

2018 ◽  
Author(s):  
L.B. Giron ◽  
S.B. Tenore ◽  
L.M. Janini ◽  
M.C. Sucupira ◽  
R.S. Diaz
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Count ◽  
Salvage Therapy ◽  
Virologic Failure ◽  
First Line ◽  
Hiv Replication ◽  
Dna Quantitation ◽  
Total Dna ◽  
Episomal Dna

AbstractBackgroundResidual HIV-1 replication among individuals under antiretroviral therapy (ART) relates to HIV micro-inflammation.ObjectivesTo determine levels of residual HIV replication markers among distinct subgroups of antiretroviral-treated individuals.Methods116 patients were distributed into 5 treatment groups: first-line suppressive ART with non-nucleoside reverse-transcriptase inhibitor (NNRTI) (n=26), first-line suppressive ART with boosted protease inhibitors (PI-r) (n=25), salvage therapy using PI-r (n=27), salvage therapy with PI-r and raltegravir (n=22) and virologic failure (n=16). Episomal and total DNA quantitation was evaluated. ELISA was used for HIV antibody and LPS quantitation.ResultsEpisomal DNA was positive in 26% to 38% of individuals under suppressive ART, being higher among individuals experiencing virologic failure (p=0.04). HIV proviral load was higher among patients with detectable episomal DNA (p=0.01). Individuals receiving initial PI-r treatment presented lower HIV antibodies (p=0.027) and LPS (p=0.029) than individuals receiving NNRTI. There was a negative correlation between episomal DNA quantitation and suppressive ART duration (p=0.04), CD4+ T-cell count (p=0.08), and CD8+ T-cell count (p=0.07).ConclusionsResidual HIV replication has been inferred among individuals under suppressive ART according to episomal DNA detection. Residual replication may decrease with longer periods of suppressive ART and higher levels of CD4+ and CD8+ T cells. The relationship between episomal DNA and total DNA suggests a replenishment of the proviral reservoir with impacts on HIV persistence. Lower antibody and LPS levels among patients with initial PI-r ART suggest these regimens may more effectively suppress HIV with higher capacity to decrease the HIV antigenic component.

scholarly journals Clinical and Virologic Outcomes Following Initiation of Antiretroviral Therapy Among Seroconverters in the Microbicide Trials Network-020 Phase III Trial of the Dapivirine Vaginal Ring

2018 ◽  
Vol 69 (3) ◽  
pp. 523-529 ◽  
Author(s):  
Sharon A Riddler ◽  
Jennifer E Balkus ◽  
Urvi M Parikh ◽  
John W Mellors ◽  
Carolyne Akello ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Disease Progression ◽  
Virologic Failure ◽  
Vaginal Ring ◽  
Phase Iii ◽  
Virologic Suppression ◽  
Cell Counts ◽  
The Impact ◽  
Hiv 1

Abstract Background A vaginal ring containing dapivirine, a non-nucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor (NNRTI), was safe and effective in preventing HIV-1 infection in African women. We examined the impact of dapivirine ring use at the time of HIV-1 acquisition on subsequent HIV-1 disease progression and responses to NNRTI-containing antiretroviral therapy (ART). Methods HIV-1 disease progression and virologic failure following initiation of ART were assessed among women who acquired HIV-1 while participating in Microbicide Trials Network–020, a randomized, placebo-controlled trial of a monthly, dapivirine vaginal ring. Results Among the 158 participants who acquired HIV-1 (65 dapivirine, 93 placebo), no differences between dapivirine and placebo participants were observed in CD4+ cell counts or plasma HIV-1 RNA over the first year after infection (prior to ART). During follow-up, 100/158 (63%) participants initiated NNRTI-containing ART (dapivirine: 39/65; placebo: 61/93); the median time to HIV-1 RNA <200 copies/ml was approximately 90 days for both dapivirine and placebo ring recipients (log-rank P = .40). Among the 81 participants with at least 6 months of post-ART follow-up, 19 (24%) experienced virologic failure (dapivirine: 6/32, 19%; placebo: 13/39, 27%; P = .42). Conclusions The acquisition of HIV-1 infection during dapivirine or placebo treatment in ASPIRE did not lead to differences in HIV-1 disease progression. After the initiation of NNRTI-containing ART, dapivirine and placebo participants had similar times to virologic suppression and risks of virologic failure. These results provide reassurance that NNRTI-based ART regimens are effective among women who acquired HIV-1 while receiving the dapivirine vaginal ring. Clinical Trials Registration NCT016170096 and NCT00514098.

scholarly journals Factors associated with non-adherence to Antiretroviral Therapy among HIV infected adolescents at Guji zone Health Facilities, South Ethiopia

2020 ◽  
Author(s):  
Lalisa Ayele Woldasemayat ◽  
Beshir Ibrahim Jiru ◽  
Zerihun Kura Edossa
Keyword(s):  
Antiretroviral Therapy ◽  
Drug Exposure ◽  
Health Facilities ◽  
Factors Associated ◽  
South Ethiopia ◽  
Depression Status ◽  
The Family ◽  
Suboptimal Adherence ◽  
Disclosure Status ◽  
High Level

Abstract Background: Suboptimal adherence results in inadequate drug exposure and increases the likelihood of viral replication and resistance, limit future therapeutic options. A high level of adherence is very crucial to maximize the usefulness of antiretroviral therapy. This study aimed to examine factors associated with non-adherence to antiretroviral therapy among adolescents in Guji Zone, South Ethiopia.Methods: Institution based case-control study design was employed on adolescent clients on antiretroviral therapy in the ART clinic of Guji zone health facilities from 26 February to 20 April 2018. Cases and controls were recruited by a consecutive sampling method. Bivariate and multivariable logistic regression was done using SPSS version 20 at 95% Confidence Interval (CI) and a precision of 5%.Results: A total of 297(101 cases and 196 controls) adolescents on ART participated in this study. Being rural residents AOR 1.9(1.1-3.6), Living with unmarried/widowed and separated caregivers AOR 2.1(1.2-3.8), living with unemployed caregivers AOR 4.2(2.0-8.9), not disclosing HIV Status AOR 5(2.8-9.4), having symptom of depression for adolescents AOR 2.7(1.5-4.9), not using reminding methods AOR 2.4(1.2-4.8) and Uses of other drugs besides ART AOR 2.6(1.5-5.0) were found to be independent factors associated with non-adherence to ART among adolescents.Conclusion: -Residence area, caregiver marital status, sources of income for the family, disclosure status, depression status, uses of reminding methods, and uses of other drugs besides ART were factors associated with non-adherence to antiretroviral therapy among adolescents. Support from peers and family can promote adolescent's adherence, as it buffers the stress associated with the illness, encourages optimism, reduces depression, and improves healthful behaviors. The provision of health education on the importance of treatments and needs for adherence should be encouraged. Uses of reminding methods, continuous monitoring of clients on ART regarding the uses of medications other than antiretroviral therapy is important.

scholarly journals Prevalence of Nonsuppressed Viral Load and Associated Factors Among Adults Receiving Antiretroviral Therapy in Eswatini, Lesotho, Malawi, Zambia, and Zimbabwe (2015-2017): Results from Population-Based Nationally-Representative Surveys

2020 ◽  
Author(s):  
Andreas D Haas ◽  
Elizabeth Radin ◽  
Avi J Hakim ◽  
Andreas Jahn ◽  
Neena Philip ◽  
...  
Keyword(s):  
Viral Load ◽  
Antiretroviral Therapy ◽  
Virologic Failure ◽  
Scale Up ◽  
Female Gender ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Second Line ◽  
Viral Load Suppression ◽  
Factors Associated

Introduction: The Joint United Nations Programme on HIV/AIDS (UNAIDS) has set a target of ≥90% of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) to have viral load suppression (VLS). We examined factors associated with nonsuppressed viral Load (NVL). Methods: We included PLHIV receiving ART aged 15-59 years from Eswatini, Lesotho, Malawi, Zambia, and Zimbabwe. Blood samples from PLHIV were analyzed for HIV RNA and recent exposure to antiretroviral drugs (ARVs). Outcomes were NVL (viral load ≥1000 copies/mL), virologic failure (VF; ARVs present and viral load ≥1000 copies/mL), interrupted ART (ARVs absent and viral load ≥1000 copies/mL), and receiving second-line ART. We calculated odds ratios and incidence rate ratios for factors associated with NVL, VF, interrupted ART, and switching to second-line ART. Results: The prevalence of NVL was 11.2%: 8.2% experienced VF, and 3.0% interrupted ART. Younger age, male gender, less education, suboptimal adherence, receiving nevirapine, HIV non-disclosure, never having married, and residing in Zimbabwe, Lesotho, or Zambia were associated with higher odds of NVL. Among people with NVL, marriage, female gender, shorter ART duration, higher CD4 count, and alcohol use were associated with higher odds for interrupted ART and lower odds for VF. Many people with VF (44.8%) had CD4 counts <200 cells/μL, but few (0.31% per year) switched to second-line ART. Conclusions: Countries are approaching UNAIDS VLS targets for adults. Treatment support for people initiating ART with asymptomatic HIV infection, scale-up of viral load monitoring, and optimized ART regimens may further reduce NVL prevalence.

scholarly journals 629. High Efficacy of Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) in African American Adults with HIV Including Those with Preexisting Resistance, Viral Blips, and Suboptimal Adherence

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S418-S418
Author(s):  
Kristen Andreatta ◽  
Michelle L D'Antoni ◽  
Silvia Chang ◽  
Aiyappa Parvangada ◽  
Ross Martin ◽  
...  
Keyword(s):  
African American ◽  
Reverse Transcriptase ◽  
Virologic Failure ◽  
Pill Count ◽  
Controlled Study ◽  
Virologic Suppression ◽  
African American Adults ◽  
Suboptimal Adherence ◽  
Tenofovir Alafenamide ◽  
Hiv 1

Abstract Background BRAAVE 2020 demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among African American adults with suppressed HIV through Week (W) 48 (Figure 1). We present resistance, viral blips, adherence, and virologic outcomes through W72. Figure 1. BRAAVE 2020 study design (phase 3, randomized, open-label, multicenter [USA], active-controlled study) and virologic suppression at weeks 24 and 48 *Allowed 3rd agents: any FDA-approved protease inhibitor, nonnucleoside reverse transcriptase inhibitor (except etravirine), integrase strand transfer inhibitor (except bictegravir), or maraviroc. Methods Enrollment criteria permitted NNRTI resistance (-R), PI-R, and certain NRTI-R (M184V/I allowed; K65R/E/N, ≥3 thymidine analog mutations [TAMs], or T69-insertions excluded) and excluded known primary INSTI-R. Preexisting drug resistance was assessed with historical genotypes and retrospective baseline proviral DNA genotyping. Adherence was calculated by pill count. Viral blips (transient HIV-1 RNA ≥50 copies/mL) and outcomes based on last available on-treatment HIV-1 RNA were assessed. Results 489 participants received B/F/TAF and had ≥1 post-switch HIV-1 RNA measurement. Baseline genotypic data from cumulative historical and/or proviral genotypes were available for 96% (468/489) in protease/reverse transcriptase and 93% (453/489) in integrase. Preexisting NRTI-R, M184V/I, ≥1 TAMs, NNRTI-R, and PI-R were observed in 15% (68/468), 11% (50/468), 8% (36/468), 22% (101/468), and 13% (61/468), respectively. Primary INSTI-R was detected post-randomization in 2% (11/453); all remained in the study and were included in efficacy analyses. Through W72, 99% (486/489) of participants had HIV-1 RNA &lt; 50 copies/mL at their last study visit, including all with baseline NRTI-R or INSTI-R (Figure 2). Mean frequency of viral blips was 1% per timepoint, and blips were not associated with virologic failure. 112 participants (23%) had &lt; 95% adherence by pill count, 98% (110/112) of whom had HIV-1 RNA &lt; 50 copies/mL at last visit, including 14 of 14 (100%) with &lt; 80% adherence. No participant discontinued due to lack of efficacy or had treatment emergent resistance to study drugs. Figure 2. Virologic suppression by preexisting resistance, viral blips, and adherence Conclusion Virologic suppression was maintained through W72 of B/F/TAF treatment, including those with preexisting resistance, viral blips, and suboptimal adherence. Continued HIV suppression and absence of treatment-emergent resistance demonstrate the efficacy of B/F/TAF in African Americans regardless of adherence or preexisting resistance to NNRTIs, PIs, or non-tenofovir NRTIs. Disclosures Kristen Andreatta, MSc, Gilead Sciences, Inc (Employee, Shareholder) Michelle L. D'Antoni, PhD, Gilead Sciences (Employee, Shareholder)Gilead Sciences, Inc (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences, Inc (Employee, Shareholder) Aiyappa Parvangada, MS Computational Biology, Gilead Sciences, Inc (Employee, Shareholder) Ross Martin, PhD, Gilead Sciences, Inc (Employee, Shareholder) Christiana Blair, MS, Gilead Sciences, Inc (Employee, Shareholder) Sean E. Collins, MD, MS, Gilead Sciences, Inc (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc (Employee, Shareholder)

scholarly journals Virologic suppression in response to antiretroviral therapy despite extensive resistance within HIV-1 reverse transcriptase after the first virologic failure

2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Marta Iglis Oliveira ◽  
Valter Romão de Souza Junior ◽  
Claudia Fernanda de Lacerda Vidal ◽  
Paulo Sérgio Ramos de Araújo
Keyword(s):  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Virologic Failure ◽  
Virologic Suppression ◽  
Hiv 1

scholarly journals Population Pharmacokinetics and Pharmacogenetics Analysis of Rilpivirine in HIV-1-Infected Individuals

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Manel Aouri ◽  
Catalina Barcelo ◽  
Monia Guidi ◽  
Margalida Rotger ◽  
Matthias Cavassini ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Plasma Concentrations ◽  
Antiretroviral Drugs ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Concentration Data ◽  
Standard Dosage ◽  
Number Of Patients ◽  
Hiv 1

ABSTRACT Rilpivirine (RPV), the latest nonnucleoside reverse transcriptase inhibitor active against HIV-1, is prescribed in a standard dosage of 25 mg once a day in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The aim of this observational study was to characterize the RPV pharmacokinetic profile, to quantify interpatient variability, and to identify potential factors that could influence drug exposure. RPV concentration data were collected from HIV-infected patients as part of routine therapeutic drug monitoring performed in our center (Laboratory of Clinical Pharmacology). A population pharmacokinetic analysis was performed with NONMEM by comparing various structural models. The influence of demographic and clinical covariates, as well as frequent genetic polymorphisms in 5 genes (CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, UGT1A1*28, and UGT1A4*2), on RPV elimination was explored. A total of 325 plasma concentration measurements were obtained from 249 HIV-positive patients. Plasma concentrations ranged from 12 to 255 ng/ml. A one-compartment model with zero-order absorption best characterized RPV pharmacokinetics. The average RPV clearance (CL) was 11.7 liters/h, the average volume of distribution was 401 liters, and the mean absorption time was 4 h. The interinterindividual variability (IIV) for CL was estimated to be 33%. None of the available demographic or genetic covariates showed any influence on RPV pharmacokinetics, but 29% of the patients were predicted to present minimal concentrations below the recently identified target cutoff value of 50 ng/ml. The variability in RPV pharmacokinetics appears to be lower than that for most other antiretroviral drugs. However, under the standard regimen of 25 mg daily, a significant number of patients might be underdosed. It remains to be investigated whether the underexposure has an impact on the development of resistance while patients are on maintenance therapy.

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