eCase - First-line ART

Key Principles and Recommended Regimens for First-line Antiretroviral Therapy

Released: May 22, 2019

Expiration: May 20, 2020

Activity Information

Activity

Progress

Course Completed

BACK | NEXT

Introduction ARV Treatment Guidelines for First-line Therapy in Adult Patients Pretherapy ARV Resistance Testing Choosing Among the Integrase Inhibitors for First-line Therapy Selection of the NRTI Pair Choosing Other Than INSTI-Based Initial Therapy Clinical Trials of NNRTI-Based vs INSTI-Based Therapy Clinical Trials of INSTI-Based vs Boosted PI-Based Therapy Clinical Trials of NNRTI-Based vs PI-Based Therapy Choosing Among the NNRTIs for First-line Therapy Choosing Among the Boosted PIs for First-line Therapy NRTI-Limiting Approaches in Initial Therapy Recommendations for Special Situations Primary Care Essentials References

Available Integrase Inhibitors
There are currently 4 INSTIs that have been approved by the FDA for treatment of ARV-naive patients. They are listed in order of development.

Raltegravir in combination with 2 NRTIs (emtricitabine/tenofovir DF or emtricitabine/tenofovir AF, depending on the guideline) is one of the recommended first-line regimens in the DHHS guidelines¹ and the EACS guidelines.⁴ The FDA-approved dose of raltegravir is 400 mg twice daily, with or without food, or 2 tablets of the newer 600-mg formulation (1200 mg total dose) once daily, with or without food. Once-daily raltegravir 1200-mg dosing using the recently approved 600-mg formulation was shown to have noninferior efficacy at both Weeks 48 and 96 as initial therapy vs twice-daily raltegravir 400 mg in the phase III ONCEMRK trial.¹⁰ All other comparative raltegravir trials discussed in this module used 400-mg twice daily dosing. Raltegravir does not require a boosting agent when used once daily or twice daily. There are no coformulated regimens containing raltegravir.

Raltegravir has also been investigated as part of an NRTI-sparing regimen. In the DHHS and IAS-USA guidelines, raltegravir is included as part of a nontraditional 2-drug regimen with darunavir plus ritonavir (both twice daily) for persons with baseline HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm³who require first-line therapy and cannot receive tenofovir DF, tenofovir AF, or abacavir.^1,2 In the EACS guidelines, raltegravir is included as part of a 2-drug regimen with darunavir plus ritonavir or cobicistat/darunavir only if CD4+ cell count is > 200 cells/mm³ and HIV-1 RNA < 100,000 copies/mL.⁴

Elvitegravir was initially approved for first-line therapy as part of the coformulated regimen cobicistat/elvitegravir/emtricitabine/tenofovir DF,¹¹ and subsequently as part of the coformulated regimen cobicistat/elvitegravir/emtricitabine/tenofovir AF.¹² Cobicistat/elvitegravir/emtricitabine/tenofovir DF and cobicistat/elvitegravir/emtricitabine/tenofovir AF are considered alternative regimens in all current treatment guidelines due to the increased likelihood of drug–drug interactions with cobicistat and the fact that elvitegravir has a lower barrier to resistance than dolutegravir or bictegravir.^1,2,4These coformulatedregimens are both administered once daily but differ in renal function thresholds for use: cobicistat/elvitegravir/emtricitabine/tenofovir DF should be reserved for those with estimated glomerular filtration rates ≥ 70 mL/min¹¹ and cobicistat/elvitegravir/emtricitabine/tenofovir AF should be used only in patients with estimated glomerular filtration rates ≥ 30 mL/min.¹² The EACS guidelines further recommend that cobicistat/elvitegravir/emtricitabine/tenofovir DF not be given to patients with estimated glomerular filtration rates < 90 mL/min unless this is the preferred treatment.⁴It should be noted that many physicians (including this author) prefer the tenofovir AF–containing regimen due to improved renal and bone safety when compared with the tenofovir DF–containing regimen. In the opinion of this author, clinicians should use the tenofovir AF–containing formulation in all settings where the single-tablet elvitegravir-based regimens are selected.

Dolutegravir, the third INSTI approved by the FDA, is administered once daily in treatment-naive patients and does not require a boosting agent. It is a recommended agent for use in first-line regimens in combination with abacavir/lamivudine (with which there is a coformulated complete regimen), emtricitabine/tenofovir DF, or emtricitabine/tenofovir AF, according to the DHHS¹and EACS⁴ guidelines and in combination with abacavir/lamivudine or emtricitabine/tenofovir AF according to IAS-USA guidelines.² In April 2019, the coformulated 2-drug regimen dolutegravir/lamivudine became the first 2-drug combination to be approved by the FDA as a complete regimen for the treatment of HIV infection in adults who are ARV naive and have no known substitutions associated with resistance to the individual components.¹³ This simplified regimen is included as part of “First-line Regimens to Be Used in Certain Clinical Situations,” specifically when abacavir, tenofovir DF, and tenofovir AF cannot be used, in the DHHS guidelines and is included among the alternative regimen recommendations in the EACS guidelines.⁴

However, it is important to note that interim results from the Tsepamo birth surveillance study in Botswana reported an increased risk of NTD in infants whose mothers became pregnant while receiving dolutegravir-based ART (0.94% of 426 births in women receiving dolutegravir-based ART vs 0.12% of 11,300 births in women in women receiving non-dolutegravir–based ART),³ prompting the DHHS and the IAS-USA to provide interim recommendations for dolutegravir use in women of childbearing age.^1,2 It is currently recommended by the DHHS, IAS-USA, and EACS that dolutegravir should not be initiated during the first trimester of pregnancy.^1,2,4 In addition, a documented negative pregnancy test is recommended by the DHHS and IAS-USA panels before starting dolutegravir in women of childbearing potential and use of dolutegravir in women should be accompanied by counseling about the potential risks of NTDs if dolutegravir is taken during/near the time of conception and during the first 12 weeks of pregnancy.^1,2

The coformulated regimen bictegravir/emtricitabine/tenofovir AF was approved by the FDA in 2018 as a complete regimen for the treatment of HIV infection in adults who are ARV naive or as a switch regimen in those who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ARV regimen for ≥ 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components.¹⁴ It is a recommended first-line regimen in the DHHS guidelines,¹ the IAS-USA guidelines,² and the EACS guidelines.⁴

Clinical Trials Comparing Integrase Inhibitors
There are no large-scale head-to-head trials comparing raltegravir and elvitegravir or comparing elvitegravir and dolutegravir in treatment-naive patients. Both raltegravir and elvitegravir were found to be noninferior to efavirenz at the primary endpoints of their respective trials.^15,16 Dolutegravir was found to be superior to efavirenz at Week 48 in the SINGLE trial (primarily due to fewer discontinuations due to adverse events)¹⁷; dolutegravir was also found to be noninferior to raltegravir in the SPRING-2 trial.¹⁸

The phase III SPRING-2 trial compared once-daily dolutegravir with twice-daily raltegravir, each with 2 NRTIs (investigator-selected abacavir/lamivudine or emtricitabine/tenofovir DF) in 822 treatment-naive patients.¹⁸ At the Week 48 primary efficacy analysis,dolutegravir was noninferior to raltegravir with 88% vs 85% of patients, respectively, with HIV-1 RNA < 50 copies/mL based on the FDA snapshot analysis. Both arms were associated with a CD4+ cell count increase of 230 cells/mm³. There were no significant differences in virologic response between the arms at Week 48 according to baseline HIV-1 RNA level or NRTI backbone. The rate of protocol-defined virologic failure was lower with dolutegravir vs raltegravir (5% vs 7%, respectively). No integrase or NRTI resistance was identified among patients in the dolutegravir arm, but integrase and NRTI resistance were identified in 1 and 4 patients, respectively, among those in the raltegravir arm.

No clinically significant changes were noted in the fasting lipid profile in either group. Dolutegravir was associated with a small increase in creatinine resulting from the anticipated inhibition of creatinine secretion of dolutegravir without affecting actual glomerular filtration rate.¹⁹ TheseIncreases in serum creatinine were evident in both groups by Week 2, but remained stable through Week 48. The mean change in estimated creatinine clearance at Week 48 was -16.5 mL/min in the dolutegravir group and -5.4 mL/min in the raltegravir group. No patients had grade 3 or 4 increases in creatinine, and no patients in either group discontinued because of renal events.

Noninferiority was maintained at Week 96 with 81% vs 76% of patients with HIV-1 RNA < 50 copies/mL.²⁰ Median CD4+ cell count increases were similar between arms through Week 96: +276 cells/mm³ with dolutegravir and +264 cells/mm³ with raltegravir. At Week 96, the rate of withdrawal from the trial was very low in both arms: 10 patients (2%) of each group. No further increase in serum creatinine was observed between Weeks 48 and 96.

The FDA approval of bictegravir/emtricitabine/tenofovir AF was as a result of the phase III GS-1490 trial in which coformulated bictegravir/emtricitabine/tenofovir AF was found to be noninferior to dolutegravir plus emtricitabine/tenofovir AF at the primary endpoint Week 48 analysis.²¹In this trial, HIV-infected treatment-naive adults with HIV-1 RNA ≥ 500 copies/mL and estimated glomerular filtration rate ≥ 30 mL/min were randomly assigned to receive fixed-dose combination bictegravir/emtricitabine/tenofovir AF (n = 320) or dolutegravir plus emtricitabine/tenofovir AF (n = 325) once daily for 144 weeks. The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 copies/mL at Week 48 by the FDA snapshot algorithm, with a prespecified noninferiority margin of -12%. At Week 48, 286 (89%) of those in the bictegravir arm and 302 (93%) of those in the dolutegravir arm achieved HIV-1 RNA < 50 copies/mL (difference -3.5%; 95% CI: -7.9% to 1.0%; P = .12), demonstrating noninferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of adverse events were similar between groups, and only 5 patients (2%) in the bictegravir group and 1 patient (< 1%) in the dolutegravir group discontinued treatment due to adverse events. Study drug–related adverse events were significantly less common in the bictegravir group than in the dolutegravir group (57 18% vs 83 26%, respectively; P = .022).

The phase III GS-1489 trial compared the 2 coformulated regimens bictegravir/emtricitabine/tenofovir AF and abacavir/dolutegravir/lamivudine for initial ART (Capsule Summary).²²In this trial, 629 HIV-infected, HLA-B*5701–negative, treatment-naive adults with HIV-1 RNA ≥ 500 copies/mL and estimated glomerular filtration rate ≥ 50 mL/min were randomly assigned to receive the oral fixed-dose combination bictegravir/emtricitabine/tenofovir AF (n = 314) or oral fixed-dose abacavir/dolutegravir/lamivudine (n = 315) once daily for 144 weeks. (In this study, patients with chronic hepatitis B virus coinfection were excluded; they were eligible for GS-1490.) At Week 48, 92.4% of patients in the bictegravir arm vs 93.0% of those in the dolutegravir arm achieved HIV-1 RNA < 50 copies/mL (difference: 0.6%; 95% CI: -4.8% to 3.6%), demonstrating noninferiority of the coformulated bictegravir regimen to the coformulated dolutegravir regimen. Similar to GS-1490, few patients discontinued treatment for adverse events related to the study drugs: 0 patients receiving bictegravir/emtricitabine/tenofovir AF vs 4 (1.3%) patients receiving abacavir/dolutegravir/lamivudine. Nausea (all grades) was more common with use of abacavir/dolutegravir/lamivudine (P < .001). No treatment-emergent resistance to any study drug was observed. Treatment assignment had no significant impact on change in renal markers, bone mineral density at spine or hip, or lipid levels at Week 48.

Bictegravir/emtricitabine/tenofovir AF is not recommended for patients with estimated creatinine clearance < 30 mL/min or in patients with severe hepatic impairment.

Choosing Among Integrase Inhibitors
When choosing among the 4 INSTIs, the following considerations might be taken into account:

Dosing:
- Raltegravir can be given as 400 mg twice daily or 1200 mg (using 2 tablets of a newer 600-mg formulation) once daily
- The elvitegravir regimen is given once daily. Elvitegravir must be given with a pharmacologic booster; that function in first-line regimens is supplied by cobicistat, a drug with no anti-HIV activity; consequently, there are more drug–drug interactions with this regimen (see below)
- Dolutegravir is given once daily in treatment-naive patients with no pharmacologic booster
- Bictegravir is given once daily without boosting
Renal function:
- Although recommended as part of a regimen with emtricitabine/tenofovir DF, raltegravir can be prescribed with other NRTIs in patients with reduced renal function. Raltegravir itself has minimal effect on renal function. The SINGLE trial also showed that raltegravir is effective with an NRTI backbone of abacavir/lamivudine, an option for patients with impaired renal function (although this combination is recommended only for those who are negative for HLA-B*5701 and have a baseline HIV-1 RNA < 100,000 copies/mL)¹
- One of the coformulated elvitegravir regimens contains tenofovir DF and is not recommended in patients with creatinine clearance < 70 mL/min (ie, the dose of tenofovir DF cannot be adjusted with the coformulated elvitegravir regimen). Cobicistat may also modestly increase creatinine levels by inhibiting tubular creatinine secretion; this happens early in treatment and persists throughout therapy with this agent.²³The other coformulated elvitegravir regimen contains tenofovir AF and is not recommended in patients with creatinine clearance < 30 mL/min. Now that cobicistat is available as a single agent, it also can be combined with a modified tenofovir DF dose if needed to reduce the risk of renal changes
  - Given the improved renal and bone safety of tenofovir AF, this author recommends the tenofovir AF coformulation over the tenofovir DF coformulation whenever elvitegravir-containing first-line regimens are chosen
- Dolutegravir has been shown to be effective with an NRTI backbone of either abacavir/lamivudine, emtricitabine/tenofovir DF, or lamivudine alone in a 2-drug NRTI-limiting first-line regimen (FDA approved for initial ART in 2019). Like cobicistat, dolutegravir has a documented effect on creatinine excretion that modestly increases creatinine levels but does not reflect an adverse impact on renal function.¹⁹
- Bictegravir/emtricitabine/tenofovir AF is not recommended for patients with estimated creatinine clearance < 30 mL/min. There are no data on the use of bictegravir with other NRTI backbones than emtricitabine/tenofovir AF.
Lipids: Raltegravir, elvitegravir, and dolutegravir have been found to have less effect on lipids than efavirenz. In the phase III GS-1878 study, which evaluated the efficacy and safety of switching virologically suppressed adult patients with HIV infection from a multitablet regimen containing a boosted PI to fixed-dose bictegravir/emtricitabine/tenofovir AF, lipid parameters significantly improved with the switch to bictegravir/emtricitabine/tenofovir AF vs continued baseline PI-based ART²⁴
Adverse events (other than renal): All 4 INSTIs are well tolerated:
- The most common adverse events seen in clinical trials of raltegravir were insomnia and headache; isolated cases of myopathy and rhabdomyolysis have been reported²⁵
- When compared with efavirenz, more patients in the elvitegravir arm experienced nausea¹⁶; other adverse events were seen in similarly low numbers with the exception of neuropsychiatric events, which were greater in the efavirenz group
- Elvitegravir is also associated with documented increase in serum creatinine
- Adverse events seen in clinical trials of dolutegravir include headache and the documented increase in serum creatinine
- Raltegravir, elvitegravir, and dolutegravir may be associated with weight gain
- Observational studies have documented discontinuation of dolutegravir among certain populations of persons with HIV due to central nervous system (CNS) adverse events²⁶
  - A retrospective analysis of clinical trials of dolutegravir found most psychiatric events were mild to moderate and discontinuation rate was low (Capsule Summary)²⁷
- In phase III clinical trials, incidence and severity of adverse events were similar between patients receiving the bictegravir regimen and those receiving dolutegravir-based regimens^21,22
Baseline HIV-1 RNA and CD4+ cell count strata:
- Raltegravir, elvitegravir, and dolutegravir have been shown to be effective over a range of viral load and CD4+ cell count strata^15,16,28; unlike efavirenz and atazanavir plus ritonavir, which appeared less effective when combined with abacavir/lamivudine in patients with high baseline viral load,²⁹ raltegravir and dolutegravir^17,30-32 have been shown to be similarly effective when combined with either emtricitabine/tenofovir DF or abacavir/lamivudine in patients with high viral load¹⁸
  - It should be noted, however, that current DHHS guidelines recommend raltegravir plus abacavir/lamivudine as a first-line regimen only in certain clinical situations and only for patients with baseline HIV-1 RNA < 100,000 copies/mL¹ as SPRING-2 has been the only trial that has studied this combination as first-line therapy in patients with HIV-1 RNA > 100,000 copies/mL (n = 115)
Drug–drug interactions:
- Raltegravir is not an inhibitor or inducer of the CYP system. Similarly, raltegravir is not an inhibitor of UDP-glucuronosyltransferases or P-glycoprotein–mediated transport. Therefore, raltegravir does not have significant interactions with drugs metabolized by these systems, including hormonal contraceptives, methadone, or other ARV agents. An update to the FDA-approved raltegravir label notes an interaction with antacids containing polyvalent cations.²⁵ There is also an interaction with rifampin seen with all INSTIs
- Coadministration of cobicistat/elvitegravir/emtricitabine/tenofovir DF or cobicistat/elvitegravir/emtricitabine/tenofovir AF is contraindicated with drugs that are highly dependent on CYP3A for clearance, including the antituberculosis drug rifampin, the statins lovastatin and simvastatin, and erectile dysfunction agents
- Dolutegravir has few drug–drug interactions. Like raltegravir, dolutegravir should not be dosed in combination with laxatives or antacids containing polyvalent cations; dolutegravir also has an interaction with metformin increasing levels of metformin. There is also an interaction with rifampin seen with all INSTIs and with the NNRTIs efavirenz and etravirine and with the PIs fosamprenavir and tipranavir
- Bictegravir is contraindicated with dofetilide due to the potential for increased and rifampin due to decreased bictegravir plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to this drug and other components of the regimen
Virologic failure:
- Upon virologic failure of either raltegravir or elvitegravir/cobicistat, resistance occurs in one third to one half of patients. Resistance to the INSTIs is associated with mutations in the integrase gene that take 1 of at least 3 distinct genetic pathways. With raltegravir, these are defined by the presence of 2 or more mutations including a signature mutation at Q148H/K/R, N155H, or Y143R/H/C plus 1 or more additional minor mutations in the Q148H/K/R pathway. Failure of elvitegravir may include mutations T66I/A/K and E92Q/G.³³Patients who remain on INSTI-based therapy while experiencing virologic failure typically experience ongoing evolution of resistance mutations, with more mutations and greater loss of susceptibility accumulating with longer time on the failing regimen.³⁴ There appears to be extensive cross-resistance between elvitegravir and raltegravir, such that patients who develop resistance to raltegravir are not anticipated to benefit from elvitegravir³⁵
  - Failure of either of these drugs is also often associated with development of resistance to 1 or both NRTIs in the background regimen as well
- On the other hand, development of resistance mutations either to INSTIs or NRTIs at virologic failure of first-line dolutegravir-based combination regimens has not yet been documented in trials of dolutegravir in treatment-naive patients^17,18,30,32
  - Two reports of potential emergence of resistance in individuals treated with dolutegravir in first-line therapy have recently appeared; in one case, baseline integrase was not sequenced^36,37
- In phase III clinical trials of bictegravir, no treatment-emergent resistance to any study drug was observed through Week 48^21,22
Pregnancy potential in women of childbearing age:
- Initial results from the Tsepamo birth surveillance study in Botswana reported an increased risk of NTD in infants whose mothers became pregnant while receiving dolutegravir-based ART (0.94% of 426 births in women receiving dolutegravir-based ART vs 0.12% of 11,300 births in women in women receiving non-dolutegravir–based ART),³ prompting the DHHS and the IAS-USA to provide interim recommendations for dolutegravir use in women of childbearing age.^1,2It is currently recommended by the DHHS, IAS-USA, and EACS not to start dolutegravir during the first trimester of pregnancy,^1,2,4 and use of dolutegravir in women should be accompanied by counseling about the potential risks of NTDs if dolutegravir is taken during/near the time of conception and during the first 12 weeks of pregnancy.^1,2 It is also recommended by the DHHS and IAS-USA panels to have a documented negative pregnancy test result before initiating dolutegravir in women of childbearing potential. The interim guidance notes that it is unclear if this potential effect could be specific to dolutegravir or if it could be a potential class effect of INSTIs

BACK | NEXT

Clinical Education Alliance Terms and Conditions

These Terms of Use ("Terms") apply to your use of the websites, mobile applications and other resources provided by Clinical Education Alliance LLC (“CEA”) and its affiliates (referred to collectively as "CEA," "us," "we" and "our") that are intended for use by healthcare professionals, which we refer to as the "CEA Network," including the personalized information and services that meet the needs and interests of users of the CEA Network such as medical news, reference content, clinical tools, applications, sponsored programs, advertising, email communications, continuing medical education, market research opportunities and discussion forums (collectively, the "Services"). You will always be able to view the most current version of these Terms by clicking on the Terms of Use link at the bottom of any page of a CEA Network property. Note that these Terms do not apply to our properties and services that display a link to different terms of use. In the event that we expand the CEA Network through our acquisition of another company and/or its properties, that company may operate its properties subject to its own terms of use accessible via a link on such properties until we integrate its practices with ours, at which point a link to these Terms will be displayed on its properties. By using the Services, you agree to these Terms, whether or not you are a registered member of the CEA Network. These Terms govern your use of the Services and create a binding legal agreement that we may enforce against you in the event of a violation. If you do not agree to all of these Terms of Use, do not use the Services!

We reserve the right to change these terms from time to time. The most current version may be viewed by clicking on the “Terms of Use” link at the bottom of designated pages on the Clinical Education Alliance Sites. Use of the Clinical Education Alliance Sites after the effective date constitutes acceptance of the amended Terms of Use. When you leave a CEA Web site and go to another Web site, different terms apply and CEA has no responsibility or liability for any content on those sites.

Clinical Education Alliance Content

The Clinical Education Alliance Sites incorporate information, including modules, capsules, journal articles, medical news, references, interactive case studies, other continuing education material, downloadable software applications, advertising, and other healthcare information, which is intended for adults who are licensed healthcare professionals. This information is not intended to serve as a substitute for the healthcare professional’s clinical judgment. If you are a consumer who chooses to read this professional-level information on Clinical Education Alliance Sites, you should not use or rely on that information as professional medical advice or use it to replace any relationship with your physician or other qualified healthcare professional or any information they may have provided to you. For medical issues or concerns, including decisions about medications and other treatments, consumers should always consult their physician or, in serious cases, seek immediate assistance from emergency personnel.

The Content on the Clinical Education Alliance Sites is developed or selected in accordance with our published Editorial Policies. However, users access and use this material at their own risk. It is the reader’s job to evaluate the accuracy of any information and results from interactive programs found on the Clinical Education Alliance Site. If you are a healthcare professional, you should rely on your professional judgment in evaluating any and all information and confirm the information contained on the Clinical Education Alliance Sites with other sources and reliable third parties before basing any treatment or advice on it. If you are a consumer, you should evaluate the information together with your physician or another qualified healthcare professional.

DISCLAIMERS AND LIMITATIONS OF LIABILITY

THE CONTENT, APPLICATIONS, SOFTWARE, AND ALL OTHER MATERIAL ON THE CLINICAL EDUCATION ALLIANCE SITES ARE PROVIDED “AS IS” AND WITHOUT WARRANTY OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, OR NONINFRINGEMENT. ALL WARRANTIES, EXPRESS OR IMPLIED, ARE HEREBY DISCLAIMED. CLINICAL EDUCATION ALLIANCE SHALL NOT BE LIABLE FOR ANY SPECIAL, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, INCLUDING, WITHOUT LIMITATION, PHYSICAL HARM OR INJURIES, LOST REVENUES, OR LOST PROFITS, RESULTING FROM THE USE OR MISUSE OF THE CLINICAL EDUCATION ALLIANCE SITES, OR ANY INFORMATION, APPLICATIONS, MATERIALS, OR SOFTWARE THEREON, EVEN IF CLINICAL EDUCATION ALLIANCE HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH DAMAGES, OR FOR ANY CLAIM BY ANOTHER PARTY. CLINICAL EDUCATION ALLIANCE DOES NOT WARRANT THAT THIS SITE OR ANY APPLICATIONS OR SOFTWARE WILL BE FREE OF BUGS, INACCURACIES, OR ERRORS, NOR DOES CLINICAL EDUCATION ALLIANCE WARRANT THAT ANY SITE, SOFTWARE, OR APPLICATION IS FREE OF VIRUSES OR OTHER HARMFUL ELEMENTS.

A user’s use of the Clinical Education Alliance Sites, and any reliance on any materials, information, software, or applications, is at the user’s own risk. You agree that you hereby release Clinical Education Alliance and its affiliates, owners, respective directors, officers, employees, advertisers, authors, and contributors from any and all liability or obligations arising from the use of the Clinical Education Alliance Sites. A user’s sole remedy for any problem or concern is to exit the Web site or application. You agree that you will indemnify and hold Clinical Education Alliance harmless for any loss, damages, or liability suffered by Clinical Education Alliance as a result of your use of any Clinical Education Alliance Site or material, application, information, or software thereon or your submission of any material to Clinical Education Alliance. Clinical Education Alliance reserves the right to restrict or limit access to this Web site.

CEA Programs, Tools, and Databases

The Clinical Education Alliance Sites include interactive programs, clinical tools, and databases intended for the use of healthcare professionals. These materials are not intended as professional advice or recommendations of particular products. Physicians and other healthcare professionals who use our interactive programs, tools, or databases should exercise their own clinical judgment as to the results. Consumers who use the tools or databases do so at their own risk.

Individuals with any type of medical condition are specifically cautioned to seek professional medical advice before beginning any sort of health treatment. For medical concerns or issues, including decisions about medications and other treatments, users should always consult their physician or other qualified healthcare professional.

Ownership of Clinical Education Alliance Sites—Copyright and Trademarks

The entire contents and design of the Clinical Education Alliance Sites, including the software applications, tools, and databases, are protected under US and international copyright laws. These materials are owned by CEA or its affiliates or are used with permission of their owners or as otherwise authorized by law. All rights are reserved, worldwide. You may look at the Clinical Education Alliance Sites, download individual articles or applications to your personal computer or handheld device, and print a reasonable number of pages for your own personal reference. You must not remove any copyright notices from our materials. We reserve all our other rights. This means you may not sell, rewrite, or modify any content or other material found on any Clinical Education Alliance Site, redistribute it, put it on your own Web site, or use it for any commercial purpose without our prior written authorization.

The names of the CEA products and services are protected by trademark laws in the United States. Any use of our trademarks or service marks requires prior written approval from CEA.

You may link to a CEA Web site if your Web site offers products, services, or information of interest to the professional healthcare community. You are not allowed to link to the Clinical Education Alliance Sites if you post illegal, obscene, or offensive content or if the link is likely to have a negative impact on CEA’s reputation. Any other use, such as framing any part of a CEA Web site or incorporating any CEA content into another Web site, product, or application, requires advance written permission from Clinical Education Alliance. Clinical Education Alliance assumes no responsibility for any Web sites or materials that are linked to Clinical Education Alliance Sites or materials.

Software Products and Applications

Clinical Education Alliance makes some software and accompanying documentation available for downloading from our Web sites and/or from iTunes. These materials are protected by copyrights under US and international law and are owned by Clinical Education Alliance or companies that have licensed the software to us. We do not transfer any ownership rights in software or documentation to you when you download it from our Web site and/or directly from iTunes. You may use the software and accompanying documentation for their intended purpose. You are not authorized to further copy or distribute the software and accompanying documentation, nor may you attempt to recreate or reverse engineer our software or applications. In addition, some software available for downloading from our Web sites and/or from iTunes is subject to US export controls. By downloading or using such software, you are representing to us that your download of such software complies with these controls.

US Government End Users

If you are affiliated with the US government, please note that the software and documentation available on our Web sites and/or directly from iTunes are “commercial items,” as that term is defined in 48 C.F.R. 2.101 (October 1995), consisting of “commercial computer software” and “commercial computer software documentation,” as such terms are used in 48 C.F.R. 12.212 (September 1995). Consistent with 48 C.F.R. 12.212 and 48 C.F.R. 227.7202-1 through 227.7202-4 (June 1995), all US government end users acquire the software and documentation with only those rights set forth herein.

Social Media, Message Boards, and Forums

Clinical Education Alliance offers users the opportunity to engage in social media interactions with both experts and other users of the sites. As with other online social media, users must exercise sound judgment in both the information that they post and in how they assess the postings of other users. As such, users are expected to adhere to the social media recommendations made by the American Medical Association when utilizing the social media capabilities of CEA sites. In particular, users must be cognizant of standards of patient privacy and confidentiality that must be maintained in all environments and must not post identifiable patient information on CEA sites. In social media interactions, users must maintain appropriate boundaries of the patient–physician/care provider relationship in accordance with professional ethical guidelines just as they would in any other context. Users acknowledge that privacy settings are not absolute and that once on the Internet, content posted by them may be copied by third parties and republished out of the control of Clinical Education Alliance. Thus, users should routinely monitor their own Internet presence to ensure that the personal information and content that they post and, to the extent possible, that is posted about them by others is accurate and appropriate.

Users are expected to refrain from submitting comments or messages that are defamatory, hateful, or obscene or that harass others. Users may not impersonate any other person or violate any other person’s or entity’s legal rights or submit falsified credentials or experiences. Users agree that they will not submit any materials that violate or infringe any copyrights, trademarks, patents, trade secret, or other intellectual property rights of any third party. Clinical Education Alliance retains all copyrights in the content posted by users to its sites. Clinical Education Alliance may adopt additional rules to govern use of social media, message boards or forums, to which users will be subject.

Copyright and Other Legal Violations

If you believe that any material on this Web site infringes your copyright, please notify us as follows, under the Digital Millennium Copyright Act (“DMCA”). To notify us, the DMCA requires that you: 1. Send an email notice to Clinical Education Alliance at customersupport@clinicaloptions.com. 2. Include the following information in your email: a. Identify the copyrighted work(s) you claim is infringed; b. Identify the material you claim is infringing the copyright(s) and give enough information for Clinical Education Alliance to locate that material; c. Include a physical or electronic signature of the copyright owner or a person authorized to act on the copyright owner’s behalf (the “Claimant”); d. Include the Claimant’s name, address, and telephone number(s); e. Include a statement that the Claimant has a good faith belief that use of the disputed material is not authorized by the copyright owner or his agent; and f. Include a statement, under penalty of perjury, that the information in the notification of copyright infringement is accurate and that the Claimant is the copyright owner or is authorized to act on behalf of the copyright owner.

If you believe any content or material on the Clinical Education Alliance Sites violates any laws, please notify customersupport@clinicaloptions.com. Please include details about your concerns and an email address for contacting you.

Governing Law

Clinical Education Alliance controls the Clinical Education Alliance Sites from its offices in the state of Virginia in the United States of America. The Clinical Education Alliance Sites can be accessed from any of the United States and from other countries worldwide. Since the laws of each state or country may differ, both you and Clinical Education Alliance agree that the laws of Virginia, without regard to conflicts of laws principles, will apply to all matters relating to use of the Clinical Education Alliance Sites and materials, including software and applications.

Clinical Education Alliance makes no representation that materials on these sites are appropriate or available for use in countries aside from the United States. Accessing the Clinical Education Alliance Sites from territories where their contents are illegal is prohibited. Those who choose to access these sites from other locations do so at their own risk and are responsible for compliance with any and all applicable local laws or regulations.

Acceptance Procedure

By downloading or accessing materials on the Clinical Education Alliance Sites and/or directly from iTunes or registering with us, you agree to all the terms and conditions in this agreement, including the Terms of Use and Privacy Policy. If you disagree with any of these Terms of Use or Privacy Policy, please refrain from using the Clinical Education Alliance Sites or materials.

Privacy Policy

Because we provide education for healthcare professionals, we pay special attention to privacy issues. The purpose of our Privacy Policy is to identify the information we may collect about you, describe the uses we may make of your information and the security measures we take to protect it, and discuss your options for controlling your information. You can review our Privacy Policy by clicking on the “Privacy Policy” link at the bottom of designated pages on the Clinical Education Alliance Sites.

Disputes

If you fail to comply with these terms, we have the right to suspend or eliminate your account and remove any information you have placed on our site, including your registration information. We may also take any legal action we think is appropriate. If there is any dispute between us concerning this agreement or your use of any Clinical Education Alliance Site or materials or applications, we both agree to submit the dispute to nonbinding mediation, followed by binding arbitration. Both the mediation and the arbitration will be governed under the rules of the American Arbitration Association, and the venue for the arbitration will be Virginia.

Questions or Concerns About Our Terms of Use

For questions or concerns about these Terms of Use, please send an email to customersupport@clinicaloptions.com

These terms of use were last updated in July 2021.