Current Treatment Modalities and Clinical Standards for HIV Patients
By Daniel Jude, PharmD, AAHIVP, CSP, Manager of Specialty Clinical Services, Fairview Specialty Services Pharmacy, Minneapolis
The world of HIV medicine is complex and can be intimidating, but there are good reasons for this. What sets HIV apart from other complex disease states are the many advances in research, drugs for treatment and delivery systems. Even though most of us are not working in settings where HIV disease state management programs are warranted, pharmacists still have an obligation to recognize areas where we can improve outcomes and patient care. My goal is to provide a high-level review of current treatment guidelines and products, dig into prevention strategies, and describe new medications expected in the near future.
Current Guidelines and Treatments
The United States DHHS Guidelines continue to be the gold standard for care of people living with HIV/AIDS (PLWHA) in the U.S. The guidelines can easily be found by typing “HIV Guidelines” into a search engine or visiting https://aidsinfo.nih.gov/guidelines. The guidelines were recently given a facelift and have a much more modern online interface.1 The PDFs are still available on the site, should you want to download a copy for reference offline. A few notable tools within the guidelines include 1) drug:drug interaction tables that address Area Under the Curve (AUC) changes for both antiretrovirals (ARVs) and the interacting medication; 2) co-infection considerations for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and tuberculosis (TB); 3) detailed ARV dosing for renal/hepatic insufficiency; 4) very in-depth review of perinatal data and recommendations on use of ARVs before, during and after pregnancy. A helpful “Tables Only” link also provides a fast way to get to key information without the full discussion included.
Current data support the long-held standard starting treatment-naïve patients on two nucleoside/nucleotide reverse transcriptase-inhibitors (NRTIs) along with one other “anchor” ARV.1 You might remember non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease-inhibitors (PIs) as being popular in the past, but that is no longer the case. Integrase strand transferase-inhibitors (INSTIs or integrase-inhibitors) now account for four out of the five “Recommended Regimens” (see table 1).1
Table 1 (adapted from the guidelines)2
INSTIs have offered generally increased tolerability over PIs and NNRTIs while offering comparable efficacy and durability.1 INSTIs as a class can interact with aluminum and/or magnesium-containing antacids if given concomitantly; it is critical to counsel patients and re-educate as necessary to prevent an easily avoided Rx:OTC interaction.1 Because of dolutegravir and elvitegravir’s hepatic clearance, drug:drug interactions are still plentiful especially since elvitegravir is given with a pharmacokinetic boosting agents, such as ritonavir or cobicistat.1 For all INSTIs a single resistance mutation is clinically significant. If resistance is suspected or proven, dolutegravir is approved for twice daily dosing.1 This could mean a patient could be prescribed a single tablet regimen (STR) of dolutegravir/abacavir/lamivudine along with another tablet of dolutegravir 12 hours later, leading to confusion for the pharmacy and patient.
Tenofovir disoproxil fumarate (TDF) has been common- place in HIV regimens. A new prodrug form was recently approved: tenofovir alafenamide.3 The new form has a longer plasma half-life, allowing the target cells to gather up the medication over a longer period of time. This allows a smaller milligram dose of the alafenamide to achieve similar efficacy. In clinical studies, the lower exposure appears to prevent two notable adverse effects of the TDF form: decrease in bone-mineral density, and renal toxicities.4,5 The DHHS guidelines have included the new prodrug in recommendations at the same strength (A) but admittedly with less evidence (II).1
While the DHHS guidelines list which regimens a naïve-patient should be offered, many patients encountered in the pharmacy will be on older and sometimes much more complex regimens. Switching a patient’s ARV regimen is a complex process, is not always appropriate, and includes multiple factors: resistance mutations, viral response, immune response, adverse effects, renal and hepatic function, experience with previous regimens, etc.1 A pharmacist should consult with an HIV specialist before offering alternative therapies.
Prevention of new HIV infections is multifaceted and includes syringe-exchange/access programs, treatment-as-prevention strategies, pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). Each of these concepts can benefit from the inclusion of pharmacists.
The Minnesota Pharmacy Syringe/Needle Access Initiative allows pharmacies to voluntarily sell up to 10 syringe/needles to a patient at a time without a prescription.6 Providing unused and clean syringes to a population decreases the sharing of syringes and helps decrease HIV and HCV transmission. In response to the HIV outbreak in Scott County, Indiana, in 2015 that included 190 new cases, a syringe-access program was initiated to help stem the overwhelming growth of new infections due to syringe sharing while connecting people to substance-abuse treatment resources.7 Minnesota pharmacists can help decrease the risk of HIV transmission by providing clean syringes at all outpatient or ambulatory care pharmacies. To learn more, please visit: http://www.health.state.mn.us. When a PLWHA is able to achieve the goal of “undetectable,” it means that their most recent viral load assay showed a level below the limits of detection. Studies have shown that patients with undetectable levels of virus have a very low risk of transmitting HIV to an uninfected partner.1 The CDC released a letter in September 2017 stating this perspective, and many organizations have begun educational campaigns equating “undetectable” to “untransmittable”.8 Pharmacists can help patients achieve the goal of “undetectable” through supportive adherence services and removing access and clinical barriers to the patient therapy.
In 2014 the FDA approved tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) to prevent HIV acquisition in high-risk HIV-negative patients. You might recognize TDF/FTC as a common NRTI backbone for treating HIV infection. The FDA also mandated a REMS program with only “Elements to Ensure Safe Use” component be created for TDF/FTC when used for PrEP.9 Health care provider educational material, screening checklists and training are available online through the FDA’s and manufacturer’s websites. Of note, a prescription for TDF/FTC for PrEP should never contain more than a total of a 90-day supply; this is due to the requirement that the patient have an HIV test performed by their provider at least every 2-3 months.
Post-exposure prophylaxis (PEP) can be broken into two sections: occupational (oPEP) and non-occupational (nPEP). Both scenarios are detailed in DHHS guideline documents.10,11 Of note, oPEP is much more straightforward due to occupational health laws and requirements. Timing is important in both, with 28-30 days of ARV regimens that need to be initiated within 48-72 hours after the time of exposure. Difficulties with nPEP include timing of presentation to care (often on weekends), insurance coverage (unexpectedly high costs with high deductible plans), psychosocial needs of patient (sexual assault victim, “blackout” situations), provider lack of knowledge (unfamiliar with urgency, order requirements) and system barriers (lack of care coordination in the ER). While some health systems and clinics have processes in place, they can be inconsistent. Pharmacists can help support by providing emotionally supportive and expedient care to nPEP patients.
Future Treatment Options
Long-acting injectables are currently being explored for treatment and prevention of HIV. Cabotegravir, a new INSTI, given with rilpivirine in a long-acting injectable form has shown to maintain 87-94% of patients virologically suppressed after an oral lead-in period.12 Both 4- and 8-week intervals of the injectable were studied along with an oral comparator, as well as the acceptability of the different regimens. Cabotegravir has also been studied on its own for PrEP use and will continue into phase III studies.13 Oral lead-ins will need to occur to ensure safe use of long-acting injectable formulations once approved; pharmacists are in a position to ensure optimal outcomes when patients transition dosage forms.
The first single-tablet regimen containing a PI is expected in the near future. Darunavir boosted by cobicistat with emtricitabine and tenofovir alafenamide (TAF) has been part of a switch study where patients were switched to this regimen after suppressed on a boosted PI plus emtricitabine and tenofovir disoproxil fumarate (TDF).14 There was no statistical difference between rates of success for those who switched versus those who did not switch. With the change from TDF to TAF in the regimen backbone, an expected increase in cystatin c-based eGFR occurred in the TAF arm.
A new oral INSTI, bictegravir, is being studied for treatment naïve patients in two head-to-head trials versus dolutegravir. Dolutegravir is paired with an abacavir/lamivudine backbone for the first trial and tenofovir alefenamie/emtricitabine in the second trial.15,16 In both studies, the bictegravir performed similarly to the dolutegravir arms. Safety data were similar except for greater nausea, neuropsychiatric and sleep-related symptoms in the dolutegravir/abacavir/lamivudine arm.
Doravirine, the first new NNRTI in many years, is being studied along with lamivudine/tenofovir disoproxil fumarate in treatment-naïve patients versus efavirenz/emtricitabine/tenofovir disoproxil fumarate.17 The doravirine arm showed similar virologic efficacy at week 48 but had significantly less neuropsychiatric adverse effects.
Regimen simplification typically means switching complex regimens for simpler regimens that preserve efficacy with higher tolerability. Multiple studies are being conducted examining if reducing regimens to either a dolutegravir or boosted-darunavir along with a single NRTI is an acceptable regimen.1 Though the studies show hopeful data, there are still not enough data at this time to recommend this type of switch outside of a clinical trial setting.
HIV treatment continues to evolve with each passing year, to the benefit of PLWHA and their quality of life. Pharmacy practice offers unique opportunities to support prevention and treatment of HIV-infection. Though it might seem intimidating, knowing where to find quality information, such as DHHS guidelines, that can aid in treatment decisions is key to supporting optimal patient outcomes.
1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf Accessed 2017 October 8.
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf Accessed 2017 October 8. Table 6.
3. Descovy Prescribing Information. Gilead Sciences. Available at https://www.descovy.com/ Accessed on 2017 October 8.
4. Arribas JR, et al. Significant Efficacy & Long-Term Safety Difference With Taf-Based Str In Naïve Adults. Croi 2017. Abstract 453.
5. Orkin C, DeJesus E, Ramgopal M, et al. Switching from rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) to rilpivirine/emtricitabine/tenofovir alafenamide (RPV/FTC/TAF): Safety and efficacy through 48 weeks. Program and abstracts of the 2016 International Congress of Drug Therapy in HIV Infection; October 23-26, 2016; Glasgow, United Kingdom. Abstract O124.
6. Minnesota Pharmacy Syringe/Needle Access Initiative. Minnesota Department of Health. Available at http://www.health.state.mn.us/divs/idepc/diseases/hiv/syringe/mnpharmacy.html Accessed on 2017 October 8.
7. Rudavsky S. An Indiana town recovering from 190 HIV cases. Indianapolis Star. Available at http://www.indystar.com/story/news/2016/04/08/year-after-hiv-outbreak-austin-still-community-recovery/82133598/ Accessed on 2017 October 8.
8. McCray E, Mermin J. Dear Colleague Letter. Centers for Disease Control and Prevention. Available at https://www.cdc.gov/hiv/library/dcl/dcl/092717.html Accessed on 2017 October 8.
9. Truvada for a Pre-Exposure Prophylaxis (PrEP) Indication. Gilead Sciences. Available at: https://www.truvadapreprems.com/ Accessed on 2017 October 8.
10. Kuhar DT, et al. Updated U.S. Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013 Nov;34(11):1238.
11. Dominguez KL, et al. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV—United States, 2016. Centers for Disease Control and Prevention. Available at https://stacks.cdc.gov/view/cdc/38856 Accessed on 2017 October 8.
12. Eron J, et al. Safety and efficacy of long-acting CAB and RPV as two drug IM maintenance therapy: LATTE-2 week 96 results. IAS 2017. Abstract MOAX0205LB.
13. Landovitz R, et al. Safety, tolerability and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected women and men: HPTN 077. IAS 2017. Abstract TUAC0106LB. ClinicalTrials.gov. NCT02178800.
14. Molina JM, et al. Efficacy and safety of switching from boosted-protease inhibitor plus emtricitabine/tenofovir disoproxil fumarate regimens to the single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in virologically-suppressed, HIV-1-infected adults through 24 weeks: EMERALD study. IAS 2017. Abstract. TUAB0101
15. Gallant J, et al. A phase 3 randomized controlled clinical trial of bictegravir in a fixed dose combination, B/F/TAF, vs ABC/DTG/3TC in treatment-naïve adults at week 48. IAS 2017. Abstract MOAB0105LB.
16. Sax PE, et al. Phase 3 randomized, controlled clinical trial of bictegravir coformulated with FTC/TAF in a fixed-dose combination (B/F/TAF) vs dolutegravir (DTG) + F/TAF in treatment-naïve HIV-1 positive adults: week 48 results. IAS 2017. Abstract TUPDB0201LB.
17. Squires KE, et al. Fixed dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naïve adults with HIV-1 infection: week 48 results of the Phase 3 DRIVE-AHEAD study. IAS 2017. Abstract TUAB0104LB.