Guideline Updates for the Treatment of Adolescents and Adults With HIV
AMY C. MIN, PHARMD, BCACP, AAHIVP
Revised DHHS and IAS–USA guidelines provide new insight for physicians managing patients with HIV.
The availability of more treatment options for HIV has made management of infections easier than ever before. With over 45 individual and fixed-dose combination antiretroviral agents approved by the US Food and Drug Administration, providers are able to select the antiretroviral regimens best suited for the patient, and selection of antiretroviral therapy should be based on updated guideline recommendations. Several guidelines on the treatment and management of HIV infection are avail­able, including but not limited to those by the US Department of Health and Human Services (DHHS), the International Antiviral Society—USA Panel (IAS–USA), the European AIDS Clinical Society (EACS), the British HIV Association (BHIVA), and the World Health Organization.1-6 These guidelines are routinely updated to reflect the current literature available. Recent updates to the DHHS and IAS—USA guidelines, as well as similarities and differences between the 2 sets, will be discussed in this article.
HIGHLIGHTS OF THE DHHS GUIDELINES
The DHHS guidelines for the use of antiretroviral agents in adults and adolescents living with HIV were updated in May 2018. Many providers refer to these guidelines because of the extensiveness of their coverage of both treatment and management recommendations for people living with HIV. The update included new data on dolutegravir and added bictegravir to the list of recommended initial regi­mens for HIV. Additional recent updates to HIV treat­ment can be reviewed in the guidelines in the section, “what to start.”1
Recent preliminary study results from a National Institutes of Health (NIH)—funded observational surveillance study in Botswana revealed possible risks associated with taking dolutegravir prior to pregnancy and through conception.7 The study identified 4 infants with neural tube defects out of 426 infants born to women living with HIV who had initiated dolutegravir prior to pregnancy and continued it through time of conception. The rate of neural tube defects in infants born to mothers living with HIV taking dolute­gravir from the time of conception was 0.94% (95% CI, 0.37 to 2.4) which was higher than the rates in those who started dolutegravir during pregnancy, 0.0% (95% CI, 0.0 to 0.13), and those who were on non-dolutegravir based antiretroviral therapy, 0.12% (95% CI, 0.07 to 2.1).7 Based on this potential safety signal, the DHHS issued a statement regarding dolutegravir use in women of childbearing potential. A documented negative pregnancy test is recommended before providers initiate dolutegravir. If patients are pregnant and within 8 weeks from their last menstrual period, the risks and benefits of staying on a dolutegravir-based antiretroviral therapy regimen versus switching to a non—dolutegravir-based antiretroviral therapy regimen should be discussed. The risk of an embryo developing neural tube defects is highest while patients are on dolute­gravir during the first 28 days after conception, prior to the time the neural tube closes in the embryo.8 Based on these new preliminary data, the DHHS recommend dolute­gravir-based regimens be initiated only in patients who do not desire pregnancy and are on effective contracep­tion.9 Additional specific recommendations can be found in the DHHS HIV treatment and perinatal guidelines.1,10 Final results from the NIH-funded study in Botswana should be avail­able after February 2019, once surveillance concludes.11
Another major update the DHHS made in March 2018 was the addition of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as one of the recommended initial regimens for most people living with HIV. This addition expands the list of recommended initial regimens for most people living with HIV to 5, counting regimens with an emtricitabine/teno­fovir alafenamide or tenofovir disoproxil fumarate backbone as 1.
Recommended initial regimens also include dolutegravir/ abacavir/lamivudine, dolutegravir plus emtricitabine/tenofovir alafenamide or tenofovir disoproxil fumarate, elvitegravir/ cobicistat/emtricitabine/tenofovir alafenamide or tenofovir disoproxil fumarate, and raltegravir plus emtricitabine/teno­fovir alafenamide or tenofovir disoproxil fumarate (see Table). The recommendation to add BIC/FTC/TAF to the list was based on the results of the GS-US-380-1490 and GS-US- 380-1489 trials, which compared BIC/FTC/TAF to dolutegravir plus coformulated emtricitabine and tenofovir alafenamide to coformulated dolutegravir, abacavir, and lamivudine, respec­tively. Both studies showed that at week 48, over 89% of treat­ment-naïve patients living with HIV in the bictegravir arms were able to achieve viral suppression.12,13 Incidence of adverse effects was also lower in the bictegravir groups than in the comparator arm and no individual in either study developed treatment-emergent resistance to any of the study drugs. Study results also support switching patients who have been virally suppressed for over 3 months with no prior history of treat­ment failure or resistance to BIC/FTC/TAF.14 With these study results, BIC/FTC/TAF is now recommended by the DHHS as one of the 5 recommended initial regimens for the treatment of most patients living with HIV.
More recently, in July 2018, the IAS—USA Panel released up-dates to the 2016 recommendations for antiretroviral drugs for treat­ment and prevention of HIV infection in adults.2 These guidelines provide another perspective on management of patients with HIV in the United States. They cover similar content to that of the DHHS HIV guidelines but are more concise. Major updates include the recommendation of unboosted integrase strand transfer inhibitor (INSTI)—based regimens, decreased frequency of routine CD4 cell count as appropriate, alternative HIV pre-exposure prophylaxis (PrEP) regimen to include on-demand dosing, and continued recommendation against Mycobacterium avium complex (MAC) prophylaxis.2 Similar to the DHHS HIV guidelines, the IAS—USA HIV guidelines also address the prelim­inary report results that recommend caution when using dolute­gravir in early pregnancy and recommend a documented negative pregnancy test prior to initiating a dolutegravir-based regimen.
HIGHLIGHTS OF THE IAS-USA HIV GUIDELINES
The IAS—USA HIV guidelines recommend only 3 initial regi­mens for the treatment of HIV: bictegravir/emtricitabine/tenofovir alafenamide, dolutegravir/abacavir/lamivudine, and dolutegravir plus emtricitabine/tenofovir alafenamide.2 These 3 unboosted INSTI regimens are recommended because they do not require pharmacokinetic boosters, have high genetic barriers to resistance, and have a low pill burden and toxicity. For these reasons, elvitegravir/cobicistat/emtricitabine/teno­fovir alafenamide or tenofovir disoproxil fumarate, and ralte­gravir plus emtricitabine/tenofovir alafenamide or tenofovir disoproxil fumarate, are not included in the initial regimen recommendations (see Table).
In its 2018 guidelines, the IAS—USA updated recommenda­tions on CD4 cell count monitoring. CD4 cell count monitoring is recommended every 6 months until the patient reaches over 250 cells/μL maintained for at least a year; monitoring can then be discontinued as long as the patient is able to maintain viral suppression. This recommendation is based on studies whose results showed little added value of CD4 cell count monitoring when the viral load is suppressed.15-17 The DHHS HIV guidelines differ, as they recommend CD4 count monitoring every 3 to 6 months for the first 2 years of antiretroviral therapy if patients are viremic or their CD4 count is less than 300 cells/ μL. The DHHS guidelines recommend that after 2 years on effective antiretroviral therapy with continued viral suppression, patients decrease CD4 monitoring to every 12 months if their CD4 count is between 300 and 500 cells/μL; optional CD4 count monitoring is recom­mended only if counts are above 500 cells/μL.
Another difference between the updated DHHS and IAS—USA guidelines is that the IAS–USA guide­lines continue to recommend against MAC prophy­laxis in patients with viral suppression on antiretroviral therapy because of the low incidence and burden of disease in the United States.18,19 Patients living with HIV are at an increased susceptibility to MAC disease if their CD4 cell count falls below 50 cells/μL, if they have a high HIV viral load, or if they have had previous opportunistic infections. The DHHS guidelines recommend that once active disease is ruled out, a patient whose CD4 count falls below 50 cells/μL receive azithromycin 1200 mg weekly or clarithro­mycin 500 mg twice daily for MAC prophylaxis.
Both the DHHS and IAS—USA HIV guidelines recommend initiating antiretroviral therapy as soon as possible after diagnosis. The IAS–USA guidelines more strongly recommend rapid initiation to include same-day starts in patients who are committed to starting antiretroviral therapy. HIV PrEP recommendations differ between the guidelines, as well, with the IAS–USA guidelines incorpo­rating newer data and recommending on-demand or event-driven PrEP (“2-1-1”) in men who have sex with men with infrequent sexual encounters as an alternative to daily PrEP for men who have sex with men (MSMs) with infrequent sexual exposures. The EACS and BHIVA guidelines also have similar recommendations for on-demand PrEP as an alternative to daily PrEP for MSMs.3,4 The PrEP guidelines which is a joint effort by the US Public Health Service with the US Centers for Disease Control and Prevention, do not recommend on-demand PrEP due to lack of data of efficacy in heterosexual men and women and persons who inject drugs. Additionally, adherence outside of a trial setting has not been evaluated. Discussion of HIV PrEP is beyond the scope of this article, and the guidelines and literature should be consulted.2,20-22 These guidelines can also be found on the DHHS guideline website.20
As the treatment and management of patients living with HIV continues to evolve and improve, the most updated versions of guidelines should be consulted. Both the DHHS and IAS—USA guidelines are commonly used in the United States and are updated on a regular basis. Although both guidelines provide similar recommendations, there are slight differences in each that provide different perspectives in the management and prevention of HIV.
Dr. Min is a clinical assistant professor with a specialty in HIV pharmacotherapy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She received a PharmD at the University of Maryland School of Pharmacy in Baltimore, Maryland, and completed a PGY-1 pharmacy practice residency at Penn Presbyterian Medical Center and a PGY-2 HIV ambulatory care/clinical pharmacogenetics residency at the University of Houston College of Pharmacy in Texas. She is an active member of the American Academy of HIV Medicine.
- DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Updated May 30, 2018. Accessed September 7, 2018.
- Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society—USA Panel. JAMA. 2018;320(4):379-96. doi: 10.1001/jama.2018.8431.
- European AIDS Clinical Society EACS Guidelines version 9.0, Updated October 2017. http://www.eacsociety.org/files/guidelines_9.0-english.pdf. Accessed September 27th, 2018.
- British HIV Association. BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015 (2016 interim update).https://www.bhiva.org/file/RVYKzFwyxpgiI/treatment-guidelines-2016-interim-update.pdf. Accessed September 7, 2018.
- World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach - second edition. who.int/hiv/pub/arv/arv-2016/en. Published June 2016. Accessed September 7, 2018.
- World Health Organization. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance. Geneva: Updated July 2018. http://apps.who.int/iris/bitstream/handle/10665/273632/WHO-CDS-HIV-18.18-eng.pdf?ua=1. Accessed September 27th, 2018.
- Zash R, Makhema J, Shapiro RL. Neural-tube defects with dolutegravir treatment from the time of conception. N Engl J Med. 2018;379(10):979-81.
- Lobo I. Birth defects: prevention and treatment. Nat Educ. 2008;1(1):19.
- Zash R, Holmes L, Makhema J, et al. Surveillance for Neural Tube Defects following Antiretroviral Exposure from Conception. AIDS 2018. https://programme.aids2018.org/PAGMaterial/PPT/6339_8312/DTG%20NTD_AIDS2018_FINAL.pptx. Accessed September 27th, 2018.
- Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed September 27th, 2018.
- Statement on DTG - Geneva 18 May 2018. World Health Organization website. who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdf. Accessed September 7, 2018.
- Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063-2072. doi: 10.1016/S0140-6736(17)32299-7.
- Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380—1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073-2082. doi: 10.1016/S0140-6736(17)32340-1.
- Daar ES, DeJesus E, Ruane P, et al. Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2018;5(7):e347-e356. doi: 10.1016/S2352-3018(18)30091-2.
- Duro R, Rocha-Pereira N, Figueiredo C, et al. Routine CD4 monitoring in HIV patients with viral suppression: is it really necessary? A Portuguese cohort [published online June 22, 2017]. J Microbiol Immunol Infect. doi: 10.1016/j.jmii.2016.09.003.
- Gale HB, Gitterman SR, Hoffman HJ, et al. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts >=300 cells/μL and HIV-1 suppression? Clin Infect Dis. 2013;56(9):1340-1343. doi: 10.1093/cid/cit004.
- Girard PM, Nelson M, Mohammed P, Hill A, van Delft Y, Moecklinghoff C. Can we stop CD4 testing in patients with HIV-1 RNA suppression on antiretroviral treatment? Analysis of the ARTEMIS trial. AIDS. 2013;27(17):2759-2763. doi: 10.1097/01.aids.0000432458.98851.c1.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents:recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed September 27th, 2018.
- Yangco BG, Buchacz K, Baker R, Palella FJ, Armon C, Brooks JT; HIV Outpatient Study Investigators. Is primary Mycobacterium avium complex prophylaxis necessary in patients with CD4 <50 cells/μL who are virologically suppressed on cART? AIDS Patient Care STDS. 2014;28(6):280-283. doi: 10.1089/apc.2013.0270.
- US Centers for Disease Control and Prevention: US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States—2017 update: a clinical practice guideline. cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf. Published March 2018. Accessed September 7, 2018.
- Molina JM, Capitant C, Spire B, et al; ANRS IPERGAY Study Group. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373(23):2237-2246. doi: 10.1056/NEJMoa1506273.
- McCormack S, Dunn DT, Desai M, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet. 2016;387(10013):53-60. doi: 10.1016/S0140-6736(15)00056-2.