AMY C. MIN, PHARMD, BCACP, AAHIVP

In 2016, the US Centers for Disease Control and Prevention estimated that 45% of all people living with HIV in the United States are over age 50.

 This patient population continues to age due to advances in HIV antiretroviral therapy (ART); with tolerable, highly effective pharmacotherapy options, there is a shift in focus to minimize long-term toxicities of lifelong ART. 

This new 2-drug regimen (2DR) comprises dolutegravir and lamivudine (DTG/3TC, [Dovato]) coformulated into 1 daily tablet. It received US Food and Drug Administration (FDA) approval on April 9, 2019, for treatment of HIV in adults with no prior ART history and no known resistance to the individual components. It is the second FDA-approved 2DR (it follows dolutegravir/rilpivirine [Juluca]) but the first approved for use in HIV treatment-naïve patients with no known mutations to the individual components. This medication, though not yet included in HIV treatment guidelines, changes what we know about combination ART and the historically recommended use of at least 3 drugs from at least 2 classes. 

DTG/3TC received its approval after the completion of 2 identical phase 3 studies: GEMINI 1 and GEMINI 2.

 Both studies are multicenter, double-blind, randomized, noninferiority, phase 3 trials that enrolled a total of 1441 patients from 192 centers across 21 countries. Participants were treatment-naïve individuals living with HIV who were 18 years or older with an HIV viral load less than 500,000 copies/mL. Patients were excluded if they had preexisting drug resistance mutations to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, or protease inhibitors. Women of childbearing potential were included if they were not pregnant or lactating and were using approved contraception. Patients were randomly assigned (1:1) to receive a 2-drug regimen of dolutegravir plus lamivudine (as 2 tablets) or a 3-drug regimen (3DR) of dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (as 2 tablets). Both the participants and the investigators were blinded to treatment assignment, made possible by overencapsulating the lamivudine and emtricitabine/tenofovir disoproxil fumarate. The primary objective of the GEMINI studies was to prove noninferior virological efficacy of the 2DR when compared with guideline-recommended 3-drug ART. 

The pooled analysis of the intention-to-treat-exposed populations of the GEMINI trials showed that dolutegravir/lamivudine met its primary endpoint, with 91% of patients achieving HIV-1 RNA of less than 50 copies/mL by week 48 compared with 93% of patients in the dolutegravir plus emtricitabine/ tenofovir disoproxil fumarate group. Of the 10 (<1%) participants (6 in the 2DR group, 4 in the 3DR group) who met criteria for virological withdrawal, defined as a decrease of HIV-1 RNA of less than 1 log10 copies/mL decrease from baseline or HIV-1 RNA greater than 200 copies/mL after week 24 or confirmed rebound of HIV-1 RNA greater than 20 copies/ mL, no patients developed any treatment-emergent resistance as confirmed by genotypic testing. 

Pooled analysis of the GEMINI 1 and 2 trials shows low incidence of reported drug-related adverse events (AEs), with 126 (18%) in the 2DR group and 169 (24%) in the 3DR group. Commonly reported AEs were similar between the 2 groups, with headache, diarrhea, and nasopharyngitis being the 3 most common. Changes in renal and bone turnover biomarkers, which can be attributed to tenofovir disoproxil fumarate, were, not surprisingly, more favorable in the 2DR group compared with the 3DR group. Suicidal ideation and behavior was reported in 2% in both groups—17 participants in the 2DR group and 12 in the 3DR group. Of these patients who reported these toxicities, 13 (76%) and 7 (58%), respectively, had a positive history of depression or suicidal behavior at baseline. 

Per the labeling of DTG/3TC, other precautions include patients coinfected with HIV and hepatitis B virus (HBV), hypersensitivity reactions, hepatotoxicity, lactic acidosis and severe hepatomegaly with steatosis, and immune reconstitution syndrome.

 When managing patients who are coinfected with HIV and HBV, an additional agent such as entecavir or tenofovir should be added on for treatment of HBV if using DTG/3TC for HIV treatment. HBV resistance to lamivudine monotherapy reaches 90% at 4 years and is no longer a preferred antiviral therapy for HBV treatment.

 Other more serious AEs, like lactic acidosis and severe hepatomegaly with steatosis, is a precaution that is historically associated with nucleoside analogues but not commonly seen with currently used NRTIs like lamivudine. 

Risk of drug—drug interactions with DTG/3TC is minimal compared with other antiretrovirals (ARVs) such as boosted-protease inhibitor-based therapies. Common drug interactions seen with the dolutegravir component of DTG/3TC include metformin (increased metformin levels) and polyvalent cations (decreased dolutegravir levels). More serious and less commonly seen drug interactions can occur with dofetilide (increased dofetilide levels) and rifampin (decreased dolutegravir levels; less commonly seen in the United States). 

Studies prior to the GEMINI 1 and 2 trials evaluated dolutegravir/lamivudine as a switch strategy for treatment-experienced patients who have been virally suppressed. DTG/3TC, however, was not studied in this patient population and is indicated only for treatment-naïve patients. De-escalation or switch studies have all been successful; however, patient sample sizes were small, and not all studies were prospective, randomized controlled trials.

 Future larger studies to confirm the results are warranted before using DTG/3TC as a simplification or switch strategy. 

Currently, the US Department of Health and Human Services HIV guidelines list DTG/3TC as an option for “initial therapy when abacavir, tenofovir alafenamide, and tenofovir disoproxil fumarate cannot be used or are not optimal.”

 This recommendation has not been updated since DTG/3TC was approved by the FDA. That approval gave a 2DR option for the initial treatment of patients newly infected with HIV without a history of ART or drug-resistant mutations affecting dolutegravir or lamivudine. With less HIV ARV drug exposure, there is the benefit of fewer long-term toxicities. Additionally, if half the potentially eligible treatment-naïve patient in the United States were initiated on DTG/3TC, the associated ART cost savings would amount to more than $500 million over 5 years.

HIV treatment has made significant progress, from past regimens consisting of upward of 10 tablets in the mornings and evenings to the current availability of single-tablet regimens. This lowers the ART pill burden to 1 tablet daily, with even some HIV treatment regimens containing just 2 active agents. This shift toward 2DR for initiation and maintenance of HIV changes how we may approach HIV treatment moving forward. DTG/3TC is an effective regimen for patients with new HIV diagnoses who have no treatment or resistance history. Some advantages and disadvantages comparing it with current recommended initial regimens for most people with HIV can be found in the 

. When 2 drugs can do the same job as 3, why are we still using 3?

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 and completed a PGY-1 pharmacy practice residency at Penn Presbyterian Medical Center in Philadelphia 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.

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Articles

For the first time, patients with new HIV diagnoses have a 2-drug regimen option. 

DTG/3TC Offers Dual-Drug Therapy for Initial HIV Treatment

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 avail&shy;able, 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.

 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.  

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 regi&shy;mens for HIV. Additional recent updates to HIV treat&shy;ment can be reviewed in the guidelines in the section, “what to start.”

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.

 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 dolute&shy;gravir 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).

 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 dolute&shy;gravir during the first 28 days after conception, prior to the time the neural tube closes in the embryo.

 Based on these new preliminary data, the DHHS recommend dolute&shy;gravir-based regimens be initiated only in patients who do not desire pregnancy and are on effective contracep&shy;tion.

 Additional specific recommendations can be found in the DHHS HIV treatment and perinatal guidelines.

 Final  results from the NIH-funded study in Botswana should be avail&shy;able after February 2019, once surveillance concludes.

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/teno&shy;fovir 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/teno&shy;fovir alafenamide or tenofovir disoproxil fumarate (see 

). 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, respec&shy;tively. Both studies showed that at week 48, over 89% of treat&shy;ment-naïve patients living with HIV in the bictegravir arms were able to achieve viral suppression.

 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 treat&shy;ment failure or resistance to BIC/FTC/TAF.

 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 treat&shy;ment and prevention of HIV infection in adults.

 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 

 Similar to the DHHS HIV guidelines, the IAS—USA HIV guidelines also address the prelim&shy;inary report results that recommend caution when using dolute&shy;gravir 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 regi&shy;mens for the treatment of HIV: bictegravir/emtricitabine/tenofovir alafenamide, dolutegravir/abacavir/lamivudine, and dolutegravir plus emtricitabine/tenofovir alafenamide.

 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/teno&shy;fovir alafenamide or tenofovir disoproxil fumarate, and ralte&shy;gravir plus emtricitabine/tenofovir alafenamide or tenofovir disoproxil fumarate, are not included in the initial regimen recommendations (see 

In its 2018 guidelines, the IAS—USA updated recommenda&shy;tions 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.

 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 recom&shy;mended only if counts are above 500 cells/μL.  

Another difference between the updated DHHS and IAS—USA guidelines is that the IAS–USA guide&shy;lines continue to recommend against MAC prophy&shy;laxis in patients with viral suppression on antiretroviral therapy because of the low incidence and burden of disease in the United States.

 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 clarithro&shy;mycin 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 incorpo&shy;rating 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.

 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.

 These guidelines can also be found on the DHHS guideline website.

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.

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Revised DHHS and IAS–USA guidelines provide new insight for physicians managing patients with HIV.  

Guideline Updates for the Treatment of Adolescents and Adults With HIV

The burden of pediatric HIV infection in the United States has decreased in the recent years. The number of patients 19 years and younger at their HIV diagnosis declined from 4250 in 2011 to 3813 in 2016.

 And among children who received the diagnosis when they were younger than 13 years, the number of perinatal infections fell to below 100 in the United States in 2016.

 This drop may be attributed to efforts focused on the prevention of HIV transmission from mother to child. Examples of such efforts include universal prenatal HIV screening, combination antiretroviral therapies (ARTs) to maximally suppress the maternal viral load, elective cesarean delivery, provision of neonatal antiretroviral (ARV) prophylaxis, and neonatal replacement feeding.

In the current era of ART, treatment options are more potent but have fewer toxicities and better adverse effect profiles. Lower pill burdens and dosing frequencies and more combination drug formulations, including single-tablet regimen (STR) options, provide multiple options to complement patients’ preferences and lifestyles. Specifically, for pediatric patients who have difficulty swallowing pills, the availability of chewable formulations, such as chewable raltegravir (Isentress), provides patients a better chance of improved adherence to achieve viral suppression and preservation of immune function.

Selecting an ARV regimen for pediatric patients living with HIV follows the same principles as treating adolescents and adults living with HIV. An ARV regimen for a treatment-naïve patient typically includes 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus another ARV agent, which can be either an integrase strand transfer inhibitor, a boosted protease inhibitor, or a non-nucleoside reverse transcriptase inhibitor.

 Other considerations include the presence of comorbidities, such as hepatitis B or C virus infection; resistance testing results; and potential for drug—drug interactions.

 Special considerations for pediatric patients include the child’s age and weight when determining appropriate dosing requirements; the palatability of the drug formulations, most commonly an issue with liquid ARVs; and the potential for long-term toxicities.

When selecting a regimen for pediatric patients living with HIV, “Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection,” which are updated regularly, should be consulted for the most up-to-date evidence-based recommendations.

 In May 2018, the guidelines were updated to increase the strength of the recommendations from moderate to strong to reflect new data that all children should receive ART, regardless of symptoms or CD4 count.

Baseline plasma viral load, CD4 count, resistance testing, complete blood count with differential, chemistries, lipid panel, urinalysis, and hepatitis B screening should be completed prior to ART initiation.

 Raltegravir plus 2 NRTIs is recommended for HIV treatment in infants at birth up until age 6 years. Other recommended regimens for children aged at least 3 to 6 years included atazanavir (Reyataz)/ritonavir (Norvir) plus 2 NRTIs or darunavir (Prezista)/ritonavir twice daily plus 2 NRTIs. In addition to raltegravir plus 2 NRTIs, for children older than 14 days up until 3 years, the guidelines recommend lopinavir/ritonavir and 2 NRTIs. For infants after birth to <14 days, the guidelines recommend raltegravir in combination with 2 NRTIs or nevirapine (Viramune) plus 2 NRTIs. For children 6 years to 12 years, the guidelines recommend a regimen of 2 NRTIs plus atazanavir/ritonavir or dolutegravir (Tivicay). For adolescents older than 12 years, if they have a sexual maturity rating (SMR) of 4 or 5, they can be treated according to the adult and adolescent guidelines. In adolescents older than 12 years with an SMR of 1 to 3, 2 NRTIs plus atazanavir/ritonavir, dolutegravir, darunavir/ritonavir, or elvitegravir/cobicistat (Tybost) can be used (

Preferred dual-NRTI regimens differ between age groups. For children from birth to <3 months, zidovudine (Retrovir) plus lamivudine (Epivir) or emtricitabine (Emtriva) is recommended. Abacavir (Ziagen) or zidovudine plus lamivudine or emtricitabine is recommended for children 3 to <6 years. For children >6 years with an SMR of 1 to 3, abacavir plus lamivudine or emtricitabine or emtricitabine/tenofovir alafenamide (Descovy) is recommended. Finally, for adolescents >12 years with an SMR of 4 or 5, the guidelines recommend referring to the adult and adolescent guidelines.

The guidelines recommend once-daily regimens and STRs whenever feasible, especially in the current era of simplified regimen options.

 outlines the pediatric age and weight requirements for using all US Food and Drug Administration—approved STRs. For pediatric patients who struggle with adherence due to pill swallowing difficulties, alternative formulations should be considered. Many recommended ARVs are also available as liquids: abacavir, lamivudine, emtricitabine, zidovudine, nevirapine, lopinavir/ritonavir, darunavir, and ritonavir. A limitation to liquid formulations, however, is their palatability. Volume is also a concern for pediatric patients in higher weight groups who require higher doses, which results in larger volumes. Other formulations are available as highlighted in the guidelines.

The guidelines have updated the ritonavir section to include information about a new pediatric oral powder formulation that can be administered in 100-mg increments. This formulation can only be used for doses of 100 mg or greater, which is recommended in children weighing at least 30 kg when used with darunavir or in children weighing at least 15 kg when used with atazanavir capsules. The guidelines prefer the oral powder formulation of ritonavir over the oral solution for children who have difficulty swallowing because the powder does not contain propylene glycol or ethanol, which can cause a range of central nervous system, respiratory, cardiac, renal, and gastrointestinal toxicities in children.

Other alternative formulations include efavirenz (Sustiva) capsules, which can be opened and sprinkled onto 1 to 2 teaspoons of age-appropriate soft foods for children who are unable to swallow capsules or tablets. Atazanavir and tenofovir disoproxil fumarate are also available in an oral powder formulation that can be mixed with 1 tablespoon of food. Raltegravir is also formulated as granules for oral suspension, which is recommended to be mixed with 10 mL of water. What may be most useful in transitioning from alternative formulations to swallowing tablets are chewable raltegravir tablets. These can be used in children weighing at least 11 kg. For all formulations of ARVs, refer to Appendix A in the guidelines.

 The guidelines also recommend pill-swallowing training, as it has been shown to improve adherence at 6 months post training.

In the current era of HIV ART, there are more formulations available for pediatric patients living with HIV. With new drug developments, therapies are easier to take with fewer toxicities. One formulation that was not discussed in the current update to the guidelines is efavirenz/ lamivudine/tenofovir disoproxil fumarate (Symfi Lo), which contains a lower dose of efavirenz (400 mg). This formulation may be useful in patients who are CYP2B6 slow metabolizers but recommendations for use will be included with the next guideline update. With time, as STR formulations are being studied in pediatric patients, more options will become available that will help facilitate better adherence in pediatric patients living with HIV. Finally, when treating these patients, the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, which are updated regularly, should be consulted.   

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. 

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Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.

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Medication advancements offer more options and formulations for treating pediatric patients living with HIV.

AMY C. MIN, PHARMD, BCACP, AAHIVP

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