Selecting an Initial ART Regimen

Purpose of This Guideline

Date of current publication: August 11, 2022 Lead author: Antonio E. Urbina, MD Contributors: Nicole Bradley, PharmD, BCPS, BCIDP; Yuman Lee, PharmD, BCIDP, AAHIVP; John M. Conry, PharmD, AAHIVP, FNAP Writing group: Steven M. Fine, MD, PhD; Rona Vail, MD; Joseph P. McGowan, MD, FACP, FIDSA; Samuel T. Merrick, MD; Asa Radix, MD, MPH, PhD; Charles J. Gonzalez, MD; Christopher J. Hoffmann, MD, MPH Committee: Medical Care Criteria Committee Date of original publication: April 27, 2017

This guideline was developed by the New York State Department of Health AIDS Institute (NYSDOH AI) for primary care providers and other practitioners who are initiating therapy in nonpregnant, antiretroviral therapy (ART)-naive adults with HIV. The guideline aims to achieve the following goals:

• Provide a clear and concise roadmap for clinicians to follow in choosing from among several equally efficacious ART regimens based on individual patient characteristics and preferences.
• Provide a list of ART regimens to avoid.
• Provide dosing considerations for individuals with renal or hepatic impairment and important drug-drug and food interactions.
• Encourage clinicians to seek the assistance of an experienced HIV care provider when treating patients with extensive comorbidities.
• Integrate current evidence-based clinical recommendations into the healthcare-related implementation strategies of the New York State Ending the Epidemic initiative.

The NYSDOH AI is publishing this guideline at a critical time: 1) prompt initiation of ART is now recommended for all individuals diagnosed with HIV; 2) identifying and linking individuals with HIV to care and treatment that achieves optimal virologic suppression are crucial to the success of the New York State Ending the Epidemic initiative; and 3) the ability of primary care providers and other clinicians in New York State to properly select initial ART is key to the successful treatment of individuals with HIV.

Introduction: The NYSDOH AI Medical Care Criteria Committee recommendations for prescribing ART regimens for treatment-naive, nonpregnant adults (age ≥18 years) with HIV-1 and without acquired resistance are based on a comprehensive review of available clinical trial data. (For guidelines specific to treatment of adolescents with HIV, please consult the DHHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV). In formulating its recommendations for New York State, this committee balanced the strength of published evidence regarding efficacy of treatment regimens with factors that influence adherence, including pill burden, tolerability, and dosing schedule. Preferred regimens are supported by evidence and have favorable adherence profiles, with lower pill burdens, fewer adverse effects, and dosing schedules that may be easier for individuals to manage. Ranking of regimens in this manner is designed to inform discussion and decision-making with patients.

How to use this guideline: Tables presenting preferred and alternative regimens appear first (see guideline section Available ART Regimens). To help guide the choice among regimens of similar efficacy, each table includes comments that address selected pertinent issues regarding each regimen, such as limitations based on a patient’s kidney function and drug-drug interactions.

Other sections of the guideline include a review of relevant issues, patient considerations, essential laboratory assessments, and the rationale for the recommendations. Reference to the expanded information is crucial for addressing factors that may be of particular importance when individualizing a patient’s treatment, such as loss of bone mineral density with a regimen that includes tenofovir disoproxil fumarate and the conflicting data on cardiac risk with abacavir (see guideline section Specific Factors to Consider and Discuss With Patients). In addition, a review of psychosocial factors and individual patient preferences may help in the selection of an initial ART regimen. Importantly, a patient-centered approach that incorporates both clinical and nonclinical issues should be prioritized.

Scope: This guideline addresses initial treatment of HIV-1 infection with ART in nonpregnant adults.

• For information regarding ART in individuals who are or who may become pregnant, see DHHS Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States.
• For recommendations regarding the treatment of HIV-2 infection, see the NYSDOH AI guideline Diagnosis and Management of HIV-2 in Adults.
• For recommendations regarding second-line ART regiments, see the NYSDOH AI guideline Second-Line ART After Treatment Failure or for Regimen Simplification.

Note on “experienced” and “expert” HIV care providers: Throughout this guideline, when reference is made to “experienced HIV care provider” or “expert HIV care provider,” those terms are referring to the following 2017 NYSDOH AI definitions:

• Experienced HIV care provider: Practitioners who have been accorded HIV Experienced Provider status by the American Academy of HIV Medicine or have met the HIV Medicine Association’s definition of an experienced provider are eligible for designation as an HIV Experienced Provider in New York State. Nurse practitioners and licensed midwives who provide clinical care to individuals with HIV in collaboration with a physician may be considered HIV Experienced Providers as long as all other practice agreements are met (8 NYCRR 79-5:1; 10 NYCRR 85.36; 8 NYCRR 139-6900). Physician assistants who provide clinical care to individuals with HIV under the supervision of an HIV Specialist physician may also be considered HIV Experienced Providers (10 NYCRR 94.2)
• Expert HIV care provider: A provider with extensive experience in the management of complex patients with HIV.

Available ART Regimens

Table

3TC: lamivudine ABC: abacavir

Note: The recommendations in this guideline pertain to initial ART regimens for adults with HIV who are not pregnant.

Table

Regimen Selection When selecting an initial ART regimen for treatment naive-patients, clinicians should: Perform genotypic HIV resistance testing results for protease (A2), reverse transcriptase (A2), and integrase (B2) genotypic resistance if the testing (more...)

Single-Tablet Regimens Versus Multi-Tablet Regimens

The advantages of STRs compared with MTRs include simplicity, convenience, and lower risk of selective nonadherence [Gardner, et al. 2008]. A recent meta-analysis demonstrated that STRs had better adherence rates when compared with MTRs of any frequency (once daily or twice daily) and had higher 48-week viral suppression rates with comparable adverse effects [Clay, et al. 2015].

In another retrospective study, INSTI-based regimens generally had greater rates of suppression and a lower probability of viral rebound after suppression in comparison to NNRTI-based regimens, regardless of whether an STR or MTR was used, but STR INSTI-based therapy was more durable [Mills(b), et al. 2016]. In the same study, STR NNRTI-based therapy led to greater rates of suppression than MTR NNRTI-based therapy [Mills(b), et al. 2016].

Table

Higher rates of renal dysfunction have been reported in individuals taking TDF in conjunction with RTV- and COBI-containing regimens [Pilkington, et al. 2020; Hill, et al. 2018; Cuzin, et al. 2017; Ryom, et al. 2013; Goicoechea, (more...)

Other studies have demonstrated better efficacy and adherence, lower cost to patients, and fewer hospital admissions associated with STRs than with MTRs [Griffith, et al. 2019; Mills(b), et al. 2016; Armstrong, et al. 2015; Maggiolo, et al. 2015; Hanna, et al. 2014; Nachega, et al. 2014; Sweet, et al. 2014; Cohen(a), et al. 2013; Colombo, et al. 2013; Raboud, et al. 2011; Bangalore, et al. 2007].

There are 3 STRs listed below as preferred regimens. It is possible that these regimens may contain 1 or more components that are not appropriate for an individual patient, do not allow for adjustment of individual components for renal function, have significant drug-drug interactions, are poorly tolerated, or may be more expensive than the individual components prescribed separately, particularly if available as generic formulations. With full adherence, any of the preferred or alternative regimens should lead to full suppression. This includes MTRs, which can be used when an STR is not possible or not tolerated. Cost and access may also be determinative factors.

For patients with impaired baseline renal function, separating the drugs into individual components and adjusting each may be appropriate (see guideline section ARV Dose Adjustments for Hepatic or Renal Impairment).

Table 2 includes initial ART regimens preferred by this committee; Table 3 lists alternative initial regimens. Table 4 lists other available ART regimens that this committee considers neither preferred nor alternative. Within each table, regimens are listed alphabetically. For specific details on choosing a regimen, see the discussions in other sections of this guideline and/or the package inserts for the drugs listed below.

Table

Initiate only in patients confirmed to be negative for HLA-B*5701, including when a “rapid-start” or “test-and-treat” initiation of ART occurs before baseline laboratory test results are available. Initiate  (more...)

Table

Initiate only in patients with CrCl ≥30 mL/min [c]. Carefully consider drug-drug interactions with COBI [Eron(a), et al. 2018].

Table

Initiate only in patients with CrCl ≥50 mL/min [c]. Use with caution in patients with depression or a history of suicidality.

Table

Reviewed and updated: Geoffrey A. Weinberg, MD, with the Medical Care Criteria Committee; May 2021 Evidence from multiple studies indicates no difference in rates of total birth defects among infants exposed to antiretroviral (ARV) medications during (more...)

General Principles in Choosing an Initial ART Regimen

Table

3TC: lamivudine ABC: abacavir

Goals of ART: The issue of when to start ART was settled with the publication of the START and TEMPRANO studies early in 2015 [Danel, et al. 2015; Lundgren, et al. 2015]. Treatment is now recommended for all individuals with confirmed HIV regardless of CD4 cell count or viral load.

The goal of ART is complete and durable suppression of plasma viremia while minimizing toxicity and maximizing quality of life. Properly selected ART may never require a change or adjustment once started. Treatment interruptions should be avoided [El-Sadr, et al. 2006].

Since the approval of ZDV on March 19, 1987, there have been 30 individual agents approved for the treatment of HIV and 1 pharmacokinetic enhancer or “booster,” COBI, which is currently used to enhance the pharmacokinetics of EVG, ATV, or DRV. RTV at treatment doses is poorly tolerated and is used only at lower doses for pharmacokinetic boosting of PIs. An additional 18 FDA-approved FDCs are also available. These FDCs include STRs, of which there are 9 currently available that provide a complete and effective treatment regimen for HIV that is combined into 1 pill for use in properly selected individuals. The goal of initial therapy is to start a regimen that suits an individual’s lifestyle and is appropriate given existing baseline medical comorbidities (see Table 5, below).

Active drugs from 2 different classes: Although regimen options for treatment-naive, nonpregnant adults are constantly evolving, the same general principles that were established with the first effective and durable therapies are still true today [Gulick, et al. 2000]. The backbone of therapy has traditionally been 2 NRTIs paired with 1 of the following: an NNRTI, a boosted PI, or a boosted or unboosted INSTI. In a large meta-analysis, INSTIs were superior to other drug classes as a third drug [Lee, et al. 2014], and DTG may have specific advantages because of the lack, to date, of documented resistance developing in ART-naive patients who initiate DTG-containing regimens [Wainberg and Mesplede 2015]. The entry inhibitors and fusion inhibitors are not recommended for initial therapy (see Table 6: Selected Drug-Drug Interactions to Discuss Before Initiating ART in Treatment-Naive Patients), but they may have a role in ART for treatment-experienced patients with extensive drug resistance (see All FDA-Approved HIV Medications, including generic and trade names).

The only 2-drug regimen that this committee recommends for ART initiation is DTG/3TC, although other dual- and even monotherapy regimens have been and continue to be studied [Cahn, et al. 2020; Cahn, et al. 2019; Baril, et al. 2016; Cahn(a), et al. 2017; Maggiolo, et al. 2016; Bedimo, et al. 2014; Cahn, et al. 2014; Raffi, et al. 2014; Taiwo, et al. 2011]. Importantly, use of DTG/3TC is recommended only after the result of HIV resistance and HBV testing are known. Further, this committee recommends against the use of DTG/3TC in patients with major NRTI resistance, including the M184V/I mutation.

If DTG/3TC is started in a patient with HBV infection, a third antiviral agent with activity against HBV should be added. Because the Gemini 1 and 2 studies restricted entry to patients with HIV-1 RNA ≤500,000 copies/mL, this committee recommends against use of DTG/3TC in patients with HIV-1 RNA >500,000 copies/mL.

TAF, a prodrug formulation for tenofovir, was developed as an alternative to TDF and has been approved as part of the following STRs:

• TAF 10 mg/FTC/COBI/EVG
• TAF 25 mg/FTC/RPV
• TAF 25 mg/FTC/BIC [FDA(a) 2018; FDA(b) 2016; FDA(c) 2016]
• TAF 10 mg/FTC/COBI/DRV [FDA(b) 2018] and the FDC TAF 25 mg/FTC [FDA(a) 2016]

Oral administration of TAF results in lower circulating levels of tenofovir in plasma and affects markers of renal toxicity and bone mineral density less adversely than does TDF [Mills(a), et al. 2016; Pozniak, et al. 2016; Sax, et al. 2015]. Bioequivalence studies in healthy volunteers show that the TAF 10 mg dose administered with COBI 150 mg is equivalent to the TAF 25 mg dose without COBI [Zack(a), et al. 2016; Zack(b), et al. 2016].

A switch study showed good maintenance of viral suppression when changing from TDF/FTC to TAF 10 mg/FTC if the third drug was a boosted PI, or to TAF 25 mg/FTC if the third drug was an unboosted NNRTI or INSTI [Gallant, et al. 2016]. Note that TAF 10 mg alone and TAF 10 mg/FTC are not currently FDA-approved.

Until further safety data are available, this committee has not included TAF 25 mg/FTC in combination with COBI or RTV as recommended regimens and recommends caution when using TAF 25 mg/FTC with regimens that contain either COBI or RTV in the setting of CrCl <50 mL/min.

COBI-boosted DRV was approved based on bioavailability studies [FDA(d) 2016; Kakuda, et al. 2014]. DRV/COBI has demonstrated comparable efficacy to RTV-boosted DRV in a single-arm study [Tashima, et al. 2014]. However, because randomized clinical trials that compare COBI- versus RTV-boosted DRV are not yet available, it has a lower strength of evidence rating. COBI-boosted ATV showed noninferiority when compared with RTV-boosted ATV with a TDF/FTC backbone in a randomized, double-blind study [Gallant, et al. 2013].

Table

INSTI-based regimens are generally the best choice for most individuals because of tolerability and durability.

All of the currently recommended preferred regimens have similar virologic efficacy when measured by an “on-treatment” metric, but adherence, the potential for drug interactions, and tolerability under real-life conditions may inform the choice of preferred versus alternative versus other regimens.

The following general conclusions can be drawn based on currently available evidence from a number of pivotal studies:

• When ABC/3TC is used as a backbone with EFV or boosted ATV, time to failure was shorter in the ≥100,000 copies/mL viral load stratum when compared with a backbone of TDF/FTC [Sax, et al. 2011; Post, et al. 2010; Sax, et al. 2009].
• DTG is as efficacious as (i.e., noninferior to) RAL [Raffi, et al. 2013] and superior to both DRV/RTV [Molina, et al. 2014] and coformulated TDF/FTC/EFV [Walmsley, et al. 2015]. DTG was superior at 48 weeks when combined with ABC/3TC as compared to TDF/FTC/EFV [Walmsley, et al. 2013].
• RAL, although dosed twice daily, has a favorable tolerability profile, provides durable virologic control [Lennox, et al. 2014; DeJesus, et al. 2012; Young, et al. 2010], and was superior to both DRV/RTV and ATV/RTV based on the cumulative incidence of virologic failure and tolerability [Lennox, et al. 2014].
• In a study of ART-naive individuals, RAL HD 1200 mg once daily was noninferior to RAL 400 mg tablets dosed twice daily [Cahn(b), et al. 2017].
• TAF/FTC/COBI/EVG as an STR was noninferior to the STR TDF/FTC/COBI/EVG, with fewer adverse effects on kidney function and bone mineral density [Sax, et al. 2015].
• In 2 separate trials of treatment-naive individuals, TAF/FTC/BIC was noninferior to both TAF/FTC and DTG [Sax, et al. 2017] and ABC/3TC/DTG [Gallant, et al. 2017].
• RPV has equivalent efficacy relative to EFV when baseline viral load is <100,000 copies/mL and is better tolerated [van Lunzen, et al. 2016; Behrens, et al. 2014; Cohen, et al. 2014; Cohen(b), et al. 2013; Cohen, et al. 2012]. But RPV should not be initiated in individuals with baseline viral load >100,000 copies/mL or CD4 counts <200 cells/mm³.
• In 2 separate trials of treatment-naive individuals, TDF/3TC/DOR was noninferior to TDF/FTC/EFV, or DRV/RTV with either TDF/FTC or ABC/3TC [Orkin, et al. 2019; Molina, et al. 2018].
• DRV/RTV once daily is better tolerated and noninferior to either ATV/RTV or LPV/RTV [Lennox, et al. 2014; Orkin, et al. 2013], although LPV/RTV shows excellent efficacy when combined with either commonly used NRTI backbone [Smith, et al. 2009] and when compared with ATV/RTV [Molina, et al. 2008]. One open-label study using ABC/3TC as the backbone combined with DRV/RTV showed good safety and efficacy [Trottier, et al. 2012].

Table

Stavudine (d4T; Zerit) Didanosine (ddI; Videx)

General Considerations With Initial ART Regimens

Table

3TC: lamivudine ABC: abacavir

The recommended ART regimens should work well for the majority of patients, but some circumstances may make 1 regimen more favorable than another for a given individual. In general, an INSTI-based regimen will be the best option for most patients [Mills(b), et al. 2016; Lee, et al. 2014]. To date, no resistance has been reported in ART-naive patients treated with DTG as part of a registrational trial of combination therapy, suggesting that this medication may be an excellent choice, particularly given its tolerability and lack of drug-drug interactions [Cevik, et al. 2020; Wainberg and Mesplede 2015]. Regimens containing a boosted PI or DTG may be more appropriate when adherence is a concern, given the higher barrier to resistance. For patients with acute symptomatic infection or advanced HIV with an opportunistic infection, some experts would use both DTG and boosted DRV together with the NRTI backbone given the possibility of transmitted NRTI resistance until genotypic information is available, at which time the regimen can be adjusted. Consultation with an experienced HIV care provider is recommended when choosing a regimen for patients with extensive comorbidities, impaired renal function, HBV or HCV coinfection, or very high viral loads.

Early clinical trials in HIV used surrogate markers, such as viral load and CD4 cell count, or clinical endpoints, such as morbidity and mortality, to demonstrate superiority of new therapies over the “gold standard” treatment of the era. One of the trials that led to the 1996 approval of IDV compared IDV alone versus ZDV/3TC versus ZDV/3TC/IDV in ZDV- treatment-experienced patients, given that, at the time, dual NRTI treatment was considered acceptable [Gulick, et al. 1997].

As treatment has evolved and become more effective, the use of clinical end points has become challenging; most trials in the current era of HIV therapy are powered to detect noninferiority when compared with standard of care. For a variety of reasons, including cost and complexity, it would be impractical to conduct head-to-head comparisons of all available regimens. Some STRs and FDCs have been approved primarily based on bioequivalence studies when compared with the individual components, such as TDF/FTC/EFV, ABC/3TC/DTG, TAF/FTC/RPV, TAF/FTC, and DRV/COBI.

Some of the cutoff values used for comparisons, such as viral load <100,000 copies/mL or CD4 count ≥200 cells/mm³, are somewhat arbitrary. For example, most studies including RPV show that its efficacy is diminished when initiated at viral loads ≥100,000 copies/mL, and 1 study showed that RPV worked less well than EFV-based therapy at a viral load of ≥500,000 copies/mL [Domingo and Ribera 2013].

Some agents have been approved based on noninferiority to the relatively less well-tolerated TDF/FTC/EFV regimen, which is, nevertheless, a potent and effective regimen for those who tolerate it well. The higher prevalence of NNRTI resistance mutations when transmitted drug resistance occurs has prompted most experts to avoid NNRTI-based regimens if treatment is indicated before genotypic resistance testing results are available [Panichsillapakit, et al. 2016; Rhee, et al. 2015; Stekler, et al. 2015]. Although coformulated TAF/FTC/COBI/EVG is approved for use at any starting viral load, reports of failure using TDF/FTC/COBI/EVG, with resistance, have been documented in individuals with very high baseline viral loads >1,000,000 copies/mL [Adams, et al. 2016; Rhee, et al. 2015].

A paucity of data is available demonstrating how different antiretroviral medications perform based on race and gender, although studies have suggested, for instance, that DRV/RTV is less well tolerated in women than in men and that discontinuation of DRV/RTV occurs at a higher rate among Black patients than among others [Smith, et al. 2012; Currier, et al. 2010].

Long-acting injectable therapy: An injectable long-acting formulation of the INSTI CAB and the NNRTI RPV (CAB/RPV LA) has been approved by the FDA as replacement ART for adults and adolescents ≥12 years old who [FDA 2021]:

• Weigh ≥35 kg
• Do not have chronic hepatitis B virus infection
• Are virally suppressed (HIV-1 RNA level <50 copies/mL) on a stable ART regimen
• Have no history of treatment failure
• Have no known or suspected resistance to either CAB or RPV

Although not FDA-approved as initial ART or for individuals with detectable viremia, the use of CAB/RPV LA as replacement ART in virally suppressed patients engaged in care may be a suitable option for those who would prefer an alternative to daily oral therapy.

Specific Factors to Consider and Discuss With Patients

Table

3TC: lamivudine ABC: abacavir

Before initiating ART, the following factors are important to consider and discuss with patients.

Age: As individuals with HIV age, they have a higher prevalence of comorbidities than younger patients with HIV and are likely to be on more non–HIV-specific medications, particularly cardiovascular or gastrointestinal agents, posing a higher risk for adverse interactions [Marzolini, et al. 2011]. For individuals older than 50 years, careful regimen selection, with the use of INSTIs when possible rather than cytochrome P450 inhibitors, such as COBI or RTV, can help minimize interactions. And use of TAF rather than TDF can lower the risk of renal and bone toxicity.

Comorbidities: Assessment for existing cardiovascular risk, renal disease or risk factors for the development of renal disease, hepatic disease, bone health, mental health, and substance use should be performed. Additionally, the risk for greater weight gain and potential exacerbation of metabolic complications with TAF- versus TDF-containing regimens, especially when combined with certain INSTI-based regimens, should be discussed prior to initiation of ART.

Cost: STRs may be favorable because of the lower copays that could be associated with fewer prescriptions. Conversely, the individual components of these regimens may be available generically as separate pills.

Dosing requirements (daily vs. twice daily): Most patients express a preference for once-daily dosing, especially if they are not taking other medications or are taking other medications that are dosed once daily. If individuals are already taking other medications that are dosed twice daily and report no adherence issues, twice-daily dosing is an acceptable option.

Drug-drug interactions: Because of some key drug-drug interactions, coadministration of some medications is to be avoided (see Table 6, below). For instance, PPIs should not be coadministered with oral RPV; however, injectable RPV can be used with PPIs. Given the availability of over-the-counter PPIs and the possibility that these drugs may be prescribed by a different care provider, this interaction is especially important to discuss with patients. In this case, to avoid unnecessary regimen changes once started, even patients who are not currently taking a PPIs should be asked whether they have needed PPIs in the past or may need them in the future. Dose limitations for metformin may also be required when combined with DTG and possibly BIC.

RTV and COBI have many significant and important interactions, including with cardiac medications. Methadone maintenance requirements may also change with some antiretroviral agents. A detailed review of all of a patient’s medications, including over-the-counter medications or supplements, is essential.

Before prescribing an ART regimen, using an automated interaction checker embedded in the electronic medical record or tools such as the following to check for potential drug-drug interactions with currently prescribed medications can help avoid serious problems:

• University of Liverpool HIV Drug Interactions Checker
• NYSDOH AI Resource: ART Drug-Drug Interactions

Table

ATV: In treatment-naive patients on boosted ATV, H₂-blockers should be taken simultaneously with ATV/RTV with food. If simultaneous dosing with food is not possible, ATV/RTV should be taken at least 10 hours after the H₂-blocker. (more...)

Food requirements: Because an individual may have a strong preference for taking medication with or without food, it is important to discuss which medications must be taken on an empty stomach, which must be taken with food, and which can be taken with or without food, as listed in Box 1, below.

Table

3TC ABC

Known adverse effects and toxicities: Review known and potential adverse effects in advance.

Number of pills: Some patients feel strongly that the fewer the number of pills, the better. For others, the greatest concern may be the ability to take all pills (regardless of the number) together once daily. Sometimes using individual agents rather than a multi-agent FDC or STR may be attractive depending on pill size. In rare cases, individuals who either cannot or will not swallow pills may need liquid formulations or pill crushing. Table 7, below, presents an abbreviated summary of commonly used ARVs and their availability in liquid formulation and/or the acceptability of crushing or dissolving them prior to ingestion.

Table

Pill size: Use images or real examples to give patients an idea of pill size before they fill the prescription. TAF/FTC/BIC and TAF/FTC/RPV are the smallest STR pills.

Pregnancy or conception planning: Individuals of childbearing potential should receive a pregnancy test and be assessed for use of contraception. When selecting an initial regimen for those who are not using effective contraception or who are contemplating pregnancy, clinicians should consult DHHS Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States.

All patients should be assessed for conception plans, which also provides an opportunity to discuss PrEP for partners without HIV. Additionally, all individuals with HIV should be informed that maintaining a plasma HIV RNA level <200 copies/mL with ART prevents sexual transmission of HIV to their partners.

Special Considerations for Comorbid Conditions

Table

3TC: lamivudine ABC: abacavir

Bone disease: TDF causes a decrease in bone mineral density in all patients after initiation of ART and should be used with caution in patients with preexisting severe osteoporosis [McComsey, et al. 2011; Stellbrink, et al. 2010; Perrot, et al. 2009]. Some experts recommend baseline bone densitometry screening for osteoporosis in postmenopausal women and in men and transgender women older than 50 years who have HIV [Aberg, et al. 2014]. The TAF formulation available currently in TAF/FTC, TAF/FTC/EVG/COBI, TAF/FTC/BIC, and TAF/FTC/RPV is an alternative, with lower markers of bone turnover in clinical trials [Bonora, et al. 2016; Pozniak, et al. 2016].

Cardiovascular risks: COBI- or RTV-containing regimens typically elevate lipids; TAF and certain INSTIs can cause greater weight gain than other ART regimens, with the potential for increased risk of metabolic complications [Łomiak, et al. 2021; Surial, et al. 2021; Bourgi(a), et al. 2020; Bourgi(b), et al. 2020; Calmy, et al. 2020; Lake, et al. 2020; Sax, et al. 2020; Venter, et al. 2020; Venter, et al. 2019]. TDF-containing regimens can have a beneficial effect on lipids [Souza, et al. 2013]. ABC has been associated with a higher risk of myocardial infarction in some studies [Marcus, et al. 2016; Choi, et al. 2011; Obel, et al. 2010; Sabin, et al. 2008; SMART/INSIGHT and D:A:D Study Groups 2008], whereas other studies have not confirmed this association [Ding, et al. 2012; Bedimo, et al. 2011; Ribaudo, et al. 2011; Brothers, et al. 2009]. Based on the available data, ABC should be used with caution in patients with multiple cardiac risk factors or known coronary heart disease; however, the absolute risk of myocardial infarction remains low, and no clear causality has been established. In the appropriate clinical circumstance, such as for a patient with impaired renal function, the use of ABC would be acceptable [Llibre and Hill 2016]. Clinicians should be made aware of the conflicting study data and share this information with patients.

Liver disease: In patients with existing liver disease of any etiology, dose adjustment of ARVs may be required depending on the severity of hepatic impairment (see guideline section ARV Dose Adjustments for Hepatic or Renal Impairment).

Mental health and substance use: Factors that may influence adherence should be addressed. There are also potential interactions between illicit (e.g., methamphetamine) and licit substances (e.g., methadone) and ARVs [Kumar, et al. 2015].

Table

Neither mental health nor substance use disorders are contraindications to initiating ART. In some special cases, delay of initiation (for as short a time as possible) may be appropriate while addressing adherence issues and possible interactions.

Renal function: TDF can cause renal tubular dysfunction, such as acquired Fanconi syndrome [Zimmermann, et al. 2006; Karras, et al. 2003]. The risk of renal impairment has been shown to be elevated in patients with preexisting renal disease, longer treatment duration, low body weight, and when used in conjunction with RTV- or COBI-boosted regimens [Mocroft, et al. 2016; Gervasoni, et al. 2013]. In general, full-dose TDF should be used with caution in patients with baseline CrCl <70 mL/min and should be adjusted or changed to an alternative agent if CrCl decreases to <50 mL/min; TAF is a better choice in these patients. As noted above, TAF 25 mg/FTC should be used with caution in boosted regimens when CrCl is <50 mL/min.

Both ATV/RTV and LPV/RTV have also been independently associated with a greater decrease in renal function over time than NNRTI-based regimens [Quesada, et al. 2015; Goicoechea, et al. 2008]. COBI, and to a lesser extent DTG, can inhibit the excretion of creatinine, with expected elevations of creatinine at initiation of therapy. However, such increases are not clinically relevant and do not significantly affect glomerular filtration rate [Lepist, et al. 2014; Koteff, et al. 2013; German(a), et al. 2012].

Although DTG is highly bound to plasma proteins and is unlikely to be removed by dialysis, it has not been studied in this population [FDA 2013]; therefore, RAL or a boosted PI with renally adjusted 3TC and either ABC or once-weekly TDF are usually the regimens of choice in this population.

Additional information on prescribing agents for patients with reduced renal function is available in the guideline section ARV Dose Adjustments for Hepatic or Renal Impairment.

Very high viral load (HIV RNA level >750,000 copies/mL): In some cases, experts will recommend use of both boosted DRV and DTG in addition to 2 NRTIs when a patient’s viral load is very high, with possible simplification once viral suppression is achieved. Numerous switch studies have demonstrated the safety of simplifying ARV regimens in virally suppressed individuals with no preexisting drug resistance [Cazanave, et al. 2015; Arribas, et al. 2014; Mills, et al. 2013; Fisher, et al. 2009]. Consultation with an experienced HIV care provider in these situations is helpful.

Table

Both COBI and DTG can cause decreased tubular excretion of creatinine and may cause a slight increase in measured creatinine. ABC has been associated with a higher risk of myocardial infarction in some studies, although not in others. No clear causal (more...)

ART-Initiation Laboratory Testing

Table

3TC: lamivudine ABC: abacavir

Baseline CD4 cell count: Some regimens should not be used when the CD4 count is <200 cells/mm³ because of an increased risk of treatment failure (see Table 8, below). When Pneumocystis jiroveci pneumonia prophylaxis is indicated, it may be prudent to defer ART for 7 to 10 days if 2 medications that may cause rash will be started, such as TMP-SMX and EFV.

Baseline HIV genotypic resistance profile: Genotypic resistance testing that includes the protease, reverse transcriptase, and integrase genes should be obtained at diagnosis (or initial visit if not done previously), but ART initiation should not be delayed pending the results [Kuritzkes, et al. 2008; Borroto-Esoda, et al. 2007].

Transmitted integrase resistance was identified in 0.7% of genotypic resistance tests obtained within 3 months of HIV diagnosis from 2013 to2017 in New York State [Wang, et al. 2019]. Similarly, 0.8% of baseline genotypic resistance tests across 23 U.S. jurisdictions of the CDC reported INSTI resistance, which had a higher prevalence (1.6%) in metropolitan areas (population 50,000 to 500,000) [McClung, et al. 2022]. Although INSTI resistance overall remains rare, most experts believe that transmission of INSTI resistance will increase over time, given that this class of ARV has become the preferred therapy for ART initiation (including rapid ART initiation) in all major guidelines.

Consultation with a care provider experienced in ART management is warranted when patients have baseline resistance that requires treatment with a regimen other than the listed preferred or alternative regimens. If treatment is indicated before genotypic resistance testing results are available, NNRTI-based regimens should be avoided because of the higher prevalence of transmitted resistance in NNRTIs than in PIs or INSTIs [Panichsillapakit, et al. 2016; Rhee, et al. 2015; Stekler, et al. 2015]. In the case of, for example, a patient with symptomatic acute HIV or advanced HIV with an opportunistic infection, some experts would include a second-generation INSTI (DTG or BIC or boosted DRV, or both together) with the NRTI backbone, given the possibility of transmitted NRTI resistance, with possible simplification once genotypic information is available.

Baseline viral load: Some regimens should not be used when the HIV RNA level is ≥100,000 copies/mL (see Table 8, below, and comments in the tables of preferred and alternative ART regimens).

Coinfections: Patients should be assessed for chronic HBV, HCV coinfection, and TB. The ART regimen for individuals with chronic HBV should treat both HIV and HBV when possible. For those planning concurrent HCV treatment or treatment for active TB, drug-drug interactions will play an important role in the selection of a regimen. The University of Liverpool HEP Drug Interactions Checker is a useful resource for identifying drug-drug interactions.

Creatinine clearance level: Some ARVs are contraindicated below a given CrCl level, and some may need adjustments that require the use of individual elements of an FDC or STR rather than the single-tablet version of the drug (see guideline section ARV Dose Adjustments for Hepatic or Renal Impairment).

Hepatic profile: Some ARVs require dose adjustment in the presence of impaired liver function; patients with abnormal liver enzyme levels or evidence of decreased synthetic function should be assessed for underlying liver disease (see guideline sections Special Considerations for Comorbid Conditions and ARV Dose Adjustments for Hepatic or Renal Impairment).

Table

When initiating ART at the time of HIV diagnosis (“rapid start”), it is not necessary to have the results of baseline laboratory tests immediately available. Laboratory tests, as indicated below, should be ordered at the time of initiation (more...)

HLA-B*5701 testing: To avoid potentially serious or life-threatening hypersensitivity reactions, HLA-B*5701 testing is mandatory before initiating ART that includes ABC [Mallal, et al. 2008; Saag, et al. 2008].

Initiation of the regimens listed in Table 8, below, is contraindicated based on the listed baseline laboratory parameters.

Table

ABC/3TC and ATV/COBI (Epzicom and Evotaz) ABC/3TC and EFV (Epzicom and Sustiva)

ARV Dose Adjustments for Hepatic or Renal Impairment

Table 9

Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment.

All Recommendations

Table

Regimen Selection When selecting an initial ART regimen for treatment naive-patients, clinicians should: Perform genotypic HIV resistance testing results for protease (A2), reverse transcriptase (A2), and integrase (B2) genotypic resistance if the testing (more...)

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Supplementary Material

Supplement: Guideline Development and Recommendation Ratings