New and Pipeline Antiretroviral Agents for the Treatment of HIV-1 Infection

It is clear that effective antiretroviral therapy (ART), when taken consistently, can reduce morbidity and mortality among persons infected with human immunodeficiency virus (HIV) and significantly lowers the risk of sexual transmission to HIV-negative partners. Given the complexities of ART, such as patient adherence, side effects, toxicities, allergies, drug-drug interactions, restricted drug formularies, socioeconomic factors and the prevalence of resistance mutations, developing new drugs and new classes for the treatment of HIV is paramount. There are several new ART formulations in various stages of development, some with novel mechanisms of action and routes of administration, being investigated for the treatment of HIV-1, pre-exposure prophylaxis (PrEP) and HIV cure. Clinicians should be cognizant of new and pipeline ART drugs, formulations and combinations, in order to reach the goals of complete virologic suppression and improved clinical outcomes in persons living with HIV (PLWH). Newly-approved agents, and drug combinations in development, should be safe, well-tolerated, long-lasting and affordable, with minimal pill burden to optimize adherence.

Introduction

Several studies have shown that combination antiretroviral therapy (ART) can reduce morbidity and mortality for those infected with human immunodeficiency virus (HIV).^1,2 When treating people living with HIV (PLWH) and acquired immune deficiency syndrome (AIDS), the goal is consistent and long-term virologic suppression, allowing CD4+ T-cell counts to rise with a commensurate reduction in the risk of opportunistic infections, HIV-associated nephropathy (HIVAN),³ AIDS-related malignancies, cardiovascular disease^4,5 and other HIV-related morbidities. It is clear that full virologic suppression can reduce transmission to HIV-negative sexual partners, as well.^6-8 It is therefore vital to choose an ART regimen that is safe and well-tolerated, minimizing the potential for adverse effects, toxicities, and drug-drug interactions. The clinician must also consider the results of genotype testing, baseline HIV viral load, baseline CD4+ T cell count, human leukocyte antigen (HLA)-B*5701 status, pill burden, allergies, comorbid conditions, history of ART adherence, and socioeconomic factors in each individual.

Given the potential complexities of ART administration, a desire to consolidate regimens to minimize pill burden, and the prevalence of HIV-1 resistance mutations, new combination therapies are available — and in the pipeline – to maximize the likelihood of adherence and virologic suppression. The worldwide burden of HIV/AIDS, about 37 million individuals as of 2014,⁹ heightens the urgency of increasing the proportion of PLWH on effective treatment. Indeed, poor adherence to medications used for chronic diseases, such as HIV, is relatively common, particularly when there is a necessity for a large pill burden or pleonastic dosing frequency.¹⁰ This makes it all the more critical to consolidate therapy and minimize side effects. Recent advances in ART medication formulations, such as single-pill complete ART and long-acting injectable agents, are making it easier for PLWH to be adherent, and for the clinician to construct somewhat simple salvage regimens for those with multiple significant resistance mutations. This article seeks to review newer ART agents, as well as those in later stages of drug development, for the treatment of HIV-1 infection.

Old Classes, New Drugs

NRTIs

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) have formed the backbone of ART regimens for decades. However, older NRTIs, such as zidovudine (AZT), stavudine (d4T) and didanosine (ddI) were found to be rife with side effects and toxicities, such as pancreatitis, mitochondrial toxicity, lactic acidosis and lipodystrophy, among others. The development of tenofovir disoproxil fumarate (TDF) — and FDA approval in this agent, in late 2001 – represented a significant leap forward for NRTI therapy, providing an effective alternative to other agents, with fewer side effects and toxicities. However, the TDF form of tenofovir has been associated with adverse renal tubular effects, including a proximal renal tubular metabolic acidosis with Fanconi syndrome^11,12 and a loss of bone mineral density.¹³ For several years, it has been acknowledged that improving the safety profile of tenofovir, particularly with an aging HIV population, would be an important step forward.

Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir which enters HIV-infected cells more efficiently than TDF, providing higher intracellular levels of tenofovir diphosphate, the active metabolite.¹⁴ TAF has shown improved in vitro antiviral activity as compared to TDF, with the ability to administer a much lower dose due to intracellular conversion of the prodrug. Because renal and bone toxicities of tenofovir are associated with higher circulating plasma levels of the drug, there is a distinct advantage provided by TAF, with 90% less tenofovir in the bloodstream as compared to the TDF form.¹⁵ In a 96-week study of TAF-based ART versus TDF-based ART, the subjects in the TAF arm were found to have a similar proportion of virologic suppression, but smaller declines in bone mineral density and more favorable changes in proteinuria, albuminuria, and tubular dysfunction. No cases of proximal tubulopathy were found in the TAF arm.¹⁶ Another study found that, in subjects with baseline renal dysfunction, changing from TDF to TAF as part of a complete ART regimen, resulted in significant improvements in proteinuria, albuminuria and tubular proteinuria (P <0.001 for all measures) accompanied by marked increases in spine and hip bone mineral density (P <0.05).¹⁷

While the TDF form should not be used in individuals with a creatinine clearance (CrCl) <70 mL/minute, the TAF form can be used to treat those with more severe renal dysfunction, down to an estimated baseline CrCl of >30 mL/minute. Therefore, while there is not yet a strong recommendation to change all patients from TDF-containing regimens to the TAF form, it is clearly prudent in those with renal insufficiency for whom abacavir (ABC) is not a suitable alternative agent. The development of TAF represents an important advancement in HIV care by reducing the potential for tenofovir-associated toxicities, particularly given the frequency with which this NRTI is used. Gilead Sciences has brought to market TAF versions of its previous combination pills, although TDF formulations are still available (see “New ART Combination Therapies”).

NNRTIs

The first generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs) included delavirdine (DLV), nevirapine (NVP) and efavirenz (EFV). As NNRTI resistance mutations have become more prevalent, particularly the K103N reverse transcriptase mutation, many of these first-generation drugs have become less commonly prescribed. In addition, hypersensitivity reactions and hepatotoxicity associated with initiating NVP in persons with higher baseline CD4+ T-cell counts have limited its use.¹⁸ EFV was a very commonly used NNRTI for several years, particularly after being co-formulated with TDF and FTC to constitute the first complete single-pill, once-daily ART regimen for the treatment of HIV-1 infection. However, EFV has fallen heavily out of favor, in part due to the commonly-encountered neuropsychiatric side effects, such as dizziness, confusion, agitation, paranoia, vivid dreams, mania and depression.^19,20 When investigators found a more than 2-fold increase in suicidal ideation, with a strong trend towards increased suicide attempts and completed suicide, in PLWH on an EFV-containing regimen,²¹ the Centers for Disease Control and Prevention (CDC) and Department of Health and Human Services (DHHS) guidelines for the treatment of HIV in adults changed, listing EFV as an alternative component of therapy rather than preferred.²²

Second generation, diarylpyrimadines NNRTIs have come to market more recently, with etravirine (ETR) FDA-approved in 2008, and rilpivirine (RPV) approved in 2011. The main advantage of second-generation agents is their activity against HIV with K103N mutations. However, these newer agents can still cause problematic neuropsychiatric side effects, although with a lower incidence compared to EFV²³ , and have their own specific limitations. For example, clinical trials have found that persons with a baseline HIV viral load >100,000 copies/mL or a CD4+ T-cell count <200 cells/mm³ have a higher risk of developing significant resistance mutations and virologic failure with RPV versus EFV.^23,24 This, along with the requirement to take RPV with a large meal and restrictions regarding antacid co-administration, makes second-generation NNRTIs somewhat less useful.

Doravirine (MK-1429) is a novel NNRTI, currently in phase 3 clinical trials. It has demonstrated potent antiretroviral activity, and is relatively safe and well-tolerated.²⁵ A small proportion of patients may experience mild neuropsychiatric side effects, such as dizziness and vivid dreams, but doravirine has a similar side effect profile as ETR and RPV with a significantly improved lipid profile compared to EFV. Of note, it retains activity against many common NNRTI-resistant mutants, including those with K103N, Y181C, G190A, E101K, E138K, and K103N/Y181C reverse transcriptase mutations.^25,26 Because of this resistance profile, there is likely very little cross-resistance between doravirine and other NNRTIs, including second generation drugs. Another potential advantage is in its metabolic profile. While other NNRTIs are strong inducers of CYP450 enzymes, doravirine is neither an inducer nor inhibitor, only functioning as a substrate of CYP3A4.²⁷ This should result in a significantly lower risk of adverse drug-drug interactions as compared to all currently available agents in the NNRTI class.

Although guidelines vary internationally, the current combined CDC/DHHS HIV treatment guidelines do not list any NNRTI-containing regimens as preferred in the treatment-naïve patient.²² This is principally due to their side-effect profiles, but there are clearly also concerns about the ease of developing resistance mutations leading to virologic failure. At this point, these agents are most often used in special cases when protease inhibitor (PI) intolerance, significant resistance mutations, or contraindications to integrase inhibitors are present. However, if doravirine is co-formulated with NRTIs and/or agents from other classes to form a once-daily, single-tablet regimen, NNRTI therapy will likely drift back into favor.

INSTIs

Integrase strand transfer inhibitors (INSTIs, “integrase inhibitors”) are a relatively new class of ART agents. Currently available INSTIs, include raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). These agents are safe and effective, demonstrating excellent antiretroviral activity. The clinician must be cognizant of the tendency of polyvalent cations (e.g. iron, calcium and magnesium) to bind INSTIs and inhibit their absorption, as well as the variable role of CYP450 metabolism for different agents within this class. However, they are currently preferred agents in the United States for PLWH who are treatment naïve, and often have a vital role in salvage therapy.

Cabotegravir (CAB, GSK-1265744) is a potent INSTI, being developed for both the treatment of HIV-1 infection and pre-exposure prophylaxis (PrEP) in HIV-negative, high-risk populations. It is currently in phase 2b trials, and the once-daily table has shown significant promise as part of a complete ART regimen.^28,29 While it is structurally very similar to DTG, with a similar resistance profile, CAB offers the potential advantage of having a long half-life, and is being investigated as a long-acting injectable.^30,31 As discussed later, injectables may have an important role in both treatment and PrEP, given the potential for improving adherence to ART therapy. Another advantage is that, like RAL, CAB does not have significant CYP3A4 metabolism. Therefore, it does not require boosting and does not have the significant drug-drug interactions of EVG.

New ART Combination Therapies

In the past two years, seven new ART combination therapies have come to the worldwide market. While not all combination pills offer a complete, effective ART regimen, the trend is to significantly consolidate drugs into fewer daily doses. This should have the effect of improving compliance by minimizing pill burden. Of note, several combination pills discussed, mirror other available co-formulations, but replacing TDF with TAF in order to reduce renal and bone toxicities.

Given the potentially adverse safety profile of TDF, there has been a shift towards using abacavir (ABC) in recent years as a core NRTI for use in a complete ART regimen. ABC, co-formulated with lamivudine (3TC) and DTG in a single, fixed-dose tablet was FDA-approved in 2014. Once-daily DTG, administered with two NRTIs, demonstrated significantly improved virologic suppression, with an improved side-effect profile, as compared to an EFV-based regimen.³² Removing the neuropsychiatric side effects of EFV led to fewer discontinuations among subjects in this study, yet another advantage over the previously favored EFV/TDF/FTC combination. DTG/ABC/3TC is now a very commonly prescribed once-daily combination regimen. However, there is a requirement to draw an HLA-B*5701 prior to initiating any ABC-containing regimen to assess the risk of developing a hypersensitivity reaction, the cost and utility of which must be considered on a case-by-case basis. Given the availability of TAF, the use of ABC-based regimens may wane in the years to come, but this combination offers a safe, effective, once-daily pill and is currently a preferred, first-line agent in the US national guidelines.²² Clinicians should note that changing from TDF/FTC to ABC/3TC, as NRTIs, can lead to a flare of hepatitis B in those who are co-infected. The patient is shifting from two highly effective agents to a single agent (3TC), and there would be a relatively high risk of developing resistance with exposure to lamivudine alone, in some cases up to 65% after five years of monotherapy.^33,34

The fixed-dose combination of TAF/FTC is now on the market. It is safe and effective when paired with an NNRTI, PI or INSTI in the treatment of HIV-1 infection,^35-37 and is used similarly as TDF/FTC. TAF/FTC contains two NRTIs, is not a complete ART regimen, and must be paired with — at minimum – a third agent from another ART class to be effective in treating HIV-1. As with other regimens using the TAF formulation of tenofovir, the major advantage is the lowered risk of tenofovir-associated toxicities as compared to TDF, due to lower levels of circulating drug. However, the clinician should note two major current differences in the use of TAF/FTC versus TDF/FTC. The use of combined TDF/FTC in HIV-negative individuals has been shown to be effective and well-tolerated in preventing the acquisition of HIV, with an efficacy of 99% in those who adhere to daily dosing.³⁸ However, the TAF formulation has not yet been given an indication for PrEP or the treatment of active hepatitis B infection, and should not be considered interchangeable with TDF/FTC in these scenarios.

The single tablet combination of boosted cobicistat-boosted EVG with TAF/FTC was the first approved TAF-containing regimen on the US market. Its use is supported by data from two 48-week non-inferiority studies which compared elvitegravir/cobicistat/TAF/FTC (EVG/c/TAF/FTC) to EVG/c/TDF/FTC.^35,36,39 These studies revealed non-inferiority with significantly fewer tenofovir-related toxicities, and this once-daily ART regimen has recently been added as a preferred, first-line agent for the treatment of naïve PLWH in the U.S. guidelines.²² EVG/c/TAF/FTC may be most useful in those who are virologically suppressed on the TDF formulation, but are experiencing renal dysfunction. A phase 3 “switch study” among virologically suppressed adults who changed from other TDF/FTC-based regimens found non-inferiority with significantly less renal and bone toxicity.⁴⁰ It remains unclear if there is a significant benefit to immediately changing to TAF-based therapies in persons with normal renal function, but this can certainly be considered on a case-by-case basis, with the clinical being cognizant from discrepancies in drug costs. The clinician should also note that both regimens still contain EVG/c, and will therefore have the same drug-drug interactions.

RPV/TAF/FTC was FDA-approved in March, 2016. This is a single pill, once-daily, fully active ART regimen, and is essentially the TAF mirror of widely available RPV/TDF/FTC. The US guidelines list this as an alternative therapy, having the same viral load-, CD4-, food- and gastric pH-based limitations of the TDF formulation. It is an effective regimen for some populations, as demonstrated by randomized clinical trials^23,41 and has less renal toxicity, as would be expected. The clinician needs to consider all RPV-based limitations of therapy, including the presence of key NNRTI resistance mutations, before using this combination drug.

A combination of DRV/c/TAF/FTC, used as a full single-tablet regimen, is currently in phase 3 trials. If found to be efficacious and safe in these studies, it will be the first single-tablet regimen to contain a PI. Phase 2 data showed non-inferiority when compared with TDF/FTC and separately cobicistat-boosted DRV, along with the expected improvements in renal and bone safety.³⁷ Currently, boosted DRV is the only PI-based ART regimen considered to be a preferred, first-line regimen in the US guidelines. This, along with the high genetic barrier to resistance of DRV,⁴² makes this single-tablet combination an exciting development. Along with drug-drug interactions associated with inhibition of CYP3A4 metabolism, the clinician must consider PI resistance mutations and PI treatment experience of each individual patient before using this fixed-dose pill. Twice-daily DRV, boosted with RTV, should still be used in PLWH who have significant PI treatment experience or have the following significant resistance mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V. Other than these limitations, DRV/c/TAF/FTC should be broadly effective, particularly in the ART-naïve patient.

Two PIs, atazanavir (ATV) and DRV, have now been combined with the pharmacokinetic booster cobicistat, removing the need to administer ritonavir (RTV), separately, in order to optimize serum drug concentrations. ATV/c and DRV/c were both FDA-approved in January, 2015, and are now widely available for use in the U.S. The major advantage is a reduction in pill burden, although only by a single daily tablet with standard dosing. The treating clinician must consider that cobicistat, like RTV, is a strong inhibitor of CYP3A4, and has similar drug-drug interactions as PIs currently in use. As well, lowered creatinine clearance (CrCl), with no actual effect on glomerular filtration rate (GFR), has been reported with the use of cobicistat due to inhibition of renal tubular creatinine secretion.⁴³ However, cobicistat can actually lead to true renal dysfunction, and neither agent should be used in patients with a CrCl of <70 mL/minute. Therefore, meticulous review of a patient’s medication list, including over-the-counter herbals such as St. John’s wort, and GFR must be taken into consideration prior to initiating therapy with either of these combination agents.

A fixed-dose tablet of RAL/3TC came to market in 2015, and has been approved by the US FDA.^44,45 However, it is only commercially available in Europe, and can currently only be obtained in the US by compassionate-use request. It is notable that approval of this combination pill is based purely on clinical trials data from studies of the individual drug components, not the fixed-dose tablet. While bioequivalence and bioavailability data show no unexpected differences with the fixed-dose product in healthy volunteers,⁴⁶ this fact should be taken into consideration prior to use. It is unclear when, or if, this product will become available for wide use in US patients.

Novel Therapies

The development of novel therapeutic targets for antiretroviral agents remains a high priority. ART agents with new mechanisms of action may offer effective virologic suppression for PLWH who have accumulated many significant resistance mutations. In addition, some novel therapies in development offer hope for use as effective PrEP, and perhaps even cure.

Long-Acting Injectables

Because ART adherence is critical to maintaining virologic suppression and reducing the risk of developing resistance mutations, long-acting formulations of ART agents are in development. The goal is to administer ART less frequently, which may provide stable and reliable drug levels while reducing the risk of missing doses and treatment fatigue. Injectables may also help to avoid issues of pill burden and gastrointestinal tract absorption. Such agents are being investigated for both treatment of active HIV-1 infection and prevention via PrEP. Injectables may be beneficial for PrEP due to less reliance on daily patient-centered adherence. Previous PrEP studies have certainly shown both that the efficacy of PrEP, and subject adherence as measured by serum drug levels, are relatively poor.³⁸ Long-acting formulations of a variety of medications have been used successfully for the treatment of other chronic diseases, including contraception⁴⁷ and psychiatric disorders⁴⁸, but ART with less frequent and more reliable drug delivery is a novel and emerging strategy in the treatment of HIV infection.

The established second-generation NNRTI RPV, currently available as a single-agent tablet and combined with either TAF or TDF (both with FTC), is being investigated as a long-acting parenteral formulation. The injectable consists of a solid drug particle nanosuspension, produced by milling of large fragments of the drug until particles within the nanometer range have been achieved.⁴⁹ Pharmacokinetic data for single-dose intramuscular (IM) administration have shown excellent concentrations in the plasma, cervicovaginal fluid and rectal fluid and tissue in both men and women, with excellent tolerance and minimal adverse events.⁵⁰ In murine models, parenteral RPV appears to be quite effective when used as PrEP, the main strategy for its use currently; however, breakthrough infection and the development of resistance mutations have been documented with lower doses.⁵¹ More human data, regarding both dose and efficacy, need to be conducted prior to considering its use as a first-line PrEP agent.

As mentioned previously, CAB is an investigational INSTI being studied, both as an oral tablet and long-acting injectable agent.^30,31 So far, data have shown it to be safe and effective, and may represent an effective component of a full treatment regimen and/or PrEP. As with other injectables, we need more clinical trial data before we can recommend the use of IM CAB for any purpose at this time.

There are several potential challenges associated with the use of long-acting injectable agents. One is the complexity of managing toxicities. While the agents in development certainly have fewer adverse effects than ART available in previous decades, the extended duration of serum levels, rather than the rapid clearance of traditional oral agents, could present major issues of drug toxicity or drug-drug interactions occur. This presents new safety concerns that must be addressed. In addition, these individual agents will still require the need for other ART drugs to form a complete “highly active” antiretroviral regimen. Therefore, the issue of patient-centered daily adherence to oral medications will still exist, at least until the time when combination injectables are available. Finally, there may be challenges unique to parenteral therapy, such as patient concerns about pain, anxiety regarding the use of needles, injection site reactions, and the use of proper technique. These considerations must always accompany the decision to initiate injectables, and should be a part of patient education and counseling prior to use.

Attachment Inhibitors

Fostemsavir is a member of a new class of ART known as attachment inhibitors. Temsavir, the active metabolite, acts by directly binding to the HIV glycoprotein (gp) 120, causing a conformational change that prevents viral attachment to the CD4 receptor.^52,53 Therefore, virus cannot attach to, or subsequently enter, the CD4+ T cell. The FDA review of fostemsavir has resulted in accelerating its development.⁵⁴ The novel mechanism of action is creating an urgency to bring this drug to market, both for treatment of PLWH who have accumulated several significant resistance mutations and, possibly for PrEP.

Entry Inhibitors

After HIV-1 gp120 binds to the CD4 receptor, it must bind a co-receptor prior to entering the cell. Maraviroc is an HIV-1 entry inhibitor that has been on the market for several years. It acts as a chemokine receptor type 5 (CCR5 co-receptor) antagonist, preventing viral entry.^55,56 Cenicriviroc is another CCR5 entry inhibitor, but it differs from maraviroc in that it exhibits dual antagonism of both CCR5 and CCR2, making it a somewhat more novel, and possibly more useful, agent. As with maraviroc, a tropism assay needs to be performed prior to initiating therapy. A randomized, phase 2b study evaluated cenicriviroc versus EFV, both paired with TDF/FTC. Cenicriviroc was found to be non-inferior, although several patients did develop resistance mutations while on the drug.⁵⁷ Phase 3 studies have yet to be performed for this agent.

The issue with specific co-receptor antagonists has always been the waning usefulness of CCR5 antagonism in a given patient over time. As an individual becomes more treatment-experienced, their virus tends to shift from CCR5 tropic to mixed, or CXCR4, tropic. This development makes selective entry inhibitors somewhat less useful, although they have been considered as possible drugs for PrEP in the future. Given their mechanism of action, this makes sense, but clinical trials have yet to occur.

Maturation Inhibitors

BMS-955176 represents yet another novel class of ART, the maturation inhibitor. BMS-955176 is a once-daily, oral maturation inhibitor that works by reversibly binding to HIV-1 gag, inhibiting the final protease-mediated cleavage.⁵⁸ The main advantage is that it retains strong activity against NRTI-, NNRTI-, PI- and INSTI-resistant virus, and may be very useful in the extremely treatment-experienced patient. Multiple studies are currently underway to evaluate the pharmacokinetics and pharmacodynamics of this agent. It is an exciting development with excellent potential across the globe.

Neutralizing antibodies

Monoclonal antibodies have been generated, targeting both the CD4 receptor and the CCR5 co-receptor, both critical cell surface proteins for entry of HIV-1 into the target lymphocyte. Ibalizumab is a non-immunosuppressive monoclonal antibody that non-competitively binds to the CD4 receptor, the essential receptor for HIV to bind to T-cells, conformationally altering the CD4-gp120 complex and inhibiting viral attachment and entry.⁵⁹ It appears to have potent antiviral activity, both in vitro and in vivo.

Ibalizumab is administered intravenously (IV), and an early clinical trial showed a significant reduction in HIV-1 RNA levels in patients who received a single dose.⁶⁰ It is available for compassionate use in the US, and is currently being evaluated in a phase 3 trial of heavily treatment-experienced PLWH.⁶¹ A formulation of ibalizumab for subcutaneous (SQ) use, and the potential for once-monthly dosing, is currently being studied as well. While the parenteral administration (IV or SQ) of ibalizumab may limit its use, somewhat, the agent should be reserved for deep-salvage regimens in those who have accumulated multiple, significant resistance mutations.

HIV Vaccines

Broadly-neutralizing antibodies targeting HIV-1, itself, has generated substantial interest, being developed as a vaccine for prevention and/or treatment of active infection. However, HIV-1 vaccines alone have not shown much promise due to the antigenic variability and heterogeneity of the virus. We know to target distinct epitopes on the viral envelope (Env), but it is clear that several other neutralizing antibodies will need to be part of any B-cell vaccine to achieve clinical benefit.⁶² Indeed, there is substantial heterogeneity between patients, inhibitory pathways and HIV antigens, making vaccine development quite difficult. Ideally, a T-cell response would be triggered, but constructing an effective T-cell vaccine is much more complex, particularly for this still, often-elusive pathogen.

Using vaccination as an HIV cure would essentially require the functional boosting of CD8+ T-cell responses to eliminate latently infected cells. So far, investigations have involved stimulation with Gag and Env peptide panels, followed by the administration of monoclonal antibodies. These antibodies are more complex than ibalizumab in the sense that they target cytokines as well, such as interleukin (IL)-10, transforming growth factor (TGF)-b, programmed death ligand (PD-L)-1, herpes virus entry mediator (HVEM), and others.⁶³ Due to the substantial heterogeneity of persons, biochemical pathways and HIV antigenic variation, immunotherapy would likely need to be individualized, an onerous and likely high-cost proposition. Competitive inhibition of CD4+ T-cell binding, possibly in combination with ART, seems to be a more promising avenue at this point.

Considerations for the Clinician

Although national guidelines provide very straightforward recommendations for preferred ART agents, particularly for use in the ART-näive patient, the clinical management of PLWH is often complex. The clinician must always consider patient preferences, pill burden, drug allergies, side effects, toxicities, co-morbid conditions, drug-drug interactions, baseline CD4+ T-cell count, baseline HIV viral load, renal function, route of administration, cost, socioeconomic pressures for the patient, HIV stigma, HLA-B*5701 status, and the results of HIV-1 genotype and/or phenotype testing when constructing a complete regimen. Over the past 20 years, essentially the era of highly-active combination ART, the trends towards the development of agents that are better tolerated, have fewer side effects and toxicities, as well as a lower pill burden, have resulted in massive leaps forward. However, non-adherence to therapy, absorption issues and drug-drug interactions can often lead to the development of resistance mutations, necessitating the advent of new drugs, new classes and new targets for therapy.

Jeremy D. Young, MD¹, MPH, and Lily Rotman, MD²¹University of Illinois at Chicago Department of Medicine, Division of Infectious Diseases, Immunology and International Medicine, ²University of Illinois at Chicago Department of Internal Medicine. The authors have no conflicts of interest to report. Corresponding Author:Jeremy D. Young, MD, MPH, Assistant Professor of Medicine, Department of Medicine, Division of Infectious Diseases, Immunology and International Medicine, University of Illinois at Chicago. 808 S. Wood Street, #888, Chicago, IL 60612. (312) 413-0579 youngj@uic.edu

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