Initial Antiretroviral Therapy in an Integrase Inhibitor Era: Can We Do Better?

INTRODUCTION

Since the world first encountered the AIDS epidemic almost four decades ago,¹ the culprit retrovirus has been identified,² its interplay with human immunity increasingly unraveled,³ and steady progress made in antiretroviral therapy (ART).⁴ The human immunodeficiency virus (HIV) field has now embraced integrase strand transfer inhibitor (INSTI)-based three-drug regimens forss first-line (initial) ART, because of their virologic and tolerability properties. Herein, we review initial ART in an INSTI era, and the emerging concepts of two-drug therapy and rapid ART initiation.

OVERVIEW OF INITIAL ANTIRETROVIRAL THERAPY IN 2019

INSTI-containing three-drug regimens are now recommended for initial ART by the US Department of Health and Human Services (DHHS), the International Antiviral Society (IAS)-USA, the World Health Organization, and the European AIDS Clinical Society.^5–8 The full set of guidelines from each of these expert groups, however, diverge (Table 1); IAS-USA is the most focused because it recommends second-generation INSTI (dolutegravir [DTG] and bictegravir [BIC])-based regimens above all others. Regimens containing the first-generation INSTIs (raltegravir [RAL] and elvitegravir [EVG]), protease inhibitors (PIs), and nonnucleoside reverse transcription inhibitors (NNRTIs) are assigned varying levels of support among the different guidelines.

Table 1:

Recommended initial ART regimens as of October 2018

	DHHS	IAS	WHO	EACS
Initial regimens	DTG/ABC/3TCa	BIC/TAF/FTC	DTG + 2 NRTIs	DTG/ABC/3TCa
	DTG + tenofovirb/FTC	DTG/ABC/3TC	EFV + 2 NRTIs	DTG + tenofovirb/FTC
	EVG/c/tenofovirb/FTC	DTG + TAF/FTC		EVG/c/tenofovirb/FTC
	RAL + tenofovirb/FTC			RAL + tenofovirb/FTC
				RPV/tenofovir/FTCb,c
				(DRV/c or DRV/r) + tenofovirb/FTC
Alternative regimens if first-line therapy unavailable or contraindicated	(DRV/c or DRV/r) + tenofovirb/FTC	DRV/c + TAF (or TDF)/FTC	ATV/r + 2 NRTIS	RAL + ABC/3TCa,d
	(ATV/c or ATV/r) + tenofovirb/FTC	DRV/r + TAF (or TDF)/FTC	LPV/r + 2 NRTIs	EFV + ABC/3TCa,d
	(DRV/c or DRV/r) + ABC/3TCa	EFV/TDF/FTC	DTG + 2 NRTIs	EFV/TDF/FTC
	(ATV/c or ATV/r) + ABC/3TCa	EVG/c/TAF (or TDF)/FTC	DRV/r + DTG + 1–2 NRTIs	(ATV/c or ATV/r) + tenofovirb/FTC
	EFV + tenofovirb/FTC	RAL + TAF (or TDF)/FTC		(DRV/c or DRV/r) + ABC/3TCa
	RPV/tenofovir/FTCb,c	RPV/TAF (or TDF)/FTCc		(ATV/c or ATV/r) + ABC/3TCa,d
	RAL + ABC/3TCa,d			(DRV/r or DRV/c) + RAL (BID)c
	DRV/r + RAL (BID)c,e
	LPV/r + 3TC (BID)a

Abbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; BIC, bictegravir; BID, twice daily; c, cobicistat; DRV, darunavir; DTG, dolutegravir; EACS, European AIDS Clinical Society; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; NRTI, nucleos(t)ide reverse transcriptase inhibitor; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization.

^aIf HLA-B*5701-negative.

^bEither TAF or TDF.

^cIf pretreatment HIV RNA level is <100,000 copies/mL and CD4 cell count is >200 cells/mm³.

^dIf HIV RNA <100,000 copies/mL.

^eRecommended only if ABC, TDF, or TAF cannot be used.

The current dominance of INSTIs in recommended initial three-drug regimens is a testament to the strengths of thisclass of antiretroviral drugs.⁹ Compared with PIs, no pharmacologic boosting (via inhibition of cytochrome P-450 3A4) is required for INSTIs, with the exception of EVG. As such, their potential for drug-drug interactions is lower. Furthermore, PIs have been linked with metabolic adverse effects (AEs), including treatment-limiting hyperbilirubinemia with boosted atazanavir¹⁰ and concerns about possible cardiovascular risk with cumulative exposure to boosted darunavir (DRV).¹¹ NNRTI-containing regimens also have certain disadvantages relative to INSTI-containing regimens. Rilpivirine must be taken with food, it has multiple medication interactions, a low barrier against resistance, and compromised efficacy in the setting of high HIV viremia (HIV-1 RNA >100,000 copies/mL) or severe immunosuppression (CD4 count <200 cells/μL).¹² Efavirenz (EFV) dominated the global landscape for several years, but has declined in popularity because of a high incidence of neuropsychiatric AEs¹³; requirement of dosing on an empty stomach¹²; low resistance barrier; and the potential for generation of the K103N mutation,¹⁴ an EFV-resistant variant that can also be transmitted. Doravirine is a recently-approved NNRTI with no food requirement, activity against some EFV-resistant variants, and better tolerability than EFV and boosted DRV.^15,16 Although doravirine has not been directly compared with an INSTI, resistance has been documented during virologic failure of initial doravirine-containing ART,¹⁶ unlike the second-generation INSTI-based three-drug regimens. Overall, the characteristics of doravirine are insufficient to challenge the dominance of INSTIs in initial ART.

INTEGRASE INHIBITOR-BASED THREE-DRUG REGIMENS

Across studies, INSTI-based three-drug regimens have exhibited high efficacy and tolerability in initial ART.⁹ RAL was shown to be noninferior to EFV and with fewer neuropsychiatric AEs.¹⁷ EVG demonstrated similar efficacy compared with EFV¹⁸ and boosted-PI based regimens,¹⁹ along with better clinical and/or laboratory tolerability. However, INSTI-specific resistance mutations have been reported during failure of RAL- or EVG-based regimens.^20,21

The second-generation INSTIs are potent, well-tolerated, and have raised the barrier to resistance.^22,23 In the SINGLE study, DTG demonstrated superiority to EFV, primarily because of lower discontinuation rates from AEs, such as rash and neuropsychiatric events.²⁴ In SPRING-2, DTG was shown to be noninferior to RAL,²⁵ whereas in the FLAMINGO trial, DTG was superior to boosted DRV.²⁶ Another large randomized trial (ARIA) demonstrated superiority of DTG over boosted atazanavir in treatment-naive women.²⁷ BIC is the most recent INSTI, and has shown noninferior virologic efficacy compared with DTG in multiple trials.^28–30 Virologic failure was exceedingly rare among individuals who adhered to and tolerated these regimens. There have been no reports of resistance emergence in clinical trials of DTG- or BIC-based triple therapy in treatment-naive persons with HIV (PWH).

Several INSTIs are available in fixed dose combination (FDC) tablets, which are often preferred by patients and may aid in adherence.³¹ EVG was the first INSTI-containing FDC as EVG/cobicistat/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Nonetheless, a propensity for drug-drug interactions (because of cobicistat) and a lower barrier to resistance relative to DTG and BIC are potential shortcomings of this regimen. DTG and BIC are available as the FDC tablets DTG/abacavir (ABC)/lamivudine (3TC) and BIC/FTC/tenofovir alafenamide (TAF), respectively, and they do not require a pharmacologic booster.^23,30 PWH with end-stage renal disease receiving hemodialysis require careful ART consideration and dosing adjustments, because such FDC tablets are not recommended in such patients.

The need for HLA-B 5701 allele testing before ABC initiation and reported associations between recent ABC use and increased risk of cardiovascular events are barriers to DTG/ABC/3TC use in some scenarios.³² In addition, DTG/ABC/3TC was associated with more gastrointestinal side effects than BIC/FTC/TAF in a head-to-head comparison, likely because of the effects of ABC.^30,33 There were also more neuropsychiatric symptoms with DTG/ABC/3TC, but no significant differences in treatment discontinuation rates.^29,33 Significant increases in total and low-density lipoprotein cholesterol were seen in the BIC/FTC/TAF arm at 96 weeks, but lipid-lowering medication use was low in each arm.³⁰ Of note, some cohort studies reported rates of neuropsychiatric adverse events with DTG that exceed those reported in randomized clinical trials,³⁴ but this is not a consistent observation among other large cohorts.³⁵

Understanding of the tolerability profile of INSTIs continues to evolve. Recently, unintentional weight gain has been associated with INSTI use in initial ART.^36–38 In the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), weight gain with INSTIs was significantly greater than was seen with NNRTI-based (but not PI-based) initial regimens, and there was an indication that the propensity for weight gain may differ between INSTIs.³⁹ Studies are ongoing to better understand the underlying mechanisms, to ascertain populations that may be at higher risk of moderate to severe weight gain,⁴⁰ and to determine the attributable risk for the different INSTIs and the metabolic/cardiovascular consequences, if any.

Some precautions and contraindications apply to INSTIs. For example, concurrent dosing with medications containing multivalent metal cations (eg, iron or calcium) may impair INSTI absorption.⁴¹ Furthermore, PWH receiving treatment of tuberculosis with rifampin experience enhanced DTG metabolism through cytochrome P-450 3A4 induction,⁴² but increasing the dosing of DTG to twice daily during concomitant rifampin use has been shown to overcome this effect and maintain antiviral efficacy.⁴³ RAL may also be used if the dose is increased to 800 mg twice daily.⁴⁴ Use of BIC, however, is precluded by concurrent rifampin use, even with twice-daily dosing.⁴⁵ Careful consideration is also needed in women who are pregnant or of child-bearing potential. Although RAL remains among first-line ART regimens for pregnant women with HIV,¹² serum EVG concentrations decline throughout pregnancy with standard dosing, which may result in virologic failure and mother-to-child transmission,⁴⁶ thus its use is not recommended as initial ART in pregnancy by DHHS or IAS-USA.^6,12 Preliminary data have also indicated an association between early DTG exposure and neural tube defects.⁴⁷ Pending additional investigation, guidelines now recommend avoiding DTG in the early stages of pregnancy and in women of child-bearing potential unless they are on effective contraception.^6,7,12 Little is known about BIC in pregnancy and it is not currently recommended.

As INSTIs take center stage in three-drug ART, so too does TAF as a replacement for TDF. TAF has more favorable renal and bone profiles, and is approved for use in individuals with glomerular filtration rate as low as 30 mL/min.^48,49 TAF can also replace TDF in those with chronic hepatitis B virus (HBV) coinfection.^50,51 Nonetheless, TDF/FTC remains among recommended initial NRTIs in the major guidelines except IAS-USA.⁶ TDF/FTC has been approved as a generic formulation, but this is not yet commercially available in the United States. Similarly, a generic TDF/3TC formulation was recently approved but is also not yet commercially available.

DUAL THERAPY

Initial ART with a second-generation INSTI plus two NRTIs has brought us closer than ever before to the ceiling of virologic efficacy and convenience, but can we do better? A frequently targeted area for improvement is the number of medications in ART regimens. The imperative for this is to lower the AEs (short- and long-term) and possibly cost of therapy without compromising efficacy or future treatment options. Although some guidelines already include boosted DRV + RAL twice daily and boosted lopinavir (LPV) + 3TC,^6,12,12 these regimens fail to meet the high bar set by contemporary INSTI-based three-drug ART, and are only listed as options when tenofovir or ABC cannot be used. Boosted DRV + RAL is further restricted to patients with viral load <100,000 copies/mL and CD4 greater than 200 cells/μL.¹² The risk of AEs including metabolic derangement, propensity for drug interactions (given the need for pharmacologic boosting), and inconvenient dosing are additional reasons why there has been limited uptake of PI-containing two-drug regimens in initial ART to date.

The prospect for broader adoption of dual therapy for initial ART has been enhanced by the advent of DTG + 3TC. This dual regimen benefits from the robust potency, resistance barrier, and tolerability of DTG coupled with 3TC, the only antiretroviral agent that has been in the DHHS guidelines since they were first published.⁵² Tolerability and long-term safety of DTG + 3TC are improved by excluding ABC and TDF, whereas the benefits of excluding TAF are less clear. It is, however, plausible that limiting NRTI exposure in general (eg, DTG + 3TC) may reduce the risk of mitochondrial toxicity. Recently, long-term use of TDF and, to a lesser extent, ABC, was associated with shortened telomere length, which may hasten immunosenescence.⁵³ Although this finding remains under investigation and no clinical associations have been made, there is a need to investigate the telomere effects of TAF, which results in higher intracellular drug exposure than TDF. 3TC, in contrast, has a remarkable record of safety, the evidence for which was recently summarized by Quercia and colleagues⁵⁴: (1) no effect in vitro on cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA), or mtDNA-encoded respiratory chain subunit II of cytochrome c oxidase after a long-term treatment⁵⁵; (2) weaker inhibition of the mtDNA polymerase gamma by the 3TC(−) enantiomer⁵⁶; and (3) 87% reduced risk of hyperlactatemia/lactic acidosis compared with regimens containing other NRTIs (including TDF, ABC, zidovudine, stavudine, and didanosine).⁵⁷ Furthermore, dual therapy with DTG + 3TC could also be a more cost-effective option if widely used. A modeling study found that if DTG + generic 3TC was used as initial therapy or for induction-maintenance by 50% of persons initiating ART in the United States and 25% of those currently virally suppressed switched to DTG+ 3TC, cost savings over 5 years could exceed $3 billion.⁵⁸

Clinical trial data in support of DTG + 3TC as initial ART have begun to accumulate. The strategy of using 3TC as part of a two-drug regimen started when Cahn and colleagues⁵⁹ reported that boosted LPV + 3TC was noninferior to standard three-drug therapy in treatment-naive PWH, regardless of baseline viral load. To sidestep the shortcomings of boosted LPV, the same group conducted the PADDLE study of DTG + 3TC and showed 90% virologic efficacy through Week 96 in 20 patients with baseline viral load less than 100,000 copies/mL and CD4 count greater than 200 cells/μL.⁶⁰ Subsequently, AIDS Clinical Trials Group (ACTG) A5353 confirmed the high efficacy of DTG + 3TC in treatment-naive participants and extended the evidence to those with baseline viral load greater than 100,000 copies/mL.⁶¹ Notably, one participant with virologic failure in A5353 developed resistance mutations to 3TC and DTG, prompting concerns about the resistance barrier of this dual regimen. Two ongoing fully powered studies (GEMIN11 and GEMINI 2) are now providing definitive data about DTG + 3TC. Noninferiority of DTG + 3TC to DTG + TDF/FTC has been demonstrated through Week 48, and follow-up will continue through Week 144.⁶² Importantly, no resistance has been reported to date in any of the individuals who have experienced virologic failure on DTG + 3TC in the GEMINI studies. As expected, changes in renal and bone biomarkers favored the TDF-free DTG + 3TC regimen. An FDC formulation of DTG + 3TC was approved in 2019.

Boosted DRV + 3TC is also being investigated for initial therapy. Although this regimen was noninferior to boosted DRV + TDF/TFC at 48 weeks in the ANDES trial,⁶³ there is reduced enthusiasm for boosted PIs in initial ART, except in specific situations. Looking into the future, the combination of doravirine and the investigational MK 8591 (a novel nucleoside reverse transcriptase translocation inhibitor) stands out as a possible two-drug candidate for treatment. Pharmacologic compatibility of this regimen was demonstrated recently,⁶⁴ and the combination is already being investigated in the induction-maintenance DRIVE2SIMPLIFY study (ClinicalTrials.gov; NCT03272347).

Although dual therapy offers some potential advantages in initial ART, there are limitations that will constrain its use. For example, the GEMINI studies excluded participants with screening viral load greater than 500,000 copies/mL, hence little is known in that subgroup, which might be of particular relevance for patients with either acute HIV or very advanced HIV disease. Furthermore, DTG + 3TC and other tenofovir-free dual regimens are contraindicated in HIV/HBV coinfection, and the strategy has not been investigated in tuberculosis coinfection or pregnancy. Data are also lacking in PWH with advanced renal disease or on hemodialysis. Notably, the current 3TC renal dosing recommendations are based on small pharmacokinetic studies that demonstrated large serum concentration increases with renal impairment. Subjects in these studies, however, tolerated 300-mg single doses or continuous 150-mg daily doses without AEs.^65,66 Because DTG does not require renal dosing adjustment, it is reasonable to consider investigating DTG + 3TC in dialysis patients.

RAPID ANTIRETROVIRAL THERAPY START

Guidelines globally now recommend ART initiation regardless of immune status.^5–8 However, treatment initiation is often delayed while waiting for results of recommended pretherapy tests, which may include CD4 count, viral load, HIV resistance genotype, hepatitis B serologies, complete metabolic panel, and HLA B5701 genotype.^5,7,8 There is now momentum toward rapid ART initiation, provided it is not contraindicated by untreated opportunistic infections.⁶ Although the definition of rapid ART has varied from ART initiation on the day of HIV diagnosis to within a few days or even 2 weeks of diagnosis, new infrastructure is commonly needed to support its implementation. Pilot programs in the United States have demonstrated significant reduction in time between HIV diagnosis and ART initiation, shorter time to viral suppression, and higher rates of durable viral suppression with early ART start,^67–69 consistent with similarly promising results from randomized trials in Haiti and sub-Saharan Africa.^70–73 By accelerating the time to suppression of plasma HIV-1, rapid ART initiation can also help optimize the benefits of undetectable = untransmissible at the population level. Rapid ART start (particularly same-day initiation) has limitations, however. It may not be for the ideal treatment strategy for every patient, and concerns about its feasibility or financial sustainability in some settings, and the potential for racial and other disparities in its implementation have surfaced.^67,69

Clearly, initiation of ART before the availability of results of baseline tests has become easier with availability of three-drug regimens that include second-generation INSTIs and TAF/FTC (ie, DTG + TAF/FTC and BIC/TAF/FTC). These regimens are safe, effective even in individuals with the most commonly transmitted resistance mutations (eg, K103N, M184V, and thymidine-analogue mutations),⁷⁴ and active against HBV. Correspondingly, the recently available FDC tablet containing boosted DRV + TAF/FTC may also be suitable for rapid ART initiation. However, two-drug regimens, including DTG + 3TC, are not recommended currently for rapid ART initiation because of concerns about potential monotherapy⁷⁵ (eg, in patients with transmitted drug resistance) and limited data on efficacy at viral loads greater than 500,000 copies/mL. Carefully designed studies with safeguards for participant safety may help understand whether there is a role for selected two-drug regimens in rapid ART initiation.

SUMMARY

INSTIs are transforming the paradigm of HIV treatment and have the potential to revolutionize HIV care delivery worldwide. DTG- or BIC-containing three-drug regimens are well-tolerated, and highly effective with a high resistance barrier, hence their dominance in initial ART. Dual therapy, such as with DTG + 3TC, is an emerging treatment option for initial ART that may promote long-term success in some patients by lowering cost and reducing AEs. Although it is generally safe to initiate DTG, BIC, or boosted DRV + TAF/FTC before the availability of baseline laboratory testing results, two-drug combinations, including DTG+3TC, are not recommended currently for rapid ART initiation.

KEY POINTS.

• Regimens containing a second-generation integrase inhibitor constitute most widely-recommended initial therapies.

• Emerging dual therapy regimens may further enhance cost effectiveness and tolerability.

• Alternative medication delivery through rapid start may further improve clinical outcomes.