Simplification Strategies to Reduce Antiretroviral Drug Exposure: Progress and Prospects

Abstract

Current US guidelines for initial therapy of HIV-1 infection recommend daily, life-long treatment with a combination of three antiretroviral drugs consisting of two nucleoside analog reverse transcriptase (RT) inhibitors and a nonnucleoside RT inhibitor or a protease inhibitor. Although this approach has been successful in reducing morbidity and mortality from HIV-1 infection, concerns remain about adverse events from chronic drug exposure, the requirement for daily medication adherence, the risk of HIV-1 drug resistance, and high treatment costs. The availability of antiretrovirals that are co-formulated and dosed once-daily have reduced pill burden and have simplified dosing schedules, but have not lowered drug exposure or cost. These limitations have stimulated research into drug-sparing strategies including intermittent therapy and simplified maintenance regimens. Randomized clinical trials have shown greater mortality with intermittent therapy compared with continuous therapy leading to rejection of this strategy. Pilot studies of simplified maintenance therapy with a ritonavir-boosted protease inhibitor alone have shown more promise, although concerns remain. This article reviews progress in simplification of antiretroviral therapy, recent clinical trial results, and prospects for the future.

Introduction

Currently recommended antiretroviral therapy requires taking medications daily and indefinitely. The interrelated issues of adverse drug effects, drug adherence, drug-drug interactions, and cost continue to stimulate research into better tolerated, simpler, and more cost-effective regimens or those that may reduce drug exposure. Complicating this issue is the fact that “simpler” therapy, defined as use of only one drug class (e.g. a ritonavir-boosted protease inhibitor), may actually involve more pills and/or more frequent dosing intervals, and possibly more adverse effects. Several approaches have been taken to simplifying therapy and reducing drug exposure including: i) once-daily dosing formulations and fixed-dose drug combinations; (ii) single drug class therapy; (iii) intermittent therapy, and (iv) induction therapy followed by simpler maintenance regimens. Drawing on relevant published or presented data, this article reviews recent successes and failures of these strategies, expands on previously published reviews of simplified therapy and examines future prospects.[1, 2]

Methods

Studies reported in this review were compiled from PubMed and Medline reference searches of English language publications and from references cited in pertinent articles. Search terms included “anti-HIV agents”, “antiretroviral therapy, highly active”, “HIV protease inhibitors”, “ritonavir”, “nucleosides”, “drug therapy, combination”, “monotherapy” and “simplified maintenance therapy”. We included clinical trials published in peer-reviewed journals that provided information on trial design, randomization, patient follow-up (minimum of 24 weeks), treatment regimens, and defined clinical and virologic outcomes. Trial designs included simplification of antiretroviral therapy, monotherapy/single agent therapy, induction-maintenance regimens, single drug-class regimens, and intermittent therapy. Abstracts from major HIV/AIDS or infectious diseases conferences were also reviewed for inclusion.

Once-Daily Dosing and Fixed Dose Drug Formulations

Once-daily dosing and lower pill number improve adherence to antiretroviral therapy.[3–5] Several antiretroviral agents are now approved for once-daily dosing by the US Food and Drug Administration (Table 1).[6] Fixed-dose combinations of nucleoside reverse transcriptase inhibitors (NRTI) incorporating two or three drugs are available in the United States (Table 1).[6] The only co-formulated protease inhibitor (PI) is lopinavir/ritonavir. Co-administration of ritonavir with other protease inhibitors requires separate doses of ritonavir, which is less convenient. The three drug combination of tenofovir, emtricitabine and efavirenz is approved for once-daily dosing in the US and is the first available fixed-dose combination tablet containing all components of a preferred antiretroviral regimen.[7] In resource-limited settings, pharmaceutical manufacturers and governments produce several generic, low price fixed-dose formulations for once or twice daily dosing.[8] Questions have been raised about the bioequivalence of such generic formulations, but clinical trial data are reassuring.[9, 10] The FDA maintains a list of antiretrovirals from foreign sources that are approved or tentatively approved, using their normal standards for authorization (available at http://www.fda.gov/oia/pepfar.htm). Products that still have marketing protection in the US are issued “tentative approval” as generics outside the US, although they meet all US standards for safety, efficacy and manufacturing.

Table 1.

Antiretroviral Agents Approved for Once-Daily Dosing, and Once- and Twice-Daily Fixed Dose Combinations Available in the United States

Antiretroviral Agents Approved for Once-Daily Dosing
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors	Abacavir
	Lamivudine
	Didanosine
	Emtricitabine
	Tenofovir
Non-Nucleoside Reverse Transcriptase Inhibitorsa	Efavirenz
Protease Inhibitors	Atazanavir +/− ritonavirb
	Fosamprenavir/ritonavirc
	Lopinavir/ritonavird
Once-daily Fixed Dose Combinations
Nucleoside / Nucleotide Reverse Transcriptase Inhibitors	Tenofovir /emtricitabine
	Abacavir/lamivudine
Protease Inhibitors	Lopinavir/ritonavird
Two drug classes	Emtricitabine/tenofovir/efavirenze
Twice Daily Fixed Dose Combinations
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors	Zidovudine/lamivudine
	Zidovudine/lamivudine/abacavir
Protease Inhibitors	Lopinavir/ritonavir
Two class regimens	None

^aOnce-daily dosing of nevirapine is virologically inferior to twice daily dosing in treatment naïve patients, and should not be used.65]

^bAtazanavir with ritonavir is the only protease inhibitor approved for once-daily dosing in treatment-experienced patients

^cOnce-daily dosing of fosamprenavir/ritonavir is approved only for treatment-naïve patients.

^dOnce-daily dosing of lopinavir/ritonavir is approved only for treatment- naïve patients; also lopinavir is the only PI co-formulated with ritonavir.

^eEmtricitabine/tenofovir/efavirenz is the only combination antiretroviral regimen available as a single pill with once-daily dosing.

Although once-daily dosing and fixed-dosed drug combinations have made therapy more convenient, they do not reduce drug exposure, side effects, or risk of resistance with continuous therapy.

Single Drug Class Therapy

NRTI

Both once-daily and fixed-dose combinations of three NRTI have been studied to reduce pill number and as a class-sparing strategy to conserve other antiretroviral drug classes for future use. Unfortunately, triple NRTI combinations for initial therapy have consistently showed greater risk of virologic failure compared with regimens containing 2 NRTI and efavirenz, especially in patients with HIV-1 RNA levels >100,000 copies/mL.[11–14] Triple NRTI combinations should only be used for initial therapy in exceptional circumstances, and should include ZDV to raise the barrier to emergence of resistance.[15, 16] Concern about potential toxicities such as lipoatrophy associated with thymidine analog-containing regimens also dampen enthusiasm for this approach.[17]

Maintenance therapy with three NRTI following induction with standard regimens has been evaluated with variable clinical trials results. [18–21] The four major randomized trials of this strategy are summarized below, in the section on Induction-Maintenance strategies. A four NRTI combination (zidovudine, abacavir, lamivudine and tenofovir) showed comparable efficacy to 2 NRTI + efavirenz in a pilot trial, but cannot be recommended for use until adequately powered comparative studies are completed.

NNRTI

NNRTI possess potent antiretroviral activity and compare favorably with PI in combination therapy.[22–24] The major shortcoming of NNRTI such as nevirapine and efavirenz is the development of class-wide cross-resistance from a single mutation, which makes these NNRTI untenable for use as single agent maintenance therapy.[25] Newer generations of NNRTI with improved resistance profiles, such as etravirine and rilpivirine, may have potential for simplified maintenance therapy although this has not been studied.[26–28]

PI

Lopinavir/ritonavir alone as initial therapy has been studied in two clinical trials. Gathe et al presented data from 30 patients with mean baseline plasma HIV-1 RNA of 262,000 copies/mL and CD4 count of 169 cells/mm³.[29] Intention to treat (ITT) analysis at week 24 revealed that 21 of 30 patients maintained plasma HIV-1 RNA levels <400 copies/mL; 21 of 22 (95%) in the as-treated analysis. No resistance to lopinavir was detected. In the MONARK trial, antiretroviral-naïve patients were randomized to lopinavir/ritonavir alone (n=83) versus lopinavir/ritonavir in combination with zidovudine/lamivudine (n=53).[30] Prior to study entry, participants had CD4 cell counts ≥100 cells/mm³ and HIV-1 RNA <100,000 copies/mL. By ITT analysis, 78% and 67% of patients in the lopinavir/ritonavir (LPV/RTV) alone arm achieved the primary study endpoint of HIV-1 RNA , < 400 copies/mL at 24 weeks, and < 50 copies/mL at 48 weeks, respectively. In the combination arm, 77% and 75% of patients achieved the 24 and 48 week endpoints, respectively. ITT efficacy comparisons between treatment arms did not show significant differences; however by on-treatment analysis of the week 48 endpoint (<50 copies/mL), LPV/RTV alone had 84% efficacy compared to 98% for combination therapy (p=0.03). No major PI resistance mutations were found by standard genotype analysis of samples from patients in the combination arm at virologic failure, but 3 of 21 patients with virologic failure in the LPV/RTV alone arm had major PI resistance mutations detected, including M46I and L76V. These findings suggest that initial therapy with a PI alone is less effective than standard combination therapy and may increase the likelihood of PI resistance with virologic failure.[30] A ritonavir-boosted PI alone may be better suited for maintenance therapy after virus suppression is achieved with standard combination therapy (reviewed in more detail below).

Intermittent Therapy

Decreased antiretroviral drug exposure may be achieved through intermittent therapy, which usually consists of pre-specified time intervals on and off therapy or is guided by the CD4 cell count.[31,32] Earlier pilot studies of short-cycle structured intermittent treatment used cycles of 7 days on therapy followed by 7 days off.[31–33] In the first trial, 10 participants were given stavudine, lamivudine, indinavir and ritonavir for up to 68 weeks. [33] Viral rebound (50–350 copies/mL) occurred during the off-treatment periods, although resistance was not detected. There were no changes in CD4 cell counts and lipids leveles declined significantly, leading the investigators to conclude that this strategy may reduce cost and toxicity. In a follow-up study of 7 day on/off cycles of therapy with an EFV-based regimen, 7 of 8 participants maintained virologic suppression for 60–84 weeks.[32] There were no changes in CD4 cell counts or lipid levels and no evidence of resistance. The FOTO study used a shorter cycle of 5 days on and 2 days off therapy. [31] Thirty subjects were enrolled, 10 on EFV-based regimens, 10 on NVP-based regimens and 10 on PI-based regimens. At 24 and 48 weeks, as-treated analysis showed that virologic suppression was maintained in 26 of 29 subjects (89.6%). None of the EFV-treated subjects developed virologic failure, which was attributed to the prolonged half-life and sustained EFV levels during the 2 day treatment interruptions.[31] No randomized trials of this strategy compared with standard continuous therapy have been performed.

Three recent trials have addressed the safety and efficacy of intermittent therapy using a CD4-count guided approach. The Trivacan ANRS 1269 trial enrolled 386 HIV-infected adults from the Côte d’Ivoire.[34] Participants were randomized to receive continuous antiretroviral therapy (CT) or CD4- guided therapy (CD4GT) with therapy interruption and re-initiation thresholds at 350 and 250 cells/mm³, respectively. Primary endpoints were severe AIDS-related morbidity and death. The incidence of severe morbidity per 100 person-years was higher in the CD4GT group (17.6) compared to the CT group (6.7; p=0.001) with the most frequent event being invasive bacterial infections. This difference led to premature closing of the study. There was no statistically significant difference in mortality.

In the Staccato Trial, CD4-guided scheduled treatment interruptions were evaluated in participants from Thailand, Switzerland and Australia.[35] 430 participants with CD4 counts greater than 350 cells/mm³ and HIV-1 RNA < 50 copies/mL were randomized to continued antiretroviral therapy (CT) or scheduled treatment interruptions (TI). Therapy was restarted after a confirmed CD4 count below 350 cells/mm³ in the TI arm. The primary study endpoints were the proportion of participants with HIV-1 RNA < 50 copies/mL at the end of the trial and cumulative antiretroviral use in both groups. Reduced medication use in the TI group, indicated as a “drug savings” compared to the CT group of 61.5%, was reported. HIV-1 RNA levels were below 50 copies/mL in 90.5% and 91.8% of the participants in the TI and CT groups, respectively. At the end of trial, the TI group had lower mean CD4 counts compared to the CT group (p=0.001), and fewer subjects maintained a CD4 cell count above 350 cells/mm³ in the TI vs. the CT group (p<0.0001). The investigators concluded that a substantial drug savings occurred in the TI group, and that treatment-related adverse events were more common in the CT group.

The SMART study [36] enrolled 5472 participants with CD4 cell counts above 350 cells/mm³, randomized to continuous or episodic therapy (CT or TI). Participants in the TI group deferred therapy until the CD4 cell count was < 250 cells/mm³. After an average follow-up of 16 months, opportunistic infections or death from any cause occurred in 120 TI participants (3.3 events per 100 person-years) compared with 47 in the CT group (1.3 events per 100 person-years) giving a hazard ratio of 2.6 (p<0.001) for the TI group. The trial was stopped prematurely and the investigators concluded that intermittent antiretroviral therapy increased the risk of opportunistic diseases. An unexpected finding was that the incidence of cardiovascular, renal and hepatic disease was higher in the TI group, contrary to the belief that antiretroviral therapy increases the risk of such adverse outcomes.

Taken together, these studies do not support intermittent therapy as a simplification strategy because of a greater risk of CD4 decline, morbidity and mortality.

Induction-Simplified Maintenance Therapy

The results of clinical trials of induction therapy followed by simpler maintenance regimens are reviewed below and summarized in Tables 2a and 2b.

Table 2.

Table 2a. Randomized Clinical Trials of Simplified Maintenance Therapy with at least 24 Weeks of Follow-up
Title	Trial Design	Sample Size	Virologic Failure by HIV-1 RNA Level	Regimen/s Evaluated	Proportion Without Virologic Failure	Comments
ACTG 343 [38]	Randomized	509	≥ 200copies/mL	ZDV/3TC/IDV	96%	Induction therapy for 24 weeks
		(316 randomized)		ZDV/3TC	77%	Results at Interim analyses by DSMB.
				IDV alone (n=103)	77%
Trilège [39, 66]	Randomized	378 enrolled	≥ 500 copies/mL	ZDV/3TC/IDV	91%	Induction therapy for 24 weeks
		(279 randomized)		ZDV/3TC	69%	Results at a median 6 month follow up.
				ZDV/IDV (n=94)	78%
ADAM [67, 68]	Randomized	62 Enrolled	>400 copies/mL once	d4T/3TC/SQV/NFV	91% (1/11 failed)	Induction for 26 weeks
		25/31 randomized	or	d4T/NFV	42% (4/7failed)	Results at a median of 36 weeks
		with 24 week data	>100 copies/mL, twice	SQV/NFV	28.6% (5/7failed)
TRIZAL [19]	Randomized	219 enrolled	≥400 copies/mL	2 NRTI + NNRTI or PI	78%	Induction for at least 6 months
		(209 randomized)		ZDV/3TC/ABC	78%	Results at 48 weeks
OK Study [41, 43, 46]	Randomized	42	>500 copies/mL once	2 NRTI + LPV/RTV	95% (20/21)	Required VL<50 c/mL ≥6 mo prior to entry
				LPV/RTV alone	81% (17/21)	69% subjects previously exposed to PI.
OK04 [44–46]	Randomized	198 randomized	>500 copies/mL, confirmed	LPV/RTV alone (n=100)	94% (94/100)	Required VL<50copies/mL for more than 6 months prior to entry
				(< 50copies/mL)	89% ** (89/100)	Primary outcome: virologic success at 48 weeks
				LPV/RTV + NRTI	90% (90/98)	Two subjects from each arm had PI & RT resistance mutations
				(< 50copies/mL)	90% ** (90/98)	One subject in the LPV/RTV alone arm had only PI resistance mutations
Abbott M03-613 [47, 49]	Randomized	155	≥500 copies/mL	LPV/RTV Alone (<50 copies/mL)	50%	Required 3 consecutive VL<50 copies/mL prior to simplification after
		2:1 randomization		(<500 copies/mL at 72 wks)	84%	Primary outcome, virologic success (VL< 50 copies/mL) at 96 weeks
				EFV+ZDV+3TC (<50 copies/mL)	61%	Resuppression to VL<50 copies/mL in 11/12 with continued LPV/RTV alone
				(<500 copies/mL at 72 wks)	91%	PI resistance in 2/15, NNRTI resistance 1/5
						Significant sparing of peripheral lipoatrophy in LPV/RTV alone arm
						Adherence & baseline CD4 cell counts were predictors of VF
KalMO [50]	Randomized	60	> 1000 copies/mL	LPV/RTV alone (n=−30)	86.7% (26/30)	Required undetectable viremia for 6 mo prior to simplification
				Triple Therapy with LPV/RTV	83.3% (25/30)	No previous history of VF, and no genotypic resistance at VF
						Subjects without VF maintained VL<80 copies/mL through 48 weeks
Opravil M, et al [18, 37]	Randomized	172 randomized	>400 copies/mL confirmed	PI + 2 NRTI (n=79)	94% (74/79)	Previous exposure to single or dual NRTI therapy and archived RT resistance were predictors of virologic failure
		163 analyzed		ABC+3TC+ZDV (n=84)	85% (69/84)	Virologic failure rates did not reach statistical significance
						Median follow-up was 84 weeks

Table 2b. Pilot Clinical Trials of Simplified Maintenance Therapy with at least 24 Weeks of Follow-up
Title	Trial Design	Sample Size	Virologic Failure by HIV-1 RNA Level	Regimen/s Evaluated	Proportion Without Virologic Failure	Comments
ESS40013 Study [20]	Randomized	484 enrolled	Failure to achieve <50 copies/ml by week 36	ABC+3TC+ZDV+EFV	79%	Virologic success <50 copies/ml at 48 weeks for subjects on maintenance therapy
		282 randomized to maintenance therapy	or	ABC+3TC+ZDV	77%	61% suppressed <50 copies/mL by week 48 on induction regimen, 26% DC rate
			>500 copies/mL confirmed post suppression			Virologic failures were 16 on triple NRTI and 8 on continued induction
						11 of 16 triple NRTI virologic failures had RT resistance detected
Trizefal study [21]	Randomized	209 randomized	Failure to achieve <50 copies/mL by week 36	ABC+3TC+ZDV+EFV Induction	31%	Primary endpoint at 72 weeks, induction 36 weeks
		114 received maintenance therapy	or	ABC+3TC+ZDV+LPV/RTV Induction	43%	45% of patients did not reach maintenance phase, primarily due to AEs
			>200 copies/ml confirmed	ABC+3TC+ZDV Maintenance		Virologic success by OT of triple NRTI maintenance arms was 63 & 75%, respectively
						Concerns for insufficient period of virologic suppression prior to simplification
ACTG 5201[57, 58]	Single Arm Pilot Study	36 enrolled	≥200 copies/mL, confirmed	ATV/RTV alone	91% (31/34)	Required VL<50 c/mL for at least 48 weeks prior to entry, primary endpoint at 24 weeks
		(34 simplified)				97% of groups plasma samples tested had VL<50 copies/mL
						No major PI resistance was detected by Single Genome Sequencing
Atazanavir/ritonavir Alone [59]	Single Arm Pilot Study	15	>20 copies/mL, confirmed	ATV/RTV alone	66% (10/15)	Required <20 copies/mL ≥12 months
						Study stopped due to 5 failures per study criteria; no resistance found
ATARITMO [56]	Single Arm Pilot Study	29 enrolled	> 400 copies/mL	ATV/RTV alone	93% (22/24)	Required no previous ART failure and VL<50 at entry
		27 reached 24				2 subjects with HIV-1 RNA >100copies/mL in CSF
		week endpoint				and seminal plasma at baseline and at week 24
Indinavir/ritonavir Alone [40]	Single Arm Pilot Study	12	>400 copies/mL or	IDV/RTV alone	100%	Required VL<50 copies/mL ≥3 mo prior to entry, follow up for 48 weeks
			> 200 copies/mL, confirmes			Median time of previous ART was 28.5 mo
Lopinavir/ritonavir Alone [69]	Single Arm Pilot Study	18	>75copies/mL	LPV/RTV alone		Switch strategy: NNRTI-based regimen to PI alone maintenance therapy
				ITT	66% (12/18)	Primary endpoint: HIV-1 VL<75copies/mL at 48 weeks
				OT	92% (12/13)	Two virologic failures, 3 withdrew due to diarrhea, 2 to diabetes
Brazilian Study [51]	Single Arm Pilot Study	27 enrolled	>40 copies/mL, confirmed	LPV/RTV Alone	63% (17/27)	9 of 10 virologic failures, resuppressed on PI based regimen
						1 of 10 with primary PI resistance, resuppressed on ATV/RTV + NRTI
						5 of 10 failures had previously failed an ARV regimen

Triple NRTI maintenance regimens

Maintenance therapy with three NRTI following induction with standard regimens has shown some promise although study results have not been consistent.[18–21, 37] The four major trials of this strategy are summarized here to illustrate the variability in outcomes. In a randomized trial by Opravil et al., 163 patients with suppressed HIV RNA for at least 6 months and no known RT mutations at codon 215, continued PI-based triple therapy (n=79) or switched to coformulated abacavir/zidovudine/lamivudine (n=84).[18] After a median follow-up of 84 weeks, virologic failure in the continuation arm occurred in 6% compared to 15% in the triple NRTI arm (p=.081). Previous exposure to single or dual NRTI therapy and archived RT resistance in baseline HIV-1 DNA samples were predictors of failure.[18, 37] In the TRIZAL study, 209 patients with no prior history of NRTI monotherapy and HIV-1 RNA levels <50 copies/mL were randomized to continued PI- or NNRTI-based regimens (n=103) or to abacavir/lamivudine/zidovudine (n=106). [19] At week 48, the proportion of subjects with virologic failure was 22% in each arm and significant improvement in lipid levels was seen in the abacavir/lamivudine/zidovudine arm.

The ESS40013 study also evaluated maintenance with abacavir/lamivudine/zidovudine alone in a randomized fashion in 484 antiretroviral naïve patients. [20] After 48 weeks of abacavir/lamivudine/zidovudine with efavirenz, 282 participants were randomized to continue this induction regimen or to simplify to abacavir/lamivudine/zidovudine. At 96 weeks, 79% of participants in the continued induction arm and 77% in the abacavir/lamivudine/zidovudine arm that continued on the maintenance phase of the study had HIV-1 RNA level <50 copies/mL by ITT analysis (missing=failure, p=0.697). Virologic failure occurred in 16 patients in the triple NRTI arm as compared to 8 in the induction arm during the maintenance period (p=0.134). Genotype testing of 19 patients with virologic failure revealed NRTI and/or NNRTI mutations in 11 of 16 patients in the abacavir/lamivudine/zidovudine arm compared with only 4 of 8 patients in the continued induction arm.[20] In a subsequent study of 209 patients, induction with abacavir/lamivudine/zidovudine with efavirenz or lopinavir/ritonavir was followed therapy with abacavir/lamivudine/zidovudine alone for 48 weeks. [21] Of patients initially induced with the PI-based regimen, 43% maintained HIV-1 RNA levels of <50 copies/mL at week 72 compared to only 31% of those who received EFV-based induction regimen. Nine subjects developed NRTI resistance during the maintenance phase, 6 from the EFV induction arm.[21] These studies underscore the variability in success of maintenance therapy with abacavir/lamivudine/zidovudine and its infrequent use.

Protease inhibitor maintenance regimens

Induction-simplified maintenance therapy was initially evaluated in the late 1990’s to decrease antiretroviral exposure and pill burden after an induction regimen had achieved viral suppression for 3 to 12 months. The results of these initial trials were mixed and generally favored continuation of the induction regimen.[38, 39] The more recent availability of potent, ritonavir-boosted protease inhibitors with better safety profiles has renewed interest in simplified maintenance therapy. Recent or ongoing clinical trials of the PIs that have been utilized for this strategy are reviewed below.

Indinavir

Kahlert et al. studied simplified maintenance therapy with ritonavir-boosted indinavir alone.[40] Twelve participants with no history of treatment failure on regimens that included indinavir/ritonavir plus 2 NRTI were included. No virologic breakthrough to >500 copies/mL was observed during 48 weeks of study, although 4 subjects experienced renal toxicity with renal calculi in 3 and elevated creatinine in 2, suggesting that indinavir is not the optimal agent for this strategy.

Lopinavir

Lopinavir/ritonavir has shown promise for simplified maintenance therapy as a result of its potency and high barrier to resistance. However, twice daily dosing, negative effects on lipid metabolism and GI upset are potential limiting factors. In the “Only Kaletra (OK)” study, Arribas et al randomized 42 participants without a history of virologic failure and receiving 2 NRTI plus lopinavir/ritonavir to lopinavir/ritonavir alone or to continued combination therapy.[41] Three virologic failures occurred in the lopinavir/ritonavir alone arm, and one participant discontinued therapy in the combination therapy arm because of hyperlipidemia. By ITT analyses at week 24, 17/21 (81%) participants in the simplified arm maintained viral suppression < 50 copies/mL compared with 20/21 (95.2%) in the combination therapy arm (p=0.34). Standard genotyping identified the V77I mutation in protease in 2 subjects with virologic failure in the lopinavir/ritonavir alone arm (one associated with L63P) and wild type protease in a third subject. All 3 subjects regained virological control after restarting two NRTI. Changes in the level of persistent viremia among subjects who remained suppressed below 50 copies/mL were evaluated using a modified Roche Amplicor HIV-1 RNA assay with a quantification limit of 3 copies/mL. Encouragingly, participants in the lopinavir/ritonavir alone arm maintained the same median level of persistent viremia, approximately 3–4 copies/mL of plasma, as did participants on the standard of care arm.[42] Fourteen of the original 21 patients (67%) maintained virologic suppression on LPV/RTV alone for 4 years.[43]

The follow-up OK04 study randomized 198 subjects with at least 6 months of antiretroviral therapy and HIV-1 RNA level below 50 copies/mL to lopinavir/ritonavir alone or lopinavir/ritonavir with 2 NRTI.[44] No previous history of virologic failure was allowed. The primary endpoint was therapeutic failure, defined as 2 consecutive HIV-1 RNA values >500 copies/mL 2 weeks apart without re-suppression to below 500 copies/mL after restarting NRTI. At 48 weeks, therapeutic success was observed in 94% vs. 90% in the lopinavir/ritonavir alone vs. the control arm, respectively. The proportions of subjects with HIV-1 RNA < 50 copies/mL by ITT (reinduction=failure) for the lopinavir/ritonavir alone vs. the control arm were 85% vs. 90% at 48 weeks (p=0.31) and 77% vs.77.6% at 96 weeks.[44, 45] The most common cause for therapeutic failure in the control arm was adverse events. In the simplified arm, the most common reason for restarting NRTI was HIV-1 RNA between 50–500 copies/mL. The authors concluded that lopinavir/ritonavir alone was non-inferior to continued combination therapy in subjects with prior viral suppression. Of the subjects with HIV-1 RNA >500 copies/mL after 96 weeks, only 2 of 16 in the lopinavir/ritonavir arm had PI resistance mutations compared with 2 of 4 subjects in the control arm.[44, 45] Ten of 12 subjects on lopinavir/ritonavir alone who restarted NRTI regained viral suppression to <50 copies/mL. [44] In a multivariate analysis of risk factors for loss of virologic suppression in both the OK and OK04 studies, lower self-reported medication adherence, lower baseline hemoglobin, and lower nadir CD4 cell count (<100 cells/mm³) were associated with virologic failure.[46]

The MO3-613 study randomized subjects to lopinavir/ritonavir + zidovudine/lamivudine followed by lopinavir/ritonavir alone after 3 consecutive months of HIV-1 RNA <50 copies/mL (n=104), vs. continuous therapy with efavirenz + zidovudine/lamivudine (n=51).[47] Fifty percent of the subjects in the lopinavir/ritonavir alone arm as compared to 61% in the efavirenz combination arm maintained viral suppression after 96 weeks on treatment (p=0.23). Protease inhibitor resistance mutations were found in 3 of 15 subjects with virologic failure in the lopinavir/ritonavir arm; however, 2 subjects had multi-class drug resistance at baseline. Two of 5 subjects with virologic failure in the efavirenz arm developed resistance, one with an NNRTI resistance mutation and one with M184V.[47] Significant risk factors for virologic failure in this trial also included lower self–reported adherence and lower baseline CD4 cell count.[48] Serial DEXA scans were available in a subset of participants. Limb fat changes from baseline were significantly different with an increase of 14% in the lopinavir/ritonavir alone arm as compared to a decrease of 9% in the efavirenz + zidovudine/lamivudine arm (p<0.001), but trunk fat changes were similar (45% and 44%, respectively, p>0.99).[49]

Nunes et al. presented data on an open label trial of 60 participants randomized to lopinavir/ritonavir alone or lopinavir/ritonavir-based triple therapy in the KalMO Study. Participants were required to have >6 months with HIV-1 RNA levels <80 copies/mL and no prior virologic failure. The primary outcome was the proportion of subjects with HIV-1 RNA <80 copies/mL at 48 weeks by ITT. In the lopinavir/ritonavir alone arm, 86.7% of participants had continued virologic suppression at 48 weeks as compared to 83.3% in the combination arm. No PI resistance was detected at virologic failure.[50]

Twenty-seven subjects with at least 6 months of HIV-1 RNA levels <40 copies/mL were switched to lopinavir/ritonavir alone in a recent pilot study.[51] Prior virologic failure on a PI-containing regimen was not exclusionary if genotype analysis identified 3 or fewer PI resistance mutations. The median number of prior regimens was 2 (range 1–5). Ten of 27 subjects experienced virologic failure, using a definition of confirmed HIV-1 RNA >40 copies/mL, five of whom had a prior history of treatment failure. This trial employed an unusually strict definition of virologic failure which likely contributed to the high failure rate reported. The study results also suggest that this strategy should not be applied to patients with a history of treatment failure on a PI-containing regimen.

Atazanavir

Atazanavir has the advantages of once-daily dosing, decreased risk of hyperlipidemia compared to other protease inhibitors, and lack of cross resistance.[52–54] Atazanavir combined with ritonavir (ATV/RTV) has shown similar potency and effectiveness to lopinavir/ritonavir in treatment-naïve patients.[55] Using an open-label, single arm design, the ATARITMO study evaluated atazanavir/ritonavir alone as simplified maintenance therapy for control of viral replication in plasma, CSF and genital secretions.[56] Prior to study entry, subjects were required to be on three drug antiretroviral therapy with HIV-1 RNA suppressed < 50 copies/mL and no prior history of virologic failure. Of 30 subjects enrolled, 27 had sustained suppression of HIV-1 RNA below 50 copies/mL at 24 weeks, one discontinued therapy at week 20, another had persistent low-level viremia below 2.5 log₁₀ copies/mL and one experienced virologic failure at week 8 but had a history of prior virologic failure on an IDV-containing regimen, in violation of the protocol. Three of 20 CSF samples obtained had HIV-1 RNA >100 copies/mL; one subject had detectable HIV-1 RNA in the CSF at both baseline and week 24. Both subjects with detectable HIV-1 RNA in CSF at baseline had previously been treated with indinavir/ritonavir alone. Semen samples were collected at baseline (n=18) and at week 24 (n=15). At week 24, 2 semen samples had HIV-1 RNA levels >100 copies/mL; one subject also had detectable HIV-1 RNA in seminal plasma at baseline.

ACTG 5201, a single arm, open-label, trial of regimen simplification to atazanavir/ritonavir alone, enrolled 36 subjects with HIV-1 RNA suppression for at least 48 weeks on their initial PI-based regimen.[57] Thirty-one subjects (91%) had continued virologic suppression through the primary endpoint at 24 weeks post-simplification. Three subjects experienced virologic failure defined as confirmed HIV-1 RNA > 200 copies/mL. Standard genotype analysis and single genome sequencing did not identify any major PI resistance mutations. [58] ATV could not be detected in plasma in two of three subjects at virologic failure. HIV-1 RNA was not detected in eight semen samples collected at 24 weeks post-simplification.

Karlstrom et al. also evaluated atazanavir/ritonavir alone as maintenance therapy in a single arm study.[59] Eligible participants had plasma HIV-1 RNA <20 copies/mL for a minimum of 12 months prior to study entry, and no history of previous PI exposure. Most were on NNRTI-based regimens. Only 15 of the planned 30 participants were enrolled. The trial was stopped prematurely after 5 instances of virologic failure occurred using a definition of confirmed HIV-1 RNA >20 copies/mL. Two of the 5 participants were receiving acid-suppressing medications prior to failure, in violation of the study protocol. All participants regained viral control after restarting the prior regimen (4) or with addition of NRTI (1). No PI resistance mutations were found at virologic failure.

Darunavir

Darunavir has the advantage over other PI of potent antiretroviral activity against protease inhibitor-resistant variants and a high genetic barrier to resistance.[60] Clinical trials of regimen simplification to darunavir/ritonavir alone are under way.

These trials of induction-maintenance therapy demonstrate that a ritonavir-boosted PI alone can maintain virologic suppression in the majority of patients, although results vary considerably depending on the patient population studied and the definition of virologic failure. The small sizes of the trials conducted to date also make their interpretation difficult. Nevertheless, the weight of evidence suggests that simplified maintenance therapy with a RTV-boosted PI should be evaluated in a well-powered non-inferiority trial compared with standard combination therapy.

Discussion

Optimizing antiretroviral therapy requires balancing efficacy with ease of administration, adverse drug effects, risk of virologic resistance, and cost. Once-daily regimens, fixed dose combination tablets, and drugs with fewer adverse effects have improved the tolerability and efficacy of therapy. Several strategies have been evaluated to decrease drug exposure, toxicity and costs, including triple NRTI regimens, intermittent therapy and simplified maintenance therapy with a ritonavir-boosted PI. At this time, triple NRTI regimens and intermittent therapy cannot be recommended because of greater risk of virologic failure in the former and increased morbidity and mortality in the latter.

Simplification of therapy to a ritonavir-boosted PI alone after prolonged virologic suppression shows promise, with lopinavir/ritonavir and atazanavir/ritonavir being the most attractive agents evaluated to date.[41, 44, 47, 50, 56, 57] Table 3 lists the potential advantages and disadvantages of simplified maintenance therapy compared with standard regimens containing 2 NRTI and a PI or NNRTI. Although most studies of simplified therapy have been small and uncontrolled, in aggregate the clinical data suggest that the majority of patients will maintain virologic suppression on a ritonavir-boosted PI alone. The potential advantages of this strategy include fewer adverse effects, particularly from thymidine analogue NRTI, lower risk of drug-drug interactions, and exposure to only one drug class, which preserves future treatment options. Virologic failure of boosted-PI maintenance therapy has been infrequently associated with PI resistance, and re-suppression of viremia is consistently achieved with the reintroduction of NRTI.[41, 44, 47, 50, 56, 57] In contrast, resistance may emerge to any of the medications and drug classes in standard combination regimens.

Table 3.

Potential Advantages and Disadvantages of Simplified Maintenance Therapy.

Potential Advantages	Potential Disadvantages
Resistance only to the simplification drug; preserves future treatment options	Lower potency; increased risk of virologic failure
Decreased risk of drug toxicity	Lack of penetration into sanctuary sites, e.g. CNS and genital tract
Fewer drug-drug interactions	Less tolerance of missed doses or variation in dosing interval
Lower cost	More frequent HIV-1 RNA monitoring

Potential disadvantages of boosted-PI maintenance therapy include poor penetration into sanctuary sites, such as the central nervous system.[61] Penetration of antiretrovirals into cerebrospinal fluid (CSF) has been shown to correlate with HIV-1 RNA suppression in CSF; however, increases in CSF HIV-1 RNA have not been observed in small numbers of patients evaluated on lopinavir/ritonavir or atazanavir/ritonavir alone.[56, 62] Incomplete suppression of viral replication in the genital tract is also a concern because potential increased risk of HIV-1 transmission from greater viral shedding. Thus far, increases in HIV-1 RNA in seminal plasma and genital tract secretions have not been detected in subsets of study participants on boosted PI maintenance therapy.[56, 57, 63]

Several studies have identified suboptimal self-reported adherence as a risk factor for virologic failure of simplified maintenance therapy suggesting that this strategy may be more vulnerable to missed doses or variations in dosing interval.[46, 48, 57] More frequent HIV-1 RNA monitoring may also be needed because of higher frequency of viremia between 50 and 500 copies/mL, which has the potential for increasing the cost of care. To address the relative cost of simplified maintenance therapy, investigators from the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) group simulated HIV-1 disease progression and costs of different treatment strategies. The model projected lower lifetime medical costs for maintenance therapy with atazanavir/ritonavir alone compared to continuous triple drug therapy, even after accounting for more frequent HIV-1 RNA monitoring.[64]

Future Prospects

The availability of new agents and new drug classes present opportunities for further exploration of simplified antiretroviral therapy. To date, treatment with the fixed dose combination of TDF/FTC/EFV is the simplest licensed regimen with demonstrated efficacy. Although it will be difficult to identify therapy that is simpler than one tablet daily, this regimen is not optimal for all patients, particularly women of child-bearing potential. Efavirenz is also vulnerable to resistance with a single mutation. The potential for development of other three drug fixed-dose combinations is under consideration with newer agents, such as TMC-278, that can be dosed once daily, and may be able to overcome these limitations of EFV.

With regard to investigational strategies, treatment success has been demonstrated in most patients maintained on lopinavir/ritonavir and atazanavir/ritonavir alone. Darunavir/ritonavir alone is under study in two European trials. Simplification of maintenance therapy to 2 potent drugs from different classes may sustain virus suppression more consistently than a ritonavir-boosted PI alone, but this strategy has yet to be evaluated. For example, treatment with an integrase inhibitor and either a protease inhibitor or nonnucleoside would avoid the additional cost, toxicity, and risk of virologic resistance from NRTI. Unanswered questions remain about the optimal length of induction therapy prior to simplification, the characteristics of patients for whom such a strategy would be effective, and the optimal agents and classes to use. Future clinical trials are warranted to address these questions, and potentially expand treatment options for patients with HIV-1 infection.