Adherence to HIV treatment regimens: systematic literature review and meta-analysis

Figures & data

Figure 1 PRISMA diagram.

Note: ^aTwo identified studies were relevant for all three objectives.^5,32
Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1 Characteristics of observational studies identified by the systematic literature review that assess the relationship between adherence and use of STR vs MTR (objective 1)

Study, year(country or region)	Study population (study period)	Sample size	Adherence measurement	Results	Did STR improve Adherence (yes/no)?
Cohen et al,^Citation33 2013 (USA)	Medicaid patients with an HIV diagnosis from 2005 to 2009 receiving complete ART (ie, two nucleoside/nucleotide reverse transcriptase inhibitors plus a third agent) for ≥60 days as STR or 2+PPD (2005–2009)	STR: 1,797 MTR: 5,584	MPR	Patients who received ART as a single pill per day were significantly more likely to be highly adherent to therapy than those who received MTR	Yes
Cooke et al,^Citation34 2014 (USA)	Managed care members with HIV and ART regimen recommended by US Department of Health and Human Services 2011 Antiretroviral Guidelines (2010–2011)	STR: 1,136 MTR: 1,241	MPR	Patients who received STRs were about 1.3-times more likely to be adherent to therapy (ie, MPR ≥90%) than those receiving more than one ART	Yes
Hanna et al,^Citation5 2014 (USA)	Any person-visit in the Women’s Interagency HIV Study during which an HIV-infected woman self-reported ART use in the previous 6 months and had a valid HIV-1 viral load measurement (2006–2013)	STR: 1,846a MTR: 5,584b	Self-reported	STR use was associated with increased adherence and virologic suppression	Yes
Kauf et al,^Citation35 2012 (USA)	Patients with ≥1 pharmacy claim for ABC-3TC or for ≥2 components of an NRTI backbone (1997–2005)	STR: 650 MTR: 1,947	MPR	Use of an STR improved adherence to a third regimen component and, thus, the likelihood of achieving the accepted standard for adherence to HIV therapy of 95%	Yes
Langness et al,^Citation36 2014 (USA)	Patients (aged ≥18 years) on any prescribed HIV ART, scheduled prescription blood pressure medication, or scheduled prescription mental health medication (2012–2013)	STR: 282 MTR: 295	PDC	People with HIV were more adherent to a once-daily STR than to a once-daily MTR	Yes
Rogato et al,^Citation37 2016 (Europe)	HIV-infected patients on an ART regimen recommended by European AIDS Clinical Society guidelines, version 7.0 (2009–2013)	STR: 404c MTR: 404c	PDC	STRs were associated with improved adherence when compared with a matched cohort of patient regimens consisting of recommended once-daily MTRs	Yes
Raffi et al,^Citation38 2015 (France)	Treatment-naïve HIV-positive patients (aged ≥18 years) (2006–2011)	STR: 76 MTR: 242	MPR	Significant benefit in terms of adherence was observed with the STR in comparison with regimens with one daily intake but no difference was observed when compared with regimens involving >1 pill once daily	Yes
Sax et al,^Citation39 2012 (USA)	Commercially insured patients in the LifeLink database with an HIV diagnosis between June 1, 2006 and December 31, 2008, and receipt of a complete ART regimen (2006–2008)	STR: 2,365 MTR: 4,708	MPR	ART consisting of a single pill per day was associated with significantly better adherence and lower risk of hospitalization in patients with HIV than in those receiving ≥3 pills per day	Yes
Sutton et al,^Citation40 2016 (USA)	Patients with HIV covered by South Carolina Medicaid (2006–2013)	STR: 580 MTR: 1,594	PDC	The STR was associated with higher adherence rates and a lower risk of hospitalization (both in the adjusted and unadjusted analyses)	Yes
Taneja et al,^Citation41 2012 (USA)	Patients (aged ≥18 years) with HIV, who began EFV/FTC/TDF or other EFV+≥2 NRTIs regimens or NVP+≥2 NRTI regimens between January 1, 2003 and September 30, 2009 (2003–2009)	STR: 1,874 MTR: 1,100	PDC	Adherence was lower for both EFV+≥2 NRTIs (MTR) and NVP+≥2 NRTIs (MTR) than for EFV/FTC/TDF (STR)	Yes
Tennant et al,^Citation32 2015 (USA)	Treatment-naïve HIV-positive patients (aged 18 years) (2007–2010)	STR: 165 MTR: 224	MPR	Treatment regimen was not predictive of adherence. A once- daily protease inhibitor-based MTR may result in comparable adherence to an STR in a rural HIV-infected population	No

Notes:

a Person visits.

b Person visits (after propensity score matching).

c After propensity score matching.

Abbreviations: ABC-3TC, abacavir and lamivudine; AIDS, acquired immune deficiency syndrome; ART, antiretroviral therapy; EFV, efavirenz; FTC, emtricitabine; HIV, human immunodeficiency virus; MPR, medication possession ratio; MTR, multiple-tablet regimen; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine-based regimen; PDC, proportion of days covered; PPD, pills per day; STR, single-tablet regimen; TDF, tenofovir disoproxil fumarate.

Figure 2 Objective 1 – meta-analysis comparing the effects of STRs and MTRs on optimal (≥95%) adherence levels. Excluding nevirapine-based regimen plus at least two nucleoside reverse transcriptase inhibitors arm in Taneja et al.⁴¹

Abbreviations: MTR, multiple-tablet regimen; STR, single-tablet regimen.

Table 2 Sensitivity analysis of moderators for the association between STR vs MTR use and adherence (objective 1)

Moderator	Category 1	Category 2	Regression coefficient (95% CI)	P-value
Daily regimen	Confirmed once daily	Unconfirmed once daily	0.09 (−0.14–0.32)	0.368
Adherence measurement	PDC	MPR	0.20 (−0.0120130.35)	0.056
Region	USA	EU	−0.32 (−0.71–0.40)	0.098

Note: The effect of study period had to be considered at the study level because this variable does not differ between STR and MTR groups in any one study.

Abbreviations: EU, European Union; MPR, medication possession ratio; MTR, multiple-tablet regimen; PDC, proportion of days covered; STR, single-tablet regimen.

Figure 3 Objective 1 – meta-analysis comparing the effects of STRs and MTRs on adherence levels (≥90% threshold).

Abbreviations: MTR, multiple-tablet regimen; STR, single-tablet regimen.

Table 3 Characteristics of studies identified by the systematic literature review that assess the effect of treatment adherence on viral suppression (objective 2)

Study, year (country or region)	Study population (study design)	Adherence measurement	Result	Did adherence improve viral outcomes (yes/no)?
Baxi et al,^Citation47 2015 (USA)	HIV-infected women reporting ART use for >1 month between April 2003 and April 2008 who provided at least one hair sample for analysis (Observational study)	Self-reported (VAS)	Higher self-reported adherence was associated with higher odds of suppression	Yes
Bonora et al,^Citation50 2014 (Italy)	Treatment-experienced HIV-infected patients (Observational study)	Self-reported (VAS)	Suboptimal adherence was associated with virological failure	Yes
Cohen et al,^Citation42 2013 (Multinational)	Treatment-naïve, HIV-infected adults (RCT)	M-MASRI	Suboptimal adherence (≤95%) was associated with lower treatment responses and higher rates of virologic failure	Yes
Dragovic et al,^Citation51 2014 (Serbia)	HIV-infected women initiating HAART (Observational study)	Compliant vs non-compliant	Multivariate analyses revealed that the single factor independently related to a favorable response to HAART was good compliance	Yes
Hanna et al,^Citation5 2014 (USA)	Any person-visit in the WIHS during which an HIV- infected woman self-reported ART use in the previous 6 months and had a valid HIV-1 viral load measurement (Observational study)	Self-reported (WIHS)	Single-tablet regimen use was associated with increased adherence and virologic suppression	Yes
Hernandez Arroyo et al,^Citation52 2013 (Spain)	Patients (either naïve or pretreated) with confirmed HIV infection who had been receiving active ART for >6 months (Observational study)	TDM/SMAQ	Improved adherence increased permanence time of the patient with undetectable plasma viral loads and improved patient lymphocyte counts	Yes
Jayaweera et al,^Citation53 2009 (USA)	Adult patients weighing 40 kg or more with no more than 7 days of prior antiretroviral therapy (Observational study)	Pill counts and AMAF	Adherence levels of ≥80% were associated with a high proportion of patients with a virological response (<400 copies/mL)	Yes
Josephson et al,^Citation43 2010 (Sweden)	Treatment-naïve HIV patients (RCT)	ACTG questionnaire	The number of missed doses (self-reported adherence) reported was not predictive of virologic failure, treatment failure, or plasma concentration of lopinavir, nor was it predictive of the viral load decline from baseline to week 4, in any of the treatment groups	No
Julian et al,^Citation54 2010 (USA)	Adult patients actively enrolled in HIV/AIDS clinic and HAART for at least 6 months and had provided at least two completed surveys (Observational study)	SPNS score	Higher adherence (SPNS score ≥10) was significantly correlated with lower viral load	Yes
Lathouwers et al,^Citation44 2011 (Multinational)	Treatment-naïve HIV-infected patients (RCT)	M-MASRI	A higher frequency of suboptimal adherence was reported in patients with virologic failure compared with patients without virologic failure	Yes
Martin et al,^Citation55 2008 (Spain)	Patients taking first-line therapy and antiretroviral- experienced patients (Observational study)	Pill count (70%), Pharmacy records (30%)	Risk of virologic failure was lowest in patients 80%–89.9% adherence and higher in patients with lower adherence (≤70%–79.9%)	Yes
Nelson et al,^Citation45 2010 (Multinational)	Treatment-naïve HIV-infected patients (RCT)	M-MASRI	In one MTR (darunavir/ritonavir), suboptimal adherence had no impact on virologic response, whereas a significantly higher virological response rate was achieved in patients optimally adherent to lopinavir/ritanovir	No
Podzamczer et al,^Citation56 2014	Adult HIV-infected patients with viral load under 1,000 copies/mL while receiving a stable ART for at least the last 3 months and switched to RPV/FTC/TDF due to intolerance of previous regimen (Observational study)	SMAQ	Switching to RPV/FTC/TDF improved adherence while maintaining a good immune and virological response	Yes
Sax et al,^Citation46 2012 (North America)	Adults (≥18 years) infected with HIV with plasma HIV-1 RNA concentrations of 5,000 copies/mL or more and no previous use of antiretroviral drugs (RCT)	Pill count	There was no difference in virologic response between an STR and standard of care, regardless of adherence levels (<95% or ≥95%)	No
Tennant et al,^Citation32 2015 (USA)	Adults (≥18 years) with HIV (Observational study)	MPR	Patients adherent to ART were 3-fold more likely than non-adherent patients to be virologically suppressed	Yes
Torres-Cornejo et al,^Citation57 2014 (Spain)	Adult HIV-infected patients with a plasma HIV-RNA concentration of less than 50 copies/mL for at least 6 months (Observational study)	Self-reported	Higher adherence and an HIV-DNA level less than 2 log10 copies/10^6 PBMCs at baseline were associated with a lower risk of virological failure	Yes
Viswanathan et al,^Citation48 2015 (USA)	HIV-positive persons on ART and followed in the Veterans Aging Cohort Study Virtual Cohort (VACS VC) (Observational study)	PDC	Adherence improved viral suppression in patients using PI-based regimens but not in patients on NNRTI regimens	No
Wilkins et al,^Citation49 2016 (Multinational)	Treatment naïve HIV-infected adults (Randomized open- label study)	M-MASRI/self- reports (VAS)	There was no significant difference between two STRs in terms of virological success, regardless of adherence levels (<95% or ≥95%)	No

Abbreviations: ACTG, AIDS Clinical Trials Group; AIDS, acquired immune deficiency syndrome; AMAF, antiviral medication adherence form; ART, antiretroviral therapy; FTC, emtricitabine; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; M-MASRI, Modified Medication Adherence Self-Report Inventory; MPR, medication possession ratio; MTR, multiple-tablet regimen; NNRTI, non-nucleoside reverse transcriptase inhibitor; PBMC, peripheral blood mononuclear cell; PDC, proportion of days covered; RCT, randomized controlled trial; RPV, rilpivirine; SMAQ, simplified medication adherence questionnaire; SPNS, Special Project of National Significance; STR, single-tablet regimen; TDF, tenofovir disoproxil fumarate; TDM, therapeutic drug monitoring; VAS, visual analog scale; WIHS, Women’s Interagency HIV Study.

Table 4 Characteristics of studies identified by the systematic literature review that assessed the effect of use of STR vs MTR on viral suppression (objective 3)

Study, year (country or region)	Study population (study period)	Adherence measurement	Results	Did STR improve viral outcomes (yes/no)?
Chakraborty et al,^Citation58 2016 (USA)	South Carolina residents, aged ≥13 years, living with HIV who have at least one viral load reported (2004–2013)	NA	Significant association between STR use and faster decline in community viral load	Yes
Dejesus et al,^Citation3 2009 (USA, Puerto Rico)	ART-experienced HIV-infected patients who are on their first ART regimen or who had documented viral suppression on a previous protease inhibitor-based regimen at the time of prior change in therapy (2006–2007)	Pill counts and self-reported VAS	Both STR and MTR resulted in comparable virologic suppression	No
DeJesus et al,^Citation59 2012 (Multinational)	Treatment-naïve patients with plasma HIV-1 RNA concentrations of ≥5,000 copies/mL and susceptibility to atazanavir, emtricitabine, and tenofovir (2011–2014)	NA	Proportion of patients with virologic success (HIV-1 RNA concentrations of ≤50 copies/mL) at week 48 did not differ significantly between regimens	No
Hanna et al,^Citation5 2014 (USA)	Any person-visit in the WIHS during which an HIV-infected woman self-reported ART use in the previous 6 months and had a valid HIV-1 viral load measurement (2006–2013)	Self-reported (WIHS)	STR use was significantly associated with virologic suppression	Yes
Tennant et al,^Citation32 2015 (USA)	Patients with HIV (aged ≥18 years) (2007–2010)	MPR	MTR was similarly likely to result in virologic suppression (OR=1.11; 95% CI=0.62–1.99)	No

Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; MPR, medication possession ratio; MTR, multiple-tablet regimen; NA, not applicable; OR, odds ratio; STR, single-tablet regimen; VAS, visual analog scale; WIHS, Women’s Interagency HIV Study.

Table S1 MEDLINE In-Process & Other Non-Indexed Citations and Ovid MEDLINE 1946–present; search conducted on September 14, 2016a

Search category	ID	Search terms
Disease	#1	(“human immunodeficiency virus” OR “HIV”)
Intervention	#2	(“once daily” OR “once a day” OR “QD” OR “single tablet” OR “single pill” OR “one pill” OR “fixed dose combination” OR “co-formulated”)
Adherence	#3	(“adherence” OR “nonadherence” OR “non-adherence” OR “adherent” OR “nonadherent” OR “non-adherent” OR adhere* OR “compliance” OR “noncompliance” OR “non-compliance” OR “compliant” OR “noncompliant” OR “non-compliant”)
Viral suppression	#4	(“viral load” OR “viral suppression” OR “virologic suppression” OR “virologic response” OR “virologic failure” OR “virologic success” OR “virological suppression” OR “virological response” OR “virological failure” OR “virological success” OR “RNA suppression” OR “RNA level” OR “RNA concentration” OR “undetectable” OR “undetectability”)
Association	#5	(compare* OR “comparison” OR associate* OR relate* OR relation* OR correlate* OR “correlation” OR cause* OR “versus” OR “vs” OR “vs.” OR “lead to” OR “leads to” OR “led to”)
RCT	#6	(“clinical trial” OR “clinical trials” OR “randomized controlled trial” OR “randomized controlled trials” OR “randomised controlled trial” OR “randomised controlled trials” OR random* OR enroll* OR “protocol” OR “open-label” OR “single blind” OR “double blind”)
Real world	#7	(“observational” OR “longitudinal” OR “retrospective” OR “prospective” OR “follow up” OR “cohort” OR “insurance” OR electronic medic* OR “claims data” OR “naturalistic” OR “pragmatic” OR “medical records” OR “registry”)
Study objectives
1. Real-world adherence with STR vs MTR	#8	#1 AND #2 AND #3 AND #7
2. Association between adherence and viral outcomes	#9	#1 AND #3 AND #4 AND #5 AND (#6 OR #7)
3. Comparative effects of STR vs MTR on viral outcomes	#10	#1 AND #2 AND #4 AND (#6 OR #7)
All	#11	#8 OR #9 OR #10
	#12	Limit 11 to yr=“2013-Current”
	#13	Limit 12 to English language

Note:

a An initial search of MEDLINE In-Process was completed on September 6, 2013 to identify any studies that were relevant to the three objectives that were published between 2006 and 2013.

Abbreviations: HIV, human immunodeficiency virus; MTR, multiple-tablet regimen; RCT, randomized controlled trial; STR, single-tablet regimen.

Table S2 Eligibility criteria

Criteria	Included	Excluded
Publication type	• Full-text original research published in English	• Non-English publications • Duplicate publication(s) of the same trials or studies • Case reports • Commentaries and letters • Recommendations/guidelines • Books/chapters/addresses/bibliographies/biographies/lectures • Non-systematic reviews • Systematic reviews and meta-analyses
Study design	• RCTs • Observational studies (retrospective studies, longitudinal studies, prospective studies, etc)	• Non-human studies • Preclinical studies • Phase 1 studies • Short-term studies (study length #10 days) • Studies interrupted or prematurely terminated
Study location	• North America and the European Union	• Including any location not in North America or the European Union
Population	• Adults (aged $18 years) diagnosed with HIV and treated with ART	• Children and adolescents (aged <18 years) • Non-HIV-positive patients • Studies conducted only in HIV subpopulation, including:  o patients infected with hepatitis B or C  ○ patients with a history of drug abuse  ○ patients with depression  o pregnant women  ○ homeless and marginally housed patients
Interventions	• Once-daily ART regimens	• Non-ART regimens • More-than-once-daily regimens
Outcomes	• Association between treatment regimen and adherence level, or • Association between adherence level and drug efficacy/effectiveness,a or • Association between treatment regimen and drug efficacy/effectivenessa	• Studies that report neither treatment adherence nor drug efficacy/effectiveness • Studies that do not report the association or comparative results

Note:

a Drug effectiveness or efficacy was measured as viral load (RNA level), viral suppression rate, viral failure rate, and undetectable RNA level.

Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; RCT, randomized controlled trial.

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