The impact of specific HIV treatment-related adverse events on adherence to antiretroviral therapy: A systematic review and meta-analysis

Figures & data

Figure 1.  Flow of citations through the screening process. *The population of interest was originally patients with chronic diseases; this was later restricted to patients with HIV.

Table 1. Characteristics of studies included in the meta-analysis.

Study	N	Study design	Follow-up period	Medications used	Country	Adherence definitions/assessment	Adherence recall period	Population characteristics	Determinant analysed
Aloisi et al. (2002)	366	Cohort	1 year	ART	Italy	• Self-reported questionnaire	6 months	• ICoNA cohort • Patients with HIV • Aged ≥ 18 years • At different stages of HIV disease • Treatment-naïve (receiving combination ART for ≥ 1 month) • Cohort at 1 year follow-up from inclusion in cohort	• Non-specific
Ammassari et al. (2001)	358	Cohort	NR	HAART	Italy	• Self-reported • Adherence defined as not having missed any HAART dose during the assessment period	3 days	• AdICoNA cohort • Receiving therapy for ≥ 1 month between May 1999 and March 2000 • Exclusion criteria were inability to complete the questionnaire, delirium or dementia and hospitalisation	• Lipodystrophy • Anxiety • Confusion • Insomnia • Nausea • Taste disturbances
Byakika-Tusiime et al. (2005)	304	Cross-sectional	N/A	• PI (indinavir, ritonavir, saquinavir, nelfinavir, lopinavir) • NNRTI (efavirenz, nevirapine, delavirdine) • NRTI (stavudine, lamivudine, didanosine, abacavir, zidovudine)	Uganda	• Self-reported • Adherence measured as the ratio of the doses reported to have been taken over the total number of doses prescribed • Adherence defined as >95% adherence to doses	3 days	• Patients with HIV • Aged ≥ 18 years • Receiving ART for ≥ 1 month	• Non-specific
da Silveira, Drachler, Leite, and Pinheiro (2003)	194	Cross-sectional	N/A	ART	Brazil	• Self-reported • Over two occasions (interval of approximately 1 month) • Arithmetic mean of two instances of 48 hours (first and second interview – doses that the patient reported taking divided by the number of doses prescribed over 4 days) • Adherence defined as >95% adherence to doses	Two occasions of 48-hour duration (i.e., 4 days total)	• Patients with HIV • Adolescent and adult patients who received ART from January 1998 to September 2000	• Non-specific
Heath, Singer, Shaughnessy, Montaner and Hogg (2002)	638	Cross-sectional	N/A	Antiretroviral medications	Canada	• Self-reported • Intentional non-adherence defined as reporting either skipping or altering dosages of selective regimen components or temporary cessation of therapy that was not recommended by the physician in response to adverse drug effects	Past year	• Patients with HIV/AIDS • Participating in a drug treatment programme • Respondents to the annual participant survey	• Non-specific
Ickovics et al. (2002)	93	Cohort from an RCT	24 weeks	HAART (NRTI, NNRTI, PI)	US	• Self-reported • Reported missed/skipped doses over 4 days prior to visits (conducted every 4 weeks) up to week 24 • Adherence calculated by number of pills skipped over the number of pills prescribed • Adherence defined as >95% adherence to doses	4 days (every 4 weeks)	• AACTG 370 was a rollover study from an initial cohort from the AACTG 306 RCT • Successfully completed ≥ 48 weeks of treatment in AACTG 306 and remained on assigned study medication • Individuals aged >12 years with documented HIV-1 infection	• Non-specific
Johnson et al. (2003)	2765	Cross-sectional	N/A	ART	US	• Self-reported • Patients indicated how many antiretroviral pills they had skipped during the assessment period • Adherence calculated by number of pills actually taken divided by number of pills prescribed • Adherence defined as >90% adherence to doses	3 days	• Adult patients with HIV from four cities (San Francisco, Los Angeles, New York and Milwaukee) • Free of severe neuropsychological impairment or psychosis • Not involved in another behavioural intervention study related to HIV	• Non-specific
Johnson et al. (2005)	2765	Cross-sectional	N/A	ART	US	• Self-reported • Adherence was calculated based on number of pills taken divided by the number of pills respondents reported being expected to take • Adherence defined as ≥ 90% adherence to doses	3 days	• Adult patients with HIV from four cities (San Francisco, Los Angeles, New York and Milwaukee) • Screened for Healthy Living Project • Free of severe neuropsychological impairment or psychosis • Not currently involved in another behavioural intervention study related to HIV	• Cough • Dermatological • Fatigue • Lipodystrophy • Sexual dysfunction • Anxiety • Insomnia • Numbness • Diarrhoea • Loss of appetite • Nausea • Vomiting
Murphy, Marelich, Huffman, and Steers (2004)	129	Cross-sectional	N/A	HAART	US	• Self-reported • Three measures of adherence over three assessment periods • Adherence assessed by asking participants how often they took their medications within the past time period on a 5- point response scale (for month-long adherence) or a 6-point response scale (for week-long/3-day adherence) • Participants were adherent if they reported taking their medication “all of the time” or “most of the time” (month-long adherence); or if they had not missed any medications in the past week/3-day period	3 days, 1 week, 1 month	• Patients diagnosed with HIV/AIDS • Prescribed HAART • CD4 count ≥ 100 • No opportunistic infections occurring 1 month prior to enrolment • No participation in any other medication adherence study • No current participation in a clinical trial • No psychiatric condition such as florid psychosis or uncontrollable paranoid delusions	• Dermatological • Numbness
Nieuwkerk, Gisolf, Sprangers, and Danner (2001)	160	Clinical trial	48 weeks	Ritonavir, saquinavir, stavudine	Netherlands, Belgium	• Self-reported • Patients were asked how many days they had taken all antiretroviral medication, how many days they had taken it more than 2 hours from time schedule, and how many days they had taken ritonavir/saquinavir together with food or after a meal	4 weeks	• Prometheus study • Patients with HIV-1	• Pain when swallowing • Taste disturbances • Tingling in mouth and tongue • Loss of appetite • Abdominal pain • Diarrhoea • Nausea • Vomiting
Pinheiro, De Carvalho-Leite, Drachler, and Silveira (2002)	195	Cross-sectional	N/A	Antiretroviral medications	Brazil	• Self-reported • Number of pills taken divided by the number of pills prescribed over the assessment period	48 hours	• Patients with HIV • Aged 17 years to 67 years • Initiated ART	• Non-specific
Remien et al. (2007)	200	Cross-sectional	N/A	ART	Brazil	• Self-reported • Adherence was based on number of missed/skipped pills during the assessment period divided by the number of pills respondents reported being expected to take	3 days	• Patients with HIV/AIDS • Recruited from two large teaching hospitals and several NGOs where HIV- positive adults receive supportive services in Rio de Janeiro	• Loss of appetite
Sarna et al. (2008)	310	Cross-sectional	N/A	Stavudine, lamivudine, nevirapine, zidovudine efavirenz, other NRTI/NNRTI combination regimens (abacavir, didanosine)	India	• Self-reported • Mean 4-day adherence was calculated by dividing the number of pills actually taken by the number of pills needed to be taken for 4 days as a percentage • Adherence defined as >90% adherence to doses	4 days	• Patients with HIV • Aged ≥ 18 years • Receiving ART for ≥ 30 days between May 2004 and August 2004	• Non-specific
Shah et al. (2007)	279	Cross-sectional	N/A	ART (NNRTI, NRTI, PI)	India	• Self-reported • Patients were considered adherent if they had taken ≥ 95% of planned doses over the assessment period	4 days	• Patients with HIV • Aged ≥ 18 years • Receiving ART for ≥ 3 months from December 2004 to April 2005 • Patients with acute illness or unaware of their HIV infection status were excluded	• Non-specific
Tadios and Davey (2006)	431	Cross-sectional	N/A	HAART	Ethiopia	• Self-reported • Patients were considered adherent if they had taken ≥ 95% of therapy correctly over the assessment period	1 week	• Adult patients with HIV/ AIDS attending three ART centres in Addis Ababa from December 2004 to January 2005	• Non-specific
Tessema et al. (2010)	504	Cross-sectional	N/A	HAART	Ethiopia	• Respondents were asked whether they had missed any doses the day prior to completing the questionnaire, and how often doses were missed in general (every day to never) • Respondents who reported that they had not forgotten a dose the day prior to the completion of the questionnaire and those that responded as never forgetting doses were categorised as adherent	1 day	• Adult outpatients with HIV/AIDS who were receiving ART for ≥ 3 months	• Non-specific
Trotta et al. (2003)	596	Cohort	1 year	PI-containing regimen and nevirapine-containing HAART regimen	Italy	• Self-reported • 16-item self-administered questionnaire • Non-adherence defined as reporting to have missed ≥ 1 dose or having ever experienced an interruption in drug supply during the assessment period	1 week	• Patients with HIV • Receiving ART for ≥ 1 month • Patients with dementia of grade two or greater or hospitalisation at enrolment were excluded	• Cough • Dermatological • Fatigue • Lipodystrophy • Sexual dysfunction • Anxiety • Confusion • Nausea • Vomiting
Wang et al. (2008)	308	Cohort	NR	ART (NNRTI, NRTI)	China	• Self-reported • Number of doses taken in the assessment period prior to interview • Adherence defined as >90% of doses taken correctly in previous week	7 days	• Patients with HIV • Returning for monthly ART follow-up at selected study sites between April 2006 and July 2006	• Dermatological
Wilson, Doxanakis and Fairley (2004)	200	Cross-sectional (observational)	28 days	ART	Australia	• Adherence was measured using the “every visit adherence questionnaire” • Percentage self-reported adherence was calculated for 4 days, 7 days and 28 days by dividing the number of doses missed in a period of time by the number of prescribed doses for that period and multiplying by 100, then subtracting this figure from 100 • Non-adherence defined as <98.2% adherence to doses	4 days, 7 days and 28 days	• Participants were recruited from the study site between October 2002 and February 2003, if they were aged ≥ 18 years, HIV-positive, and currently using ART	• Non-specific
Note: AACTG, Adult AIDS Clinical Trial Group; AdICoNA, Adherence Italian Cohort of Antiretroviral-Naïve patients; AIDS, acquired immune deficiency syndrome; ART, antiretroviral therapy; CD4, cluster of differentiation 4; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; ICoNA, Italian Cohort of Antiretroviral-Naïve patients; NGO, non-governmental organisation; N/A, not applicable; NR, not reported; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RCT, randomised controlled trial; US: United States.

Figure 2.  Forest plot of meta-analyses of ORs pertaining to the effects of treatment-related general AEs on adherence. Each OR represents a pooled estimate for the corresponding adverse health outcome. All meta-analyses were conducted using a random effects model. *This OR was calculated using multiple studies and data from mutually-exclusive sub-groups within the same study. CI, confidence interval; I² , heterogeneity index; OR, odds ratio.

Figure 3.  Forest plot of meta-analyses of ORs pertaining to the effects of treatment-related mental health AEs on adherence. Each OR represents a pooled estimate for the corresponding adverse health outcome. All meta-analyses were conducted using a random effects model. CI, confidence interval; I² , heterogeneity index; OR, odds ratio.

Figure 4.  Forest plot of meta-analyses of ORs pertaining to the effects of treatment-related sensory AEs on adherence. Each OR represents a pooled estimate for the corresponding adverse health outcome. All meta-analyses were conducted using a random effects model. *This OR was calculated using multiple studies and data from mutually-exclusive sub-groups within the same study. ‡This OR was derived from mutually-exclusive sub-groups in a single study. CI, confidence interval; I² , heterogeneity index; OR, odds ratio.

Figure 5.  Forest plot of meta-analyses of ORs pertaining to the effects of treatment-related gastrointestinal AEs on adherence. Each OR represents a pooled estimate for the corresponding adverse health outcome. All meta-analyses were conducted using a random effects model. *This OR was calculated using multiple studies and data from mutually-exclusive sub-groups within the same study. ‡This OR was derived from mutually-exclusive sub-groups in a single study. CI, confidence interval; I² , heterogeneity index; OR, odds ratio.

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