A review of cardiovascular and renal function monitoring: a consideration of older adults with HIV

Figures & data

Table 1 Major studies of cardiovascular risk in HIV-positive patients with or without cART

Study	Population	Design	Outcomes
Currier et al^Citation31	HIV+ Males (n = 20,742) HIV+ Females (n = 7,771) Non-HIV+ Males (n = 970,259) Non-HIV+ Females (n = 2,084,437)	Historical cohort	HIV group RR for CHD by ART or not ART (Covariate adjusted) 18–33 y 2.06 (95% CI, 1.42–2.99; P < 0.001) 34–49 y 1.08 (95% CI, 0.91–1.28; P > 0.05) 50–65 y 0.79 (95% CI, 0.63–1.00; P > 0.05) 66 or older 1.15 (95% CI, 0.65–2.04; P > 0.05)
Obel et al^Citation32	HIV+ (n = 3,953) Non-HIV+ (n = 373,856) Age: <45	Historical cohort	Adjusted relative risk was significantly higher in HAART cohort 2.12 (95% CI, 1.62–2.76) RR did not increase after 8 years of follow up
Friss-Moller et al^Citation33	HIV+ Patients (n = 23,468) Age: 34–45 (IQR)	Prospective cohort	Exposure to cART and rate of MI – RR 1.26 (95% CI, 1.12–1.41; P < 0.001)
Bozzette et al^Citation35	HIV+ Patients (n = 41,213) 98.2% male Age: 35–55	Historical cohort (VA population)	Serious CV event: HR 1.05 (95% CI, 1.05–1.06) Death: HR 1.03 (95% CI, 1.03–1.03) Pre-existing vascular disease: HR 4.01 (95% CI, 3.39–4.76)
Lichtenstein et al^Citation36	HIV+ Patients (n = 2,005) Age: 42 (median)	Prospective observational cohort	CVD incidence (per 100 person years) 1.32 vs 3.27 (P = 0.002) Exposure vs non-exposure to HAART, respectively
El-Sadr et al^Citation37	HIV+ Patients (n = 5,472) Drug Conservation Group (treatment <250 CD4 cells/mm^3) (n = 2,720) Viral Suppression Group (n = 2,752) Age: 38–50 (IQR)	Open-label, randomized	Major Cardiovascular, Renal, or Hepatic Disease HR 1.7 (95% CI, 1.1–2.5) in Drug Conservation Group as opposed to cART
Lang et al^Citation38	HIV+ Patients (n = 74,958) Age: 41–54 (IQR)	Case-control	Risk of MI Abacavir OR 2.01 (95% CI, 1.11–3.64) (Overall exposure to cART not measured)

Abbreviations: +, positive; ART, antiretroviral therapy; cART, combination antiretroviral therapy; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HAART, highly active antiretroviral therapy; HR, hazards ratio; IQR, interquartile range; MI, myocardial infarction; OR, odds ratio; RR, relative risk; VA, Veterans Affairs; y, years; vs, versus, HIV, human immunodeficiency virus.

Table 2 Cardiovascular risks for specific antiretroviral therapies

Study	Population	Design	Outcome
Classes
Friis-Moller et al^Citation39	Cohort (n = 23,437) MI (n = 345) Age (median): 39 (with MI)	D:A:D, retrospective case-control	RR of MI per year of PI exposure 1.16 (95% CI, 1.10–1.23) RR of MI per year of NNRTI exposure 1.05 (95% CI, 0.98–1.13)
Worm et al^Citation44	MI (n = 580) Without MI (n = 32,728) Age (median): 49 (with MI), 44 (without MI)	D:A:D, retrospective case-control	Adjusted RR of MI: Indinavir, cumulative exposure (per year) 1.12 (95% CI, 1.07–1.18) Lopinavir-ritonavir, cumulative exposure 1.13 (95% CI, 1.05–1.21) Nelfinavir, cumulative exposure 1.04 (95% CI, 0.98–1.11) Saquinavir, cumulative exposure 1.04 (95% CI, 0.98–1.11) Efavirenz, cumulative exposure, 1.02 (95% CI, 0.96–1.08) Nevirapine, cumulative exposure 0.97 (95% CI, 0.92–1.03) Didanosine, recent exposure 1.41 (95% CI, 1.09–1.82) Abacavir, cumulative exposure 1.07 (95% CI, 1.00–1.14); recent exposure 1.70 (95% CI, 1.17–2.47) Tenofovir, cumulative exposure 1.04 (95% CI, 0.91–1.18); recent exposure 1.14 (95% CI, 0.85–1.53) No association with zidovudine, stavudine, lamivudine, or tenofovir
Protease Inhibitors (older)
Holmberg et al^Citation40	HIV+ (n = 5,672) 17,712.4 person years Age (median/range): 47 (28–67)	HOPS, prospective observational cohort	MIs (n = 21) per number of patients Protease inhibitors: 19/3,247 No protease inhibitors 2/2,425 OR 7.1 (95% CI, 1.6–44.3) Adjusted HR 6.5 (95% CI, 0.9–47.8)
Jutte et al^Citation41	HIV+ (n = 1,324) PI use (n = 373)	Retrospective cohort	MI PI use (n = 5), 1.06/100 person years (95% CI, 0.42–2.24) No PI use (n = 3), 0.21/100 person years (95% CI, 0.06–0.54; P = 0.025)
Klein et al^Citation42	HIV+ (n = 4,159) 14,823 person-years Age (median): 42	Retrospective cohort	Acute MI: No PI use (n = 19) PI use (n = 28) Age adjusted MI hospitalization rates: No PI exposure: 4.4 (95% CI, 2–6.7) PI exposure 4.3 (95% CI, 2.4–6.1)
Mary-Krause et al^Citation43	HIV+ (n = 34,976) 88,029 person-years History of MI: Age (mean): 41.9 No MI: Age (mean): 37.7	FHDH, Prospective cohort	Relative hazard for MI PI 2.56 (95% CI, 1.03–6.34; P = 0.04) NRTI 0.93 (95% CI, 0.19–4.65; P = 0.93); NNRT 1.38 (95% CI, 0.67–2.83; P = 0.38) Exposure to PI: <18 months: 8.2 (95% CI, 4.7–11.7) per 10,000 patient-years 18–29 months: 15.9 (95% CI, 7.9–23.9) per 10,000 patient-years ≥30 months: 33.8 (95% CI, 15.4–52.1) per 10,000 patient-years
Bozzette et al^Citation48	HIV+ (n = 36,766) Age <35 years = 17.6% 25–55 years = 71.3% >55 years = 11%	Retrospective cohort of patients using VA services compared to typical US patients	HR for admission for cardiovascular disease for 24 months of exposure: NRTIs 0.88 (95% CI, 0.63–1.22) PIs 1.23 (95% CI, 0.78–1.93) NNRTIs 1.09 (95% CI, 0.56–2.09)
Davidet al^Citation49	Case Angina (n = 8); MI (n = 8) Control (n = 32) Age (median): 43 years (ICVD); 45 years (control)	Retrospective case-control	Number of patients with cardiovascular disease (case vs control) NNRTI Case 0 vs control 0 (P = 0.09) NRTI Case 190 vs control 130 (P = 0.02) PI Case 118 vs control 64 (P = 0.46)
Atazanavir
Monforte et al^Citation46	301,907 person-years	D:A:D study Prospective cohort	Incidence of MI No drug exposure: 0.28 (95% CI, 0.26–0.3) per 100 person-years Drug exposure (3 or more years): 0.2 (0.12–0.32) per 100 person-years
Didanosine
Lang et al^Citation38	HIV+ (n = 74,958) MI (n = 423) Median age Cases (n = 289) Age (median/IQR): 47 (41–54) Age (median/IQR): 46 (40–54)	FHDH, Prospective, observational cohort	Cumulative exposure 0.91 (95% CI, 0.82–1.01; P = 0.06) Cumulative, recent, and past exposure 0.88 (95% CI, 0.77–1.01; P = 0.07) No risk associated with lamivudine, stavudine, tenofovir,zalcitabine, zidovudine, efavirenz, or nevirapine No risk associated with indinavir +/− ritonavir, nelfinavir, saquinavir +/− ritonavir Amprenavir or fosamprenavir +/− ritonavir Cumulative: 1.57 (95% CI, 1.24–2; P = 0.001) Cumulative, recent, and past: 1.56 (95% CI, 1.21–2.01; P = 0.001) Lopinavir/ritonavir Cumulative: 1.37 (95% CI, 1.13–1.65;), P = 0.002 Cumulative, recent, and past: 1.34 (95% CI, 1.09–1.64; P = 0.005)
SMART/INSIGHT and D:A:D^Citation47	HIV+ (n = 4,544) Didanosine use (n = 643) Age (median/IQR): 44 (38–50)	Prospective cohort	HR (multivariable) in viral suppression arm CVD, major 1.06 (95% CI, 0.43–2.58) Clinical MI 1.89 (95% CI, 0.35–10.2) CVD, minor 1.03 (95% CI, 0.35–3.03) CVD, expanded definition 0.86 (95% CI, 0.40–1.85) HR (multivariable) for new ischemic abnormalities on EKG in viral suppression arm 0.81 (95% CI, 0.59–1.12)
Sabin et al^Citation50	HIV+ (n = 33,347) 157,912 person-years Age (median/range): 49 (24–92)	Prospective cohort	Cumulative exposure (per year) 1.06 (95% CI, 1.01–1.12; P = 0.03) Recent exposure (within 6 months) 1.49 (95% CI, 1.14–1.95; P = 0.003) Past exposure 1.08 (95% CI, 0.84–1.39; P = 0.54)
Abacavir
SMART/INSIGHT and D:A:D^Citation47	HIV+ (n = 4,544) Abacavir use (n = 1,019) Median age: 45 (39–51)	Prospective cohort	Adjusted HR (multivariable) in abacavir, not didanosine arm CVD, major 1.80 (95% CI, 1.04–3.11) Clinical MI 4.25 (95% CI, 1.39–13.0) CVD, minor 2.70 (95% CI, 1.51–4.83) CVD, expanded definition 1.91 (95% CI, 1.25–2.92)
ACTG A5001/ALLRT^Citation51	HIV+ (n = 5,056) Abacavir use: (n = 1,704) Median age: 37% population ≥45: 23% (n = 1,182)	Historical Observational cohort	Hazard Ratio of exposure to abacavir and MI 1 year: 0.7 (95% CI, 0.2–2.6) 6 year: 0.6 (95% CI, 0.3–1.4)

Abbreviations: CI, confidence interval; CVD, cardiovascular disease; D:A:D, Data Collection on Adverse Events of Anti-HIV Drugs; FHDH, French Hospital Database on HIV; HR, hazards ratio; hsCRP, high-sensitivity C-reactive protein; HIV, human immunodeficiency virus; HOPS, HIV outpatient study; ICVD, ischemic cardiovascular disease; IL6, interleukin-6; IQR, interquartile range; MI, myocardial infarction; NRTI, non-nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; OR, odds ratio; PI, protease inhibitor; PY, patient-years; RR, relative risk; vs, versus; SMART, Strategies for Management of Antiretroviral Therapy.

Table 3 Renal risks with tenofovira

Study	Population	Design	Outcome
Scherzer^Citation64	(n = 10,841) Age (mean): 46 (VA population)	Cohort	Tenofovir exposure (Multivariate adjustment) Proteinuria: HR 1.34 (95% CI, 1.25–1.45; P < 0.0001) Rapid decline: HR 1.11 (95% CI, 1.03–1.18; P = 0.0033) CKD: HR 1.33 (95% CI, 1.18–1.51; P < 0.0001)
Dauchy et al^Citation65	(n = 399) Age (median, IQR): 47.4 (IQR 42.5–54) Aquitaine cohort	Cohort	Tenofovir exposure: Proximal renal tubular dysfunction: OR 1.23 per year (95% CI, 1.02–1.47; P = 0.028)
Mocroft et al^Citation108	(n = 6,843) Age (median, IQR): 43 (38–50) 103 centers in Europe, Israel, and Argentina, EuroSIDA study group	Prospective cohort	Tenofovir exposure (multivariable adjustments) Incidence of CKD per year: 1.16 (95% CI, 1.06–1.25; P < 0.0001)
Laprise et al^Citation86	(n = 1,043) Age (median, IQR): 39.3 years (34–45.2) Montreal, Canada	Prospective cohort	Tenofovir exposure: HR 1.63 (95% CI, 1.26–2.1) Cumulative eGFR loss: 1 year: −3.05 (P = 0.17) 2 years: −4.05 (P = 0) 3 years: −2.42 (P = 0.23) 4 years: −3.09 (P = 0.119)
Monteagudo-Chu et al^Citation87	(n = 230) Age (mean) Tenofovir: 52.6 Abacavir: 50.2 Bronx, NY (VA)	Retrospective chart review assessing progression of CKD from stages 0–1 to 2–5 with abacavir as control	Tenofovir (vs abacavir): progression of CKD Stage 2: 48.8% vs 23.7% (P < 0.001) Stage 3: 5.8% vs 0% (P = 0.28) Progression to CKD stage 2: HR 2.12 (95% CI, 1.41–3.18;P < 0.001) Progression to CKD stage 3: HR 4.91 (95% CI, 1.02–23.7; P = 0.048)
Calza et al^Citation88	(n = 324) Age (median, IQR) Tenofovir exposed: 42.5 (34.2–50.1) Tenofovir unexposed: 42.9 (33.6–51.4)	Retrospective cohort	Tenofovir exposed (Multivariable adjusted) eGFR decline: HR −5.1 (95% CI, −7.6 to −3.28; P < 0.0021)
Beaudrap et al^Citation89	(n = 324) Age (mean): Tenofovir: 40 No tenofovir: 38 Senegal, eGFR 1,215	Cohort	eGFR change from baseline at 12 months Tenofovir: −10.4 mL/min No tenofovir: +4.33 mL/min
Horberg et al^Citation90	(n = 1,647) Age (median, IQR): Tenofovir: 43 (37.9–49.5) No Tenofovir: 41.5 (35–49) Kaiser Permanente health maintenance organization	Retrospective cohort	Tenofovir exposure vs No tenofovir exposure over 104 weeks eGFR decline: −7.6 mL/min/1.73 m^2 (95% CI, −9.2 to −5.9; P < 0.001) Development of proximal tubular dysfunction: RR 5.23 (95% CI, 2.08 to 13.1; P = 0.004)
Post et al^Citation91	(n = 385) Age (median): 37 76 centers in Europe ASSERT study	Randomized Once daily abacavir/lamivudine versus tenofovir/emtricitabine both with efavirenz	Abacavir/lamivudine/efavirenz vs tenofovir/emtricitabine/efavirenz Change eGFR (from baseline): 0.953 (95% CI, −1.445 to 3.351, P = 0.435) Renal tubular dysfunction (marker): increase risk in tenofovir/emtricitabine/efavirenz arm (P < 0.0001)
Ryom et al^Citation92	(n = 22,603) Age (median, IQR): 39 (33–44) D:A:D study	Prospective cohort	Cumulative tenofovir exposure (aIRR) Progression of eGFR ≤70 mL/min/1.73 m^2: 1.18 per year (95% CI, 1.12–1.25) Progression to CKD: 1.08 per year (95% CI, 0.97–1.21)

Note:

a Published studies completed after the Meta-analysis by Cooper et al.⁸⁵

Abbreviations: CKD, chronic kidney disease; CI, confidence interval; D:A:D, Data Collection on Adverse Events of Anti-HIV Drugs; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IQR, interquartile range; OR, odds ratio; RR, relative risk; VA, Veterans Affairs; vs, versus.

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