Comparative effectiveness of tenofovir in HIV-infected treatment-experienced patients: systematic review and meta-analysis

Figures & data

Table 1 Characteristics of included studies

Study	Centers Country	Recruitment period Follow-up	Number randomized (n)	Prior antiretroviral therapy	Experimental, Comparator	Age (years), Median (IQR)	Sex (% female)	Baseline CD4-cells/mm^3, Median (IQR)	Baseline HIV-RNA (copies/mL)	Outcomes
TDF/FTC vs. ABC/3TC
Calza 2009^39	n.r. Italy	01/2006 to 06/2007 48 weeks	E: 47, C: 42	PI-based ART including thymidine analog	E: TDF/FTC + ATV/r, C: ABC/3TC + ATV/r	E: 37.2 (13.9), C: 36.3 (13.1)^a	E: 32, C: 29	E: 611 (209), C: 658 (272)a	<50	Rash, RF, CD4-cell count, LDL-cholesterol, HDL-cholesterol, TC, TG, HIV-RNA
ROCKET I^37,46	Multicenter UK	03/2008 to 03/2009 12 weeks	E: 79, C: 80	ABC/3TC + EFV	E: TDF/FTC + EFV, C: ABC/3TC + EFV	E: 42 (36–48), C: 44 (40–50)	E: 23, C: 18	E: 459 (377–604), C: 450 (371–584)	<50^b	CVD, RF, TG
ROCKET II^38	Multicenter Italy, Spain, Germany, Austria	09/2008 to 10/2009 12 weeks	E: 42, C: 43	ABC/3TC + LPV/r	E: TDF/FTC + LPV/r, C: ABC/3TC + LPV/r	E: 46.0 (38–51), C: 43.0 (38–48)	E: 17, C: 28	E: 507 (386–633), C: 525 (385–718)	<50	Rash, RF
SWIFT^35	Multicenter USA	n.r. 48 weeks	E: 155, C: 156	3TC/ABC plus boosted PI	E: TDF/FTC + PI/r, C: ABC/3TC + PI/r	E: 46 (22–66), C: 46 (22–75)^c	E: 17, C: 14	E: 532 (354–725), C: 532 (382–728)	<200	CVD, Rash, RF, mortality, fractures, CD4-cell count, LDL-cholesterol, HDL-cholesterol, TC, eGFR, HIV-RNA
Other Regimens
2Lady^32^,^d	Multicenter Cameroon, Burkina Faso, Senegal	01/2010 to 10/2012 48 weeks	E: 152, C: 145	n.r. (but naïve to TDF, ddI, ABC, DRV/r, LPV/r)	E: TDF/FTC + LPV/r, C: ABC + ddI + LPV/r	E: 38 (34–45), C: 38 (33–47)	E: 74, C: 72	E: 199 (92–318), C: 195 (100–288)	≥1000	AIDS, mortality, HIV-RNA
ACTG 5095 Substudy^45^,^e	Multicenter USA	06/2003 to 02/2004 79 weeks	E: 85, C: 85	ZDV/3TC/ ABC	E: ZDV/3TC/ABC+TDF, C: ZDV/3TC/ABC+EFV	E: 38 (33–43) C: 38 (32–44)	E: 21, C: 20	E: 446 (275–593), C: 457 (314–636)	<200	AIDS, CVD, Rash, mortality, HIV-RNA
GS-98–902^30^,^f	Multicenter USA	09/1998 to 03/2000 ^g 24 weeks	E: 56, C: 28	≤4 ART agents; Not specified	E: TDF 300 mg, C: Placebo	E: 41, C: 41^h	E: 6, C: 7	E: 381, C: 298 h	400 to 100000	RF, mortality
Loutfy 2007^16	Multicenter Canada	08/2002 to 02/2004 48 weeks	E: 50, C: 22	2 nucleoside analogs, 1 PI;NNRTI naive; ^i	E: TDF/3TC+LPV/r, C: current PI containing ART	E: 44.1 (38.7–49.9), C: 45.6 (38.2–56.1)	E :2, C: 5	E: 487 (298–703), C: 598 (450–737)	<50	AIDS, mortality, CD4-cell count, TG, HIV-RNA
McComsey 2012^42	Single-center USA	05/2005 to 11/2007 48 weeks	E: 24, C: 26	ART, including tNRTI	E: ART + TDF, C: ART, including tNRTI + uridine	E: 48 (43–51), C: 48 (41–51)	E: 14, C: 14	E: 532 (334–858), C: 578 (439–781)	<400	Mortality, CD4-cell count, LDL-cholesterol, TG, BMD, BF, HIV-RNA
Milinkovic 2007^31^, ^j	Single-center, n.r.	01/2004 to 05/2004 24 weeks	E: 17, C: 22	PI or non-NRTI, and d4T40	E: TDF, C: d4T40	E: 45 (42–48), C: 43 (36–49)	Total: 7	E: 529 (336–810), C: 569 (417–811)	<200	Fractures
PREPARE^43^,^44^,^k	Multicenter Netherlands	06/2006 to 12/2007 48 weeks	E: 74, C: 68	ZDV/3TC + NNRTI or PI	E: TDF/FTC, C: ZDV/3TC	E: 47 (43.0–54.0), C: 45.0 (38.5–49.5), Total: 46.0 (8.9)a	E: 7, C: 25	E: 490.0 (376.0–630.0), C: 485.5 (373.5–640.0)	<50	eGFR, BMD
							Total: 5	Total: 579 (238)a
RAVE^41	Multicenter UK	01/2003 to 10/2003 48 weeks	E: 52, C: 53	D4T or ZDV, PI	E: TDF, C: ABC	E: 42 (24–61), C: 43 (29–70)^l	E: 6, C: 13	E: 486 (334–706), C: 521 (314–723)^c	<50	Rash, CD4-cell count, LDL-cholesterol, HDL-cholesterol, TC, TG, BF, HIV-RNA
RECOMB^46	Multicenter Spain	05/2006 to 09/2008 72 weeks	E: 39, C: 41	HAART regimen containing ZDV+3TC plus NNRTI or PI	E: TDF/FTC + ATV/r, C: ZDV/3TC	E: 44 (10.6), C: 44 (7.4)a	E: 28, C: 10	E: 655 (505–789), C: 504 (363–756)	<50	CVD, RF, mortality, fractures, CD4-cell count, LDL-cholesterol, HDL-cholesterol, TC, TG, BF, HIV-RNA
STAR^17	Multicenter Thailand	05/2008 to 11/2009 24 weeks^m	E: 100, C: 100	PI-naive NNRTI (nevirapine, EFV) + 2 NRTIs^n	E: TDF/3TC/LPV/r, C: mono-LPV/r	E: 38.2 (6.9), C: 36.8 (6.8)a	E: 52, C: 33	E: 211 (134), C: 194 (123)a	≥1000	AIDS, mortality
Swap^47,48	Single-center Denmark	06 to 12/2008 48 weeks^o	E: 20, : 20	ZDV/3TC	E: TDF, C: ABC	E: 46 (8.7), C: 50 (11.9)a	E: 30, C: 45	E: 540 (206), C: 567 (256)a	<50^p	Rash, LDL-cholesterol, HDL-cholesterol, TC, TG, BMD
Sweet^33,34	Multicenter UK, Ireland	n.r. 48 weeks	E: 125, C: 125	ZDV/3TC + EFV	E: TDF/FTC+EFV, C: ZDV/3TC+EFV	E: 42 (8.8), C: 42 (9.1)a	E: 14, C: 18	n.r.	<400	QoL, RF, mortality, CD4-cell count, LDL-cholesterol, HDL-cholesterol, TC, TG, eGFR, HIV-RNA
Totem^40	Multicenter France	09/2005 to 04/2007 12 weeks^q	E: 48, C: 49	ART (NRTI, NNRTI, PI)^r	E: TDF/FTC, C: prior ART	E: 50 (42–58), C: 43 (39–50)	E: 17, C: 9	E: 463 (314–674), C: 559 (337–714)	<200^s	RF

Notes: /r: Ritonavir-boosted; 3TC: Lamivudine; ABC: Abacavir; ATV: Atazanavir; ART: antiretroviral therapy; BF: body fat; BMD: bone mineral density; C: Comparator group (not TDF-containing); CVD: Cardiovascular Disease; d4T: Stavudine; ddI: Didanosine-EC; DRV: Darunavir; DTG: Dolutegravir; E: Experimental group (TDF-containing regimen); EFV: Efavirenz; eGFR: estimated glomerular filtration rate; FTC: Emtricitabine; LPV: Lopinavir; MVC: Maraviroc; n.r.: Not Reported; NRTI: Nucleoside Reverse Transcriptase Inhibitor; NVP: Nevirapine; QoL: Quality of life; RAL: Raltegravir; RF: Renal failure; TC: Total cholesterol; TG: Triglycerides TDF: Tenofovir Disoproxil Fumarate; tNRTI: thymidine Nucleoside Reverse Transcriptase Inhibitor; ZDV: Zidovudine.

Reported are medians (with interquartile range) if not otherwise specified.

^a Mean (SD).

^b 96.2% (TDF) and 92.2% (control) had HIV-RNA levels below 50 copies/mL at baseline.

^c Median (range).

^d Abstract /poster only; the study had three arms; we compared the arm TDF/FTC + LPV/r with the control ABC + ddI + LPV/r as both contain LPV/r. We did not analyze the arm TDF/FTC + DRV/r.

^e Substudy; main trial was not eligible because patients were originally ART-naïve.

^f The study has four arms; we did not analyze two arms with TDF 75mg and TDF 150mg as these are uncommon doses; the placebo-arm crossed-over to TDF 300mg at 24 weeks – we used data only until week 24.

^g Study period; recruitment period not reported.

^h Mean.

ⁱ Prior TDF in TDF-group 8% and in control-group 0%.

^j The study has three arms; we did not analyze the arm with stavudine 30 mg as this is an uncommon dose.

^k Substudy; a publication for the main trial could not be identified.

^l Not indicated whether mean or median; (range).

^m Systematic treatment switch at week 24 – we used data only until week 24.

ⁿ Overall, 5% had prior TDF.

^o Discontinuation after 48 weeks; reason not reported.

^p "Undetectable" viral load.

^q Systematic treatment switch to TDF in week 12 – we used only data from before.

^r Unclear if patients had prior TDF. Authors list prior NRTIs, TDF could be among the item “other” with 4 and 9%.

^s 98% of the participants had HIV-RNA levels below 200 copies/mL at baseline, 72% (TDF) and 76% (control) had HIV-RNA levels below 50 copies/mL at baseline.

Figure 1 Study selection process

Note: “*” describes an included study not providing any additional pertinent data (i.e. beyond what the main publication(s) from which we extracted data already provided).

Table 2 Summary of results

Outcome ART-pretreatment	No. of stu-dies	No. of patients	Effect estimate	95% CI	I^2 (%)
Mortality
Non-naïve	9	1598 (10 events)	RR 0.69	0.20 to 2.37	0
Naïve	18	7582 (106 events)	RR 0.88	0.60 to 1.30	0
Combined	27	9180 (116 events)	RR 0.86	0.60 to 1.25	0
Fractures
Non-naïve	3	427 (3 events)	RR 0.65	0.08 to 5.18	0
Naïve	5	4007 (126 events)	RR 0.97	0.68 to 1.37	0
Combined	8	4434 (129 events)	RR 0.96	0.68 to 1.35	0
CD4-cell count
Non-naïve	7	826	−13.76 cells/mm^3	−37.63 to 10.12	44.8
Naïve	14	5177	0.50 cells/mm^3	−15.35 to 16.34	72.2
Combined	21	6003	−2.40 cells/mm^3	−16.84 to 12.03	76.6
Virological failure
HIV-RNA threshold in copies/mL
Non-naïve
<50	8	1300 (1027 events)	RR 1.02	0.98 to 1.07	12.6
<200	4	881 (739 events)	RR 1.02	0.98 to 1.07	0
<400	1	310 (244 events)	RR 1.03	0.92 to 1.16	–
Naïve
<50	16	6244 (4980 events)	RR 1.03	0.99 to 1.07	50
<200	3	2489 (2349 events)	RR 1.02	1.00 to 1.04	30
<400	8	3422 (2776 events)	RR 1.03	0.97 to 1.09	59
LDL-cholesterol
Non-naïve	7	786	−4.71 mg/dL	−9.80 to 0.37	42.7
Naïve	6	2214	−9.42 mg/dL	−12.16 to −6.78	17.5
Combined^a	13	3000	−7.57 mg/dL	−10.37 to −4.78	42.2
HDL-cholesterol
Non-naïve	6	759	−2.04 mg/dL	−4.68 to 0.59	67.1
Naïve	6	2294	−2.97 mg/dL	−2.97 to −1.57	40.1
Combined	12	3053	−2.38 mg/dL	−3.83 to −0.93	63.3
Total cholesterol
Non-naïve	6	771	−12.05 mg/dL	−20.76 to −3.34	73.4
Naïve	8	2435	−18.35 mg/dL	−22.73 to −13.98	55.1
Combined	14	3206	−15.88 mg/dL	−20.18 to −11.59	67.8
Triglycerides
Non-naïve	8	878	−14.33 mg/dL	−23.73 to −4.93	2.0
Naïve	8	2431	−29.84 mg/dL	−38.37 to −21.31	0
Combined	16	3309	−22.82 mg/dL	−29.35 to −16.30	4.5
eGFR^b
Non-naïve	3	501	−3.50 ml/min	−7.35 to 0.36	33.2
MDRD	2	482	−3.04 ml/min/1.73 m^2	−7.80 to 1.72	65.4
C-G	3	501	−4.48 ml/min	−6.56 to −2.41	0
Naïve	8	3586	−3.55 ml/min	−5.99 to −1.11	76.0
MDRD	3	1856	−0.77 ml/min/1.73 m^2	−2.92 to 1.39	47.7
C-G	5	1742	−6.26 ml/min	−9.42 to −3.10	70.7
Combined	11	4087	−3.49 ml/min	−5.56 to −1.43	70.1
MDRD	5	2338	−1.55 ml/min/1.73 m^2	−3.67 to 0.56	58.2
C-G	8	2243	−5.62 ml/min	−7.62 to −3.62	53.5
BMD
Non-naïve
Hip	3	124	−2.46%	−3.9 to −1.03	51.5
Lumbar	3	125	−1.52%	−2.69 to −0.34	35.0
Naïve
Hip	3	943	−1.38%	−1.81 to −0.95	0
Lumbar	3	961	−1.25%	−1.78 to −0.72	0
Combined
Hip	6	1067	−1.64%	−2.15 to −1.13	25.3
Lumbar	6	1086	−1.32%	−1.78 to −0.85	0

Number of analyzed patients, summary effect estimates, and standard deviations reported here differ slightly from the separate analyses in naïve and non-naïve patients as the amount of studies used to impute missing data differed per meta-analysis. Results not using the additional imputation information are shown in our previous work⁵ and in the Webappendix.

^a Significantly stronger effects of TDF-regimens on LDL-cholesterol in ART-experienced patients in meta-regression analysis (p = 0.028). There was no interaction in the other outcomes.

^b Combined estimates using MDRD, where available, otherwise Cockcroft-Gault.

BMD: bone mineral density; C-G: Cockcroft-Gault; eGFR: estimated glomerular filtration rate; MDRD: modification of diet in renal disease.

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