Title: Monitoring for renal toxicity in people receiving tenofovir and on tenofovir toxicity and how it affects disability-adjusted life-years and quality-adjusted life-years

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Title: Monitoring for renal toxicity in people receiving tenofovir and on tenofovir toxicity and how it affects disability-adjusted life-years and quality-adjusted life-years

1. PICO question ... 1

2. Search strategy ... 2

3. Flow diagram of screening process ... 6

4. Evidence summaries ... 7

5. Bibliography of included studies ... 8

5.1. Systematic review on monitoring and diagnostic tests ... 8

5.2. Systematic review on toxicity in adults ... 9

5.3. Systematic review on toxicity in children and adolescents ... 16

5.4. Systematic review on toxicity during pregnancy ... 16

5.5. Systematic review on how tenofovir toxicity affects disability-adjusted life-years and quality- adjusted life-years ... 17

5.6. Evidence from non-randomized (observational) studies with high risk of bias ... 18

1. PICO question

a Renal toxicity monitoring with ARV regimen containing tenofovir (TDF)

P Adults (including pregnant or breastfeeding women), adolescents and children living with HIV using TDF-containing regimens

I Baseline + regular urinalysis and creatinine testing and other tests in all individuals (or baseline + regular urinalysis in high-risk groups)

C No laboratory monitoring (or baseline + regular urinalysis and creatinine testing and other tests in high-risk groups)

O Renal toxicity, tolerability, monitoring

b Incidence and determinants of toxicity related to TDF and how it affects disability- adjusted life-years (DALYs) and quality-adjusted life-years (QALYs)

P Adults (including pregnant or breastfeeding women), adolescents and children living with HIV

I Use of TDF-containing regimens C Use of non-TDF-containing regimens

O Renal toxicity, bone toxicity, mortality related to toxicity, tolerability, morbidity related to

toxicity, severity definition

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This work was commissioned by the World Health Organization and carried out by Basel Institute for Clinical Epidemiology &

Biostatistics, University Hospital Basel, Switzerland

2

2. Search strategy

Embase (OvidSP): 1974-2012/wk 34 Searched 26 August 2012

1 tenofovir disoproxil/ or tenofovir disoproxil.rn. (2070) 2 tenofovir.ti,ab,ot. (3279)

3 (Apropovir or viread or atripla or tavin or tentide or Complera).af. (1006) 4 (TDF or TFV or PMPA).ti,ab,ot. (2144)

5 (gs 1278 or "gs 4331 05" or gs 433105 or gs1278 or "gs4331 05" or gs433105).ti,ab,ot. (1) 6 or/1-5 (5866)

7 human immunodeficiency virus/ or human immunodeficiency virus 1/ or human immunodeficiency virus 2/ (119389)

8 (hiv or hiv1 or hiv2).ti,ab,ot,hw. (242265)

9 (humanimmunodeficiency virus or human immunedeficiency virus or human immun$ deficiency virus).ti,ab,ot,hw. (506)

10 (human immun$ adj2 deficiency virus).ti,ab,ot,hw. (482) 11 or/7-10 (265330)

12 6 and 11 (3310)

13 animal/ or animal experiment/ (3415620)

14 (rat or rats or mouse or mice or murine or rodent or rodents or hamster or hamsters or pig or pigs or porcine or rabbit or rabbits or animal or animals or dogs or dog or cats or cow or bovine or sheep or ovine or monkey or monkeys).mp. (5520490)

15 or/13-14 (5520490)

16 exp human/ or human experiment/ (13832063) 17 15 not (15 and 16) (4439203)

18 12 not 17 (3197)

19 limit 18 to embase (2928)

20 remove duplicates from 19 (2927)

Medline (OvidSP): 1946-2012/08/wk 3 Searched 26.8.12

1 (tenofovir or 147127-20-6).af. (2354)

2 (Apropovir or viread or atripla or tavin or tentide or Complera).af. (83) 3 (TDF or TFV or PMPA).ti,ab,ot. (1341)

4 (gs 1278 or "gs 4331 05" or gs 433105 or gs1278 or "gs4331 05" or gs433105).ti,ab,ot. (1) 5 or/1-4 (3168)

6 exp HIV/ or exp HIV Infections/ (240297) 7 (hiv or hiv1 or hiv2).ti,ab,ot,hw. (235344)

8 (humanimmunodeficiency virus or human immunedeficiency virus or human immun$ deficiency virus).ti,ab,ot,hw. (389)

9 (human immun$ adj2 deficiency virus).ti,ab,ot,hw. (386) 10 or/6-9 (275804)

11 5 and 10 (2007)

12 animals/ not (animals/ and humans/) (3678890)

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13 11 not 12 (1924)

14 remove duplicates from 13 (1837)

Medline In-Process Citations (OvidSP): up to 2012/08/24 Medline Daily Update (OvidSP): up to 2012/08/24

Searched 26.8.12

1 (tenofovir or 147127-20-6).af. (194)

2 (Apropovir or viread or atripla or tavin or tentide or Complera).af. (5) 3 (TDF or TFV or PMPA).ti,ab,ot. (104)

4 (gs 1278 or "gs 4331 05" or gs 433105 or gs1278 or "gs4331 05" or gs433105).ti,ab,ot. (0) 5 or/1-4 (240)

6 exp HIV/ or exp HIV Infections/ (189) 7 (hiv or hiv1 or hiv2).ti,ab,ot,hw. (8218)

8 (humanimmunodeficiency virus or human immunedeficiency virus or human immun$ deficiency virus).ti,ab,ot,hw. (19)

9 (human immun$ adj2 deficiency virus).ti,ab,ot,hw. (19) 10 or/6-9 (8230)

11 5 and 10 (153)

12 animals/ not (animals/ and humans/) (2070) 13 11 not 12 (153)

14 remove duplicates from 13 (150)

CENTRAL (Cochrane Central Register of Controlled Trials): Issue 8: 2012 http://www.thecochranelibrary.com

Searched 26.8.12

#1 tenofovir or 147127-20-6 345

#2 Apropovir or viread or atripla or tavin or tentide or Complera 11

#3 (TDF or TFV or PMPA):ti,ab 171

#4 (gs-1278 or gs-4331-05 or gs-433105 or gs1278 or gs4331-05 or gs433105):ti,ab 0

#5 (#1 OR #2 OR #3 OR #4) 399

#6 MeSH descriptor HIV explode all trees 2247

#7 MeSH descriptor HIV Infections explode all trees 6722

#8 (hiv or hiv1 or hiv2):ti,ab,kw 8833

#9 (human immun* deficiency virus):ti,ab 95

#10 (humanimmunodeficiency virus):ti,ab,kw 0

#11 (human immunedeficiency virus):ti,ab,kw 0

#12 (#6 OR #7 OR #8 OR #9 OR #10 OR #11) 9374

#13 (#5 AND #12) 291

#14 (#13) 251 - [limited to CENTRAL]

LILACS (Latin American and Caribbean Health Sciences): up to 2012/08/23 http://lilacs.bvsalud.org/en/

Searched 26.8.12

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4

Terms (date limits applied in Endnote) Records

((tenofovir or 147127-20-6 or Apropovir or viread or atripla or tavin or tentide or Complera or TDF or TFV or PMPA or gs-1278 or gs-4331-05 or gs-433105 or gs1278 or gs4331-05 or gs433105) AND (MH:C02.782.815.616.400 or MH:C02.800.801.400 or MH:C20.673.480 or "Infecciones por VIH" or

"Infecções por HIV" or HIV or MH:B04.820.650.589.650.350 or MH:B04.909.777.731.589.650.350 or hiv or hiv1 or hiv2 or

"humanimmunodeficiency virus" or "human immunedeficiency virus" or

"human immun$ deficiency virus"))

0 (tenofovir or 147127-20-6 or Apropovir or viread or atripla or tavin or tentide or Complera or TDF or TFV or PMPA or gs-1278 or gs-4331-05 or gs-433105 or gs1278 or gs4331-05 or gs433105)

38 Total 38

Spanish and Portuguese translations of MeSH terms identified using the DECS (Health Sciences Descriptors) thesaurus:

http://decs.bvs.br/I/homepagei.htm

Science Citation Index (SCI) (Web of Knowledge): 1970-2010/08/24 Searched 26 August 2012

Advanced search (Lemmatization off)

# 12 1,775 #10 not #11

# 11 2,432,712 TS=(cat or cats or dog or dogs or animal or animals or rat or rats or hamster or hamster or feline or ovine or canine or bovine or sheep)

# 10 1,872 #4 and #9

# 9 203,798 #5 or #6 or #7 or #8

# 8 480 TS=(human NEAR/2 immun* NEAR/2 deficiency NEAR/2 virus)

# 7 10 TS=(human NEAR/2 immunedeficiency NEAR/2 virus)

# 6 4 TS=(humanimmunodeficiency NEAR/2 virus)

# 5 203,693 TS=(hiv or hiv1 or hiv2)

# 4 2,951 #1 OR #2 OR #3

# 3 2 TS=(gs-1278 or gs-4331-05 or gs-433105 or gs1278 or gs4331-05 or gs433105)

# 2 303 TI=(TDF or TFV or PMPA)

# 1 2,800 TS=(tenofovir or 147127-20-6 OR Apropovir or viread or atripla or tavin or tentide or Complera)

WHO Global Health Library (Internet): 1970-2010/08/24 http://www.globalhealthlibrary.net/php/index.php

Searched 26 August 2012

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Terms Records (tenofovir or 147127-20-6 or Apropovir or viread or atripla or tavin or tentide

or Complera or TDF or TFV or PMPA or gs-1278 or gs-4331-05 or gs- 433105 or gs1278 or gs4331-05 or gs433105)

3454

(3382 Medline)

(33 LILACS)

Total (excluding Medline & LILACS records) 39

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6

References after duplicates removed (n=4188)

Titles and abstracts of references screened (n=4188)

References excluded (n=3635)

Full texts screened for eligibility (n=553)

Included:

Topics (number of studies / number of publications)

• Monitoring, RCTs (1/7)

• Diagnostic tests (3/3)

• Toxicity in adults, RCTs/RCT combinations (18/42)

• Renal toxicity in adults, cohorts (7/10)

• Bone toxicity in adults, cohorts (3/3)

• Toxicity in children, cohorts (2/2)

• Birth defects in pregnancy, prospective studies (6/6)*

• Other toxicity in pregnancy than birth defects, prospective studies (3/3)

• Mortality, RCTs (13/19)

• Mortality, cohort (1/1)

• Proteinuria, cohorts (2/2)

• Economic studies (6/6)

• High-risk cohorts (6/6)

*Data from several studies have been included in a single registry (APR).

Note

Some studies are relevant to several topics: the most prominent being the studies on mortality, for which the publications identified for the systematic review on the toxicity of tenofovir in adults were used (18 RCTs/RCT combinations, of which 13 RCTs provided data mortality), and 1 further pertinent prospective cohort study was identified. During the review process, WHO requested information on proteinuria, which was additionally considered.

3. Flow diagram of screening process

Electronic literature search in:

• MEDLINE (via OvidSP)

• MEDLINE In-Process Citations (via OvidSP)

• MEDLINE Daily Update (via OvidSP)

• EMBASE (via Ovid SP)

• CENTRAL (Cochrane Central Register of Controlled Trials)

• LILACS (Latin American and Caribbean Health Sciences)

• Science Citation Index (SCI) (Web of Knowledge)

• WHO Global Health Library (Internet)

Date of last search: 26 August 2012

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4. Evidence summaries

(Project 1: Renal toxicity monitoring with an ARV regimen containing TDF and project 4: incidence and determinants of toxicities related to TDF and its impact in DALYs or QALYs)

A review on toxicities associated with the use of tenofovir (TDF) in adults showed that TDF is associated with a modest reduction of glomerular renal function and bone mineral density in short and medium term.

Data from ten randomized control trials were pooled showing a mean difference in estimated glomerular filtration rate (7 studies at 48 weeks and 3 studies >48 weeks) of -2.31 mL/min (95%CI -3.93 to -0.70) among people using TDF compared to control. Data from 6 studies showed a mean decrease of bone mineral density in the lumbar spine of 1.34% (95%CI 1.73 to 0.95) and data from 5 studies a mean decrease of bone mineral density in hip of 1.39 (95%CI 1.77 to 1.00) among people receiving tenofovir.

However, data on the risk for major clinical events (such as mortality, renal failure and, bone fractures) were limited and showed no difference between TDF and control users. An observational analysis of data from the DART trial showed that CKD (defined as GFR <60 ml/min/1.73 m2 or 25% decrease if <60 ml/

min/1.73 m2 pre-ART; confirmed >3 months) was a rare event but was more frequent among people starting antiretroviral therapy (ART) with tenofovir than with abacavir or nevirapine (5.9% versus 3.1%

and 2.1 % through 4 years, respectively; global P<0.001).

The review presented available but limited data on monitoring and long-term safety. A “post-hoc”

subgroup analysis of one randomized trial showed no evidence that 12-weekly creatinine/eGFR

monitoring of those taking TDF impacted the outcomes of development or worsening of chronic kidney disease (CKD), and with the monitoring, the incidence of severe eGFR was only modestly reduced.

However, as TDF renal toxicity can result in a tubular defect, this damage may not be adequately measured by glomerular filtration rate alone as was used in this sub analysis. Evidence from two cohort studies with low risk of bias indicates a higher risk of proteinuria in TDF exposed ART recipients.

Whether other tests, e.g. proteinuria measured by spot urine, are better suited to monitor TDF related renal toxicity compared to eGFR remains unclear. There is an urgent need for more research on these topics.

The review found no evidence from high quality research with low risk of bias in children or adolescents to make a valid assessment of TDF related renal or bone toxicity.

Finally, the review found no signal for an increase of malformation with intrauterine TDF exposure,

based on data from the Antiretroviral Drug Registry. Although cohort studies do not indicate a higher risk

of growth retardation from HIV-infected mothers with TDF exposure during pregnancy, firm conclusions

cannot be drawn due to the limited number of infants and observation time. More research is needed on

the effect on intrauterine TDF exposure and during breastfeeding on growth parameters among infants.

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5. Bibliography of included studies

5.1. Systematic review on monitoring and diagnostic tests

Table 1. References of relevant RCTs

Study ID Reference

DART Trial Studies meeting inclusion criteria

DART 2009

DART Trial Team. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. Lancet, 2009, 375:123-131

.

Gibb 2012 GIBB, D. M., KIZITO, H., RUSSELL, E. C., CHIDZIVA, E., ZALWANGO, E., NALUMENYA, R., SPYER, M., TUMUKUNDE, D., NATHOO, K., MUNDERI, P., KYOMUGISHA, H., HAKIM, J., GROSSKURTH, H., GILKS, C. F., WALKER, A. S., MUSOKE, P. & TEAM, D. T. 2012. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Medicine, 9, e1001217.

Reid 2008 REID, A., STOEHR, W., WALKER, A. S., WILLIAMS, I. G., KITYO, C., HUGHES, P., KAMBUGU, A., GILKS, C. F., MUGYENYI, P., MUNDERI, P., HAKIM, J., GIBB, D. M. & Development of Antiretroviral Therapy Trial 2008. Severe renal dysfunction and risk factors associated with renal impairment in HIV-infected adults in Africa initiating antiretroviral therapy. Clinical Infectious Diseases, 46, 1271-1281.

Stöhr 2011 STOHR, W., REID, A., WALKER, A. S., SSALI, F., MUNDERI, P., MAMBULE, I., KITYO, C., GROSSKURTH, H., GILKS, C. F., GIBB, D. M. & HAKIM, J. 2011. Glomerular dysfunction and associated risk factors over 4-5 years following antiretroviral therapy initiation in Africa. Antiviral Therapy, 16, 1011-1020.

DART Trial Additional publications on the trial taken into consideration

DART 2010 DART-Trial Team 2010. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. Lancet, 375, 123- 31.

DART 2008a DART Trial Team. Fixed duration interruptions are inferior to continuous treatment in African adults starting therapy with CD4 cell counts <200 cells/µl. AIDS 2008;22(2):237-47.

DART 2008b DART Trial Team. (2008) Twenty-four-week safety and tolerability of nevirapine vs. abacavir in combination with zidovudine/lamivudine as first-line antiretroviral therapy: a randomized double-blind trial (NORA). Trop Med Int Health 13: 6–16.

Table 2. Included studies for diagnostic tests of renal function Study ID References of studies meeting the inclusion criteria

Ravasi 2009 RAVASI, G., LAURIOLA, M., TINELLI, C., BRANDOLINI, M., UGLIETTI, A. & MASERATI, R.

2009. Comparison of glomerular filtration rate estimates vs. 24-h creatinine clearance in HIV-positive patients. HIV Medicine, 10, 219-228.

Labarga 2010 LABARGA, P., ALBALATE, M., BARREIRO, P., ALVAREZ, E., MARTIN-CARBONERO, L., PINILLA, J., VISPO, E., MEDRANO, J., SANCHEZ, C. A. & SORIANO, V. Glomerular filtration (GF) determined by creatinine clearance (CCR) in 24 hours urine and Cockcroft & Gault (cg) and

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Study ID References of studies meeting the inclusion criteria

modification of diet in renal disease (MDRD) equations in a large cohort of HIV+ patients.

Retrovirology. Conference: 16th International Symposium on HIV and Emerging Infectious Diseases, Marseille, France, 24–26 March 2010.

Vrouenraets 2012 VROUENRAETS, S. M. E., FUX, C. A., WIT, F., GARCIA, E. F., BRINKMAN, K., HOEK, F. J., VAN STRAALEN, J. P., FURRER, H., KREDIET, R. T., REISS, P. & Prepare Study Group 2012. A comparison of measured and estimated glomerular filtration rate in successfully treated HIV-patients with preserved renal function. Clinical Nephrology, 77, 311-320.

5.2. Systematic review on toxicity in adults

Table 31. Included RCTs for assessment of toxicity of tenofovir Study ID Reference

A5202 (A5224s)- Trial

Studies meeting inclusion criteria

McComsey 2012 MCCOMSEY, G. A., KITCH, D., DAAR, E. S., TIERNEY, C., JAHED, N. C., MELBOURNE, K., HA, B., BROWN, T. T., BLOOM, A., FEDARKO, N. & SAX, P. E.

2012. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir. AIDS, 26, 1371-1385.

McComsey 2011a MCCOMSEY, G. A., KITCH, D., DAAR, E. S., TIERNEY, C., JAHED, N. C., TEBAS, P., MYERS, L., MELBOURNE, K., HA, B. & SAX, P. E. 2011. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir:

AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. Journal of Infectious Diseases, 203, 1791-1801.

McComsey 2011b MCCOMSEY, G. A., KITCH, D., SAX, P. E., TEBAS, P., TIERNEY, C., JAHED, N. C., MYERS, L., MELBOURNE, K., HA, B. & DAAR, E. S. 2011. Peripheral and central fat changes in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or efavirenz: ACTG study A5224s. Clinical Infectious Diseases, 53, 185- 196.

A5202 Studies meeting inclusion criteria

Daar 2011 DAAR, E. S., TIERNEY, C., FISCHL, M. A., SAX, P. E., MOLLAN, K., BUDHATHOKI, C., GODFREY, C., JAHED, N. C., MYERS, L., KATZENSTEIN, D., FARAJALLAH, A., ROONEY, J. F., PAPPA, K. A., WOODWARD, W. C., PATTERSON, K., BOLIVAR, H., BENSON, C. A. & COLLIER, A. C. 2011. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1: a randomized trial. Annals of Internal

Medicine, 154, 445-456.

Sax 2011 SAX, P. E., et al. 2011. Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results. JOURNAL OF

INFECTIOUS DISEASES, 204, 1191-201.

Sax 2009 SAX, P. E., TIERNEY, C., COLLIER, A. C., FISCHL, M. A., MOLLAN, K., PEEPLES, L., GODFREY, C., JAHED, N. C., MYERS, L., KATZENSTEIN, D., FARAJALLAH, A., ROONEY, J. F., HA, B., WOODWARD, W. C., KOLETAR, S. L., JOHNSON, V. A., GEISELER, P. J. & DAAR, E. S. 2009. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. New England Journal of Medicine, 361, 2230-2240.

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10 Study ID Reference

ASSERT Studies meeting inclusion criteria

Moyle 2010a MOYLE, G. J., STELLBRINK, H. J., COMPSTON, J., ORKIN, C., ARRIBAS, J., DOMINGO, P., GRANIER, C., PEARCE, H., SEDANI, S. & WALLI, R. Comparison of bone and renal toxicities in the ASSERT study: final 96 week results from a prospective randomized safety trial. Antiviral Therapy. 12th International Workshop on Adverse Drug Reactions and Co-Morbidities in HIV, London, United Kingdom, 4–6 April 2010.

Post 2010 POST, F. A., MOYLE, G. J., STELLBRINK, H. J., DOMINGO, P., PODZAMCZER, D., FISHER, M., NORDEN, A. G., CAVASSINI, M., RIEGER, A., KHUONG-JOSSES, M.-A., BRANCO, T., PEARCE, H. C., GIVENS, N., VAVRO, C. & LIM, M. L. 2010. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. Journal of Acquired Immune Deficiency Syndromes, 55, 49-57.

Stellbrink 2009a STELLBRINK, H. J., MOYLE, G., ORKIN, C., ARRIBAS, J. R., PEARCE, H. & ZUCCHI, P. Comparison of renal and bone toxicities, and CV serum risk markers, in the ASSERT study: 48-week results from a prospective randomised trial. HIV Medicine. 12th European AIDS Conference, EACS, Cologne, Germany, 11–14 November 2009.

Stellbrink 2010 STELLBRINK, H. J., ORKIN, C., ARRIBAS, J. R., COMPSTON, J., GERSTOFT, J., VAN WIJNGAERDEN, E., LAZZARIN, A., RIZZARDINI, G., SPRENGER, H. G., LAMBERT, J., STURE, G., LEATHER, D., HUGHES, S., ZUCCHI, P. & PEARCE, H. 2010.

Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study.

Clinical Infectious Diseases, 51, 963-972.

BICOMBO/

STEAL (pooled analysis)

Amin 2009 AMIN, J., DE LAZZARI, E., EMERY, S., HUMPHERIES, A., GATELL, J. M., MARTINEZ, E., CARR, A. & COOPER, D. A. Simplification with fixed-dose tenofovir- emtricitabine or abacavir-lamivudine in adults with HIV infection: meta-analysis of two randomized, non-inferiority trials BICOMBO and STEAL. HIV Medicine. 12th European AIDS Conference, EACS, Cologne, Germany, 11–14 November 2009.

Bicombo Studies meeting inclusion criteria

Martinez 2010 MARTINEZ, E., ARRANZ, J. A., PODZAMCZER, D., LONCA, M., SANZ, J.,

BARRAGAN, P., KNOBEL, H., RIBERA, E., GUTIERREZ, F., VALERO, S., CLOTET, B., DALMAU, D., SEGURA, F., ARRIBAS, J. R., BARRUFET, P., SANTOS, I., PAYERAS, A., DE LAZZARI, E., PICH, J. & GATELL, J. 2010. Long-term outcomes of switching to fixed-dose abacavir/lamivudine (ABC/3TC) or tenofovir/ emtricitabine (TDF/FTC): 3-year results of the BICOMBO study. Journal of the International AIDS Society, 13, P43.

Martinez 2009 MARTINEZ, E et al. 2009. A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or

tenofovir/emtricitabine in HIV-1-infected patients with virological suppression. Journal of Acquired Immune Deficiency Syndromes, 51, 290-7.

GS903/GS934 (pooled analysis)

Gallant 2008 GALLANT, J. E., WINSTON, J. A., DEJESUS, E., POZNIAK, A. L., CHEN, S. S., CHENG, A. K. & ENEJOSA, J. V. 2008. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS,

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Study ID Reference 22, 2155-2163.

GS903 Studies meeting inclusion criteria

Gallant 2004b GALLANT, J. E., STASZEWSKI, S., POZNIAK, A. L., DEJESUS, E., SULEIMAN, J. M.

A. H., MILLER, M. D., COAKLEY, D. F., LU, B., TOOLE, J. J. & CHENG, A. K. 2004.

Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral- naive patients: a 3-year randomized trial. Journal of the American Medical Association, 292, 191-201.

Izzedine 2005 IZZEDINE, H., HULOT, J. S., VITTECOQ, D., GALLANT, J. E., STASZEWSKI, S., LAUNAY-VACHER, V., CHENG, A. & DERAY, G. 2005. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naive HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrology Dialysis Transplantation, 20, 743-746.

Law 2006 LAW, M., PULS, R., CHENG, A. K., COOPER, D. A. & CARR, A. 2006. Evaluation of the HIV lipodystrophy case definition in a placebo-controlled, 144-week study in antiretroviral- naive adults. Antiviral Therapy, 11, 179-186.

GS934 Studies meeting inclusion criteria

Arribas 2008 ARRIBAS, J. R., POZNIAK, A. L., GALLANT, J. E., DEJESUS, E., GAZZARD, B., CAMPO, R. E., CHEN, S.-S., MCCOLL, D., HOLMES, C. B., ENEJOSA, J., TOOLE, J. J.

& CHENG, A. K. 2008. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. Journal of Acquired Immune Deficiency Syndromes, 47, 74-8.

DeJesus 2010 DEJESUS, E., POZNIAK, A., GALLANT, J., ARRIBAS, J., BORG, P., ZHOU, T. &

WARREN, D. Improvement in fasting lipids but minimal recovery of limb fat were seen 96 weeks after switching from lamivudine/zidovudine (CBV) plus efavirenz (EFV) to fixed-dose efavirenz/emtricitabine/tenofovir df (ATR) in HIV-infected patients. Canadian Journal of Infectious Diseases and Medical Microbiology. 19th Annual Canadian Conference on HIV/AIDS Research: New Challenges, New Commitments, CAHR 2010 Saskatoon, SK, Canada, 13–16 May 2010. 21 (3 SUPPL. SB) (pp 46B), 2010.

Gallant 2006 GALLANT, J. E., DEJESUS, E., ARRIBAS, J. R., POZNIAK, A. L., GAZZARD, B., CAMPO, R. E., LU, B., MCCOLL, D., CHUCK, S., ENEJOSA, J., TOOLE, J. J. & CHENG, A. K. 2006. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. New England Journal of Medicine, 354, 251-260.

Pozniak 2006 POZNIAK, A. L., et al. 2006. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients – virologic, immunologic, and morphologic changes – a 96-week analysis. Journal of Acquired Immune Deficiency Syndromes, 43, 535-540.

Kalead Studies meeting inclusion criteria

Pinola 2010 PINOLA, M., LAZZARIN, A., ANTINORI, A., CAROSI, G., DI PERRI, G., MORONI, M., VULLO, V., PASTORE, G., NORTON, M. & DI LUZIO PAPARATTI, U. 2010.

Lopinavir/ritonavir + tenofovir dual therapy versus lopinavir/ritonavir-based triple therapy in HIV-infected antiretroviral naive subjects: the Kalead Study. Journal of Antivirals and Antiretrovirals, 2, 056-062.

HEAT Studies meeting inclusion criteria

Smith 2009 SMITH, K. Y., PATEL, P., FINE, D., BELLOS, N., SLOAN, L., LACKEY, P., KUMAR, P.

N., SUTHERLAND-PHILLIPS, D. H., VAVRO, C., YAU, L., WANNAMAKER, P. &

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12 Study ID Reference

SHAEFER, M. S. 2009. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS, 23, 1547-1556.

PROGRESS Studies meeting inclusion criteria

Baran 2010 BARAN, R. W., DIETZ, B., FREDRICK, L. M., TIAN, M. & PODSADECKI, T. HRQoL improves in treatment-naive HIV-1 subjects initiated on lopinavir/ritonavir (LPV/r) with raltegravir (RAL) or tenofovir/emtricitabine (TDF/FTC). Journal of the International AIDS Society. 10th International Congress on Drug Therapy in HIV Infection, Glasgow, United Kingdom, 7–11 November 2010.

Qaqish 2011 QAQISH, R. B., TRINH, R., TIAN, M., FREDRICK, L., PODSADECKI, T., NORTON, M.

& NILIUS, A. Bone mineral density (BMD) analysis in antiretroviral (ART)-naive subjects taking lopinavir/ritonavir (LPV/r) combined with raltegravir (RAL) or

tenofovir/emtricitabine (TDF/ FTC) for 96 weeks in the PROGRESS Study. Antiviral Therapy. 13th International Workshop on Adverse Drug Reactions and Co-morbidities in HIV, Rome, Italy, 14–16 July 2011. 16 (pp A8), 2011.

Reynes 2011 REYNES, J., LAWAL, A., PULIDO, F., SOTO-MALAVE, R., GATHE, J., TIAN, M., FREDRICK, L. M., PODSADECKI, T. J. & NILIUS, A. M. 2011. Examination of noninferiority, safety, and tolerability of lopinavir/ritonavir and raltegravir compared with lopinavir/ritonavir and tenofovir/ emtricitabine in antiretroviral-naive subjects: the PROGRESS study, 48-week results. HIV Clinical Trials, 12, 255-67.

Reynes 2012 REYNES J, TRINH R, PULIDO F, SOTO-MALAVE R, GATHE J, QAQISH R, TIAN M, FREDRICK L, PODSADECKI T, NORTON M, NILIUS A. 2012. Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses, 2013, 29, 256-65.

RAVE Studies meeting inclusion criteria

Moyle 2006 MOYLE, G. J., SABIN, C. A., CARTLEDGE, J., JOHNSON, M., WILKINS, E.,

CHURCHILL, D., HAY, P., FAKOYA, A., MURPHY, M., SCULLARD, G., LEEN, C. &

REILLY, G. 2006. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS, 20, 2043-2050.

ROCKET I Studies meeting inclusion criteria

Cooper 2010b COOPER, V., HORNE, R. & EWAN, J. 2010. Switching to Atripla (EFV/FTC/TDF) from Kivexa (ABC/3TC) plus EFV leads to improved perceptions of treatment: results from the ROCKET 1 study. Journal of the International AIDS Society, 13, P42.

Moyle 2010c MOYLE, G., ORKIN, C., FISHER, M., ANDERSON, J., DHAR, J., WANG, M. H. &

EWAN, J. 2010. Switching from Kivexa + efavirenz to Atripla reduces total cholesterol in hypercholesterolemic subjects: final results of a 24-week, randomized study. Journal of the International AIDS Society, 13, P80.

Orkin 2010 ORKIN, C., MOYLE, G., FISHER, M., WANG, H. & EWAN, J. Switching from Kivexa [KVX] ABC/3TC + efavirenz [EFV] to Atripla [ATR] (EFV/FTC/TDF) reduces cholesterol in hypercholesterolemic subjects: preliminary results of a 24-week randomized study. HIV Medicine. 2nd Joint Conference of the British HIV Association and the British Association for Sexual Health and HIV, Manchester, United Kingdom, 20–23 April 2010.

STEAL Studies meeting inclusion criteria

MARTIN 2009 MARTIN, A., BLOCH, M., AMIN, J., BAKER, D., COOPER, D. A., EMERY, S. & CARR, A. 2009. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir- lamivudine: a randomized, 96-week trial. Clinical Infectious Diseases, 49, 1591-601.

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Bloch 2010 BLOCH, M., MARTIN, A., AMIN, J., EMERY, S., CARR, A., BAKER, D. & COOPER, D.

A. Predictors of limb fat changes in patients switched to tenofovir-emtricitabine or abacavir- lamivudine. Antiviral Therapy. 12th International Workshop on Adverse Drug Reactions and Co-Morbidities in HIV, London, United Kingdom, 4–6 November 2010. 15 (pp A7), 2010.

Date of Publication: 2010. 2010.

Haskelberg 2011 HASKELBERG, H., HOY, J., AMIN, J., EBELING, P. R., EMERY, S. & CARR, A. Lower fat mass and lower bone formation predict greater bone loss with tenofovir in HIV-infected adults. Antiviral Therapy. 13th International Workshop on Adverse Drug Reactions and Co- morbidities in HIV, Rome, Italy, 14–16 July 2011. 16 (pp A6-A7), 2011.

Haskelberg 2012 HASKELBERG, H. et al. 2012. Changes in bone turnover and bone loss in HIV-infected patients changing treatment to tenofovir-emtricitabine or abacavir-lamivudine. PLoS ONE, 7, e38377.

Martin 2011 MARTIN, A. et al. Predictors of limb fat gain in HIV positive patients following a change to tenofovir-emtricitabine or abacavir-lamivudine. PLoS ONE, 6, e26885.

Study 902 Studies meeting inclusion criteria

Schooley 2002 SCHOOLEY RT, RUANE P, MYERS RA, BEALL G, LAMPIRIS H, BERGER D, et al.

Tenofovir DF in antiretroviral-experienced patients: Results from a 48-week, randomized, double-blind study. AIDS, 2002;16(9):1257-63.

Study 907 Studies meeting inclusion criteria

Squires 2003 SQUIRES, K., et al. 2003. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Annals of Internal Medicine, 139, 313-20.

SWEET Studies meeting inclusion criteria

Fisher 2009 FISHER, M., et al. 2009. A randomized comparative trial of continued

zidovudine/lamivudine or replacement with tenofovir disoproxil fumarate/emtricitabine in efavirenz-treated HIV-1-infected individuals. Journal of Acquired Immune Deficiency Syndromes, 51, 562-8.

Moyle 2007 MOYLE, G., et al. 2007. A randomized comparison of the safety of continued zidovudine plus lamivudine (Combivir, CBV) versus switching to tenofovir DF plus emtricitabine (Truvada, TVD) each plus efavirenz (EFV) in stable HIV-infected persons: results of a planned 24-week analysis. Antiviral Therapy, 12, L34-L34.

SWIFT Studies meeting inclusion criteria

DeJesus 2011 DEJESUS, E., CAMPO, R., BREDEEK, F., WANG, H., DAU, L. & FRALICH, T. SWIFT study: switching from lamivudine/ abacavir (3TC/ABC) to emtricitabine/tenofovir DF (FTC/TDF) improved fasting lipid parameters while maintaining virologic suppression.

Antiviral Therapy. 13th International Workshop on Adverse Drug Reactions and Co- morbidities in HIV, Rome, Italy, 14–16 July 2011. 16 (pp A55-A56), 2011.

Henry 2012 HENRY, K., DEJESUS, E., CAMPO, R., BREDEEK, U. F., WANG, H., DAU, L., PIONTKOWSKY, D. & BOSSE, M. 2012. SWIFT: switching from lamivudine/abacavir to emtricitabine/tenofovir improved lipids while maintaining virologic suppression in older HIV subjects. HIV Medicine, 13, 25-25.

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14 Table 4. Included non-randomized studies reporting on renal toxicity outcomes without high risk of bias

DART Studies meeting inclusion criteria

Reid 2008 REID, A., et al. 2008. Severe renal dysfunction and risk factors associated with renal impairment in HIV-infected adults in Africa initiating antiretroviral therapy. Clinical Infectious Diseases, 46, 1271-1281.

Stöhr 2011 STÖHR, W., REID, A., WALKER, A. S., SSALI, F., MUNDERI, P., MAMBULE, I., KITYO, C., GROSSKURTH, H., GILKS, C. F., GIBB, D. M. & HAKIM, J. 2011.

Glomerular dysfunction and associated risk factors over 4-5 years following antiretroviral therapy initiation in Africa. Antiviral Therapy, 16, 1011-1020.

EuroSIDA Studies meeting inclusion criteria

Mocroft 2010 MOCROFT, A., KIRK, O., REISS, P., DE WIT, S., SEDLACEK, D., BENIOWSKI, M., GATELL, J., PHILLIPS, A. N., LEDERGERBER, B. & LUNDGREN, J. D. 2010.

Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS, 24, 1667-1678.

Ryom 2010 RYOM, L., et al. Chronic kidney disease in patients with normal eGFR at baseline: results from EuroSIDA. Journal of the International AIDS Society. 10th International Congress on Drug Therapy in HIV Infection, Glasgow, United Kingdom, 7–11 November 2010.

ICONA cohort Studies meeting inclusion criteria

Tordato 2011 TORDATO, F., COZZI LEPRI, A., CICCONI, P., DE LUCA, A., ANTINORI, A., COLANGELI, V., CASTAGNA, A., NASTA, P., LADISA, N., GIACOMETTI, A., D’ARMINIO MONFORTE, A. & GORI, A. 2011. Evaluation of glomerular filtration rate in HIV-1-infected patients before and after combined antiretroviral therapy exposure. HIV Medicine, 12, 4-13.

Johns Hopkins database

Studies meeting inclusion criteria

Gallant 2009 GALLANT, J. E. & MOORE, R. D. 2009. Renal function with use of a tenofovir- containing initial antiretroviral regimen. AIDS, 23, 1971-5.

Gallant 2005 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40(8):1194-8.

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NADIS Studies meeting inclusion criteria

Flandre 2011 FLANDRE, P., PUGLIESE, P., CUZIN, L., BAGNIS, C. I., TACK, I., CABIE, A., POIZOT-MARTIN, I., KATLAMA, C., BRUNET-FRANCOIS, C., YAZDANPANAH, Y. & DELLAMONICA, P. 2011. Risk Factors of chronic kidney disease in HIV-infected patients. Clinical Journal of the American Society of Nephrology, 6, 1700-1707.

Swiss HIV Cohort Study

Fux 2007 FUX, C. A., et al. 2007. Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study. Antiviral Therapy, 12, 1165- 1173.

Veterans Affairs HIV Clinical Case

Registry (VACCR)

Scherzer 2012 SCHERZER, R., ESTRELLA, M., LI, Y., CHOI, A. I., DEEKS, S. G., GRUNFELD, C. &

SHLIPAK, M. G. 2012. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS, 26, 867-875.

Table 5. Included non-randomized studies reporting on bone toxicity outcomes without high risk of bias

Veterans Affairs HIV Clinical Case

Registry (VACCR)

Bedimo 2012 BEDIMO, R., MAALOUF, N. M., ZHANG, S., DRECHSLER, H. & TEBAS, P. 2012.

Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS, 26, 825-831.

Veterans Aging Cohort Study Virtual Cohort (VACS-VC)

Womack 2011 WOMACK J.A., et al. 2011. Veterans Aging Cohort Study Project Team. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One, 16;6(2):e17217.

Women’s Interagency HIV Study

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Yin 2010 YIN M.T., SHI Q., HOOVER D.R., ANASTOS K., SHARMA A., YOUNG M., LEVINE A., COHEN M.H., SHANE E., GOLUB E.T., TIEN P.C. 2010. Fracture incidence in HIV- infected women: results from the Women’s Interagency HIV Study. AIDS, 24(17):2679- 86.

5.3. Systematic review on toxicity in children and adolescents

Table 6. Included studies for assessment of toxicity of tenofovir in children and adolescents RCTs Studies meeting inclusion criteria

Della Negra 2012 DELLA NEGRA, M., DE CARVALHO, A. P., DE AQUINO, M. Z., DA SILVA, M. T. N., PINTO, J., WHITE, K., ARTERBURN, S., LIU, Y.-P., ENEJOSA, J. V., CHENG, A. K., CHUCK, S. L. & RHEE, M. S. 2012. A randomized study of tenofovir disoproxil fumarate in treatment-experienced HIV-1 infected adolescents. Pediatric Infectious Disease Journal, 31, 469-73.

2952

Rosso 2008 ROSSO, R., NASI, M., DI BIAGIO, A., REPETTO, E., DENTONE, C., PINTI, M., NEMES, E., FERRARESI, R., MUSSINI, C., ESPOSITO, R., VISCOLI, C. & COSSARIZZA, A. 2008. Effects of the change from stavudine to tenofovir in human immunodeficiency virus-infected children treated with highly active antiretroviral therapy: Studies on mitochondrial toxicity and thymic function. Pediatric Infectious Disease Journal, 27, 17-21.

1266

Vigano 2005 VIGANO, A., ALDROVANDI, G. M., GIACOMET, V., MERLO, M., MARTELLI, L., BERETTA, S., LURASCHI, P., ROMBOLA, G. & MORA, S. 2005. Improvement in dyslipidaemia after switching stavudine to tenofovir and replacing protease inhibitors with efavirenz in HIV-infected children.

Antiviral Therapy, 10, 917-924.

1732

Cohort studies Studies meeting inclusion criteria Andiman 2009 (Pediatric

AIDS Clinical Trials Group Study 219/219C)

ANDIMAN, W. A., et al. 2009. Incidence of persistent renal dysfunction in human immunodeficiency virus-infected children: associations with the use of antiretrovirals, and other nephrotoxic medications and risk factors.

Pediatric Infectious Disease Journal, 28, 619-25.

3511

Camacho-Gonzalez 2012 Camacho-Gonzalez et al. Tenofovir associated proximal renal tubular dysfunction in HIV-positive children and adolescents: 19th International AIDS Conference: Abstract no. MOPE066

Provided by WHO / Handsearch

5.4. Systematic review on toxicity during pregnancy

Table 72. Included studies comparing the toxicity in pregnancy of regimens with TDF versus regimens without TDF (included congenital abnormalities)

Study ID/study name

Reference Included studies APR Registry

APR Interim 2012 The Antiretroviral Pregnancy Registry Interim Report January 1989 through January 31 2012. Issued June 2012 http://www.apregistry.com/forms/interim_report.pdf access November XX 2012

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Studies that are part of the APR registry

Bussmann 2007 Bussmann H, Wester CW, Wester CN, et al. Pregnancy rates and birth outcomes among women on efavirenz-containing highly active antiretroviral therapy in Botswana. J Acquir Immune Defic Syndr 2007;45(3):269-273.

CDC Centers for Disease Control and Prevention. Metropolitan Atlanta Congenital Defects Program 6-Digit code defect list. To access an electronic copy of the code list, go to

http://www.cdc.gov/ncbddd/birthdefects/MACDP.html DART Trial

Gibb 2012 GIBB, D. M., et al. 2012. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Medicine, 9, e1001217.

NISDI-Study

Joao 2010 Joao EC, Calvet GA, Krauss MR, Hance LF, Ortiz J, Ivalo SA, Pierre R, Reyes M, Watts H, Read JS for the NISDI Perinatal Study Group. Maternal antiretroviral use during pregnancy and infant congenital anomalies: the NISDI Perinatal Study. J Acquir Immune Defic Syndr 2010;53(2):176-185.

WITS

Watts 2007 Watts DH, Li D, Handelsman E, Tilson H, Paul M, Foca M, Vajaranant M, Diaz C, Tuomala R, Thompson B. Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. J Acquir Immune Defic Syndr 2007; 44: 299-305.

Table 8. Included studies on intrauterine exposure with regimens with TDF versus regimens without TDF (included studies on toxicity other than congenital abnormalities)

Study ID/study name

Reference Included studies DART Trial

Gibb 2012 GIBB, D. M., et al. 2012. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Medicine, 9, e1001217.

Siberry 2012 Siberry GK et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS 2012;26(9):1151-9.

Ransom 2012 Ransom C et al. Association of tenofovir disoproxil fumarate with neonatal growth. 19th International AIDS Conference: Abstract no.MOPE062.

5.5. Systematic review on how tenofovir toxicity affects disability-adjusted life-years and quality-adjusted life-years

Table 9. Included economic studies

Study ID References of studies meeting inclusion criteria

Bendavid 2011 BENDAVID, E., GRANT, P., TALBOT, A., OWENS, D. K. & ZOLOPA, A. 2011. Cost-effectiveness of antiretroviral regimens in the World Health Organization’s treatment guidelines: a South African analysis. AIDS, 25, 211-220.

Bischof 2009 Bischof M et al. Cost-effectiveness of first line co-formulated dual nucleoside antiretroviral therapies combined with efavirenz in HIV-infected adults in Switzerland. Unpublished report and Bucher HC IAS 2009 Abstract 1224.

Brogan 2011 BROGAN, A. J., TALBIRD, S. E. & COHEN, C. 2011. Cost-effectiveness of nucleoside reverse transcriptase inhibitor pairs in efavirenz-based regimens for treatment-nave adults with HIV infection in

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18 the United States. Value in Health, 14, 657-664.

Colombo 2011 COLOMBO, G. L., COLANGELI, V., DI BIAGIO, A., DI MATTEO, S., VISCOLI, C. & VIALE, P.

2011. Cost-effectiveness analysis of initial HIV treatment under Italian guidelines. ClinicoEconomics and Outcomes Research, 3, 197-205.

Jouquet 2011 JOUQUET, G., BYGRAVE, H., KRANZER, K., FORD, N., GADOT, L., LEE, J., HILDERBRAND, K., GOEMAERE, E., VLAHAKIS, N., TRIVINO, L., MAKAKOLE, L. & CLEARY, S. 2011. Cost and cost-effectiveness of switching from d4T or AZT to a TDF-based first-line regimen in a resource- limited setting in rural Lesotho. Journal of Acquired Immune Deficiency Syndromes, 58, e68-74.

Von Wyl 2012 VON WYL, V., CAMBIANO, V., JORDAN, M. R., BERTAGNOLIO, S., MINERS, A., PILLAY, D., LUNDGREN, J. & PHILLIPS, A. N. 2012. Cost-effectiveness of tenofovir instead of zidovudine for use in first-line antiretroviral therapy in settings without virological monitoring. PLoS ONE, 7, e42834.

5.6. Evidence from non-randomized (observational) studies with high risk of bias

Table 10. Non-randomized studies reporting on tenofovir-related toxicity outcomes not deemed appropriate to supplement the results of the RCT (high risk of bias)

California Collaborative Treatment Group (CCTG)

Goicoechea 2008 GOICOECHEA, M., LIU, S., BEST, B., SUN, S., JAIN, S., KEMPER, C., WITT, M., DIAMOND, C., HAUBRICH, R. & LOUIE, S. 2008. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. Journal of Infectious Diseases, 197, 102-108.

Chi 2010 Studies meeting inclusion criteria

Chi 2010 CHI, B. H., MWANGO, A., GIGANTI, M., MULENGA, L. B., TAMBATAMBA- CHAPULA, B., REID, S. E., BOLTON-MOORE, C., CHINTU, N., MULENGA, P. L., STRINGER, E. M., SHENEBERGER, R., MWABA, P. & STRINGER, J. S. A. 2010.

Early clinical and programmatic outcomes with tenofovir-based antiretroviral therapy in Zambia. Journal of Acquired Immune Deficiency Syndromes, 54, 63-70.

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Table 11. Non-randomized studies reporting limited information on tenofovir-related drug toxicity with high risk of bias

Reginald 2012 Studies meeting inclusion criteria

Reginald 2012 REGINALD, O. O., HARUNA, M. M., SANI, G. B., ERIC, T. A., ADEBOLA, O. T., MATHEW, I., CHIGOZIE, I., BILKISU, U. & IBRAHIM, A. A. 2012. Adverse reactions associated with antiretroviral regimens in adult patients of a university teaching hospital HIV program in Zaria, Northern Nigeria: an observational cohort study. Journal of Antivirals and Antiretrovirals, 4, 006-013.

Parkes-Ratanshi 2009

Parkes-Ratanshi 2009 PARKES-RATANSHI, R., WAKEHAM, K., LEVIN, J., KATENDE, D., NABIRYO, C., GROSSKURTH, H., LALLOO, D. & KAMALI, A. 2009. Anaemia in a rural cohort of HIV-infected Ugandans receiving either AZT- or non AZT-containing antiretroviral regimens. HIV Medicine, 10, 33.

Quiros-Roldan 2010 Studies meeting inclusion criteria

Quiros-Roldan 2010 QUIROS-ROLDAN, E., et al. Evolution of estimated creatinine clearance by gender and type of HAART in previously naive patients over 96 week follow-up. Infection. Italian Conference on AIDS and Retroviruses, ICAR 2010, Brescia, Italy, 20–22 June 2010. 38 (pp 48-49), 2010.

Title: Monitoring for renal toxicity in people receiving tenofovir and on tenofovir toxicity and how it affects disability-adjusted life-years and quality-adjusted life-years