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Antiretroviral regimens for patients with HIV who fail first-line antiretroviral therapy

  1. Eliza H Humphreys1,*,
  2. Larry W Chang2,
  3. Jamal Harris3

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 16 JUN 2010

Assessed as up-to-date: 31 MAR 2010

DOI: 10.1002/14651858.CD006517.pub3


How to Cite

Humphreys EH, Chang LW, Harris J. Antiretroviral regimens for patients with HIV who fail first-line antiretroviral therapy. Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD006517. DOI: 10.1002/14651858.CD006517.pub3.

Author Information

  1. 1

    University of California, San Francisco, Global Health Sciences, San Francisco, California, USA

  2. 2

    Johns Hopkins School of Medicine, Division of Infectious Diseases, Department of Medicine, Baltimore, MD, USA

  3. 3

    University of California, San Francisco, Department of Pediatrics, San Francisco, California, USA

*Eliza H Humphreys, Global Health Sciences, University of California, San Francisco, 50 Beale Street, Suite 1200, San Francisco, California, 94105, USA. elizahumphreys@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 16 JUN 2010

SEARCH

 
Characteristics of included studies [ordered by study ID]
Fox 2006

MethodsOpen-label randomised controlled trial in 12 European countries during June 1999 to May 2002.


Participants136 adults with virological failure randomised and 131 intitiated assigned treatment, which was to maintain lamivudine in clinician-chosen follow-up regimen (On-3TC, n=65) or not (Off-3TC, n=66). Two a priori subgroups analysed based on prior regimen exposure (strata A, 1 prior regimen with 3TC n=55; and strata B, more than one prior regimen with 3TC n=76).


InterventionsRegimen maintaining 3TC (On-3TC) or not (Off-3TC). Remainder of regimen chosen by clinician.


Outcomes1. Average area under the curve minus baseline of mean reduction in log10 HIV RNA copies/mL after 48 weeks

2. Mean log10 HIV RNA reductions

3. Clinical nonfatal adverse events

4. Nucleotide distances substudy looking at evolutionary distances and number of nucleotide changes that occured from baseline sequences.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputerized block randomization performed at CHIP

Allocation concealment?Low riskPer communication with author, allocation by central fax

Blinding?
All outcomes
High riskOpen-label study.

Incomplete outcome data addressed?
All outcomes
Low riskFor primary outcome

Free of selective reporting?Low risk

Free of other bias?Unclear riskSupported by Glaxo Wellcome in early phases

Hull 2009

MethodsRetrospective cohort


Participants184 patients with documented M184V mutations and subsequently began a boosted PI regimen. 117 patients were resistant to 3TC with or without NNRTI mutations (no PI-mutations or other NRTI mutations) followed at British Columbia HIV Drug Treatment Center 2000-2006


InterventionsRegimen A: 3TC or FTC + NRTI + bPI

Regimen B: 3TC or FTC + NRTI + bPI + additional active agent(s)

Regimen C: 2 NRTIs + bPI +/- additional active agents (sparing 3TC or FTC)


Outcomes1. Time to HIV-1 RNA suppression


NotesAnalysis is on 117 patients with M184V


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear risksee NOS scale

Allocation concealment?Unclear risksee NOS scale

Blinding?
All outcomes
Unclear risksee NOS scale

Incomplete outcome data addressed?
All outcomes
Unclear risksee NOS scale

Free of selective reporting?Unclear risksee NOS scale

Free of other bias?Unclear risksee NOS scale

Murphy 2008

MethodsRetrospective cohort


Participants184 patients requiring second-line regimen in Durban, South Africa among 3,000 starting ART between the years 2004-2007. First-line for majority was d4T/3TC/EFZ.


InterventionsLPV/r based second-line ART


Outcomes1. primary outcome virologic suppression at six months with evaluation of subgroups based on: 1) NRTI backbone (ddI containing vs not); 2) One prior regimen or more than one prior regimen; 3) indication for second-line regimen (failure vs adverse drug effect/other).

2. adverse effects

3. lipid outcomes


NotesAbstract, limited information and no apparent adjusting in analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear risksee NOS scale

Allocation concealment?Unclear risksee NOS scale

Blinding?
All outcomes
Unclear risksee NOS scale

Incomplete outcome data addressed?
All outcomes
Unclear risksee NOS scale

Free of selective reporting?Unclear risksee NOS scale

Free of other bias?Unclear risksee NOS scale

Pujades-Rodriguez 2008

MethodsDescriptive analysis using individual patient data from 62 MSF-supported HIV centres in 26 countries between 2001 and 2006.


Participants370 (0.8%) out of 48,338 patients on second-line regimen after NNRTI first-line; >15 years of age.


Interventions51% on LPV-based second-line regimen, 43% on NFV-based second-line; 56% on boosted PI. ZDV-ddI (34%) and ABC-ddI (22%) most common backbone in second-line treatment.


Outcomes1. Probability of remaining on first-line ART

2. Rate of switch to second-line ART

3. Probablilities of remaining alive and in care at 12 and 24 months after first- and second-line therapy initiation

4. Comparison of probabilities of remaining alive and in care in patients started on second-line or not (among patients on ART for more than 19.8 months)

5. Description of patient characteristics at start of ART and switch

6. Factors associated with death and loss to follow-up.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear risksee NOS scale

Allocation concealment?Unclear risksee NOS scale

Blinding?
All outcomes
Unclear risksee NOS scale

Incomplete outcome data addressed?
All outcomes
Unclear risksee NOS scale

Free of selective reporting?Unclear risksee NOS scale

Free of other bias?Unclear risksee NOS scale

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

de Mendoza 2006Observational study of 389 PI-experienced patients comparing performance of six different boosted PI-based regimens. PIs are not components of WHO-recommended first-line ART.

Dragsted 2003Randomized, open-label, multicentre, Phase IV trial comparing SQV/r to IDV/r based regimens in 306 patients, most of whom were PI-experienced (61%). Trial was not powered to detect differences in outcomes based on PI-experience, nor are outcomes reported by PI-experience. PIs are not components of WHO-recommended first-line ART.

Dragsted 2005Randomized, open-label, multicentre, Phase IV trial comparing LPV/r to SQV/r-based regimens in 324 treatment-naive and treatment-experienced patients, 52% of whom were PI-experienced. Authors did not differentiate results among ART-naïve and experienced patients, nor among experienced patients who had previously used PIs. PIs are not components of WHO-recommended first-line ART.

Gomo 2008An analysis of 91 patients from the DART trial who switched to second-line therapy and were evaluated for changes in lipid profiles.  All patients had LPV/r-based second-line therapy (regimens included LPV/r +NNRTI or LPV/r + NNRTI + ddI or LPV/r +TDF + ddI/3TC/AZT) after triple nucleoside first-line therapy (in 91%). Lipid profiles were not an outcome we considered.

Hosseinipour 2009Evaluation of adults in two large urban ART clinics in Malawi with clinical failure on first-line ART. Second-line ART with AZT/3TC/TDF/LPV/r was started in 101 participants who were followed for clinical and immunological and virological outcomes. There is no comparison group.

Sproat 2005Observational study comparing virologic response of 586 patients in the UK from 1998-2000 who were switched to ddI- or non-ddI-containing regimens in the presence or absence of the M184V mutation. Outcomes were factors related to virologic and immunologic success by multivariate analysis. Regimen-specific details regarding first- and second-line ART not provided.

 
Characteristics of ongoing studies [ordered by study ID]
ANRS12169

Trial name or titleEvaluation of Three Strategies of Second-line Antiretroviral Treatment in Africa (Dakar - Bobo-Dioulasso - Yaoundé) (2LADY)

MethodsRandomized, open-label, active control, parallel assignment, efficacy study

Participants450 patients over the age of 18 years meeting the following criteria:

  • Documented HIV-1 infection regardless of clinical stage and CD4 lymphocyte count


  • Patient with treatment failure after first-line antiretroviral treatment with a combination including a NNRTI and two NRTIs, failure being defined as two measurements (at 1 month intervals) of plasma HIV RNA levels >1000 copies/mL after at least six months of uninterrupted treatment


  • Adherence (>80%) to first- line ART (questionnaire) at pre-inclusion


  • Patient agrees not to take any concomitant medication during the trial without informing the investigator


  • For women in childbearing age: negative pregnancy test at inclusion, with no plan of pregnancy in the coming 12 months and agreeing to use mechanical contraception (with or without hormonal contraception) during the study

InterventionsArm A:

emtricitabine/tenofovir + lopinavir/ritonavir
Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + Lopinavir 200 mg/Ritonavir 50 mg two tablets in the morning and two tablets in the evening

Arm B:
abacavir + didanosine + lopinavir/ritonavir
Didanosine 1 entero-coated capsule/day in fasting conditions (dosage 250 mg if weight <60 kg, 400 mg if weight >60 kg) + abacavir 300 mg 1 tablet in the morning and in the evening + Lopinavir 200 mg/Ritonavir 50 mg two tablets morning and evening

Arm C:
emtricitabine/tenofovir + darunavir + ritonavir
Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + darunavir 400 mg 2 tablets + ritonavir 100 mg 1 capsule, in a single dose with food

OutcomesPrimary outcome:

  • Proportion of patients with plasma HIV RNA <50 copies/mL at 48 weeks.


Secondary outcomes:

  • Clinical outcome (AIDS events, non-AIDS events, death, undesirable effects) at 48 weeks


  • Proportion of patients with plasma HIV RNA <200 and 50 copies/mL at 24 weeks ]


  • Proportion of patients with plasma HIV RNA <200 copies/mL at 48 weeks


  • Variation of circulating CD4+ lymphocyte count at 24, 48 weeks


  • Treatment discontinuation at 24, 48 weeks


  • Tolerance, particularly the occurrence of hypersensitivity syndromes, renal impairment, and changes in lipids profile, gastrointestinal complains and lipodystrophy at 24, 48 weeks


  • Changes in anthropometric measures at 24, 48 weeks


  • Adherence (measured by pill count and questionnaire) at 24, 48 weeks


  • Frequency of resistance mutations after second-line treatment failure (HIV RNA >1000 copies/mL) at 24, 48 weeks

Starting dateNovember 2009

Contact information

NotesBurkina Faso, Cameroon, Senegal

EARNEST

Trial name or titleEurope-Africa Research Network for Evaluation of Second-line Therapy (EARNEST)

MethodsTreatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Participants1200 patients with the following inclusion criteriaL:

  • Previously documented HIV infection on at least one standard antibody-based test


  • Age 12 years and above


  • Taking two-NRTI + NNRTI-based regimen continuously for at least 12 months


  • Naive to PI therapy


  • Good adherence to ART in the 12 weeks prior to screening defined as no more than 10% of doses missed


  • Clinically stable and receiving treatment for any known opportunistic infections


  • HIV treatment failure defined by one or more of clinical, immunological or virological criteria defined in the protocol, including VL and CD4 at screening visit


  • Willing and able to give informed consent


  • Able to attend for regular study follow-up visits

InterventionsArm I: lopinavir/ritonavir 400mg/100mg twice daily plus two NRTIs (The choice of NRTIs will be at the discretion of the managing clinician and based on the local standard of care and drug availability, taking into account patient's previous drug exposure and side effects on first-line therapy)

Arm II: lopinavir/ritonavir 400mg/100mg twice daily plus
raltegravir (400mg) twice daily

Arm III: lopinavir/ritonavir 400mg/100mg twice daily plus
raltegravir (400mg) twice daily for the first 12 weeks only

OutcomesPrimary Outcome Measures:

  • Good HIV disease control defined as a composite endpoint consisting of all of: - No new WHO stage 4 events - CD4 count >250 cells/mm3 - viral load <10,000 copies/mL or >10,000 copies/mL with no PI resistance mutations at week 96


Secondary Outcome Measures:

  • Good HIV disease control


  • Proportion with CD4 cell count >250 cells/mm3 at 96 and 144 weeks


  • Proportion with new or recurrent WHO stage 4 event at 96 and 144 weeks


  • Proportion of patients with plasma viral load <50 copies at week 48, week 96 and week 144


  • Adverse events


  • Quality of life change from randomisation


  • Neurocognitive function change from randomisation


  • Healthcare costs

Starting dateOctober 2009

Contact information

NotesMalawi, Uganda, Zimbabwe

HIV NAT

Trial name or titleSecond-Line Therapy Antiretroviral in Patients Who Failed Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) - Based Regimens

MethodsTreatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Participants200 patients who meet the following inclusion criteria:

  • Age ≥18 years


  • HIV seropositive


  • Have had NNRTI-based HAART in the past for at least six months


  • Naïve to PIs


  • Plasma HIV RNA ≥1000 copies/mL


  • Signed written informed consent

InterventionsArm I:
LPV/r 400mg/100mg orally q12h for 48 weeks

Arm II:
LPV/r + two NRTIs (TDF/FTC or TDF/3TC)
TDF/FTC (Truvada) 1 pill orally q 24 hr or TDF 300mg orally q 24 hr/3TC 300mg orally q 24 hr (or 3TC 150mg orally q 12 hr) for 48 weeks

OutcomesPrimary Outcome Measures:
To evaluate the 48-week efficacy and safety between 2 NRTIs plus lopinavir/ritonavir (LPV/r) and LPV/r monotherapy in patients failing a standard NNRTI-based treatment regimen at 48 weeks

Secondary Outcome Measures:
1. To evaluate the short-term 24-week efficacy and safety of LPV/r monotherapy and interim analyses when 50% of the patients in each arm have reached 24 weeks after randomisation

2. To define risk factors for monotherapy failure in HIV-treated individuals at 48 weeks

Starting dateMay 2008

Contact information

NotesThailand

NCT00931463

Trial name or titleA Trial of 2 Options for Second Line Combination Antiretroviral Therapy Following Virological Failure of a Standard Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI)+2N(t)RTI First Line Regimen (SECOND-LINE)

MethodsTreatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Participants550 patients who meet the following inclusion criteria:

  • HIV-1 positive by licensed diagnostic test


  • Aged 16 years or older (or minimum age as determined by local regulations or as legal requirements dictate)


  • Have received first antiretroviral regimen consisting of an NNRTI plus two N(t)RTIs for at least 24 weeks


  • No change in ART within 12 weeks prior to screening


  • Failed first-line NNRTI plus two N(t)RTI combination therapy according to virological criteria defined by two consecutive (at least 7 days apart) HIV RNA results of greater then 500 copies/mL


  • No prior or current exposure to HIV PIs and/or HIV integrase inhibitors


  • Able to provide written informed consent

InterventionsArm I. ritonavir-boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily + 2-3N(t)RTIs

Arm II. ritonavir-boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily + raltegravir 400 mg twice daily

OutcomesPrimary outcome measure: the proportion of participants with HIV RNA <200 copies/mL 48 weeks after randomisation

Secondary Outcome Measures:
virological, immunological, safety and ART endpoints at 48 weeks

Starting dateSeptember 2009

Contact information

Notes48 Study Locations

SARA (ISRTCN53817258)

Trial name or titleSecond-line Anti-Retroviral therapy in Africa: a randomised trial to evaluate the feasibility of maintenance monotherapy with ritonavir-boosted lopinavir (Aluvia® tablets) following initiation with 24 weeks of combination therapy in second-line anti-retroviral therapy in Africa (SARA)

MethodsThree-centre open-label randomised pilot trial

Participants240 patients with the following inclusion criteria:

1. Enrolled in the DART trial (http://www.controlled-trials.com/ISRCTN13968779)
2. Failed first-line ART (clinically/immunologically) and having completed 24 weeks of second-line combination ART including ritonavir-boosted lopinavir (as either Aluvia® heat-stable tablets or Kaletra® capsules)
3. Documented informed consent
4. Life expectancy of at least three months

InterventionsArm 1: Continued combination Aluvia-containing ART

Arm 2: Maintenance with Aluvia monotherapy

The dose of Aluvia is two tablets twice a day (each tablet is 200 mg of lopinavir with 50 mg of ritonavir) for both arms. All drugs are taken orally

OutcomesPrimary outcomes:

1. Change in CD4 count at 24 weeks after randomisation (efficacy)
2. Any Serious Adverse Event (SAE), which is not HIV related only (safety)

Secondary outcomes:

1. Progression to a new or recurrent WHO stage 4 HIV event or death
2. Progression to a new or recurrent WHO stage 3 or 4 HIV event or death
3. Change in CD4 count from SARA randomisation to 48, 72 and 96 weeks
4. Any grade 3 or 4 adverse events
5. HIV RNA viral load (performed retrospectively) at 12, 24, 36, 48, 72 and 96 weeks
6. Adherence as measured by questionnaire and pill counts
7. Health economic outcomes

Starting dateJuly 2007

Contact information

NotesUganda, Zimbabwe

 
Comparison 1. Maintaining lamivudine or not

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 mortality00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

2 Disease progression00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

3 Adverse events00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

4 Adherence/tolerability/retention00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 5 Proportion achieving viral suppression1131Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.92, 1.80]

 6 immunologic outcome1131Mean Difference (IV, Fixed, 95% CI)11.0 [-10.09, 32.09]

 
Summary of findings for the main comparison. Lamivudine in second-line therapy

Lamivudine in second-line therapy

Patient or population: patients with first-line ART failure
Settings: Resource limited settings
Intervention: Lamivudine
Comparison: No lamivudine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

No lamivudineLamivudine

Mortality - not measuredSee commentSee commentNot estimable-See commentOne death in Off-3TC arm reported from Table 1

Disease progression - not measuredSee commentSee commentNot estimable-See commentNot reported

Severe adverse events
Follow-up: 48 weeks
See commentSee commentNot estimable1131
(1 study)
⊕⊕⊝⊝
low2,3,4
No difference in adverse events between arms; 43/94 (45.7%) in On-3TC arm and 51/94 (54.3%) in Off-3TC arm (p=0.25)

Adherence/tolerability/retention - not reportedSee commentSee commentNot estimable-See commentNot reported

Proportion achieving VL <50 copies/ml
Follow-up: 48 weeks
455 per 1000587 per 1000
(419 to 819)
RR 1.29
(0.92 to 1.8)
131
(1 study)
⊕⊕⊝⊝
low2,3,4

Change from baseline in CD4
Follow-up: 48 weeks
The mean change from baseline in cd4 in the control groups was
77 cells/mm35
The mean Change from baseline in CD4 in the intervention groups was
11 higher
(10.09 lower to 32.09 higher)
131
(1 study)
⊕⊕⊝⊝
low2,3,4

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Numbers reported are non-fatal clinical adverse events per arm/total adverse events (which occurred among 49 participants). Further information not reported.
2 Open-label study; not downgraded for this. Partial funding from Industry in early phases of trial; also not downgraded for this (low risk of bias since study drug not favoured significantly by results).
3 Clinician-optimized regimen; patients not from low-resource settings (study population from European countries).
4 Few events
5 Mean change from baseline CD4 count estimated from median and IQR using methods described in Hozo 2005
 
Table 1. Example of search strategies

SearchMost Recent QueriesTimeResult

#22Search (#18 AND #19) NOT (animals [mh] NOT human [mh]) Limits: Publication Date from 1995/01/01 to 2009/07/1513:32:19617

#21Search (#18 AND #19) NOT (animals [mh] NOT human [mh])13:26:51624

#20Search #18 AND #1913:24:02626

#19Search (zidovudine OR lamivudine OR stavudine or didanosine OR emtricitabine OR nevirapine OR efavirenz OR tenofovir OR abacavir OR atazanavir OR lopinavir/ritonavir OR darunavir OR fosamprenavir OR indinavir OR saquinavir OR ritonavir OR nelfinavir OR tipranavir OR Trizivir OR Combivir OR Kaletra OR Truvada OR Duovir OR Viraday OR Triomune OR Odivir)13:20:1023441

#18Search #3 AND #16 AND #1710:07:571473

#17Search TREATMENT FAILURE10:07:35153495

#16Search #10 OR #11 OR #12 OR #1510:06:53347813

#15Search MEDICATION ADHERENCE OR ADHERENCE10:05:5653496

#12Search (SECOND-LINE THERAPY) OR (SECOND-LINE TREATMENT) OR (SECOND-LINE ANTIRETROVIRAL THERAPY) OR (SECOND-LINE ANTIRETROVIRAL TREATMENT)10:03:316787

#11Search SALVAGE THERAPY10:01:2914918

#10Search (DRUG RESISTANCE) OR (DRUG RESISTANCE, VIRAL) OR (ANTIVIRAL DRUG RESISTANCE) OR (ANTIVIRAL DRUG RESISTANCES)10:01:15277283

#3Search #1 AND #209:50:4366143

#2Search Antiretroviral Therapy, Highly Active[MeSH] OR Anti-Retroviral Agents[MeSH] OR Antiviral Agents[MeSH:NoExp] OR ((anti) AND (hiv[tw])) OR antiretroviral*[tw] OR ((anti) AND (retroviral*[tw])) OR HAART[tw] OR ((anti) AND (acquired immunodeficiency[tw])) OR ((anti) AND (acquired immunedeficiency[tw])) OR ((anti) AND (acquired immuno-deficiency[tw])) OR ((anti) AND (acquired immune-deficiency[tw])) OR ((anti) AND (acquired immun*) AND (deficiency[tw]))09:49:4899298

#1Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MH]09:49:32253117

 
Table 2. Newcastle Ottawa Scale

ItemHull 2009Murphy 2008Pujades Rodriguez 2008

Representativeness of cohort111

Selection of nonexposed cohort111

Ascertainment of Cohort111

Outcome of interest not present at start of study101

Comparability of cohorts 1101

Comparability of cohorts 2002

Assessment of outcome110

Long enough follow-up010

Adequacy of follow-up011

TOTAL667