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Co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection and AIDS

  1. Muki S Shey1,*,
  2. Eugene J Kongnyuy2,
  3. Samuel M Alobwede3,
  4. Charles S Wiysonge4

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 13 JAN 2013

DOI: 10.1002/14651858.CD005481.pub3


How to Cite

Shey MS, Kongnyuy EJ, Alobwede SM, Wiysonge CS. Co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection and AIDS. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD005481. DOI: 10.1002/14651858.CD005481.pub3.

Author Information

  1. 1

    University of Cape Town, Health Sciences Faculty, Clinical Infectious Diseases Research Initiative (CIDRI), Cape Town, Western Cape, South Africa

  2. 2

    Reproductive Health Solutions, Salisbury, UK

  3. 3

    Partners in Sexual Health, Cape Town, South Africa

  4. 4

    Stellenbosch University, Centre for Evidence-based Health Care, Faculty of Medicine and Health Sciences, Cape Town, South Africa

*Muki S Shey, Clinical Infectious Diseases Research Initiative (CIDRI), University of Cape Town, Health Sciences Faculty, Anzio Road, Observatory, Cape Town, Western Cape, 7925, South Africa. shehushey@yahoo.fr.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 28 MAR 2013

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Characteristics of included studies [ordered by study ID]
Gulick 2004

MethodsSequence generation: Patients were randomly assigned with equal opportunity to the treatment arms. Treatment allocation was stratified by screening HIV-1 RNA levels (<100,000 copies/ml or >=100,000 copies/mL)
Allocation concealment: Adequate (central remote randomisation)
Blinding: Participants, providers, and assessors all blinded.
Loss-to-follow-up: When the triple nucleoside arm was stopped, after a median of 32 weeks, 83 participants (7%) had discontinued the study for various reasons including withdrawal of consent (n=21) and loss to follow-up (n=21).
Analysis: performed on an intention-to-treat basis and included all follow-up data.


ParticipantsAntiretroviral-naive HIV-1-infected adults recruited from 33 units of The AIDs Clinical Trials Group (ACTG) in the US.
Exclusion criteria:
Immunomodulator investigational therapy or vaccines within previous 30 days, weight less than 40kg, pregnancy, or lactation.
N=1147
Male 81%, mean age 38 (SD 9) years, whites 40%, blacks 36%, Hispanics 21%, mean HIV-1 RNA level 4.85 log(10) copies/mL [SD 0.70), mean CD4 cell count = 234 cells/mm3 (SD187). No significant levels between treatment arms.


InterventionsEligible subjects were randomly allocated to one of three regimens given orally at standard doses and intervals:
Regimen A: zidovudine (ZDV)–lamivudine(3TC)–
abacavir (ABC) [Trizivir].
Regimen B: ZDV–3TC [Combivir] + efavirenz
Regimen C: ZDV–3TC–ABC + efavirenz.
Participants took a total of seven pills per day (including placebos), divided into two doses.
In the event of treatment-limiting toxic effects of study drugs, the identity of the implicated drug was allowed to
be revealed and substitution of another drug in the same class was permitted. Stavudine could be substituted for ZDV, didanosine could be substituted for ABC, and nevirapine could be substituted for efavirenz..


Outcomes1. Virologic failure i.e. two successive HIV-1 RNA values of 200 or more copies/ml at least 16 weeks after randomisation.
2. HIV-1 RNA level of less than 200 copies/ml and with a level below 50 copies/ml.
3. Change in CD4 cell count from base line
4. Adverse events


NotesThe study was reviewed annually for safety and
efficacy by the data and safety monitoring board.
The second annual review showed differences between the triple-nucleoside regimen and each of the efavirenz-containing regimens that met prespecified stopping guidelines, and the DSMB recommended stopping the triple-nucleoside portion of the study, continuing double-blind follow-up of the other two groups, and analysing and presenting the results with the data for the triple-nucleoside group compared with the pooled data from the efavirenz groups. At the time of stopping the triple-nucleoside arm, the median duration of follow-up was 32 weeks.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomly assigned with equal opportunity to the treatment arms. Treatment allocation was stratified by screening HIV-1 RNA levels. Such an elaborate randomisation sequence is likely to have been computer-generated.

Allocation concealment (selection bias)Low riskCentral remote randomisation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and providers blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors all blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskWhen the triple-nucleoside arm was stopped in the Gulick 2004 trial after a median of 32 weeks, 83 participants (7%) had discontinued the study for various reasons, including withdrawal of consent (2%) and loss to follow-up (2%).

Selective reporting (reporting bias)Low riskNo

Kumar 2006

MethodsSequence generation: Patients were "randomized 1:1:1" suggesting block randomisation, but no detail of method of generating the randomisation sequence was given.
Allocation concealment: Not described.
Blinding: Participants - No.
Providers - No.
Assessors - Unclear.
Loss to follow-up:
26.4%(23/87) for Trizivir, 24.2% (22/91) in COM/NFV, and 14.5%(12/83) in d4T/3TC/NFV groups.
Analysis: performed on an intention-to-treat basis.


ParticipantsPartcipants recruited from 34 outpatient sites in USA, Puerto Rico, Guatemala, Dominican Republic & Panama.
Inclusion criteria:
Documented HIV infection; naive or limited experience with antiretroviral therapy; age >= 18 years; CD4+ count > 50 cells/microL; 1000 copies/ml < HIV-1 RNA < 200,000 copies/ml. Exclusion criteria: pregnancy, lactation, , no antihyperlipidaemic or antidiabetic medications.
N=261
Male 50%, median age 34 (range 18-60) years , Whites 20.9%, Blacks 39.8%, Hispanics 37.0%, median HIV-1 RNA level 4.44 log(10) copies/ml [range2.23-5.77), median CD4 cell count = 339 cells/mm3 (range19-1269),
median total cholesterol 163mg/dl (92-267), median triglycerides 107 mg/dl (range38-597)
No significant levels between treatment arms.


InterventionsPatients meeting entry criteria were randomised 1:1:1 to:
Regimen A: Trizivir twice daily.
Regimen B: Combivir + nelfinavir 1250 twice daily.
Regimen C: Stavudine 40 mg + 3TC 150 mg + nelfinavir 1250 mg twice daily.
At enrolment participants were stratified into two groups based on their screening
plasma HIV-1 RNA level: <1000–100,000 copies/mL or
>100,000–200,000 copies/mL.


Outcomes1. Change from baseline in LDL cholesterol.
2. Virologic failure i.e. two successive HIV-1 RNA values of 200 or more copies/ml at least 16 weeks after randomisation.
2. HIV-1 RNA level of less than 200 copies/ml and with a level below 50 copies/ml.
3. Change in CD4 cell count from base line
4. Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were "randomized 1:1:1" suggesting block randomisation, and presumable computer-generated.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and providers not blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.

Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up: 26.4% for Trizivir, 24.2% in COM/NFV, and 14.5% in d4T/3TC/NFV groups.

Selective reporting (reporting bias)Low riskNo

Kumar 2009

MethodsSequence generation: Patients were "randomized 1:1:1" suggesting block randomisation, but no detail of method of generating the randomisation sequence was given.

Allocation concealment: Adequate (central randomisation).

Blinding: No blinding

Loss to follow-up: 9% (12/138) in the ABC/3TC/ZDV and 10% (14/140) in the ATV + 3TC/ZDV groups

Analysis: Performed on an intent-to-treat exposed basis


Participants279 subjects recruited between May 2004 and March 2005 from 46 sites in USA and Mexico.

Inclusion Criteria: HIV-1 infection, 18 years or older, ART-naive, and plasma HIV-1 RNA >=5000 but <200,000c/ML and CD4+ cell count >= 100 cells/mm3.

Exclusion criteria: Patients were excluded if they had medical conditions or required medications that could compromise their safety or interfere with drug absorption, if they had protocol-specific abnormal laboratory values.

N=279

79% male and racially diverse (>50% non-white race or ethnicity), 82% had HIV-1 RNA <100,000c/mL at baseline.


InterventionsPatients meeting inclusion criteria were randomized 1:1 to receive ABC/3TC/ZDV (Trizivir®) twice daily or ATV (once daily) + 3TC/ZDV (twice daily).


Outcomes1. HIV-1 viral load

2. CD4+/CD8+ lymphocyte subsets

3. Clinical chemistry

4. Hematology

5. Serum lipid panels

6. Insulin

7. Hemoglobin


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were "randomized 1:1:1" suggesting block randomisation, and presumable computer-generated.

Allocation concealment (selection bias)Low riskCentral randomisation

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding: No blinding

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up: 9% in the ABC/3TC/ZDV and 10% in the ATV + 3TC/ZDV groups

Selective reporting (reporting bias)Low riskNo

Shapiro 2010

MethodsSequence generation: Computer-generated randomisation sequence

Allocation concealment: Patients were randomised 1:1:1 to Trizivir, Kaletra or Combivir by block permutation according to clinical site. Randomisation was assigned by calling the Data Management Centre in Gaborone (Central randomisation).

Blinding: Not described

Loss to follow-up: 15/285 in Trizivir group, 13/275 in kaletra group, and 5/170 in observational group left the study but reasons not given.

Analysis: Not mentioned


Participants560 pregnant women with HIV-1 infection were recruited between 2006 and 2008 in Botswana.

Inclusion criteria included confirmed HIV-1 infection, age at least 18yrs, 26 to 34 weeks of gestation, haemoglobin level of at least 8.0g/deciliter, absolute neutrophil count of at least 1000 cells per cubic millimeter, alanine aminotransferase and aspartate aminotransferase levels at most 2 times the upper limit of normal and women who preferred to exclusively feed their babies by formula were excluded.


InterventionsPatients meeting inclusion criteria were randomised 1:1 to receive ABC/3TC/ZDV (Trizivir®) twice daily or co-formulated lopinavir and ritonavir (Kaletra) twice daily + 3TC/ZDV (Combivir) twice daily.


OutcomesHIV viral load(viral suppression to <400 and <50 copies/ml)

Mother-to-child transmission intrapartum and postpartum

Adverse events


NotesStudy protocol available at: http://www.nejm.org/doi/suppl/10.1056/NEJMoa0907736/suppl_file/nejmoa0907736_protocol.pdf


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAll randomisation assignments were made based upon computer-generated lists

Allocation concealment (selection bias)Low riskCentral randomisation

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up: 5.2% in the Trizivir® and 5.1% in Keletra® arms left the study for reasons that are not stated.

Selective reporting (reporting bias)Low riskNo

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ait-Khaled 2002Abacavir, lamivudine, zidovudine not used as a fixed-dose combination.

Cahn 2004Abacavir, lamivudine, zidovudine not used as a fixed-dose combination.

d'Ettorre 2009Abstract and article not available and authors did not respond to article request.

Feinberg 2003Abacavir, lamivudine, zidovudine not used as a fixed-dose combination.

Matheron 2003Abacavir, lamivudine, zidovudine not used as a fixed-dose combination.

Munderi 2010Abacavir, lamivudine, zidovudine not used as a fixed-dose combination.

Ndembi 2010Abacavir, lamivudine, zidovudine not used as a fixed-dose combination.

Shao 2009Co-formulated abacavir-lamivudine-zidovudine not compared to PI or NNRTI regimens

Sprenger 2010Co-formulated abacavir-lamivudine-zidovudine used as maintenance therapy

Staszewski 2001Abacavir, lamivudine, zidovudine not used as a fixed-dose combination.

Vibhagool 2004Abacavir, lamivudine, zidovudine not used as a fixed-dose combination.

 
Comparison 1. Fixed-dose NRTI versus PI or NNRTI

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

 1 Virologic failure31687Risk Ratio (M-H, Random, 95% CI)1.14 [0.56, 2.31]

 2 Virologic suppression (<400copies/ml)42247Odds Ratio (M-H, Random, 95% CI)0.73 [0.39, 1.36]

 3 Virologic suppression (<50copies/ml)42247Risk Ratio (M-H, Random, 95% CI)0.97 [0.75, 1.25]

 4 CD4 cell count31687Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.11, 0.09]

 5 Severe adverse events42247Risk Ratio (M-H, Random, 95% CI)1.22 [0.78, 1.92]

 6 Hypersensitivity42242Risk Ratio (M-H, Random, 95% CI)4.04 [0.41, 40.02]

 
Summary of findings for the main comparison. Co-formulated abacavir-lamivudine-zidovudine compared to NNRTIs or PIs for initial treatment of HIV infection

Co-formulated abacavir-lamivudine-zidovudine compared to NNRTIs or PIs for initial treatment of HIV infection and AIDS

Patient or population: Antiretroviral-naive HIV infected patients
Settings: Any country setting (i.e. low-, middle-, or high-income)
Intervention: Co-formulated abacavir-lamivudine-zidovudine
Comparison: Non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based therapy

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

Assumed riskCorresponding risk

NNRTIs or PIsCo-formulated abacavir-lamivudine-zidovudine

Virologic failure
2 successive HIV-1 RNA >= 200copies/ml at 16+ weeks after randomisation
Follow-up: mean 48 weeks
115 per 1000131 per 1000
(64 to 266)
RR 1.14
(0.56 to 2.31)
1687
(3 studies)
⊕⊕⊕⊝
moderate1

Virologic suppression
Viral load < 50 copies/ml
Follow-up: mean 48 weeks
732 per 1000710 per 1000
(549 to 915)
RR 0.97
(0.75 to 1.25)
2247
(4 studies)
⊕⊕⊕⊝
moderate1

CD4 cell count
Follow-up: mean 48 weeks
The mean CD4 cell count ranged across control groups from
415-634 cells per cubic millimetres
The mean CD4 cell count in the intervention groups was
0.01 lower
(0.11 lower to 0.09 higher)
1687
(3 studies)
⊕⊕⊕⊝
moderate1

Severe adverse events
Follow-up: mean 48 weeks
116 per 1000142 per 1000
(90 to 223)
RR 1.22
(0.78 to 1.92)
2247
(4 studies)
⊕⊕⊕⊝
moderate1

Hypersensitivity reactions
Follow-up: mean 48 weeks
44 per 1000178 per 1000
(18 to 1000)
RR 4.04
(0.41 to 40.02)
2247
(4 studies)
⊕⊕⊕⊝
moderate1

*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 The estimate of effect has wide confidence intervals, which extend from appreciable benefit to appreciable harm