Intervention Review

You have free access to this content

Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples

  1. Andrew Anglemyer1,
  2. George W Rutherford1,*,
  3. Tara Horvath1,
  4. Rachel C Baggaley2,
  5. Matthias Egger3,
  6. Nandi Siegfried4,5

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 30 APR 2013

Assessed as up-to-date: 26 FEB 2013

DOI: 10.1002/14651858.CD009153.pub3


How to Cite

Anglemyer A, Rutherford GW, Horvath T, Baggaley RC, Egger M, Siegfried N. Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD009153. DOI: 10.1002/14651858.CD009153.pub3.

Author Information

  1. 1

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

  2. 2

    World Health Organization, Department of HIV/AIDS, Geneva, Switzerland

  3. 3

    Institute of Social and Preventive Medicine, Institute of Social Medicine, Bern, Switzerland

  4. 4

    University of Cape Town, Department of Psychiatry and Mental Health, Faculty of Health Sciences, Cape Town, South Africa

  5. 5

    University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, California, USA

*George W Rutherford, Global Health Sciences, University of California, San Francisco, San Francisco, California, 94105, USA. GRutherford@psg.ucsf.edu.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 30 APR 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Birungi 2012

MethodsObservational cohort


Participants550 heterosexual couples attending a clinic in Uganda


InterventionsART


OutcomesIncident HIV Infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy protocol was not available. Risk of bias unclear.

Selective reporting (reporting bias)Unclear riskStudy protocol was not available. Risk of bias unclear.

Other biasUnclear riskNo statement

Cohen 2011

MethodsRandomised controlled trial


Participants1750 serodiscordant couples enrolled in nine countries with CD4 counts from 350-550 cells/µL


InterventionsImmediate ART vs delayed ART until CD4 falls below 250


OutcomesIncident HIV infection (all and virologically linked)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe method of sequence generation is not explicitly stated but as permuted block randomisation with stratification was used, it is assumed this was done by computer and we judged it to be at low risk of bias.

Allocation concealment (selection bias)Unclear riskRandom allocation in a 1:1 ratio was performed in the RCT. The article does not specify how allocation was concealed.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskUnblinded study but biological endpoints make bias less likely.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence of attrition bias.

Selective reporting (reporting bias)Low riskNo evidence of reporting bias.

Other biasLow riskNo evidence of other bias.

Del Romero 2010

MethodsObservational cohort


Participants648 heterosexual couples attending a clinic in Madrid, Spain, from 1989 to 2008


InterventionsART


OutcomesIncident HIV Infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up. All subjects accounted for.

Selective reporting (reporting bias)Low riskNo evidence of reporting bias.

Other biasLow riskNo evidence of other bias.

Donnell 2010

MethodsObservational cohort


ParticipantsHeterosexual African adults who were seropositive for both HIV and herpes simplex virus type II (HSV-2) and their HIV-uninfected sexual partners. Three thousand four hundred eight couples were enrolled from seven countries (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia).


InterventionsART


OutcomesIncident HIV Infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Low riskSubjects lost to follow up discussed.

Selective reporting (reporting bias)Low riskNo evidence of reporting bias.

Other biasLow riskNo evidence of other bias.

Jia 2012

MethodsNational-level data of HIV testing and treatment from the National Centre for AIDS/STD Control and Prevention


ParticipantsAll individuals in China who have tested positive for HIV


InterventionsART


OutcomesHIV incidence


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Low riskSubjects lost to follow up or with missing data were discussed.

Selective reporting (reporting bias)Unclear riskStudy protocol was not available. Risk of bias unclear.

Other biasUnclear riskNo statement

Lu 2010

MethodsObservational cohort


Participants1927 heterosexual couples between January 2006 and December 2008 for testing and treatment at county hospitals in China


InterventionsART


OutcomesIncident HIV Infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy protocol was not available. Risk of bias unclear.

Selective reporting (reporting bias)Unclear riskStudy protocol was not available. Risk of bias unclear.

Other biasLow riskThough unknown in what direction, bias is potentially present as a result of unavailable person-time data for treated and untreated couples.

Melo 2008

MethodsObservational cohort


Participants93 discordant couples, in which the female member of the couple was infected in 67 (72%) and the male in 26 (28%).


InterventionsART


OutcomesIncident HIV Infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Low riskSubjects lost to follow up discussed.

Selective reporting (reporting bias)Low riskNo evidence of reporting bias.

Other biasLow riskNo evidence of other bias.

Musicco 1994

MethodsObservational cohort


ParticipantsA cohort of 436 monogamous HIV-uninfected female sexual partners of HIV-infected men recruited from 16 centres in Italy


InterventionsZidovudine


OutcomesIncident HIV Infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy protocol was not available. Risk of bias unclear.

Selective reporting (reporting bias)Low riskNo evidence of reporting bias.

Other biasLow riskNo evidence of other bias.

Reynolds 2011

MethodsObservational cohort


Participants250 HIV-discordant couples from Rakai, Uganda.


InterventionsART


OutcomesIncident HIV Infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy protocol was not available. Risk of bias unclear.

Selective reporting (reporting bias)Low riskNo evidence of reporting bias.

Other biasLow riskNo evidence of other bias.

Sullivan 2009

MethodsObservational cohort


Participants2,993 HIV-discordant couples in Rwanda and Zambia followed from 2002 to 2008


InterventionsART


OutcomesIncident HIV Infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomised study

Allocation concealment (selection bias)High riskNon-randomised study

Blinding (performance bias and detection bias)
All outcomes
High riskNon-randomised study

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy protocol was not available. Risk of bias unclear.

Selective reporting (reporting bias)Low riskNo evidence of reporting bias.

Other biasLow riskNo evidence of other bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Baeten 2010ART was not given

Barreiro 2006All index cases received ART

Brill 2003ART was not given

Bunnell 2006All index cases received ART

Bunnell 2008All index cases received ART

Fideli 2001ART was not given

Gray 2001ART was not given

Kayitenkore 2006ART was not given

Mehendale 2004ART was not given

Operskalski 1997ART was not given

Peters 2008ART was not given

Peterson 2007ART was not given

Quinn 2000ART was not given

Ragni 1998ART was not given

Tovanabutra 2002ART was not given

Wawer 2005ART was not given

 
Comparison 1. Delayed vs Immediate ART (RCTs)

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

 1 Linked Incident HIV Infection1Rate Ratio (Fixed, 95% CI)0.04 [0.00, 0.27]

 2 All Incident HIV Infection1Rate Ratio (Fixed, 95% CI)0.11 [0.04, 0.32]

 3 Severe or Life-Threatening Adverse Events (Grade 3 or 4)11763Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.84, 1.33]

 4 Grade 3 or 4 Laboratory Abnormalities11763Risk Ratio (M-H, Fixed, 95% CI)1.49 [1.25, 1.77]

 
Comparison 2. Treated with ART vs Not Treated with ART (Observational Studies)

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

 1 Incident HIV Infection9Rate Ratio (Random, 95% CI)0.58 [0.35, 0.96]

 
Comparison 3. Treated with ART vs Not Treated with ART (Observational Studies, sensitivity analysis)

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

 1 Incident HIV Infection7Rate Ratio (Random, 95% CI)0.36 [0.17, 0.75]

 
Comparison 4. Treated with ART vs Not Treated with ART (< 200, 200-349, and ≥350 CD4 Cells/µL Subgroup Analysis) (Observational Studies)

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

 1 Incident HIV Infection5Rate Ratio (Random, 95% CI)Subtotals only

    1.1 Less than 200 CD4
5Rate Ratio (Random, 95% CI)0.12 [0.02, 0.81]

    1.2 200-350 CD4
4Rate Ratio (Random, 95% CI)0.66 [0.47, 0.92]

    1.3 More than 350 CD4
3Rate Ratio (Random, 95% CI)0.12 [0.01, 1.99]

 
Comparison 5. Treated with ART vs Not Treated with ART (Female/Male Subgroup Analysis) (Observational Studies)

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

 1 Incident HIV Infection3Risk Ratio (Random, 95% CI)Subtotals only

    1.1 Female Index Case
3Risk Ratio (Random, 95% CI)0.39 [0.13, 1.18]

    1.2 Male Index Case
3Risk Ratio (Random, 95% CI)0.11 [0.01, 1.62]

 
Comparison 6. Treated with ART vs Not Treated with ART (Subgroup Analysis: Low-/Middle-Income vs High-income)) (Observational Studies)

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

 1 Incident HIV Infection9Rate Ratio (Random, 95% CI)Subtotals only

    1.1 Low/Middle Income Country
7Rate Ratio (Random, 95% CI)0.53 [0.29, 0.97]

    1.2 High Income Country
2Rate Ratio (Random, 95% CI)0.77 [0.33, 1.83]

 
Summary of findings for the main comparison. Antiretroviral Therapy for HIV Prevention in Serodiscordant Couples (Part A)

Antiretroviral Therapy for HIV Prevention in Serodiscordant Couples (Part A)

Patient or population: Serodiscordant couples
Settings: Botswana, Brazil, China, India, Italy Malawi, Kenya, Rwanda, South Africa, Spain, Thailand, Uganda, United States of America, Zambia and Zimbabwe
Intervention: Antiretroviral Therapy

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

Assumed riskCorresponding risk

ControlAntiretroviral therapy

Virologically linked HIV incidence (RCT)17 per 10005,81 per 1000

(0 to 5)5,8
Rate Ratio 0.04
(0.00 to 0.27)
1750

(1 study)
⊕⊕⊕⊕
high5,8

HIV incidence (observational studies)54 per 10001,231 per 1000
(19 to 51)1,2
Rate Ratio 0.58
(0.35 to 0.96)
46204
(9 studies)
⊕⊕⊕⊝
moderate3

HIV incidence (observational studies--sensitivity analysis)48 per 10001,217 per 1000
(8 to 36)1,2
Rate Ratio 0.36
(0.17 to 0.75)
46560
(7 studies)
⊕⊕⊕⊝
moderate4,5

HIV incidence: CD4 subgroups (<200 cells/µL) (observational studies)48 per 10002,66 per 1000
(1 to 39)2,6
RR 0.12
(0.02 to 0.81)
26594
(5 studies)
⊕⊕⊝⊝
low5,7,8

HIV incidence: CD4 subgroups (200-350 CD4 cells/µL) (observational studies)28 per 10002,618 per 1000
(13 to 26)2,6
RR 0.66
(0.47 to 0.92)
9595
(4 studies)
⊕⊝⊝⊝
very low3,8,9

HIV incidence: CD4 subgroups (350 or more CD4 cells/µL) (observational studies)25 per 10002,63 per 1000
(0 to 49)2,6
RR 0.12
(0.01 to 1.99.)
13426
(3 studies)
⊕⊕⊝⊝
low5,8,10

Virologically linked HIV incidence: CD4 subgroups (350 or more CD4 cells/µL) (RCT)17 per 10005,81 per 1000

(0 to 5)5,8
RR 0.04
(0.00 to 0.27)
1750

(1 study)
⊕⊕⊕⊕
high5,8

*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).
RCT: randomised controlled trial; 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 Less than 5% of sample was imputed due to missing information in the denominator.
2 Numerators and Denominators taken from text where possible. Numbers were not used to calculate the relative effect estimates.
3 Rate Ratio ˜ 0.50
4 Two studies were removed due to differences in intervention or incomplete data.
5 RR < 0.35
6 Due to missing information in the denominator and/or numerator, some data were imputed from text.
7 No person time available for 3 out of 5 studies.
8 Few events and/or wide confidence interval.
9 No person time available for 2 out of 4 studies.
10 No person time available for 1 out of 3 studies.
 
Summary of findings 2. Antiretroviral Therapy for HIV Prevention in Serodiscordant Couples (Part B)

Antiretroviral Therapy for HIV Prevention in Serodiscordant Couples (Part B)

Patient or population: Serodiscordant couples
Settings: Botswana, Brazil, China, Italy, Kenya, Rwanda, South Africa, Spain, Tanzania, Uganda, and Zambia
Intervention: Antiretroviral Therapy

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

Assumed riskCorresponding risk

ControlAntiretroviral therapy

HIV incidence: gender subgroup (female cases)74 per 10001,229 per 1000
(10 to 88)2
RR 0.39
(0.13 to 1.18)
15608
(3 studies)
⊕⊕⊝⊝
low3,4
Observational studies only

HIV incidence: gender subgroup (male Cases)48 per 10001,25 per 1000
(0 to 78)1,2
RR 0.11
(0.01 to 1.62)
25073
(3 studies)
⊕⊕⊝⊝
low3,4
Observational studies only

HIV incidence: low-/middle-income countries54 per 10001,229 per 1000
(16 to 53)1,2
RR 0.53
(0.29 to 0.97)
45029
(7 studies)
⊕⊕⊝⊝
low3,5
Observational studies only

HIV incidence: high income countries31 per 10001,224 per 1000
(10 to 57)1,2
RR 0.77
(0.33 to 1.83)
1061
(2 studies)
⊕⊝⊝⊝
very low3
Observational studies only

*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 Numerators and denominators taken from text where possible. Numbers were not used to calculate the relative effect estimates.
2 Due to missing information in the denominator and/or numerator, some data were imputed from text.
3 Few events and/or wide confidence interval.
4 RR ˜ 0.35
5 Rate Ratio ˜ 0.50