pico 4 should antiretroviral therapy (art) be offered to hiv-infected partners in serodiscordant...
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PICO 4 Should antiretroviral therapy (ART) be offered to
HIV-infected partners in serodiscordant couples to
reduce HIV transmission to uninfected partners?
PICO 5Should ART be started earlier than clinically indicated for the HIV-infected individuals in serodiscordant partnerships to reduce HIV
transmission to uninfected partners?
George W. Rutherford, M.D.
Cochrane HIV/AIDS Group, University of California, San Francisco, USA
WHO consultant
Searches
Principal investigators of ongoing trials have been contacted
Databases (01 Jan 1987 – 01 Dec 2010) PubMed EMBASE Cochrane “CENTRAL” Web of Science LILACS Also searched grey literature
Total of records 1814
Duplicates removed 331
Records screened 1483
Records excluded 1458
Full-text articles obtained 25
Studies included in review 7
(PICO 4 and PICO 5)
PICO 4 framework
P opulation Serodiscordant couples (heterosexual)I ntervention ART for the HIV-infected partnerC omparison No ART for the HIV-infected partnerO utcomes
Q4: Should ART be offered to HIV-infected partners in serodiscordant couples to reduce HIV transmission to uninfected partners?
1. Incident HIV infection in the previously uninfected partner
2. Acquisition of primary drug-resistant HIV by previously HIV-uninfected partner
3. Adverse events and side effects of ART4. HIV-related mortality5. HIV-related morbidity6. Quality of life (both partners)
Outcomes: PICO 4
Outcomes Relative importance( rank 1→9 most critical) Comment
HIV incidence 9 Critical
HIV incidence (sensitivity) 9 Critical
Acquisition of primary drug-resistant HIV by previously HIV-negative partner
9 Critical
Adverse events / side-effects of ART 8 Critical
HIV-related mortality 8 Critical
HIV-related morbidity 7 Important
Quality of life 7 Important
Summary of studiesAuthor, year Population Findings
Del Romero 2010 Heterosexual couples attending a clinic in Madrid, Spain from 1989 to 2008
• 648 couples analyzed (ART)• Incident HIV infection (overall) Rate ratio 0.21 (95% CI 0.01-3.75)• Incident HIV infection (index partner’s CD4 < 200) Risk ratio 0.16 (95% CI 0.01-2.59)• Incident HIV infection (index partner’s CD4 200-350) Risk ratio 0.10 (95% CI 0.01-1.26)• Incident HIV infection (index partner’s CD4 ≥350) Risk ratio 0.17 (95% CI 0.01-2.92)
Donnell 2010 Heterosexual African adults who were positive for both HIV and HSV in Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia
• 3,408 couples analyzed (ART)• Incident HIV infection (overall) Rate ratio 0.08 (95% CI 0.01-0.57)• Incident HIV infection (index partner’s CD4 < 200) Rate ratio 0.00 (95% CI 0.00-0.04)• Incident HIV infection (index partner’s CD4 200-350) Rate ratio 0.65 (95% CI 0.10-4.35)• Incident HIV infection (index partner’s CD4 ≥350) Rate ratio 0.00 (95% CI 0.00-0.15)
Summary of studies (continued)Author, year Population Findings
Melo 2008 Heterosexual discordant couples • 93 couples studied (ART)• Incident HIV infection (overall) Rate ratio 0.10 (95% CI 0.01-1.67)• Incident HIV infection (index partner’s CD4 < 200) Risk ratio 0.30 (95% CI 0.01-6.28)• Incident HIV infection (index partner’s CD4 200-350) Risk ratio 0.33 (95% CI 0.02-5.76)
Musicco 1994 A cohort of heterosexual couples in Italy in which men where infected and women were uninfected
• 436 monogamous couples recruited from 16 centers in Italy (AZT monotherapy)
• AZT main exposure• Incident HIV infection (overall)
Rate Ratio 0.88 (95% CI 0.36-2.16)
Reynolds 2009 An observational cohort of HIV discordant couples in Rakai, Uganda
• 193 couples analyzed (ART)• Incident HIV infection (overall) Rate ratio 0.23 (95% CI 0.01-3.83)
Summary of studies (continued)Author, year Population Findings
Sullivan 2009 Heterosexual discordant couples in Rwanda and Zambia followed from 2002-2008
2993 couples studied (ART)Incident HIV infection (overall) Rate ratio 0.21 (95% CI 0.08-0.56)
Wang 2010 A cohort of heterosexual couples testing and seeking treatment at county hospitals in China in 2006 to 2008
1927 heterosexual couples studied (ART)Incident HIV infection (overall) Risk ratio 1.44 (95% CI 0.88-2.44)
Author(s): Anglemyer, Andrew; Kennedy, Gail, Rutherford, George Date: 2010-12-22 Question: Should ART be offered to HIV-positive partners in serodiscordant couples to reduce HIV transmission to HIV-negative partners? Settings: Spain, Africa, Brazil, Italy, and China Bibliography: Del Romero 2010; Donnell 2010; Melo 2008; Reynolds 2009; Sullivan 2009; Wang 2010; Musicco 1994
Summary of Findings Quality assessment
No. of patients Effect
No. of studies
Design Limitations Inconsistency Indirectness Imprecision Other
considerations Antiretroviral
Therapy control
Relative effect
(95% CI)
Absolute effect
Quality Importance
HIV Incidence
7 observational studies
no serious limitations
no serious inconsistency
no serious indirectness
no serious imprecision
strong association1
77/1869 (4.1%)2,3
355/4809 (7.4%)2,3
Rate Ratio 0.37 (0.14 to 0.97)
47 fewer per 1000 (from 2 fewer to
63 fewer)
MODERATE
CRITICAL
HIV Incidence (Sensitivity)
5 observational studies
serious4 no serious inconsistency
no serious indirectness
no serious imprecision
very strong association5
5/759 (0.7%)2,3 316/1409 (22.4%)2,3
Rate Ratio 0.17 (0.08 to 0.37)
186 fewer per 1000 (from 141 fewer to
206 fewer)
MODERATE
CRITICAL
1 Rate Ratio < 0.50 2 Less than 5% of sample was imputed due to missing information in the denominator. 3 Numerators and Denominators taken from text where possible. Numbers were not used to calculate the relative effect estimates. 4 Two studies were removed due to differences in intervention or incomplete data. 5 RR < 0.20
GRADE evidence profile
GRADE evidence profile
Author(s): Anglemyer, Andrew; Kennedy, Gail, Rutherford, George Date: 2010-12-22 Question: Should ART be offered to HIV-positive partners in serodiscordant couples to reduce HIV transmission to HIV-negative partners? Settings: Spain, Africa, Brazil, Italy, and China Bibliography: N/A
Summary of Findings Quality assessment
No. of patients Effect
No. of studies
Design Limitations Inconsistency Indirectness Imprecision Other
considerations Antiretroviral
Therapy control
Relative effect
(95% CI)
Absolute effect
Quality Importance
HIV-related mortality
-- Not measured CRITICAL
Acquisition of primary drug-resistant HIV by previously HIV-negative partner
-- Not measured CRITICAL
Adverse events and side-effects of ART
-- Not measured CRITICAL
HIV-related morbidity
-- Not measured IMPORTANT
Quality of life
-- Not measured IMPORTANT
Quality of evidence:PICO 4
Moderate quality evidence: Estimate of effect is somewhat certain
•Rated down for study limitations and precision issues.•Rated up for strong associations. •No studies explored impact of ART on many critical or important outcomes
Risk assessment:PICO 4
• Del Romero 2010: Genitourinary infections occurred in 8 (5.6%) of 144 treated couples during follow up and in 62 (16.0%) of 388 untreated couples.
• Wang 2010: Of 1369 treated couples, 266 (19.4%) switched• 259 (97.4%) of these switched due to an adverse event• 3 other patients developed resistance
Risk-benefit tableFactor Explanation / Evidence Judgment
Quality of Evidence
Strong evidence from six of seven observational studies of a benefitThere is no definitive RCT completed; a large one (HPTN052) is in the field and will be until 2015.
Moderate. An estimate of effect is somewhat certain.
Balance of Benefits vs. Harms
There is moderate quality evidence suggests that 2-63 fewer infections would occur per 1000 couples who received ART. If two outlier studies (Musicco and Wang) are excluded (sensitivity analysis) 141-206 fewer infections would occur per 1000 couples who received ART. No studies explored the impact of ART among serodiscordant couples on the following adverse outcomes: • Acquisition of primary drug resistant HIV by uninfected partner• Adverse events and side effects of ART• HIV-related mortality• HIV-related morbidity• Quality of life.
Benefits may outweigh harms, but rigorous RCTs and large observational studies of adverse events among serodiscordant couples are needed.
Risk-benefit table (continued)
Values and preferences
There is a feeling of optimism that new possibilities are emerging for HIV-positive people to live with less anxiety about infecting negative partners, and with more hope for healthy conception and childbirth options. Providers of HTC for couples must be well-informed about all of the options involving treatment for prevention so that couples can understand the implications and be free to make fully informed choices about these fundamental aspects of their lives.
At the same time, care must be taken to ensure that no one is pressured to take an approach to HIV prevention that they are not comfortable with. These are personal and joint decisions.
Supportive if choices are fully informed
Cost and feasibility
Appropriate in settings where ART is regularly provided
Generally conforms to national and international guidelines
Not a major issue
Proposed recommendation
Statement: Antiretroviral therapy should be offered to HIV-infected partners in serodiscordant couples to reduce HIV transmission to uninfected partners.
Overall grade of recommendation: Direction: For / Against Strength: Strong / Conditional
PICO 5 framework
P opulation Serodiscordant couples (where infected partner has a CD4 >350 cells)I ntervention ART for the HIV-infected partner, earlier than clinically indicatedC omparison ART for the HIV-infected partner, according to existing clinical guidelinesO utcomes
Q5: Should ART be started earlier than clinically or immunologically indicated for the HIV-positive individuals in serodiscordant partnerships to reduce HIV transmission to HIV-negative partners?
1. Incident HIV infection in the previously uninfected partner2. Acquisition of primary drug-resistant HIV by previously HIV-
uninfected partner3. Adverse events and side effects of ART4. HIV-related mortality5. HIV-related morbidity6. Quality of life (both partners)
Outcomes: PICO 5
Outcomes Relative importance( rank 1→9 most critical) Comment
HIV incidence 9 Critical
HIV incidence (sensitivity) 9 Critical
Acquisition of primary drug-resistant HIV by previously uninfected partner
9 Critical
Adverse events / side-effects of ART 8 Critical
HIV-related mortality 8 Critical
HIV-related morbidity 7 Important
Quality of life 7 Important
Summary of studiesAuthor, year Population Findings
Del Romero 2010 Heterosexual couples attending a clinic in Madrid, Spain from 1989 to 2008
• 648 couples analyzed (ART)• Incident HIV infection (overall) Rate ratio 0.21 (95% CI 0.01-3.75)• Incident HIV infection (index partner’s CD4 < 200) Risk ratio 0.16 (95% CI 0.01-2.59)• Incident HIV infection (index partner’s CD4 200-350) Risk ratio 0.10 (95% CI 0.01-1.26)• Incident HIV infection (index partner’s CD4 > 349) Risk ratio 0.17 (95% CI 0.01-2.92)
Donnell 2010 Heterosexual African adults who were positive for both HIV and HSV in Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia
• 3,408 couples analyzed (ART)• Incident HIV infection (overall) Rate ratio 0.08 (95% CI 0.01-0.57)• Incident HIV infection (index partner’s CD4 < 200) Rate ratio 0.00 (95% CI 0.00-0.04)• Incident HIV infection (index partner’s CD4 200-350) Rate ratio 0.65 (95% CI 0.10-4.35)• Incident HIV infection (index partner’s CD4 > 349) Rate ratio 0.00 (95% CI 0.00-0.15)
Summary of Studies (continued)Author, year Population Findings
Melo 2008 Heterosexual discordant couples • 93 couples studied (ART)• Incident HIV infection (overall) Rate ratio 0.10 (95% CI 0.01-1.67)• Incident HIV infection (index partner’s CD4 < 200) Risk ratio 0.30 (95% CI 0.01-6.28)• Incident HIV infection (index partner’s CD4 200-350) Risk ratio 0.33 (95% CI 0.02-5.76)
Reynolds 2009 An observational cohort of HIV discordant couples in Rakai, Uganda
• 193 couples analyzed (ART)• Incident HIV infection (overall) Rate ratio 0.23 (95% CI 0.01-3.83)
Ongoing HPTN 052 Trial
A randomized trial of ART for prevention of transmission in HIV discordant couples in Brazil, India, Malawi, Thailand, Zimbabwe
Phase III, two-arm, multi-site, randomized trial of serodiscordant couples in which the index case’s CD4 is >350. Couples were randomized to receive ART at first day of enrollment or to wait for treatment initiation (couples in the second group waited until index case had two consecutive CD4 measurements in which CD4 cell count was below 250 or developed ADI).
GRADE evidence profile
Author(s): Anglemyer, Andrew; Kennedy, Gail, Rutherford, George Date: 2010-12-22 Question: Should Antiretroviral Therapy be started earlier than clinically indicated for the HIV-positive individuals in serodiscordant partnerships to reduce HIV transmission to HIV-negative partners? Settings: Spain, Africa, Brazil, Italy, and China Bibliography: Del Romero 2010; Donnell 2010; Melo 2008; Reynolds 2009
Summary of findings Quality assessment
No of patients Effect
No of studies
Design Limitations Inconsistency Indirectness Imprecision Other
considerations Antiretroviral
Therapy control
Relative (95% CI)
Absolute Quality
Importance
HIV Incidence: CD4 Subgroups (350 or more CD4 cells/µ)
2 observational studies
no serious limitations
no serious inconsistency
serious1 very serious2 very strong association3
0/147 (0%)4,5 61/3284 (1.9%)4,5
RR 0.02 (0 to 2.87)
18 fewer per 1000 (from 19
fewer to 35 more)
VERY LOW
CRITICAL
HIV Incidence: CD4 Subgroups (<350 cells)
4 observational studies
no serious limitations
no serious inconsistency
no serious indirectness6
very serious2 very strong association3
1/263 (0.4%) 61/1653 (3.7%)
RR 0.16 (0.04 to
0.66)
31 fewer per 1000 (from 13
fewer to 35 fewer)
LOW
CRITICAL
1 No person time available for 1 out of 2 studies. 2 Few events and/or wide confidence interval. 3 RR < 0.20 4 Numerators and Denominators taken from text where possible. Numbers were not used to calculate the relative effect estimates. 5 Due to missing information in the denominator and/or numerator, some data were imputed from text. 6 No person time available for 3 out of 4 studies.
GRADE evidence profile
Author(s): Anglemyer, Andrew; Kennedy, Gail, Rutherford, George Date: 2010-12-22 Question: Should Antiretroviral Therapy be started earlier than clinically indicated for the HIV-positive individuals in serodiscordant partnerships to reduce HIV transmission to HIV-negative partners? Settings: Spain, Africa, Brazil, Italy, and China Bibliography: N/A
Summary of Findings Quality assessment
No. of patients Effect
No. of studies
Design Limitations Inconsistency Indirectness Imprecision Other
considerations Antiretroviral
Therapy control
Relative effect
(95% CI)
Absolute effect
Quality Importance
HIV-related mortality
-- Not measured CRITICAL
Acquisition of primary drug-resistant HIV by previously HIV-negative partner
-- Not measured CRITICAL
Adverse events and side-effects of ART
-- Not measured CRITICAL
HIV-related morbidity
-- Not measured IMPORTANT
Quality of life
-- Not measured IMPORTANT
Quality of evidence:PICO 5
Very low quality of evidence:Any estimate of effect is very uncertain.
• Rated down for study limitations, precision issues, and indirectness.• Rated up for strong association. •Most studies did not explore impact of ART among couples with ≥350 cells on most critical or important outcomes.
Risk assessment:PICO 5
• Del Romero 2010: Genitourinary infections occurred in 8 (5.6%) of 144 treated couples during follow up and in 62 (16.0%) of 388 untreated couples.
Risk-benefit table:≥350 CD4 cells/µL
Factor Explanation / Evidence Judgment
Quality of Evidence
No evidence of benefitThere is no definitive RCT completed; a large one (HPTN052) is in the field and will be until 2015.
Very low quality. Any estimate of effect is very uncertain.
Balance of Benefits vs. Harms
Very low quality evidence from two studies suggests that between 19 fewer and 35 more infections would occur per 1000 discordant couples that receive ART.There are no studies that explored the impact of ART among serodiscordant couples on the following adverse outcomes: Acquisition of primary drug resistant HIV among previously uninfected partner•Adverse events and side effects of ART•Earlier HIV resistance•HIV-related mortality•HIV-related morbidity•Quality of life.
No clear evidence of benefit or harm. Rigorous RCTs and large observational studies of adverse events among serodiscordant couples are needed.
Risk-benefit table (continued)
Values and preferences
There is a feeling of optimism that new possibilities are emerging for HIV-positive people to live with less anxiety about infecting negative partners, and with more hope for healthy conception and childbirth options. Providers of HTC for couples must be well-informed about all of the options involving treatment for prevention so that couples can understand the implications and be free to make fully informed choices about these fundamental aspects of their lives.
At the same time, care must be taken to ensure that no one is pressured to take an approach to HIV prevention that they are not comfortable with. These are personal and joint decisions.
Supportive if choices are fully informed
Cost and feasibility
Costs and ability to pay for ART when not clinically indicated will vary enormously across settings (both by economics and by HIV prevalence).
This option may be particularly relevant for couples who cannot or do not want to use condoms.
Cost may be a significant issue in resource-limited settings
Proposed recommendation
Statement: Antiretroviral therapy should/should not be offered to HIV-infected partners with ≥350 CD4 cells/µL who don’t meet clinical criteria for ART in serodiscordant couples to reduce HIV transmission to uninfected partners.
Overall grade of recommendation: Direction: For / Against Strength: Strong / Conditional
Six-study sensitivity analysis
Sensitivity analysis with all but Musicco included
Absolute risk reduction and number needed to treat by CD4 stratum
CD4 stratum
(cells per µL)
Number of
studies
Incidence per 1,000 person-years Proportion of benefit
Number needed to treatUntreated
couplesTreated couples
Absolute risk
reduction
<200 4 158 16 142 77% 7.04
200-349 3 35 12 23 13% 43.7
≥350 2 19 0 19 10% 52.6
Total 4 212 28 184 100% 5.4
ART for prevention of HIV transmission, summary rate ratios by CD4 cell stratum
Rutherford GW, Anglemyer A, Egger M, Siegfried N. Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples. Cochrane Databse Syst Rev 2011 (in press).