PICO 4 Should antiretroviral therapy (ART) be offered to HIV-infected partners in serodiscordant couples to reduce HIV transmission to uninfected partners? PICO 5 Should 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 records1814 Duplicates removed331 Records screened1483 Records excluded1458 Full-text articles obtained25 Studies included in review7 (PICO 4 and PICO 5)

PICO 4 framework P opulation Serodiscordant couples (heterosexual) I ntervention ART for the HIV-infected partner C omparison No ART for the HIV-infected partner O 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 ART 4.HIV-related mortality 5.HIV-related morbidity 6.Quality of life (both partners)

Outcomes: PICO 4 Outcomes Relative importance ( rank 1→9 most critical) Comment HIV incidence9Critical HIV incidence (sensitivity)9Critical Acquisition of primary drug-resistant HIV by previously HIV- negative partner 9Critical Adverse events / side- effects of ART 8Critical HIV-related mortality8Critical HIV-related morbidity7Important Quality of life7Important

Summary of studies Author, yearPopulationFindings Del Romero 2010 Heterosexual couples attending a clinic in Madrid, Spain from 1989 to couples analyzed (ART) Incident HIV infection (overall) Rate ratio 0.21 (95% CI ) Incident HIV infection (index partner’s CD4 < 200) Risk ratio 0.16 (95% CI ) Incident HIV infection (index partner’s CD ) Risk ratio 0.10 (95% CI ) Incident HIV infection (index partner’s CD4 ≥350) Risk ratio 0.17 (95% CI ) Donnell 2010Heterosexual 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 ) Incident HIV infection (index partner’s CD4 < 200) Rate ratio 0.00 (95% CI ) Incident HIV infection (index partner’s CD ) Rate ratio 0.65 (95% CI ) Incident HIV infection (index partner’s CD4 ≥350) Rate ratio 0.00 (95% CI )

Summary of studies (continued) Author, yearPopulationFindings Melo 2008Heterosexual discordant couples 93 couples studied (ART) Incident HIV infection (overall) Rate ratio 0.10 (95% CI ) Incident HIV infection (index partner’s CD4 < 200) Risk ratio 0.30 (95% CI ) Incident HIV infection (index partner’s CD ) Risk ratio 0.33 (95% CI ) 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 ) Reynolds 2009An observational cohort of HIV discordant couples in Rakai, Uganda 193 couples analyzed (ART) Incident HIV infection (overall) Rate ratio 0.23 (95% CI )

Summary of studies (continued) Author, yearPopulationFindings Sullivan 2009 Heterosexual discordant couples in Rwanda and Zambia followed from couples studied (ART) Incident HIV infection (overall) Rate ratio 0.21 (95% CI ) Wang 2010A cohort of heterosexual couples testing and seeking treatment at county hospitals in China in 2006 to heterosexual couples studied (ART) Incident HIV infection (overall) Risk ratio 1.44 (95% CI )

GRADE evidence profile

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 table FactorExplanation / EvidenceJudgment Quality of Evidence Strong evidence from six of seven observational studies of a benefit There is no definitive RCT completed; a large one (HPTN052) is in the field and will be until 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) 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: A ntiretroviral 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 indicated C omparison ART for the HIV-infected partner, according to existing clinical guidelines O 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 partner 2.Acquisition of primary drug-resistant HIV by previously HIV- uninfected partner 3.Adverse events and side effects of ART 4.HIV-related mortality 5.HIV-related morbidity 6.Quality of life (both partners)

Outcomes: PICO 5 Outcomes Relative importance ( rank 1→9 most critical) Comment HIV incidence9Critical HIV incidence (sensitivity)9Critical Acquisition of primary drug-resistant HIV by previously uninfected partner 9Critical Adverse events / side- effects of ART 8Critical HIV-related mortality8Critical HIV-related morbidity7Important Quality of life7Important

Summary of studies Author, yearPopulationFindings Del Romero 2010 Heterosexual couples attending a clinic in Madrid, Spain from 1989 to couples analyzed (ART) Incident HIV infection (overall) Rate ratio 0.21 (95% CI ) Incident HIV infection (index partner’s CD4 < 200) Risk ratio 0.16 (95% CI ) Incident HIV infection (index partner’s CD ) Risk ratio 0.10 (95% CI ) Incident HIV infection (index partner’s CD4 > 349) Risk ratio 0.17 (95% CI ) Donnell 2010Heterosexual 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 ) Incident HIV infection (index partner’s CD4 < 200) Rate ratio 0.00 (95% CI ) Incident HIV infection (index partner’s CD ) Rate ratio 0.65 (95% CI ) Incident HIV infection (index partner’s CD4 > 349) Rate ratio 0.00 (95% CI )

Summary of Studies (continued) Author, yearPopulationFindings Melo 2008Heterosexual discordant couples 93 couples studied (ART) Incident HIV infection (overall) Rate ratio 0.10 (95% CI ) Incident HIV infection (index partner’s CD4 < 200) Risk ratio 0.30 (95% CI ) Incident HIV infection (index partner’s CD ) Risk ratio 0.33 (95% CI ) 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 ) 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

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 FactorExplanation / EvidenceJudgment Quality of Evidence No evidence of benefit There is no definitive RCT completed; a large one (HPTN052) is in the field and will be until 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: A ntiretroviral 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-yearsProportion of benefit Number needed to treat Untreated couples Treated couples Absolute risk reduction < % %43.7 ≥ %52.6 Total %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).