Interventions to reduce HIV sexual transmission within discordant couples

Paul Collini and Angela Obasi

Executive summary/Key messages

There are four steps necessary to enable prevention of transmission of HIV within heterosexual serodiscordant couples. 1. Index case is diagnosed with HIV, 2. This person discloses their status to their partner, 3. The partner learns his or her (HIV seronegative or seropositive) status and the couple is identified as discordant (steps 1, 2, and 3 can occur together in couples testing), 4. Actions are taken to reduce the likelihood of transmission. We looked for evidence that assessed the effects of interventions to reduce sexual transmission of HIV in serodiscordant couples.

Partner notification strategies We found no RCTs undertaken in resource poor settings. One
systematic review undertaken in a resource-rich setting found that offering a choice between provider (third party) and patient referral and patient referral alone was associated with increased rates of partner notification.

Voluntary counselling and testing One RCT found that couples reported decreased rates of
unprotected sexual intercourse following voluntary counselling and testing (VCT) compared with receiving only health information, but these couples were also more likely to suffer family disownment. Cohort studies also found that rates of unprotected sexual intercourse decreased after VCT compared with before VCT.

Studies assessing outcomes of disclosure We found no RCTs; an RCT would be impractical to

conduct given the ethical issues surrounding disclosure. One systematic review of observational studies suggested that HIV status disclosure was not associated with increased relationship break up, and positive outcomes were more frequent than negative outcomes.

Condom use We found no RCTs; an RCT of condom use is unlikely to be conducted. Observational studies suggest that condom use in serodiscordant couples is associated with 80% reductions in HIV transmission. Male circumcision We found no RCTs that assessed serodiscordant couples. Data from one RCT undertaken in men with HIV, which found a clear benefit from male adult circumcision in reducing risk of HIV transmission, coupled with observational data from one longitudinal study comparing rates of HIV in circumcised and uncircumcised serodiscordant couples suggest that circumcision may be an effective intervention in serodiscordant couples. There was no increased risk of HIV attributed to surgery in the RCT and in the observational study, circumcision had usually occurred during childhood so no data for surgery related risk of developing HIV were available. Circumcision has the theoretical potential to increase HIV transmission in the post-surgical healing period. There is also a potential increase in risk if surgery is conducted with nonsterile instruments, and if the perception of protection leads to increased risk taking behaviour. However, we found no studies assessing these risks.
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Sexually transmitted infection (STI) treatment Studies of individuals in resource poor settings have demonstrated that sexually transmitted infection (STI) treatment can reduce risk of HIV transmission.[28] [29] It follows that a similar benefit would likely be realised by identifying and treating the STIs of serodiscordant couples, either through prompt syndromic management or traditional laboratory based diagnosis and treatment. In light of this, it would now be unethical to conduct an RCT of STI treatment in this population. Highly active antiretroviral treatment (HAART) We found no RCTs; an RCT in
serodiscordant couples would be unethical to conduct given the known effectiveness of HAART in individuals with HIV. Cohort studies suggest that HIV transmission is less likely with lower viral load in serodiscordant couples and that transmission risk is greatest in the first months after acquiring HIV infection.

Partner notification to increase disclosure We found no RCTs undertaken in resource poor

settings. One systematic review undertaken in a resource-rich setting found that offering a choice between provider (third party) and patient referral and patient referral alone was associated with increased rates of partner notification. Observational data suggest that women are less likely to disclose their HIV status if they have been tested for HIV in an antenatal setting rather than through voluntary counselling and testing (VCT). Increased disclosure was associated with being younger, having been in the relationship for longer, increased literacy, and knowing others with HIV. There were also higher rates of disclosure among women with lower socioeconomic status. Barriers to disclosing were fears of accusation of infidelity, abandonment (and so loss of economic support), and discrimination. Between violence 4% and15% of women also reported experiencing violence from their partner following disclosure.

Introduction
The HIV seronegative partners of people with HIV are the group of individuals who are at greatest risk of contracting HIV through sexual transmission. As measures to decrease sexual transmission among the general population have been seen to be effective, it is likely that specific interventions targeted at this high risk group could bring additional benefit. This paper has looked for the evidence behind any such interventions in resource poor settings.

Scope of the problem

Where a person who is HIV seropositive is in a relationship with a HIV seronegative partner the couple is described as being HIV serodiscordant. The nature of the relationship defining a couple is not uniformly defined. Studies have used various definitions including legally married, being in a common law marriage, cohabiting for a period such as 6 months, or being the stated primary or regular partner. The prevalence of serodiscordant couples in populations varies. In sub-Saharan Africa studies have found rates of 320% in the general population, and higher rates of 2035% in studies of those presenting to voluntary counselling and testing (VCT) services.[1] In a longitudinal study of couples in Tanzania, risk of HIV for a seronegative partner in a serodiscordant couple was several fold higher than that of partners in seroconcordant HIV negative couples (RR 57.9, 95% CI 12 to 244).[2] Similar increased risk was seen in the Rakai cohort in Uganda, where females in serodiscordant marriages are reported as having twice the infection risk of males.[3] [4] Couples may have poor understanding of what it means to be serodiscordant. A number of misconceptions have been noted in a descriptive study from Uganda.[1] There was belief that both people in the couple were infected but tests had failed to detect this, belief that the HIV seronegative partner was somehow immune to HIV, belief that God was protecting the HIV seronegative partner, and that gentler sex offered protection to the HIV seronegative partner. Such explanations were also found among some of the counsellors in this study. 2
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Studies have found that certain interventions reduce HIV sexual transmission or promote risk reducing behavioural change in high risk groups. Condom use and condom use plus sexually transmitted infection (STI) treatment in sex workers and their clients[5] and within the general community, mass media interventions aimed at condom promotion and HIV/AIDS education, peer led behavioural interventions and school based programmes,[6] VCT,[7] and STI treatments[8] have all been shown to be effective. Particular difficulties exist for discordant couples in adopting these changes in behaviour. Once diagnosed, the HIV seropositive individual must disclose their status to their partner and alert them to their need for testing. This leads to the awareness of serodiscordance. To reduce risk, the approaches such as ABC (abstinence, being faithful, and using condoms) may not be appropriate. Being faithful will not decrease HIV risk transmission and may not be easy to adopt. Abstinence and condom use require the agreement of both partners, who may not have equal negotiating positions, with societal pressure to have children and gender inequality making it difficult for both, but particularly the women, to adhere to such measures. It must also be remembered that one partner has HIV, and will need access to care and treatment, ideally with the support of their HIV seronegative partner. Thus there are four steps necessary to enable prevention of transmission of HIV within heterosexual serodiscordant couples. 1. Index case is diagnosed with HIV, 2. This person discloses their status to their partner, 3. The partner learns his or her (HIV seronegative or seropositive) status and the couple is identified as discordant (steps 1, 2, and 3 can occur together in couples testing), 4. Actions are taken to reduce the likelihood of transmission. Interventions acting at any step could reduce transmission rates. Many of these interventions are not specific to serodiscordant couples (increasing uptake of VCT, increasing use of condoms, treating STI), while some are specific (partner notification, couples testing). In this paper interventions were considered where they have been assessed in the context of serodiscordant relationships. The primary outcome of interest is reduced HIV transmission. Surrogate outcomes, such as rates of protected intercourse, have also been used in studies and have been included.

Guidelines
United Nations Programme on HIV/AIDS (UNAIDS) have issued guidelines on prevention of HIV sexual transmission in the general population. They emphasise giving information on safer sex including male and female condom use, abstinence, delayed onset of sexual debut, mutual fidelity, decreasing the number of sexual partners, comprehensive and appropriate sexual education, and early and effective treatment of STIs.[9] We are not aware of guidance on prevention of sexual transmission of HIV for serodiscordant couples. Disclosure is recognised as an important prevention goal.[10] Guidance is to undertake measures to increase disclosure to sexual partners at risk of HIV through the encouragement of ethical partner counselling. Improved counselling is advocated to minimise the number of patients who refuse to notify partners. The institution of national policies and legislation mechanisms should also be provided for notification without consent (where necessary) and for the protection of those who disclose. Responsibility among communities to protect themselves and each other from HIV transmission is to be encouraged.[11]

Key questions relevant to resource poor settings

What are the effects of interventions to increase disclosure of HIV status within serodiscordant couples? Partner notification 3
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Voluntary counselling and testing (VCT)

What are the outcomes of disclosure within couples where one partner has HIV? What are the effects of interventions to reduce HIV transmission rates within serodiscordant couples? Condom use Male circumcision Managing sexually transmitted infections (STIs) Highly active antiretroviral treatment (HAART)

Outcomes
For questions on interventions to improve disclosure and reduce HIV transmission Incidence of new HIV infection in HIV seronegative partners of serodiscordant couples. Behaviours that are surrogates for reduced HIV transmission (because without long follow up and large sample size, HIV transmission is difficult to measure). Condom use Frequency of sexual intercourse (with primary or non-primary partner) Adverse effects of interventions For questions on outcomes of disclosure Effects on relationship. Adverse effects of interventions.

Methods
The search was undertaken in July 2006. The following sources were searched for systematic reviews, randomized controlled trials and cohort studies: Medline, Embase, Cochrane Database of Systematic Reviews, CENTRAL, Database of Reviews of Effects, HTA Database, Trip Database, AIDsearch, African Journals Online, African Index Medicus, Global Index Medicus, LILACS, Index Medicus for South East Asia Region. Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies, and then sent to the author for further assessment of the full articles. The author placed emphasis on systematic reviews of RCTs and RCTs in resource poor settings. Where RCT data were lacking, cohort studies were considered. Studies referenced by included studies were also considered. Studies were included if they assessed the effects of an intervention or looked for modifiable risk factors for HIV transmission among heterosexual serodiscordant couples. Studies were excluded if they considered primarily homosexual couples, intravenous drug using populations, or were from resource rich settings.

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What are the effects of interventions to increase disclosure of HIV status within serodiscordant couples? Partner notification strategies
Introduction
Where the first partner has been tested, the process of encouraging the partner to be tested comes through a variety of partner notification strategies, including patient referral (disclosure by the patient themselves) or various types of third party notification strategies. This is important both for the HIV seropositive index partner who will not wish to transmit the virus and the non-index partner who will want to know their status and how best to manage and respond to their risk of illness. In studies of women tested for HIV (most in the antenatal setting) from Africa and South East Asia rates of disclosure by women to their male partners in resource poor settings range from 17% to 86%.[12] Less is known about rates at which men disclose their status to their female partners.

Evidence summary
We found no RCTs undertaken in resource poor settings. One systematic review undertaken in a resource-rich setting found that offering a choice between provider (third party) and patient referral and patient referral alone was associated with increased rates of partner notification.

Benefits and harms

We found no studies that looked at interventions to improve partner notification (using strategies such as patient referral (disclosure), contract referral, provider referral, or outreach assistance; see glossary) in resource poor settings. Approaches in resource rich settings have used different means of partner notification for HIV and other sexually transmitted infections. These include patient referral or disclosure, contract referral, outreach assistance, and provider referral (see glossary). Even so, evidence from resource rich settings is also sparse. We found one systematic review (search date 2001, 1 RCT, 74 subjects) where HIV seropositive index cases were offered a choice between provider and patient referral or patient referral alone. This strategy was associated with increased rates of partner notification.[14] However, no outcomes on HIV transmission were measured, the trial had a high refusal rate (> 50%), and most participants were homosexual men.

Comment
One meta-analysis of non-comparative studies (search date December 2001, 17 studies, > 3200 HIV seropositive women, > 2000 HIV status not specified) has examined the factors associated with disclosure by women following non-couple VCT.[12] They were less likely to disclose if they had been tested for HIV in an antenatal setting rather than through voluntary counselling and testing (VCT). Increased disclosure was associated with being younger, having been in the relationship for longer, increased literacy, and knowing others with HIV. There were also higher rates of disclosure among women with lower socioeconomic status. Barriers to disclosing were fears of accusation of infidelity, abandonment (and so loss of economic support), and discrimination. Between violence 4% and15% of women also reported experiencing violence from their partner following disclosure.

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We are aware of data presented (in abstract form) in July 2006 from The AIDS Support Organization (TASO) in Uganda that found higher rates of partner (spouses) accepting VCT when counsellors visited them compared with when they were simply invited to attend the clinic.[13]

Voluntary counselling and testing (VCT)

Introduction
An alternative approach to partner notification is for couples to be counselled and tested together. This became more popular during the 1990s, probably because more couples presented for premarital testing.[15] One study that aimed to recruit couples for testing managed to involve a third of those invited.[16] In voluntary counselling and testing (VCT), people freely choose to have an HIV test. As well as discovering their status, they receive counselling and education about HIV. This is done with full consent and confidentiality. The aims of VCT are to ease the acceptance of (HIV seropositive) serostatus; to promote and facilitate behaviour change (to reduce risk of transmission, including the provision of condoms); to provide access to interventions for preventing mother to child transmission; to facilitate referral to social and peer support; and to promote access to early medical care for opportunistic infections and sexually transmitted infection, antiretroviral treatment, and preventive treatment for tuberculosis.

Evidence summary
One RCT found that couples reported decreased rates of unprotected sexual intercourse following voluntary counselling and testing (VCT) compared with receiving only health information, but these couples were also more likely to suffer family disownment. Cohort studies also found that rates of unprotected sexual intercourse decreased after VCT compared with before VCT.

Benefits
RCTs We found no RCTs of voluntary counselling and testing (VCT) that reported specific outcomes for serodiscordant couples. We found one RCT that assessed the effects of VCT in couples who were either HIV serodiscordant or seroconcordant (see table 1).[7] VCT was compared with giving health information on behavioural change without any HIV test in 586 couples. The couple was defined as the two partners who enrolled together in the study irrespective of marriage. The results of the RCT should be treated with caution as 14.7% were lost to follow up and men (but not women) randomised to the health intervention reported more unprotected sexual intercourse at baseline than men randomised to VCT; this may have biased the results in favour of VCT. The RCT found a significantly greater reduction in self reported rates of unprotected intercourse between enrolment and follow up (at a median 7.3 months later) for those receiving VCT compared with those assigned a session of health information. This was sustained through until a second follow up visit at 13.9 months. There was more than 90% agreement for reports from male and female partners, but the study may be limited because at baseline there was a significantly higher rate of unprotected intercourse reported by men but not women assigned to the health intervention group. Furthermore, the decrease in rates of unprotected intercourse were significant for both interventions. Post hoc analysis showed that those couples where one or both were HIV seropositive were significantly less likely to report unprotected intercourse than seroconcordant HIV seronegative couples. The incidence of new HIV infection was not measured.

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Observational studies We found five prospective cohort studies undertaken in resource poor settings. Rates of condom use before VCT were uniformly very low and rose to around 5070% after VCT in most studies (See table 1).[17][18][19][20][21] The first prospective study of a cohort of 818 serodiscordant cohabiting couples was conducted in Zambia.[17] Participants were interviewed separately about frequency of sexual intercourse with and without condoms at baseline (before VCT) and every 3 months after for a median of 12 months. A couple was defined as two partners cohabiting for at least 6 months at time of enrolment. After VCT, the proportion of sexual encounters that were protected greatly increased compared with baseline (before VCT; Table1). In 584/818 [71%] couples who had at least 12 months follow up, the serodiscordant couples where the male partner was HIV seronegative had more sexual intercourse with or without condoms than those where the male was HIV seropositive (see table 1). In a second prospective cohort study conducted in Rwanda, cohabiting male partners of 684 women who already knew their HIV status were given counselling and re-testing (for those previously tested) at baseline and then at 1 year follow up. Sixty-six of the 684 (9.6%) couples were serodiscordant.[18] Self reported rates of condom use before and after VCT were compared and the proportion of serodiscordant couples using condoms regularly rose greatly at 1 year (see table 1). There was a corresponding drop in the number of monthly episodes of unprotected sexual intercourse over the study. The effect was largest for those couples where the male partner had learned his discordant status (either HIV seropositive or seronegative) for the first time. The authors concluded that male focused counselling had a beneficial effect for serodiscordant couples (see table 1). In the third study conducted in Haiti, 475 serodiscordant couples (defined as regular sex partners) were prospectively followed and received ongoing counselling after initial counselling and testing. Regular condom use and free condom provision increased among 177 who remained sexually active over a median follow up of 20 months (see table 1).[19] The fourth prospective study followed 53 discordant cohabiting couples in Rwanda for 1 year after testing and both group and individual education and counselling and condom provision. Condom use greatly increased after VCT (see table 1).[20] In the fifth prospective cohort study in the Zaire/Democratic Republic of Congo, 149 discordant married couples received monthly counselling and free condom provision after HIV diagnosis.[21] Very few used condoms at baseline but use increased at 1 month and continued to increase at 18 months in the people who remained in the study.

Harms
RCTs A follow up report from the study performed in Kenya, Tanzania, and Trinidad assessed outcomes other than behaviour change after VCT.[23] Couples who underwent VCT rather than simply receiving health information showed trends towards experiencing more HIV seronegative life events (break up of marriage, break up of sexual relationship, physical abuse, and neglect or disowning by families). However, only the risk of neglect or family disownment (3% with VCT v 1% with health information) was significantly increased. A group of serodiscordant female HIV seropositive couples were more likely to report relationship break up compared with couples with other HIV status (20% with serodiscordant female HIV seropositive couples v 07% with couples with other HIV status; P < 0.08). Participants in serodiscordant female seropositive couples were least likely to report the strengthening of a sexual relationship (P < 0.005).

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Observational studies In a study that offered VCT to men (and their wives) from two businesses in the Zaire/Democratic Republic of Congo, 18/168 (11%) serodiscordant couples experienced acute psychological distress, mostly involving conflict between the partners. All but three couples (who divorced) were able to resolve their problems with intensive counselling.[21]

Comment
All the studies showed that an intervention of VCT which included risk reduction education is associated with reduced unprotected sexual intercourse. Two studies found that this effect was stronger if the male partner was HIV seronegative.[20] [21] However, a descriptive study not involving VCT in Uganda found that condom use was higher in couples where the male partner was HIV seropositive.[22] It is not possible to calculate combined effect across these studies as they did not measure outcomes similarly (proportion of couples using condoms regularly, rates of unprotected intercourse), had different length of follow up (720 months), and different interventions (one counselling episode or regular repeated counselling). The observational studies are also liable to selection bias (only those who agreed to VCT) and surveillance bias (self reported condom use) that cannot be measured. One challenge to behaviour change advocated during VCT is the sociocultural pressure and desire to have children. The studies we identified did not provide any data on this issue. Two studies show that some couples who learn their status in VCT do suffer negative consequences.[21] [23] However, the evidence is insufficient to measure what the relative negative effects are for couples who receive VCT and those that do not.

What are the outcomes of disclosure within couples where one partner has HIV?
Evidence summary
We found no RCTs; conducting an RCT would be impractical to conduct given the ethical issues surrounding disclosure. One systematic review of observational studies suggested that HIV status disclosure was not associated with increased relationship break up, and positive outcomes were more frequent than negative outcomes.

Benefits and harms

RCTs We found no RCTs; an RCT would be impractical to conduct given the ethical issues surrounding disclosure. Cohort studies A systematic review of observational studies where the woman was the index case was found.[12] These studies did not always identify the serostatus of the partners (if tested) or report whether the couples were HIV serodiscordant or seroconcordant HIV positive. In the meta-analysis of disclosure by HIV seropositive women (to their sexual partners), the studies that looked at outcomes reported that most of the time outcomes were positive and no association was found with relationship break up.[12] However, where negative outcomes occurred they involved blame, anger, stigma, depression, and abandonment. 8
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What are the effects of interventions to reduce HIV transmission rates within serodiscordant couples?
Condom use
Evidence summary
We found no RCTs; an RCT of condom use is unlikely to be conducted. Observational studies suggest that condom use in serodiscordant couples is associated with 80% reductions in HIV transmission.

Benefits
RCTs We found no RCTs; an RCT of condom use is unlikely to be conducted.

Observational studies We found one systematic review assessing the effects of condoms on transmission of HIV (search date March July 2000, 14 cohort studies).[24] Effectiveness of condom use was estimated by indirect comparison of the incidence of HIV seroconversion in serodiscordant couples from a variety of studies who either reported 100% (always) or 0% (never) using condoms. The review did not report how it defined couple. If the HIV seronegative partner had other risk factors for HIV (intravenous drug user or receipt of blood products) or was a commercial sex worker the study was excluded from the review. Only studies of heterosexual transmission were included. The overall incidence of HIV in those always using condoms was 1.14/100 patient years (95% CI 0.56/100 patient years to 2.04/100 patient years; 11 seroconversions/587 participants) compared with 6.68/100 patient years (95% CI 4.78/100 patient years to 9.10/100 patient years; 40 seroconversion/276 participants) in those how never used condoms. This represented an overall effectiveness of 82.9% for condom use in preventing HIV transmission. Four of the studies included in the review were from resource poor settings (Rwanda, Haiti, Zambia, and Zaire/Democratic Republic of Congo) and all of these included counselling and education with free condom provision. Three studies also included vaginal spermicide provision. The incidence for these studies alone were 1.95/100 person years (5/177 participants) in people who always used condoms and 8.91/100 person years (19/103 participants) in people who never used them, giving a protection of 78% calculated by the author). There were limitations to this review. It is an indirect comparison of studies and, although the 13 studies reporting incidence for risk in people who always used condoms were homogenous, those studies giving incidence in people who never used condoms reported a wide range of results. Furthermore, other factors were not fully controlled for (e.g. the likely association of non-condom use with other risk behaviours such as having multiple sexual partners). Thus, this evidence must be treated with caution.

Harms
No study has reported on any measure of harm arising from the use of condoms.

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Male circumcision Evidence summary

We found no RCTs that assessed serodiscordant couples. Data from one RCT undertaken in men with HIV, which found a clear benefit from male adult circumcision in reducing risk of HIV transmission, coupled with observational data from one longitudinal study comparing rates of HIV in circumcised and uncircumcised serodiscordant couples suggest that circumcision may be an effective intervention in serodiscordant couples. There was no increased risk of HIV attributed to surgery in the RCT and in the observational study, circumcision had usually occurred during childhood so no data for surgery related risk of developing HIV were available. Circumcision has the theoretical potential to increase HIV transmission in the post-surgical healing period. There is also a potential increase in risk if surgery is conducted with non-sterile instruments, and if the perception of protection leads to increased risk taking behaviour. However, we found no studies assessing these risks.

Benefits
RCTs We found no RCTs that assessed the effect of circumcision of male partners of serodiscordant couples. Observational studies One longitudinal observational study conducted in serodiscordant couples found an association between circumcision and decreased risk of developing HIV. A total of 415 serodiscordant couples were identified (retrospectively) from a cohort in rural Uganda who had been followed prospectively for a median of 22.5 months.[27] Couples were either legally married or in consensual union, defined as a culturally accepted long term sexual relationship. All received voluntary counselling and testing (VCT), educational intervention about HIV transmission risk and condom use, and free condoms. Over the period of study, there was increased risk of infection if the HIV seronegative partner was uncircumcised (16.7/100 person years with no circumcision v 0/100 person years with circumcision; P < 0.001). There was a non-significant trend towards increased risk for HIV seronegative women whose HIV seropositive male partners were uncircumcised (13.2/100 person years with no circumcision v 5.2/100 person years with circumcision; reported as not significant, P value not reported).

Harms
In the RCT, 3.8% of 1568 men reported adverse events related to the surgery in the first month.[25] These were usually pain, excessive bleeding, swelling, or problems with the appearance. Nevertheless, by 3 months, 98.5% were very satisfied with the outcome. There were no cases of HIV attributed to the surgery. In the observational study, circumcision had usually occurred during childhood so no data for surgery related risk of developing HIV were available.[27]

Comment
There is evidence from other populations suggesting that male circumcision reduces transmission of HIV. One RCT in South Africa randomised over 3000 men with HIV (< 2% had regular partners) to circumcision or control (no circumcision). At a median follow up of 18.1 months the trial was stopped as it had already found a significant reduction in HIV transmission (0.85/100 patient years with circumcision v 2.1/100 patient years with no circumcision; RR 0.40, 95% CI 0.24 to 0.68; P < 0.001).[25] This corresponded to a protective effect of 60%. This evidence is supported by a systematic review and meta-analysis of 15 earlier observational studies which found an adjusted relative risk reduction of 0.42 (95% CI 0.34 to 0.54).[26] 10
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An RCT in serodiscordant couples will be necessary to fully demonstrate effects of circumcision in this population. Harms from circumcision may be related to the surgery, and clearly it will be necessary to ensure full infection control procedures are followed if the surgery itself is not to contribute to the risk of HIV transmission. In the post-surgical healing period, men may be at increased risk of acquiring HIV and will need to be abstinent from intercourse. Believing that circumcision protects from HIV acquisition may potentially lead to increased risk taking behaviour (more unprotected intercourse with more different partners) and reduce the protection afforded by circumcision or even increase HIV transmission risk.

Managing sexually transmitted infections (STIs)

Evidence summary
Studies of individuals in resource poor settings have demonstrated that sexually transmitted infection (STI) treatment can reduce risk of HIV transmission.[28] [29] It follows that a similar benefit would likely be realised by identifying and treating the STIs of serodiscordant couples, either through prompt syndromic management or traditional laboratory based diagnosis and treatment. In light of this, it would now be unethical to conduct an RCT of STI treatment in this population.

Observational studies Two studies have shown that genitourinary infection is associated with increased transmission risk. A case control study compared STI prevalence in women in serodiscordant cohabiting couples. Forty-five initially HIV seronegative women from a longitudinal cohort of serodiscordant couples who seroconverted between baseline and 3 months were compared with 45 matched female controls (randomly selected from the cohort) who remained HIV seronegative for at least 6 months.[30] Laboratory results retrospectively collected from the medical records showed that the presence of vaginal candida infection and Trichomona vaginalis in wet preparations were significantly lower in women who did not seroconvert (candida infection: 2/45 [4%] in women who did not seroconvert v 9/35 [26%] in women who did seroconvert; OR 0.12, 95% CI 0.04 to 0.36; P < 0.001; Trichomona vaginalis infection: 5/45 [11%] in women who did not seroconvert v 9/35 [26%] in women who did seroconvert; OR 0.35, 95% CI 0.16 to 0.76; P = 0.008) . There were rates of syphilis rapid plasma reagin (RPR) positivity (9/45 [20%] in women who did not seroconvert v 9/40 [23%] in women who did seroconvert; OR 0.84, CI 0.43 to 1.65) or gonorrhoea gram stains (0/45 [0%] in women who did not seroconvert v 1/35 [3%] in women who did seroconvert; OR not reported). A longitudinal observational study conducted in serodiscordant couples (married or in a long lasting consensual relationship) found that HIV transmission to the HIV seronegative partner was more common where the HIV seropositive partner had genital discharge or dysuria (20.7 new HIV infections/100 patient years with genital discharge or dysuria v 11.7 new HIV infections/100 patient years with no genital discharge or dysuria; P < 0.05). However, the effect of genital ulcer disease (GUD) in increasing transmission of HIV was not significant (14/102 new HIV infections/100 patient years with GUD v 76/659 new HIV infections/100 patient years with no GUD; significance assessment not reported).[27] A later paper that only looked at 235 monogamous couples from this cohort did find an association between GUD and increased HIV transmission. A more sensitive analysis was made of the presence of GUD, which found a significant increase in the risk of seroconversion in people who had ulcers compared with those who did not (adjusted RR 2.04, 95% CI 1.04 to 3.99).[31]

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Comment
These two studies show that genitourinary infection is associated with increased risk of HIV transmission within serodiscordant couples. However, association is not proof of causality. In the first study, it is possible that acute seroconversion occurred undetected at baseline and may have led to the vaginal candida (and not the reverse).[30] Nonetheless, the authors conclude that continued presence of candida at follow up 3 months later in these individuals makes such an explanation unlikely. Acute retroviral syndromes are unlikely to explain the increased prevalence of trichomonal infection in this study or genitourinary discharge and dysuria in the second study.[27] Given the association found in these studies and that STI treatment in high risk groups and the general population has been seen to reduce HIV risk in resource poor settings, it seems likely that STI treatment would have a similar benefit in serodiscordant couples.[5] [29]

Highly active antiretroviral treatment (HAART)

Evidence summary
We found no RCTs; an RCT in serodiscordant couples would be unethical to conduct given the known effectiveness of HAART in individuals with HIV. Cohort studies suggest that HIV transmission is less likely with lower viral load in serodiscordant couples and that transmission risk is greatest in the first months after acquiring HIV infection.

Benefits and harms

No studies were found examining the effect of highly active antiretroviral treatment (HAART) on the rates of transmission of HIV in serodiscordant couples. Observational studies of increased viral load as a risk factor for transmission Data are available from a longitudinal study of serodiscordant couples (married or in long lasting consensual relationship) in Rakai in Uganda. Increasing viral load was significantly associated with increased risk of HIV transmission from HIV seropositive to HIV seronegative partners in discordant couples, with a significant increase in risk with every log increase in viral load (RR 2.45, 95% CI 1.85 to 3.26). The study also reported increased rates of HIV infection in partners of those who had an AIDS defining illness (27.3/100 patient years with AIDS defining illness v 11.4/100 patient years with no AIDS defining illness; P < 0.05).[27]

Comment
As lower viral load is associated with lower sexual transmission of HIV in discordant couples, it could be predicted that an intervention (HAART) that lowers viral load might have the same benefit. This is seen for other routes of transmission, for example, using antiretroviral treatment in pregnant women is known to reduce vertical transmission of HIV in resource poor settings. However, concerns have been raised that HAART and the perception of decreased transmission risk could lead to increased sexual risk taking in industrialised settings.[32] Perhaps more importantly, other data from the Rakai cohort in Uganda have been presented demonstrating that the incident risk of HIV transmission per coital act is many times higher in the first 2.5 months following first infection compared with the later.[31] Since HAART would not be indicated so early in infection, its (later) use may only have a modest impact on transmission. Comparative studies of cohorts of discordant couples that do and do not use HAART are needed, though prospective randomised trials of HAART looking at this outcome would not be ethical.

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Table 1: Voluntary counselling and testing

Ref [7] Population Multicentre RCT 586 couples from Kenya, Tanzania, and Trinidad Proportion of males and females who were HIV seropositive not reported Intervention Baseline v VCT (included personalised risk assessment and risk reduction training + free condoms) at first follow up (mean 7.3 months) and second follow up (13.9 months) Baseline v health information (15 minute video and discussion about HIV-1 transmission and condom use + free condoms) at first follow up (mean 7.3 months) and second follow up (13.9 months) Outcome Self reported rates of unprotected intercourse with VCT v health information: OR 0.72, 95% CI 0.53 to 0.99; P = 0.014 Rates of unprotected intercourse at baseline v first follow up v second follow up: Men with VCT: 77% at baseline v 58% (P < 0.0001)* at first follow up v 54% (P < 0.0001)* at second follow up Men with HI: 82% at baseline v 70% at first follow up (P = 0.001)* v 56% at second follow up (P < 0.0001)* Women with VCT: 80% at baseline v 63% at first follow up (P = 0.0001)* v 57% at second follow up (P < 0.0001)* Women with HI: 81% at baseline v 67% at first follow up (P = 0.001)* v 52% at second follow up (P < 0.0001)* *significance is compared with baseline There was high agreement (> 90%) between male and female reporting Self reported condom use: Proportion of serodiscordant couples using condoms: < 3% at baseline v 80% at 12 months Proportion of regular serodiscordant attendees (332 couples assessed) using condoms: 23% always used condoms v 50% always except on 2 occasions (between follow up) used condoms Comments Methods: Couples who had enrolled together for study randomised to VCT or receipt of health information Limitations: 14.7% were lost to follow up. Only some of the couples were serodiscordant (proportion not reported). Men (but not women) randomised to HI reported more unprotected sexual intercourse at baseline than men randomised to VCT.

[17]

Prospective cohort 963 couples from Zambia 425 couples with male

Baseline v VCT (testing, counselling, condom skills training, and free condoms) at 3 monthly intervals over 12 months follow up

Methods: Couples were recruited from a same day VCT centre. Limitations: 234/818 did not complete 12 months follow up Additional counselling at 3 months follow up on request only Self reported condom use

HIV
seropositive, female HIV seronegative 393 couples with male

HIV
seronegative , female

HIV
seropositive 818/963 couples

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enrolled at least 12 months before study end [18] Prospective cohort 684 couples (66 serodiscorda nt) from Rwanda 43/66 [65%] couples with male HIV seropositive, female HIV seronegative 23/66 [35%] couples with male HIV seronegative , female Baseline v VCT (men received educational group session and group discussion about HIV prevention and contraception) at 12 months follows up. Both partners received HIV testing and individual counselling. Overall proportion of regular condom users (consensus between male and female): 5% at baseline v 65% at 1 year Reported rates of unprotected and protected monthly intercourse (mean episodes/month) averaged for all 66 serodiscordant couples. Male reports: Unprotected: 3.5 at baseline v 0.7 at 1 year Protected: 2.5 at baseline v 5.9 at 1 year Female reports: Unprotected: 6.0 at baseline v 1.4 at 1 year Protected: 3.3 at baseline v 7.3 at 1 year Methods: 684 couples were identified from a cohort of women previously counselled and tested for HIV. 66 were serodiscordant. All of the women and 29 of the men knew their status before enrolment Limitations: Women had known their status for as long as 3 years before the start of the study

HIV
seropositive In 29 couples both partners already knew their status Prospective cohort 475 couples from Haiti 81% couples with male

[19]

Baseline v VCT at 3 monthly follow up for median of 20 months Regular counselling and free condom provision at every visit

Self reported condom use (always) in sexually active couples (177 couples): 0% at baseline v 24% (95% CI 18% to 30%) at study end

Methods: Person referred to free HIV testing centre asked to bring regular partner. 475 couples were discordant and met inclusion criteria (consented, lived within 30 km of centre and ambulatory). 177 couples were sexually active during the study Limitations: 49% of HIV seropositive partners died during study Self reported condom use

HIV
seropositive, female HIV seronegative 19% couples with male

HIV
seronegative , female

HIV
[20] seropositive Prospective cohort 53 couples from Rwanda 30/53 [57%] Baseline v VCT (educational video and social worker led group discussion about HIV prevention at enrolment only) at Self reported condom use (all couples): 4% at baseline v 57% at 1 year In 71% of couples followed up, significantly higher rates of sexual intercourse (both protected and Methods: Women recruited in a longitudinal study whose male partners volunteered for counselling and testing. Discordant couples enrolled. Limitations: Self reported condom

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couples with male HIV seropositive, female HIV seronegative 23/53 [43%] couples with male HIV seronegative , female

1 year follow up.

unprotected) if male was seronegative: 70% male seropositive, female seronegative v 87% male seronegative, female seropositive; P < 0.01

use

HIV
[21] seropositive Prospective cohort 149 couples from Zaire/Demo cratic Republic of Congo 80/149 [54%] couples with male HIV seropositive, female HIV seronegative 69/149 [46%] couples with male HIV seronegative , female Baseline v VCT (regular counselling and free condom provision) at 18 months follow up Self reported condom use: < 5% had ever used at baseline v 77% always used at 18 months follow up Higher rates of sexual intercourse (both protected and unprotected) if male was seronegative: 62% male seropositive, female seronegative v 82% male seronegative, female seropositive; P = 0.012 Methods: Men and female partners at two businesses invited to have HIV testing and counselling. Serodiscordant couples were identified and followed up monthly for 18 months. 149 completed more than 6 months, 140 completed 18 months follow up Limitations: Self reported condom use

HIV
seropositive HI, health information; Ref, reference; VCT, voluntary counselling and testing.

Glossary
Contract referral Also known as conditional referral. Index patients are encouraged to inform their partners, with the understanding that health service personnel will notify those partners who do not visit the health service within a contracted time period. Outreach assistance At the request of patients, partners are notified by members of an outreach team indigenous to the community, who do not disclose the name of the patient to the partners. Patient referral Health service personnel encourage index patients to inform partners directly of their possible exposure to sexually transmitted infections. Provider referral Third parties (usually health service personnel) notify partners identified by index patients, without disclosing the name of the patient to the partners.

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References
1. Bunnell RE, Naddozi J, Marum E, et al. Living with discordance: knowledge, challenges, and prevention strategies of HIV-discordant couples in Uganda. AIDS Care 2005;17:9991012. 2. Hugonnet S, Mosha F, Todd J, et al. Incidence of HIV infection in stable sexual partnerships: a retrospective cohort study of 1802 couples in Mwanza Region, Tanzania. J Acquir Immune Defic Syndr 2002;30:7380. 3. Serwadda D, Gray RH, Wawer MJ, et al. The social dynamics of HIV transmission as reflected through discordant couples in rural Uganda. AIDS 1995;9:745750. 4. Carpenter LM, Kamali A, Ruberantwari A, et al. Rates of HIV-1 transmission within marriage in rural Uganda in relation to the HIV sero-status of the partners. AIDS 1999;13:10831089. 5. Merson MH, Dayton JM, OReilly K. Effectiveness of HIV prevention interventions in developing countries. AIDS 2000;14(suppl 2):S68S84. 6. Cochrane Collaborative Review Group. Evidence Assessment: Strategies for HIV/AIDS Prevention, Treatment and Care. The Cochrane Collaborative Review Group on HIV Infection and AIDS. January 2004. Available online at: http://www.igh.org/Cochrane/pdfs/EvidenceAssessment.pdf .Last accessed 4 September 2006. 7. The Voluntary HIV-1 Counseling and Testing Efficacy Study Group. Efficacy of voluntary HIV-1 counselling and testing in individuals and couples in Kenya, Tanzania, and Trinidad: a randomised trial. Lancet 2000;356:103112. 8. Sangani P, Rutherford G, Wilkinson D. Population-based interventions for reducing sexually transmitted infections, including HIV infection. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. 9. UNAIDS. Intensifying HIV prevention: a UNAIDS policy position paper. Available online at: http://data.unaids.org/publications/irc-pub06/jc1165-intensif_hiv-newstyle_en.pdf. Last accessed 4 September 2006. 10. UNAIDS. Counseling and HIV/AIDS. Geneva: Technical update, UNAIDS Best Practice Collection, 1997. 11. UNAIDS/WHO. Opening up the HIV/AIDS epidemic: guidance on encouraging beneficial disclosure, ethical partner counselling and appropriate use of HIV case-reporting. Geneva: UNAIDS Best Practice Collection, 2000. Available online at: http://www.who.int/ethics/topics/opening_up_ethics_and_disclosure_en_2000.pdf. Last accessed 4 September 2006. 12. Medley A, Garcia-Moreno C, Mc Gill S, et al. Rates, barriers and outcomes of HIV serostatus disclosure among women in developing countries: implications for prevention of mother-to-child transmission programmes. Bull World Health Organ 2004;84:299307. Available online at: http://whqlibdoc.who.int/bulletin/2004/Vol82-No4/bulletin_2004_82(4)_299-307.pdf . Last accessed 4 September 2006 13. King R, et al. Disclosure of HIV serostatus to sexual partners by Ugandan HIV-infected men and women. The 2006 HIV/AIDS Implementers Meeting of the Presidents Emergency Plan for AIDS Relief, Durban, South Africa, 2006. [Abstract] 16
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14. Mathews C, Coetzee N, Zwarenstein M, et al. Strategies for partner notification for sexually transmitted diseases. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. 15. Baryarama F, Kalule J, Gumisiriza E, et al. Couple counseling and HIV testing in Uganda: four years experience at the AIDS information centre. Int Conf AIDS 1996;11:250. 16. McKenna SL, Muyinda GK, Roth D, et al. Rapid HIV testing and counseling for voluntary testing centers in Africa. AIDS 1997;11:S103S110. 17. Allen S, Meinzen-Derr J, Kautzman M, et al. Sexual behavior of HIV discordant couples after HIV counseling and testing. AIDS 2003;17:733740. 18. Roth DL, Stewart KE, Clay OJ, et al. Sexual practices of HIV discordant and concordant couples in Rwanda: effects of a testing and counselling programme for men. Int J STD AIDS 2001;12:181188. 19. Deschamps MM, Pape JW, Hafner A, et al. Heterosexual transmission of HIV in Haiti. Ann Intern Med 1996;125:324330. 20. Allen S, Tice J, Van de Perre P, et al. Effect of serotesting with counselling on condom use and seroconversion among HIV discordant couples in Africa. BMJ 1992;304:16051609. 21. Kamenga M, Ryder RW, Jinqu M, et al. Evidence of marked sexual behavior change associated with low HIV-1 seroconversion in 149 married couples with discordant HIV-1 serostatus: experience at an HIV counselling center in Zaire. AIDS 1991;5:6167. 22. Serwadda D, Gray RH, Wawer MJ, et al. The social dynamics of HIV transmission as reflected through discordant couples in rural Uganda. AIDS 1995;9:745750. 23. Grinstead OA, Gregorich SE, Choi KH, et al. Positive and negative life events after counselling and testing: the Voluntary HIV-1 Counselling and Testing Efficacy Study. AIDS 2001;15:10451052. 24. Weller S, Davis-Beaty K. Condom effectiveness in reducing heterosexual HIV transmission. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. 25. Auvert B, Taljaard D, Lagarde E, et al. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2005;2:e298. [See comment] 26. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2000;14:23612370. 27. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000;342:921929. 28. Nzila N, Laga M, Thiam MA, et al. HIV and other sexually transmitted diseases among female prostitutes in Kinshasa. AIDS 1991;5:715721. 29. Grosskurth H, Mosha F, Todd J, et al. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomised controlled trial. Lancet 1995;346:530536. 30. Hester RA, Kennedy SB. Candida infection as a risk factor for HIV transmission. J Womens Health (Larchmt) 2003;12:487494.

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31. Wawer MJ, Gray RH, Sewankambo NK, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis 2005;191:14031409. 32. Crepaz N, Hart TA, Marks G. Highly active antiretroviral therapy and sexual risk behavior: a metaanalytic review. JAMA 2004;292:224236.

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