Studies in North America [1,2], Europe [3–5], and sub-Saharan Africa [6–10] report that 20–50% of HIV-infected men and women desire children. The contribution of intended conception to incident HIV infection is unknown, but likely represents a large proportion given high fertility rates and the importance of having children in most HIV endemic areas [11–13]. In most sub-Saharan African countries, up to half of those living with HIV report a serodiscordant partner and estimates suggest that up to 60% of new infections occur between stable, heterosexual, serodiscordant couples [14–16]. As men and women with HIV live longer, healthier lives, safer conception counseling for HIV-serodiscordant couples is a reproductive right [17–19] and should be included as a public health strategy to reduce HIV incidence among men, women, and their children in settings with generalized HIV epidemics [20,21▪▪,22▪]. Integrating effective HIV prevention strategies into comprehensive reproductive counseling is a rational step to protect uninfected partners and their children and to make progress towards eliminating HIV.
Several strategies allow HIV-serodiscordant couples to conceive with minimal transmission risk to the uninfected partner (Table 1) [23–33,34▪▪,35,36,37▪▪,38▪▪,39▪▪,40–42]. For female-positive couples (F+M−), the safest option is vaginal insemination without intercourse (man ejaculates into a condom or cup and the contents are introduced via condom reversal or needle-less syringe) timed to peak fertility. This can be completed at home and confers zero risk to the male partner . For male-positive serodiscordant couples (M+F−), laboratory techniques can isolate sperm (which do not harbor HIV) from seminal plasma and leukocytes . ‘Washed’ or processed sperm can be introduced via intrauterine insemination or in-vitro fertilization with or without intracytoplasmic sperm injection [29,45,46]. Although there are no randomized, controlled trials (RCTs), sperm processing centers report 4638 M+F− inseminations, a 50% pregnancy rate, and no recorded HIV-transmissions [28–31]. These findings suggest the process is safe and effective, but it remains challenging for most people to access due to costs and limited availability [46–48].
For M+F− serodiscordant couples, who cannot access sperm processing, and F+M− couples unwilling to carry out insemination without intercourse, vaginal intercourse without condoms coupled with adjunct risk reduction strategies can reduce HIV transmission while allowing for conception [49–51]. Adjunct strategies include medical male circumcision (MMC) for F+M− couples [25–27], treatment for STIs [40,41], limiting unprotected sex to peak fertility, and the use of ARVs-as-prevention (Table 1). Recent data indicate that antiretroviral therapy (ART) for the infected partner and pre-exposure prophylaxis (PrEP) for the uninfected partner may offer benefits for HIV-serodiscordant couples who choose to conceive. The purpose of this article is to review how ARVs-as-prevention can be incorporated into comprehensive reproductive health counseling for serodiscordant couples.
Incorporating risk reduction methods into a couple's sexual practice requires mutual HIV testing and disclosure, understanding HIV transmission risks, knowledge of and access to risk-reduction strategies, a relationship in which sexual practices and reproductive decisions are considered, discussed, negotiated, and practiced, and ability to adhere to risk-reduction strategies [52▪]. Mutually disclosed serodiscordant couples, who carry out equitable discussions about sex, conception, and family planning are likely a rare population [53–55]. We apply the data to the context of mutually disclosed serodiscordant couples while acknowledging that prior to offering safer conception strategies, mutual HIV-testing, disclosure, and communication must be supported as an essential first step in any reproductive counseling program [21▪▪,52▪].
Antiretrovirals for prevention
We present data supporting the use of ART for the infected partner and antiretroviral PrEP for the uninfected partner as HIV prevention for heterosexual discordant couples, demonstration projects which apply these strategies to periconception risk, and make recommendations for the use of ARVs for prevention for serodiscordant couples who choose to conceive.
Data supporting antiretroviral therapy for the infected partner as prevention
Observational data first published over a decade ago show that low plasma HIV RNA is associated with decreased sexual HIV transmission [36,56,57]. ART for the infected partner was associated with a 92% reduction in HIV-acquisition risk among uninfected partners in a secondary analysis of the Partners in Prevention Trial  and ecologic data show an association between lowering community-level viral load (through increased testing and treatment) and decreased HIV incidence [58,59].
In the HIV Prevention Trials Network Study 052, 1763 mutually disclosed HIV-serodiscordant couples in which the infected partner had a CD4 cell count between 350 and 550 cells/mm3 were randomized to ART at enrolment or upon decline in CD4 to 250 or fewer cells per μl or onset of AIDS-defining illness. Early therapy was associated with a 96% reduced risk of genetically linked transmissions [34▪▪]. For couples who attempt natural conception, delaying sex without condoms until the infected partner is on ART with a suppressed plasma viral load can dramatically reduce HIV transmission.
Data supporting oral or topical pre-exposure prophylaxis for the uninfected partner
With PrEP, an HIV-uninfected individual uses antiretroviral medications continuously or before and after exposure to minimize HIV acquisition. In CAPRISA-004, high-risk HIV-uninfected heterosexual women randomized to pericoital 1% tenofovir vaginal gel versus placebo had a 39% reduction in HIV acquisition [60▪▪]. Conversely, the Microbicide Network VOICE trial arm of tenofovir gel was halted due to lack of efficacy; details are not yet available. An additional efficacy study of pericoital tenofovir gel is enrolling and alternative topical antiretrovirals are under investigation (http://www.avac.org).
In the first completed placebo-controlled trial of oral, daily emtricitabine/TDF(FTC/TDF) as PrEP, HIV acquisition was reduced by 44% among HIV-seronegative men or transgender women having sex with men . In the Partners PrEP trial, HIV acquisition was reduced by 67% and 75% among HIV-serodiscordant couples taking oral TDF or FTC/TDF, respectively, without significant differences by sex [37▪▪]. Having detectable drug levels was associated with 86% risk reduction for TDF and 90% risk reduction for those in the FTC/TDF arm. In the CDC TDF2 trial, HIV acquisition was reduced by 63% among men and women taking daily FTC/TDF [38▪▪]. In contrast, the FEM-PrEP trial of daily FTC/TDF and the VOICE trial arm of oral TDF for heterosexual women were halted for futility [39▪▪,62,63]. These divergent findings may relate to adherence [39▪▪,64] and qualitative data from partners PrEP participants, who had high adherence, suggest stable serodiscordant couples were motivated to adhere to PrEP in order to preserve the relationship [65▪▪]. These data support the application of daily, oral PrEP to minimize periconception HIV transmission among uninfected men and women with an HIV-infected partner not eligible for, failing, or not taking ART. PrEP may further reduce periconception transmission when the infected partner has viral suppression on ART. These data informed the recent US Food and Drug Administration approval of FTC/TDF as PrEP for at-risk HIV-uninfected men and women .
Demonstrations of antiretrovirals-as-prevention for safer conception
Barreiro et al. studied serodiscordant couples (40 M+F− and 22 F+M−) who attempted timed, natural conception while the infected partner was on ART (for at least 6 months), resulting in 76 pregnancies, 68 live births, 0 sexual transmissions, and 1 case of perinatal HIV transmission. Vernazza et al.[67▪▪] followed 37 M+F− couples through 170 cycles of periovulatory unprotected intercourse while the infected partner was on ART and the uninfected partner was taking tenofovir or FTC/TDF as PrEP: ‘women achieved a 75% pregnancy rate with no documented seroconversions or adverse events’. Women were counseled to take tenofovir or FTC/TDF on the morning of the urine-measured luteinizing hormone (LH) peak, repeated 24 h later, and followed by intercourse about 36 h after the LH peak.
These series suggest the feasibility of ARV-based safer conception. While the numbers are too small to draw conclusions about safety, safer conception packages including ART, PrEP, timed conception, STI treatment, and MMC (for F+M− couples) are likely to confer nearly zero risk of HIV transmission when adherence is high. Given the risks, couples currently assume to attempt conception, the risk reduction may be considerable [22▪].
Based on the current data, we recommend the following approach for couples, who choose to attempt conception through intercourse (see Table 2).
* ART: Conception attempts should be delayed until the infected partner is on ART with a suppressed viral load [21▪▪,68▪], or for at least 6 months [69–72]. ART should be continued for life [73,74].
* PrEP initiation: The uninfected partner should take daily oral FTC/TDF PrEP starting before anticipated peak fertility. Although protection may be conferred within 24 h of the first dose, starting PrEP at the onset of menses will help to ensure maximal protection (based on pharmacokinetics and human behavior) during peak fertility [75–77]. Additional antiretroviral agents, formulations, and dosing schedules may be appropriate in the future pending additional data.
* PrEP discontinuation: Couples should be encouraged to resume condom use and discontinue PrEP once pregnancy is confirmed; as early as 21 days postconception with urine pregnancy testing, or 14 days postconception based on the first day of a missed period . Concerns about fetal ARV exposure for M+F− couples, cost, toxicities, animal data, and the simpler protocol motivate the recommendation to stop PrEP when pregnancy is achieved. Post-exposure prophylaxis for 28-days prevents simian HIV acquisition among macaques [79,80], however there are no human data to suggest whether post-exposure prophylaxis is required on top of PrEP and partner viral load suppression. Animal studies do not support a long period of post-exposure prophylaxis after PrEP [81,82]. Oral PrEP trials administered continuous prophylaxis, but women with pregnancies discontinued PrEP; data regarding this subgroup will inform future practice [83▪▪].Couples who achieve pregnancy are at particular risk for transmitting and acquiring HIV [84–86] and condom use once pregnancy is achieved must be emphasized. For F+M− couples with insurmountable obstacles to condom use, continuing PrEP for the uninfected male through pregnancy should be considered. Given limited PrEP data in pregnant women (although many HIV-infected women take TDF and FTC/TDF with few reported problems ), we cannot currently formally recommend PrEP continuation for M+F− couples during pregnancy. However, for many women the risk reduction benefits of PrEP will outweigh the possible toxicities.
* PrEP without ART: For M+F− couples in which the infected partner does not meet local criteria for or want to take ART, or who are not willing to delay conception attempts, PrEP coupled with timed sex and STI treatment is an optional risk reduction strategy. For F+M− couples, we hesitate to recommend PrEP for the man without ART for the infected woman. In most cases, a woman should start ART for her own health regardless of pregnancy, and treatment may reduce the risk of pregnancy-associated mortality for HIV-infected women [88,89]. In addition, for women with pregnancy, ART initiation is often recommended soon after pregnancy to prevent vertical transmission [72,90–92]; more time on ART and viral load suppression at conception are associated with reduced risk of perinatal transmission [93,94]. For women who do not need – or meet local criteria – to initiate ART for their own health and wish to avoid ART during early embryogenesis, periconception PrEP for the uninfected male with ARV initiation for the woman during pregnancy may be reasonable.
* Non-ARV prevention: ARV use should be combined with sex without condoms limited to peak fertility and STI treatment. For F+M− couples, MMC should be pursued.
No data exist to assess whether PrEP is a necessary adjunct for serodiscordant couples wherein the infected partner is on effective ART, however the highest level of protection is likely achieved by combining ART and PrEP. A public health approach may select one of these strategies: ART for the infected partner provides the highest-level of protection, but uninfected-partner PrEP is an effective risk reduction option when the infected partner is not reliably taking ART. Time-limited, periconception PrEP limits many potential drawbacks to continuous PrEP, including cost, adherence, toxicity, and behavioral risk compensation; additionally, it provides an opportunity to engage high-risk, uninfected individuals in prevention [48,95].
Limitations of antiretrovirals-as-prevention for safer conception
Differential HIV suppression in the genital tract and blood plasma may limit effectiveness of infected-partner ART as a safer conception strategy. Three to forty percentage of men and women with suppressed plasma viral load have detectable virus in the genital tract [96▪,97–100] and genital viral load correlates (independent of plasma load) with HIV transmission risk [96▪]. Studies of how genital shedding affects transmission, and which antiretrovirals best suppress replication in genital compartments will further define strategies [76,101–104].
Concerns about tenofovir teratogenicity (FDA Class B) may limit deployment of periconception PrEP for women. Trials including systemic or topical tenofovir as PrEP excluded women with plans for pregnancy, although many women in these trials became pregnant [39▪▪,83▪▪] and reports on pregnancy outcomes are expected. The International Antiretroviral Pregnancy Registry reports outcomes for 1219 babies with first trimester exposure to tenofovir: 27 had birth defects, a prevalence of 2.2% (95% confidence interval 1.5, 3.2%), within the range observed in the general population  and WHO. and US Perinatal Guidelines recommend tenofovir in regimens initiated during pregnancy [90–92]. Fetal safety should be considered in future PrEP development. If topical preparations prove effective and nonspermicidal, these may provide protection with limited systemic effects.
HIV-exposed uninfected children born to women taking ARVs may have worse health outcomes than unexposed infants [105–108]. Teasing out the effects of exposure to ARVs versus HIV is ongoing. Guidelines recommend including ARV exposure in the child's medical history and having a low threshold to evaluate these children for mitochondrial toxicity . Periconception PrEP as we propose results in minimal ARV exposure during embryogenesis.
ART-mediated viral load suppression and PrEP efficacy are highly dependent on adherence [39▪▪,60▪▪,61,109–111,112▪▪]. Stable serodiscordant partners may be motivated to adhere to ARVs for prevention [65▪▪] and several studies suggest that individuals may modify risk behavior in order to prevent their child from acquiring HIV [22▪,113–115]. Stable serodiscordant couples who choose to conceive may be able to adhere to ARV prevention strategies and represent a priority group to consider for application of ARVs-as-prevention.
Additional considerations for serodiscordant couples who attempt conception
Financing of ARVs-as-prevention will depend on additional efficacy and effectiveness data, costs, and recommendations from governmental and international bodies. ARVs-as-prevention will be most cost-effective for high-risk populations with excellent adherence to effective strategies [116▪,117,118]. Oral PrEP for HIV-serodiscordant couples attempting conception is predicted to avert 1–10% of new infections, with a cost of US$2000–8000 per infection prevented [116▪]. The model assumes high risk outside of these interventions and does not account for a decreased risk of perinatal transmission or expected benefits of engaging uninfected partners in prevention.
Periconception risk-reduction interventions that include ARVs will require healthcare worker involvement. Cross-sectional studies show that people living with HIV welcome safer conception advice from providers, but providers are not routinely discussing fertility desires or plans [13,22▪,119,120▪▪,121,122]. With improved prevention opportunities, work to help clinicians increase assessments of fertility plans and provide risk reduction counseling and interventions will be needed.
Preconception counseling for HIV-serodiscordant couples should include couples-based HIV testing, counseling, supported disclosure, and education about serodiscordance [21▪▪,54]. When couples understand their HIV status and transmission risks, we recommend a discussion of the options for having children. For those who choose to have children, we recommend a baseline fertility assessment to limit HIV exposure among those unlikely to conceive. Additional fertility evaluations should be pursued if initial assessments predict conception challenges or if pregnancy is not achieved after 6 months of conception attempts. We recommend the following baseline preconception evaluation for men and women living with HIV and their partners:
1. For individuals and couples living with HIV and their partners
a. Couples-based HIV testing, counseling, supported disclosure.
b. Education about serodiscordance, HIV transmission risk.
c. Assess plans for having children.
2. For those considering reproduction
a. Education about HIV transmission risks and periconception risk reduction strategies. (Table 1)
b. Fertility evaluation
i. Woman's age, menstrual cycles
ii. Both partners’ fertility history
iii. Semen analysis when possible (especially if male partner infected).
iv. Additional fertility workup dictated by history (e.g. abnormal menses, advanced maternal age).
v. Full fertility workup (based on local standard) if no pregnancy after 6 months of conception attempts.
3. For those who choose to attempt conception
a. Standard of care preconception screening (STI screen, serologies for rubella, hepatitis B virus, cervical cancer screening) and immunizations (Tdap, MMR, HBV as appropriate).
b. Education re. timing peak fertility.
c. Referral to MMC (for F+M− couples).
d. ART: standard evaluation prior to initiation of ART, adherence counseling, supported disclosure to other supports.
e. PrEP (if indicated) evaluation: serum Cr, HBV, adherence counselling.
Advances in ARV-based prevention dramatically increase safer conception options for HIV-serodiscordant couples. The standard of care in resource-rich settings has become sperm processing and assisted reproduction for M+F− couples, yet costs and limited access make this a difficult option for most. Given discordant genital and plasma viral loads, it is appropriate to recommend sperm processing for M+F− couples, who can access it, but for those who cannot or prefer other options, ARVs-as-prevention are an excellent alternative.
To further develop safer conception options for serodiscordant couples, additional research into effectiveness of ARVs-as-prevention, efficacy of topical PrEP agents, impacts of topical and systemic PrEP on pregnancy and pregnancy outcomes, how providers advise serodiscordant couples about safer conception practices, and how couples consider, negotiate and implement these practices in diverse settings is needed. Safer conception guidelines and policies are needed to facilitate and promote safer conception practices for HIV-serodiscordant couples who choose to conceive.
In order to minimize periconception HIV-transmission among serodiscordant couples, conception attempts should be delayed until the infected partner is on ART. For M+F− couples, ART for the infected partner may be combined with sperm processing or intercourse timed to peak fertility, PrEP for the uninfected partner, and STI treatment. For F+M− couples not willing to carry out nonintercourse insemination, we recommend infected-partner ART, MMC, sex without condoms timed to peak fertility, PrEP for the uninfected partner, and STI treatment. We recommend daily dosing of PrEP starting at menses and continuing until pregnancy is achieved. In cases where the infected partner does not want, meet criteria, or cannot adhere to ART, we recommend PrEP for the uninfected partner. Healthcare workers should be educated about these options to facilitate deployment.
L.T.M. is supported by a K23 award (MH095655). J.A.S. is supported by the William and Flora Hewlett Foundation. We thank Dr. David R. Bangsberg and Dr. Matthew J. Ehrlich for important contributions to the article.
Conflicts of interest
The authors report no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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In this secondary analysis of the Partners PrEP trial, TDF drug levels were compared between participants who acquired HIV (17 from TDF arm, 12 from FTC/TDF arm) and randomly selected participants who did not acquire HIV. Thirty-five percent of those assigned to TDF and 25% of those assigned to FTC/TDF had detectable plasma TDF at seroconversion. Eighty-three percent of samples from uninfected controls in the TDF arm and 81% of controls from the FTC/TDF arm had detectable TDF. Detectable TDF was thus associated with an 86% reduction in HIV acquisition risk in the TDF arm and with a 90% reduction in risk for the FTC/TDF arm.
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This modeling study examines the cost-effectiveness of potential prevention strategies for serodiscordant couples in South Africa. Modeled scenarios include PrEP from time of serodiscordance diagnosis, PrEP only up until ART for the positive partner, PrEP up until 1 year after ART for the positive partner, and PrEP for serodiscordant couples who choose to conceive.
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