Approximately half of HIV-discordant heterosexual couples in the United States want children. Oral antiretroviral preexposure prophylaxis, if effective in reducing heterosexual HIV transmission, might be an option for discordant couples wanting to conceive. Couples should receive services to ensure they enter pregnancy in optimal health and receive education about all conception methods that reduce the risk of HIV transmission. In considering whether preexposure prophylaxis is indicated, the question is whether it contributes to lowering risk in couples who have decided to conceive despite known risks. If preexposure prophylaxis is used, precautions similar to those in the current heterosexual preexposure prophylaxis trials would be recommended, and the unknown risks of preexposure prophylaxis used during conception and early fetal development should be considered. Anecdotal reports suggest that oral preexposure prophylaxis use is already occurring. It is time to have open discussions of when and how preexposure prophylaxis might be indicated for HIV-discordant couples attempting conception.
The reproductive health needs of HIV-uninfected men and women in the United States with HIV-infected spouses/partners have not been fully recognized or met. Data to estimate the number of such couples in the United States are available from a population-based sample of HIV-infected persons in care in 1996. Most HIV-infected men (58%) and women (70%) had a primary partner or a spouse: of those, 54% of the men and 52% of the women reported that the primary partner or spouse was HIV-negative, and another 20% of the men and 22% of the women reported that the primary partner or spouse was of unknown HIV serostatus. Of the men and women with an HIV-negative primary partner or spouse, 46% of the men and 51% of the women intended to have one or more children. In 2006, of an estimated 1.1 million persons living with HIV infection, approximately 239,600 heterosexuals were of peak reproductive age, namely, 13-49 years. These 2 reports together suggest that there are more than 140,000 HIV-serodiscordant heterosexual couples in the United States, approximately half of whom want additional children.
Some HIV-discordant couples seek reproductive assistance, and many practice unsafe measures to conceive. According to one survey, among 50 HIV-discordant couples interested in undergoing assisted reproduction to avoid transmission to the negative partner, 20% engaged in unprotected intercourse with the intent to achieve pregnancy.
Several assisted reproductive technology (ART) approaches have been developed to reduce the risk of HIV transmission during attempted conception. However, barriers such as expense, lack of fertility clinics offering services to couples affected by HIV, state laws and regulations barring access to some ART approaches for persons affected by HIV, conflicting professional and governmental guidelines, and societal stigmas, mitigate against access and use. HIV-discordant couples in the United States need more accessible options for safer conception. Oral antiretroviral preexposure prophylaxis (PrEP) may be one such option.
PrEP
Safety and efficacy trials of a once-daily oral dose of tenofovir disoproxil fumarate (TDF, brand name Viread; Gilead Sciences, Inc, Foster City, CA) or tenofovir combined with emtricitabine (FTC, brand name Truvada; Gilead Sciences, Inc) for the prevention of HIV acquisition by uninfected persons are currently underway. The first phase-III trial recently showed that PrEP was safe and provided an average of 44% (95% confidence interval [CI], 15–63%) additional protection against HIV infection for men who have sex with men (MSM). Among those using PrEP on 90% or more days in a visit interval, HIV risk was reduced by roughly 73% (95% CI, 41–88%), but it was reduced by only about 21% (95% CI, from a 52% reduction to a 31% increase) when used less than 90% of days in a visit interval. Phase III trial results for men and women at risk of acquisition during heterosexual intercourse are not expected until 2013. A phase II trial among high-risk women in West Africa showed preliminary safety and another safety study among young adults in Botswana is expected to report results in 2011. It is important to consider the possibilities PrEP presents for HIV-discordant couples, and what additional information may be required.
Many preventive public health achievements, such as the use of antiretrovirals (ARVs) to prevent mother-to-child HIV transmission (PMTCT), are believed to have been successful because of well coordinated and timely planning for translation from trials to programs. Following that model, the Centers for Disease Control and Prevention (CDC) has engaged city and state health departments, professional associations, academic researchers, and clinical and nonclinical providers, advocacy organizations and other stakeholders in discussions to guide planning activities to assist with the safe, appropriate, equitable and effective introduction of PrEP into prevention activities for various populations if proven effective and safe. In 2009 and again in 2010, research clinicians from CDC participated in meetings of technical experts and stakeholders to discuss the potential use of PrEP by serodiscordant couples wanting to conceive. In these meetings, the term “PrEP-ception” has been used to describe PrEP’s use for safer conception. Attendees at one or both meetings included representatives from several agencies in the US Department of Health and Human Services (eg, Food and Drug Administration, National Institutes of Health), members from national medical associations (eg, American Academy of Family Physicians, Society of Maternal-Fetal Medicine), National Association of State and Territorial AIDS Directors, obstetric and pediatric clinicians, infectious disease specialists, an ethicist, and others. This article presents some of the key topics discussed during those meetings.
Options for all discordant couples
All couples should receive preconception care services (ie, evidence-based risk screening, health promotion, and interventions) that will enable them to enter pregnancy in optimal health. There are 3 methods that might be used, either alone or in combination, by discordant couples wishing to conceive in the near or immediate future to reduce the amount of exposure to HIV for the uninfected partner during conception attempts ( Figure ).
The first method is treating the infected partner with a combination of ARV medications to achieve maximal reduction of HIV plasma RNA, or viral load, ideally to undetectable levels. If highly-active antiretroviral therapy is initiated for conception purposes, decisions about ongoing therapy after conception should be managed in accordance with the treatment guidelines.
A second method is limiting conception attempts to the periovulation period. Barriero et al reported results from a retrospective study of 62 serodiscordant couples who engaged in timed unprotected sex, while the infected partner was on suppressive ARV treatment, in which 22 female partners were HIV-positive and 40 male partners were HIV-positive. Of the 76 pregnancies achieved, there were 68 live births, no HIV transmission between partners and 1 case of mother-to-child HIV transmission. An additional study of 21 couples using timed unprotected intercourse for conception has reported results of PrEP (tenofovir 36 and 12 hours before intercourse for the negative woman) combined with HIV suppression by ARVs in the positive male. Conception occurred in 15 (70%) of women, 11 (52%) within 3 cycles; none of the 21 women acquired HIV. An over-the-counter luteinizing hormone (LH)-detection kit could also be used by testing the woman’s urine daily during the week of expected ovulation. When urine LH is detected, ovulation should occur within 24-36 hours, indicating an ideal time for conception. If conception is not achieved after a few attempts, some clinicians might consider ovulation induction agents such as clomiphene citrate. However, these medications alter the hormonal milieu, and there are no data regarding their effect on HIV transmission or acquisition.
A third method, essential but insufficient if used alone, is to screen both partners for sexually transmitted infections (STI) and treat for any found. STIs have been shown to both increase HIV shedding into genital fluids of the infected partner and increase the presence of cells susceptible to HIV infection in the uninfected partner.
Couples with infertility may consider in vitro fertilization (IVF) alone or with intracytoplasmic sperm injection (ICSI) to increase their chances of a successful pregnancy, although substantial cost and clinical expertise is required.
Options for HIV+ women with HIV− male partners
Reducing HIV transmission to an uninfected male partner can be assisted by elective male circumcision with at least 6 weeks of healing before an unprotected conception attempt. A metaanalysis of 3 randomized control trials showed that male circumcision can reduce transmission during unprotected penile-vaginal intercourse by up to 60%. The majority of adult men born in the United States were circumcised as infants, but in recent years, rates of infant circumcision have declined and many recent immigrants are from countries where most men are not circumcised.
Another option available to achieve conception while eliminating exposure of an uninfected male partner to HIV is artificial insemination, either via intravaginal insemination (IVI) or intrauterine insemination (IUI). A low-technology method of IVI is recovery of fresh semen from a condom or sterile cup and intravaginal insertion using either a soft disposable pipette or a syringe (without needle). With IUI, a clinician inserts the semen into the uterine cavity using a sterile, flexible catheter.
Because male circumcision is not fully protective, PrEP for the uninfected, circumcised male could be considered if conception will be attempted with timed, unprotected intercourse. However, if IVI is used, PrEP would not be indicated because there is no male exposure to infected vaginal fluids.
Options for HIV+ men with HIV− female partners
To essentially eliminate the risk of HIV exposure for women, semen collection and processing to remove HIV (“sperm washing”) can be done and then coupled with another technique for fertilization such as IUI, IVF, or ICSI. Studies report that, using these techniques, more than 1080 pregnancies have been achieved without HIV infection among 2003 women with HIV-infected male partners. Six states including Delaware, Illinois, Indiana, Iowa, South Dakota, and Tennessee have laws preventing the use of HIV-infected sperm in ART. Louisiana makes an exception if the donor sperm is from the wife’s spouse. Even among states that do permit access, some clinics may limit or deny services to HIV-infected persons, despite federal antidiscrimination laws that may apply to infertility clinics. In addition, there are conflicting professional and governmental organization guidelines regarding the procedure for this population.
No studies have yet been reported that combine PrEP with sperm-washing techniques. This may be because transmissions are so uncommon with simpler, more available methods—especially in combination (ARV treatment of the positive partner, timed intercourse, ± PrEP)—that the addition of a technically complex, expensive, and limited availability technology, such as sperm washing seems unwarranted.
For an uninfected female partner in a discordant couple, conception is not the only risk period for the woman. There is evidence that the risk of acquiring HIV infection is higher during pregnancy and breastfeeding than when not pregnant. In addition, should she acquire HIV at conception or during her pregnancy, the risk of transmission to her infant might be greater than if she had been HIV-positive before conception perhaps because of the high viral load during acute infection. Continuing PrEP through the pregnancy (and frequent HIV testing) may be needed to protect both mother and child when consistent condom use is not practiced.
Clinical issues for PrEP use
Only recently have tenofovir or emtricitabine been used in trials with HIV-uninfected persons for prevention of HIV acquisition. Neonatal health and other pregnancy outcomes in uninfected women who conceive while taking these medications are being studied in current PrEP trials, although contraception is provided and pregnancy discouraged. In addition, safety, pharmacokinetic, and efficacy studies using these 2 drugs are being conducted for PMTCT antenatally and during breastfeeding ( Table 1 ).
| No. | ID | Title | Antiretroviral drugs |
|---|---|---|---|
| Oral dosing | |||
| 1 | NCT00204308 | Maternal TDF and FTC to reduce NNRTI resistance mutations after intrapartum NVP | TDF+FTC |
| 2 | NCT00334256 | Tenofovir/emtricitabine for PMTCT in Africa and Asia (ANRS 12109 TEmAA) | TDF+FTC |
| 3 | NCT01061151 | Evaluating strategies to reduce mother-to-child transmission of HIV infection in resource-limited countries | ZDV, NVP, TDF+FTC, 3TC+ZDV, LPV+RTV |
| 4 | NCT00936195 | Universal use of EFV-TDF-FTC and AZT-3TC-LPV/r combinations for HIV-1 PMTCT in pregnant and breastfeeding women: a phase-III trial | EFV+TDF+FTC, ZDV+3TC+LPV+RTV |
| 5 | NCT00099632 | Comparison of 3 anti-HIV regimens to prevent nevirapine resistance in women who take nevirapine during pregnancy | TDF+FTC, 3TC+ZDV, LPV+RTV, NVP |
| 6 | NCT00076791 | Safety of TDF and emtricitabine/TDF in HIV-infected pregnant women and their infants | TDF, TDF+FTC |
| 7 | NCT00625404 | FEM-PrEP (Truvada; Gilead Sciences, Inc, Foster City, CA): study to assess the role of Truvada in preventing HIV acquisition in women | TDF+FTC |
| 8 | NCT00557245 | Preexposure prophylaxis to prevent HIV-1 acquisition within HIV-1 discordant couples (PartnersPrEP) | TDF, TDF+FTC |
| 9 | NCT00705679 | Safety and effectiveness of tenofovir 1% gel, TDF, and emtricitabine/TDF tablets in preventing HIV in women | TDF, TDF+ FTC |
| 10 | NCT01066858 | Study of effects of tenofovir on bone health and kidneys during pregnancy and breastfeeding | TDF |
| 11 | NCT01125696 | Safety study of a tenofovir-containing drug regimen for the prevention of mother-to-child transmission of HIV and HBV | TDF+3TC+LPV+RTV, ZDV+3TC+EFV |
| 12 | NCT00448669 | Botswana TDF/FTC oral HIV prophylaxis trial | TDF+FTC |
| Gel dosing | |||
| 13 | NCT00540605 | Blood levels of tenofovir gel in HIV-uninfected pregnant women planning cesarean delivery | TDF |
| 14 | NCT01136759 | Tenofovir gel in pregnancy and lactation | TDF |
| 15 | NCT00705679 | Safety and effectiveness of tenofovir 1% gel, TDF, and emtricitabine/TDF tablets in preventing HIV in women | TDF |
| 16 | NCT00441298 | Safety and effectiveness study of a candidate vaginal microbicide for prevention of HIV (CAPRISA 004) | TDF |
| Infant follow-up | |||
| 17 | NCT01209754 | EMBRACE (evaluation of maternal and baby outcome registry after chemoprophylactic exposure) | Any given in HIV prevention trials |
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