(Last updated: August 6, 2015; last reviewed: August 6, 2015)
For Couples Who Want to Conceive
For Discordant Couples:
Discordant Couples with HIV-Infected Women:
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
For couples in which one or both partners are HIV-infected, optimal health should be attained before attempting conception; infected partners should be receiving combination antiretroviral therapy (cART) and demonstrate sustained suppression of plasma viral load below the limits of detection.
For concordant or serodiscordant couples who want to conceive, expert consultation is recommended so that approaches can be tailored to specific needs, which may vary from couple to couple.
Before attempting to conceive, both partners should be screened for genital tract infections. Treatment of such infections is important because genital tract inflammation is associated with genital tract shedding of HIV.1-5
Before conception is attempted, the HIV-infected partner should be receiving cART and demonstrate sustained suppression of plasma viral load below the limits of detection. Observational studies have demonstrated a decreased rate of transmission of HIV in heterosexual serodiscordant couples among whom the index partners were on cART compared with those not on therapy.6-8 HPTN 052 was a randomized clinical trial designed to evaluate whether immediate versus delayed initiation of cART by HIV-infected individuals with CD4 T lymphocyte (CD4) cell counts of 350 to 550 cells/mm3 could prevent sexual transmission of HIV among serodiscordant couples. Most of the participants were from Africa (54%), with 30% from Asia and 16% from North and South America. This study showed that earlier initiation of cART led to a 96% reduction in transmission of HIV to the uninfected partner. Of 28 cases of HIV infection documented to be genetically linked to the infected partner, 27 occurred in the 877 couples in which the HIV-infected partner delayed initiation of cART until the CD4 cell count fell below 250 cells/mm3, whereas only one case of HIV infection occurred in the 886 couples with an HIV-infected partner who began immediate cART; 17 of the 27 transmissions in the delayed-therapy group occurred in individuals with CD4 cell counts >350 cells/mm3. The majority of transmissions (82%) were observed in participants from Africa. Thus this randomized trial clearly demonstrated that provision of treatment to infected individuals can reduce the risk of transmission to their uninfected sexual partners.9
Use of cART reduces but may not completely eliminate the risk of HIV sexual transmission in couples who have decided to conceive through unprotected intercourse.10 It is important to recognize that no single method (including treatment of the infected partner) is fully protective against transmission of HIV. Effective cART that decreases plasma viral load to undetectable levels is also associated with decreased concentration of virus in genital secretions. In a prospective study of 2,521 African HIV-infected serodiscordant couples, higher genital HIV RNA concentrations were associated with greater risk of heterosexual HIV-1 transmission and this effect was independent of plasma HIV concentrations.11 Each log10 increase in genital HIV-1 RNA levels increased the risk of female-to-male or male-to-female HIV transmission by 1.7-fold.11 Discordance between plasma and genital viral loads has been reported, and individuals with an undetectable plasma viral load may have detectable genital tract virus.12-14 In addition, antiretroviral (ARV) drugs vary in their ability to penetrate the genital tract.15
Starting cART before conception in HIV-infected women may also reduce the risk of perinatal transmission. Data suggest that early and sustained control of HIV viral replication may be associated with decreasing residual risk of perinatal transmission,16,17 but not complete elimination of the risk of perinatal transmission.17 In addition, reports are mixed on the possible effects of cART on prematurity and low birthweight, with some but not all data suggesting that such outcomes may be more frequent in women on ARV drugs at conception.18-20
The implications of initiating therapy before conception solely for prevention of sexual and/or perinatal transmission should be discussed with the couple. These issues include the potential risks versus benefits of stopping or continuing the regimen after conception in the man or postpartum in the woman, and the need for strict adherence to achieve a plasma viral load below the limits of detection. Consultation with an expert in HIV care is strongly recommended.
For HIV-discordant couples in which the woman is the HIV-infected partner, the safest form of conception is artificial insemination, including the option to self-inseminate with the partner’s sperm during the periovulatory period. Condom use should be advised at all times.
For HIV-discordant couples in which the man is the HIV-infected partner, the use of donor sperm from an HIV-uninfected man with artificial insemination is the safest option. When the use of donor sperm is unacceptable, the use of sperm preparation techniques coupled with either intrauterine insemination or in vitro fertilization with intracytoplasmic sperm injection has been reported to be effective in avoiding seroconversion in uninfected women and offspring in several studies.21-23 Sperm preparation should utilize optimal methods that can detect the presence of HIV. Couples should also consider the cost and other possible complications of in vitro fertilization. More data are needed to demonstrate the complete efficacy of these techniques, and couples should be cautioned that there may be a small risk of transmission of HIV to the uninfected partner and to their offspring.22 Semen analysis is recommended for HIV-infected men before conception is attempted because HIV, and possibly cART, may be associated with a higher prevalence of semen abnormalities such as low sperm count, low motility, higher rate of abnormal forms, and low semen volume. If such abnormalities are present, the uninfected female partner may be exposed unnecessarily and for prolonged periods to her partner’s infectious genital fluids when the likelihood of conceiving naturally is low or nonexistent.24-27
Discordant couples who do not have access to these reproduction services (i.e., artificial insemination, sperm preparation, in vitro fertilization) and who still want to try to conceive after comprehensive counseling should be advised that timed, periovulatory unprotected intercourse after the infected partner has achieved plasma viral load below the limits of detection (with use of condoms at all other times) may reduce but not completely eliminate the risk of sexual transmission.22 HIV-uninfected women who become pregnant should be regularly counseled regarding consistent condom use to decrease their risk of sexual transmission of HIV and the possible risk of perinatal transmission (see Monitoring of HIV Uninfected Pregnant Women with a Partner Known to be HIV Infected).
Periconception pre-exposure prophylaxis (PrEP) may offer an additional option to minimize risk of transmission of HIV within discordant couples. PrEP is use of ARV medications by an HIV-uninfected individual to maintain blood and genital drug levels sufficient to prevent acquisition of HIV. Many studies have demonstrated that PrEP reduces the risk of HIV acquisition in both men and women, with minimal risk of incident ARV resistance. Other trials failed to demonstrate PrEP efficacy, likely related to suboptimal levels of adherence.9,28-33 Table 4 summarizes clinical trials of PrEP.34
|TDF2||1,219 sexually active adults; 55% male, 45% female; 94 % unmarried; approximately 90% aged 21–29
||Botswana||Daily oral TDF/FTC
||>30% did not complete study; cannot draw definitive conclusions for women and men separately.
|PIP||4,758 heterosexual serodiscordant couples; 38% HIV-negative female, 68% HIV-negative male partner; 98% married; median age 33
||Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, Zambia
||Daily oral TDF or TDF/FTC
||67% protection with TDF alone; 75% protection with TDF/FTC
||Discordant couples may be a distinct, unique population.
||1,951 heterosexual women aged 18–35 at high risk of infection
||Kenya, South Africa, Tanzania
||Daily oral TDF/FTC
||Trial discontinued for futility in April 2011.
||Adherence assessment with monthly clinical samples to measure drug concentration is pending.
|5,029 heterosexual women aged 18–45 in high-prevalence areas
||Uganda, South Africa, Zimbabwe
||Daily oral TDF or daily oral TDF/FTC or daily topical TFV gel
||No study drug significantly reduced the risk of HIV acquisition. HIV incidence was 5.7 per 100 person years; effectiveness was -48.8% for TDF, -4.2% for TDF/FTC, and 14.7% for TDF gel.
||Adherence to study drugs was low; TFV was detected in 30% of the oral TDF arm, 29% in the oral TDF/FTC arm, and 25% in the TDF gel arm.
||1,763 heterosexual serodiscordant couples; 50% HIV-negative female, 50% HIV-negative male partner; 94% married; 61% aged 26–40 years
||Botswana, Kenya, Malawi, South Africa, Zimbabwe, Brazil, India, Thailand
||Immediate or delayed cART in HIV-infected partner
||96% protection on immediate cART
||Suppression of viraemia on therapy assured by routine monitoring.
|Key to Acronyms: cART = combination antiretroviral therapy; TDF = tenofovir disoproxil fumarate; TFV = tenofovir; FTC = emtricitabine
Source: Adapted from: Kashuba et al., Pre-exposure prophylaxis for HIV prevention: how to predict success: Table Antiretroviral-based HIV prevention studies. Lancet. 2012;379(9835): 2409-2411.
PrEP may offer an additional strategy for safer conception. Couples should be advised to use condoms at all times except during periovulatory intercourse. Several studies evaluating the efficacy of PrEP in heterosexual discordant couples planning pregnancy are ongoing but complete data are not yet available. One study evaluated timed intercourse with PrEP in 46 heterosexual HIV-discordant couples with an HIV-uninfected female partner. The male HIV-infected partners were receiving cART and had undetectable plasma HIV RNA levels. One dose of oral tenofovir disoproxil fumarate (tenofovir) was taken by the women at luteinizing hormone peak and a second oral dose was taken 24 hours later. None of the women became HIV infected and pregnancy rates were high, reaching a plateau of 75% after 12 attempts.35
Only daily dosing of combination tenofovir and emtricitabine is currently Food and Drug Administration-approved for use as PrEP. Adherence is critical. The use of continued PrEP is recommended for anyone who is at ongoing risk of HIV acquisition.
Pregnancy and breastfeeding are not contraindications to PrEP.36-40 Currently, there is no reported increase in congenital anomalies among children born to women exposed to tenofovir (2.3%) or to emtricitabine (2.4%) during the first trimester.41 Data from studies of infants born to HIV infected mothers and exposed to tenofovir through breast milk suggest limited drug exposure.42-44 Condom use should be encouraged in pregnancy because several studies have reported increased incidence of HIV acquisition during pregnancy, which may also lead to increased perinatal transmission.
The utility of daily oral PrEP when the HIV-infected partner is receiving cART has not been studied. If clinicians elect to use PrEP for HIV-uninfected women or men in serodiscordant couples, the couples should be educated about the potential risks and benefits and all available alternatives for safer conception. The Centers for Disease Control and Prevention (CDC) recommends that an HIV-uninfected partner planning pregnancy with an HIV-infected partner start daily oral tenofovir plus emtricitabine beginning 1 month before conception is attempted and continued for 1 month after conception is attempted.45 Recommended laboratory testing should include HIV diagnostic testing at baseline then every 3 months, renal function testing at baseline and then every 6 months, and pregnancy testing at baseline and every 3 months. Testing for hepatitis B virus (HBV) infection, should be performed when initiating PrEP. HBV -uninfected individuals should be vaccinated if they have not received HBV vaccination or they lack immunity to HBV. Individuals receiving PrEP should be educated about symptoms associated with acute HIV infection and advised to contact their providers immediately for further evaluation, should symptoms occur. HIV-uninfected partners should undergo frequent HIV testing to detect HIV infection quickly. If HIV infection is documented, the PrEP ARV agents should be discontinued to minimize selection of drug-resistant virus, measures should be instituted to prevent perinatal transmission if pregnancy has occurred and attempts at conception stopped if pregnancy has not occurred, and the patient should be referred to an HIV specialist immediately. Individuals with chronic HBV should be monitored for possible hepatitis flares when PrEP is stopped.46 Clinicians are strongly encouraged to register HIV-uninfected women who become pregnant while receiving PrEP with the Antiretroviral Pregnancy Registry.
Both partners should be on cART with maximum viral suppression before attempting conception. Periovulatory unprotected intercourse (with use of condoms at all other times) is a reasonable option. The risk of HIV superinfection or infection with a resistant virus is negligible when both partners are on cART and have fully suppressed plasma viral loads.47
The National Perinatal HIV Hotline (1-888-448-8765) is a resource for a list of institutions offering reproductive services for HIV concordant/serodiscordant couples.
The CDC has issued guidelines for the use of PrEP in sexually active heterosexual adults.45
Monitoring of HIV-Uninfected Pregnant Women with Partners Known to Be HIV-Infected
HIV-uninfected women who present during pregnancy and indicate that their partners are HIV-infected, like all pregnant women, should be notified that HIV screening is recommended and they will receive an HIV test as part of the routine panel of prenatal tests unless they decline. These women also should receive a second HIV test during the third trimester, preferably before 36 weeks’ gestation, as is recommended for high-risk women. Furthermore, pregnant women who present in labor without results of third-trimester testing should be screened on the labor and delivery unit with an expedited serum HIV test, preferably a fourth-generation antigen/antibody expedited HIV test. If at any time during pregnancy a clinician suspects that a pregnant woman may be in the “window” period of seroconversion (i.e., she has signs or symptoms consistent with acute HIV infection), then a plasma HIV RNA test should be used in conjunction with an HIV antigen/antibody fourth-generation test. If the plasma HIV RNA is negative, it should be repeated in 2 weeks. HIV-uninfected pregnant women with HIV-infected partners should always use condoms during sexual intercourse to prevent acquisition of HIV. Women should be counseled regarding the symptoms of acute retroviral syndrome (i.e., fever, pharyngitis, rash, myalgia, arthralgia, diarrhea, and headache) and the importance of seeking medical care and testing if they experience such symptoms.
Pregnancy and breastfeeding are not contraindications to PrEP, and PrEP should be considered in HIV-seronegative pregnant women who are at ongoing risk of HIV acquisition. However, the use of daily oral PrEP during pregnancy and lactation has not been well studied (see section on Serodiscordant Couples).
Women who test HIV seropositive on either conventional or rapid HIV tests should receive appropriate evaluation and interventions to reduce perinatal transmission of HIV, including immediate initiation of appropriate cART and consideration of elective cesarean delivery according to established guidelines (see Transmission and Mode of Delivery). In cases where confirmatory test results are not readily available, such as with rapid testing during labor, it is still appropriate to initiate interventions to reduce perinatal transmission (see Infant Antiretroviral Prophylaxis).
Women with HIV-infected partners who test HIV seronegative should continue to be regularly counseled regarding consistent condom use to decrease their risk of sexual transmission of HIV. Women with primary HIV infection during pregnancy or lactation are at high risk of transmitting HIV to their infants.48,49