Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Preconception Counseling and Care for HIV-Infected Women of Childbearing Age
Reproductive Options for HIV-Concordant and Serodiscordant Couples
(Last updated:3/28/2014; last reviewed:3/28/2014)
For Couples Who Want to Conceive
For Both Concordant (Both Partners are HIV-Infected)/Discordant Couples:
- Expert consultation is recommended so that approaches can be tailored to specific needs, which may vary from couple to couple (AIII).
- Partners should be screened and treated for genital tract infections before attempting to conceive (AII).
- The HIV-infected partner should attain maximum viral suppression before attempting conception (AIII).
For Discordant Couples:
- Combination antiretroviral therapy (cART) for the infected partner may not be fully protective against sexual transmission of HIV.
- Periconception administration of antiretroviral pre-exposure prophylaxis (PrEP) for HIV-uninfected partners may offer an additional tool to reduce the risk of sexual transmission (CIII). The utility of PrEP of the uninfected partner when the infected partner is receiving cART and has a suppressed viral load has not been studied.
Discordant Couples with HIV-Infected Female:
- The safest conception option is artificial insemination, including the option of self-insemination with a partner’s sperm during the peri-ovulatory period (AIII).
Discordant Couples with HIV-Infected Male:
- The use of donor sperm from an HIV-uninfected male 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 should be considered (AII).
- Semen analysis is recommended for HIV-infected males before conception is attempted to prevent unnecessary exposure to infectious genital fluid when the likelihood of getting pregnant is low because of semen abnormalities (AIII).
|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 are HIV-infected, optimal health should be attained before attempting conception. The infected partner should be on combination antiretroviral therapy (cART) and have achieved maximal suppression of HIV infection.
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. If any such infections are identified, they should be treated because genital tract inflammation is associated with genital tract shedding of HIV.1-5
Before conception is attempted, maximal viral suppression is recommended for individuals who are on combination antiretroviral therapy (cART). 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 ART 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. Data from this study showed that earlier initiation of cART led to a significant 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 ART until the CD4 cell count fell below 250 cells/mm3
, whereas only 1 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. These are the first data from a randomized trial to demonstrate that provision of treatment to infected individuals can reduce the risk of transmission to their uninfected sexual partners.9
Based on the results from HPTN 052, initiation of cART would be recommended for the infected partner in a serodiscordant couple who has a CD4 cell count of ≤550 cells/mm3
if the couple wishes to conceive. Initiation of cART is also recommended for HIV-infected individuals with CD4 cell counts >550 cells/mm3
, although the benefit of cART in reducing sexual transmission from individuals with higher CD4 cell counts has not been determined.
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.10
increase in genital HIV-1 RNA levels increased the risk of female-to-male or male-to-female HIV transmission by 1.7-fold.10
Discordance between plasma and genital viral loads has been reported, and individuals with an undetectable plasma viral load may have detectable genital tract virus.11-13
In addition, antiretroviral (ARV) drugs vary in their ability to penetrate the genital tract.14
Thus, maximal plasma viral suppression may not completely eliminate risk of heterosexual transmission. Although use of cART may not eliminate all risk of sexual transmission, it may contribute to lowering risk in couples who have decided to conceive through unprotected intercourse despite known risks.
Reducing the risk of perinatal transmission is another potential rationale for starting cART before conception in HIV-infected women. Data suggest that early and sustained control of HIV viral replication may be associated with decreasing residual risk of perinatal transmission,15,16
but that does not completely eliminate the risk of perinatal transmission.16
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.17,18
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 willingness and ability of the HIV-infected partner to commit to potential lifelong therapy, the potential risks versus benefits of stopping or continuing the regimen after conception in the male or postpartum in the female, and the need for strict adherence to achieve maximal viral suppression. Consultation with an expert in HIV care is strongly recommended.
For HIV-discordant couples in which the female 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 peri-ovulatory period. Condom use should be advised at all times.
For HIV-discordant couples in which the male is the HIV-infected partner, the use of donor sperm from an HIV-uninfected male 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 has been reported to be effective in avoiding seroconversion in uninfected women and offspring in several studies.19-21
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 about the potential risk of transmission of HIV to the uninfected partner and to their offspring.20
Semen analysis is recommended for HIV-infected males 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 getting pregnant naturally is low or nonexistent.22-25
Discordant couples who do not have access to assisted reproduction services and who still want to try to conceive after comprehensive counseling should be advised that timed, peri-ovulatory unprotected intercourse after the infected partner has achieved maximal viral suppression (with use of condoms at all other times) may reduce but not completely eliminate the risk of sexual transmission.20
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. Others did not show benefit, which is likely related to adherence issues.9,26-31
Table 4 summarizes clinical trials of PrEP.32
Click here to view this table as an image
Table 4. Clinical Trials of Pre-Exposure Prophylaxis
||1,219 sexually active adults; 55% male, 45% female; 94 % unmarried; approximately 90% aged 21–29 years
||Daily oral TDF/FTC
|>30% did not complete study; cannot draw definitive conclusions for women and men separately.
||4,758 heterosexual serodiscordant couples; 38% negative-female, 68% negative-male partner; 98% married; median age 33 years
|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 years 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 years in high-prevalence areas
|Uganda, South Africa, Zimbabwe
|Daily oral TDF or daily oral TDF/FTC or daily topical TFV gel
|No study drug significanrly 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% negative-female, 50% 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
|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., Antiretroviral-based HIV prevention studies: Lancet 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 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.33
Only combination tenofovir/emtricitabine is being evaluated currently in ongoing heterosexual PrEP trials. Adherence is critical. The use of continued PrEP is recommended for anyone who is at ongoing risk of HIV acquisition.
Pregnancy is not a contraindication to PrEP. However, the use of daily oral PrEP during pregnancy and lactation has not been well studied in HIV-uninfected women with HIV-infected partners. 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. Continuation of PrEP during pregnancy can be considered.34-38 Currently, there is no reported increase in congenital anomalies among children born to women exposed to tenofovir (2.4%) or to emtricitabine (2.5%) during pregnancy, including in the first trimester.39
It will be important to have outcome studies that examine adverse events, including risk of congenital abnormalities. In addition, 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. Laboratory testing for HIV infection, baseline renal function, and chronic hepatitis B virus (HBV) infection should be performed before initiating PrEP. Hepatitis B-uninfected individuals should be vaccinated. Individuals receiving PrEP should be monitored for potential side effects such as renal dysfunction and clinical toxicities. They 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 and measures should be instituted to prevent perinatal transmission if pregnancy has occurred and attempts at conception stopped if it has not. Refer patient to HIV specialist immediately. Individuals with chronic HBV should be monitored for possible hepatitis flares when PrEP is stopped.40 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.41
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 Centers for Disease Control and Prevention has issued guidelines for the use of PrEP in sexually active heterosexual adults.42
Monitoring of HIV-Uninfected Pregnant Women with Partners Known to Be HIV-Infected
Clinicians may increasingly be seeing HIV-uninfected women who present during pregnancy and indicate that their partners are HIV-infected. They, 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 with a rapid HIV test on the labor and delivery unit. 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 antibody test. If the plasma HIV RNA is negative, it should be repeated in 2 weeks. All 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, headache) and the importance of seeking medical care and testing if they experience such symptoms.
Pregnancy is not a contraindication to PrEP and 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 HIVseronegative 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.43,44
- Mitchell C, Hitti J, Paul K, et al. Cervicovaginal shedding of HIV type 1 is related to genital tract inflammation independent of changes in vaginal microbiota. AIDS Res Hum Retroviruses. 2011;27(1):35-39. Available at http://www.ncbi.nlm.nih.gov/pubmed/20929397.
- Johnson LF, Lewis DA. The effect of genital tract infections on HIV-1 shedding in the genital tract: a systematic review and meta-analysis. Sex Transm Dis. 2008;35(11):946-959. Available at http://www.ncbi.nlm.nih.gov/pubmed/18685546.
- Anderson BL, Firnhaber C, Liu T, et al. Effect of trichomoniasis therapy on genital HIV viral burden among African women. Sex Transm Dis. 2012;39(8):638-642. Available at http://www.ncbi.nlm.nih.gov/pubmed/22797689.
- Blish CA, McClelland RS, Richardson BA, et al. Genital inflammation predicts HIV-1 shedding independent of plasma viral load and systemic inflammation. J Acquir Immune Defic Syndr. 2012;61(4):436-440. Available at http://www.ncbi.nlm.nih.gov/pubmed/22878424.
- Homans J, Christensen S, Stiller T, et al. Permissive and protective factors associated with presence, level, and longitudinal pattern of cervicovaginal HIV shedding. J Acquir Immune Defic Syndr. 2012;60(1):99-110. Available at http://www.ncbi.nlm.nih.gov/pubmed/22517416.
- Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet. 2010;375(9731):2092-2098. Available at http://www.ncbi.nlm.nih.gov/pubmed/20537376.
- Del Romero J, Castilla J, Hernando V, Rodriguez C, Garcia S. Combined antiretroviral treatment and heterosexual transmission of HIV-1: cross sectional and prospective cohort study. BMJ. 2010;340:c2205. Available at http://www.ncbi.nlm.nih.gov/pubmed/20472675.
- Lu W, Zeng G, Luo J, et al. HIV transmission risk among serodiscordant couples: a retrospective study of former plasma donors in Henan, China. J Acquir Immune Defic Syndr. 2010;55(2):232-238. Available at http://www.ncbi.nlm.nih.gov/pubmed/21423851.
- Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505. Available at http://www.ncbi.nlm.nih.gov/pubmed/21767103.
- Baeten JM, Kahle E, Lingappa JR, et al. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. Sci Transl Med. 2011;3(77):77ra29. Available at http://www.ncbi.nlm.nih.gov/pubmed/21471433.
- Cu-Uvin S, DeLong AK, Venkatesh KK, et al. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS. 2010;24(16):2489-2497. Available at http://www.ncbi.nlm.nih.gov/pubmed/20736815.
- Sheth PM, Kovacs C, Kemal KS, et al. Persistent HIV RNA shedding in semen despite effective antiretroviral therapy. AIDS. 2009;23(15):2050-2054. Available at http://www.ncbi.nlm.nih.gov/pubmed/19710596.
- Politch JA, Mayer KH, Welles SL, et al. Highly active antiretroviral therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex with men. AIDS. 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22441253.
- Taylor S, Davies S. Antiretroviral drug concentrations in the male and female genital tract: implications for the sexual transmission of HIV. Curr Opin HIV AIDS. 2010;5(4):335-343. Available at http://www.ncbi.nlm.nih.gov/pubmed/20543610.
- Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS. 2008;22(8):973-981. Available at http://www.ncbi.nlm.nih.gov/pubmed/18453857.
- Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child transmission of HIV-1 despite a maternal viral load <500 copies/ml at delivery: a case-control study nested in the French perinatal cohort (EPF-ANRS CO1). Clin Infect Dis. 2010;50(4):585-596. Available at http://www.ncbi.nlm.nih.gov/pubmed/20070234.
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- Bujan L, Sergerie M, Moinard N, et al. Decreased semen volume and spermatozoa motility in HIV-1-infected patients under antiretroviral treatment. J Androl. 2007;28(3):444-452. Available at http://www.ncbi.nlm.nih.gov/pubmed/17215546.
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