**4. Fertility management**

Fertility management for PLWHIV should be comprehensive and involve cART, specific management for factors associated with infertility, and AFT while minimizing the risk of horizontal and vertical transmission of HIV.

#### **4.1. Combination antiretroviral therapy**

With advances in the development of antiretroviral agents, cART has become more potent and effective, more tolerable and convenient to administer, and less toxic. Current guidelines recommend that PLWHIV should receive cART when they are willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence, regardless of the CD4 cell count level.[67] The benefits of early cART among persons with a CD4 cell count above 500 cells/mm3 were demonstrated in a recent large-scale randomized trial that showed a reduction in mortality, AIDS-related events, and non–AIDS-related events in those started on cART immediately versus waiting until the CD4 cell count fell below 350 cells/mm3 .[68] The currently recommended initial cART regimens consist of a backbone of two NRTIs and any one drug from the following drug classes: non-NRTI, protease inhibitor with a booster, or integrase inhibitor with or without a booster.[67, 69, 70] The initial cART regimens recommended by different consensus guidelines are shown in Table 2. A patient-specific regimen from these lists will be chosen based on convenience of administration, adverse reactions, local availability, cost, and health plan coverage. The goals of cART are immunologic response, defined as an increase in CD4 cell count, and virologic response, defined as HIV RNA suppression below the lower limit of detection. By extending life expectancy and improving overall health, immunity, and quality of life from cART, cART is expected to improve fertility outcomes. Achieving a sustained virologic response is particularly important to reduce the risk of HIV horizontal and vertical transmission during conception attempts, pregnancy, and delivery.


**Note:** 3TC, lamivudine; ABC, abacavir; DHHS, the U.S. Department of Health and Human Services; DRV/r, ritonavirboosted darunavir; DTG, dolutegravir; EACS, European AIDS Clinical Society; EFV, efavirenz; EVG/c, cobicistat-boosted elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization.

**Table 2.** Recommended first-line combination antiretroviral therapy regimens based on consensus guidelines

#### **4.2. Specific management for factors associated with infertility**

#### *4.2.1. Management of biological factors*

Immunosuppression and wasting syndrome can be improved by cART. In addition, PLWHIV who are taking cART with sustained immunologic and virologic responses will have reduced incidences of OIs, such as tuberculosis, salmonellosis, toxoplasmosis, cryptococcosis, CMV infection, and candidiasis. NRTIs selected for the backbone of a cART regimen should have the least toxicity on mitochondria to minimize the impact on oocytes and sperm. These "safer" NRTIs include tenofovir, abacavir, lamivudine, and emtricitabine.[67, 69, 70] Good general health and less physical stress are associated with normal ovulation and menstrual cycles in HIV-infected women, whereas cART improves overall sperm parameters among HIV-infected men. STIs, OIs, and other infections should be promptly diagnosed and treated to prevent damage to the genital organs. It is important that sex partners of patients with STIs should be counseled, tested, and treated accordingly.

Hypogonadism should be recognized early, correctly diagnosed, and treated in HIV-infected men. Testosterone treatment is indicated in men with low serum concentrations of testosterone and any of the following signs or symptoms including low libido and/or hypogonadal symptoms, low bone mineral density, low body mass, or weight loss despite virologic response to cART. Prior to initiation of testosterone replacement therapy, patients should be evaluated for coexisting depression and psychosocial stressors along with baseline laboratory studies including complete blood count, a metabolic panel, lipid panel, and a prostate-specific antigen (PSA). Long-term effects of suppression of the hypothalamic–pituitary–gonadal axis, promot‐ ing malignancy of the prostate gland and cardiovascular diseases, in those older than 60 years should be carefully monitored. Patients with a history of prostate cancer, a palpable prostate nodule, or an elevated PSA should not be prescribed testosterone replacement therapy.[34, 71] The routes of testosterone administration should be based on the patient's preference and include transdermal patch, gel, and intramuscular injection. For injections, the initial dose is 200 mg every 2 weeks or 100 mg every week. The dose can be titrated based on testosterone levels measured midway between injections aiming for the mid-normal reference range. Testosterone replacement therapy should continue as long as there are symptomatic benefits and no adverse effects.

#### *4.2.2. Management of psychological and social factors*

in those started on cART immediately versus waiting until the CD4 cell count fell below 350

NRTIs and any one drug from the following drug classes: non-NRTI, protease inhibitor with a booster, or integrase inhibitor with or without a booster.[67, 69, 70] The initial cART regimens recommended by different consensus guidelines are shown in Table 2. A patient-specific regimen from these lists will be chosen based on convenience of administration, adverse reactions, local availability, cost, and health plan coverage. The goals of cART are immunologic response, defined as an increase in CD4 cell count, and virologic response, defined as HIV RNA suppression below the lower limit of detection. By extending life expectancy and improving overall health, immunity, and quality of life from cART, cART is expected to improve fertility outcomes. Achieving a sustained virologic response is particularly important to reduce the risk of HIV horizontal and vertical transmission during conception attempts,

**DHHS 2015 EACS 2015 WHO 2013**

ABC + 3TC + DTG ABC + 3TC + DTG TDF + FTC/3TC + EFV

TDF + FTC + EVG/c

TDF + FTC + RPV

**4.2. Specific management for factors associated with infertility**

**Note:** 3TC, lamivudine; ABC, abacavir; DHHS, the U.S. Department of Health and Human Services; DRV/r, ritonavirboosted darunavir; DTG, dolutegravir; EACS, European AIDS Clinical Society; EFV, efavirenz; EVG/c, cobicistat-boosted elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil

Immunosuppression and wasting syndrome can be improved by cART. In addition, PLWHIV who are taking cART with sustained immunologic and virologic responses will have reduced incidences of OIs, such as tuberculosis, salmonellosis, toxoplasmosis, cryptococcosis, CMV infection, and candidiasis. NRTIs selected for the backbone of a cART regimen should have the least toxicity on mitochondria to minimize the impact on oocytes and sperm. These "safer" NRTIs include tenofovir, abacavir, lamivudine, and emtricitabine.[67, 69, 70] Good general health and less physical stress are associated with normal ovulation and menstrual cycles in HIV-infected women, whereas cART improves overall sperm parameters among HIV-infected men. STIs, OIs, and other infections should be promptly diagnosed and treated to prevent

**Table 2.** Recommended first-line combination antiretroviral therapy regimens based on consensus guidelines

.[68] The currently recommended initial cART regimens consist of a backbone of two

cells/mm3

186 Genital Infections and Infertility

pregnancy, and delivery.

TDF + FTC + EVG/c or TAF + FTC + EVG/c

TDF + FTC + DTG TDF + FTC + DTG

TDF + FTC + RAL TDF + FTC + RAL TDF + FTC + DRV/r TDF + FTC + DRV/r

fumarate; WHO, World Health Organization.

*4.2.1. Management of biological factors*

Knowledge about HIV and its epidemiology, routes of transmission, clinical course, long-term prognosis, and benefit of cART is critical to PLWHIV in reducing HIV transmission to their sexual partners and improvinge their adherence and outcomes. A previous study demon‐ strated that increased reproductive intention was associated with patient optimism regarding cART efficacy.[72] To overcome the challenges in pregnancy, birth, and parenting, PLWHIV should be informed about the recent advances in antenatal, perinatal, and postnatal care to prevent HIV transmission to their newborns. Family planning counseling should be provided to prepare them for child rearing and to cope with any problems they may face. Issues on reproductive care access for PLWHIV are very new for many developing countries, because the main goals for HIV care in these countries are currently improving access to HIV testing and treatment. Financial burdens, medical coverage, and availability of centers that can provide AFT need to be considered when developing and implementing local, regional, and national policies or guidelines for the reproductive care of PLWHIV. In the meantime, physicians who care for PLWHIV should update their knowledge to optimally assess and manage fertility issues among persons with HIV infection. HIV stigmatization may be reduced by campaigns and specific interventions that are appropriate and feasible for each locale.

#### **4.3. Assisted fertility therapy**

Relevant issues to be considered regarding fertility treatment in PLWHIV include risk of HIV horizontal transmission in serodiscordant heterosexual couples and methods to reduce HIV transmission. Generally, the rate of HIV heterosexual transmission is approximately 1 per 500 to 1 per 1,000 episodes of unprotected sexual intercourse.[3] However, the risk of transmission can increase significantly if there are genital tract infections from STIs or OIs, trauma with sex, lack of male circumcision, and high plasma HIV RNA levels in seroposi‐ tive persons.[73, 74] Thus, a thorough evaluation is needed before AFT. History including a detailed history of their HIV infection and any associated complications, recent CD4 cell counts and HIV RNA levels, past and current cART regimens, history of antiretroviral drug resistance, ongoing HIV risk behaviors, and fertility problems should be obtained. Physical examination should focus on signs relevant to causes of infertility, genital organs, and Pap smear in women. An HIV-infected partner should be treated with cART until HIV RNA suppression has been achieved prior to AFT. Partners who have STIs need to be treated to reduce transmission risks of HIV and STI-associated pathogens. Trauma during sexual intercourse should be avoided or minimized, and safer sex practices should be encouraged outside the conception attempts. Proposed algorithm for fertility management among HIVinfected couples is shown in Figure 2.

Post-exposure prophylaxis (PEP) with cART in uninfected partners may be used after the unprotected sexual intercourse (conception attempt). Although there have not been welldesigned studies in human that assess the efficacy of this intervention, the benefits of HIV transmission reduction have been shown in an animal study and a retrospective study of health care workers exposing to body fluids of HIV-infected persons.[75, 76] The recommended PEP regimens that are also safe if the pregnancy does occur are combined tenofovir, emtricitabine, and ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or raltegravir.[77] PEP should be initiated as soon as possible after HIV exposure but within 48 hours and should be continued for 28 days. Because of its demonstrated efficacy, tenofovir–emtricitabine (TDF/FTC) once daily for pre-exposure prophylaxis (PrEP) administered to the seronegative partner is now the preferred approach to reduce the risk of HIV transmission among serodiscordant couples. Among heterosexual couples, pericoital tenofovir vaginal gel was the first PrEP intervention that showed a 39% efficacy at reducing HIV acquisition among high-risk South African women.[78] Several other randomized controlled trials have demonstrated the benefit of PrEP at reducing HIV acquisition among HIV-negative at-risk individuals including 1) the iPrEx study that demonstrated 44% reduction in the incidence of HIV among men who have sex with men taking daily oral TDF/FTC,[79] 2) the Partners-PrEP study that demonstrated 75% and 67% reduction in the incidence of HIV among serodiscordant couples taking daily oral TDF or TDF/FTC, respectively, in Africa,[80] and 3) the TDF2 study that demonstrated 62% reduction in the incidence of HIV among heterosexual men and women taking daily oral TDF/ FTC in Botswana.[81] Pharmacokinetic data suggest that PrEP should begin at least 1 week before unprotected sex for optimal benefit. The uninfected partners who choose to take PEP and/or PrEP need to be regularly screened and monitored for HIV infection and adverse effects of the drugs in PEP and/or PrEP regimens.[67, 77]

In regards to limiting risk of HIV vertical transmission, cART given to HIV-infected women antenatally and avoiding breastfeeding can reduce the rate of transmission from 25–40% to less than 1%.[67] Invasive procedures, such as amniocentesis, chorionic villus sampling, and use of fetal scalp electrodes, should be avoided in HIV-infected women because these can

**Note:** cART, combination antiretroviral therapy; HIV, human immunodeficiency virus; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; IVF, in vitro fertilization; OIs, opportunistic infections; PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis; RNA, ribonucleic acid; STIs, sexually transmitted infections.

**Figure 2.** Proposed algorithm of fertility management in HIV-infected couples

500 to 1 per 1,000 episodes of unprotected sexual intercourse.[3] However, the risk of transmission can increase significantly if there are genital tract infections from STIs or OIs, trauma with sex, lack of male circumcision, and high plasma HIV RNA levels in seroposi‐ tive persons.[73, 74] Thus, a thorough evaluation is needed before AFT. History including a detailed history of their HIV infection and any associated complications, recent CD4 cell counts and HIV RNA levels, past and current cART regimens, history of antiretroviral drug resistance, ongoing HIV risk behaviors, and fertility problems should be obtained. Physical examination should focus on signs relevant to causes of infertility, genital organs, and Pap smear in women. An HIV-infected partner should be treated with cART until HIV RNA suppression has been achieved prior to AFT. Partners who have STIs need to be treated to reduce transmission risks of HIV and STI-associated pathogens. Trauma during sexual intercourse should be avoided or minimized, and safer sex practices should be encouraged outside the conception attempts. Proposed algorithm for fertility management among HIV-

Post-exposure prophylaxis (PEP) with cART in uninfected partners may be used after the unprotected sexual intercourse (conception attempt). Although there have not been welldesigned studies in human that assess the efficacy of this intervention, the benefits of HIV transmission reduction have been shown in an animal study and a retrospective study of health care workers exposing to body fluids of HIV-infected persons.[75, 76] The recommended PEP regimens that are also safe if the pregnancy does occur are combined tenofovir, emtricitabine, and ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or raltegravir.[77] PEP should be initiated as soon as possible after HIV exposure but within 48 hours and should be continued for 28 days. Because of its demonstrated efficacy, tenofovir–emtricitabine (TDF/FTC) once daily for pre-exposure prophylaxis (PrEP) administered to the seronegative partner is now the preferred approach to reduce the risk of HIV transmission among serodiscordant couples. Among heterosexual couples, pericoital tenofovir vaginal gel was the first PrEP intervention that showed a 39% efficacy at reducing HIV acquisition among high-risk South African women.[78] Several other randomized controlled trials have demonstrated the benefit of PrEP at reducing HIV acquisition among HIV-negative at-risk individuals including 1) the iPrEx study that demonstrated 44% reduction in the incidence of HIV among men who have sex with men taking daily oral TDF/FTC,[79] 2) the Partners-PrEP study that demonstrated 75% and 67% reduction in the incidence of HIV among serodiscordant couples taking daily oral TDF or TDF/FTC, respectively, in Africa,[80] and 3) the TDF2 study that demonstrated 62% reduction in the incidence of HIV among heterosexual men and women taking daily oral TDF/ FTC in Botswana.[81] Pharmacokinetic data suggest that PrEP should begin at least 1 week before unprotected sex for optimal benefit. The uninfected partners who choose to take PEP and/or PrEP need to be regularly screened and monitored for HIV infection and adverse effects

In regards to limiting risk of HIV vertical transmission, cART given to HIV-infected women antenatally and avoiding breastfeeding can reduce the rate of transmission from 25–40% to less than 1%.[67] Invasive procedures, such as amniocentesis, chorionic villus sampling, and use of fetal scalp electrodes, should be avoided in HIV-infected women because these can

infected couples is shown in Figure 2.

188 Genital Infections and Infertility

of the drugs in PEP and/or PrEP regimens.[67, 77]

increase the risk of fetal/infant exposure to maternal body fluids. Cesarean section instead of normal vaginal delivery can further reduce the risk of maternal-infant transmission in HIVinfected pregnant women whose HIV RNA has not been suppressed following cART. United States guidelines use a HIV RNA level of >1,000 copies/mL at 34–36 weeks gestation as a threshold for recommending Cesarean section, whereas European guidelines recommend a threshold of >50 copies/mL.[67, 69] Women who achieve virologic suppression near term can proceed with vaginal delivery without increased transmission risk. Antiretroviral prophylactic regimens for newborns of HIV-infected mothers should be prescribed based on the risk of transmission. In general, AZT is recommended for the first 4–6 weeks of life with additional medications added if the mother did not achieve viral suppression. HIV-infected mothers should not breastfeed their babies due to the risk of transmission via breast milk.

#### *4.3.1. AFT when only the female partner is infected*

If a woman is HIV infected and her male partner is uninfected, HIV transmission can be avoided by using homologous insemination with the male partner's sperm. However, if this option is not feasible, such as the desire to become pregnant naturally, couples should limit unprotected sexual intercourse to the time of ovulation (timed intercourse) using ovulation kits or basal body temperature monitoring to predict ovulation. These measures allow couples to limit the number of unprotected sexual encounters. In addition, the HIV-infected women should be on cART with a suppressed viral load. The male partner may choose to take PEP and/or PrEP to reduce the risk of HIV transmission; however, these options are not as safe as homologous insemination.[82]

#### *4.3.2. AFT when only the male partner is infected*

Conception between an HIV-infected man and his HIV-uninfected female partner is more complicated. The risk of HIV transmission can be reduced by using timed intercourse when the HIV-infected man's plasma HIV RNA is undetectable on cART. However, the HIV transmission of timed intercourse in this setting has been reported to be associated with inconsistent condom use outside the conception attempt.[83] Thus, the practice of timed intercourse alone to prevent HIV transmission to the female partner is not generally recommended in this setting.[82] Additional PEP and/or PrEP may be used to reduce HIV transmission. A study of serodiscordant couples, in which the woman was treated with oral tenofovir taken shortly before and after each unprotected sexual encounter, showed that none of the women became infected with HIV and pregnancy rates reached 75% after 12 attempts. [84] Based on available data, once-daily TDF/FTC for the women would generally be recommended throughout the conception period in countries where resources are available for PrEP.

Sperm preparation and testing prior to intrauterine insemination (IUI) have been described as methods to reduce the chance of HIV transmission to the uninfected female partner. The sperm preparation involves a three-step process.[3, 82] First, the liquefied semen is filtered through a Percoll gradient. Next, the isolated spermatozoa are washed to eliminate seminal plasma and hyperosmotic gradient media. Finally, a modified swim-up method recovers highly motile spermatozoa from leukocytes. After this process, the final sperm specimen is tested by polymerase chain reaction assays for the presence of HIV. If this final specimen tests negative, it is used for insemination. In men with severe dyspermia, the final swim-up step that removes infected leukocytes cannot be performed and thus the semen should be tested for HIV DNA. Utilizing this process, 1,600 inseminations were performed in 513 HIV-uninfected women and resulted in 228 pregnancies. At 1-year follow-up, none of the children older than 3 months of age and none of the mothers became HIV infected.[85] In addition, studies reviewing world‐ wide data in 2004 and data from several centers demonstrated no HIV transmission to the uninfected female partners who were inseminated using sperm washing and IUI.[86, 87]

There have been recent data supporting the use of IVF/ICSI to reduce HIV transmission to uninfected women. A 10-year retrospective study of 181 serodiscordant couples undergoing IVF/ICSI, in which sperm was prepared using a modified density-gradient centrifugation and the swim-up method, revealed no HIV infection among the uninfected women and their 170 children.[88] Another study from the Center for Reproductive Assisted Techniques for HIV in Europe reported no evidence of seroconversion in any uninfected partners or children on follow-up.[86] Unfortunately, these techniques are generally prohibitively expensive. Al‐ though the data on efficacy and safety of the AFT techniques are encouraging, the potential risk of HIV transmission is not completely eliminated and more studies are required. Until then, serodiscordant couples should also be counseled about other safer options, including using donor sperm, donor embryo, adoption, or not having children.[82] If couples want to have their own biological children, they should be informed about available risk reduction techniques and the availability of centers that can provide effective methods of sperm preparation and testing. Fertility centers should use approved study protocols with informed consent and provide appropriate follow-up of sexual partners and their children.

#### *4.3.3. AFT when both partners are infected*

threshold of >50 copies/mL.[67, 69] Women who achieve virologic suppression near term can proceed with vaginal delivery without increased transmission risk. Antiretroviral prophylactic regimens for newborns of HIV-infected mothers should be prescribed based on the risk of transmission. In general, AZT is recommended for the first 4–6 weeks of life with additional medications added if the mother did not achieve viral suppression. HIV-infected mothers

If a woman is HIV infected and her male partner is uninfected, HIV transmission can be avoided by using homologous insemination with the male partner's sperm. However, if this option is not feasible, such as the desire to become pregnant naturally, couples should limit unprotected sexual intercourse to the time of ovulation (timed intercourse) using ovulation kits or basal body temperature monitoring to predict ovulation. These measures allow couples to limit the number of unprotected sexual encounters. In addition, the HIV-infected women should be on cART with a suppressed viral load. The male partner may choose to take PEP and/or PrEP to reduce the risk of HIV transmission; however, these options are not as safe as

Conception between an HIV-infected man and his HIV-uninfected female partner is more complicated. The risk of HIV transmission can be reduced by using timed intercourse when the HIV-infected man's plasma HIV RNA is undetectable on cART. However, the HIV transmission of timed intercourse in this setting has been reported to be associated with inconsistent condom use outside the conception attempt.[83] Thus, the practice of timed intercourse alone to prevent HIV transmission to the female partner is not generally recommended in this setting.[82] Additional PEP and/or PrEP may be used to reduce HIV transmission. A study of serodiscordant couples, in which the woman was treated with oral tenofovir taken shortly before and after each unprotected sexual encounter, showed that none of the women became infected with HIV and pregnancy rates reached 75% after 12 attempts. [84] Based on available data, once-daily TDF/FTC for the women would generally be recommended throughout the conception period in countries where resources are available

Sperm preparation and testing prior to intrauterine insemination (IUI) have been described as methods to reduce the chance of HIV transmission to the uninfected female partner. The sperm preparation involves a three-step process.[3, 82] First, the liquefied semen is filtered through a Percoll gradient. Next, the isolated spermatozoa are washed to eliminate seminal plasma and hyperosmotic gradient media. Finally, a modified swim-up method recovers highly motile spermatozoa from leukocytes. After this process, the final sperm specimen is tested by polymerase chain reaction assays for the presence of HIV. If this final specimen tests negative, it is used for insemination. In men with severe dyspermia, the final swim-up step that removes infected leukocytes cannot be performed and thus the semen should be tested for HIV DNA. Utilizing this process, 1,600 inseminations were performed in 513 HIV-uninfected women and

should not breastfeed their babies due to the risk of transmission via breast milk.

*4.3.1. AFT when only the female partner is infected*

*4.3.2. AFT when only the male partner is infected*

homologous insemination.[82]

190 Genital Infections and Infertility

for PrEP.

While HIV seroconcordant couples do not have the same concerns about HIV transmission as do HIV serodiscordant couples, the risk of transmission of different strains of HIV between each other or superinfection exists. HIV superinfection in seroconcordant couples has been reported to increase the risk of HIV RNA rebound and decrease in CD4 cell count following immune reactivation.[89] The best way to minimize the risk of superinfection and optimize reproductive outcomes for couples and their offspring is to use cART to achieve HIV RNA suppression in both partners prior to conception attempts.

#### **4.4. Healthcare workers and cross-contamination risks**

Healthcare workers are at risk of exposure to blood-borne pathogens, including HIV through patient care. However, if standard universal precautions to prevent the transmission of infectious diseases are followed, the risk of acquiring these pathogens is very small and is not sufficient to deny reproductive services to PLWHIV. To date, there have been no reports of occupational HIV transmission to health care workers performing AFT, suggesting that the risk of transmission is extremely low. Theoretical concerns about contaminating other gametes and embryos stored in the same laboratory from cross-contamination have been raised. To date, no such event has been reported. To avoid this risk, it is recommended that samples from HIV-infected persons be processed in a separate laboratory or designated space within the main laboratory and to use a dedicated storage tank.[82]
