Reproductive issues present ongoing challenges for HIV clinicians

The challenges of protecting HIV-exposed infants begin before conception and continue until the child has been weaned.

WHO guidelines recommend that women with HIV who are pregnant and/or breast- feeding receive antiretroviral therapy for their own health and for prophylaxis against transmission to the baby. Some health officials also said they believe that women in these populations should be assigned to ART regardless of CD4 count or viral load.

However, the safest, most effective ART treatment strategies during pregnancy and breast-feeding continue to be debated, and the discussion is further muddled by socioeconomic disparities.

“The literature and the clinical agenda have not yet caught up with the desire for children among people with HIV,” Deborah Cohan, MD, MPH, associate professor in the department of obstetrics, gynecology and reproductive sciences at the University of California San Francisco, and medical director of the Bay Area Perinatal AIDS Center, told Infectious Diseases in Children. “We have only recently discovered fertility plans for people with HIV as an area of research. It is a basic reality that is being dealt with around the world — but slowly.”

Current ART research

There is a growing body of evidence indicating that the level to which ART penetrates the genital tract in men and women may be important to the risk for transmission between partners and, ultimately, transmission to the baby.

In February, Clavel and colleagues presented results on a study of raltegravir (Isentress, Merck Sharp Dohme) penetration into the female genital tract at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.

Drug concentrations at 13.6 hours (13.0 hours to 14.5 hours) after the last drug intake were 93 ng/mL (48 ng/mL to 167 ng/mL) in blood plasma and 235 ng/mL (135 ng/mL to 775 ng/mL) in cervicovaginal fluid among 14 women in France. The researchers wrote that the increased raltegravir concentration in the genital tract may contribute to increased virological control and, consequently, reduced mother-to-child transmission rates.

In other study results presented at CROI, Lambert-Niclot and colleagues investigated the level of darunavir (Prezista, Centocor Ortho) penetration into the male genital tract. The free/total blood plasma ratio for darunavir concentration was 7.2% (5.9%-9.0%); the seminal plasma/blood plasma ratio for drug concentration was 8.6% (5.7%-22.2%). These data indicated favorable penetration of the drug into the male genital tract, according to the researchers.

Once a woman becomes pregnant, a whole new set of HIV prevention challenges emerges, according to Arlene D. Bardeguez, MD, MPH, professor and director of HIV services in the department of obstetrics, gynecology and women’s health at the New Jersey Medical School in Newark.

“Research indicates that most protease inhibitors do not cross the placenta,” she said. “They are purely for maternal protection.”

Nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors cross the placenta. “Those drugs load the baby and protect it,” Bardeguez said in an interview. “At the moment, we are sort of maxed out in terms of what we can do to protect the baby. If the mother is linked to care and if the HAART regimen is centered, the likelihood of transmission is low.”

Cohan said, “For a woman on HAART who is suppressed in pregnancy and delivery, the risk of transmission is less than 1%.”

Despite these low transmission rates, in areas where clinics are fewer, physicians have been forced to look at other maternal–fetal prevention strategies, including single-dose nevirapine.

In Africa, a model involving a single dose of nevirapine at the beginning of labor was adopted because most women do not receive adequate preventive or prenatal care. However, the use of single- dose nevirapine carries a high risk for the development of resistant virus in mothers and their newborns who may become infected despite prophylaxis.

Elaine J. Abrams, MD, professor of pediatrics and epidemiology at Columbia University’s College of Physicians and Surgeons and Mailman School of Public Health, said that the nevirapine model provided a strong and simple introduction to preventing maternal-fetal transmission in low-resource settings.

“Single-dose nevirapine is good, but not adequate,” she said in an interview. “The price you pay for these regimens and the low transmission rates that they come with is the high risk of resistance.”

In another study presented at CROI, data indicated that mothers who were administered single-dose nevirapine were at risk for passing on resistant HIV virus to their breast-feeding infant.

Sandra Dross, of Seattle Children’s Research Institute in Washington, and colleagues analyzed a subset of infants from a larger study conducted in Mozambique, Africa, who tested negative for HIV infection at birth and positive one month or later. Nine of 24 infants included in the study exhibited nevirapine-resistant HIV-1 infection. Specimens taken from eight of these infants were 100% positive for resistant virus. Seven infants had follow-up specimens available, and all showed continued high levels of resistant virus.

Data such as those from Dross and colleagues make the issue of single-dose nevirapine a hotly contested one among physicians, some of whom argue that the single-dose method is better than nothing at all, whereas others argue that using this method is advocating a different standard of care in developing nations than in the United States. (See Point/Counter for more on this issue.)

Cohan said the ART issue during breast-feeding was investigated as part of the Mma Bana Study conducted among 700 women in Botswana, Africa.

The aim of this study was to determine the optimal ART regimen to prevent mother-to-child transmission during pregnancy and after delivery while also protecting infants from the dangers of breast milk substitutes and early weaning.

Women with lower CD4 counts were assigned to nevirapine and lamivudine/zidovudine (Combivir, Viiv Healthcare), and those with higher CD4 counts were randomly assigned to lopinavir/ritonavir (Kaletra, Abbott)/Combivir or abacavir/zidovudine/lamivudine (Trizivir, Viiv Healthcare).

Study researchers noted at the time of birth, equal proportions of women taking triple NRTI treatment (96%), protease inhibitor-based therapy (93%) and treatment that included nevirapine (94%) had a viral load less than 400 copies/mL, and similar proportions of those women maintained viral suppression throughout breast-feeding.

Maternal-fetal transmission of HIV was low in all three groups of women, less than 2% in all study arms. Only two transmissions occurred during the breast-feeding period, the researchers concluded.

Policy issues

Recommendations from WHO call for lifelong ART for all pregnant women with CD4 counts ≤350 cells/mm³ or who have advanced clinical disease. The recommendations also state that:

• Pregnant women in need of ART for their own health should be administered ART;
• CD4 testing is critical for determining ART eligibility and should be widely available;
• For women not eligible for ART, combination prophylaxis with either AZT or a three-drug regimen should begin in the second trimester and be linked with postpartum prophylaxis;
• In settings where breast-feeding is the preferred infant feeding option, prophylaxis is recommended.

WHO officials, however, have acknowledged that prevention of mother-to-child transmission services often are established as vertical programs that lack sufficient integration with other reproductive health programs that share similar goals.

Sofia Gruskin, JD, MIA, director of the Program on International Health and Human Rights in the department of global health and population at Harvard School of Public Health, recently mediated a conference at the Harvard School that addressed a variety of issues involving reproductive issues and women with HIV, including the gaps in research and how those gaps are related to public policy.

“When you take a set of guidelines from the international level and filter it down through national and local governments and then through local clinics and health care providers, without adequate attention, a lot is potentially lost in the translation,” she said in an interview. “Though guidelines from international organizations ought to be beneficial, the reality is that without sufficient resources to implement them adequately, they may impact the lives of women with HIV who are trying to have children in unintended ways.”

Other recommendations regarding safe delivery from The American College of Obstetricians and Gynecologists include that if a woman has a level of more than 1,000 HIV RNA copies/mL near delivery, she should be offered elective cesarean section before the onset of labor.

The recommendation came in the wake of a meta-analysis of prospective studies that examined the effect of cesarean section on transmission risk. It was observed that the risk for transmission decreased among women who were not assigned to ART or zidovudine monotherapy. The odds of mother-to-child transmission decreased by 50% among women who underwent prelabor cesarean section delivery compared with other modes of delivery. However, no such benefit has been observed among women receiving ART.

Whether a cesarean delivery can have a beneficial effect among women with plasma HIV RNA loads measuring less than 1,000 copies/mL remains unclear.

Communication from physicians

Cohan said that more focus needs to be placed on training health care providers in issues ranging from counseling serodiscordant couples about fertility and safer sex methods to addressing birth control, and matters such as performing abortions.

“There is an increasing body of research showing adults with HIV in discordant relationships,” Cohan said. “As these adults with HIV are living longer, their life goals and priorities are shifting, and that includes wanting children. Safe conception and delivery among these couples has introduced a whole new set of clinical challenges.” (See sidebar.)

For those women who are trying to prevent pregnancies, Cohan said that an intrauterine device is an underutilized form of contraception for women with HIV. “This method is a great way of preventing unwanted pregnancies that also allows for a quick return to fertility,” she said.

Even in countries where abortion is legal, some providers are uncomfortable performing the procedure on women with HIV, according to Gruskin. “Ironically, in settings where it is not legal, we know of providers sterilizing women or performing abortions due to fear of delivering an HIV–positive baby,” she said.

Gruskin said that many of these issues could be handled by training health care providers on implementing new guidelines and on delivering appropriate messages in a way that allows their patients to make informed choices.

Cohan said that focusing on women with HIV who are in monogamous relationships and desire to have children may be a good place to continue spreading clear and appropriate messages.

“This is a very teachable moment,” she said. “This may be the one time in a woman’s life when she can really get it together and focus all of her attention on her health. We need to capitalize on this moment in any way that we can and hope that the message gets through.” – by Rob Volansky

What is your opinion of nevirapine as a way to prevent mother-to-child transmission of HIV?

For more information:

• Anderson BL. Clin Infect Dis. 2009;48:449-455.
• Clavel C. #608. Presented at: 17th Conference on Retroviruses and Opportunistic Infections; Feb. 16-19, 2010; San Francisco.
• Lambert-Niclot S. #610. Presented at: 17th Conference on Retroviruses and Opportunistic Infections; Feb. 16-19, 2010; San Francisco.
• Peterson L. PLoS. 2007;doi:10.1371/journal.pctr.0020027.