Antenatal Care - Treatment
All women have a right to a safe pregnancy (Freedman et al., 2005), including women living with HIV. There are proven strategies that improve the health of the mother during pregnancy and reduce the risk of mother-to-child transmission of HIV. The most important strategy is for the woman to access health care services where she can be evaluated for the use of antiretroviral drugs. "Antenatal care must include 'fast-tracking' [women living with HIV] into programmes providing holistic care, including treatment with HAART... [with] HIV care to be integrated into routine antenatal care, and not [maintained] as a separate programme" (Sebitloane and Mhlanga, 2008: 496 and 498).
"...Each new pediatric HIV infection is considered a missed opportunity for prevention" (Abrams, 2007: 705).Antiretroviral treatment is vital to ensuring safe motherhood and reducing vertical transmission. Even in historical contexts where mono or duo therapy was used, dramatic reductions were seen in vertical transmission. For example, a retrospective study analyzed demographic data for 13,583 infants born between 2000 and 2006 from birth until age two in South Africa found that when PMTCT programs became available in 2001, mortality of infants under age two declined 36% and after antiretrovirals became available in 2004, declined another 20% (Ndirangu et al., 2010). While the risk of vertical transmission is dramatically reduced to 2% (Fowler et al., 2010) through the use of triple therapy for the mother, vertical transmission can still occur (Read, 2010).
Some scientists have argued "universal maternal HAART could largely eliminate the overall MTCT risk" (Becquet et al., 2009a: 1942). Women who are on a HAART regimen [for their own health] have the least risk of perinatal transmission, estimated at 1% (Stek, 2008). "Tritherapy, which has mainly been aimed at protecting the mother's health, has proven very profitable to the child as well" (Kouanda et al., 2010a: 848). In addition, women on HAART [for their own health] have a much greater likelihood of an expanded lifespan, which results in a better quality of life for the woman herself and reduces the likelihood of an intergenerational effect for orphans and vulnerable children.
However, not all pregnant women access treatment. Globally, nearly two-thirds of pregnant women do not even know their HIV status (WHO et al., 2011b). In 2007, only 12% of pregnant women identified as HIV-positive during antenatal care were assessed to determine whether they were eligible to receive antiretroviral therapy for their own health, and only 9% of those HIV-positive women who received PMTCT services received HAART (UNAIDS, 2009e). In 2008, 24% of HIV-positive pregnant women were assessed with a CD4 cell count for ART eligibility for their own health (Zolfo et al., 2010). In 2010, among 99 low- and middle-income countries reporting data, an estimated 45% of pregnant women who were known to be HIV-positive were assessed, either through clinical staging or CD4 count, for their eligibility to receive antiretroviral therapy (UNAIDS, 2011a). The WHO notes that, in 2010, among an estimated 571,000 pregnant women who were eligible for treatment due to their CD4 count, only 25% or 197,000 women received HAART (WHO et al., 2011b). "Data on numbers of women who have had clinical staging and CD4 cell count testing and who require and receive antiretroviral treatments, as well as the antiretroviral prophylaxis regimens that are given to women not receiving treatment, are needed" (Mofenson, 2010b: S144). Studies have also found that pregnant women who qualified for HAART did not access HAART due to "competing life priorities, such as... seeking food and shelter, as major barriers to accessing HIV care" (Muchedzi et al., 2010). [See also Provision and Access and Orphans and Vulnerable Children]
Because TB is a risk factor for increased vertical transmission (Gupta et al., 2011), HIV-positive women are pregnant should be considered for routine TB preventive therapy (Marais, 2011). "...Prevention of TB among HIV-infected mothers should be considered as part of a well-functioning HIV MTCT program. The exceptionally high TB and transmission risk provides additional motivation to carefully monitor all HIV-infected women for TB during and after pregnancy" (Marais, 2011: 305). [See Preventing, Detecting and Treating Critical Co-Infections]
Good Antenatal Care is Essential for Safe Motherhood
Clinical exams, rapid syphilis tests, tetanus toxoid, supplementation with iron and folic acid are all considered the standard of care for pregnant women (Villar et al., 2001). Of critical importance is to inform women, their partners, families and communities of the danger signs during pregnancy and ensure access to emergency obstetric care. Antenatal care is also an opportunity for HIV counseling and testing. Women who test HIV-negative still need information and support to remain HIV-negative. [See Prevention for Women, Prevention for Key Affected Populations, and Strengthening the Enabling Environment] Women who test HIV-positive need to be informed of their treatment options, both for their own health and to prevent vertical transmission. Women who test HIV-positive also need information and counseling concerning infant feeding options. Improving quality of care in maternal health services can increase the likelihood that women will go to health facilities in case of obstetric emergencies, thus increasing the chances of positive maternal and infant health outcomes (Gay et al., 2003). Women living with HIV also need sexual and reproductive health services and treatment for critical co-infections. Further efforts are needed to screen and treat pregnant women for co-infections that potentially increase mortality for women and their infants. [See also Meeting the Sexual and Reproductive Health Needs of Women Living With HIV and Preventing, Detecting and Treating Critical Co-Infections] "Given that the primary users of antenatal services in sub-Saharan Africa are young women under the age of 30 years, transforming delivery of PMTCT programs with greater emphasis on couple counseling, preventing unwanted pregnancies, keeping HIV-negative mothers uninfected, early initiation of HIV-infected mothers on antiretroviral treatment and ensuring safe infant feeding practices could make a substantial difference to current maternal and infant mortality rates and life expectancy patterns in women in these settings" (Abdool Karim et al., 2010a: S125-S126).
Syphilis co-infection can be especially dangerous in pregnancy, particularly for HIV-positive pregnant women. There is some evidence that HIV-syphilis co-infection may increase the risk of perinatal HIV transmission. While numerous countries have policies to provide universal screening for syphilis for pregnant women, not enough women are actually screened and treated in practice. In 2007, WHO estimated that syphilis prevalence in pregnant women in Africa ranges from 415% (WHO and UNAIDS, 2007). As a result, infants are dying from syphilis despite access to ARVs for mothers and infants (Peeling et al., 2004). Universal screening and treatment for syphilis in pregnancy could prevent 492,000 syphilis-related stillbirths and perinatal deaths per year in sub-Saharan Africa (Saloojee et al., 2004). Syphilis testing and treatment in conjunction with HIV testing can prevent congenital syphilis and may reduce HIV transmission. Screening for TB in pregnancy, especially in settings of high HIV prevalence, is also needed (Mnyani and McIntyre, 2010; Smart, 2012a).
Antenatal care is also an opportunity to discuss with pregnant women and their partners the benefits of infant male circumcision, which may reduce HIV acquisition and transmission when the infant becomes sexually active. Male circumcision has now been shown in three randomized clinical trials to reduce the risk of HIV acquisition for men by 50-60% (Auvert et al., 2005; Bailey et al., 2007; Gray et al., 2007). Male circumcision at birth as part of postnatal care could result, upon sexual initiation and for his lifetime, in a reduction in the risk of HIV acquisition and transmission (Weiss et al., 2009; Nagelkerke et al., 2007). [See also Voluntary Medical Male Circumcision]
"Structural factors in country health systems are one of the largest challenges to implementing effective programs for prevention of MTCT of HIV infection. At the country level, maternal, newborn, and child health services, in which programs for prevention of MTCT are targeted, are usually separate from programs, laboratories, and services for treatment and care of HIV infection. Thus, antepartum and postpartum care systems are not equipped to test all women for HIV, conduct CD4 cell count testing to stage disease in HIV-infected women, and provide antiretroviral treatment to women who need it and antiretroviral prophylaxis to others" (Mofenson, 2010a: S144). [See also Structuring Health Services to Meet Women’s Needs]
Lifelong ARV Treatment Is Recommended for Women Living with HIV
Women living with HIV who have access to triple therapy can expect a close-to-normal life span and a reduction in the risk of vertical transmission. "The best way to ensure that infants are not born with HIV or acquire it during breastfeeding is to provide HIV-positive women the care they need for their own disease" (ITPC, 2009: 11). The 900-1,200 new cases of HIV in babies in developing countries every day could be prevented (ITPC, 2009; UNAIDS, 2009d).
The development of ARV regimens to treat pregnant women and prevent vertical transmission is evolving and implementation varies around the world. For instance, in Western Europe, the initiation of ARV therapy in pregnant women proceeds according to the same CD4 count measurements as are used to initiate therapy within the general population, with the goal of full suppression of HIV by the third trimester of pregnancy (European AIDS Clinical Society, 2009). By contrast, in the United States, ARV therapy is now recommended for all pregnant women, regardless of their CD4 counts (Panel on Antiretroviral Guidelines for Adults and Adolescents, 2009).
In 2010, the WHO released new recommendations for the use of ARVs in pregnant women. The new guidelines represent the current consensus on best international practice for the use of ARVs in pregnant women in developing country settings for both the maintenance of the woman's own health and the prevention of mother-to-child transmission of HIV (WHO, 2010i). These guidelines recommend lifelong antiretroviral drug regimens for women who need ARVs to protect their own health (based on severe or advanced clinical disease or with the CD4 count at or below 350 cells/cubic mm, regardless of symptoms) and short-term prophylactic regimens to decrease the risk of HIV transmission to the baby during pregnancy, labor and delivery and throughout the breastfeeding period (based on CD4 cell counts above 350 or for women who do not require ARVs for their own health). Short-term prophylactic regimens delivered to the baby during delivery and the breastfeeding period (should the mother choose to breastfeed) are also recommended and are discussed in the Delivery and Postpartum sections. Of note, the recommendation for initiating ARV treatment for pregnant women has been raised from a CD4 count of 200 cells/cubic mm to a CD4 count of 350 cells/cubic mm, regardless of clinical staging of disease (WHO, 2010i).
Not all countries provide lifelong triple therapy and WHO has recommended eligibility criteria based on both scientific and economic considerations. For women who do not meet a country's eligibility criteria for ARV treatment for her own health, initiation of short-term treatment to prevent vertical transmission is now recommended at 14 weeks gestation instead of 28 weeks gestation (WHO, 2010i). Some governments continue to use single dose nevirapine to reduce vertical transmission with the rationale that this reduces costs. It should also be noted that an analysis of the cost-effectiveness of the 2009 WHO guidelines compared to the standard of care in Nigeria for prevention of vertical transmission found that triple antiretroviral therapy may be more cost-effective than the standard short-course antiretroviral therapy (Shah et al., 2011).
"The intervention that would have the most substantial impact on HIV-related maternal deaths and perinatal infections throughout the world is the initiation of lifelong antiretroviral therapy in pregnant and lactating women infected with HIV-1 who meet the treatment criteria" (Mofenson, 2010a: 2316). Recent PEPFAR guidance has endorsed antiretroviral therapy for pregnant women "for their own health as medically indicated" (PEPFAR, 2011a). UNICEF has recently promoted gender equality within UNICEF programs (UNICEF, 2010b).
There Are Unknown Effects to Discontinuing Treatment Postpartum
As noted, the recent WHO guidelines (WHO, 2010i), state that women with CD4 counts below 350 should receive HAART for their own treatment needs; however, "poor ability to assess clinical stage and limited or no access to CD4 cell counts, particularly in resource-poor settings, continue to represent major hurdles" to implementation of the new WHO guidelines (Zolfo et al., 2010: 288). Nonetheless, when a woman is on HAART with CD4 counts below 350, HAART will improve her own health and drastically reduce vertical transmission. Studies have found that starting HAART at CD4 counts up to 500 increases survival (Cohen et al., 2011b). [See also Treatment] When a woman has CD4 counts above 350, current recommendations are to have the woman go on ARVs during pregnancy, at labor and delivery or postpartum for the duration of breastfeeding. It is unknown at this time whether women who have CD4 counts above 350 and who go on HAART to prevent perinatal transmission should continue with HAART following pregnancy or breastfeeding or should stop and resume HAART when their CD4 counts go below 350. While it is clear that those who go on ARV therapy for their own treatment needs should not interrupt treatment (Fauci, 2009a; SMART, 2006), treatment interruption for women who are on HAART purely to prevent perinatal transmission rather than for their own health needs has never been evaluated. "The risk for maternal health of stopping... maternal triple ARV prophylaxis after breastfeeding cessation is unknown" (WHO, 2010i: 47) -- especially if an HIV-positive woman has multiple pregnancies. These unknown short- and long-term effects have also been noted by the US Department of Health and Human Services and the Panel on Antiretroviral Guidelines for Adults and Adolescents (USHHS, 2011: 46; Panel on Antiretroviral Guidelines for Adults and Adolescents, 2009).
A study funded by NIH (www.clinicaltrials.gov), begun in January 2010 with results expected in 2015 should answer this vital question. The PROMISE Study (Promoting Maternal-Infant Survival Everywhere) is a multi-national clinical trial in 18 countries that is being conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group. It will examine the long-term effects on the health of women who initiate ARV therapy as prophylaxis to prevent vertical transmission and then stop treatment in addition to comparing the effectiveness of different drug combinations for the treatment of PMTCT (NIAID, 2010; McIntyre, 2011).
"The difficult question here is whether HAART should or should not be stopped postpartum in women who were not eligible for HAART" (Chama et al., 2010: 365).For women and their providers, this remains a critical issue. [Stopping] could be risky, increasing the risk of mortality and "will need to be tailored to the evolving knowledge in this field" (Becquet et al., 2009a: 1939). Currently, US guidelines recommend that pregnant HIV-positive women with CD4 counts under 500 be initiated on lifelong antiretroviral therapy (USHHS, 2011). In addition, HIV-positive women having second pregnancies and stopping and starting triple ARVs leads one researcher to note that "...initiation of life-long ART at first pregnancy for all women may be beneficial" (French et al., 2012). Pregnant women who stop triple ARVs and then restart at the end of breastfeeding may have high viral rebounds and thus be at higher risk of vertical transmission in a second pregnancy (Zolfo et al., 2010). "Pregnant women who stop triple ARVs and then restart at the end of breastfeeding may have high viral rebounds and thus be at higher risk of vertical transmission in a second pregnancy" (Cavallo et al., 2010: 112).
Others have argued that since clinical staging performs poorly in identifying pregnant women for ART and there are still many barriers to obtaining CD4 cell counts that "universal ART initiation among HIV-positive pregnant women, irrespective of CD4 cell count or clinical staging is a potentially superior strategy for the prevention of vertical transmission and the improvement of mothers health" (Zolfo et al., 2010: 287). "Universal start of combination ART during pregnancy is standard of care in resource-rich settings; why not implement it in countries where HIV/AIDS is the leading cause of mortality among women in reproductive age and an important contributor to infant mortality?... Life-long continuation of combination ART beyond the breastfeeding period would certainly facilitate implementation and avoid seemingly contradictory messages around ART, 'ART is lifelong' and PMTCT 'ART may be stopped'" (Zolfo et al., 2010: 288).
In addition, given the recent study showing that treatment may reduce transmission, treating pregnant women with triple ART and keeping them on ART may also reduce transmission to their male sex partners (Cohen et al., 2011b). [See also Treatment as Prevention] In an article from July 2011, the Minister of Health of Malawi stated that because access to CD4 cell count is minimal, and because the total fertility rate is 5.6 births per woman -- making repeat pregnancies highly likely, because stopping and starting triple therapy could lead to viral rebounds, because HAART reduced the risk of TB, because of concerns that stopping and starting ARVs will lead to drug resistance, and due to the reduced risk of transmission by people living with HIV who are on HAART, "the message that triple therapy must be taken for life and on a daily basis from the start is simple" (Schouten et al., 2011: 282), Malawi has proposed to "offer all HIV-infected pregnant women lifelong ART" (Schouten et al., 2011: 282).
In April 2012, WHO released a programmatic update providing countries with the option of "providing the same triple ARV drugs to all HIV-infected pregnant women beginning in the antenatal clinic setting but continuing this therapy for all of these women for life" (WHO, 2012b: 1). Until April 2012, WHO recommended that pregnant women who accessed HAART with CD4 counts above 350 (i.e., for PMTCT prophylaxis) should continue "through the end of the breastfeeding period" (WHO, 2010i: 19); implying that women can stop HAART at the end of breastfeeding if their CD4 count remains above 350. Until the results from the PROMISE study are available, the question about what this might mean for the womans future treatment options remains.
Providers Should Consult the Most Recent Guidelines Regarding Medications Effect in Pregnancy
Health care providers should evaluate the most recent evidence when considering which ARVs to use for pregnant women. Currently, there is no evidence of a significant increased risk of birth defects associated with the appropriate antiretroviral treatment before conception or during the first trimester (Antiretroviral Pregnancy Registry Steering Committee, 2007 cited in Coll et al., 2008). A review of treatment options found that prophylaxis with the antibiotic co-trimoxazole is still advisable for persons with CD4 counts under 200, even if they are on HAART. Experts advise that once viral load is undetectable, co-trimoxazole is no longer required. While co-trimoxazole is potentially teratogenic, WHO recommends its use throughout pregnancy because the risk of life-threatening infection among women with low CD4 counts or symptomatic HIV infection may outweigh other risks (Watts and Mofenson, 2006). However, co-trimoxazole "should not be used as a substitute for the availability of HAART regimens for pregnant women with advanced disease but rather as an adjunct" (Watts and Mofenson, 2006: 1480). Single-dose nevirapine is no longer recommended for the prevention of vertical transmission and a number of countries have phased out its use. WHO is working with countries to disaggregate data on what regimens are currently being used for prevention of vertical transmission (UNAIDS, 2011a).
Nevirapine Resistance Is a Concern in Future Treatment Options
Nevirapine increases the numbers of infants with HIV-free survival, but may prejudice future treatment for the HIV-positive infant (Lockman et al., 2007; Coffie et al., 2008). For women who have received nevirapine already for PMTCT, and then access HAART, there are some concerns that prior use of nevirapine may hinder treatment. A study with 114 women in the U.S. found resistance rates of up to 43% in women who had pregnancy-limited antiretroviral treatment (Paredes et al., 2010). A study of 872 women in Zambia found that HAART was less effective among women who had been exposed to single dose nevirapine (Kuhn et al., 2009b). The OCTANE trial conducted in seven African counties (South Africa, Kenya, Zimbabwe, Botswana, Zambia, Malawi and Uganda) found that women who had history of single dose nevirapine therapy had an increased risk of virological failure and death when treated with a nevirapine based regimen (Lockman et al., 2010). WHO no longer recommends single dose nevirapine for pregnant women living with HIV (WHO, 2010i). "...Single dose nevirapine prophylaxis is moderately effective but induces viral load resistance in HIV-1 infected mothers and infants" (Becquet et al., 2009b: 1938). The problem of drug resistance can be reduced by combining single-dose nevirapine with short courses of lamivudine (with or without zidovudine) for seven days after delivery but "none of these approaches fully eliminate the selection of drug-resistant virus" (Becquet et al., 2009b: 1938). Despite the fact that nevirapine may prejudice treatment options for mothers and transmit nevirapine resistance to their infants (Kiptoo et al., 2008), in 2010, 11% of pregnant women, or 150,000 women in 33 countries received single dose nevirapine (WHO et al., 2011b), prejudicing the mother's HIV treatment options (Bulterys et al., 2010; Gingelmaier et al., 2010).
Questions Remain About ARVs and Infant Exposure
"With the availability of antiretroviral drugs increasing globally, WHO's expanded recommendations will lead to a rapidly growing number of antiretroviral-exposed, HIV uninfected children. Total exposure of these uninfected infants to antiretroviral drugs will start in utero and continue until the end of breastfeeding. The exposure period to these drugs could be up to 2 years, yet there are limited data on safety. There is now an urgent need to better understand the consequences of extended exposure to HIV and antiretroviral drugs on HIV-uninfected children to contribute to improved monitoring and management of potential adverse effects" (Heidari et al., 2012a: 290). "The immense benefits of antiretroviral drug use during pregnancy for PMTCT and maternal health far outweigh potential adverse effects identified to date. However, there are limited data on long-term effects of in utero antiretroviral exposure on uninfected children, and combination regimens have been in use for only about 10-15 years" (Heidari et al., 2012a: 294). "Continued evaluation of uninfected children with in utero ARV exposure for long-term adverse outcomes is important" (Williams et al., 2010a: e250; Cavarelli and Scarlatti, 2011).
Further information about treatment in general can be found in that section. For the most recent WHO treatment guidelines for safe motherhood and prevention of vertical transmission (WHO, 2010i), see: http://www.who.int/hiv/pub/mtct/antiretroviral2010/en/index.html
Treatment guidelines for the US may also be adaptable to certain country contexts:http://www.aidsinfo.nih.gov/guidelines/