Karin Nielsen, MD, MPH
During the opening session of this year's ICAAC there were somber predictions that the highly active antiretroviral therapy (HAART) of today could become the failed antiretroviral therapy of tomorrow. The euphoric optimism of a few years ago, based on the development of potent protease inhibitors, was dampened by the knowledge that there is no evidence of eradication of disease, and that latent reservoirs promptly release virus upon cessation of therapy. Yet amidst the concerns over therapy failure, drug toxicities, and development of genotypic resistance mutations, one of the speakers reminded the audience of the continuing success story that is the reduction of mother-to-child HIV transmission via prompt identification and treatment of HIV-infected pregnant women and their infants.
Although great strides have been made in the last 5 years, there are still many issues regarding the optimal management of the pregnant woman with HIV, including identification of the safest and most cost-effective approach, as well as complex issues of implementation of these findings in developing countries where control of the epidemic in women and children is desperately needed. Extensive information about recent advances in the area of maternal-fetal transmission was reviewed, including issues of medical care, obstetrical, virologic, and immunologic factors involved in the pathogenesis of HIV perinatal transmission, recent clinical trials, and antiretrovirals (including toxicity data). Dr. Carmen Zorrilla from the University of Puerto Rico and Dr. Lisa Frenkel of the University of Washington thoroughly summarized the available facts and discussed recent controversies at a Meet-the-Experts Roundtable session.[4,5]
Starting in 1993, a dramatic decline in mortality rates of HIV/AIDS patients was noted in the United States, including the population of HIV-infected women of childbearing age, leading in turn to higher numbers of pregnant women infected with HIV. The continued heterosexual expansion of the epidemic also contributed to this finding. Reviewing the overall management of pregnant women with HIV, Dr. Zorrilla mentioned that prophylaxis of opportunistic infections during pregnancy should not be different from that of the HIV-infected nonpregnant patient. Trimethoprim-sulfamethoxazole for PCP prophylaxis and azithromycin for Mycobacterium avium complex prophylaxis should be instituted where warranted. In addition management of a wide spectrum of infectious diseases such as tuberculosis, syphilis, and bacterial vaginosis should not differ in this population.
Although opinions vary among specialists in the field, there is consensus that HIV disease in pregnant women should be treated with antiretroviral regimens that would not be considered substandard in nonpregnant women. Many recommend treatment should be instituted at a threshold HIV RNA level of 5000 to 10,000 copies/mL. Others recommend treating all patients, regardless of HIV RNA levels. There is also ongoing discussion on whether this threshold should be lowered, given that the relationship between HIV RNA and risk of disease progression may differ in women compared with men.
Regardless of this observation, however, use of antiretroviral regimens during pregnancy has changed in the last 5 years. Data on 1201 pregnant women in the WITS study showed that vertical transmission rates were 18% in 1990, peaked at 23% in 1993, and fell to 3.9% by 1998. Analysis of the specific antiretrovirals used in this population indicated that today approximately one third of the women followed still receive zidovudine (ZDV) monotherapy. ZDV and a second antiretroviral, usually lamivudine (3TC), are used by another third of the population studied. The remaining 33% to 35% of women enrolled in this study are being prescribed triple antiretroviral regimens or HAART.
Zidovudine monotherapy is still the official recommendation for management of HIV-infected pregnant women whose health status is such that therapy would not normally be indicated. However, official recommendations may lag behind current clinical practice and emerging data. The use of ZDV and 3TC during pregnancy has become popular in both North America and Europe since there is a more substantial improvement of plasma virus load (a stronger antiretroviral effect) and more protection against development of high-level ZDV genotypic resistance mutations. Specialists agree that HAART is unquestionably warranted when plasma HIV RNA levels reach a specific threshold. Nevirapine has been used as part of HAART or as a single drug given to the mother at the time of delivery and to the infant for prevention of transmission, as seen in the HIVNET 012 study and the ongoing PACTG 316. Yet, many questions arise about the use of HAART during pregnancy:
º Should HAART be offered to pregnant women for the purpose of prevention of perinatal transmission?
º Should there be a lower threshold for institution of HAART (for instance 1000 HIV RNA copies/mL plasma)?
º Should HAART be interrupted postpartum in women with HIV RNA less than 5000 copies/mL, especially since there are valid concerns about adherence to more complex regimens during the postpartum period?
Many studies have reported the strong association between an increased virus load and an increased risk of perinatal transmission.[9-13] To date a number of relatively small studies from developed countries have shown that perinatal transmission in women who are receiving HAART and have undetectable HIV RNA levels is zero. For example, Dr. Zorrilla highlighted a study by Morris and colleagues which reviewed protease inhibitor use in 89 pregnancies; data were available for 85 deliveries and the HIV transmission rate was zero. Similar small European studies were recently presented at the Global Strategies Conference for Prevention of HIV Transmission from Mothers to Infants held in Montreal in September 1999. PACTG 185, a study comparing HIV-specific immunoglobulin (HIVIG) vs placebo in women receiving zidovudine also reported no perinatal transmission in women with HIV RNA levels below the detectable range. There was no added benefit of HIVIG and both arms reported transmission rates of approximately 4%. Although these studies have indicated that transmission of HIV with undetectable HIV RNA levels appears to be an extremely rare event, a definite HIV RNA threshold below which no vertical transmission occurs has not been identified.
If HAART achieves the goal of reducing HIV load to undetectable levels and virus load is a significant risk factor for perinatal transmission, then HAART in pregnancy may be the way to go. However, there is controversy about stopping potent antiretroviral therapy in women postpartum. Some specialists fear an increase in virus replication following total suppression could lead to development of resistance, while others counter that poor adherence during the postpartum period could contribute to antiretroviral resistance.
Untreated women with undetectable virus loads are NOT the same as treated women with undetectable virus loads, since in untreated women there is no postexposure prophylaxis benefit to the infant and there is always the risk that virus levels may increase at any given moment. Dr. Zorrilla suggested that one should consider antiretroviral therapy in this population, at least at the time of delivery so that the infant may receive antiretroviral prophylaxis.
Because of so many unknowns concerning the use of antiretrovirals during pregnancy, Dr. Zorrilla reminded the conveners of the creation of the Antiretroviral Pregnancy Registry approximately 2 years ago. Such registries are pivotal for monitoring potential adverse effects, including maternal toxicities and teratogenicity. The Antiretroviral Pregnancy Registry may be contacted at 1-800-258-4263 (US and Canada) or 1-910 251-9087 (international).
In February of this year, Dr. Stephan Blanche presented data from his prospective perinatal cohort at the Retrovirus Conference in Chicago. At the time he described two cases of fatal mitochondrial toxicity syndromes in HIV-exposed infants who were uninfected and had been exposed to ZDV plus 3TC in utero. These data were recently published, and the French researchers have described 8 HIV uninfected children within their cohort (including the 2 patients above) with relatively diverse clinical findings attributable to mitochondrial dysfunction syndrome. Five patients have had neurologic findings and the other 3 are symptom-free. Persistent lactic acidosis was demonstrated in 5 patients.
These data generated significant concern and prompted an extremely thorough review of CDC, NIH/PACTG, and WITS databases in the US. The nucleoside safety review is ongoing, but of 15,229 children exposed in utero to antiretrovirals, no deaths within the cohort could be attributed to mitochondrial toxicity syndrome. This led the researchers to conclude that there is no evidence for fatal mitochondrial toxicity in children perinatally exposed to nucleoside analogue antiretrovirals in the US. Given the very diverse and nonspecific findings of mitochondrial toxicity syndrome, however, careful monitoring of perinatally exposed cohorts is warranted.
A recent publication has reviewed data on 234 infants exposed to intravenous ZDV in 076. After 4.2 years of follow-up, no deaths or cancers were noted, no effect on growth or cognitive development was described. Two children had ophthalmic involvement and 1 child had cardiomyopathy. Animal studies to evaluate antiretrovirals for potential toxicity and teratogenicity are also crucial. Efavirenz, for instance, has been associated with gross neurologic abnormalities in primate studies, and its use is contraindicated during pregnancy. It is unknown whether teratogenicity occurs in humans.
It is for these reasons that large-scale, long-term follow-up studies like PACTG 219 exist, where infants exposed perinatally to antiretrovirals are followed until 21 years of age. Perhaps even longer-term follow-up is warranted, since pathology could still be found after decades of exposure. One has to remember, however, that the vast majority of perinatally HIV-infected children in the developing world do not have the luxury of decades of survival. The benefits of avoiding perinatal HIV infection clearly outweigh potential theoretical risks of exposure.
Perinatal transmission of antiretroviral-resistant strains of virus is reason for concern and has been shown to occur, although only rarely to date. In ACTG 076, after a mean 3 months of exposure to ZDV, a 1% rate of low-level resistance mutations to ZDV was observed in pregnant women. High-level resistance mutations were not seen.
Previous studies have demonstrated that advanced maternal illness, maternal drug use, low vitamin A levels (in African studies), preterm deliveries, and breastfeeding have been associated with an increased risk of mother-to-child transmission. Vertical transmission rates in African countries, where antiretrovirals are not routinely used during pregnancy, have been approximately 25%. These rates are higher than those in countries where HIV-infected mothers do not breastfeed, even in the absence of antiretroviral therapy, reflecting the fact that breastfeeding is generally estimated to carry an excess transmission risk of 14%. Studies in Africa indicate that the risk appears to be highest in the first weeks of life, carrying a 4% to 6% risk between 6 weeks to 6 months. However, there is risk present throughout the duration of breastfeeding. A study by Miotti and colleagues reported a .7% monthly risk of acquisition of infection between 1 to 5 months of age, .6% between 6 to 11 months, .3% between 12 to 17 months, and .2% from 18 to 23 months. The declining rate of transmission could be an indication that the more susceptible infants are infected in early life, rather than that there is a lower risk of acquisition of infection later.
Mastitis has been shown to also increase the risk of transmission of HIV by breastfeeding. Virus load in breast milk was shown to be higher in transmitting mothers with mastitis. A recently published study conducted in Durban, South Africa, demonstrated higher rates of vertical transmission in infants who received mixed feedings, compared with exclusive breastfeeding. At day 1 of life, all infants had similar perinatal transmission rates of approximately 6%, which reflected in utero infection. By 3 months of age, 15% of exclusively breastfed infants were infected, versus 24% of infants who received breast milk and dietary supplementation and 19% of exclusively formula-fed infants. A possible explanation of these controversial data is that a higher rate of gastrointestinal infections prompted by the use of formula would facilitate transmission of the virus present in breast milk in the population receiving mixed feeds. A second study from Africa conducted in Nairobi compared transmission rates between formula-fed and breastfed infants. This study observed an excess transmission risk of 16.2% in the breastfed arm; 37% of breastfed infants versus 20% of formula-fed infants were HIV infected on long-term follow-up. Transmission via breast milk was highest in the first weeks of life, and by 6 months of age 75% of breast milk infections had already occurred. At 24 months of age mortality rates were comparable between both arms (24% for breastfed infants vs 20% for formula-fed).
In summary, breastfeeding is associated with a significant risk of HIV transmission, and limits the potential of short-course antiretroviral regimens to minimize HIV transmission rates in the developing world (see below). Creative strategies for reduction of breast milk transmission in the developing world, particularly in Africa, are a MUST if this epidemic is too be contained.
HIV perinatal transmission risk factors of particular concern in industrialized countries include maternal virus load at delivery, mode of delivery (higher rates with vaginal or nonelective Cesarean sections), prolonged rupture of amniotic membranes. and presence of chorioamnionitis. The placenta is recognized as a functional barrier, since without concurrent use of antiretrovirals it prevents at least 75% of perinatal HIV infections. There have been reports that the placenta is able to downregulate CXCR4 expression. Placental histologic pathology appears to facilitate HIV transmission from mother to infant.
Other risk factors include immunologic factors. Decreased CD4+ cell counts have long been reported to be associated with an increased likelihood of transmission. A recent study found that there is an increased risk of vertical transmission of HIV with higher concordance rates in class I HLA types between mother and child. The researchers hypothesize that the infant's immune cells are more likely to react against infected maternal cells that are genetically distinct and in this way circumvent infection. Another study has indicated that genetic polymorphisms in the regulatory region of CCR5 may also influence transmission.
The results of the widely publicized meta-analysis on mode of delivery and perinatal HIV transmission were reviewed. With data on more than 8000 patients, this study demonstrated a significant difference in perinatal transmission rates (19% to 10%) between vaginal and nonelective Cesarean sections versus elective C-sections in patients who did not receive antiretroviral therapy. With concurrent use of antiretroviral therapy (the full 076 regimen) differences in transmission rates between both groups were 7% versus 2%. Data from the 15 contributing studies were obtained at a time when HAART were not available. Hence, there is no information as to whether elective C-sections would provide any added benefit for women on HAART with undetectable HIV RNA levels.
In a randomized trial of mode of delivery, Semprini and colleagues also reported significantly lower rates of HIV transmission among women randomized to elective C-sections. Fever, bleeding, and anemia rates were not significantly different between both groups. An analysis of the WITS study data demonstrated a 19% total morbidity rate for elective C-sections, with an 11% infection rate. Vaginal deliveries had infection rates of 8% for instrumented deliveries and 4% for noninstrumented deliveries. The odds ratio (OR) for infection was 3.0 for elective C-sections, 6.0 for nonelective C-sections, and 4.7 for diabetes. Dr. Zorrilla commented that the population of women in this study changed over time (the study started in 1989) since initially study participants tended to be women with higher-risk behaviors more prone to medical complications.
If given the choice between elective C-sections and antiretroviral treatment, it is clear that the latter is a much better choice, since treatment prevents in utero infection and also provides postexposure prophylaxis to the infant. Women who might benefit from elective C-sections include those who were antiretroviral-naive at delivery, those who had persistent or rising HIV RNA titers, and those with concerns regarding adherence to the antiretroviral regimen during pregnancy. Unquestionably, for all women, postpartum morbidity is higher with C-sections. Yet the procedure is relatively well accepted by women living with HIV. The possibility of an elective C-section should be discussed with patients, and with balanced information provided by their physicians, they should ultimately be the ones to decide whether they want an elective procedure. Dr. Zorrilla recommended that postpartum morbidity data should not be the single factor to be considered in the decision-making process.
Since the results of PACTG 076 were first reported, many perinatal intervention trials have been and continue to be conducted around the world. The classic 076 trial showed the efficacy of the three-part ZDV-containing regimen (to the mother during gestation, intrapartum, and 6 weeks to the infant) in reducing vertical transmission rates from 25.5% to 8.3%. The recent Thailand trial demonstrated a 51% reduction of vertical transmission from 18.9% in the placebo group to 9.4% in the ZDV group when this drug was initiated at >/= 36 weeks of gestation and orally every 3 hours during labor. There was no breastfeeding in the study population and no drug was delivered to the infant for postexposure prophylaxis. A similar trial was conducted in Abidjan, but in a population of breastfeeding women. The efficacy of ZDV in reducing perinatal transmission in this trial was 37%. At 6 months of age, HIV infection rates were 18% in the ZDV group of infants and 27.5% in the placebo group. A recent follow-up presentation demonstrated that the efficacy of the short-course peripartum ZDV regimen in this breastfeeding population fell to 30% by 450 days of age (21% in the ZDV arm vs 31% in the placebo arm).
The Petra trial, also conducted in Africa (Uganda, Tanzania, and South Africa), evaluated the use of ZDV in combination with 3TC in a three-arm regimen in 1447 women. The first group of women initiated therapy at 36 weeks and received intrapartum drugs, with the infant receiving treatment for 1 week. In the second arm, treatment was started intrapartum and the infant received 1 week of combination therapy. The third arm received only intrapartum treatment, and a fourth group received placebo. Breastfeeding rates approached 100% in Uganda and Tanzania but were 60% in Durban and 25% in Johannesburg. The overall rate for the cohort was 69%. Transmission rates at 6 weeks were 7.8%, 10.2%, 15.7%, and 16.5% for first, second, third, and placebo arms, respectively. Thirty-two percent of deliveries were via C-section. A multivariate logistic regression analysis demonstrated that C-section had a protective effect in the first and second arms (OR of 0.48 and 0.60, respectively), but no protective effect in arm 3 and the placebo group. This analysis saw no effect of breastfeeding on perinatal transmission rates at 6 weeks, but the duration of breastfeeding at that point was potentially too short to influence the efficacy of perinatal antiretroviral regimens. CD4+ cell count was also found to be an independent predictor of vertical transmission of HIV.
The recently published HIVNET 012 trial conducted in Uganda compared the efficacy of short courses of zidovudine versus nevirapine (NVP) for prevention of perinatal transmission. Women were randomized to one dose of nevirapine at onset of labor and one dose of the drug to infants within 72 hours of birth, versus a loading dose of oral ZDV at onset of labor followed by ZDV every 3 hours until delivery and 1 week of drug twice daily to the infant. At 3 days of age transmission rates were equivalent for ZDV and NVP (10.4% and 8.2%) which reflects in utero transmission. At 6-8 weeks of age, rates were 21.3% and 11.9% for ZDV and NVP, respectively, and by 14-16 weeks, rates were 25.1% and 13.1%. The efficacy of NVP when compared with ZDV was 47% greater. This trial has generated potential controversy with regard to issues of implementation. Some argue that in populations where HIV seroprevalence is extremely high it will be cost-effective to treat all pregnant women without prior counseling and testing, although this view has been subject to much debate.
It is clear from these studies and others that antiretroviral therapy can reduce rates of perinatal HIV transmission if instituted within 48 hours of birth. The postexposure prophylaxis of the infant was critical to the success of nevirapine in the HIVNET trial. Wade and collaborators also demonstrated the importance of initiating therapy with ZDV within 48 hours of life in order to decrease perinatal HIV transmission rates. In this analysis, women who received full 076 compatible regimens had transmission rates of 6%, but transmission rates were 10% if treatment was started with labor and continued in the infant, and 9% if given only to the infant within the first 2 days. After that period transmission rates were 18.4%, statistically comparable to no treatment at all (26.6%).
At the end of the session it was evident that so much progress has been achieved in the prevention of HIV mother-to-child transmission, yet so much still remains to be achieved. Progress is slowly being transformed into practice.
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