Mechanisms and Timing of Perinatal Transmission
Sophie Le Cœur, MD, PhD
Institut National d'Etudes Démographiques, Paris, France; NT-PHPT, Chiang Mai, Thailand
Over the past ten years, many studies have been conducted to assess the risk of perinatal transmission, its timing and the mechanisms. The ACTG 076 trial, aside from its results on prevention of perinatal transmission, also brought many insights to these issues. It is now known that perinatal transmission can occur in utero, at delivery, or after delivery through breastfeeding. In women who do not breastfeed, up to 80% of HIV transmission may occur during late pregnancy or at delivery.
Factors that affect the risk of transmission relate to the mother, the virus itself, the placenta, the fetus, the labor and delivery process, the newborn, and breastfeeding. Among maternal factors, advanced disease stage during pregnancy and impaired immunity have been associated with increased risk of transmission in most studies. Micronutrient deficiencies, particularly of Vitamin A, have also been associated with an increased risk of transmission. All of these factors, however, may be surrogates for high maternal viral load, which might be the primary risk factor for transmission. The role played by viral phenotype and genotype is less clear. Transmission may not be random and some strains may be more easily transmitted than others. If we consider these maternal factors as leads for possible interventions, the first option is to decrease viral replication with antiretrovirals. We may also try to boost the maternal immune response to HIV by giving specific antibodies or using a vaccine. Finally, Vitamin A supplementation is being tested in Africa, specifically in Tanzania and Malawi, and could be very promising for developing countries since this supplementation could be implemented with all pregnant women, even without testing.
The role of the placenta is still unclear. In terms of intervention, the main options are to block viral replication with an antiretroviral and to protect the placental barrier by preventing and treating STDs and avoiding causes of chorioamnionitis, such as smoking or drug use.
Exposure of the skin and mucosal surfaces of the infant to maternal blood and secretions during delivery may be a major route of infection. Transmission may be a function of cervico-vaginal viral load and the local HIV specific immune response. In terms of intervention, decreasing viral load with antiretrovirals is likely to be efficacious by reducing viral load in the genital tract. Use of local/topical virucides has also been envisioned. However, a clinical trial of vaginal disinfection with chlorhexidine in Malawi showed that birth canal cleansing was not efficacious in preventing mother-to-child transmission of HIV.
Obstetrical factors have been shown to play a significant role. Transmission is increased in women who had membrane rupture several hours before delivery. On the contrary, Cesarean section is associated with decreased transmission. A clinical trial testing the protective effects of C-section is under way in Europe.
On the newborn side, possible interventions include pre/post-exposure prophylaxis with antiretrovirals and immunization. In ACTG 076, there was transmission from some mothers who had undetectable plasma viremia, and treatment with ZDV produced a median reduction of only 0.24 log in plasma RNA levels. Therefore, the minimal change in the RNA level can account for only a small part of the treatment effect, and one should consider alternative explanations for the success of the intervention. Antiretrovirals given to the mother can prevent HIV infection from establishing itself in the fetus realizing a sort of "pre/post-exposure prophylaxis" of HIV infection in the fetus.
Finally, when infants are breastfed, the risk of transmission may be related to the duration of breastfeeding, the time of exposure, the infectivity of the milk and the presence of HIV antibodies in the milk. The most effective and obvious means of preventing postnatal transmission is to avoid breastfeeding. However, there are many situations associated with poverty, lack of clean water, and poor sanitation where bottle feeding would pose a greater risk to the infant than HIV itself.
Almost none of these interventions discussed here is exclusive. On the contrary, it may be a combination of them that will bring perinatal transmission rates closer to zero.
Perinatal HIV-1 Transmission Rate in Thailand
Virat Sirisanthana, MD
Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
The Thai nationwide HIV seroprevalence sentinel surveillance revealed an HIV epidemic among female commercial workers in 1989, 16 months after the explosive spread among intravenous drug users (IDU). This epidemic among female commercial sex workers was followed by successive waves of transmission to their non-IDU clients, then to "low-risk" non-prostitute wives and girlfriends of these men in the general population.1 This was reflected tragically by the fact that the national median seroprevalence among prenatal clinic attendees increased from 0% in 1989 to 2.3% in June 1995.2 This rate decreased slightly to 1.8% in June 1996.3
The spread of HIV among the female population in the upper northern provinces came earlier than the epidemic in 1989, since the oldest symptomatic HIV-infected children found in Chiang Mai were born in 19874. The HIV seroprevalence of these pregnant women in the northern provinces, which include Chiang Mai, Chiang Rai, Phayao, Mae Hong Son, Lampang and Lamphun, were three to five times higher than the median value of the country. Although the maternal and pediatric epidemics are most severe in the upper north provinces, they have spread now to all areas of the country.
Studies from provinces in the Upper North of Thailand on the rate of vertical HIV transmission ranged from 37% to 45 %, as shown in Table 1.5-9 Children in these reports were born in the early years of the epidemic (1989 to 1992). Most of them were breastfed. The diagnosis of HIV infection was either persistence of HIV antibodies beyond 18 months of age or having AIDS indicative diseases as a cause of death. The more recent published report from Phayao10 and the preliminary results of the ongoing studies in Bangkok (68/281=24,%), 11 Songkla,12 Chiang Rai (21/99=22%),13 and Chiang Mai (12/52=23%),14 reveal lower transmission rates. These were children who were born mostly after 1994 and were not have breastfed. The criteria of the diagnosis of HIV infection were the same as the previous published reports.
Follow-Up in the Longitudinal Study
Thirty-six newborns who were born to HIV-infected mothers between January 1989 and July 1992 were followed in a prospective study at Chiang Mai University Hospital, Chiang Mai, Thailand.6 Fifteen children (41.7%; 95% Confidence Interval: 26% to 58%) were infected.
As of March 1997, two (aged 6.5 and 7.5) of these 15 infected children were asymptomatic, while the other 13 children were symptomatic. The nonspecific findings of HIV infection in this group were similar to those seen in European and African published studies, namely failure to thrive, thrush, generalized lymphadenopathy, hepatomegaly, splenomegaly, chronic fever, and chronic or recurrent diarrhea. Other clinical features also presented, namely lymphoid interstitial pnemonitis, HIV encephalopathy (brain atrophy with basal ganglion calcification), and recurrent common bacterial infection. Documented opportunistic infections included Pneumocystis carinii pneumonia (three episodes), cytomegalovirus pneumonia (one episode), E. coli septicemia (one episode), disseminated Penicillium marneffei infection (one episode), and varicella-zoster infection (one episode).
None of non-HIV-infected children died. Ten children in the HIV-infected group died. Causes of death were severe pneumonia in seven children (three had Pneumocystis carinii pneumonia, one had cytomegalovirus pneumonia, and three had no etiologic diagnosis), disseminated Penicillium marneffei infection in one child, chronic fever in one child, and severe encephalopathy in one child. The age of those who died ranged from three to 60 months. Half of our patients died within two years. These patients received neither Pneumocystis carinii prophylaxis nor any antiretroviral agent.
Although the number of cases in this longitudinal study was small, the findings showed that the clinical manifestations of perinatally acquired HIV infection could roughly be divided into two groups, namely the "rapid progressor" group and "slow progressor" group. The rapid progressors were those who developed severe symptoms early in life (<18 months), namely opportunistic infection and/or severe encephalopathy. Most in this group died before the age of two years.
The slow progressors had a long asymptomatic phase (two to seven years). The clinical manifestations were mild, such as lymphoid interstitial pneumonitis, parotitis, and recurrent common bacterial infections. When they become older, they might develop opportunistic infections associated with a low CD4+ count.
With the report showing that the prevalence of HIV infections among northern Thai men had decreased from 10.4% to12.5% in 1991 and 1993 to 6.7% in 1995,15 and the national median seroprevalence among prenatal clinic attendees had decreased from 2.3% in June 1995 to 1.8% in June 1996, together with intervention during the antenatal, delivery and postnatal period (zidovudine administration and avoidance of breastfeeding), the number of new perinatally HIV-infected children may start to decline.
References
1. Weniger BG, Limpakarnjanarat K, Ungchusak K et al. Epidemiology of HIV infection and AIDS in Thailand. AIDS 1991; 5(suppl 2):S71-S85.
2. Ministry of Public Health, Division of Epidemiology. The 13th round of HIV sentinel serosurveillance, up to June 1995, Thailand (in Thai). Wkly Epidemiol Surv Rep (Thailand) 1995; 26(Suppl 13).
3. Thaineua V. The HIV/AIDS Epidemic in the North: Epidemiology and Public Health. Abstract presented at The Second International Symposium on Pediatric AIDS in Thailand, Chiang Mai, Thailand, March 24-26, 1997.
4. Sirisanthana V. Demographic and clinical characteristic of symptomatic vertical HIV-infected children at Chiang Mai University Hospital. J Infect Dis Antimicrob Agents 1996; 13:89-93.
5. Laouthaiwatana S. Vertical transmission of HIV infection and measures to decrease the risk of mother to child transmission (in Thai). The Bulletin of Lampang Hospital 1995; 16:151-58.
6. Sirisanthana V, Hemmadhun D. Maternal-infant human immunodeficiency virus transmission in Chiang Mai (in Thai). Thai Journal of Pediatrics 1994; 33:193-200.
7. Aou P, Rattanasirisap P, Harnsuthivejkul R, Puapunwatana S, Nettkul R. Study of incidence of HIV infection in children with HIV-positive mothers at Chiang Rai Provincial Hospital (in Thai). Thai Journal of Pediatrics 1993; 32:169-73.
8. Gulgolkarn V. Prospective study of infants born to HIV-seropositive women in Lampang Hospital (in Thai). The Bulletin of Lampang Hospital 1994; 15:1-13.
9. Sriminipurn U. Maternal-infant human immunodeficiency virus transmission in Phayao (in Thai). Buddhachinaraj Medical Journal 1994; 11:78-84.
10. Sriminipurn S. Maternal-infant human immunodeficiency virus transmission and breastfeeding in Phayao Hospital (in Thai). Buddhachinaraj Medical Journal 1996; 13:41-47.
11. Shaffer N. Update on the Bangkok collaborative HIV perinatal short-course ZDV intervention trial. Abstract presented at The Second International Symposium on Pediatric AIDS in Thailand, Chiang Mai, Thailand, March 24 to 26, 1997.
12. Dr. Bunyarat. Had Yai Hospital, Songkla. Personal communication.
13. Trairattanapa K et al. Perinatal HIV transmission rate at Chiang Rai Hospital. Personal communication.
14. Rangsiyanond P. Personal communication.
15. Nelson KE et al. Changes in sexual behavior and a decline in HIV infection among young men in Thailand. NEJM 1996; 335:297-303.
Perinatal HIV Infection: Present Strategies for Prevention
Kenneth McIntosh, MD
Children's Hospital, Boston, USA
The present strategies for prevention of the vertical transmission of HIV from mother to infant lie in three broad areas: obstetrical approaches, immunologic approaches, and antiretrovirals.
Obstetrical approaches to prevention are of considerable importance. It is likely, although not rigorously proven, that the minimization of skin and mucosal breaks will reduce the possibility of transcutaneous infection of the baby during birth. It has been shown now in several studies that the period of ruptured membranes should be kept as short as possible. In some instances, this is best accomplished by either elective or semi-elective Cesarean section, and it seems likely that this is the mechanism by which C-section reduces the rate of transmission. Systematic birth canal cleansing has been attempted without success, although it seems important to explore all avenues of approach in this potentially cost-effective strategy.
Immunologic approaches are based on the hepatitis B virus concept, assuming that most transmission occurs at or around the time of delivery and that a combination of passive and active immunization will be effective in blocking this transmission. Vaccines would have the great advantage of being affordable and possibly offering prevention throughout the period of breastfeeding. At this stage, however, vaccines are still a concept rather than a reality. It may be that when a suitable vaccine does appear, its efficacy will be first demonstrated in the vertical transmission setting, taking advantage of the attack rate of about 10% under controlled circumstances. Passive protection using HIVIG is presently under investigation (ACTG 185, other), and protocols to test neutralizing monoclonal antibodies are in development.
At the present time, the most promising avenue of approach is through the use of antiretroviral drugs. There are three key questions here: (1) How do they work? (2) When should they be given? (3) Which ones are best?
Studies which were part of ACTG 076 showed that some mechanism other than reduction in viral load was the dominant mechanism of action of zidovudine (ZDV) in the prevention of vertical transmission. It seems highly likely that this mechanism was true intracellular prophylaxis: zidovudine entered the fetus or the infant's HIV-susceptible cells and was transformed into the active form (i.e., the triphosphate), so that when the virus entered the cell it was unable to initiate infection. Reduction of viral load, which recently has gained much popularity, was clearly not the major mechanism of action of ZDV in ACTG 076. It is still an attractive strategy, but has yet to be proven effective in this setting.
The best drugs for prophylaxis would cross the placental barrier and be present in the fetal/infant susceptible cells in high concentration and in an active form, preventing the virus from establishing an infection in the first place. Some reverse transcriptase inhibitors satisfy these requirements. The best drugs for reduction in viral load would act solely on the mother and would be well tolerated by pregnant women. Several protease inhibitors are candidates.
The question of when antiretrovirals should be given is also critical. The enormous success of ACTG 076 raises the question of whether ZDV prevented every preventable transmission during the period it was administered, and the most effective way to improve on ZDV would be to administer drug throughout pregnancy. If more than two-thirds (or all?) of infections are transmitted "around delivery" then we should concentrate on the 3rd trimester and maximize the effect at that time. With a drug like ZDV, it is possible that shorter administration is better, to minimize the production of resistant virus.
Choice of drugs is going to depend on a number of factors, including resistance patterns in the prevalent virus strains, safety, maternal compliance, and cost. In the United States, it turns out that there are difficult issues related to the balance between maternal needs and the needs of the infant.
