Selected Highlights on HIV Transmission, Women & Children: HAART reduces perinatal transmission

Great strides have been made in the area of perinatal HIV transmission in the developed world, but these accomplishments are moving much more slowly into developing countries where resources are limited. In a lecture at Retrovirus Dr. Mary Fowler from the Centers for Disease Control and Prevention (CDC) presented a hopeful overview of the most recent statistics regarding perinatal HIV transmission in the United States and Europe. Pediatric AIDS Clinical Trials Group (PACTG) studies 247 and 367 recently reported transmission rates of only 2.7% and 3%. In PACTG 316, a randomized trial of nevirapine vs placebo in addition to other antiretrovirals at the time of labor and delivery (abstract LB7) the observed transmission rate was 1.1%. Interestingly, this study also found adding NVP at labor & delivery did not improve transmission rates which could be cause the rates were so low already. Medical practices have changed, and today, as reflected in PACTG 367, 78% of women use multiple antiretrovirals during pregnancy, including 42% using protease inhibitors. Of course, we know the situation is much more discouraging in developing countries, particularly in Africa.

Reducing viral load in pregnant mother reduces transmission to newborn

In a lecture delivered by Robert Janssen from the CDC he talked about how the reduction in perinatally acquired HIV is predominantly due to reduction in viral load, although some studies suggest c-section contributes (use of & need for c-section is controversial), as well as other factors. He showed data from Bangkok demonstrating transmission from to neonate is directly related to maternal viral load, as a number of other studies have shown. In the Bangkok study when the maternal viral load at delivery was:

<5600 copies/ml transmission was about 4%
    5600-13,000 - 12%
 13,000-33,800 - 25%
 33,800-93,000 - 30%
          >93,000 - 40%

In abstract 517 at this conference, Ioannidis and colleagues found (7 European and U.S. prospective studies of maternal infant-transmission) only 44 cases of vertical HIV-1 transmission among 1,202 women with HIV-1 RNA <1000 copies/ml at or close to delivery. The transmission rate was only 8/834 (1.0%) for mothers receiving antiretroviral treatment during pregnancy and/or delivery vs. 36/ 368 (9.8%) for untreated mothers. In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment, cesarean section, greater birth weight and higher CD4 cell count.

Janssen reported that from 1992- end of 99 perinatally acquired HIV in the US from 33 reporting sites declined by about 81% and AZT use during pregnancy increased to around 90%.

Can Reducing viral load reduce sexual transmission?

Janssen mentioned two studies in Africa in which viral load was higher in cases of transmission between heterosexual couples than in couples where transmission did not occur (Quinn et al Uganda NEJM 2000, 4.9 vs 4.6 log, p=.01; and Fideli et al 7th CROI, 5.04 vs 4,56 log, p<0.001). This suggests that reducing viral load can reduce the risk of transmission between partners. Several studies have demonstrated a correlation between plasma viral load & genital fluid viral load. And HAART reduces viral load in both compartments. However, even when seminal viral load is undetectable cell associated viral load is often present. On the other hand, animal data suggests transmission by cell associated virus is much more difficult than by cell free virus. So, the data suggests HAART may reduce the risk of transmission during exposure by sex or drug use, but the evidence remains indirect. Even if viral load is not detectable HIV DNA is present in semen cell and its crucial to bear in mind transmission is possible. This means, even WHEN VIRAL LOAD IS UNDETECTABLE, VIRUS IS PRESENT & A PERSON CAN TRANSMIT HIV.

Janssen said that overall knowledge of one's HIV status can be an effective public health measure because it helps to promote behavior change and it provides the opportunity for treatment, which may help reduce transmission rates in addition to promoting health and well-being.

CDC SAFE Program to Increase HIV Status Testing

The CDC is initiating the SAFE program whose goals include increasing from 70% to 95% the number of people who know their HIV status. This program will encourage people to seek testing through a new media campaign called "Know Now". The campaign will target neighborhoods with high HIV incidence. The campaign will target using radio and neighborhood activities such as community based organizations. The campaign will begin later this year as a pilot program in 5 cities. The program will also try to increase the availability of testing. Through the use of HIV rapid tests (saliva or quick stick), which are not yet available in the USA, they hope to increase testing availability by outreach at community based organizations, emergency rooms, and correctional facilities. Janssen said the next step for SAFE is to increase entry for HIV+ individuals into health care & preventive services. He presented some interesting data from 1998. For people diagnosed with HIV & AIDS at the same time, 88% got their first CD4 count test within 3 months. But for people who were diagnosed with only HIV, 57% did not get a CD4 count test, and 33% got one within 3 months. This suggests there is a need for better linkages from free-standing testing sites to care facilities. The is program hopes to help encourage these improved linkages. Janssen showed data from '98-'99 on 17,000 patients who were eligible to receive HAART and <70% received HAART. The gap between ethnic groups narrowed over time from '97 to '99. Rates for STDs (including syphilis) are increasing in large cities among HIV+ men who have sex with men showing unprotected sex is occurring.

Mitochondrial Toxicity in Children Born to Mothers Using ART

Although HAART greatly reduces perinatal transmission, there are some related concerns. In abstract 625B JF Delfraissy and a research group from France reported on symptoms of mitochondrial dysfunction in children born to HIV-infected mothers. They are conducting an ongoing "exhaustive" search for symptoms consistent with mitochondrial dysfunction in the French cohort (n=4083). The are looking at uninfected children over 6 months of age with & without perinatal exposure to ART. She qualified the findings by saying the diversity of symptoms & difficulty in confirming or ruling out a mitochondrial origin (whether the problem was really due to mitochondrial dysfunction) makes this work difficult. She reported finding that symptoms consistent with persistent mitochondrial dysfunction are significantly more frequent in the children exposed to ART. Of the 2200 children exposed to ART from 1986-1999, 101 files were selected and 9 had mild suspicion of mitochondriopathy, 6 had strong suspicion of mitochdriopathy, and 10 had confirmed mitochondriopathy. In the group of 1874 children who were not exposed to ART 23 files were selected and 0 cases were found.

Ruth Dickover from UCLA presented a talk on her interesting study assessing env gene diversity in 23 perinatally infected infants with well defined rates of progression and followed from birth between 1989 and 1995. She found HIV-1 env diversity in early infancy correlates with disease progression in these children. In this study, children followed from birth with rapid progression demonstrated low quasispecies diversity which persisted over time. This coincided with high viral loads and dramatic declines in T-cells. Conversely, infants with slow progression exhibited rapid development of quasispecies diversity over time. Children who were treated with ART showed a change in quasispecies diversity patterns, which occurred several months following initiation of therapy.

HIV+ Children Appear to Progress More Quickly if Mother's Viral Load is High & CD4 is Low

Elaine Abrams from Harlem Hospital reported on a multi-center prospective study of HIV perinatal transmission & pediatric disease progression in 4 urban centers from 1985-1999. She describes the affect of the mother's health status & demographics on the newborn's probability of AIDS progression & death. Of 354 HIV-infected mother-infant pairs 144 pairs were available for the viral load analysis because they had maternal viral load test results available close to delivery.
--Time to death was significantly shorter for infants born to women with high viral loads at delivery: at 24 months, 48% of children died born to women with VL >100,000 vs 8% with VL <25,000 (p<0.006)
For the CD4 analysis, 262 infant-mother pairs were available and there was a shorter time to AIDS progression & death if the mother's CD4 count was <200 at delivery. Of course, the use of ART during pregnancy can reduce viral load & increase CD4s.

Gender Differences in CD4 & Viral Load in Newborns

It's been reported that in early disease women's viral load can be 50% lower than in men. Jane Pitt and colleagues from Columbia University in NYC reported in differences they found in children. She reported that menstrual cycle studies suggest that the differences in adults could be related to hormones. She studied 878 female (92 HIV-infected) and 892 male (94 HIV-infected) children born to HIV-infected women. She found relative & absolute CD4 counts were significantly higher in females compared to males in both infected & uninfected. Viral load was lower but not significantly at all post-birth time points measured through the first 18 months in infected females compared to males (time averaged midpoint difference was 0.4 log). But she reported there was no difference in clinical progression. She said in her abstract that since there is a more similar hormonal environment in female & male children compared to adults, "genetically programmed non-hormonal mechanisms should be considered in seeking explanations for gender difference". As with adults, I think we need much longer follow-up to see if there are differences in clinical progression and pathogenesis studies should be conducted to better understand these differences.