Brooks Jackson, M.D.
The Hopkins HIV Report - May 1999

In March 1999 five important studies were published regarding the use of antiretrovirals to reduce mother to infant transmission. The results of the ACTG 076 study in which HIV-infected U.S. and French pregnant women with baseline CD4 cell counts over 200 cells/mm³ (median 550/mm³) received 500 mg daily of AZT starting between 14-34 weeks gestation with intravenous AZT in delivery and 8 mg/kg/day orally to the infant for 6 weeks were published in 1994. This randomized, double-blind, placebo-controlled trial demonstrated a significant reduction in HIV transmission at 18 months from 25.5% (CI: 18.4%-32.5%) to 8.3% (CI: 3.9%-12.8%), or a 67.5% reduction.

Building on that success, Pediatric ACTG 185 was carried out as a two-arm, randomized, double-blind, placebo-controlled trial in which one arm of pregnant women received the ACTG 076 regimen plus a monthly dose of 200 mg/kg of intravenous immune globulin (IVIG), and the other arm received the ACTG 076 AZT regimen plus a monthly 200 mg/kg dose of intravenous HIV immune globulin (HIVIG) preparation starting at 20-30 weeks gestation. The infants of the women received the same randomized study treatment as the mother, with infants receiving intravenous HIVIG or IVIG (200 mg/kg) within 12 hr of birth [Stiehm et al. JID 1999;179:567]. This study demonstrated that the transmission rate in the AZT/HIVIG arm (4.1%) was not significantly different in the AZT/IVIG arm (6%, p=0.36). Interestingly, only one of 9 (11%) infected infants in the HIVIG group had a positive culture at birth compared with 5 of 13 (38%) in the IVIG group, suggesting that if HIVIG had a biologic effect it was primarily on reducing in utero, but not intrapartum, transmission.

Despite the fact that all women in PACTG 185 had CD4 cells counts less than 500 cells/mm³, and 22% had CD4 cell counts less than 200/mm³ at baseline, the transmission rates of both arms were unexpectedly lower than the 8.3% transmission rate in the AZT arm of ACTG 076, with a 5.0% overall transmission rate. The results of PACTG 185 were somewhat disappointing as it was hoped that the addition of HIVIG would further reduce HIV transmission, just as hepatitis B immune globulin is able to reduce the rate of hepatitis B infection in newborns of HBsAg positive mothers. However, the study did find that in women with CD4 counts less than 200 cells/mm³ or who had started AZT during pregnancy, the transmission rate in the HIVIG/AZT arm was 3.2% vs. 10.3% in the IVIG/AZT arm (p=0.06). Unfortunately, the unexpectedly low overall transmission rate limited the power of PACTG 185 to detect a treatment effect, and it is, therefore, not possible to determine whether passive immunization with HIVIG lowers perinatal transmission. In addition, it cannot be determined whether IVIG, which served as a control in the trial, might have had a nonspecific effect on lowering HIV transmission.

Three phase III, randomized, placebo-controlled trials using short course AZT regimens in Thailand and the Ivory Coast were reported in the March 6th issue of the Lancet [Shaffer et. al., Lancet 1999;353:773; Wiktor et. al., Lancet 1999;353:781; Dabis et. al., Lancet 1999; 786]. The trial in Thailand, sponsored by the CDC and the Thai government, involved randomizing HIV infected pregnant women to either placebo or 300 mg of AZT taken orally twice a day starting at 36 weeks gestation until labor, when 300 mg AZT was taken orally every three hours until delivery. The mothers did not breastfeed in this study, and no AZT was given to the infants. The estimated transmission risk was 9.4% at two and six months of age vs. 18.9% (CI: 13.2%-24.2%) in the placebo arm, or a 51% reduction in transmission (p=0.006). The regimen was safe and well tolerated. Women receiving AZT had a 0.56 log decrease in plasma HIV RNA, which explained approximately 80% of the treatment effect, compared with the 0.24 log decrease seen in ACTG 076, which explained only 11% of the treatment effect. Such a difference might be due to different populations studied, different HIV subtypes, the duration of drug regimen, or sample processing.

A similar trial in a breastfeeding population in the Ivory Coast was conducted by the CDC and the Ivory Coast government using the same regimen as in the Thailand trial. The estimated transmission risks in the placebo and AZT groups were 21.7% and 12.2% at 4 weeks of age (p=0.05), and 24.9% and 15.7% (p=0.07) at 3 months of age. Efficacy was 44% at age 4 weeks and 37% at 3 months. The regimen was safe and well tolerated. The French and Ivory Coast government conducted a similar trial using a nearly identical regimen and found that the HIV transmission risk at 6 months was 18.0% in the AZT group vs. 27.5% in the placebo group, with a relative efficacy of 0.38 (p=0.027).

The four-arm PERTA study, conducted by UNAIDS in three African countries, was presented by Joseph Saba at the 6^th Conference on Retroviruses and Opportunistic Infections in Chicago in February [Abstract S7]. This trial randomized mother infant pairs to four treatments, including a placebo, and found the following results:

Thus, very short course combination therapy to the mother (beginning in labor) with treatment of the child for the first week of life was very effective, similar to a longer course of treatment for the mother with postpartum treatment to the child. These results suggest that treatment of infants during the first week of life is probably very important, particularly in a setting where breastfeeding is routine. It should be noted that as a result of ongoing breastfeeding the risk of transmission may increase as follow up continues for 18 months.

These successful trials in Thailand and Africa provide hope that the risk of HIV transmission from mother to infant can be reduced in developing countries where the ACTG 076 regimen is neither affordable nor feasible. Considering that approximately 1600 HIV infected infants are born every day in the developing world compared with less than one per day in the United States, these studies, though demonstrating slightly less efficacy, represent a major advancement. Unfortunately, the AZT regimen or even the short course AZT/3TC regimens are still likely to cost approximately $50, even with GlaxoWellcome's reduction in the price of AZT and the anticipated price reduction of 3TC. It is unlikely that these regimens will be made widely available to HIV infected women in the poorest countries. One antiretroviral drug regimen that offers considerable promise is a single 200 mg dose of nevirapine to the mother at onset of labor with or without a single dose of nevirapine (2 mg/kg) to the newborn within 72 hr of birth. The Johns Hopkins-Makerere University Collaboration recently reported the results of the Phase I/II HIVNET 006 trial conducted in Uganda using this regimen [Musoke et. al., AIDS 1999:13:479-486]. The regimens were well tolerated by mothers and infants. The half-life of nevirapine in the mothers and infants was 61 hr and 54 hr, respectively, with maternal and infant serum nevirapine concentration greater than 10 times the IC50 of nevirapine 7 days after the single maternal dose in all mothers and infants who delivered more than one hour after receiving drug. Infants who received a single dose at 72 hr of life had significantly higher nevirapine levels at day 7 of life compared with those whose mothers only received nevirapine in labor (383 ng/ml vs. 220 ng/ml, respectively). The maternal plasma HIV RNA levels declined by at least 1.3 log in all mothers by day 7 after a single dose of nevirapine, which is greater than the 0.56 log decrease seen with AZT in the Thai trial. The median breast milk nevirapine levelwas 103 ng /ml, or roughly 10 times the IC50 7 days after the single dose in labor. Such a regimen, if effective, would likely cost less than $4.00 per mother-infant pair and would be widely applicable. The HIVNET 012 trial is now underway comparing this nevirapine regimen to AZT given at onset of labor only to the mother and daily dosing of AZT to the infant during the first week of life. The results of this trial should be available in the summer of 1999.

In conclusion, antiretroviral prophylaxis of mother-infant pairs is extremely effective. With many women on HAART therapy during pregnancy, it is likely that there will probably be less than 200 HIV infected infants born in the United States this year. However, in developing countries, despite recent progress, there is still a great need for shorter, inexpensive, effective regimens.

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©1999. The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Sharon McAvinue, Managing Editor. Website: Johns Hopkins AIDS Service.

The original of this article can be found at http://www.hopkins-aids.edu/publications/report/may99_2.html