By Liz Highleyman

One of the first major antiretroviral drug success stories was the use of zidovudine (AZT; Retrovir) monotherapy to dramatically lower the rate of mother-to-child HIV transmission during pregnancy and delivery.

In high-income countries such as the U.S., HIV positive pregnant women are urged to use a complete ART regimen to achieve full viral load suppression, rather than single or dual drugs, and are advised not to breast-feed their infants. The latest treatment guidelines, in fact, recommend that all pregnant women with HIV should receive combination ART.

In resource-limited countries such as those in sub-Saharan Africa -- where HIV prevalence among pregnant women may reach as high as 50% -- expectant mothers are still often treated with the ACTG 076 regimen of zidovudine monotherapy during pregnancy and labor, and for the infant for 6 months after birth. Women who do not receive prenatal care prior to delivery may be given a single dose of nevirapine (Viramune). Combination ART is often reserved for people with a CD4 cell count below 200 cells/mm3 -- as opposed to the U.S. threshold of 350 cells/mm3 -- or clinical symptoms of immune suppression.

Furthermore, due to competing risks related to unclean water and inadequate nutrition, the World Health Organization (WHO) advises HIV positive mothers to breast-feed exclusively for 6 months if replacement feeding is not "acceptable, feasible, affordable, sustainable, and safe."

But studies increasingly show -- and advocates increasingly demand -- that pregnant and breast-feeding women in low-income countries should receive the same standard of care as those in high-income areas: full combination ART using effective and well-tolerated drugs. Several studies presented in Cape Town support such a paradigm shift.

Mma Bana Study

The Mma Bana study included 560 HIV positive pregnant women in Botswana with a CD4 cell count above 200 cells/mm3 (median about 400 cells/mm3). Starting between 26 and 34 weeks of gestation and continuing through 6 months after delivery, the women were randomly assigned to receive either 3 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) -- zidovudine, lamivudine, and abacavir in the Trizivir fixed-dose coformulation -- or else the protease inhibitor lopinavir/ritonavir (Kaletra) plus zidovudine/lamivudine in the Combivir coformulation.

In addition, another 170 women with a CD4 cell count < 200 cells/mm3 (median about 150 cells/mm3) started zidovudine/lamivudine plus nevirapine, which is not recommended for women with CD4 counts > 250 cells/mm3.

All the women also received extra zidovudine during labor. All infants received a single dose of nevirapine after delivery and zidovudine for 4 weeks.

At the time of delivery, 96% of women taking Trizivir, 93% of those taking lopinavir/ritonavir, and 94% of those taking nevirapine had HIV RNA < 400 copies/mL. Furthermore, similar percentages also maintained virological suppression during breastfeeding (92%, 93%, and 95%, respectively).

Rates of mother-to-child HIV transmission were very low in women taking all 3 regimens: 1.8% with Trizivir, 0.4% with lopinavir/ritonavir, and 0.6% with nevirapine, differences that did not reach statistical significance. Most cases of transmission occurred during pregnancy and from women with higher baseline viral loads and shorter durations of ART prior to delivery. However, 2 cases occurred during breast-feeding in the Trizivir arm, including 1 from a woman with HIV RNA < 50 copies/mL.

Birth outcomes were good overall. However, women taking lopinavir/ritonavir were significantly more like to give birth prematurely (25%, compared with 15% taking Trizivir and 10% taking nevirapine) and women on nevirapine were more likely to have still-births (7%, compared with 3% in the Trizivir group and 2% in the lopinavir/ritonavir group). Infant mortality was 2%-4% across the 3 arms. 13% of infants born to women in the Trizivir group, 17% in the lopinavir/ritonavir group, and 15% in the nevirapine group had a low birth weight.

This study -- with the lowest rate of mother-to-child transmission seen to date in a randomized study of HIV treatment during pregnancy and breast-feeding in a resource-limited setting -- demonstrated that extended combination ART is highly effective in preventing vertical transmission.

Beth Israel Deaconess Medical Center, Harvard University, Boston, MA; Harvard School of Public Health, Boston, MA; Botswana-Harvard AIDS Institute, Gaborone, Botswana; Brigham and Women's Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA; National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, MD; GlaxoSmithKline, Greenford, UK; Abbott Virology, Miami, FL; Botswana Ministry of Health, Gaborone, Botswana.

BAN Study

The BAN (Breastfeeding, Antiretroviral and Nutrition) study included 2367 HIV positive mothers in Malawi with a CD4 count > 250 cells/mm3. All women received single-dose nevirapine during labor followed by zidovudine/lamivudine for 1 week. The overall rate of mother-to-child HIV transmission was 5%.

A week after birth, mother-infant pairs were randomly allocated into 3 groups receiving either maternal therapy with zidovudine/lamivudine plus lopinavir/ritonavir (no infant therapy), or infant treatment with nevirapine monotherapy for 28 weeks (no maternal therapy), or no further ART for either mother or baby (enrollment in the control arm was halted early). All women also received nutritional supplements.

All mothers breast-fed for 6 months than rapidly weaned their babies within 1 month using a special weaning food provided by the study.

By the end of 28 weeks, the rate of mother-to-child HIV transmission was 1.8% in the infant nevirapine arm and 3.0% in the maternal ART arm, both significantly lower that the 6.4% rate in the untreated arm. Similarly, the risk of a combined endpoint of HIV transmission or infant death was 2.9% in the infant nevirapine arm, 4.7% in the maternal ART arm, and 7.6% in the untreated arm.

Severe side effects were uncommon, with no differences in severe (grade 3 or 4) toxicities across the 3 arms, including adverse events related to nevirapine hypersensitivity reactions.

UNC Project, Lilongwe, Malawi; University of North Carolina, Chapel Hill, NC; U.S. Centers for Disease Control and Prevention, Division of Reproductive Health, Atlanta, GA; Principia International, Chapel Hill, NC; Kamuzu Central Hospital, Lilongwe, Malawi.

Kesho Bora Study

Conducted in Kenya, South Africa, and Burkina Faso, the Kesho Bora study included 824 HIV positive pregnant women with a CD4 count between 200 and 500 cells/mm3.

Participants were randomly assigned to receive either extended combination ART consisting of zidovudine/lamivudine plus lopinavir/ritonavir from the third trimester through 6 months after delivery (at which point they were advised to stop breast-feeding), or else short-course treatment with zidovudine monotherapy from week 28-36 of gestation until 1 week after delivery, plus single-dose nevirapine at the time of delivery. All infants received single-dose nevirapine after delivery and zidovudine for 1 week.

Women were given the option of receiving free formula or exclusively breast-feeding for 6 months with rapid weaning; about 77% of women in both arms breast-fed at some point -- for an average duration of 21 weeks -- and about 45% breast-fed exclusively for the first 3 months.

At all time points, HIV transmission rates were lower in the combination ART arm compared with the short-course therapy arm: 1.8% vs 2.2% at birth, 3.3% vs 4.8% at 6 weeks, 4.9% vs 8.5% at 6 months, and 5.5% vs 9.5% at 1 year. Overall, this accounted for a 42% risk reduction in the combination therapy arm.

Looking at infant mortality, 6.3% of babies born to mothers in the combination arm died during the first year, compared with 10.0% of infants in the short-course therapy arm, a 37% risk reduction (though it did not reach statistical significance).

Further analysis revealed that the reduced risk of transmission with combination ART was only statistically significant among mothers with a baseline CD4 count of 200-350 cells/mm3, not those with 350-500 cells/mm3.

The researchers emphasized that since the greatest benefit was seen in women with 200-350 cells/mm3, this group should be a priority for expanded treatment efforts.

World Health Organization, Department of Reproductive Health and Research, Geneva, Switzerland.

DREAM Study

A retrospective analysis of the DREAM (Drug Resource Enhancement against AIDS and Malnutrition) program also showed that extended maternal ART continuing during breast-feeding reduced the risk of mother-to-child HIV transmission.

DREAM offers HIV care and treatment for some 75,000 adults and children in 10 sub-Saharan African countries. Pregnant women in the program with a CD4 cell count below 350 cells/mm3 receive nevirapine plus either zidovudine/lamivudine or stavudine/lamivudine starting at week 14 of gestation and continuing indefinitely. Women with higher CD4 cell counts receive the same regimen from week 25 of gestation until the end of weaning (closer to recommendations in high-income countries, except for breast-feeding).

In an analysis of nearly 3000 infants with available test results at 1 month after birth, the transmission rate was 0.7%. As transmissions due to breast-feeding added up, the cumulative rate rose to between 1.4% and 1.9% at 6 months. The cumulative 6-month infant mortality rate was 2.1% (nearly 8% of infants were lost to follow-up).

Not surprisingly, the researchers found that the transmission rate was significantly lower for women who received at least 1 dose of ART before delivery compared with those first treated during delivery (0.9% vs 5.5%).

In contrast with the Kesho Bora study, the reduction in transmission associated with ART was seen at all CD4 counts, though overall rates were lower at higher maternal CD4 levels. Among women with < 350 cells/mm3, the combined 6-month rates of HIV transmission or infant death were 3.1% with > 30 days of maternal ART vs 8.8% with < 30 days. For women with 350 cells/mm3, the corresponding rates were 1.8% vs 2.1%, respectively.

Based on these findings, the researchers concluded, "The benefits of HAART during pregnancy for HIV-1 [prevention of mother-to-child transmission] are extensive to women with higher CD4 counts. Best results occur with longer duration of treatment."

The DREAM team also reported that other pregnancy outcomes were improved among mothers who took combination ART for more than 30 days compared with those treated for a shorter period or not at all. Maternal mortality rates were 0.7% vs 7.4% in the extensively treated and minimally treated groups, and spontaneous abortion/still-birth rates were 4.3% vs 25.7%, respectively.

The researchers concluded that "HAART was strongly associated with improved pregnancy outcomes including reduction in prematurity, regardless of CD4 strata.

Community of Sant'Egidio, DREAM program, Rome, Italy; LUMSA University, Rome, Italy; University of Tor Vergata, Public Health, Rome, Italy; DREAM Program, Community of S. Egidio, Blantyre, Malawi; DREAM Program, Community of S. Egidio, Maputo, Mozambique; UCLA, Pediatrics, Los Angeles, CA; DREAM Program, Community of S. Egidio, Lilongwe, Malawi; DREAM Program, Community of S. Egidio, Balaka, Malawi; DREAM Program, Community of S. Egidio, Rome, Italy.

WHO Guidelines

Given the growing body of data supporting extended duration combination ART for women during pregnancy and for both mothers and infants during breast-feeding, WHO is now reviewing its 2006 recommendations, which currently advise short-course therapy for prevention of mother-to-child transmission.

New guidelines are expected to be released by the end of the year, and many experts believe they are likely to recommend combination therapy using ore drugs and longer duration of treatment even in resource-limited settings, thereby benefiting the health of both HIV positive mothers and their children.

8/04/09

References

R Shapiro, M Hughes, A Ogwu, and others. A randomized trial comparing highly active antiretroviral therapy regimens for virologic efficacy and the prevention of mother-to-child transmission among breastfeeding women in Botswana (The Mma Bana Study). 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract WeLBB101.

C Chasela, M Hudgens, D Jamieson, and others. Both maternal HAART and daily infant nevirapine are effective in reducing HIV-1 transmission during breastfeeding in a randomized trial in Malawi: 28 week results of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract WeLBC103.

I de Vincenzi and others (Kesho Bora Study Group). Triple-antiretroviral prophylaxis during pregnancy and breastfeeding compared to short-ARV prophylaxis to prevent mother-to-child transmission of HIV-1: the Kesho Bora randomized controlled clinical trial in five sites in Burkina Faso, Kenya and South Africa. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract LBPeC01.

MC Marazzi, G Liotta, J Haswell, and others. Extended use of highly active antiretroviral therapy (HAART) during pregnancy in Southern Africa is highly protective in HIV-1 prevention of mother-to-child-transmission (PMTCT) also in women with higher CD4 cell counts. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract TuAC101.

MC Marazzi, L Palombi, K Nielsen-Saines, and others. Favorable pregnancy outcomes with reduction of abortion, stillbirth, and prematurity rates in a large cohort of HIV+ women in Southern Africa receiving highly active antiretroviral therapy (HAART) for prevention of mother-child transmission (PMTCT). Abstract TuAC102.

Other source
Reuters. WHO may change ARV guidelines for pregnant mothers. July 22, 2009.

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