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 HIV and Coverage of the
16th Conference on Retroviruses and
Opportunistic Infections (CROI 2009)

 February 8 - 11, 2009, Montreal, Canada

Is Tenofovir an Option for Prevention of Mother-to-child HIV transmission?

By Liz Highleyman

The use of antiretroviral therapy by HIV positive mothers during pregnancy and labor and babies for a brief period after birth can reduce the risk of mother-to-child HIV transmission to less than 2%. Zidovudine (AZT; Retrovir) was the drug first studied for this purpose, and single-dose nevirapine (Viramune) is widely used in resource-poor countries.

As reported at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, researchers are studying tenofovir (Viread, also in the Truvada and Atripla combination pills) as another option for preventing mother-to-child transmission. (Note: pregnant women should not use Atripla because it contains efavirenz, which has been linked to birth defects).

One of the most widely used HIV medications, tenofovir (oral, injected, and in a vaginal microbicide) has been studied for pre-exposure prophylaxis (PrEP) of HIV infection, with promising results in animals and in humans.
Tenofovir appears to reduce the risk of transmission via vaginal, rectal, and oral HIV exposure, so it makes sense that it also may be effective for perinatal transmission.

HTPN 057

Mark Mirochnick and colleagues with the HTPN 057 Protocol Team looked at the safety, tolerability, and pharmacokinetics (PK) of tenofovir administered to HIV-infected pregnant women during labor and to their infants during the first week of life.

This Phase 1 trial included 53 HIV positive pregnant women in Malawi (n = 41) and Brazil (n = 12) and their newborns. In Cohort 1, women received a single 600 mg dose of tenofovir at the onset of labor or 4 hours prior to Cesarean section. Delivery occurred a median 2.9 hours (range 0.3 to 14.6) after dosing. In Cohort 2, mothers did not take tenofovir, but infants received 3 doses of 4 mg/kg tenofovir as soon as possible after birth and at days 3 and 5.

Samples were collected for PK analysis before and after each dose. The PK target was to keep infant tenofovir concentrations above 50 ng/mL, the mean trough (lowest between doses) concentration in non-pregnant adults.

Amniotic fluid samples were collected from the 12 women who delivered by Cesarean section (4 scheduled, 8 emergency), and breast milk was collected from mothers who breast fed (as recommended in resource-limited settings).


Tenofovir was generally well tolerated, with no severe adverse events considered to be related to the study drug.

At the time of delivery, the median maternal tenofovir concentration was 122 ng/mL, ranging from undetectable to 527 ng/mL.

The median cord blood tenofovir concentration was 76 ng/mL (range undetectable to 191), with 66% reaching a level above the 50 ng/mL target.

The median amniotic fluid tenofovir concentration (measured in 5 women) was 259 ng/mL (range 142-725).

In Cohort 1, the median maternal area under the curve (AUC) tenofovir concentration was 4221 ng/mL.

The median maternal maximum tenofovir concentration (Cmax) was 448 ng/mL, and the median time to reach this level (Tmax) was 1 hour.

In Cohort 2, the infant AUC concentration was 4013 ng/mL at Day 0, 2365 ng/mL at Day 3, and 1631 ng/mL at Day 5.

The median infant Cmax levels were 200, 78, and 87 ng/mL, respectively, with a Tmax of 2 hours.

14% of infants had a trough tenofovir concentration above 50 ng/mL on Day 3, and 10% did so on Day 5.

Tenofovir was detectable in just 4 of 25 (16%) breast milk samples collected during 1st week of life, with a median concentration of 13 ng/mL (range 6-18).

Based on these findings, the researchers concluded, "Tenofovir exposure after dosing in labor was similar to that observed in non-pregnant adults.
"Tenofovir was concentrated in amniotic fluid," they continued. "One-third of cord blood concentrations were < 50 ng/ml. After infant dosing, tenofovir elimination was rapid and nearly all infants fell below 50 ng/ml before day 3 and 5 doses."

The investigators are currently evaluating larger maternal and infant tenofovir doses in an attempt to improve these measures.

Boston Univ School of Med, Boston, MA; Univ of Malawi College of Med, Blantyre, Malawi; Brotherhood of Santa Casa of Misericordia of Sao Paulo, Brazil; Federal Univ of Minas Gerais School of Med, Belo Horizonte, Brazil; Johns Hopkins Univ, Baltimore, MD; David Geffen School of Med, Univ of California, Los Angeles, CA; Statistical Ctr for HIV/AIDS Res and Prevention, Seattle, WA; NIAID, NIH, Bethesda, MD; Natl Inst of Child Health and Human Development, NIH, Bethesda, MD; Makerere Univ-Johns Hopkins Univ Res Collaboration, Kampala, Uganda.


Researchers with the PACTG/IMPAACT 394 Study Team already have some data using 900 mg tenofovir. Patricia Flynn and colleagues evaluated the pharmacokinetics, safety, and tolerability of a single dose of oral tenofovir administered alone and in combination with single-dose emtricitabine (Emtriva) in HIV-1-infected pregnant women and their infants.

At the 2006 CROI, the researchers reported data on the PK and safety of 600 mg oral tenofovir administered to mothers and babies. They observed no adverse events, but blood concentrations in pregnant women were lower than expected.

This year, they presented data on 900 mg tenofovir, both alone and in combination with 600 mg emtricitabine (the Truvada pill), given to 15 mothers at the onset of active labor or 4 hours prior to delivery by scheduled Cesarean section. All women were at 34 weeks or more of gestation. Their median HIV RNA level at study entry was 1.53 log10 copies/mL (range 0.95 to 3.17 log10). All women took complete HAART regimens that did not otherwise include tenofovir. The median time from tenofovir dosing to delivery was 7 hours (range 1.5 to 21).

The 16 live-born infants received 4 mg/kg tenofovir alone or in combination with 3 mg/kg emtricitabine, according to the same assignment as their mothers. They also received the standard-of-care ACTG 076 zidovudine regimen. The median time from birth to tenofovir dosing was 5.5 hours (range 1.8 to 11).

Maternal blood samples were obtained 7 times over 24 hours post-dosing, umbilical cord blood was sampled, and infant samples were collected 5 times over 36 hours post-dosing.


Tenofovir and tenofovir/emtricitabine were safe and well tolerated in all 15 mothers and 16 infants.

PK findings from the tenofovir and tenofovir/emtricitabine groups were similar, so results from the 2 groups were combined.

The maternal tenofovir concentration at delivery was 108.5 ng/mL (range 0 to 381.0).

The cord blood tenofovir concentration was 68.3 ng/mL (range 0 to 224.2), exceeding the target of 50 ng/mL in 10 of 15 tested infants (67%).

The median maternal AUC tenofovir concentration was 2519.4 ng/mL, but was quite variable (range 822.5 to 5676.8).

The median maternal Cmax was 456.2 ng/mL and the median Tmax was 2 hours (range 1 to 12 hours).

The median infant AUC concentration was 1840.7 ng/mL, also highly variable (range 882.6 to 7930.7)

The median infant tenofovir Cmax was 101.4 ng/mL, with a median Tmax of 4 hours (range 4 to 24).

The 9 women who delivered vaginally had lower AUC (38% less) and Cmax (62%) tenofovir concentrations compared with the 5 who had Cesarean sections, but these differences did not reach statistical significance.

Tenofovir Cmax increased by 83% using the 900 mg compared with the previous 600 mg dose, but AUC remained similar.

None of the infants were infected with HIV.

None of the mothers developed a new K65R resistance mutation by week 12.

"Tenofovir is safe and demonstrated an acceptable absorption profile," the investigators concluded. "Maternal tenofovir AUC and tenofovir placental transfer is sufficient to achieve cord blood concentrations with antiretroviral activity."

"Tenofovir exposures were lower in infants suggesting either altered absorption or more rapid clearance," they continued. "The appropriate dosing schedule in infants to maintain effective concentrations over the first days of life remains to be determined."

St Jude Children's Res Hosp, Memphis, TN; Boston Med Ctr, Boston Children's Hosp, Boston, MA; Statistical and Data Analysis Ctr, Harvard School of Public Health, Boston, MA; Univ of Med and Dentistry of New Jersey, Newark, NJ; Univ of North Carolina at Chapel Hill, Chapel Hill, NC; Gilead Sciences, Foster City, CA; Natl Inst of Child Health and Human Development, NIH, Rockville, MD; and Henry M Jackson Foundation, Div of AIDS, NIAID, NIH, Bethesda, MD.



M Mirochnick, G Kafulafula, R Kreitchmann, and others (HPTN 057 Protocol Team). Pharmacokinetics of Tenofovir Disoproxil Fumarate after Administration to HIV-1-infected Pregnant Women and their Newborns. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Abstract 940.

P Flynn, M Mirochnick, D Shapiro, and others (PACTG/IMPAACT 394 Study Team). Single-dose Tenofovir Disoproxil Fumarate with and without Emtricitabine in HIV-1-infected Pregnant Women and Their Infants: Pharmacokinetics and Safety. CROI 2009. Montreal, Canada. February 8-11, 2009. Abstract 939.















































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