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Combined Treatment With HAART Increases the Thymic Output in HIV-Infected Pregnant Women

February 13, 2003

  • PACTG 353: Combined Treatment With HAART (NFV/3TC/ZDV) Increases Thymic Output in HIV-Infected Pregnant Women (Poster 891)
    Authored by Y. Bryson, R. Dickover, A. Stek, M. Mirochnic, J. Connor, L. Mofensen, H. Watts, S. Huang, M. Hughes, B. Cunningham, L. Purdue, D. Wara, Y. Asfaw, E. Smith, PACTG 353 Team
    View the original abstract

PACTG 353 was a phase I prospective study to assess the pharmacokinetics of nelfinavir (NFV, Viracept) when given in combination with AZT (ZDV, zidovudine, Retrovir) and 3TC (lamivudine, Epivir) and to assess the safety and tolerance of the triple combination therapy in HIV-1-infected women during pregnancy and postpartum and in HIV-exposed infants. This study opened in 1997 enrolling a total of 33 pregnant subjects. It closed on March 27, 2002. A significant increase in CD4 T cells was observed in women between baseline and delivery.

HAART has been shown to increase T cells and T cell rearrangement excision circle (TREC) levels in HIV-infected adults and children with viral suppression. TRECs are pieces of episomal DNA that are produced in thymic tissue as stem cells differentiate into T cells. They do not replicate during cell division, and thus levels in the peripheral blood may decline in states of decreased thymic output, increased cell death (apoptosis), or increased peripheral expansion of T cells. It is thought that the increase in TRECs that are observed on HAART represent an increase in thymic output. There is limited data using TREC levels to evaluate the effect of HAART on thymic output during pregnancy.

The PACTG 353 investigators quantitated TREC levels in PBMC from 19/28 women completing PACTG 353 with available PBMCs at baseline, delivery and six-12 weeks postpartum. Thirteen of 19 of the women were naive to antiretroviral therapy at study entry. DNA was prepared from cryo-preserved PBMC by guanidinium lysis/column purification. TRECs were quantitated in one microgram patient PBMC DNA using the Taqman real-time PCR system. All reactions were run in triplicate and TREC copy numbers were determined by comparison with a standard curve.

At baseline, the median maternal CD4 T-cell count was 403 and the median peripheral blood TREC level was 1,634 copies/mg PBMC DNA. At the time of delivery, the median CD4 T-cell count among the 19 women studied increased to 486 (p<0.01) and median TREC levels increased to 4,998 copies/mg (p<0.01).

Following delivery, maternal CD4 and TREC levels showed slight but not significant decreases in median to 476 and 3,785 copies/mg respectively. Of note, HIV viral loads increased post delivery, which makes me question the adherence of the mothers postpartum.

Unfortunately, the information on adherence was unavailable. TREC levels at six-12 weeks postpartum still remained significantly higher than baseline levels (p<0.01). The 13 antiretroviral-naive mothers showed a larger-fold median increase in TRECs over gestation than the six non-naive mothers (6.8-fold vs. 1.5-fold); however, due to small population size, this difference was not statistically significant. The largest increases in PBMC TREC levels were found among women who were naive to antiretroviral therapy at entry and had low initial TREC copy numbers.

This is a small study and there are many questions regarding the immunologic and virologic changes that occur during pregnancy and there is uncertainty as to how precise TREC levels are as a quantitative indicator of thymic output. Subjects enrolled between 14-34 weeks gestation and median gestational date for the 28 women was not available.

It would be interesting to evaluate changes during the first trimester and for a longer duration after delivery. I also do not know if there is any information on TREC levels in non-HIV-infected women during pregnancy. This would be a very useful comparison.

We do know from other observational studies that adherence to HAART falls off dramatically in the early postpartum period so the fact that this study reported a slight decrease in CD4 and rebound viremia is not surprising -- if this was in fact related to adherence rather than biological reasons.

Further studies exploring the immunologic and virologic changes in women particularly during pregnancy are warranted. Given the small duration of follow-up postpartum it remains unclear if pregnancy itself boosts TRECs or simply was representative of women starting HAART. The slight decrease postpartum may represent non-adherence and one would want to follow these women for a prolonged period to see if TRECS remain increased in those with complete viral suppression compared with those who fail or discontinue HAART.

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This article was provided by TheBodyPRO. It is a part of the publication The 10th Conference on Retroviruses and Opportunistic Infections.
See Also
What Did You Expect While You Were Expecting?
HIV/AIDS Resource Center for Women

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