HIV+ Pregnant Women and Antiretroviral Treatment

A Viral Biorealm page on the family HIV+ Pregnant Women and Antiretroviral Treatment

The human immunodeficiency virus (HIV) has been a global epidemic for over 30 years. If untreated, HIV progresses to acquired immunodeficiency syndrome (AIDS), which is almost surely fatal. Approximately 33 million people worldwide are infected with HIV [1]. HIV is transmitted by multiple methods; sexually, via contact with contaminated blood, and from mother to child in utero being the primary ones [2].

Pharmaceutical advertisement for reducing mother-to-child-transmission.[1].

At least half of the global HIV+ population are female. Women of child-bearing age must consider their options for preventing viral transmission to their children. Mother to child transmission (MTCT) is the leading cause of HIV in children [12]. MTCT has been a topic of great research and, by following guidelines, it is now possible for an HIV+ mother can have an HIV- child. In well-resourced countries the rate of MTCT is <1% [3]. In poorly-resourced countries the rate of MTCT is decreasing but still hovers around 35% [5]. Worldwide access to pharmaceuticals and healthcare are critical in reducing MTCT. Eliminating MTCT is a priority as it makes possible ending the perpetuation HIV/AIDS between generations and brings us a large step closer to ending the HIV epidemic.

There are five main criteria for a successful HIV- pregnancy: 1) antiretroviral therapy for the mother, 2) semen washing (if the father is HIV+), 3) alternative insemination, 4) specialized obstetrical care (usually including a caesarian section), and 5) formula feeding. Access to all five of these criteria is what determines a low rate of MTCT. Of these criteria, antiretroviral therapy for the mother is the most effective in reducing MTCT [4].

Even more than in regards to other HIV+ patients, antiretroviral regimens for pregnant women must be especially carefully considered. The woman will be on ARV's for the duration of her pregnancy, exposing the vulnerable and developing fetus to a high concentration of drugs for a prolonged period of time. Drugs considered suitable for HIV+ patients may not be safe for a pregnant women. First-line drugs, those which are highly effective and cause few side effects, are the main regimens prescribed to pregnant women [13]. When treating an HIV+ pregnant woman it is important to balance three factors: health of the HIV+ mother, limiting probability of HIV transmission to the child, and limiting ARV side effects to the child and mother [3]. Some women do not know they are HIV+ until their blood is tested during a pregnancy exam. These women are typically not put on ARV therapy until their second trimester, to minimize drug exposure to the fetus [12].

Zidovudine

Zidovudine (ZDV), also known as azidothymidine (AZT) is widely used as antiretroviral therapy [7]. First made in 1964 for cancer treatment, ZDV was the first ARV available and is known as one of the most effective pharmaceuticals in history [8]. Zidovudine is also the drug most commonly prescribed, and is still the only one licensed in the United States specifically for use in HIV+ pregnant women [3].

An overview of the HIV replication cycle showing where NRTI and NNRTI drugs are effective. [2].

Zidovudine is a nucleoside reverse-transcriptor inhibitor (NRTI), also known as a competitive inhibitor. It is effective by binding to host DNA and effecting a process known as chain termination. Once activated by phosporylation, ZDV binds to the host DNA without a 3'-hydroxyl group, thereby halting any further elongation. Viral RNA is no-longer able to replicate in the host DNA and cause infection [14].

ZDV is best suited for women in wealthy countries with strong healthcare infrastructure. Treatment is expensive and intensive. Oral doses must be taken five times daily during pregnancy, then intravenous infusion during labor and a six-week oral regimen for the newborn [9]. When followed correctly, this treatment is highly effective in reducing MTCT and shows very few side effects to the child. The reality is that most HIV+ women do not have access to proper ZDV treatment.

Tenofovir

Tenofovir (TDF) is, like zidovudine, a nucleotide reverse-transcriptase inhibitor antiretroviral drug. Tenofovir is commonly used to treat patients with Hepatitis B, but is also applicable for HIV+ patients. Tenofovir has found a niche market among HIV+ patients with renal or hepatic dysfunction, because the drug is safe and effective for them [10]. This drug is widely used with HIV+ pregnant women, though it is newer and less common than zidovudine.

Tenofovir is a NRTI much the same as zidovudine, except that it is a prodrug. It is administered in an inactive form (tenofovir disoproxil fumarate), then activated by the metabolic process. The prodrug is more easily and efficiently absorbed and distributed by the body [14].

TDF is safer than ZDV for pregnant women and their children, while still drastically reducing the rate of mother-to-child transmission. TDF is also more easily administered to women around the world. While a single-dose form of tenofovir does exist and is shown to be highly effective in reducing MTCT, the most common dosage is a once-daily tablet [11].

Nevirapine

Nevirapine was approved for use in adults and children in the United States in 1998. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Different from NRTI's, Nevirapine is effective by binding to an enzyme rather than DNA. NNRTI's are known as non-competetive inhibitors [14].

Sociological Differences in Treatment Objectives

The stark contrast in prevalence of MTCT between countries is due to many factors. At this time, 90% of mother-to-child transmission occurs in sub-Saharan Africa [12]. The primary contributing factor is financial- poorly-resourced countries are not able to afford expensive antiretroviral medications or the physicians to administer them. Similarly, impoverished women cannot afford caesarian section births or the cost of formula feeding [12]. It is critical that the women in these countries are better provisioned with ARVs and medical attention during and after pregnancy.

The priorities concerning mother-to-child transmission are sociologically dependent. In well-resourced countries where the rate of MTCT is >1%, the focus is now on designing ARV regimens with the lowest rate of birth defects [3]. Conversely, the main objective in poorly-resourced countries is to make ARVs available and reduce the rate of MTCT [3].

Side Effects for the Mother

Side Effects for the Child

The Impact of Formula Feeding

Gallus gallus domesticus showing obvious signs of late-stage CAV infection. [3].

The Future of MTCT

References

[1] Barton-Knott, Sophie. 2011. Nearly 50% of People Who are Eligible for Antiretroviral Therapy Now Have Access to Lifesaving Treatment. UNAIDS press release. http://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2011/november/20111121wad2011report/.

[2] Centers for Disease Control and Prevention. 2010. HIV Transmission. http://www.cdc.gov/hiv/resources/qa/transmission.htm.

[3] Foster, C., H. Lyall, B, Olmscheid, G. Pearce, S. Zhang and D. Gibb. 2009. Tenofovir Disproxil Fumarate in Pregnancy and Prevention of Mother-to-Child-Transmission of HIV-1: Is it Time to Move on From Zidovudine? HIV Medicine. 10: 397-406.

[4] Giaquinto, C., E. Ruga, D. Rossi, I. Grosch-Worner, J. Mok, I. Jose, I. Bates, F. Hawkins, C. Guevara, J. Pena, J. Garcia, J. Lopez, M. Garcia-Rodriguez, F. Asensi-Botet, M. Otero, D. Perez-Tamarit, et al. 2005. Mother-to-Child-Transmission of HIV Infection in the Era of Highly Active Antiretroviral Therapy. Clinical Infectious Diseases. 40: 458-465.

[5] Onyango, Rosebella O. 2006. Mother-To-Child Transmission of HIV/AIDS. Towards Unity for Health Women and Health Taskforce. Maseno University, Maseno Kenya.

[6] Shacklett, B. and R. Greenblatt. 2011. Immune Responses of HIV in the Female Reproductive Tract, Immunologic Parallels with the Gastrointestinal Tract, and Research Implications. American Journal of Reproductive Immunology. 65: 230-241.

[7] Broder, Samuel. 2009. The Development of Antiretroviral Therapy and its impact on the HIV-1/AIDS Pandemic. Antiviral Research. 85: 1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815149/pdf/nihms153574.pdf

[8] "A Failure Led to Drug Against Aids." The New York Times. September 20, 1996. http://www.nytimes.com/1986/09/20/us/a-failure-led-to-drug-against-aids.html

[9] Wiktor, S., E. Ekpini, J. Karon, J. Nkengasong, C. Maurice, S. Severin, T. Roels, M. Kouassi, E. Lackritz, I. Coulibaly and A. Greenberg. 1999. Short-Course Oral Zidovudine for Prevention of Mother-to-Child Transmission of HIV-1 in Abidjan, Cote d'Ivoire: A Randomized Trial. The Lancet. 353: 781-785.

[10] Kearney, B., K. Yale, J. Shah, L. Zhong and J. Flahery. 2006. Pharmacokinetics and Dosing Recommendations of Tenofovir Disoproxil Fumarate in Hepatic or Renal Impairment. Clinical Pharmacokinetics. 45: 1115-1124.

[11] Siberry, G., P. Williams, H. Mendez, G. Seage et al. 2012. Safety of Tenofovir use During Pregnancy: Early Growth Outcomes in HIV-exposed Uninfected Infants. AIDS. 26: 1151-1159.

[12] World Health Organization Geneva. 2004. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants. Geneva, Switzerland.
[13] Hammer, S., J. Eron, P. Reiss et al. 2008. Antiretroviral Treatment of Adult HIV Infection. The Journal of the American Medical Association. 300: 555-570.

[14] Rong, L., M. Gilchrist, Z. Feng and A. Perelson. 2007. Modeling Within-Host HIV-1 Dynamics and the Evolution of Drug Resistance: Trade-Offs Between Viral Enzyme Function and Drug Susceptibility. Journal of Theoretical Biology. 247: 804-818. Page authored by Ellen Gaglione for BIOL 375 Virology, September 2010