Pertinent Topics on HIV Infection Among Women: Prevention, Lipodystrophy and Drug-Drug Interactions
The following sections represent an overview of key points from the 2003 Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the U.S. (available at www.aidsinfo.nih.gov under guidelines, perinatal) and/or the 11th Conference on Retroviruses and Opportunistic Infections (CROI) -- February 8-11, 2004, San Francisco, CA.
Prevention of Vertical Transmission of HIV Infection
Efficacy of Antiretroviral Therapy
Mother-to-child transmission (MTCT) may be prevented by treating the mother and/or her baby with antiretroviral therapy (ART). Studies have shown a 66% reduction or greater in vertical transmission with different antiretroviral treatment strategies, including both mono- and combination therapy. The first of these studies, initially reported in 1994, showed that the HIV-1 transmission rate for infants who received placebo was 22.6%, compared with 7.6% for those who received zidovudine (AZT). This translates into a 66% reduction in risk for transmission in those who received treatment compared to those who received placebo. Other studies have shown similar results. One study compared nevirapine given to women at the onset of labor and infants at 48-72 hours of life with a very short regimen of AZT given orally during labor and to the infant for the first week of life. In this study, transmission of HIV among the infants at six weeks of age was 12% in the nevirapine arm verses 21% in the AZT arm -- a reduction in transmission of nearly 50%. Another study reports transmission rates of 12.3% for nevirapine compared with 9.3% with AZT combined with lamivudine (3TC). In the U.S., the standard recommendation for infant prophylaxis is six weeks of AZT, regardless of whether the woman has had antepartum, intrapartum, or postpartum ART (for details of AZT dosing in neonates, see perinatal guidelines website noted in the introduction to this article).
It is unclear how intrapartum AZT prophylaxis works as maternal viral load suppression does not fully explain the observed efficacy. The efficacy beyond viral load suppression may be related to the fact that AZT is metabolized into the active triphosphate form within the placenta, which has not been observed with other nucleosides, such as ddI or ddc. Some concerns relating to the safe administration of AZT in pregnancy have been raised with regard to the drug causing disruption in the maternal-fetal barrier, with subsequent observed cytotoxic in vitro effects of AZT on the human placenta. However, this has not translated into obvious clinical sequelae in the infant thus far, and the data as presented above do clearly support its use in terms of reduction of HIV transmission to the infant. Whether it relates to increased risk for preterm labor and premature birth, low fetal birth weight, or other more serious clinical events is yet to be determined.
Combination ART appears to have an even greater effect in reducing HIV transmission. In one of these studies, the transmission rate was 10.4% among women who received AZT alone, 3.8% among women who received combination therapy without protease inhibitors (PIs), and 1.2% among women who received combination therapy with PIs. Because of concerns relating to antiretroviral resistance among infected mothers and infants exposed to monotherapy, particularly nevirapine as discussed earlier, the use of combination therapy may be more prudent in the U.S. since it is widely available. Counseling women about the potential for resistance and the long-term effect it may have for her with regard to future antiretroviral options is vital and should be taken into consideration when choosing an appropriate regimen for her. For more detailed information on choosing different strategies in treating pregnant women with HIV infection, please refer to the Heppigram in this issue.
Initial Evaluation and Antiretroviral Considerations for HIV-infected Pregnant Women With Regard to Safety and Toxicity
Initial evaluation of an HIV-infected pregnant woman should include an assessment of HIV-1 disease status, including evaluation of the degree of existing immunodeficiency determined by CD4 count, the risk for disease progression determined by the level of plasma RNA, history of prior or current antiretroviral therapy, gestational age, and supportive care needs, and recommendations regarding options for ART based on the history of previous treatment. The benefits of ART for a pregnant woman must always be weighed against the risk of adverse events to the woman and the baby. These considerations must be carefully thought out and discussed with the patient so that she can make an informed decision. Many women who have begun ART before pregnancy require adjustment of the regimen during the pregnancy due to either (1) intolerance during pregnancy especially in the first trimester, (2) possible dosing changes due to physiologic changes associated with pregnancy, (3) potential long- and short-term effects of the drug(s) on the fetus and newborn, and/or (4) discontinuing agents with potential for reproductive toxicity. As with all pregnant women, those receiving ART should be evaluated and closely monitored for hyperglycemia, anemia, and hepatic toxicity and should be offered optimal nutritional status.
Data are limited regarding the safety of antiretroviral drugs in pregnancy and recommendations for use are based on animal toxicity data, anecdotal experience, registry data, and clinical trials. Data are conflicting as to whether the use of combination ART during pregnancy is associated with preterm delivery. Until more is known, these women should be monitored carefully for pregnancy-related toxicities/complications.
Toxicities related to nucleoside analog drugs, such as symptomatic lactic acidosis and hepatic steatosis, may have a female preponderance, and these conditions have similarities to rare but life-threatening complications in pregnancy, such as acute fatty liver and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets). Whether these conditions are increased during pregnancy among women treated with nucleosides is unknown, though there are published case reports that suggest this may be true. The clinician should have a low threshold for considering and screening for any of these mentioned toxicities in a pregnant patient on ART. Among babies born to HIV-infected mothers taking nucleoside therapy during pregnancy, there are conflicting data as to whether these infants are at increased risk for mitochondrial dysfunction, believed to be the etiology behind lactic acidosis and hepatic steatosis. However, this condition, though often fatal when it occurs in infants, appears to be rare.
Regarding the use of non-nucleoside reverse transcriptase inhibitors, the development of severe nevirapine-associated skin rash has been reported to be 5.5 to 7.3 times more common in women than men, and has been reported in pregnant women. Hepatic toxicity with systemic symptoms due to nevirapine was 3.2-fold more common in women than men. In a summary analysis from 17 clinical trials of nevirapine use, women with higher CD4 counts (>250 cells/mm3) were 9.8 times more likely than women with lower CD4 counts (<250 cells/mm3) to experience symptomatic, rash-associated, nevirapine-related hepatotoxicity. It is unknown if pregnancy increases this risk. At the 11th CROI, it was reported that women were significantly less likely to have an adverse reaction to nevirapine when it was started during pregnancy compared to women not pregnant. However, Martinson, et al. reported at CROI that even though use of nevirapine significantly reduced vertical transmission, with HIV occurring in only 8.6% of births among 623 women. Nevirapine-resistant virus occurred in 38.8% of mothers and in 42.4% of infants.
Although it is known that PIs are associated with hyperglycemia, new-onset diabetes mellitus, exacerbation of existing diabetes, and diabetic ketoacidosis, it is not known if they increase the risk of pregnancy-associated hyperglycemia, and therefore, glucose levels should be closely monitored in these patients. Please refer to this month's HIV 101 on page 6 for a complete list of currently available antiretroviral drugs with known safety/toxicity information for each drug in pregnancy.
Breastfeeding and HIV Transmission Risk
In the U.S., breastfeeding among HIV-infected women is not recommended due to risk of HIV transmission, which occurs at a rate of about 7 to 14 percent. According to the World Health Organization's recommendations for MTCP, when replacement feeding is acceptable, feasible, affordable, sustainable and safe, avoidance of all breastfeeding by HIV-infected mothers is recommended. For information pertaining to appropriate recommended scenarios for HIV-1 resistance testing among pregnant women and mode of delivery relating to vertical transmission of HIV, please refer to the perinatal guidelines cited in the introduction to this article.
Antiretroviral Pregnancy Registry
The Antiretroviral Pregnancy Registry is designed to collect observational, nonexperimental data regarding antiretroviral exposure during pregnancy for the purpose of assessing the potential teratogenicity of the drugs. The registry does not use patient names, and the staff tracks birth outcome follow-up information. For more information on this registry please refer to resources
in this issue.
Clinical Update on Lipodystrophy Syndrome Associated With HIV Infection and Antiretroviral Therapy
The reported prevalence of lipodystrophy ranges anywhere from two to 84%, depending on the definition used and the ease of recognition among patients and providers. Tien et al. reported the estimated incidence of lipoatrophy, or fat loss, and lipohypertrophy, or fat gain, among women with and without HIV infection from the Women's Interagency HIV Study (WIHS). The syndrome is evaluated for by both the participants via questionnaires detailing noticeable body changes and by the researchers via anthropometric measurements at regular intervals. The authors performed a 30-month incidence analysis among 810 women, 605 of whom were HIV-infected and 210 of whom were HIV-uninfected. Overall, among HIV-infected women, the incidence of lipoatrophy was higher (nearly double) than that among the uninfected women after adjusting for age and race, whereas there was no statistically significant difference in central lipohypertrophy seen between the two groups and a lower incidence of peripheral hypertrophy among HIV-infected women. Their findings suggest that peripheral and central lipoatrophy associated with HIV infection appears prevalent among women and that peripheral lipoatrophy in combination with central lipohypertrophy is uncommon.
How different antiretroviral drugs affect the development of lipodystrophy is still largely unknown, though thought to be related most commonly to the use of prolonged PI therapy with or without specific nucleosides or non-nucleosides, such as d4T, ddI, ddc or efavirenz. Murphy et al. presented data at CROI suggesting that patients who received DDI plus d4T had an increased risk of peripheral lipoatrophy over four years and that indinavir was associated with lipohypertrophy. In another study reported at CROI evaluating whether changing ART can hasten or alter the lipodystrophy syndrome, the authors reported no effect over 24 months after switching patients from a PI to an efavirenz-, nevirapine-, or abacavir-based regimen.
Important Drug-Drug Interactions Associated With Estrogen Use Among HIV-infected Women on Antiretroviral Therapy
Ritonavir has a drug-drug interaction with oral contraceptives (OCPs), such as ethinyl estradiol, levonorgestrel, norelgestromin, norethindrone, and norgestrel, in which the level of hormone may be decreased enough to cause contraceptive failure. Thus, this is of consideration in any patient for whom a ritonavir-boosted regimen is being offered. Increasing the dose of OCPs and/or suggesting alternative forms of contraception to the patient may best handle this interaction. The same interaction occurs with amprenavir, though amprenavir levels may also decrease when co-administered with OCPs, thus decreasing the effect of amprenavir and increasing the risk for resistant HIV. For another PI, atazanavir, it is recommended that the lowest effective dose of OCPs be used, as this drug increases the OCP level. It is recommended that no OCPs be used in conjunction with nevirapine due to strong drug-drug interactions. There does not appear to be any significant drug-drug interaction with the use of OCPs and any of the nucleoside reverse transcriptase inhibitors, efavirenz, delavirdine, saquinavir, indinavir, or nelfinavir. Of note, there does not appear to be any significant drug-drug interaction with medroxprogsterone acetate (Depo-Provera®) and antiretrovirals.
The American College of Obstetrics and Gynecology (ACOG) recommends that all women of childbearing age -- HIV-infected and HIV-uninfected alike -- be offered reproductive health care as part of routine medical treatment. Both incarcerated women and those living in the free world should receive information on birth control options, prevention of sexually transmitted diseases (STDs), prenatal vitamins if a pregnancy is desired, risk factors for HIV infection and other co-morbid conditions should a pregnancy occur, and optimal prevention and treatment of these conditions in order to preserve the overall health of the woman and her baby. Informing incarcerated women about these issues is particularly critical, as they often lack access to care before and after incarceration. In 1995, the United States Public Health Service issued recommendations for universal prenatal HIV-1 counseling and testing, including voluntary counseling and testing for all pregnant women in the U.S. HIV testing of all inmates should be encouraged in correctional settings where reasonable HIV counseling and treatment can be provided. This option affords inmates a chance to make positive changes in their lives and improve their overall health while incarcerated. For women identified as HIV-infected, the focus of care is not only on assessment of her stage of infection and antiretroviral options, but also (1) education regarding HIV transmission risks to her baby during pregnancy and breastfeeding, as well as medical interventions to prevent MTCT, (2) helping her understand and cope with realistic expectations for a future pregnancy, and (3) offering effective contraception strategies that will optimize her health before, during, and after such a pregnancy may occur. These are just some of the complex psychosocial issues that an HIV-infected woman may confront. Ultimately, choices impacting her reproductive health are up to the woman alone. As health care providers however, we can facilitate what may be difficult decisions for our patients by addressing them with honesty, compassion and respect.
Bethany Weaver, D.O., M.P.H., is Acting Instructor of Medicine at the University of Washington Center for AIDS & STD Research (CFAR) and Northwest Correctional Medicine Education Program. Disclosures: Pfizer stockholder.
- Antiretroviral Pregnancy Registry Research Park, 1011 Ashes Drive, Wilmington, NC 28405, Tel: 800.258.4263, Fax: 800.800.1052, www.APRegistry.com.
- ACOG technical bulletin. Number 205-May 1995. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 1995 Aug 50 (2):201-7.
- Bershoff-Matcha SJ, Mundy LM, Henry JV. 11th CROI; February 8-11,2004; San Francisco, CA. Abstract 939.
- Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Clin Infect Dis. 2001. 32(1):124-9.
- Boxwell DE, Styrt BA. 39th ICAAC. San Francisco, CA. September 26-29, 1999. Abstract 1284.
- Bristol-Myers Squibb Company. Healthcare Provider Important Drug Warning Letter. January 5, 2001.
- CDC. MMWR. 1995. 44 (No. RR-7):1-15.
- Collier AC, Helliwell RJ, Keelan JA, et al. Toxicol Appl Pharmacol. 2003;192:164-73.
- Cooper ER, et al. J Acquir Immune Defic Syndr. Hum Retrovirol. 2002. 29(5):484-94.
- Corey L, et al. J Acquir Immune Defic Syndr. 2004 Mar 15;35(5):435-445.
- Dabis F, et al. 14th IAS. Barcelona, Spain, July 7-12, 2002. Abstract. ThOrD1428.
- Dancis J et al. J Acquir Immune Defic Syndr. Hum Retrovirol, 1993. 6(1):2-6.
- Dorenbaum A et al. JAMA. 2002. 288(2):189-98.
- Dube MP, Sattler FR. AIDS Clinical Care. 1998. 10(6):41-4.
- Eastone JA, Decker CF. Ann Intern Med. 1997. 27(10):948.
- Fisac et al. Metoabolic changes in patients switching from a protease inhibitor-containing regimen to abacavir, efavirenz, or nevirapine: 24-month results of a randomized study. Abstract 78.
- Fiscus SA, et al. Pediatr Infect Dis J. 2002. 21(7):664-8.
- Food and Drug Administration. Food and Drug Administration, Public Health Service, Department of Health and Human Services. Rockville, MD: June 11, 1997.
- Guay LA, et al. Lancet. 1999. 354(9181):795-802.
- Imperiale SM, Stern JO, Love JT, et al. 4th International Workshop on Adverse Events and Lipodystrophy in HIV. San Diego, CA. September 22-25, 2002. Abstract 87.
- Johnson KM, Alarcon J, Watts DM, et al. AIDS. 2003 Mar 7;17(4):605-12.
- Kuhn L, Stein Z, and Susser M. Paediatric & Perinatal Epidemiology. 2004. 18 (1): 10-16.
- Knudtson E, Para M, Boswell H, Fan-Havard P. Obstet Gynecol. 2003. 101(5 Pt 2):1094-7.
- Lallemant M, et al. N Engl J Med. 2000. 343(14):982-91.
- Lallemant M, et al. 14th International AIDS Conference, Barcelona, Spain. July 7-12, 2002. Abstract. LbOr22.
- Langlet P, Guillaume M-P, Devriendt J, et al. Gastroenterol 2000; 118 (suppl 2): Abstract 6623. (101st Annual meeting of the American Gastroenterological Association, San Diego, CA. May 21-24, 2000).
- Laurence J., Lessons from the 11th Conference on Retroviruses and Opportunistic Infections. AIDS Reader. 2004;14:151-53.
- Luzzati R, Del Bravo P, Di Perri G, et al. Lancet. 1999. 353(9156):901-2.
- Lyons F, Hopkins S, McGeary A., et al. 2nd IAS conference on HIV Pathogenesis and Treatment. Paris, France. July 13-16, 2003. (late breaker).
- Mandelbrot L, Kermarrec N, Marcollet A, et al. AIDS, 2003. 17(2):272-3.
- Mandelbrot L, et al. JAMA, 2001. 285(16):2083-93.
- Martinson N, Morris L, Gray G, et al. 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, CA. Abstract 38.
- Mazhude C, Jones S, Murad S, et al. AIDS. 2002. 16(11):1566-8.
- Moodley et al. J Infect Dis. 2003. 187(5):725-35.
- Murphy R, Katlama C, Weverling GJ, et al. 11th CROI; February 8-11, 2004; San Francisco, CA. Abstract 718.
- Petra Study Team. Lancet, 2002. 359(9313):1178-86.
- Sandberg JA, et al. Toxicologist. 1994. 14:434.
- Sarner L, Fakoya A. Sex Transm Infect. 2002. 78(1):58-9.
- Shaffer N, et al. Lancet. 1999. 353(9155):773-80.
- Shaffer N, et al. N Engl J Med. 1999. 340(13):1042-3.
- Sperling RS, et al. N Engl J Med. 1996. 335(22):1621-9.
- Stern JO, Love JT, Robinson PA, et al. 14th International Workshop on Adverse Events and Lipodystrophy in HIV. San Diego, CA. September 22-25, 2002. Abstract LBOr15.
- Stiehm ER, et al. J Infect Dis. 1999. 179(3):567.
- Tien PC, Cole SR, Williams CM, et al. J Acquir Immune Defic Syndr. 2003;34:461-66.
- Visnegarwala F, Krause KL, Musher DM. Ann Intern Med. 1997. 127(10):947.
- Wade, et al. N Engl J Med, 1998. 339(20):1409
- World Health Organization. WHO Technical Consultation on behalf of the UNFPA/UNICEF/WHO/UNAIDS Inter-Agency Task Team on Mother-to-Child Transmission of HIV. Geneva: World Health Organization, 2001. Report No. WHO/RHR/01.28.