Continuation of Postpartum Antiretroviral Therapy in a Cohort of Women Infected With Human Immunodeficiency Virus

JANAC et Tedaldi Vol. al. 13, / Postpartum No. 1, January/February Antiretroviral Therapy 2002

Continuation of Postpartum Antiretroviral Therapy in a Cohort of Women Infected With Human Immunodeficiency Virus Ellen Tedaldi, MD, Suzanne Willard, CRNP, Joanne Gilmore, CRNP Catherine Holdsworth, CRNP, Sheila Dix-Lassiter, MSN, Peter Axelrod, MD

A common dilemma for HIV-positive pregnant women is the issue of continuation or cessation of antiretroviral therapy (ART) postpartum. Current guidelines for ART during pregnancy offer no specific recommendations for postpartum ART care. The objective of this study was to ascertain characteristics that would predict cessation or continuation of ART postpartum. In this study, prenatal and medical clinic records were reviewed retrospectively for a cohort of 29 HIV-infected pregnant women who were seen in the Temple University High Risk obstetrics practice from 1997 to 1998. All women took ART during pregnancy, except for one who received IV AZT and nevirapine during labor. HIV-specific medical care was provided concurrently during the time of the woman’s obstetrics visit by a nurse practitioner and a clinical nurse specialist in consultation with the physician. Factors that were included for review included race, age, use of ART at the time of pregnancy diagnosis, type of ART during pregnancy, CD4 count, HIV-1 ribonucleic acid polymerase chain reaction (RNA PCR) levels, current substance use, disclosure of HIV status to current partner, years of HIV infection, prior HIV infected child, and whether this was a first pregnancy. The two groups of women were divided between those who discontinued ART postpartum and those who continued ART. The data were analyzed with the Kruskal-Wallis test for two groups, or calculations of risk ratios with Fisher’s exact test. Study results indicated that 15 out of 29 women (51%) continued ART postpartum. The significant factors for continuation included Latina ethnicity (risk ratio = 0.24, confidence interval = 0.06-

0.87), CD4 < 200 mm3 (p = .04), and a greater number of drugs in the antiretroviral regimen 3 versus 2 (p = .05). This study showed that postpartum continuation of ART was associated with identified Latina ethnicity, lower CD4 counts, and a greater number of drugs in the pregnancy regimen. Further study is recommended to understand the clinical impact of intermittent ART, the strategies for postpartum therapy adherence, and clinical follow-up. Key word: antiretroviral therapy, pregnancy, HIV-1, adherence

The care of women who are HIV-positive and pregnant has many confounding factors. The impact of the Adult Clinical Trials Group (ACTG) 076 trial as well as subsequent studies has shown dramatic effects in decreasing the rate of perinatal transmission (Connor et al., 1994). Although current guidelines recommend the use of antiretroviral therapy (ART) for pregnant HIV-infected women (U.S. Public Health Service Task Force [USPHS], 2000), there has been a paucity of studies on the adherence to the therapy postpartum Ellen Tedaldi, MD, is a professor in the Department of Medicine at Temple University Hospital. Suzanne Willard, CRNP, MCP/Hahnemann University, College of Nursing. Joanne Gilmore, CRNP, Presbyterian Medical Center, Section of Infectious Diseases. Catherine Holdsworth, CRNP, Department of Medicine, Temple University Hospital. Sheila Dix-Lassiter, MSN, Department of Medicine, Temple University Hospital. Peter Axelrod, MD, Department of Medicine, Temple University Hospital.

JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 13, No. 1, January/February 2002, 60-65 Copyright © 2002 Association of Nurses in AIDS Care

Tedaldi et al. / Postpartum Antiretroviral Therapy

(Morris & Harwell, 1999). A recent pharmacy claimsbased analysis demonstrated a low percentage (32.4%) of pregnant women who adhered to antiretroviral regimens in the last 2 months of pregnancy (Laine et al., 2000). The experience with continuation of ART for the postpartum patient has not been detailed extensively. With prenatal care generally provided by obstetricians and postpartum care provided by HIV specialists or primary care physicians, women may receive fragmented care. Women may choose to discontinue ART once the risk of vertical transmission is over, or they may continue therapy to maintain or improve their own clinical, virologic, and immunologic status. In this study, we attempt to identify demographic, clinical, and epidemiological factors that may predict continuation or cessation of ART in the postpartum setting in a cohort of pregnant, HIV-infected women.

Method Data Sources and Study Population A retrospective review was conducted of prenatal and medical charts of a specific cohort of 29 HIVinfected pregnant women who received care in a single, urban, academic health care center from 1997 to 1998. This cohort represented the entire population of known HIV-infected women in the high-risk obstetrics practice during that time. The study period was chosen because combination therapy, including protease inhibitor therapy, was used increasingly in ART regimens for nonpregnant individuals. The care setting selected was unique in that the prenatal program was set up as a “one-stop shopping” model with obstetrical care provided by perinatologists and HIV specialty care provided by a nurse practitioner and clinical nurse specialist concurrently during the prenatal visit. They collaborated with a physician from the HIV medicine section to recommend ART and monitoring. In addition, patients were assessed for eligibility for ACTG-sponsored perinatal clinical trials. The clinical nurse specialist’s function was to provide intensive education about HIV infection and treatment and recruit patients for clinical trials. The program also provided a targeted care manager from a local AIDS service organization to assist

61

the women with nonmedical needs assessment (e.g., housing, drug treatment referral). A weekly interdisciplinary case review was conducted to ensure communication about care issues and adherence with appointments. This team of physician, nurse practitioners, clinical nurse specialist, and case manager made treatment decisions collaboratively. The women could choose to continue their postpartum care with the same medical team. Four women did not follow with this team after delivery; however, their medical records were available for review from their primary medical provider. The other 25 women transitioned with their infants to a family program based at a pediatric hospital facility. Mothers and infants received postpartum care concurrently during visits in the pediatric immunology clinic. Outcome Measures Charts were reviewed for postpartum antiretroviral usage. Patients who were prescribed therapy in the 6 months following delivery and reported medication use were classified as continuing ART. Patients who reported nonadherence to treatment or who did not have any identifiable medical follow-up postpartum were classified as discontinuing therapy. Demographic and Clinical Data Data were collected on age, ethnicity, education level, parity, illicit drug use, current tobacco use, duration of HIV infection, history of a previous pregnancy with an HIV-infected child, and reported disclosure of HIV status to the current sexual partner. HIV-1 RNA PCR levels and CD4 measurements were obtained from the laboratory computer and medical charts. Current and past antiretroviral drug therapy information was extracted from these same records without confirmation by pharmacy claims. Assessment of antiretroviral usage was conducted by examining patient self-reporting, as shown in the medical record.

Analysis For each woman in the cohort, it was determined whether she continued or discontinued ART. The factors analyzed for possible association included age,

62

JANAC Vol. 13, No. 1, January/February 2002

race, years of education, use of ART prior to this pregnancy, type of prenatal ART, current substance use, years of HIV infection, prior history of an HIV infected child, disclosure of HIV status to current sexual partner, parity, time to initiation of prenatal care, and CD4 count and plasma HIV RNA values. Continuous variables were analyzed with the Kruskal-Wallis test for two groups. Categorical variables were analyzed with Fisher’s Exact Test. A twotailed p value of ≤ .05 was considered to be statistically significant. In stratified analyses of categorical variables, summary relative risks were calculated using Mantel-Haenszel weighted estimates (Mantel & Haenszel, 1959).

Table 1. Prepartum Antiretroviral Regimens Antiretroviral Regimens NRTI ZDV +3TC NRTI + NNRTI ZDV + 3TC + NVP ddC + 3TC +NVP NRTI + PI ZDV + 3TC + NEL ZDV + 3TC + SQV D4T + 3TC + NEL NRTI + NNRTI + PI D4T + 3TC + NVP + NEL

Number

Percentage

12

44

10 1

37 4

1 1 1

4 4 4

1

4

Results

NOTE: NRTI = nucleoside reverse transcriptase inhibitors; NNRTI = non-nucleoside reverse transcriptase inhibitors; PI = protease inhibitor; ZDV = Zidovudine; 3TC = Lamivudine; D4T = Stavudine; NVP = Nevirapine; ddC = Zalcitabine; NEL = Nelfinavir; SQV = Saquinavir.

Of the 29 HIV-infected women seen in the obstetrics clinic, 52% continued ART in the 6-month postpartum period. One woman who refused prepartum ART received IV Zidovudine (ZDV) and oral Nevirapine (NVP) during labor. Twenty-seven women accepted combination ART during pregnancy, and one woman took monotherapy with ZDV. Among the 27 women on combination therapy, 12 (41%) took two drugs, whereas 15 (52%) took three or more drugs. Perinatal transmission occurred in one infant (rate of 3%). The child was delivered by C-section to a 17year-old with primigravida, sporadically on ZDV/ 3TC/NVP with a CD4+ cell count of 464 cells/µl, a positive purified protein derivative, and pelvic inflammatory disease at time of pregnancy diagnosis. The prenatal regimens of the 27 women varied widely: 12 had two nucleoside reverse transcriptase inhibitors (NRTIs); 11 had two NRTIs and 1 nonnucleoside reverse transcriptase inhibitor (NNRTI); 4 had two NRTIs and a protease inhibitor (see Table 1). Of the women, 34% had HIV-1 RNA levels lower than 400 copies/m, the lower limit of detection, at any point in the pregnancy. Associations between demographic and clinical factors and treatment continuation are shown in Table 2. Continuation of therapy was associated with Latina ethnicity (83%, RR = .24, CI = 0.06-0.87), lower CD4 count (median count 321 with p = .004), and greater numbers of drugs in the perinatal regimen (three vs.

two drugs, p = .05). Thirty-four percent of the women had plasma HIV-1 RNA levels (viral load) < 400 copies at any point in the pregnancy. Virologic control did not predict continuation of therapy, however (p = .12, CI = 0.93-3.88). Of the virologic factors that predicted continuation of therapy, a low CD4 count of less than 200 cells/mm3 was significant (p = .04). The combination of low CD4 count, higher number of drugs in the antiretroviral regimen, and greater continuation of postpartum therapy suggests that the more immunosuppressed women maintain treatment for reasons other than interruption of perinatal transmission. Absolute CD4 counts varied in individual women during the study period. The median lowest CD4 count was lower in women who continued ART than in those who stopped treatment (CD4 =321 vs. 552 cells/mm3, p = .004). Because the ethnicity of the study patients and their immune status might not be independent of one another, we performed a stratified analysis in an attempt to control for possible confounding. Latina ethnicity was significantly associated with postpartum therapy adherence even after controlling for CD4 count (crude RR for discontinuation of treatment was 0.24, with an adjusted RR of 0.23; data not shown). Similarly, CD4 count was an independent predictor of drug continuation (crude RR for discontinuation of treatment in patients with CD4 counts was less than the median .71; adjusted RR = .70).

Tedaldi et al. / Postpartum Antiretroviral Therapy

63

Table 2. Factors Associated With Discontinuation of Antiretroviral Therapy Postpartum Factor Race/ethnicity African American Caucasian Latina Substance use Tobacco Cocaine Disclosure to partner Previous HIV-positive child First pregnancy HIV-RNA PCR < 400 copies during pregnancy Number of drugs in regimen Two Three Four

n

Risk Ratio

Confidence Interval

p Value

11 6 12

1.89 1.53 0.24

0.89-4.03 0.74-3.19 0.06-0.87

6 6 11 6 3

1.53 1.63 0.91 0.29 0.67

0.74-3.19 0.76-3.47 0.41-2.01 0.05-1.83 0.13-3.36

.39 .37 .88 .16 1.00

10

1.90

0.93-3.88

0.12 .05

.1 .39 .01*

14 1 2

NOTE: RNA PCR = ribonucleic acid polymerase chain reaction.

Several other maternal factors did not influence the continuation of antiretroviral therapy postpartum. Age and years of education were not significantly associated with maintaining therapy (p = .12 and .14, respectively). Of the cohort, 79% reported use of tobacco and/or illicit drugs (62% tobacco, 21% cocaine). Neither factor was significantly associated in the continuation of therapy postpartum (p = .38). Seven women (27%) were diagnosed with HIV infection during the current pregnancy. These women were neither more nor less likely to continue therapy (p = .8). Parity also did not influence continuation. Only three women were primigravidas. One stopped therapy, and two continued therapy postpartum for a relative risk ratio (RR) of .67 (CI = 0.13, 3.46; p = 1.0). One maternal factor that did not reach statistical significance but demonstrated a trend toward continuation of therapy was having an HIV-infected child. Six (21%) of the 29 women already had a perinatally infected child. Five of those women reported continuation of ART for an RR of .29 for continuation of therapy, p = .16 (confidence interval [CI] = 0.05, 1.83). Although few psychosocial maternal factors were included in this analysis, we did abstract information about disclosure of HIV infection status to the patient’s current sexual partner. This information was noted in the nursing or social work notes primarily and rarely in the physician prenatal record. Eighteen

(62%) of 29 women did not have documentation of disclosure of their HIV status to their current partner. Disclosure, however, appeared not to be significantly related to continuation of therapy (p = .88, CI = 0.412.01). There was no documentation in the medical record about reasons for nondisclosure. The time from last menstrual period to first obstetrical visit varied with a median of 94 days for those who discontinued therapy postpartum and 127 days for those who did not (p = .72). Six women (21%) were on any type of ART prior to this pregnancy. Delays in initial prepartum evaluation did not predict cessation of HIV therapy.

Discussion Despite acceptance of some form of prenatal ART by all the women in this small cohort, 48% of them discontinued therapy in the 6-month period postpartum. The factors associated with continuation of therapy in this cohort, however, suggest that pregnant HIVinfected women who are more advanced in their HIV infection or who are of Latina ethnicity will not interrupt postpartum ART. When ZDV monotherapy was the treatment recommendation for perinatal HIV prevention, many women had to decide whether to continue this inadequate regimen for their own HIV infec-

64

JANAC Vol. 13, No. 1, January/February 2002

tion. With the newer guidelines emphasizing treatment of the pregnant woman based on her individual clinical status (USPHS, 2000), the continuation to postpartum therapy is even more complicated. In this inner-city cohort, age was not a significant factor in medication continuation. Of the women, 61% were older than age 30. As reported elsewhere, age is not a predictor of medication adherence (Singh, 1999). Other considerations that may influence the women’s decision to cease treatment include elimination of the immediate need to interrupt vertical transmission, the parenting demands on the women, the medical care needs of the infant with HIV, and prophylactic therapy. Such women are balancing their own immunologic, virologic, and clinical imperatives for treatment with those of the newborn and any other children. The present study suggests that women with a stronger indication for ART for themselves (i.e., lower CD4 count) will be more likely to continue treatment. Studies have generally found varying correlations with race, ethnicity, and adherence (Johnston & Ahmad, 1998; Ohmit & Schuman, 1998). The Latina women in this cohort did not differ in their stage of HIV infection (CD4 < 200 cells/mm3) compared to the other women. Other unrecognized factors may explain the difference by ethnicity in continuation rates (e.g., prevalence of depression, presence of social supports) (Catz, 2000; Hecht, 1998; Mostashari & Riley, 1998). One predictor to adherence has been the relationship between the clinician and patient (Chesney, 2000). The physician who participated in this study is bilingual and conducted the clinical visits in the language most comfortable for the women, usually Spanish. Further studies should be conducted to investigate the impact of language concordance as a predictor for adherence. The overall rates of ART continuation seen in the present study are consistent with the poor longterm adherence to ART reported in other HIV-1 infected persons (Gallant & Block, 1998; Lucas, Chaisson, & Moore, 1999). There are several limitations to the present study. ART continuation is based on self-report by the patient with no corroboration of pharmacy usage. Postpartum therapy in fact may be less than reported. Only the first 6 months of the postpartum period were analyzed; the duration of ARI usage beyong that point is unknown. There are limited HIV-1 RNA levels postpartum to

correlate with reported medication usage. As this was a retrospective review, we did not ask the women directly the reason that they discontinued therapy. Factors that have been reported to affect medication usage in women include forgetting to take medication, side effects, depressed mood, life stressors, anxiety, and pain (Kalichman, Ramachandran, & Catz, 1999). Previous studies have indicated that prenatal treatment in an HIV-specific setting where clinical trials are conducted correlated with improved adherence. Our study showed that despite such a health care setting with minimal transition issues from obstetrical to medical and pediatric care, medication continuation was still problematic. The clinical implications of discontinuation of ART in this setting are unknown. The unstructured treatment interruption that occurs postpartum if a woman discontinues ART may cause decline in CD4 cells and HIV-1 viral rebound. The subsequent immediate and long-term virologic or immunologic changes have not been investigated in this unique scenario. During pregnancy itself, HIV-infected women have a fall in the absolute CD4 count and percentages that may persist postpartum (Landers, Martinez de Tejada, & Coyne, 1997). These alterations in CD4 percentages that occur with pregnancy generally have not resulted in progression of HIV disease. The postpartum woman’s response to subsequent antiretroviral regimens has also not been examined rigorously. ART usage in parturient women is an area in need of critical investigation. There are many complex issues in the prescription of, adherence to, and durable response to ART. The balancing act of prevention of perinatal transmission and maintenance of maternal health needs additional emphasis on the clinical outcomes for the HIV-infected postpartum woman. Addendum. One author has recently cared for two women who were not part of the study group; however, their history was consistent with these women. They were both women who had been pregnant, were on ART for about 6 months postpartum, and returned to care within the second 6 months after the initial pregnancy with planned pregnancies. Both women had resistant virus on genotype assay, both had undetectable viral loads and C-section delivery, and both also had HIV-positive infants. This further gives power the

Tedaldi et al. / Postpartum Antiretroviral Therapy

importance of engaging women in their care and the understanding of long-term adherence to medication regimes.

References Catz, S. L. (2000). Patterns, correlates, and barriers to medication adherence among persons prescribed new treatments for HIV disease. Health Psychology, 19(2), 124-133. Chesney, M. A. (2000). Factors affecting adherence to antiretroviral therapy. Clinical Infectious Disease, 30(Suppl. 2), S171-S176. Connor, E. M., Sperling, R. S., Gelber, R., Kiselev, P., Scott, G., O’Sullivan, M. J., Van Dyke R., Bey, M., Shearer W., & Jacobsen R. J. (1994). Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. Reduction of maternal-infant transmission of human immunodeficiency virus Type 1 with zidovudine treatment. New England Journal of Medicine, 331, 11731180. Gallant, J. E., & Block, D. S. (1998). Adherence to antiretroviral regimens in HIV-1 infected patients: Results of a survey among physicians and patients. Journal of the International Association of Physicians AIDS Care, 4(5), 32-35. Hecht, F. M. (1998). Measuring HIV treatment adherence in clinical practice. AIDS Clinical Care, 10(8), 57-59. Johnston, B. E., & Ahmad, K. (1998). Adherence to highly active antiretroviral therapy among HIV-infected patients of the inner city. Int. Conf AIDS 1998; Abstract No. 32389. Kalichman, S. C., Ramachandran, B., Catz, S. (1999). Adherence to combination antiretroviral therapies in HIV patients of low health-literacy. Journal of General Internal Medicine, 14(5), 267-273.

65

Laine, C., Newschaffer, C. J., Zhang, D., Cosler, L., Hauck, W. W., Turner, B. J. (2000). Adherence to antiretroviral therapy by pregnant women infected with human immunodeficiency virus: A pharmacy claims-based analysis. OB Gyn, 952, 167-173. Landers, D. V., Martinez de Tejada, B., & Coyne, B. A. (1997). HIV Disease in pregnancy: Immunology of HIV and pregnancy. Ob Gyn Clinics 24 (4), 821-831. Lucas G. M., Chaisson R. E., & Moore R. D. (1999). Highly active antiretroviral therapy in a large urban clinic: Risk factors for virologic failure and adverse drug reactions. Ann Intern Med, 131, 81-87. Mantel, N., & Haenszel, W. (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Ins. 22, 719-748. Morris, A. B., & Harwell, J. I. (1999). The impact of antepartum versus postpartum adherence to HAART, infant AZT, and maternal and infant office visits. 1999 National Conference on Women and HIV/AIDS; Abstract P92. Mostashari F., & Riley E. (1998). Acceptance and adherence with antiretroviral therapy among HIV-infected women in a correctional facility. J Acquir Immune Defic Syndr Hum Retrovirol, 18(4), 341-348. Ohmit, S., & Schuman, P. (1998). Adherence to antiretroviral therapy among women in HIV Epidemiology Research Study (HERS) and Women’s Inter-Agency HIV Study (WIHS). 1998 International Conference on AIDS, 12, 590; Abstract 32347. U.S. Public Health Service Task Force. (2000, February). Recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. Retrieved May 2, 2001, from www.hivatis.org