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Gender Differences in Lymphocyte Populations, Plasma HIV RNA Levels, and Disease Progression in a Cohort of Children Born to Women Infected With HIV

^a Department of Pediatrics, Columbia University, New York, New York
^b National Institute of Child Health and Human Development, Bethesda, Maryland
^c Clinical Trials and Surveys Corp, Baltimore, Maryland
^d Department of Pediatrics, University of Illinois, Chicago, Illinois
^e Department of Pediatrics, State University of New York, Brooklyn, New York
^f Department of Pediatrics, University of Massachusetts, Worcester, Massachusetts
^g Department of Pediatrics, Baylor University College of Medicine, Houston, Texas
^h Department of Pediatrics, University of Puerto Rico, San Juan, Puerto Rico

	ABSTRACT

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OBJECTIVE. We sought to document gender differences in lymphocyte subsets and plasma RNA levels in a pediatric cohort with presumed minimal hormonal differences (on the basis of age).

METHODS. Blood samples from antiretroviral therapy-treated, HIV-infected children (n = 158) and HIV-uninfected children (n = 1801) who were enrolled in the Women and Infants Transmission Study were analyzed at specified study intervals with consensus protocols, and various parameters were compared.

RESULTS. Antiretroviral therapy-treated, HIV-infected female children had, on average, 0.38 log₁₀ copies per mL lower plasma RNA levels than did their male counterparts, but lymphocyte differences were not noted in this cohort. Despite their higher plasma RNA level, a greater proportion of male children survived through 8 years of age. There were no gender differences with respect to the age of diagnosis of HIV, time to antiretroviral therapy after diagnosis of HIV, or type of antiretroviral therapy. Lymphocyte differences were noted for uninfected children.

CONCLUSIONS. Plasma RNA levels differed among antiretroviral therapy-treated, HIV-infected children according to gender, in a manner similar to that noted in previous pediatric and adult studies. Lymphocyte subsets varied according to gender in a cohort of HIV-exposed but uninfected children. Most importantly, overall mortality rates for this cohort differed according to gender.

Key Words: HIV • gender

Abbreviations: WITS—Women and Infants Transmission Study • ECS—European Collaborative Study • CDC—Centers for Disease Control and Prevention • ART—antiretroviral therapy • REACH—Reaching for Excellence in Adolescent Care and Health

Gender differences in lymphocyte populations and plasma HIV RNA copy number have been examined in multiple large cohort studies involving adolescents and adults. In general, HIV-infected women have greater CD4⁺ cell counts (+70–100 cells per µL) and percentages (+5%)^1,2 and lower HIV RNA values (0.17–0.78 log units),^3,4 compared with HIV-infected men, in the first 4 to 5 years of infection. Those analyses were limited largely to treatment-naive or minimally treated patients, and rates of disease progression were not consistently different.^5,6 Other studies examined gender differences in response to potent combination therapies, with similarly mixed results.^7–9 In addition, although CD4⁺ cell counts were found to be higher in cohorts of HIV-negative women, compared with HIV-negative men,¹⁰ such differences were not noted in a large cross-sectional analysis of healthy children.¹¹

One hypothesis for the observed differences in HIV RNA copy number and lymphocyte subsets between female and male patients with HIV infection has been the effect of postpubertal sex hormones. The current study was undertaken with the supposition that the hormonal environment of infants and of prepubertal children varies less than that of adults. We examined gender differences with respect to lymphocyte subsets and with respect to HIV RNA copy number and disease progression (for patients with perinatally acquired HIV) among children born to HIV-infected women in the Women and Infants Transmission Study (WITS) cohort.

	METHODS

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Patient Group and Study Design
The population studied included all singleton and first-born twin infants of HIV-infected pregnant women recruited into the WITS between 1989 and September 2003. These mother-infant pairs were recruited and studied at 6 clinical sites in Boston, New York City (2 sites), Chicago, Houston, and Puerto Rico. Infant infection status was determined with HIV DNA polymerase chain reaction assays and/or HIV cultures. Infants with 2 positive determinations from samples drawn on different dates were considered infected. One infant was categorized as HIV infected through consultation with a clinical working group set up to review clinical and laboratory information for children for whom inadequate laboratory diagnostic data had been obtained. This infant was not included in the mortality analysis, because the exact date when this infant became HIV positive was not available. Infants with 2 negative determinations (at 1 month of age and 1 at 4 months of age) and no positive determinations were considered uninfected.

Clinical and laboratory assessments were performed at birth, at 1, 2, 4, 6, 12, 18, and 24 months of age, and then yearly for uninfected children and every 6 months for HIV-infected children. These analyses were restricted to data from birth through 8 years of age, to minimize the potential impact of pubertal change on outcomes. Flow cytometry was performed by laboratories with approved performance in the National Institute of Allergy and Infectious Diseases, Division of AIDS, immunology quality assurance program, with AIDS Clinical Trials Group consensus protocols for 2- and 3-color flow cytometry.¹² HIV RNA quantification was performed with the Roche Amplicor HIV-1 monitor test, in laboratories with approved performance in the National Institute of Allergy and Infectious Diseases, Division of AIDS, virology quality assurance program, with the AIDS Clinical Trials Group consensus protocol.¹³ These tests were performed for HIV-infected infants at every visit. Disease progression was measured with clinical and immunologic criteria set forth in the Centers for Disease Control and Prevention (CDC) classification of disease for HIV-infected children.¹⁴

Statistical Analyses
Analyses of baseline characteristics were performed with either a ² test for categorical variables or an F test for continuous variables, to determine whether there were gender differences at baseline. These analyses were performed separately for 3 subgroups, namely, HIV-infected children who were treated with antiretroviral therapy (ART), HIV-infected but untreated children, and HIV-exposed but uninfected children.

Longitudinal data analyses were performed for the following measures: total lymphocyte counts, white blood cell counts, absolute and relative counts of lymphocytes with CD3⁺CD4⁺, CD3⁺CD8⁺, CD3^–CD16⁺CD56⁺, and CD19⁺ immunophenotypes, and log₁₀ HIV RNA levels for HIV-infected children. The same measures, with the exception of log₁₀ HIV RNA levels, were also analyzed for HIV-uninfected children. Gender differences were examined by fitting a generalized estimating equations model,¹⁵ which included terms for gender, age, and gender-age interaction, to each of the measures. The purpose of including the interaction term was to determine whether the gender effect changed with age. Because the measures were not linear with age, we modeled with a set of dummy variables to account for the nonlinearity of the effect. Modeling the age effect in this manner allows for changes in the shape of the adjusted mean profiles with respect to age. Additional covariates included in the generalized estimating equations models for ART-treated, HIV-infected children were time-dependent ART use, birth group (defined according to when a child was born, ie, on or before February 28, 1994, between March 1, 1994, and July 31, 1996, or on or after August 1, 1996), mother's race, mother's use of illicit hard drugs during pregnancy, mother's use of alcohol during pregnancy, and preterm birth. Maternal hard drug use was defined as the use of cocaine, methadone, heroin, or any illicit injectable drugs. Maternal drug use was ascertained through self-reports and/or urine toxicologic tests. Preterm birth was defined as <37 weeks of gestation. For the HIV-infected but untreated children, gender differences were evaluated after adjustment for age, mother's race, mother's hard drug use during pregnancy, maternal alcohol use during pregnancy, and preterm birth.

The birth group covariate defines the time period in which children were born and reflects the level of ART exposure a child might have acquired in utero. Adjustment with this covariate was necessary because of the changing use of ART in the 3 different time periods. ART prophylaxis of perinatal transmission was not proven before 1994, and only a limited number of women used ART for their own health. From 1994 to the middle of 1996, zidovudine monotherapy was used by almost all women to prevent perinatal HIV transmission. From the middle of 1996 onward, zidovudine continued to be used for prevention of perinatal HIV transmission but the protease inhibitor class of antiretroviral agents became available and many pregnant women received combination ART for their own health. Adjustment according to birth group ensured that comparisons were not made between the 3 different time periods. Clinical site was also examined, to confirm that there was no significant intersite laboratory effect.

Analysis of disease progression was performed with the Kaplan-Meier method; the gender difference was assessed with the log-rank test. A sensitivity analysis to evaluate more thoroughly the gender difference in disease progression was performed with stratified Cox proportional-hazards regression analyses. Mortality risk factor analysis was performed with Wilcoxon rank-sum tests.

	RESULTS

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Demographic Features of HIV-Uninfected Subjects
The uninfected group consisted of 1801 children, of whom 896 were male and 905 were female. Forty-eight percent of the population was black, 35% Hispanic, 11% white, and 6% other or unknown. Twenty-six percent of the children were born before March 1, 1994, 22% between March 1, 1994, and July 31, 1996, and 52% on or after August 1, 1996. The mean number of visits was 9 during the study period. There was no difference in the distribution of any of the baseline variables tested between male and female infants (Table 1).

View larger version (8K): [in this window] [in a new window]   FIGURE 1 Time to death for ART-treated, HIV-infected children, according to gender.

Additional Factors That Might Affect Mortality Rates
To investigate more thoroughly any potential differences in survival rates according to gender, we examined several parameters that might have affected mortality rates in this cohort. For the 79 male infants and 78 female infants who were diagnosed as having HIV on the basis of laboratory studies and were treated with ART, the median ages at diagnosis were 32 and 31 days, respectively (P = .68). Within this cohort, 109 patients started ART, at a median age of 111 days for male infants and 115 days for female infants (P = .47). No differences in the type of ART used were noted (ie, monotherapy, 48 male and 42 female infants; dual therapy, 10 male and 8 female infants; combination therapy, 1 male and 0 female infants; P = .55). Overall, there were 58 CDC class C events (27 male and 31 female infants), with no statistical differences according to gender in the types of events (P = .80) (Table 5). There seemed to be trends toward a greater number of diagnoses of Candida esophagitis among female children and encephalopathy among male children, but the numbers were small. Of note, death as a result of Pneumocystis pneumonia infection occurred for 3 of 4 female patients and 2 of 5 male patients. All 9 case patients were born within the 4-year period between February 1990 and February 1994, and there was no gender difference in the median age at diagnosis of Pneumocystis pneumonia (138 days for male patients and 333 days for female patients; P = .30). The small sample size limited the power to detect differences of statistical significance.

	DISCUSSION

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Numerous studies documented lower plasma RNA values for HIV-infected women, compared with HIV-infected men, after adjustment for CD4⁺ cell counts.^{3–5,19–24} Although it did not make a direct gender-based comparison, the REACH study documented a negative correlation between plasma RNA levels and CD4⁺ cell counts for both adolescent men and women.²⁵ CD4⁺ cell count is used generally as a surrogate measure for time since infection. Whether this is a valid approach has been questioned, and several reports compared plasma RNA levels with and without controlling for CD4⁺ cell count, with similar conclusions. These discrepancies have been noted in incident^4,21 and prevalent^19,20,23 cases of disease. A recent meta-analysis²⁶ of 15 published studies demonstrated a combined –0.23-log unit difference in plasma RNA values for women, compared with men. However, only 1 study⁵ showed a statistical difference in AIDS onset or mortality rates relative to these 2 standard clinical laboratory parameters. Several published reports indicated that mortality rates related to HIV disease and responses to therapy seemed to be no different for women versus men, despite the potential for women to begin ART later in their disease course.^9,21,27

The European Collaborative Study (ECS) examined these issues in a longitudinal pediatric cohort. In contrast to the adult studies, the ECS, examining 186 HIV-infected children up to 12 years of age, found higher CD4⁺ cell, CD8⁺ cell, and total lymphocyte counts for boys than for girls.²⁸ In a separate analysis of the same cohort reported 1 year earlier,²⁹ the investigators documented 0.25- to 0.5-log unit lower plasma RNA levels for females than for males, without evidence of statistically different rates of disease progression. We report gender-based differences in plasma RNA measurements between ART-treated, HIV-infected female and male children, similar to results reported previously for adult patients. We noted a mean –0.38-log unit difference in plasma RNA values for female children, which falls well within the ranges of values from adult studies and the values found by the ECS for pediatric patients.

Historically, survival advantages were seen for adult male patients but, after controlling for other variables, including intravenous drug use, alcohol use, socioeconomic status, and access to care, these advantages disappeared. We found a significant survival advantage for male children despite their higher plasma RNA levels. This survival advantage remained statistically significant after a sensitivity analysis was performed. The survival difference could not be explained on the basis of age at HIV diagnosis, age at initiation of ART, or type of therapy used. The potential role of adherence in these results could not be tested. Virtually all of the patients in this cohort were receiving monotherapy or dual therapy with nucleoside analogues. The mortality results could reflect the nature of the therapy (for example, the potency of zidovudine versus didanosine monotherapy). It was not possible to test this hypothesis with the current data set, because individual drugs were not recorded; only the drug class was specified. One child received combination therapy. A larger cohort analysis might elucidate a factor or factors integral to these findings. In addition, a comparison of female and male children receiving potent combination therapy may prove useful. If mortality differences persist among patients receiving current standard-of-care treatment, then it may be necessary to reevaluate the approach to initiating therapy for pediatric patients.

Currently, postpubertal hormonal differences have been invoked as one potential means of explaining gender differences in plasma RNA levels. In vitro, estrogen inhibits tumor necrosis factor- production, and tumor necrosis factor- has been shown to be important in HIV-1 expression.³⁴ Our results seem to contradict this assumption, because all of the children were prepubertal.

We found significant gender and racial differences in almost all of the immunologic parameters tested for our population of HIV-exposed but uninfected children. Of the variables that were comparable to the ECS analysis, there was general agreement that female children had greater CD4⁺ cell and total lymphocyte counts and lower CD8⁺ cell counts, compared with male children. Children born to black mothers had lower overall lymphocyte counts and subset counts than did children born to white mothers. These results, in comparison with a recent cross-sectional analysis of healthy, HIV-nonexposed children up to 18 years of age,¹¹ raise some interesting issues.

Pediatric AIDS Clinical Trials Group 1009 studied immunologic parameters, determined with 3-color flow cytometry, cross-sectionally in a large cohort of healthy children and adolescents. The rationale for the study was based on the need for reference ranges of cell counts and subsets for this population, for comparison in other analyses. After adjustment for laboratory variation, the researchers found no statistically significant gender or racial differences, and they suggested that a single standard could be used for all pediatric populations.¹¹ Our analysis and the analysis by the ECS suggest that children who have been exposed to HIV and ART but remain uninfected have differences in lymphocyte subsets that are based on gender and race. The WITS also adjusted for laboratory variation and found that gender and racial effects remained statistically significant, which is in contrast to the Pediatric AIDS Clinical Trials Group 1009 study. Among factors that might be invoked to explain these observed differences are potential adverse mitochondrial effects, resulting from HIV exposure, ART exposure, or both, on the developing fetus and the possibility of effects on immunologic parameters among these children. In addition, the nature of the 2 studies (cross-sectional versus prospective) may have influenced the results.

	CONCLUSIONS

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We report gender differences in plasma RNA levels between ART-treated, HIV-infected, female and male children. This result is in agreement with previous work published by the ECS and is in general agreement with published adult literature. However, we found no difference between male and female children with respect to lymphocyte counts. This result is in contrast to previous work published by the ECS, and it may reflect the generally small number of HIV-infected children analyzed in this data set. This finding requires confirmation in other pediatric cohorts, because of the implications for therapeutic decision-making. We also noted gender and racial differences among HIV-uninfected children for most immunologic parameters analyzed, which is in contrast to a previously published study of healthy children and adolescents.¹¹ A comparison of these 2 cohorts might resolve this controversy but, if the findings are validated statistically, then there is the possibility that HIV-exposed children have subtle immunologic perturbations that need to be characterized fully.

Finally, we report a significant survival advantage for HIV-infected male children treated with ART, despite their higher plasma RNA values. This advantage was significant even after a sensitivity analysis. It could not be explained on the basis of readily available parameters such as age at HIV diagnosis or type of ART. However, few children were treated with more than monotherapy and, before the implications of these results are considered more thoroughly, an analysis of children receiving potent combination therapy should be performed. If the data remain significant, then it may warrant a reevaluation of our treatment strategies.

	ACKNOWLEDGMENTS

 
Additional support was provided by local clinical research centers, as follows: Baylor College of Medicine (Houston, TX), National Institutes of Health (NIH) grant GCRC RR000188; Columbia University (New York, NY), NIH grant GCRC RR000645.

Principal investigators, study coordinators, program officers, and funding NIH were as follows: Clemente Diaz and Edna Pacheco-Acosta (University of Puerto Rico, San Juan, PR; NIH grant U01 AI 034858); Ruth Tuomala, Ellen Cooper, and Donna Mesthene (Boston/Worcester site, Boston, MA; NIH grant 9U01 DA 015054); Phil LaRussa and Alice Higgins (Columbia Presbyterian Hospital, New York, NY; NIH grant U01 DA 015053); Sheldon Landesman, Edward Handelsman, and Ava Dennie (State University of New York, Brooklyn, NY; NIH grant U01 HD 036117); Kenneth Rich and Delmyra Turpin (University of Illinois at Chicago, Chicago, IL; NIH grant U01 AI 034841); William Shearer, Susan Pacheco, and Norma Cooper (Baylor College of Medicine, Houston, TX; NIH grant U01 HD 041983); Joana Rosario (National Institute of Allergy and Infectious Diseases, Bethesda, MD); Robert Nugent (National Institute of Child Health and Human Development, Bethesda, MD); Vincent Smeriglio and Katherine Davenny (National Institute on Drug Abuse, Bethesda, MD); and Bruce Thompson (Clinical Trials and Surveys Corp, Baltimore, MD; NIH grant N01 AI 085339); scientific leadership core: Kenneth Rich (principal investigator) and Delmyra Turpin (study coordinator) (NIH grant 1 U01 AI 050274-01).

	FOOTNOTES

 
Accepted Jan 19, 2006.

Address correspondence to Marc Foca, MD, Department of Pediatrics, Division of Infectious Diseases, Morgan Stanley Children's Hospital of New York Presbyterian, 622 W. 168th St, VC-4 East, Room 449H, New York, NY 10032. E-mail: mdf10{at}columbia.edu

This work was presented at the 8th Conference on Retroviruses and Opportunistic Infections; February 4–8, 2001; Chicago, IL.

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

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1. Delmas MC, Jadand C, De Vincenzi I, et al. Gender difference in CD4⁺ cell counts persist after HIV-1 infection: SEROCO Study Group. AIDS. 1997;11 :1071 –1073[ISI][Medline]
2. Prins M, Robertson JR, Brettle RP, et al. Do gender differences in CD4 cell counts matter? AIDS. 1999;13 :2361 –2364[CrossRef][ISI][Medline]
3. Anastos K, Gange SJ, Lau B, et al. Association of race and gender with HIV-1 RNA levels and immunologic progression. J Acquir Immune Defic Syndr. 2000;24 :218 –226[ISI][Medline]
4. Sterling TR, Lyles CM, Vlahov D, Astemborski J, Margolick JB, Quinn TC. Sex differences in longitudinal human immunodeficiency virus type 1 RNA levels among seroconverters. J Infect Dis. 1999;180 :666 –672[CrossRef][ISI][Medline]
5. Farzadegan H, Hoover DR, Astemborski J, et al. Sex differences in HIV-1 viral load and progression to AIDS. Lancet. 1998;352 :1510 –1514[CrossRef][ISI][Medline]
6. Junghans C, Ledergerber B, Chan P, Weber R, Egger M. Sex differences in HIV-1 viral load and progression to AIDS: Swiss HIV Cohort Study. Lancet. 1999;353 :589[ISI][Medline]
7. Moore AL, Mocroft A, Madge S, et al. Gender differences in virologic response to treatment in an HIV-positive population: a cohort study. J Acquir Immune Defic Syndr. 2001;26 :159 –163[CrossRef][ISI][Medline]
8. Moore AL, Sabin CA, Johnson MA, Phillips AN. Gender and clinical outcomes after starting highly active antiretroviral treatment: a cohort study. J Acquir Immune Defic Syndr. 2002;29 :197 –202[ISI][Medline]
9. Moore AL, Kirk O, Johnson AM, et al. Virologic, immunologic, and clinical response to highly active antiretroviral therapy: the gender issue revisited. J Acquir Immune Defic Syndr. 2003;32 :452 –461[ISI][Medline]
10. Maini MK, Gilson RJ, Chavda N, et al. Reference ranges and sources of variability of CD4 counts in HIV-seronegative women and men. Genitourin Med. 1996;72 :27 –31[ISI][Medline]
11. Shearer WT, Rosenblatt HM, Gelman RS, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112 :973 –980[CrossRef][ISI][Medline]
12. AIDS Clinical Trials Group. Immunology. Available at: http://aactg.s-3.com/immlab.htm. Accessed January 21, 2006
13. AIDS Clinical Trials Group. Virology. Available at: http://aactg.s-3.com/virlab.htm. Accessed January 21, 2006
14. Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Recomm Rep. 1994;43 (RR-12):1–10
15. Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986;42 :121 –130[CrossRef][ISI][Medline]
16. Neu N, Leighty R, Adeniyi-Jones S, et al. Immune parameters and morbidity in hard drug and human immunodeficiency virus-exposed but uninfected infants. Pediatrics. 2004;113 :1260 –1266[Abstract/Free Full Text]
17. Rudy BJ, Wilson CM, Durako S, Moscicki AB, Muenz L, Douglas SD. Peripheral blood lymphocyte subsets in adolescents: a longitudinal analysis from the REACH project. Clin Diagn Lab Immunol. 2002;9 :959 –965
18. Douglas SD, Rudy B, Muenz L, et al. Peripheral blood mononuclear cell markers in antiretroviral therapy-naive HIV-infected and high risk seronegative adolescents: Adolescent Medicine HIV/AIDS Research Network. AIDS. 1999;13 :1629 –1635[CrossRef][ISI][Medline]
19. Evans JS, Nims T, Cooley J, et al. Serum levels of virus burden in early-stage human immunodeficiency virus type 1 disease in women. J Infect Dis. 1997;175 :795 –800[ISI][Medline]
20. Lyles CM, Vlahov D, Farzadegan H, et al. Comparison of two measures of human immunodeficiency virus (HIV) type 1 load in HIV risk groups. J Clin Microbiol. 1998;36 :3647 –3652[Abstract/Free Full Text]
21. Sterling TR, Vlahov D, Astemborski J, Hoover DR, Margolick JB, Quinn TC. Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. N Engl J Med. 2001;344 :720 –725[Abstract/Free Full Text]
22. Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter: AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med. 1996;335 :1091 –1098[Abstract/Free Full Text]
23. Rezza G, Lepri AC, d'Arminio Monforte A, et al. Plasma viral load concentrations in women and men from different exposure categories and with known duration of HIV infection: I.CO.N.A. Study Group. J Acquir Immune Defic Syndr. 2000;25 :56 –62[CrossRef][ISI][Medline]
24. Donnelly CA, Bartley LM, Ghani AC, et al. Gender difference in HIV-1 RNA viral loads. HIV Med. 2005;6 :170 –178[CrossRef][ISI][Medline]
25. Holland CA, Ellenberg JH, Wilson CM, et al. Relationship of CD4⁺ T cell counts and HIV type 1 viral loads in untreated, infected adolescents: Adolescent Medicine HIV/AIDS Research Network. AIDS Res Hum Retroviruses. 2000;16 :959 –963[CrossRef][ISI][Medline]
26. Napravnik S, Poole C, Thomas JC, Eron JJ Jr. Gender difference in HIV RNA levels: a meta-analysis of published studies. J Acquir Immune Defic Syndr. 2002;31 :11 –19[ISI][Medline]
27. Nicastri E, Angeletti C, Palmisano L, et al. Gender differences in clinical progression of HIV-1-infected individuals during long-term highly active antiretroviral therapy. AIDS. 2005;19 :577 –583[ISI][Medline]
28. European Collaborative Study. Are there gender and race differences in cellular immunity patterns over age in infected and uninfected children born to HIV-infected women? J Acquir Immune Defic Syndr. 2003;33 :635 –641[ISI][Medline]
29. European Collaborative Study. Level and pattern of HIV-1 RNA viral load over age: differences between girls and boys? AIDS. 2002;16 :97 –104[CrossRef][ISI][Medline]
30. Friedland GH, Saltzman B, Vileno J, Freeman K, Schrager LK, Klein RS. Survival differences in patients with AIDS. J Acquir Immune Defic Syndr. 1991;4 :144 –153
31. Santoro-Lopes G, Harrison LH, Moulton LH, et al. Gender and survival after AIDS in Rio de Janeiro, Brazil. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;19 :403 –407[ISI][Medline]
32. Tu XM, Meng XL, Pagano M. Survival differences and trends in patients with AIDS in the United States. J Acquir Immune Defic Syndr. 1993;6 :1150 –1156
33. Morgello S, Mahboob R, Yakoushina T, Khan S, Hague K. Autopsy findings in a human immunodeficiency virus-infected population over 2 decades: influences of gender, ethnicity, risk factors, and time. Arch Pathol Lab Med. 2002;126 :182 –190[ISI][Medline]
34. Shanker G, Sorci-Thomas M, Adams MR. Estrogen modulates the expression of tumor necrosis factor mRNA in phorbol ester-stimulated human monocytic THP-1 cells. Lymphokine Cytokine Res. 1994;13 :377 –382[ISI][Medline]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Foca, M. Search for Related Content PubMed PubMed Citation Articles by Foca, M. Related Collections Infectious Disease & Immunity Related AAP Red Book topics: Human Immunodeficiency Virus...

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