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The Relationship between Virus Load Response to Highly Active Antiretroviral Therapy and Change in CD4 Cell Counts: A Report from the Women's Interagency HIV Study

  1. Jack A. DeHovitz1,2,
  2. Andrea Kovacs4,
  3. Joseph G. Feldman1,
  4. Kathryn Anastos3,
  5. Mary Young6,
  6. Mardge Cohen7,
  7. Stephen J. Gange8,
  8. Sandra Melnick9 and
  9. Ruth M. Greenblatt9
  1. 1Department of Preventive Medicine and Community Health, New York
  2. 2Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York
  3. 3Department of Medicine, Catholic Medical Centers of New York, New York
  4. 4Division of Pediatric Infectious Diseases, University of Southern California, Los Angeles, San Francisco
  5. 5Department of Medicine, University of California, San Francisco
  6. 6Department of Medicine, Georgetown University, Washington, DC
  7. 7Department of Medicine, Cook County Hospital, Chicago, Illinois
  8. 8Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland
  9. 9Analytic Epidemiology Research Branch, National Cancer Institute, Bethesda, Maryland
  1. Reprints or correspondence: Dr. Jack A. DeHovitz, Box 1240, State University of New York, Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11201 (jdehovitz{at}downstate.edu).

  1. Presented in part: 37th annual meeting of the Infectious Diseases Society of America, Philadelphia, November 1999 (abstract 332).

 
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Abstract

The relationship between the pattern of virus load response to highly active antiretroviral therapy (HAART) and CD4 lymphocyte response was assessed in a cohort of 249 human immunodeficiency virus (HIV) type 1—infected women at 3 times: 1 before and 2 after initiation of therapy, with follow-up of 6–12 months. Patients with a durable response to HAART (i.e., >1 log decrease in HIV-1 RNA sustained for the study periods) had a continuous and significant increase in CD4 cell counts over time, whereas those with no response (<0.5 log decrease in HIV-1 RNA) had a slight decline. Patients with a mixed response (initial decrease >1 log, followed by a subsequent decrease <0.5 log) had an increase in CD4 cell count, followed by a plateau. The trend in CD4 cell count differed significantly by response to HAART, with those patients who experienced a durable response having significantly higher CD4 cell counts than others.

The benefit of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) type 1 infection has been attributed primarily to its suppression of viral replication, as demonstrated in clinical trials [1]. As a result, the recommended goal of such therapy is to maintain the virus load below the level of quantitation with the most sensitive assay available [2]. Nonetheless, virologic success rates reported from randomized trials typically have not been replicated in clinical settings. In contrast to the 70%–90% success rates observed in clinical trials [3, 4], several reports suggest that only ⩽50% of patients in nonstudy settings achieve this level of suppression [5, 6]. In the Women's Interagency HIV Study (WIHS), a multicenter prospective study of the natural history of HIV infection in women, a clear benefit from HAART overall was observed [7]. However, as expected, not all women responded to antiretroviral therapy.

Nonetheless, patients experiencing virologie failure of HAART may still derive immunologie benefit. Several observational studies have reported that even those patients who have virologie failure may have a sustained positive CD4 cell count response [5, 6, 8]. In one study [5], the CD4 response was not different in those with a complete virologie response at 48 weeks versus those who had a durable but partial response during the same time. In an earlier publication from a Swiss cohort [8, 9], interruption of HAART was associated with a significant decrease in CD4 cells, suggesting that adherence to HAART, not viremia, is the most significant factor in predicting CD4 cell count. Analysis of drug resistance mutations in that study demonstrated mutations in both the reverse transcriptase and protease domains [9]. Those results suggest that both small reductions in virus load and diminished viral fitness in mutated viruses could explain the relatively stable CD4 counts in patients who have persistent viremia. Such information could dramatically alter current therapeutic strategies, if confirmed in larger cohorts. However, it is unknown how the pattern of virus load response over time influences changes in CD4 cell counts.

The WIHS cohort is uniquely positioned to help answer this question. Data on serial virus loads and CD4 cell counts, as well as information on the antiretroviral therapy use of participants, have been collected at 6-month follow-up visits. We studied a group of women on HAART for 6–12 months, to assess the determinants of the CD4 response in the setting of continued antiretroviral therapy.

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Methods

Study population

The WIHS methods and baseline cohort characteristics have been described elsewhere [10]. Briefly, between October 1994 and November 1995, 2059 HIV-infected women were enrolled in the WIHS at 6 sites, including New York City (2 sites), Chicago, Los Angeles, the San Francisco Bay area, and Washington, DC. Participants were recruited through HIV primary care sites, drug treatment facilities, and community-based outreach. The sample in the WIHS was similar to that of female subjects reported with AIDS in the United States on the basis of age, race/ethnicity, and risk exposure category. Women were examined at 6-month intervals, at which interviewer-administered questionnaires and comprehensive physical and gynecological examinations were given.

Inclusion criteria

Data for the present study were restricted to 3 visits for each woman who reported using HAART. The first visit was at baseline, before the use of HAART began. Women had to be on HAART continuously during the next 2 follow-up visits after the baseline visit to be eligible for this study. Because a patient could have started HAART at any time between the baseline visit and the first follow-up visit, the length of follow-up was 6–12 months. HAART for this study was defined as therapy consisting of 2 nucleoside inhibitors plus either a protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor.

Laboratory methods

Whole peripheral blood was collected in sodium citrate cell preparation tubes (Vacutainer; Becton-Dickinson, Franklin Lakes, NJ) at each visit. Quantification of HIV-1 RNA in plasma was performed with the isothermal nucleic acid sequence—based amplification method (Organon Teknika, Durham, NC). The HIV-1 RNA determinations were performed in laboratories that participated in the National Institutes of Health Virology Quality Assurance Laboratory proficiency testing program. The lower limit of quantification was 4000 copies/mL. T cell subsets were determined with standard flow cytometry performed in laboratories certified by the AIDS Clinical Trials Groups.

Outcomes

A durable response to HAART was defined as a ⩾1 log decrease in HIV-1 RNA from baseline that was sustained during both of the follow-up visits. A mixed response was defined as a decrease ⩾1 log in HIV-1 RNA from baseline to the first follow-up visit and a decrease <0.5 log from baseline to the second follow-up visit. A nonresponse occurred when the reduction in HIV-1 RNA was <0.5 log decrease from baseline to each of the 2 follow-up visits. At the time virus load was assessed, the level of detection was limited to 4000 copies/mL. As a result, we excluded 31 subjects with virus loads <14,000 at baseline who could not experience a 1-log decrease in virus load.

Data analysis

A multivariate repeated-measures model was used to analyze changes in CD4 response for the durable and mixed responder groups relative to the nonresponders, while adjusting for race/ethnicity, education, age at baseline, pre-HAART HIV RNA level, and use of cocaine, heroin, or methadone at any time before use of HAART Analyses also were conducted for the logarithmic and square root transformations of CD4 cell counts. Models were tested for assumptions of normality, sphericity, equality of variance-covariance matrices, and goodness of fit. Analyses for the transformed data, which met all these assumptions, produced results similar to those for the original counts, and therefore only the model for untransformed data is presented. The adjusted mean CD4 cell counts are least-squares estimates and equal the value that would be expected for a balanced design that includes the independent variables in the model as well as the covariates at their mean levels. All analyses were conducted by SAS software, version 7.0 (SAS Institute, Cary, NC).

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Results

Two hundred forty-nine women qualified for inclusion into the study. Fifty-nine percent of the women were ⩾35 years old; median age at study entry was 37 years. Thirty-five percent of the women had less than a high school education. Fifty percent of the women were black, 21% were white, and 27% were Hispanic. Twenty-seven percent of the women reported use of drugs (cocaine, heroin, or methadone) at some time during follow-up. Median CD4 cell count and virus load were 182/mm3 and 64,317 copies/mL at the start of HAART, respectively.

Twenty-three percent of the women had no HIV RNA response to HAART, 43% had a mixed response, and 34% had a durable HIV RNA response. Response to HAART did not differ statistically by initial CD4 cell count, ethnicity, drug use, age, or education (data not shown). The mean CD4 cell count increased significantly more during the study period among women with a durable HIV RNA response to HAART than among the others (P < .001; figure 1). Among women with no HIV RNA response, the CD4 cell count rose and then declined. Among women with a mixed response, the CD4 cell count rose and then remained constant, whereas among women with a durable HIV RNA response, the CD4 cell count rose continuously over the 3 study visits.

Figure 1
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Figure 1

Observed mean CD4 counts and 95% confidence intervals (CIs) over 3 time points, by response to highly active antiretroviral therapy (HAART).

Figure 2 shows the expected mean CD4 cell counts during each of the 3 study visits by response to HAART, adjusted for age, initial HIV RNA, ethnicity, education, and drug use. By use of multiple comparison analysis, the trend in adjusted CD4 cell counts among women with a durable HIV RNA response differed significantly from the trends among women with mixed or no HIV RNA response. Differences between women with mixed and no HIV RNA response did not reach statistical significance (P = .16). The differences noted above were found whether actual CD4 cell counts or their logarithmic or square root transformations were used.

Figure 2
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Figure 2

Expected mean CD4 cell counts over 3 time periods, by response to highly active antiretroviral therapy (HAART), adjusted for age, ethnicity, education, drug use, and baseline human immunodeficiency virus RNA level.

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Discussion

The results of this multicenter study of HIV-infected women confirm those of previous studies reporting that a mixed response to HAART results in a CD4 cell count higher than baseline, but significantly lower than that seen with a durable response [9]. Patients in this study with no virologic response to HAART had no change in their CD4 cell count. One study, consisting of almost all male subjects, found that CD4 cell response was directly and independently related to the degree of viral suppression below the pretreatment baseline [11]. Our results in women are consistent with this finding. Assuming that CD4 cell count is a reliable surrogate of disease state, these results indicate that, at least in those patients with no virologic response, therapy has little or no benefit. However, it remains possible that clinical benefit is conferred by HAART in the absence of both virologie and immunologie response.

There are emerging data to suggest that lack of viral fitness during antiretroviral therapy may provide clinical and immunologie benefit beyond that resulting from quantitative reductions in HIV-1 RNA in response to the drug therapy. For example, in vivo data have demonstrated that protease mutant HIV-1 replication in lymphoid tissue is slower than that of wild-type virus [12]. Other investigators have found that both nel-finavir-and saquinavir-selected resistant mutant HIV-1 have impaired replication characteristics relative to wild type [13]. Additional evidence from the WIHS indicates that coreceptor utilization may also change in the presence of HAART, potentially resulting in decreased virulence [14].

There may be clinical benefits even without any immunologie effect in patients with no virologie response or viral rebound. A follow-up study of the Swiss cohort [8] measured clinical response in patients in their cohort. At 30 months of follow-up, the risk of disease progression (new clinical AIDS event or death) was 6.6% in those who maintained undetectable virus loads, 9% for those who had viral rebound, and 20% for those who never achieved a full response. There was no difference in clinical outcomes in this study between those who had a durable response versus those with viral rebound (after controlling for baseline CD4). In the United States, the Collaborations in HIV Outcomes Research cohort gave similar results. In patients followed for ⩾6 months, those maintained at 400–20,000 HIV-1 RNA copies/mL were no more likely to develop new AIDS-defining conditions than were those maintained below 400 copies/mL [15].

There are some limitations to our study. First, the determination of use of HAART was based on subject report during a 6-month interval, and we were not able to independently assess the accuracy of the report or the impact of adherence on these findings. However, other studies in the WIHS cohort have shown that correlation was high between self-reported adherence to HAART and virus load (T. Wilson, personal communication). Second, at the time virus load was assessed, the level of detection was limited to 4000 copies/mL, which is far above current tests. However, we did not define durable response by undetectability; rather, we used log decline as our measure. Finally, the impact of virus load on suppression of CD4 cell count was limited to a measurement period of a maximum of 12 months.

In sum, we have found that there was no improvement in immune function among women in whom HAART did not lead to a reduction in HIV RNA. Clearly, the clinical implications of this finding need to be further assessed.

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Acknowledgments

Data for this study were collected by the Women's Interagency HIV Study Collaborative Study Group, with centers (principal investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); Connie Wofsy Study Consortium, San Francisco (Ruth Greenblatt and Herminia Palacio); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and Data Coordinating Center, Baltimore (Alvaro Munoz and Stephen J. Gange).

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Footnotes

  • Informed consent was obtained from all study subjects, and human experimentation guidelines of the US Department of Health and Human Services were followed. Institutional review board approval was obtained at all participating institutions.

  • Financial support: cooperative agreement issued by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Child Health and Human Development (NICHHD), the National Institute on Drug Abuse (NIDA), the National Institute for Dental Research (NIDR), the Agency for Health Care Policy and Research (AHCPR), and the National Cancer Institute (NCI; grants UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-HD-32632, UO1-AI-42590, and NO1-AI-35161). The Women's Interagency HIV Study is funded by the NIAID, with supplemental funding from the NCI, the NICHHD, the NIDA, the NIDR, the AHCPR, and the Centers for Disease Control and Prevention.

  • A list of the centers and principal investigators of the Women's Interagency HIV Study follows the text.

  • Received May 8, 2000.
  • Revision received July 13, 2000.
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  1. J Infect Dis. (2000) 182 (5): 1527-1530. doi: 10.1086/315875
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