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Long-Term Clinical Outcome of Human Immunodeficiency Virus–Infected Patients with Discordant Immunologic and Virologic Responses to a Protease Inhibitor–Containing Regimen

  1. Christophe Piketty1,
  2. Laurence Weiss1,
  3. François Thomas2,
  4. Ali Si Mohamed2,
  5. Laurent Belec1 and
  6. Michel D. Kazatchkine1
  1. 1Department of Immunology, INSERM U430 and Université Pierre et Marie Curie, and
  2. 2Department of Microbiology, Hôpital Européen Georges Pompidou, Paris, France
  1. Reprints or correspondence: Dr. C. Piketty, Service d’Immunologie Clinique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France (christophe.piketty{at}egp.ap-hop-paris.fr).

  1. Presented in part: 40th meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, September 2000 (abstract 1910).

 
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Abstract

Within a prospective cohort of 150 human immunodeficiency virus (HIV)–infected patients who began first-line protease inhibitor therapy in 1996, the outcome of 42 patients with discrepant virologic and immunologic responses to antiretroviral treatment at 12 months was analyzed at 30 months of treatment. The incidence of AIDS-defining events and deaths (14%) in the group of patients with immunologic responses in the absence of a virologic response was higher than that in full-responder patients (2%); yet, the incidence in this group was lower than that in patients with no immunologic response, despite a virologic response (21%), and was lower than that in patients without an immunologic or virologic response (67%; P<.0001, log-rank test). Differences in outcome were significant (relative risk, 6.9; 95% confidence interval, 1.9–39.3) when factors for progression were compared with those of responder patients. The results support the relevance of the CD4 cell marker over plasma HIV load for predicting clinical outcome in patients who do not achieve full immunologic and virologic responses

About 30% of human immunodeficiency virus (HIV)–infected patients receiving highly active antiretroviral therapy (HAART; a triple-drug combination therapy including a protease inhibitor) exhibit a sustained CD4 T cell response, despite the therapy’s failure to kill the virus, or have persistently low CD4 cell counts, despite a significant decrease in plasma virus load [1–5]. Limited information is available on the long-term outcome of patients with such discrepant responses to therapy. Of particular interest are patients with sustained CD4 cell increases for whom therapy has failed to kill virus and for whom recent evidence suggests that they share a risk similar to that of complete-responder patients for clinical progression in the first 12–24 months of therapy [2, 4, 6]. Several mechanisms have been proposed to account for such paradoxical immunologic responses, including the prevention of T cell apoptosis by protease inhibitors [7–10], an alteration in T cell turnover kinetics [11], and changes in viral fitness associated with acquired resistance mutations to protease inhibitors [12–14]

In the present study, we analyzed the long-term clinical, virologic, and immunologic outcomes of a cohort of 150 protease inhibitor–naive, antiretroviral-experienced patients with advanced HIV disease. The patients were treated initially with indinavir combined with 2 nucleoside analogues

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Patients and Methods

Patient populationFrom April through October 1996, 150 HIV-seropositive patients attending the outpatient clinics of Hôpital Broussais (Paris), who initiated HAART were recruited into a prospective study. HIV-1–seropositive individuals (as assessed by ELISA and Western blot) who had not used protease inhibitor were eligible for study participation. No exclusion criteria related to CD4 cell count or plasma HIV RNA were applied. Safety monitoring and AIDS-defining events and deaths were recorded throughout the study. Information was collected through periodic chart reviews

CD4 cell counts and plasma HIV-1 RNA levelsAbsolute numbers of CD4 T cells were determined by flow cytometry, using a FACScan cytofluorometer and Cellquest software (both from Becton Dickinson). CD4 cell counts were obtained 2 weeks before initiation of HAART (baseline) and every 3 months thereafter. Plasma HIV RNA levels were determined by means of the branched DNA signal amplification assay (Quantiplex HIV-RNA 2.0; Chiron). The threshold of the assay in plasma was 500 copies/mL. Plasma virus load was determined within 2 weeks before baseline and every 3 months thereafter

Immunologic and virologic responses at 12 months of follow-upAn immunologic response to therapy was defined as an increase in CD4 cell count from baseline of ⩽100×106 cells/L at 12 months. A virologic response to treatment was defined as a decrease in plasma HIV RNA level ⩾1 log or as achieving plasma HIV RNA level <500 copies/mL. Using this definition, we could classify patients into 4 categories: (1) patients who had an immunologic and virologic response to therapy (I+V+), (2) patients who had no immunologic or virologic response to therapy (I−V−), (3) patients who had a sustained increase in CD4 cell counts in the absence of a significant decrease in plasma HIV RNA levels or with a transient decrease in plasma HIV RNA levels at 1 measure point (I+V−), and (4) patients who had decreased plasma HIV loads in the absence of an increase in CD4 cell count (I−V+)

Long-term immunologic and virologic responsesA long-term immunologic response to treatment was defined as a sustained increase in CD4 cell counts >100×106 cells/L from baseline at 30 months of follow-up. A long-term virologic response was defined as a decrease in plasma HIV RNA levels of ⩾1 log from baseline or as achieving plasma HIV RNA levels <500 copies/mL throughout the 30 months of follow-up

Patients who had been followed for >12 but <30 months were classified according to the their last available CD4 cell counts and plasma HIV RNA level

Data analysisBaseline values of mean plasma virus loads and CD4 cell counts were compared with follow-up values. Fisher’s exact test or χ2 test was used to compare distribution ratios. The nonparametric Kruskal-Wallis analysis of variance test was used to compare mean virus loads and CD4 cell counts between patient groups. Further comparison between 2 groups was done by using the Mann-Whitney U test. Wilcoxon’s signed&amp;rank test was used to compare baseline and follow-up values for individual patients

The times to AIDS-defining event and death were compared according to virologic and immunologic responses by means of Kaplan-Meier survival estimates and log-rank tests. For patients with a previous AIDS diagnosis, only new AIDS-defining events were considered; recurring events were not considered. A Cox proportional hazards model with death and AIDS-defining event as outcome was constructed to allow for the univariate comparison of survival as a function of the following parameters: age at baseline, sex, group of transmission, previous AIDS status, CD4 cell counts at entry (less than or >100×106/L), plasma HIV RNA level at baseline, duration of antiretroviral therapy before study inclusion, change of nucleoside reverse-transcriptase inhibitors (NRTIs) at the time of initiation of HAART, previous zidovudine monotherapy (yes or no), and patterns of virologic and immunologic responses at 12 months (I+V+, I−V−, I+V−, and I−V+). All significant predictive factors in a univariate analysis then were entered simultaneously in a multivariate Cox model and were backward selected (remove P⩽.1). For survivors, follow-up was censored at the date of the most recent follow-up visit

Data were analyzed by use of a statistical software package (Statview 5; SAS institute)

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Results

Overall outcome after 30 months of HAARTAll 150 patients were naive for protease inhibitors and previously had received an NRTI for a mean of 35.0±2.0 months. The patient population included 126 men and 24 women with a mean age of 39.0 years (range, 26–70 years). The study population included 100 men who have sex with men (66.7%), 25 injection drug users (16.7%), 14 patients infected through heterosexual intercourse (9.3%), and 3 patients who had received contaminated blood products (2.0%). The mode of transmission of HIV was unknown for 8 patients (5.3%). Sixty-two patients (41%) had presented with ⩾1 AIDS-defining event before initiation of HAART. All patients were given indinavir (800 mg, 3 times/day) with 2 NRTIs as first-line HAART at the time of inclusion in the study. Nucleoside analogues were zidovudine, stavudine, or lamivudine. Whenever possible, the patients were given NRTIs that they had not previously received. Twenty-six patients (17%) were changed to 2 new nucleosides, 52 (35%) received 1 new nucleoside, and 72 (48%) continued receiving recycled nucleosides, since they began therapy with indinavir

The mean follow-up on treatment of the cohort was 30.7±0.5 months (median, 32.1 months; range, 6–36 months), corresponding to 383 person-years. Seven patients were lost to follow-up after 12 months. No patient had an extended treatment interruption. Mean±SE baseline values for CD4 cell counts and plasma HIV RNA levels were 72.7×106±5.4×106 cells/L and 4.77±0.07 log copies/mL, respectively. Of the 150 patients, 70 (47%) had a CD4 cell count <50×106 cells/L at baseline. Fourteen patients (9%) died during follow-up: 12 deaths were related to AIDS, including cerebral lymphoma (1 patient), non-Hodgkin’s lymphoma (4), severe primary pulmonary hypertension (2), cytomegalovirus infection (4), and pneumococcal pneumonitis (1). The 2 deaths that were not attributed to AIDS were due to colorectal neoplasia (1) and suicide (1). The 2 cases of severe pulmonary hypertension were considered to be related to HIV infection [15], since no other risk factor was identified. AIDS-free survival at 30 months was 88%

Eighteen non-fatal AIDS-related events were observed in 18 patients, including disseminated Mycobacterium avium complex infection (5 patients), cytomegalovirus infection (4), non-Hodgkin’s lymphoma (4), cerebral lymphoma (1), toxoplasmic encephalitis (1), Kaposi’s sarcoma (1), progressive multifocal leukoencephalitis (1), and visceral leishmaniasis (1)

Eighty-two patients (55%) discontinued indinavir treatment during follow-up after a mean of 16.2±0.9 months of use because of side effects, treatment failure, or their physician’s decision. Second-line HAART included ritonavir and saquinavir (38 patients), ritonavir (20 patients), nelfinavir (18 patients), saquinavir (4 patients), and nevirapine (2 patients)

Overall changes in CD4 cell counts and in plasma HIV RNA levels during follow-up are shown in table 1. The mean increase in CD4 cell counts at 30 months was 294×106 cells/L. The increase in CD4 cell counts did not differ between patients with a CD4 cell count <50×106 cells/L at baseline and those with a CD4 cell count >50×106 cells/L at baseline (310.5±30.8 vs. 281.0±25.4; P=.4). Seventy-nine percent of the patients had a CD4 cell count >200×106 cells/L at 30 months of follow-up. The mean decrease in plasma HIV RNA levels was 1.53 log copies/mL. Sixty-three patients (60%) achieved plasma HIV loads <500 copies/mL at 30 months

Figure 1
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Figure 1

Changes in CD4 cell counts and plasma human immunodeficiency virus (HIV) RNA levels, according to immunologic and virologic status within the first 12 months of highly active antiretroviral treatment. A CD4 cell count changes±SE. B Mean plasma HIV RNA level changes±SE. No. of patients evaluated at each time point is shown. I+V+, patients with an immunologic and virologic response to therapy; I+V−, patients with a sustained increase in CD4 cells in the absence of a significant decrease in plasma HIV RNA or with a transient decrease in plasma HIV RNA; I−V+, patients with a decreased plasma HIV virus load without an increase in CD4 cell count; I−V−, patients without an immunologic or virologic response to therapy.

Figure 2
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Figure 2

Kaplan-Meier curve of progression to a new AIDS-defining event or to death, according to immunologic and virologic status within the first 12 months of highly active antiretroviral therapy. I+V+, patients with an immunologic and virologic response to therapy; I+V−, patients with a sustained increase in CD4 cell count in the absence of a significant decrease in plasma human immunodeficiency virus (HIV) RNA levels or with a transient decrease in plasma HIV RNA levels; I−V+, patients with a decreased plasma HIV load without an increase in CD4 cell count; I−V−, patients without an immunologic or virologic response to therapy

Table 1
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Table 1

Changes in CD4 cell counts and plasma human immunodeficiency virus (HIV) load in a cohort of patients with advanced HIV disease receiving highly active antiretroviral therapy

Immunologic and virologic responses to therapyAt 12 months of follow-up, 90 patients (60%) were classified as full immunologic and virologic responders (I+V+), 28 patients (19%) were immunologic responders in the absence of a significant decrease in plasma HIV RNA (I+V−), 14 patients (9%) were virologic responders without having a significant increase in CD4 cell counts (I−V+), and 18 patients (12%) had no immunologic or virologic response to therapy (I−V−). As reported elsewhere [2], there was no significant difference in the response to HAART among these groups on the basis of sex, transmission risk group, Centers for Disease Control and Prevention disease classification, CD4 cell count, or plasma HIV RNA level at baseline. There also was no significant difference among groups in terms of mean time receiving NRTIs before protease inhibitor treatment, the proportion of patients who had received previous zidovudine monotherapy, and the proportion of patients having received a new nucleoside analogue within the first month of initiation of indinavir therapy. A difference among groups was observed with regard to age: I−V+ patients were older than patients in the other groups (46.1±2.7 vs. 38.2±0.68 years; P=.003)

Figure 1 shows the change in CD4 cell counts and plasma HIV RNA levels during the 30 months of follow-up, according to the patients’ immunologic and virologic responses after 12 months of therapy. The mean increase in the absolute number of CD4 cell counts at 30 months was 352×106 cells/L in I+V+ patients, 251×106 cells/L in I+V− patients, 137×106 cells/L in I−V+ patients, and 30×106 cells/L in I−V− patients. At the same time, mean plasma HIV RNA levels had decreased by 1.83 log copies/mL in I+V+ patients, 1.10 log copies/mL in I+V− patients, 1.31 log copies/mL in I−V+ patients, and 0.47 log copies/mL in I−V− patients

Table 2 shows the number and percentage of patients with immunologic and virologic responses at the end of follow-up, according to their initial responses after 12 months of HAART. Among the immunologic and virologic responder patients (I+V+), 83 (92%) remained full responders during follow-up, of whom 39 (47%) were switched to a second-line protease inhibitor during follow-up. Twenty-three (82%) of the 28 patients with an immunologic response in the absence of a virologic response (I+V−) within the first 12 months were changed to a regimen containing a second-line protease inhibitor, and 10 of the 23 were later switched to a third-line protease inhibitor–containing regimen. Despite the changes in antiretroviral treatment, 13 (47%) of the 28 patients had the same pattern of discordant immunologic and virologic responses during the 30 months of follow-up. Six (43%) of the 14 patients with a virologic response in the absence of an immunologic response (I−V+) at 12 months became both immunologic and virologic responders during the 30 months of follow-up. Five patients in this group were changed to a second-line protease inhibitor regimen. Fourteen (78%) of the 18 nonresponder patients (I−V−) at 12 months remained nonresponders during follow-up, despite changes in therapy

Table 2
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Table 2

Long-term (30 months) immunologic and virologic responses of patients with advanced human immunodeficiency virus (HIV) disease receiving highly active antiretroviral therapy, according to their initial responses within the first 12 months of follow-up

Clinical outcome according to the pattern of initial immunologic and virologic response to treatmentAccording to a Kaplan-Meier analysis of progression to new AIDS-defining events or AIDS-related death, the percentage of patients who progressed clinically after 30 months of HAART was 2.2% among I+V+ patients, 14.3% among I+V− patients, 21.4% among I−V+ patients, and 66.6% among I−V− patients (P<.0001; figure 2). For the purpose of the analysis, patients were removed from the cohort once a defined end point occurred. Deaths unrelated to AIDS were not taken into account for the analysis

As determined by univariate analysis, the following were risk factors associated with clinical progression and death among patients who received HAART for 30 months: CD4 cell counts <100×106 cells/L at baseline, plasma HIV RNA levels at baseline, AIDS-defining event before study inclusion, previous zidovudine monotherapy, and duration of antiretroviral therapy before study inclusion. The relative risk (RR) of clinical progression was 51.0-fold higher (95% confidence interval [CI], 11.3–229.8) in the I−V− group than in the I+V+ responder group (P<.0001). Patients in the I+V− group had a 6.5-higher (95% CI, 1.2–35.8) risk of progression than did patients in the I+V+ group (P=.03) but a 0.12-lower (95% CI, 0.04–0.4) risk than did patients in the I−V− group (P=.0004). Patients in the I−V+ group also had a higher risk of progression than did patients in the I+V+ group (RR, 9.7; 95% CI, 1.6–58.4; P=.01) and a 0.2-lower (95% CI, 0.05–0.7; P=.01) risk than I−V− nonresponder patients. When all significant predictive factors were adjusted in a multivariate analysis, patients in the I+V− group remained at higher risk of progression than I+V+ responder patients (RR, 6.9; 95% CI, 1.9–39.3; P=.02) and at lower risk than I−V− nonresponder patients (RR, 0.1; 95% CI, 0.03–0.35; P=.0003). Patients in the I−V+ group also demonstrated a higher risk of progression than patients in the I+V+ group (RR, 13.3; 95% CI, 2.1–84.7; P=.006) and at lower risk than I−V− nonresponder patients (RR, 0.2; 95% CI, 0.06–0.9; P=.03)

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Discussion

We report on the outcome at 30 months of HAART in a cohort of antiretroviral-experienced patients with advanced HIV disease and early discrepant responses to HAART. The overall efficacy of HAART in the cohort was reflected by the high percentage of patients (67%) who had an increase in CD4 cell counts >100×106 cells/L and a decrease in HIV virus load >1.0 log/mL or who achieved persistent HIV RNA plasma levels <500 copies/mL throughout follow-up. The latter figures are within the range of those recently reported by Gulick et al. [16], which confirms the long-term efficacy on immunologic and virologic surrogate markers of triple combination therapy with a protease inhibitor in patients with advanced HIV disease

Forty-two (28%) of the 150 patients in the cohort had discrepant immunologic and virologic responses to therapy within the first 12 months of follow-up. None of the following factors was predictive of a discrepant response to HAART: sex, past history of AIDS-related events, baseline CD4 cell count <50×106 cells/L (before zidovudine monotherapy), mean time using NRTIs before initiation of protease inhibitors, or recycling of nucleoside analogue. Patients with a virologic response in the absence of an immunologic response were older than patients with other patterns of response to treatment. The latter findings are consistent with reports indicating that the magnitude of immune restoration is dependent on thymic activity, which decreases with age [17–19]

Twenty-eight patients (19%) in the cohort had a significant increase in CD4 cell count; however, they did not have a decrease ⩾1.0 log copies/mL in plasma HIV load or achieve plasma HIV RNA levels <500 copies/mL throughout the first 12 months of follow-up. The mean increase in CD4 cells in patients of this group was significantly lower than that in complete responder patients at 30 months (352.4 × 106 ± 22.0 × 106/L vs. 250.7 × 106 ± 46.3 × 106; P=.01). Deeks et al. [5] reported that the mean increase in CD4 cell count at 96 weeks of HAART was associated directly and independently with virus suppression below pretreatment baseline HIV load [20]

In the present study, both univariate and multivariate analysis demonstrated that the percentage of deaths and the percentage of patients experiencing an AIDS-defining event was higher in I+V− individuals than in full immunologic and virologic responder patients. The association between the I+V− pattern of response to HAART and progression to AIDS and death was confirmed after adjusting the groups for baseline CD4 cell counts, baseline HIV RNA levels, previous AIDS-defining event, duration of previous NRTI therapy, and previous zidovudine monotherapy (RR, 6.9). To some extent, these results diverge from those that indicate that I+V− patients had no significant increase in risk of progression within a shorter period of follow-up [2, 4, 20]. The analysis of the data from the Swiss HIV cohort study suggested that, at 30 months of follow-up, patients with viral rebound did not have a higher risk for progression than did patients who reached and maintained undetectable virus loads [6]. In the latter study, the analysis did not take into account the immunologic response. It should be emphasized that, in our study, 86% of the I+V− patients remained free of any AIDS-related event at 30 months of follow-up

The virologic and immunologic characteristics of patients whose CD4 cell counts increase, despite the lack of significant virologic response to HAART, remain unclear. We have provided evidence that, in such patients, the proportion of memory CD4+ T cells and the expression of activation markers were higher and that the production of IL-2 remained lower than that in full responder patients [21]. Several reports have shown that the prevalence and patterns of mutations in the protease gene and viral dynamics in patients with discrepant CD4 T cell responses do not differ from those in patients who do not have an immunologic and virologic response to therapy [1, 14, 21]. There is evidence that the viruses recovered from these individuals, which contain multiple drug-resistance mutations, have decreased fitness in thymic tissue that may permit the regeneration of T cells, despite a persistently elevated virus load [12, 22]

The risk of progression of I+V− patients was significantly lower than that of I−V+ patients and much lower than that of I−V− nonresponder patients. Thus, whereas 86% of I+V− patients are alive and remain free of AIDS-related events at 30 months, this proportion was 79% in the I−V+ patients and 33% in I−V− patients (P<.001)

Our results support the predominance of the CD4 marker over plasma HIV load for predicting clinical outcome in patients who do not achieve a full immunologic and virologic response. Thus, although it may be tempting to switch therapy in patients with discrepant responses to improve the virologic response, there is a potential risk of using most of the available classes of antiretroviral drugs too early in patients with an overall high rate of clinical responses. This may be particularly true for patients with an immunologic response in the absence of a virologic response. In addition, despite the changes in protease inhibitor treatment, half the patients with discrepant CD4 response had the same pattern of immunologic and virologic response during the long-term follow-up. Caution must also be taken not to switch therapy too early on the basis of plasma HIV RNA levels, since a recent study has shown that CD4 cell counts have a better prognostic value than plasma HIV load in patients with advanced HIV disease [23]. Our data emphasize the difficulty in deciding when and how to switch therapy in patients with discrepant responses to HAART, particularly in those with immunologic but not virologic responses. More efforts should be made to determine the threshold of plasma HIV load above which the risk of immunologic and clinical failure becomes significant

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Footnotes

  • Patients provided signed written consent before participating in the study.

  • Financial support: Agence Nationale de Recherches sur le SIDA; SIDACTION; INSERM; Merck Sharp and Dohme, France.

  • Received November 13, 2000.
  • Revision received January 30, 2001.
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  1. J Infect Dis. (2001) 183 (9): 1328-1335. doi: 10.1086/319861
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