Abstract
Background
The clinical implications of a failure to achieve high CD4 cell counts while receiving virally suppressive highly active antiretroviral therapy (HAART) are uncertain.
Methods
We analysed data from HIV-infected men participating in the Multicenter AIDS Cohort Study (MACS) to elucidate associations between CD4 cell counts achieved during virally suppressive HAART and risks of AIDS or death. Inclusion criteria were: CD4 cell count <200 cells/μL before HAART initiation; ≥ viral load (VL) determinations after HAART initiation; and sustained viral suppression, defined as all VL <50 HIV-1 RNA copies/mL, but allowing a single VL of 50–1000 copies/mL.
Results
One hundred and twenty-one men were included; median age was 42 years. After first VL <50 copies/mL, six participants had a new AIDS diagnosis and seven died. The median CD4 cell count change/year (cells/μL) after first VL <50 copies/mL was zero among patients who either developed AIDS or died vs. 39 among those who did not meet either endpoint (P = 0.119). After controlling for time from HAART initiation to first VL <50 copies/mL, age at first VL <50 copies/mL, history of AIDS and antiretroviral therapy (ART) experience before HAART, the hazard ratio for AIDS or death at CD4 cell count of ≤200 vs. >350 cells/μL was 10.7 (P = 0.013), and at CD4 cell count of 201–350 vs. >350 cells/μL was 8.54 (P = 0.014).
Conclusion
In this cohort, lower CD4 cell count at the time of viral suppression was associated with increased risk of AIDS or death.
Keywords: AIDS, CD4 cell count, death, viral load
Introduction
A poor immune response, characterized by absent or modest improvements in CD4 T-cell counts, occurs in 5–27% of patients who achieve suppression of plasma HIV-1 RNA (viral load, VL) to undetectable levels while receiving highly active antiretroviral therapy (HAART) [1–3]. There is substantial interest in therapies that could boost CD4 cell counts in poor immune responders, although it is unproven that such interventions are safe and of long-term benefit. This clinical dilemma is complicated by data suggesting that sub-optimal increases in CD4 cell counts during HAART may not lead to adverse clinical outcomes if maximal suppression of plasma viraemia has been achieved. Thus, when Pneumocystis jiroveci pneumonia (PCP) prophylaxis was discontinued in 19 patients with HAART-driven VL suppression to <50 HIV-1 RNA copies/mL and a median CD4 cell count of only 138 cells/μL, no patient developed PCP during 261 patient months of follow-up [4]. This contrasts with the 20 cases of PCP per 100 patient months reported in a nested cohort study of untreated patients with CD4 cell counts <200 cells/μL [5]. Accordingly, clinical studies of agents aimed at boosting CD4 cell counts during virally suppressive HAART may be justifiable only if additional clinical benefit is likely.
Patients and methods
We analysed data on clinical outcome, viral suppression and sub-optimal CD4 cell counts during HAART in the Multicenter AIDS Cohort Study (MACS), a prospective, observational study of natural and treated histories of HIV-1 infection among men who have sex with men in the United States [6–8]. A total of 6972 men were recruited (4954 in 1984–1985, 668 in 1987–1991 and 1350 in 2001–2003) at four centres located in: Baltimore, MD, USA; Chicago, IL, USA; Los Angeles, CA, USA; and Pittsburgh, PA, USA. The institutional review boards at each of the participating centres approved the MACS protocols, and informed consent was obtained from all participants. Participants returned every 6 months for detailed interviews, physical examinations, quality-of-life assessments, and blood collection for concomitant laboratory testing and storage. Reactive enzyme-linked immunosorbent assays (ELISAs) with confirmatory Western blot tests were used to determine HIV-1 infection status. Plasma HIV-1 RNA levels were measured using the Roche Ultrasensitive RNA polymerase chain reaction (PCR) assay (Hoffman-LaRoche, Nutley, NJ, USA) with a lower detection limit of 50 copies/mL. T-cell sub-set levels were quantified using standardized flow cytometry [9]. AIDS was defined using the 1993 Centers for Disease Control (CDC) case definitions [10], excluding cases identified only by low CD4 cell counts. HAART use was defined according to the Department of Health and Human Services (DHHS)/Kaiser Panel guidelines [11], and summarised at each visit. The date of HAART initiation was defined as the midpoint between the last visit at which no HAART use was reported and the first visit at which such use was reported. Participants included in this analysis were restricted to those with: (i) CD4 cell count <200 cells/μL before HAART initiation; (ii) at least two VL measurements after HAART initiation; and (iii) all VL<50 copies/mL (participants with a single VL rebound to a level <1000 copies/mL with resuppression to <50 copies/mL at next measurement were included). We examined time from first VL<50 copies/mL post-HAART initiation to AIDS-defining illness or death using Cox proportional hazards models. For the analysis, the time from HAART initiation to first VL<50 copies/mL, age at first VL<50 copies/mL, history of AIDS and ART experience before HAART were treated as fixed covariates. The CD4 cell count about 6 months before the visit at which a participant was evaluated for AIDS or was found to have died was examined as a time-varying covariate. A variety of sources were used to obtain death information, including the Social Security Death Index, National Death Index, death certificates, autopsy records, local public health departments, obituaries, notification by the participant's physician, family or friends, and information gathered from other studies or hospitals.
Results
The 121 men who met inclusion criteria had a median age of 42 years at first VL<50 copies/mL; 65% were White, 15% were African American and 20% were Hispanic. Twenty-three per cent had a history of AIDS before the first VL<50 copies/mL; 54% were ART-naïve prior to starting HAART. The median time from HAART initiation to first VL<50 copies/mL was 0.99 years after excluding men who enrolled in 2001–2003 (n = 53). The reason for this exclusion was that this sub-group started HAART before entering the MACS, thus complete information on time from HAART initiation to first VL<50 copies/mL was not available. Compared to the 68 men who started HAART in the MACS, the 53 men who started HAART before enrolment were younger (median age = 39 vs. 45 years) at the time of HAART initiation, and were more likely to be African American (26% vs. 6%) or Hispanic (38% vs. 6%), ART-naïve pre-HAART (77% vs. 35%) and hepatitis C virus (HCV) co-infected (13% vs. 7%).
Six participants had a new AIDS diagnosis after achieving first VL<50 copies/mL and seven died. The causes of death were sepsis and liver failure (one), pulmonary oedema and AIDS (one), lactic acidosis and oesophageal cancer (one), laryngeal cancer (one), coronary artery disease (one), liver failure caused by chronic hepatitis B (one) and unknown (one). Table 1 shows the characteristics of the study participants stratified by endpoint of AIDS, death, or either AIDS or death. Median CD4 cell count at first VL<50 copies/mL was 198 cells/μL among participants who developed AIDS vs. 275 cells/μL among those who did not develop AIDS (P = 0.049); 153 cells/mL among patients who died vs. 278 cells/μL among those who survived (P = 0.028); and 191 cells/mL among participants who developed AIDS or died vs. 288 cells/μL among those who did not meet either of these endpoints (P = 0.008). The median CD4 cell count change per year was 0 cells/μL among patients who developed AIDS vs. 39 cells/μL for patients who did not (P = 0.050); 0 cells/μL for patients who died vs. 38 cells/μL among those who did not (P = 0.357); and 0 cells/μL for patients who either developed AIDS or died vs. 39 cells/μL among those who met neither of these endpoints (P = 0.119). The duration of viral suppression was not significantly different between event and non-event groups: AIDS vs. non-AIDS, P = 0.389; death vs. survival, P = 0.249; AIDS or death vs. no AIDS or death, P = 0.976 (all P-values were obtained from median test).
Table 1.
Characteristics of 121 men in the Multicenter AIDS Cohort Study stratified by the following endpoints: AIDS, death, and either AIDS or death
| AIDS (n = 6) | Non-AIDS (n = 115) | Death (n = 7) | Non-death (n = 114) | AIDS or death (n = 12) | Non-AIDS and non-death (n = 109) | |
|---|---|---|---|---|---|---|
| Nadir pre-HAART CD4 T-cell count (cells/μL) | 64 (26, 103) |
74 (32, 141) |
71 (62, 152) |
74 (30, 135) |
73 (46, 115) |
74 (31, 138) |
| Pre-HAART CD4 T-cell count (cells/μL) | 111 (40, 148) |
87 (42, 156) |
86 (82, 152) |
91 (40, 156) |
77 (91, 150) |
87 (41, 156) |
| Pre-HAART plasma VL (log10 HIV-1 RNA copies/mL) | 5.1 (4.5, 5.2) |
5.1 (4.5, 5.6) |
5.0 (4.2, 5.7) |
5.1 (4.5, 5.5) |
5.1 (4.4, 5.6) |
5.1 (4.5, 5.5) |
| ART-naïve (%) | 50 | 54 | 29 | 55 | 42 | 55 |
| History of AIDS (%) | 67 | 21 | 29 | 23 | 42 | 21 |
| Time from HAART initiation to first VL < 50 copies/mL (years)* | (n = 6) 1.2 (1.0, 3.2) |
(n = 62) 0.8 (0.3, 3.5) |
(n = 6) 2.2 (0.3, 6.1) |
(n = 62) 1.0 (0.4, 3.2) |
(n = 11) 1.2 (0.3, 4.1) |
(n = 57) 0.9 (0.3, 3.3) |
| Age at first VL < 50 copies/mL (years) | 45 (44, 48) |
44 (39, 49) |
48 (43, 56) |
44 (39, 48) |
46 (44, 51) |
44 (39, 48) |
| CD4 T-cell count at first VL < 50 copies/mL (cells/μL) | 198 (167, 207) |
275 (180, 392) |
153 (101, 262) |
278 (193, 392) |
191 (140, 235) |
288 (193, 392) |
| CD4 T-cells change/year after first visit at which VL was < 50 copies/mL (cells/μL) | 0 (0, 4) |
39 (11, 73) |
0 (0, 51) |
38 (11, 73) |
0 (0, 48) |
39 (12, 75) |
| Duration of VL < 50 copies/mL (years) | 7.7 (3.5, 9.1) |
4.3 (3.0, 6.0) |
2.4 (0.5, 4.5) |
4.4 (3.1, 6.4) |
4.0 (1.7, 7.7) |
4.4 (3.0, 6.1) |
Values are medians (interquartile range), unless noted otherwise.
Excluding those who initiated HAART before enrolment during 2001-2003.
ART, antiretroviral therapy; HAART, highly active antiretroviral therapy; VL, viral load.
After controlling for time from HAART initiation to first VL<50 copies/mL, age at first VL<50 copies/mL, history of AIDS and ART experience before HAART, the hazard ratio for AIDS when CD4 cell count was ≤200 compared to >350 cells/μL after first VL<50 copies/mL was 5.96 (P = 0.194). Comparing those with CD4 cell count of 201–350 vs. >350 cells/μL, the hazard ratio was 5.44 (P = 0.176). The hazard ratio for death at CD4 cell count ≤200 vs. >350 cells/μL after first VL<50 copies/mL was 22.8 (P = 0.014), and 10.8 (P = 0.059) when comparing those who achieved CD4 cell count of 201–350 cells/μL to those with counts >350 cells/μL. The hazard ratio for AIDS or death at CD4 cell counts ≤200 vs. >350 cells/μL was 10.7 (P = 0.013). At CD4 cell count of 201–350 vs. >350 cells/μL, the hazard ratio for AIDS or death was 8.54 (P = 0.014) (Table 2). After controlling for the duration of suppression in the model of AIDS and AIDS or death (which had more events), the hazard ratios were unchanged. The model with duration of suppression for death did not converge because of the small number of events and/or possible multivariate dependencies, where several variables may predict another variable. To address concerns about potential lack of opportunity to see a rise in CD4 cell counts because of early deaths, we further censored the analysis to the maximum length of time since the deaths (5 years) plus 6 months to allow the event to occur, but the hazard ratios remained unchanged.
Table 2.
Risk of AIDS or death by CD4 cell count while plasma viral load was <50 HIV-1 RNA copies/mL
|
Hazard ratio (95% CI) for AIDS* (P-value) |
Hazard ratio (95% CI) for death* (P value) |
Hazard ratio (95% CI) for AIDS or death* (P value) |
|
|---|---|---|---|
| CD4 cell count ≤200 cells/μL | 5.96 (0.40, 87.8) (0.194) |
22.8 (1.89, 275) (0.014) |
10.7 (1.65, 70.0) (0.013) |
| CD4 cell count 201-350 cells/μL | 5.44 (0.47, 63.4) (0.176) |
10.8 (0.92, 127) (0.059) |
8.54 (1.54, 47.2) (0.014) |
Compared to having CD4 cell count >350 cells/μL while plasma viral load was <50 copies/mL.
CI, confidence interval.
Discussion
In this cohort of men with HAART-induced plasma HIV suppression, lower CD4 cell counts at the time of viral suppression were associated with increased risk of AIDS or death. An important limitation is that we were unable to obtain stable estimates from the analysis stratified by nadir CD4 cell count because the number of events was small. Nevertheless, these findings suggest that higher CD4 cell counts are desirable even in patients with HAART-induced viral suppression. Several therapeutic agents have generated interest as potential interventions to improve CD4 cell counts in patients receiving HAART, but results have been disappointing so far. Most significantly, interleukin-2, a cytokine that promotes lymphocyte proliferation, was demonstrated to improve CD4 cell counts in two large randomized studies but was not protective against opportunistic pathogens or death [12–14]. Maraviroc, a CCR5 receptor antagonist, also increases CD4 cell counts through mechanisms that are poorly understood but appear to be independent of its anti-HIV activity [15]. However, the clinical consequences of maraviroc-induced CD4 cell count increases in persons who have already achieved viral suppression, if any, are still unknown. Overall, this analysis of MACS data demonstrated an association between higher CD4 cell count at the time of viral suppression and decreased risk of death. This finding provides clinical endpoint evidence in support of further investigation of novel interventions that may improve CD4 cell counts and clinical outcomes in virally suppressed poor immune responders.
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