Sub-optimal CD4 reconstitution despite viral suppression in an urban cohort on Antiretroviral Therapy (ART) in sub-Saharan Africa: Frequency and clinical significance
© Nakanjako et al; licensee BioMed Central Ltd. 2008
Received: 22 July 2008
Accepted: 28 October 2008
Published: 28 October 2008
A proportion of individuals who start antiretroviral therapy (ART) fail to achieve adequate CD4 cell reconstitution despite sustained viral suppression. We determined the frequency and clinical significance of suboptimal CD4 reconstitution despite viral suppression (SO-CD4) in an urban HIV research cohort in Kampala, Uganda
We analyzed data from a prospective research cohort of 559 patients initiating ART between 04/04–04/05. We described the patterns of SO-CD4 both in terms of:- I) magnitude of CD4 cell increase (a CD4 count increase < 50 CD4 cells/μl at 6 months, <100 cells/μl at 12 months; and <200 cells/μl at 24 months of ART) and II) failure to achieve a CD4 cell count above 200 cells/μl at 6,12 and 24 months of ART. Using criteria I) we used logistic regression to determine the predictors of SO-CD4. We compared the cumulative risk of clinical events (death and/or recurrent or new AIDS-defining illnesses) among patients with and without SO-CD4.
Of 559 patients initiating ART, 386 (69%) were female. Median (IQR) age and baseline CD4 counts were 38 yrs (33–44) and 98 cells/μl (21–163) respectively; 414 (74%) started a d4T-based regimen (D4T+3TC+NVP) and 145 (26%) a ZDV-based regimen (ZDV+3TC+EFV). After 6, 12 and 24 months of ART, 380 (68%), 339 (61%) and 309 (55%) had attained and sustained HIV-RNA viral suppression. Of these, 78 (21%), 151 (45%) and 166 (54%) respectively had SO-CD4 based on criteria I), and 165(43%), 143(42%) and 58(19%) respectively based on criteria II). With both criteria combined, 56 (15%) and 129 (38%) had SO-CD4 at 6 and 12 months respectively. A high proportion (82% and 58%) of those that had SO-CD4 at 6 months (using criteria I) maintained SO-CD4 at 12 and 24 months respectively. There were no statistically significant differences in the incidence of clinical events among patients with [19/100PYO (12–29)] and without SO-CD4 [23/100PYO (19–28)].
Using criteria I), the frequency of SO-CD4 was 21% at 6 months. Majority of patients with SO-CD4 at 6 months maintained SO-CD4 up to 2 years. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.
Published definitions of suboptimal CD4 reconstitution among patients with viral suppression
Duration of follow up
Baseline CD4 count
Median (IQR) cells/μl
Definition of SO-CD4
Clinical events among suboptimal responders versus complete responders
596 ART-naïve patients at a community HIV clinic in Cape Town, South Africa
2 NRTIs + 1 NNRTI
Increase < 50 cells/μl at 12 months
1914 ART naïve in HIV clinics in Africa, Latin America and Asia (ART-LINC)
2 NRTIs +1 NNRTI
2 NRTIs + PI (29%)
Increase < 50 cells/μl at 6 months
Prospective observational cohort of 404 ART naïve patients in an HIV clinic at the University of Alabama, Birmingham, US
Mean = 214(SD 260)
2 NRTIs +1 NNRTI
2 NRTIs + PI (40%)
Increase < 50 cells/μl at 6 months
Patients with discordant CD4 and virologic responses were 2.28 times more likely to develop opportunistic infections/death aOR 2.28(1.31–4.00)
21 ART naïve patients attending an Immunology clinic at 2 sites in the US (Ohio and San Francisco)
Increase < 100 cells/μl at 1 year
Retrospective study of 446 patients at an HIV center in the Institute for Tropical diseases, Belgrade
52% ART naïve
Mean 115 ± 95
2 NRTIs + PI (34%)
2 NRTIs+1 NNRTI
Absolute CD4 count of < 400 cells/μl at 2–3 years
Clinical events were no higher among virologic only responders than complete CD4 & virologic responders
EuroSida study – Prospective cohort of 8500 ART naïve patients in 63 hospitals of 20 European countries;
2 NRTIs + PI (86%)
2NRTIs +NNRTI (10.8%)
Increase < 50 cells/μl at 6 months
Prospective cohort of I62 ART experienced but PI -naive patients at an HIV clinic in France
Mean 69 ± 5.0
2 NRTIs + PI
Increase < 50 cells at 12 months
Higher Incidence of AIDS-defining events among virologic only responders (4/7) than complete responders (7/92) [P = 0.07]
Prospective cohort of 2236 PI naïve patients from 68 hospitals in France
Increase < 50 cells/μl at 6 months
Patients with only good virologic responses were 3 times more likely to develop an AIDS-defining illness/death than complete responders RR 3.38 (2.28–5.02)
Swiss cohort study – 293 ART naïve patients
2NRTIs +PI (98%)
Absolute CD4 count below 500 cells/μl at 5 yrs
Higher incidence of CD4 category B events among incomplete responders (13.3%) than incomplete responders (9.6%) p > 0.05
Patients and methods
The Infectious Diseases Institute (IDI) is a private-public partnership institution that is a center of excellence in HIV care, training, and research at Makerere University Medical School and Mulago Teaching Hospital in Kampala, Uganda. Since 2004, the IDI clinic (IDC) has provided free care to HIV positive patients, and by December, 2007, IDC had enrolled 20,000 patients into HIV care, of whom 13,000 are in active follow-up and 4700 have initiated ART according to WHO and Uganda Ministry of Health guidelines. The clinic has 15 exam rooms and is staffed by 20 physicians, 30 nurses, and 10 counselors and patients are reviewed monthly. The drugs are provided by the Global Fund (a generic combined formulation of stavudine [d4T, lamivudine [3TC], and nevirapine [NVP] or by the US President's Emergency Plan for AIDS Relief (a combined formulation of zidovudine [ZDV] and 3TC plus efavirenz [EFZ]/nevirapine [NVP]. Our research was approved by the Uganda National Council of Science and Technology.
Study subjects, procedures and measurements
From April 2004 to April 2005, 559 consecutive HIV-infected patients initiating ART were enrolled into a prospective observational research cohort if they attended the clinic regularly (having attended at least 2 clinic visits in the 6 months prior to ART initiation). Daily co-trimoxazole prophylaxis was provided and patients allergic to co-trimoxazole were given dapsone. Adherence to ART was encouraged by at least 3 individual and group counseling sessions. Patients are reviewed monthly by the general clinic physicians that evaluated among others; adherence to medication, toxicities and acute infections. Patients are evaluated by the study physicians every 3 months or earlier if they develop any illness. HIV RNA viral loads, complete blood counts and CD4 lymphocyte counts are tested at 6 monthly intervals.
Definitions of suboptimal CD4 reconstitution despite sustained viral suppression (SO-CD4)
In this study, we used (i) previously used definitions of SO-CD4 in terms of the magnitude of the CD4 cell increase [a CD4 count increase of < 50 CD4 cells/μl after 6 months of ART [3-6]; <100 cells/μl increase after 12 months ; and <200 cells/μl after 24 months; and (ii) failure to achieve a CD4 cell count above a threshold of 200 cells/μl at 6, 12 and 24 months; the critical CD4 count below which patients remain highly susceptible to opportunistic infections.
Patients were included in the analysis if they had attained and sustained HIV-RNA viral load ≤ 400 copies per ml at 6, 12 and 24 months. The chi square test was used to compare the baseline clinical characteristics of patients with and without SO-CD4 and the level of significance was 0.05. Proportions of patients with SO-CD4 were calculated using the two criteria independently and with the two criteria combined. The combination of the two criteria was the intersection of patients with SO-CD4 on both criteria I) and II). Logistic regression by stepwise model selection was used to analyze predictors of SO-CD4. The independent variables included age, sex, baseline CD4 cell counts, body mass index (BMI), baseline hemoglobin, initial ART regimen, magnitude of CD4 increase in first 6 months and Hepatitis B surface Antigen sero-status. Variables were included in the multivariate model if they had a p value ≤ 0.25 on bivariate analysis. The proportions of clinical events were examined among patients with and without SO-CD4. In addition, the cumulative risk of development of AIDS-related clinical events was estimated by Kaplan-Meier analysis. Patients were censored on the occurrence of an AIDS-related clinical event (the primary outcome) as required by the survival analysis technique. Differences between the survival curves were tested using the log-rank test.
Baseline characteristics of patients with sustained viral suppression over 24 months in the Infectious Diseases. Institute research cohort
Duration of HAART
6 months (N = 380)
12 months (N = 339)
24 months (N = 309)
CD4 increase < 50 cells/μl
CD4 increase ≥ 50 cells/μl
CD4 increase < 100 cells/μl
CD4 increase > 100 cells/μl
CD4 increase < 200 cells/μl
CD4 increase > 200 cells/μl
Age (yrs), [median (IQR)]
BMI increase [median (IQR)]
HAART regimen initiated
Baseline CD4 count [Median(IQR)]
Hepatitis BSAg *
(270 tests done)
Suboptimal CD4 reconstitution
Suboptimal CD4 reconstitution and clinical events among patients with sustained viral suppression in the infectious.
Duration of HAART
0–6 months (N = 380)
6–12 months (N = 339)
12–24 months (N = 309)
i)SO-CD4 magnitude definition
iii) Definitions i & ii combined
With both criteria combined, 56/380 (15%), 129/339 (38%) and 3/309 (1%) had SO-CD4 after 6, 12 and 24 months of ART respectively. Of the patients with SO-CD4 at 6 months, 42/56 (75%) still had SO-CD4 after 12 months of therapy.
Predictors of SO-CD4
Patients with baseline CD4 counts of 50–199 cells/μl were more likely to have SO-CD4 than those with baseline CD4 counts of 0–49 cells/μl at 6 months [OR 2.5(1.1–5.5) P = 0.03] and at 12 months [OR 2.9(1.6–5.4) P = 0.001]. In addition, patients who initiated zidovudine-containing ART regimen were more likely to have SO-CD4 than patients on stavudine-containing ART at 6 months [OR 4.5(2.4–8.3) P < 0.001] and at 12 months [3.6(2.0–6.4) P < 0.001]. Other factors like age, sex, body mass index and hemoglobin level were not significant predictors of SO-CD4.
Clinical significance of suboptimal CD4 reconstitution
In this population with good rates of viral suppression as was previously reported , the frequency of SO-CD4, using the CD4 increase criteria, was 21%, 45% and 54% at 6,12 and 24 months respectively. Our findings are comparable to results from other developing countries (Africa, Latin America and Asia) where 19% of patients had SO-CD4 using a similar criteria of a CD4 increase of < 50 cells/μl after 6 months of ART . Similarly, the frequency of SO-CD4 at 6 and 12 months is comparable to what has been reported in industrialized countries that used similar criteria [4, 11, 13]. Overall, our results show similar profiles of CD4 reconstitution in both the developing and industrialized countries despite the challenges with infrastructure for care delivery in sub-Saharan Africa.
We found that patients with baseline CD4 counts of 50–199 cells/μl were about 3 times more likely to have SO-CD4 than those with baseline CD4 counts of 0–49 cells/μl. Our results are similar to reports from South Africa where patients in the lower CD4 stratum had a higher gradient of CD4 increase . This is contrary to previous reports that advanced pre-treatment immunodeficiency is associated with diminished capacity to restore quantitative and functional CD4 T cell responses during antiretroviral therapy [14, 15]. We attribute our results to the peripheral expansion and/or redistribution of CD4 T cells that is described in the initial phase of CD4 reconstitution on ART . Our results imply that the CD4 increase criteria of SO-CD4 is not enough in a setting where patients present to hospitals and HIV care units with untreated advanced HIV disease [1, 17]. In addition, we used a threshold of 200 cells/μl below which patients were classified as SO-CD4 since this gives an indication of the general susceptibility to opportunistic infections. Using the CD4 threshold criteria, we found that 43%, 42% and 19% had SO-CD4 at 6, 12 and 24 months respectively; thereby remaining at risk of opportunistic infections.
Patients that initiated therapy with a zidovudine-containing regimen were 3.6 times more likely to develop SO-CD4 than patients on a d4T-containing regimen and we attribute this to the myelosuppressive effects of zidovudine . We interpret these results cautiously because only 26% of our patients initiated a zidovudine-containing regimen and they were not randomized. However, evidence in the US shows that use of a protease inhibitor (PI)-based regimen is protective against poor immune reconstitution [6, 19] because PIs modulate activation of peripheral blood CD4 T cells and decrease their susceptibility to apoptosis . Since the long term prognosis of patients exhibiting discordant responses remains unknown , we need to explore the use of the newer and less toxic first line regimens  for patients at risk of SO-CD4.
Age was not a significant predictor of SO-CD 4 in our study and this is consistent with what was reported in a US cohort . However, some previous studies showed that age above 30 years was associated with SO-CD4 [5, 11] because it correlated with thymic involution yet preserved thymic function is necessary for adequate CD4 T cell recovery [11, 23]. Similarly, hepatitis B co-infection did not predict SO-CD4 as was recently reported that hepatitis B co-infection had no impact on the response to ART regarding viral suppression and immune recovery.
Majority of the patients with SO-CD4 after 6 months, using either of the criteria, still had SO-CD4 at 12 months despite sustained HIV-RNA viral suppression. Since patients with SO-CD4 at 6 months are likely to maintain the phenomenon, they may need evaluation of the recovery of CD4 cell function, more so in Africa where there is an increased background risk of opportunistic infections. It is possible that the CD4 cells do not recover both in absolute numbers and function because of the high levels of T-cell activation in Africans due to frequent infections by the various pathogens endemic in the region [10, 25, 26].
It is also likely that these patients may require extended periods of prophylaxis against opportunistic infections. Our analysis was however limited to recovery of peripheral CD4 T cell counts and not CD4 T cell function. We recommend studies to examine other markers of recovery of immunological function among patients with SO-CD4.
We found that about a third of the opportunistic infections occurred among patients with SO-CD4 reconstitution as defined by either the CD4 increase or the threshold criteria. Similar to what has been reported in other cohorts, most of the AIDS-related events occurred in the first 6 months [27–29] and the spectrum of opportunistic infections was similar to what was found among patients at Mulago hospital where most patients with advanced HIV disease were hospitalized with severe bacterial pneumonias and tuberculosis . More AIDS-related events were recorded among patients without SO-CD4 and we postulate that immune reconstitution inflammatory syndrome (IRIS) contributed to this difference . However, Kaplan-Meier analysis showed no statistically significant differences in the rates of AIDS-related clinical events among patients with and without SO-CD4 in the setting of HIV-RNA viral suppression. On the contrary, in industrialized countries, patients with SO-CD4 (using similar criteria) have previously been reported to have a higher risk of developing an AIDS-related clinical events [4, 30]. In the Swiss cohort, suboptimal responders had a 1.5 fold higher incidence of opportunistic infections than the complete CD4 responders . However, we are cautious to compare our results with the latter cohort because the authors used a CD4 threshold below 500 cells/μl after 5 years of ART to define SO-CD4 at a frequency of 35.8%. We need to consider SO-CD4 after longer periods of follow up like has been done in the industrialized countries. Our results add to the emphasis that viral load testing is required for monitoring patients on ART in resource limited settings  especially those patients that present with unsatisfactory CD4 reconstitution in order to guide treatment decisions for this subgroup of patients.
The findings in this study are strengthened by the relatively homogenous study population of ART-naive individuals receiving ART at a single facility using standardized clinical protocols. Our patients used NNRTI-based ART regimen that are used in most HIV care facilities in Africa so our results can be generalized to most patients in Africa however they are limited to patients with sustained HIV-RNA viral suppression which, among others, is the ultimate goal of ART. We need to design studies of interventions for patients on ART with poor immune reconstitution and minimize the time spent with CD4 counts below the 200 cells/μl critical threshold. It is important to note that adherence to ART and previous exposure to ART were not considered to contribute to SO-CD4 in our study since all patients were naïve to ART and patients were included in the analysis only if they had HIV-RNA viral load < 400 copies/ml which we used as a proxy for good adherence.
The frequency of SO-CD4 is high in SSA and many of the patients with SO-CD4 at 6 months maintain the phenomenon up to 2 years of therapy. However, the rates of AIDS-related clinical events were no higher in those with SO-CD4. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.
The authors thank the Infectious Disease Institute research cohort team and all the patients in who participated in this study. We acknowledge Yuka Munabe and Robert Colebunders for their support in reviewing this paper.
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