A key objective of antiretroviral therapy (ART) is to reach and maintain sufficiently high CD4+ cell counts in order to provide long-term protection against opportunistic infections. Current UK and European guidelines suggest starting ART in asymptomatic individuals at a CD4+ cell count below 350 cells/μl . However, a high proportion of HIV-positive people present for care at a late stage of HIV infection and the average CD4+ cell count at ART initiation remains low [2,3]. In 2011, the Health Protection Agency reported that 47% of individuals newly diagnosed with HIV had a CD4+ cell count below 350 cells/μl, with 26% of individuals being severely immunocompromised at diagnosis (CD4+ cell count <200 cells/μl) . Concerns have been raised over the potential that damage to the immune system could be irreversible if ART is deferred in people with very low CD4+ cell counts . These concerns appear to arise from evidence from studies which aimed to assess whether CD4+ cell counts for people on ART with maximum viral load suppression continue to increase in the long term and reach levels seen in HIV-negative individuals [6–12].
As some people experience poor immunological responses despite virologically effective long-term ART , it remains important to investigate the risk of failing to achieve recovery to key thresholds despite regular engagement in HIV care and consistent viral load suppression, particularly among people starting ART with low CD4+ cell counts. Therefore, the aim of this study was to investigate the proportion of people in the UK Collaborative HIV Cohort Study (UK CHIC Study) who start ART with a CD4+ cell count below 100 cells/μl and fail to achieve an adequate CD4+ cell count response (>100, >150, >200, >350, >500 cells/μl), despite regular monitoring and consistent viral load suppression.
The UK CHIC Study collates routinely collected data from HIV-positive individuals seen for care at some of the largest clinical centres in the UK. In brief, centres collect data on demographic information, ART history, laboratory data and AIDS diagnoses . Eligible participants from the 2011 update of the UK CHIC Study had not previously taken ART before 1 January 2000, and had started treatment with a regimen consisting of any combination of at least three antiretroviral drugs, with a CD4+ cell count below 100 cells/μl, with at least 2 years of follow-up on ART. Participants were further required to have achieved viral load suppression (≤50 copies/ml) by 9 months after starting ART and to have maintained this degree of suppression for every viral load assessment throughout up to 5 years of follow-up. Further to this, to ensure that our sample included individuals with closely monitored HIV infection (to minimize the possibility that patients may have been viraemic between visits), participants were required to be regularly engaged with HIV care, defined as 6 months or less between each consecutive viral load assessment, from the start of ART through to the censoring date. We calculated the proportion of people starting ART with CD4+ cell count below 100 cells/μl who failed to achieve CD4+ recovery to key thresholds (>100, >150, >200, >350, >500 cells/μl) by the time of last follow-up, or 5 years from start of ART, whichever occurred first (censoring date for analysis).
Of all UK CHIC participants, 21 512 started ART with at least three drugs after 1 January 2000, having previously been treatment-naive. Of these, 2366 were excluded because they either had no pre-ART CD4+ cell count or no CD4+/viral load measures. Of the remaining 19 146 participants, 3528 had started ART with a CD4+ below 100 cells/μl. Of these, 987 participants were excluded for having less than 2 years of follow-up and a further 1442 were excluded because they did not maintain consistent viral load suppression throughout observed follow-up. Finally, 699 participants were excluded because they were categorized as an infrequent attender (≥6 months between viral load measurements). Thus, of the initial 24 215 participants in the UK CHIC study, 400 were included in the analysis.
Of the 400 participants, 52 were censored at the time of reaching 5 years of follow-up on ART, 278 were censored at the cut-off for data collection for the 2011 cohort, six were censored due to death and the remaining 64 were censored due to loss to follow-up. The median [interquartile range (IQR)] pre-ART CD4+ cell count was 38 (14–65) cells/μl. Participants were 44% black, 46% white, 10% other/mixed race/not known, 69% male with a median age of 40 years at start of ART. Mode of HIV acquisition was 55% through sex between men and women, 37% through sex between men, 2% through injection drug use and 6% other/not known.
The Kaplan–Meier plot in Fig. 1 shows the proportion of individuals who achieved CD4+ cell count recovery to key thresholds by up to 5 years on ART. Of the 400 participants, 2 (0.5%), 8 (2%), 28 (7%), 131 (33%) and 259 (65%) failed to achieve a CD4+ cell count more than 100, 150, 200, 350 and 500 cells/μl by the censoring date, respectively. The highest on-ART CD4+ cell count for the two participants who failed to reach more than 100 cells/μl were 21 and 90 cells/μl, and the median (IQR, range) highest on-ART CD4+ cell count over follow-up in those who failed to achieve a CD4+ cell count of more than 150, 200, 350 and 500 was 118 (100–128, 21–50), 173 (140–179, 21–200), 267 (210–311, 21–350) and 350 (265–424, 21–500) cells/μl, respectively. Kaplan–Meier estimates suggested that the median time to recovery to more than 100, 150, 200, 350 and 500 cells/μl was 0.23, 0.55, 0.98, 2.6 and 4.9 years, respectively. The proportion of people reaching a CD4+ cell count of more than 100, 150, 200, 350 and 500 cells/μl after 1 year on ART was 88, 70, 50, 14 and 3%, respectively, and the proportion reaching these thresholds after 3 years on ART was 98, 95, 90, 59 and 25%, respectively.
Six (2%) of the 400 participants died before the censoring date [recorded cause of death: HIV death, primary effusion lymphoma, metastatic carcinoma (n = 2), unknown (n = 2)]; the median (IQR, range) final CD4+ cell count in this group was 232 (120–375, 64–380) cells/μl. Of the 52 participants with at least 5 years of follow-up, only one (2%) participant did not achieve a CD4+ cell count above 200 cells/μl. The highest on-ART CD4+ cell count for this participant was 191 cells/μl. Table 1 presents various patient characteristics separately for participants who did not achieve CD4+ recovery to key thresholds.
The study, in accordance with another study , has demonstrated that discordant responses, whereby an individual's CD4+ cell count fails to recover to any significant degree despite consistent viral load suppression, is rare in a highly selected subgroup of patients with consistent viral load suppression and regular engagement with care.
To set the context of attaining a CD4+ cell count above the thresholds discussed in our study, it is helpful to consider the risk of AIDS at different CD4+ cell count strata. In a study which looked at the incidence of AIDS stratified by latest CD4+ cell count in the EuroSIDA cohort, the incidence of AIDS in the CD4+ cell count strata 21–50, 51–100, 101–200 and 201–350 cells/μl was 23.4, 10.5, 4.3 and 1.5 per 100 person-years , respectively. These figures demonstrate the clinical significance, in terms of reducing risk of serious disease, of reaching relatively low CD4+ cell count thresholds (100, 150, 200 cells/μl) in people who are severely immunocompromised.
Discordant responses have been associated with an increased risk of disease progression and death [16–18]. In our study, six of the 400 participants included in the analyses died before the censoring date, three of whom had a final CD4+ cell count 150 cells/μl or less. This finding highlights the increased risk of death or disease progression in people who are severely immunocompromised and illustrates that although we have shown that the vast majority of patients will recover CD4+ cell counts to key thresholds if they survive and maintain viral load suppression, there is a risk that some patients will not survive. This finding reinforces the need for close monitoring in people with very low CD4+ cell counts, as well as the need to reduce late presentation. Of the 348 individuals who had less than 5 years follow-up on ART, 64 were censored before 2011; therefore, despite regular attempts to link to the national death register, we cannot rule out the possibility that some of these people may have died.
The biological mechanism behind why CD4+ restoration, despite full viral load suppression, is much slower in some than others remains unclear. Several factors have been found to be associated with poorer restoration of CD4+ cells [19,20], including advancing age [5,21].
A number of limitations should be considered regarding our study. One caveat concerns the difficulty in determining true discordant responses. This may arise if certain patients adapt their adherence behaviour prior to viral load measurements. A consequence of this could be that although a patient does not have a recorded viral load above 50 copies/ml, it could be difficult to rule out the possibility that they may, in fact, have had poor adherence and associated periods of raised viral loads between visits. This was the rationale for excluding participants who were defined as infrequent attenders to clinic visits, so that potential periods of intermittent raised viral loads would be minimized. Our analysis was also limited by the fact that we were unable to determine whether patients were taking concomitant medications (e.g. contrimoxazole) or had other infections that could have impacted upon their CD4+ cell count recovery. Furthermore, by the nature of the question we were addressing, the patients included in our analyses were a highly select group of individuals with intensive viral load monitoring and no known episodes of low-level viraemia. By focusing on this subgroup, we have excluded a large proportion of the HIV-positive population, so consideration should be given to whether there are biases due to other features of the selected subgroup which might lead to better CD4+ recovery apart from their successful viral load suppression. Lastly, our Kaplan–Meier plots should be interpreted with caution due to the fact that we censored follow-up in the small number of people who died, so the curves reflect the probability of recovery conditional on survival. Also, we assume that censoring due to death or end of follow-up is independent of the probability of CD4+ cell count recovery, which, in the former case at least, may well not strictly hold, which could result in some bias.
In conclusion, given a person starting ART with very low CD4+ cell count (median 38 cells/μl in our study) survives, is regularly engaged in HIV care and maintains consistent viral load suppression, there is over a 90% chance of reaching a CD4+ cell count above 200 cells/μl by 3 years. Nonetheless, it remains very important to diagnose patients earlier and to explore ways of improving immune restoration.
J.L.O. undertook the statistical analyses with guidance from A.N.P. and C.A.S. J.L.O. drafted the article with A.N.P., C.A.S., C.J.S. and F.C.L. All other authors contributed to the interpretation of results. All authors have read and approved the final manuscript.
UK CHIC Steering Committee: Jonathan Ainsworth, Jane Anderson, Abdel Babiker, David Chadwick, Valerie Delpech, David Dunn, Martin Fisher, Brian Gazzard, Richard Gilson, Mark Gompels, Phillip Hay, Teresa Hill, Margaret Johnson, Stephen Kegg, Clifford Leen, Mark Nelson, Chloe Orkin, Adrian Palfreeman, Andrew Phillips, Deenan Pillay, Frank Post, Caroline Sabin (PI), Memory Sachikonye, Achim Schwenk, John Walsh, Alan Winston, Nicky Mackie.
Central Co-ordination: UCL Research Department of Infection & Population Health, Royal Free Campus, London (Teresa Hill, Susie Huntington, Sophie Jose, Andrew Phillips, Caroline Sabin, Alicia Thornton); Medical Research Council Clinical Trials Unit (MRC CTU), London (David Dunn, Adam Glabay).
Participating centres: Research Department of Infection and Population Health, UCL, Royal Free Campus (Caroline Sabin); Imperial College Healthcare Trust, London (Nicky Mackie, Alan Winston, John Walsh); North Middlesex University Hospital NHS Trust, London (Jonathan Ainsworth); Homerton University Hospital NHS Trust, London (Jane Anderson); MRC Clinical Trials Unit, London (David Dunn); South Tees Hospitals NHS Foundation Trust, Middlesbrough (David Chadwick); Public Health England Centre for Infections (PHE CfI), London (Valerie Delpech); Brighton and Sussex University Hospitals NHS Trust, Brighton (Martin Fisher); Chelsea & Westminster Hospital NHS Foundation Trust, London (Brian Gazzard, Mark Nelson); Mortimer Market Centre, University College London Medical School (Richard Gilson); North Bristol NHS Trust, Bristol (Mark Gompels); St George's Healthcare NHS Trust, London (Phillip Hay); Royal Free Hampstead NHS Trust, London (Margaret Johnson); South London Healthcare NHS Trust, London (Stephen Kegg); The Lothian University Hospitals NHS Trust, Edinburgh (Clifford Leen); York Teaching Hospital NHS Foundation Trust (Fabiola Martin); Barts and The London NHS Trust, London (Chloe Orkin); University Hospitals of Leicester NHS Trust (Adrian Palfreeman); King's College Hospital NHS Foundation Trust, London (Frank Post); UK Community Advisory Board (Memory Sachikonye).
This work was funded by the Medical Research Council, UK (Grant numbers G0000199, G0600337 and G0900274).
Conflicts of interest
There are no conflicts of interest.
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