Persons with untreated HIV-1 infection typically progress to AIDS at rates proportional to ‘set-point’ plasma viremia [1,2], but there are rare individuals (often termed ‘elite controllers’ [3,4]) with spontaneous control of viremia (SCV) without antiretroviral therapy (ART). Although viral genetic defects have been reported [5–8], the majority are infected with competent viruses [7,9,10] and SCV is attributable to poorly understood immune factors . Genetic screenings have consistently identified human leukocyte antigen class I (HLA-I) as the major determinant of SCV [11,12], although a third or more of persons with SCV have no alleles known to be associated with protection .
The prevalence, demographics, and long-term outcome of SCV are poorly defined. Beyond HLA-I, the role of race is unknown. Many SCV cohorts have been predominately men, and the role of sex is undefined. Finally, few data address the durability of SCV, and influence of the abovementioned factors is underexplored. Here, we assess the frequency, demographics, and outcomes of 53 persons with SCV identified within a group of 29 811 demographically diverse HIV-1-infected persons.
Materials and methods
Study participants, definition of spontaneous control of viremia, and loss of spontaneous control of viremia
In total, 46 524 AIDS Healthcare Foundation (AHF) electronic medical records (Centricity, General Electric Healthcare) from the Los Angeles and Miami metropolitan areas (23 679 and 22 845, respectively) were scanned for persons with three or more plasma viremia measurements spanning at least a year, resulting in 29 811 persons. These were screened for HIV-1-infected persons with SCV defined as at least three consecutive plasma viremia measurements <50 RNA copies/ml spanning at least a year in the absence of ART [14,15]. This screening included all patients in care at AHF clinics (solely outpatient care), mostly public patients without private insurance. Records were reviewed for HIV-1 serologies, viremia, CD4+ T-cell measurements, viral hepatitis B and C serologies, and prescribed medications, all information from the routine care of patients in the clinics. Date of study entry was the initial date of care at AHF. Estimated duration of HIV-1 infection was conservatively calculated as time from first reported positive HIV-1 serology. Loss of SCV was defined by three consecutive plasma viremia measurements ≥50 RNA copies/ml or a single measurement ≥1000 copies/ml. Isolated viremia measurements ≥50 RNA copies/ml not meeting the definition of SCV loss (nonconsecutive) were considered ‘blips’. Follow-up was censored at time of loss of SCV, initiation of ART (not considered loss of SCV), or last available viremia measurement.
Comparisons between persons with versus without SCV and persons with SCV who remained aviremic versus those who became viremic during follow-up were performed using Wilcoxon test and χ2 or Fisher's exact tests. For the SCV group, Kaplan–Meier survival curves were generated for time to loss of SCV, including comparisons between subgroups of race, age, and sex using log-rank tests. Cox proportional hazards modeling for time to viremia was performed including age at infection, hepatitis C virus (HCV) infection status, race, and sex as covariates. Rate of blood CD4+ T-cell level decline during the observation period was estimated using linear mixed-effects modeling with random intercept and fixed-effect covariates of age at time of infection, initial blood CD4+ T-cell level, duration of infection at entry, race, sex, viremic status (persistent SCV versus breakthrough viremia), follow-up time, and the interaction of each covariate with follow-up time, with age at time of infection, initial blood CD4+ T-cell level, and duration of infection at entry, centered at the mean. All analyses were conducted using SAS 9.4 (Cary, North Carolina, USA) or Stata 12 (College Station, Texas, USA).
Normal distribution model for viremia measurements
Viremia measurements <50 RNA copies/ml plasma (<1.7 log10 units) were considered censored. Measurements were assumed to be reasonably independently normally distributed, based on several studies that ‘elite controllers’ generally have very similar mean viremia levels in the range of 1–5 RNA copies/ml plasma, which is a much smaller range than the variability of viremia measurements within persons with typical chronic infection [16–19]. The procedure Tobit (Stata 12) was used to make maximum likelihood estimates for the mean and SD of combined viremia measurements for persons with sustained versus nonsustained SCV during observation. For each of these datasets the full density and the histogram for uncensored observations were graphed together. The histogram was scaled to set its area equal to the area of the corresponding normal density above 1.7 log10 units viremia.
Institutional review board approval
The study was reviewed and approved by the Biomedical Research Institute of America (BioMed IRB), San Diego, California, USA.
Demographics of persons with HIV-1 infection and spontaneous control of viremia
Of 46 524 medical records of HIV-1-infected persons reviewed, 29 811 had adequate viremia measurements for screening, of which 53 (0.18%) were identified as persons with SCV (three consecutive plasma HIV-1 RNA tests <50 copies/ml spanning at least a year without ART, Supplemental Figure S1 and Supplemental Table S1, http://links.lww.com/QAD/B54). In total, 26 (49%) were women, 24 (45%) were men, and three (6%) were transgender (male to female). The group included 33 (62%) black, 17 (32%) white (including four Latino), one (2%) Asian, and two (4%) other/unspecified races. Of 26 self-reported routes of transmission, 24 (45%) were sexual, and two (4%) were via intravenous drug use. Of 18 screened for HLA B*5701, two (11%) had the allele, including two of seven (29%) whites, zero of 10 blacks, and zero of one Asian. Of 47 study participants tested for HCV-reactive antibodies, eight were seropositive, of which five had detectable plasma HCV RNA, and an additional person had detected plasma HCV RNA without serologic testing.
At beginning of observation, median age was 44.8 years [interquartile range (IQR), 36.0–50.4) and minimum duration of infection (using date of infection conservatively estimated as first reported positive HIV-1 serology) was a median of 2.2 years (IQR 0.03–11.8). Median age at the estimated time of HIV-1 infection was 35.1 years (IQR 27.1–42.4). Mean blood CD4+ T-cell level at study entry was 882 cells/μl (SD 344, range 279–1863). Follow-up during SCV was a median of 3.6 years (IQR 2.3–7.6). During observation, nine persons developed viremia after a mean of 6.1 years (SD 3.5, range 1.5–11.3) and five persons initiated ART without preceding development of viremia.
Frequency of spontaneous control of viremia differs by sex and race
SCV prevalence, calculated from the 29 811 persons screened, varied by sex and race (Fig. 1). Women were significantly more likely to have SCV than men (26/4517 = 0.58% versus 24/24 603 = 0.10%, P < 0.001). Blacks were more likely to have SCV than whites (33/10 089 = 0.33% versus 17/16 559 = 0.10%, P < 0.001). These two factors appeared independent; highest frequency was among black women (20/2841 = 0.70%), and lowest frequency was among white men (11/15 064 = 0.07%), with white women (5/1238 = 0.40%) and black men (11/6899 = 0.16%) intermediate. Pairwise comparisons between these four groups were statistically significant for black women versus white men (P < 0.0001), black women versus black men (P < 0.0001), and white women versus white men (P = 0.0004). These data suggest that sex and race are determinants of SCV prevalence.
Progression to viremia typically occurs over years and may vary by demographic group
Nine persons lost SCV during observation off ART; median time to loss was 5.5 years (IQR 3.4–9.4). The rate of loss was relatively linear over the estimated duration of infection (Fig. 2a), corresponding to 1.22% per year, or a half-life of 40.8 years. Black and white races appeared similar with rates of 1.20 versus 1.03% per year (Fig. 2b). Comparing halves of younger versus older estimated ages at time of infection (Fig. 2c, mean age 26.9 ± 4.4 versus 44.3 ± 7.1 years, respectively), there was a statistically insignificant trend for faster loss of SCV in the younger versus older subgroup. Comparing sexes (Fig. 2d, excluding the three male to female transgender persons), there was a larger but statistically insignificant difference for faster progression in women versus men (1.38 versus 0.53% per year, P = 0.50 by log-rank test). This difference was reduced if the three transgender persons (two of three of whom had observed loss of SCV) were included in the male group (Fig. 2e), and increased if they were included in the female group (Fig. 2f) although differences remained statistically insignificant. In the Cox regression model, adjusting for estimated age at infection, HCV status, black versus white race, and sex, transgender (male to female) status was significantly associated with faster progression compared with native female sex (hazard ratio 24.3, P = 0.037). Finally, considering the 18 persons with observed ‘blips’ of plasma viremia ≥50 RNA copies/ml versus 35 without (Fig. 2g), those with blips had significantly greater progression (−2.27 versus −1.23% per year, P = 0.04 by log-rank test).
Higher frequency of intermittently detectable viremia ‘blips’ is associated with loss of spontaneous control of viremia
Because the definition of SCV is arbitrarily based on a limit of detection, ‘blips’ of plasma viremia ≥50 RNA copies/ml were assessed. Comparing those with sustained SCV (44 persons) versus those who lost SCV (nine persons) during observation, blip magnitudes were not obviously different (Supplemental Table S2, http://links.lww.com/QAD/B54 and Fig. 3a versus Fig. 3b) or rising before loss of SCV (Fig. 3c). However, blip frequencies were generally lower for the sustained SCV group, observed in 5.8 (28/484) versus 15.9% (10/63) viremia measurements (Supplemental Table S2, http://links.lww.com/QAD/B54). This difference appeared consistent across 5-year intervals after estimated time of HIV-1 infection (Supplemental Table S2, http://links.lww.com/QAD/B54 and Fig. 4a), and blip frequency did not appear to accelerate before loss of SCV (Supplemental Table S3, http://links.lww.com/QAD/B54).
Blip magnitudes suggested set-point viremia levels <50 RNA copies/ml plasma
Blip magnitude distributions of both groups were consistent with the tails of log-normal curves censored at the limit of detection (Fig. 4b), in agreement with the known log-normal distribution of plasma viremia in general [1,2]. By censored curve fitting to a normal distribution (Supplemental Figure S2, http://links.lww.com/QAD/B54), the estimated means of viremia for the sustained and nonsustained SCV groups were 4.5 and 6.7 RNA copies/ml plasma, respectively (not statistically significantly different), consistent with biological observations of persistent low level viremia in persons with SCV [16–19]. These data suggested that blips reflected variation around stable mean values <50 copies/ml.
Blood CD4+ T-cell level showed overall stability in persons during spontaneous control of viremia (without antiretroviral therapy)
Counts across all persons plotted versus estimated duration of infection showed no clear overall pattern over time (Fig. 5a). For the 40 study participants with serial observations spanning at least 2 years of SCV without ART (33 and seven persons with sustained versus nonsustained SCV during observation, respectively), slopes of blood CD4+ T-cell levels varied with a normal distribution centered near zero cells/μl per year, without a clear difference between those observed to sustain versus lose SCV during observation (Fig. 5b). Comparisons of women versus men and blacks versus whites also showed no significant differences (not shown).
In a mixed-effects model (excluding the three transgender study participants) including all CD4+ T-cell observations during SCV, the overall slope for change in CD4+ T-cell count (assuming mean values in the cohort for age at estimated time of infection, baseline blood CD4+ T-cell level, duration of infection, white race, male sex, and sustained SCV) was slightly negative at −9.8 cells/μl per year (Supplemental Table S4, http://links.lww.com/QAD/B54). The slope was more negative by −17.7 in the nonsustained SCV group compared with the SCV group, although this difference was not statistically significant. Higher initial blood CD4+ T-cell levels at entry and older age at infection were significantly associated with more negative slopes (by −0.02, P = 0.008, and −1.9, P < 0.0001, respectively). There was no significant change in slope by race or sex.
Studies of persons with SCV (’elite control’) are challenging given the widely varying definitions of SCV, rarity of SCV, and heterogeneity of these persons in terms of factors such as sex, race, coinfections, route of infection that could influence prevalence and outcome of SCV, and monitoring. Prior reports have examined isolated persons and not the prevalence of SCV in demographic context, with few exceptions (Supplemental Table S5, http://links.lww.com/QAD/B54). Olson et al. compared various definitions of ‘elite control’ in over 17 000 persons (from Europe, Canada, Australia, and sub-Saharan Africa) followed from time of seroconversion. Their three most stringent definitions included one similar to ours (three consecutive plasma viremia measurements <75 RNA copies/ml spanning more than 1 year, without ‘blips’ >1000). Grabar et al. examined SCV in more than 27 000 French patients under care for chronic infection, using a more limiting definition of asymptomatic ART-naïve persons infected at least 10 years with 90% of viremia measurements <500 RNA copies/ml and the most recent measurement <50 RNA copies/ml. Lambotte et al. studied SCV from a partially overlapping French cohort of 2851 persons using a similar definition. Okulicz et al. described SCV in a cohort of over 4400 US persons under care for chronic infection, defining SCV as at least three undetectable plasma viremia measurements using varying sensitivities of 400, 200, or 50 RNA copies/ml, spanning at least one year.
Across these four studies, the overall prevalence of SCV varied (Supplemental Table S5, http://links.lww.com/QAD/B54). Using definitions of SCV similar to ours, Olson et al. and Okulicz et al. reported prevalences of 0.55 and 0.56%, and using more stringent criteria Grabar et al. and Lambotte et al. reported 0.25 and 0.53%, compared with our lower rate of 0.18%. Explanations for this discrepancy might include our lower limit of viremia detection (50 RNA copies/ml) compared with theirs (ranging from 75 to 500 copies/ml), differences in patient enrollment (i.e. longer duration of infection before enrolling for care at AHF versus the other cohorts) or monitoring (frequency of viremia measurements), or demographic differences between cohorts. A cross-sectional study of single measurement viremia set-point levels in 330 persons about 10 months after infection quoted rates of 0.3% (1/330 persons) <20 RNA copies/ml or 3.6% (12/330 persons) <200 RNA copies/ml , suggesting that our lower plasma viremia cutoff contributed in part to our lower prevalence of SCV.
Known differences in the pathogenesis of infection based on sex and race would suggest that SCV varies according to these characteristics. To our knowledge, our data provide the most detailed breakdown of SCV prevalence by sex and race available. We observe significantly higher prevalence of SCV among women (0.38%) versus men (0.062%). Olson et al. and Okulicz et al. did not specify SCV prevalence in women versus men, but contain enough sex information to infer female versus male rates as 0.92 versus 0.44% and 1.18 versus 0.49%, respectively (Supplemental Table S5, http://links.lww.com/QAD/B54), in agreement with our findings and also consistent with multiple studies showing that viremia is generally lower in women than men [22–27]. We also find SCV prevalence may be higher in blacks than whites, 0.19 versus 0.07%, respectively. Okulicz et al. did not observe this difference (0.55 versus 0.66%, respectively), although their study differed in SCV criteria and smaller sample size (Supplemental Table S5, http://links.lww.com/QAD/B54). Our finding is consistent with reported lower viremia levels in blacks versus whites with chronic HIV-1 infection [26–28]. Considering sex and black/white race, these appear to be independent factors in prevalence of SCV (Fig. 1). Again, a potential caveat is the duration of infection before presenting for care; for example, we cannot exclude that earlier presentation of women or blacks contributes more observation of SCV compared with men or whites, respectively.
Few studies have defined durability of SCV. Olson et al. depicted a figure showing 52 of 95 persons losing SCV between ∼2 and ∼22 years of follow-up but did not explicitly provide survival data for loss of SCV; our examination of their data (censored survival) indicates a linear drop-off with a slope of −4.25% per year (r2 = 0.90, not shown). This is greater than our rate of −1.22% per year, perhaps because they followed persons from seroconversion and, therefore, included shorter duration SCV that may have been missed in our cohort; alternatively, they could have overestimated SCV loss if asymptomatic persons were more likely to drop out of follow-up (to be censored).
Several studies have noted intermittent ‘blips’ of detectable viremia in ‘elite controllers’, which we also observed. Because our definition for SCV loss includes consecutive detectable viremia measurements, it is not surprising that significantly fewer blips were observed in persons with sustained versus nonsustained SCV, and persons with no observed blips versus observed blips during observation exhibited significantly slower progression to loss of SCV. More interestingly, although we did not observe statistically significantly different blip magnitudes in these comparisons, the magnitudes appeared to fit censored log-normal distributions with means below the limit of detection. Our estimates are consistent with prior reports that ‘elite controllers’ have persistent plasma viremia averaging 1–5 RNA copies/ml [16–19], and suggest that blips do not reflect intermittent viral replication in the setting of quiescent infection, but rather represent persistent viremia with normal biologic and/or assay variability for spanning the limit of detection. This strongly suggests that persons with SCV are not qualitatively different, but rather represent an extreme in the continuum of log-normally distributed plasma viremia set-point levels (which are inversely correlated to rate of disease progression) across persons with untreated HIV-1 infection [1,2].
To our knowledge, our report is the first to examine loss of SCV comparing sexes and races. Unfortunately, small numbers limited statistical power for such comparisons. However, the observation that women lost SCV more rapidly than men is consistent with reports that women progress more rapidly than men despite lower set-point viremia levels in early infection [22–24,26,27]. We did not note a difference between blacks and whites, however, despite reports suggesting more rapid progression in the former [26–28]. Unfortunately, there have been too few Asians in studies of SCV to estimate prevalence or outcomes in that race, and there are only rare descriptions of SCV in East and South Asians [29,30] despite the large numbers of persons infected in China and India. Okulicz et al. reported a rate of none of 73, and we found one of 601 (0.17%), perhaps suggesting that SCV is rarer in Asians. Associations of HLA-I types with disease outcome have been heavily weighted toward persons of white (European) and black (African) ancestries, limiting statistical power to identify HLA associations for prevalent HLA-I types in other races such as Asians . Indeed, although other studies of persons with SCV have observed the ‘protective’ HLA B*5701 type at frequencies from 44 to 85% [8,13,32], only two of 18 persons tested in our cohort had this type, both white.
Finally, data on the long-term clinical outcomes for SCV are somewhat limited, but generally agree that disease progression is relatively slow or absent consistent with the known inverse relationship between ‘set-point’ viremia level and rate of progression to AIDS [1,2]. The reported rate of blood CD4+ T-cell loss in persons with SCV varies, likely because of varying definitions of ‘elite control’ and biologic variability between persons. For example, Okulicz et al. observed that average blood CD4+ T-cell levels rose for 8 years of infection from ∼650 to ∼950 cells/μl and then remained stable, inferring that more than 90% of persons maintain counts above 350 cells/μl for 20 years, whereas Lambotte et al. described more consistent loss with blood CD4+ T-cell slopes ranging from −40 to more than +12 cells/μl per year. Our data show wide biologic variability between persons, spanning these prior observations, and generally fit the relationship between ongoing viremia and disease progression, with SCV reflecting low ongoing viremia (below the standard limit of detection) associated with slow loss of blood CD4+ T cells. Again, this suggests that persons with SCV are not qualitatively different than those with persistently detectable viremia, but simply reflect a quantitative extreme among infected persons.
In summary, we provide detailed observations of SCV in a diverse cohort of nearly 30 000 persons. The prevalence of SCV varies according to race and sex, and the natural history of untreated SCV may also be affected by these demographics, although larger studies will be required for reliable comparisons. The pattern of viremia ‘blips’ in persons with SCV likely reflects set-point viremia levels below the limit of standard detection assays with biological and/or assay variability that yields occasional values within the detectable range. Persons observed to lose SCV had higher frequencies of these blips, possibly reflecting higher set-point viremia levels (still in the undetectable range) than persons who maintained SCV. These findings support the concept that persons with SCV are not qualitatively distinct from other persons with HIV-1 infection, but rather represent an extreme in the continuum of viremia containment and disease progression.
O.O.Y. conceived the study, analyzed data, and wrote the manuscript. W.G.C. analyzed data and cowrote the manuscript. R.E. analyzed data. D.L. analyzed data. K.W.C. analyzed data and cowrote the manuscript.
The work was funded by the AIDS Healthcare Foundation; additional support was provided by the UCLA AIDS Institute Center for AIDS Research via the National Institute of Allergy and Infectious Diseases at the Institutes of Health (grant AI028697).
Conflicts of interest
There are conflicts of interest.
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