Predictors of virologic response in persons who start antiretroviral therapy during recent HIV infection
Karris, Maile Y.a; Kao, Yu-tinga; Patel, Dereka; Dawson, Matthewa; Woods, Steven P.a; Vaida, Florina; Spina, Celsaa,b; Richman, Douglasa,b; Little, Susana; Smith, Davey M.a,b
aUniversity of California San Diego, La Jolla
bVeterans Administration San Diego Healthcare System, San Diego, California, USA.
Correspondence to Maile Y. Karris, MD, University of California San Diego, La Jolla, California, USA. E-mail: firstname.lastname@example.org
Received 2 July, 2013
Revised 11 November, 2013
Accepted 11 November, 2013
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).
Objective: Despite evidence supporting antiretroviral therapy (ART) in recent HIV infection, little is known about factors that are associated with successful ART. We assessed demographic, virologic, and immunologic parameters to identify predictors of virologic response.
Design: A 24-week observational study of ART on persons enrolled within 6 months of their estimated date of infection (EDI) evaluated baseline demographics and the collection of blood and gut specimens.
Methods: Flow cytometry analyses of blood and gut lymphocytes allowed characterization of CD4+ and CD8+ T cells at study entry and end. Additional assessments included soluble CD14 (sCD14), lipopolysaccharide, CD4+ T-cell counts, and HIV RNA levels.
Results: Twenty-nine participants initiated ART, and 17 achieved undetectable HIV RNA by study end. A longer time from EDI to ART, older age, higher sCD14, lower proportions of central memory CD4+ T cells, and higher proportions of activated CD8+ T cells were associated with detectable viremia. Multivariable logistic regression found only older age and elevated sCD14 were independently associated with persistent viremia. Additionally, we observed that ART in recent infection did not result in discernible recovery of CD4+ T cells in the gut.
Conclusion: In persons who started ART within 3–33 weeks from EDI, age and microbial translocation were associated with detectable HIV RNA. As observed in other cohorts, ART in recent infection did not improve proportions of total CD4+ T cells in gut-associated lymphoid tissue (GALT). This lends support to further evaluate the use of more potent ART or regimens that protect the GALT in recent HIV infection.
Starting antiretroviral therapy (ART) within the first year of HIV infection (recent infection) can decrease transmission [1,2], lower the immune activation setpoint , minimize latent cellular reservoirs [4,5], improve B-cell function , and normalize CD4+ cell counts . Despite open questions about the ‘personal health benefit’ of starting ART during recent HIV infection [8,9], a growing consensus supports this approach [10,11]. To be maximally effective, ART should suppress viral replication to as low as possible as fast as possible. The longer HIV replicates in the presence of ART, the longer the delay in immune reconstitution and the higher the risk for development of drug resistance . This can be especially important when ART is started during the earliest stages of HIV infection, which is marked by very high viral loads  and levels of immune activation . To evaluate sociodemographic, immunologic, and virologic factors associated with suppression of HIV RNA levels on ART (<40 copies/ml) during recent infection, we conducted an observational study nested within the San Diego Primary Infection Cohort (SD PIC).
Participants were identified through the San Diego Early Test (http://theearlytest.ucsd.edu) and Lead the Way (http://leadthewaysd.com) HIV screening campaigns, with estimated stage and duration of infection determined, as previously described in published studies of persons with acute HIV infection [14,15]. All participants underwent informed consent as approved by the University of California San Diego, institutional review board. Clinical laboratories, assessments of alcohol (Alcohol Use Disorders Identification Test, AUDIT) and methamphetamine use (Drug Abuse Screening Test, DAST) , and immunologic and virologic investigations were performed at study entry (week 0) and end of study (week 24). ART was generally encouraged, though treatment was not provided. Treatment management was provided by participants’ primary care providers. Participants could choose to start ART at any time after study entry. Clinical laboratory tests included CD4+ and CD8+ T-cell subsets and HIV RNA levels (Amplicor; Roche, Indianapolis, Indiana, USA) performed at baseline and week 24. HIV drug resistance tests were performed at baseline (Monogram Biosciences, San Francisco, California, USA).
Estimated date of infection
An estimated date of infection (EDI) was determined for all participants as previously reported . The San Diego Primary Infection Cohort (SD PIC) algorithm utilizes the dates of each participant's detuned HIV enzyme immunoassays (Vitros ECi assay; Ortho-Clinical Diagnostics, High Wycombe, UK), HIV western blot, and HIV-1 nucleic acid testing (Procleix HIV-1/HCV Assay: Chiron, Emeryville, California, USA and Genprobe, San Diego, California, USA) to determine EDI .
Fresh peripheral blood was collected from participants at weeks 0 and 24 of study and processed using density gradient centrifugation to obtain viable peripheral blood mononuclear cells (PBMCs); PBMCs were washed and aliquoted into tubes at concentration of 1 million PBMCs/200 μl staining buffer prior to incubation with conjugated antibodies (Becton Dickinson and Co., Franklin Lakes, New Jersey, USA) to CD3 (APC-Cy7), CD4 (PerCP), CD8 (Pac-Blue), CD45RO (PE), CD27 (APC), CCR5 (FITC), CCR7 (PE-Cy7), HLA-DR (FITC), CD38 (PE-Cy7), CCR6 (PE-Cy7), and CXCR5 (APC) . Conjugated antibodies to FoxP3 (FITC), human IgG1 (FITC), and intracellular Ki67 (FITC) were used with fixation and permeability buffers (eBioscience, San Diego, California, USA) for intracellular staining assays, per manufacturer instructions. Samples were run on a BD FACSCanto II instrument (BD Biosciences, San Jose, California, USA) and data analyzed with FlowJo software (Tree Star Inc., Ashland, Oregon, USA).
All study participants were invited to participate in concurrent immunologic investigations, requiring gut biopsies. Participants who consented to this procedure underwent standard colonoscopy by a board certified gastroenterologist, with 10–20 punch biopsies obtained at the ileal-cecal and rectosigmoid junctions. These participants were co-enrolled in a separate study and underwent biopsies at additional time points (week 0, 12, 24, and 48). These biopsies were immediately processed through a cell strainer to produce single cell suspensions prior to being viably frozen. To limit interassay variability, longitudinal samples from individual participants were viably thawed and evaluated in parallel by flow cytometry, after all samples had been collected. Conjugated antibodies added to the single cell suspensions included CD3 (APC-Cy7), CD4 (PerCP), CD8 (Pac-Blue), CD45RO (PE), CD27 (APC), CCR5 (FITC), CCR7 (PE-Cy7), IgG1 (FITC), and Ki67 (FITC). Samples were run on a BD FACS Canto II cytometer and data analyzed with FlowJo software.
Markers of microbial translocation
Blood plasma samples were collected from participants at weeks 0 and 24. Lipopolysaccharide (LPS) was measured using the Limulus ameboctyte Lysate QCL-1000 assay (Lonza Inc. Allendale, New Jersey, USA) and soluble CD14 (sCD14), by the Quantikine ELISA Human sCD14 Immunoassay (R&D Systems, Minneapolis, Minnesota, USA).
For all the summary statistics, median and interquartile range (IQR) were reported. For analyses involving participants who achieved undetectable viral RNA and those who did not by study end, we repeated the analyses by removing all study participants who had less than 4 weeks of ART by study end. The demographic characteristics were compared between participants with and without detectable HIV RNA at week 24. We used the independent samples Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical variables.
Linear regression was used for the association between lymphocyte factors and continuous predictors (age, sCD14). Logistic regression with Firth's penalized-likelihood correction  was used for the association between virologic response at week 24 and lymphocyte factors. To adjust for other factors of interest, the multivariable logistic regression was used predicting HIV RNA suppression as a function of the following covariates at baseline: age, weeks from EDI to ART, time on ART, log10 HIV RNA copies/ml, CD4+ cell, sCD14, and LPS. The model was started with all these covariates as predictors and then backward selection with 0.20 level P value is applied to derive the final model. Although time on ART was accounted for in the multivariable model, for statistical completeness, analyses were repeated excluding the two participants who had less than 4 weeks of ART by study end for univariable and multivariable analyses. The odds ratios (ORs) are interpreted in the following way: OR more than 1 means the odds of viral load suppression at week 24 increases for one unit increment in the covariate; OR less than 1 means the odds of viral load suppression at week 24 decreases for one unit increment in the covariate. All of the covariates are continuous.
The lymphocyte levels in the gut-associated lymphoid tissue (GALT) over time were analyzed using mixed effect linear regression, on the transformed logit scale log(p/(1-p)), which is appropriate for proportions, with random intercept, accounting for the subject effect for repeated measures. The standardized regression coefficient (std. β) and 95% confidence interval were reported.
Due to the exploratory nature of the analyses, biomarkers were tested symmetrically at the 0.05 level and no correction for multiple comparison was applied. Proper transformation was applied when needed.
From October 2009 to April 2011, 46 men with recent infection were enrolled into the study (Fig. 1). Participants presented a median of 6.2 weeks (IQR 2.57–10.57) from EDI. Of these, three were lost to follow-up prior to study completion and were removed from evaluation. The remainder of participants had a median age of 28 years (IQR 23–39), 14 years of education (IQR 12.5–16), and identified themselves as white (84%), Asian (7%), black (7%), and other (2%); 35% reported Hispanic ethnicity. The median viral load at study entry was 4.95 log10 HIV RNA copies/ml (IQR 4.05–5.51) and CD4+ cell count was 609 cells/μl (IQR 431–713). Overall, 29 (69%) individuals chose to start ART during the study period. Those who opted to start ART had a trend for higher levels of education by Wilcoxon rank-sum (median 16 vs. 13 years, P = 0.06) than those who did not start. Otherwise, these groups were indistinguishable by all other baseline demographic measures. Measures of alcohol and methamphetamine use were also evaluated, and these measures did not differ in persons who started ART and those who did not.
Characteristics of persons who achieved a virologic response
Of the 29 study participants who started ART, 17 (58.6%) achieved undetectable HIV RNA (<40 copies/ml) during this 24-week observational study (Table 1). All persons on ART were 100% adherent by self-report. The median HIV RNA at study end (week 24) for the 12 persons who did not have an undetectable HIV RNA was 2.75 log10 HIV RNA copies/ml (IQR 2.71–2.84). Of all persons starting ART, three (10%) initiated a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, six (21%) started a regimen that contained an integrase inhibitor, and 20 (69%) began a boosted protease inhibitor-based regimen. All had a background of tenofovir and emtricitabine. Although limited by small numbers in each group, ART regimen was not predictive of achieving undetectable HIV RNA by study end (Table 1). Additionally, drug resistance at baseline measured by mutation penalty scores did not differ between the two groups .
In univariable analyses, persons who achieved undetectable HIV RNA by study end were more likely to have started ART earlier in their course of HIV infection than those who did not (median 11.9 weeks from EDI vs. 20 weeks, P = 0.03) and unsurprisingly had longer times on ART by end of study. A trend existed suggesting persons who did not achieve an undetectable HIV RNA were also older in age (median 27 vs. 35 years, P = 0.07). At study entry, there were no statistical differences in other sociodemographic factors including education, ethnicity, methamphetamine abuse, alcohol abuse, or clinical factors such as HIV RNA levels or CD4+ cell counts (Table 1). Univariable and multivariable logistic regression was performed with predictors of interest at baseline (age, weeks from EDI to ART, time on ART, log10 HIV RNA copies/ml, sqrt CD4+, sCD14, and LPS), revealing that lower sCD14 levels and younger age were independently predictive of achieving undetectable HIV RNA (Fig. 2a and b, Table 2). The observational nature of this study resulted in participants having unstructured time on ART necessitating the multivariable model, which adjusted for time on ART. However, within the cohort of persons on ART who did not achieve an undetectable HIV RNA were two persons who were on ART for less than 4 weeks by study end. Additional analyses removing these two participants did not change the results of the univariable or multivariable analyses. All other participants received ART for more than 4 weeks.
Gut-associated lymphoid tissue
Seven participants had gut biopsies available, and all chose to start immediate ART. Their median presentation to study was 3.4 weeks from EDI (IQR 3.4–4.1 weeks), and by study end, the median weeks on ART was 23 weeks (IQR 23–23.5 weeks). Only one participant who provided gut biopsy samples and started ART did not achieve an undetectable HIV RNA in blood plasma during study. This one participant did not have GALT immunologic factors at baseline or after 24 weeks of observation that appeared statistically different from the remainder of participants. Mixed effects linear regression was used to determine whether starting ART had any impact on GALT lymphocytes. Despite all of gut biopsy participants receiving greater than 22 weeks of ART by study end, numbers of GALT CD4+ T cells did not increase over time (std. β = 0.203, P = 0.19; Fig. 3a). Additionally, no significant associations were observed between duration of infection prior to ART and modulation of T-cell phenotypic subsets or proliferation at study end; however, ART started in recent infection was associated with significant decreases over time in CD4+ central memory (std. β = −0.477, P < 0.001) and CD8+ central memory (std. β = −0.59, P < 0.001) T cells, with a reciprocal increase in CD8+ effector T cells (std. β = 0.551, P < 0.001; Fig. 3b–d).
Soluble CD14 as a predictor of virologic response
HIV enteropathy is associated with increased intestinal permeability and microbial translocation ; thus, we evaluated whether specific HIV-induced lymphocyte changes in GALT were associated with sCD14 levels. No correlation was identified between sCD14 and GALT immunologic factors at baseline. However, at week 24, sCD14 levels were negatively correlated with proportions of central (β = −29.3, P = 0.008) and effector (β = −24.392, P = 0.008) memory CD4+ T cells, and effector memory CD8+ T cells (β = −8.042, P = 0.048) in the blood (Supplemental Figure 1, http://links.lww.com/QAD/A454). These associations remained significant even when adjusting for CD4+ cell numbers and HIV RNA levels in the multivariable analysis. No associations existed between sCD14 levels and proportions of activated, immunosenescent, or regulatory T cells at any time point.
Age as a predictor of virologic response
To identify factors that may explain why older age was associated with persistent viremia, we evaluated the correlations between the age of all the participants who started ART with sociodemographic factors (education, drug/alcohol use, ethnicity or race), blood, and GALT immunologic factors using linear regression. No sociodemographic factors correlated with age, but week 0 naive CD4+ and CD8+ T cells were negatively correlated with age (β = −0.72, P = 0.014 and β = −0.28 P = 0.037; Supplemental Figure 2, http://links.lww.com/QAD/A454). Age maintained a consistent association only with naive CD4+ T cells at week 0 (β = −0.87, P = 0.001) with multivariable analysis covaried by log10 HIV RNA and total CD4+ cell count. There was no correlation between age and cellular immune activation, regulatory T cells, immunosenescent (CD45RO+CD28−) T cells, LPS, or sCD14 at any time point.
Immunologic factors associated with virologic response
T-cell immune activation (especially of CD8+ T cells) is a well described predictor of clinical progression . To evaluate whether T-cell factors prior to initiation of ART (at week 0) differed between those who achieved undetectable plasma HIV RNA and those who did not, we measured T-cell phenotypic subsets, markers of cellular activation (HLADR, CD38), and proliferation (cellular ki67) using logistic regression. Participants who achieved undetectable HIV RNA with ART had lower proportions of central memory CD4+ T cells [OR = 0.813 (95% confidence interval, CI 0.626–0.991), P = 0.039] and lower proportions of proliferating central memory CD4+ T cells [OR = 0.874 (95% CI 0.715–0.996) P = 0.043] at study entry. Significance remained when the data were reanalyzed without the two study participants who had been on ART for less than 4 weeks. No differences existed in the percentages of CD4+ T-cell activation markers, or proliferation levels, between participants who did and did not achieve a virologic response. However, persons who did have a virologic response exhibited a trend toward lower proportions of regulatory T cells [OR = 0.548 (95% CI 0.257–1.033) P = 0.063] than those participants who did not. None of these observations remained significant after adjusting for baseline covariates (age, EDI to ART, weeks on ART, log10 HIV viral load, CD4+ cell, sCD14, and LPS) in logistic regression (Supplemental Table 1, http://links.lww.com/QAD/A454).
Examination of CD8+ T cells at study entry demonstrated that persons achieving undetectable HIV RNA had higher percentages of central memory, and effector memory CD8+ T cells, as well as higher proportions of activated effector memory, and activated and proliferating effector CD8+ T cells (Supplemental Table 1, http://links.lww.com/QAD/A454). Significance remained even after the data were reanalyzed without the two study participants who had been on ART for less than 4 weeks. This could suggest that a more robust effector CD8+ T-cell response contributes to a virologic response. However, after adjusting for covariates selected under the same process described above in the multivariable analysis, there were no immunologic factors that remained significantly different between groups.
The goal of this study was to identify sociodemographic, neurocognitive, and immunologic factors associated with achieving undetectable HIV RNA when ART is started in recent infection. The main finding is that after adjusting for confounders in a multivariable model of logistic regression, higher levels of sCD14 at baseline and older age were independently associated with persistent viremia, whereas baseline CD4+ T cells, HIV RNA, ART regimen, level of neurocognitive impairment, alcohol abuse, and methamphetamine abuse were not. Additionally, univariable analyses suggested that higher proportions of central memory CD4+ T cells may be favorable for HIV suppression during ART, whereas higher proportions of mature and activated CD8+ T cells are not. However, these findings did not stand up against multivariable analyses.
To evaluate the impact of HIV on the gut, this study evaluated gut biopsies and sCD14 and LPS as markers of microbial translocation  because both are independently predictive of HIV mortality and disease progression [24,25]. Although previous associations have been described between viral load and sCD14 levels , to our knowledge this is the first study to link baseline sCD14 with virologic response during ART. Although limited by the number of participants providing gut biopsies, we also observed that starting ART in early HIV infection did not improve recovery of CD4+ T-cell proportions in GALT, despite all participants starting ART within 30 days of EDI. Thus, the ‘4-week window of opportunity’ to start ART in acute and early HIV infection to achieve normal CD4+ T-cell recovery does not appear to apply to the GALT CD4+ T-cell population . This may in part be due to collagen deposition preventing repopulation of the GALT . We also observed a significant and continued loss of central memory CD4+ T cells over time in the GALT despite ART. This could possibly be due to ongoing HIV replication in GALT, as previously described  or due to cell-mediated death of latently infected CD4+ T cells, especially in the presence of significantly increasing proportions of effector CD8+ T cells [26–31].
Enrollment of participants during recent infection provides a unique opportunity to investigate pathogenic effects of HIV infection from the start (e.g. GALT CD4+ T-cell depletion, immune activation)  and to determine what factors are associated with achieving an undetectable viral load during ART. The association of older age with persistent viremia was a particularly interesting finding because previous studies of ART in established infection have associated younger age with virologic failure [30,31,33–35]. This has presumed to be in part due to better adherence and engagement in care in older persons [36,37]. Studies of the effect of age on the progression of HIV infection do suggest older persons have a poorer prognosis [38–40]. In the pre-HAART era, one cohort study revealed that age at seroconversion impacts disease progression by demonstrating that 22.4% of persons less than 26 years of age developed AIDS within 8 years after seroconversion compared with 35.1% for those aged 26–34 years and 58.1% for those persons more than 35 years of age . The proposed reason for this observation was that older participants had a reduced capacity to generate new CD4+ T cells due to thymic deterioration . Initiation of ART can overcome the decrease in thymic output associated with both HIV infection and older age , but even in the post-HAART era, older age is still associated with higher rates of immunologic failure [44–48]. This is supported by our study, in which age was negatively correlated with percentages of naive CD4+ and CD8+ T cells in peripheral circulation and positively correlated with more mature CD4+ and CD8+ T-cell subsets (central memory and effector memory). The ability to mount a primary response to new antigens, that is, acute HIV infection in our study, depends on the availability of naive T cells . Perhaps, the observation of older age as a negative prognostic factor for early virologic response was influenced by the availability of naive T cells. Control of HIV replication is also dependent on the degree of T-cell avidity, functionality, and clonal turnover , qualities that are also affected by age . Unfortunately, specific evaluation of T-cell functionality was beyond the scope of this study and we did not arrive at a clear pathogenic reason for the observed association between older age and prolonged viremia during ART.
This study has a number of limitations. First, the main limitation of this study was that it was not a randomized clinical trial and study participants were allowed to start ART during any time of cohort observation. However, most of the participants evaluated in this study did complete at least 6 weeks of ART (93%) by study end. Although timing of ART from time from enrollment and EDI were carefully considered in our multivariable analyses, individual differences in time of ART is another a limitation of this observational cohort study. Second, our observations were limited by the small number of patients enrolled. Specifically only seven participants volunteered to undergo terminal ileum biopsies. This greatly limits our study's power to detect meaningful GALT mechanisms associated with viral suppression; however, our limited data do suggest that ongoing depletion of CD4+ central memory T-cell subsets occurs even when ART is initiated in recent infection. Third, we did not collect drug levels, nor did we have baseline measures of participant kidney or liver function (measured by community primary care physicians but not in our database), which limited our adherence measures to self-report and prevented us from assessing possible individual differences between ART metabolism . Finally, this study was not designed to conclusively determine the pathologic mechanisms for study observations. For example, we did not have the capacity to measure HIV RNA or DNA, or HIV-specific CD8+ T cells in GALT and could not conclude the cause for continued decline in central memory CD4+ T cells in GALT.
In conclusion, this study demonstrated that both lower levels of sCD14 and younger age at initiation of ART during recent infection were predictive of who achieved undetectable plasma HIV RNA. These findings provide insight into some barriers for virologic response during ART, but the exact mechanisms underlying the negative association of age and microbial translocation with the ability to achieve rapid viral suppression remain unclear. Future studies, specifically in persons with acute HIV infection, may lead to a further understanding of whether there truly is an immunologic benefit of using more potent ART regimens and GALT-protective regimens in this population.
The authors would like to thank the UCSD Center For AIDS Research (CFAR), specifically Neal Sekiya and Parris Jordan for performing the flow cytometry, and virologic evaluations used in this study.
This work was supported by grants from the National Institutes of Health: P01-DA12065, AI69432, AI043638, MH62512, MH083552, AI077304, AI36214, AI047745, AI74621, AI080353, the James B. Pendleton Charitable Trust, and RN07-SD-702 from the California HIV Research Program as well as partially supported by the National Institutes of Health, Grant KL2 RR031978, for years 1 & 2 of CTSA funding and KL2TR00099 during year 3 and beyond of CTSA funding. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Conflicts of interest
There are no conflicts of interest.
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