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Virologic failure is uncommon after treatment initiation during acute HIV infection

Crowell, Trevor A.; Phanuphak, Nittaya; Pinyakorn, Suteeraporn; Kroon, Eugene; Fletcher, James L.K.; Colby, Donn; Tipsuk, Somporn; Karnsomlap, Putthachard; Laopraynak, Naphassanant; O’Connell, Robert J.; Robb, Merlin L.; Ananworanich, Jintanatfor the RV254SEARCH010 Study Group

doi: 10.1097/QAD.0000000000001148
CLINICAL SCIENCE
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SDC

Objective: In chronic HIV infection, initiation of antiretroviral therapy (ART) typically induces swift HIV RNA declines and virologic suppression within 24 weeks. The objective of this study was to investigate viral dynamics and common criteria for treatment success after ART initiation during acute HIV infection (AHI).

Methods: Participants were prospectively enrolled and offered ART during AHI from May 2009–June 2015 in Bangkok, Thailand. Regimens included tenofovir, lamivudine or emtricitabine, and efavirenz with or without raltegravir and maraviroc. Participants were monitored for several HIV RNA end points: one-log reduction at week 2; two-log reduction at week 4; less than 1000 copies/ml at week 24; and less than 200 copies/ml at week 24. Factors associated with each end point, time to suppression, and virologic blips were explored.

Results: Two hundred and sixty-four Thai participants initiated ART during AHI. Their median age was 27 years and 96% were men. At 2 weeks, 6.5% had not achieved a one-log reduction in HIV RNA. At 4 weeks, 11.0% had not achieved a two-log reduction. At 24 weeks, 1.1% had not achieved HIV RNA less than 1000 copies/ml and 1.5% had not achieved HIV RNA less than 200 copies/ml. Participants who initiated ART during Fiebig I demonstrated a shorter median time to virologic suppression than did all other stages combined, [4 (interquartile range 2–8) vs. 8 (interquartile range 4–12) weeks, P < 0.001] and 7.3% had subsequent blips (16.1% in other stages, P = 0.23).

Conclusion: Virologic failure is uncommon in individuals who initiate ART during AHI. ART initiation during AHI is efficacious and clinicians can monitor for virologic failure after 24 weeks of therapy.

Supplemental Digital Content is available in the text

aU.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring

bHenry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA

cSEARCH

dHIV-NAT, Thai Red Cross AIDS Research Centre

eArmed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

Correspondence to Trevor A. Crowell, MD, PhD, U.S. Military HIV Research Program, 6720A Rockledge Drive, Suite 400 Bethesda, MD 20817, USA. Tel: +1 301 500 3990; fax: +1 301 500 3666; e-mail: tcrowell@hivresearch.org

Received 23 March, 2016

Revised 26 April, 2016

Accepted 27 April, 2016

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).

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Introduction

Current guidelines for the management of HIV recommend that antiretroviral therapy (ART) be offered to all persons living with HIV, regardless of CD4+ T-cell count or duration of infection [1–4]. Initiation of ART during acute HIV infection (AHI) could offer particular benefit to patients by limiting the establishment of latent viral reservoirs [5–9], decreasing systemic inflammation [8–10], and improving immune reconstitution [5,11]. The immediate goal of therapy initiated during AHI, as in chronic infection, is virologic suppression. However, the optimal strategies of monitoring for virologic suppression and identifying virologic failure after initiation of ART during AHI have not been defined.

Based on data about viral dynamics after ART initiation during chronic HIV infection, it is generally expected that patients will achieve a one-log decline in HIV RNA within 1–2 weeks of initiating ART and a two-log decline within 4 weeks [12–14]. Failure to meet these early milestones predicts failure to achieve longer term virologic suppression [13,14]. Guidelines generally recommend that an individual be prescribed ART for at least 6 months, or 24 weeks, before a determination of virologic failure can be made [1–4]. However, there are notable differences in viral dynamics between acute and chronic HIV infection. For example, AHI is characterized by a rapid rise in plasma viremia over the first several weeks that peaks around 5–6 log10 copies/ml and then downtrends to reach a steady-state viremia in chronic infection that is generally 1–2 log10 copies/ml below the peak value [15]. Such differences may limit the utility of common standards for monitoring the response to ART when it is initiated during acute infection.

The purpose of this analysis is to explore viral dynamics and the usefulness of common criteria for treatment success in a cohort of individuals who initiated ART during AHI.

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Methods

Study population

The ongoing RV254/SEARCH010 cohort study (clinicaltrials.gov NCT00796146) recruits individuals who present for HIV screening at the Thai Red Cross AIDS Research Centre in Bangkok and are found to be acutely infected using a previously-published algorithm [16]. Briefly, samples are screened using a 4th generation (4thG) immunoassay that detects HIV antigen and HIV IgM. Nonreactive samples undergo pooled nucleic acid testing (NAT) and reactive samples are tested using a less-sensitive 2nd generation (2ndG) immunoassay sensitive to HIV IgG only. Individuals are recruited into the study if they have either a nonreactive 4thG immunoassay and a positive NAT or a reactive 4thG immunoassay and a nonreactive 2ndG immunoassay.

Participants in RV254/SEARCH010 are offered immediate initiation of ART via a separately funded protocol (clinicaltrials.gov NCT00796263). They undergo serial interviews, physical examinations, and phlebotomy. This analysis includes all Thai participants who enrolled in the cohort and initiated ART during Fiebig stages I–V between 7 May 2009 and 16 June 2015.

All participants provided written informed consent prior to enrollment in the cohort. The research protocol was approved by institutional review boards at Chulalongkorn University, Bangkok, Thailand, and the Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

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Antiretroviral therapy

All participants were prescribed ART that included efavirenz 600 mg once daily, tenofovir disoproxil 300 mg once daily, and either emtricitabine 200 mg once daily or lamivudine 300 mg once daily. The first 10 participants to enroll received additional therapy with raltegravir 400 mg twice daily and maraviroc 600 mg twice daily for the first 24 weeks of participation in the cohort. Participants who enrolled between 29 January 2010 and 8 May 2014, were randomized in a 1:1 ratio to receive either the three-drug or five-drug regimen. Subsequent enrollees received the three-drug regimen. Medication changes were rare but allowed in cases of intolerance, resistance, or drug unavailability as previously described [9].

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Laboratory assessments and HIV staging

HIV RNA was measured in the plasma using either the Roche Amplicor HIV-1 Monitor Test v1.5 or the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Test v2.0 (Roche Diagnostics, Branchburg, New Jersey, USA), with lower limits of detection of 50 and 20 copies/ml, respectively. Assessments for virologic response to ART were performed after 2, 4, 8, 12, 16, 20, and 24 weeks of therapy and then every 12 weeks thereafter. AHI staging was based on the sequential development of serologic markers of infection as described by Fiebig et al. [15]. Briefly, detectable HIV RNA without other markers is considered Fiebig I, development of p24 antigen indicates Fiebig II, IgM antibody indicates Fiebig III, an indeterminate Western blot indicates Fiebig IV, and a positive Western blot without the p31 band indicates Fiebig V.

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Virologic response to ART

Participants were monitored for several virologic end points that are commonly considered indicative of an optimal response to therapy when it is initiated during chronic HIV infection. These included a one-log reduction in HIV RNA by week 2 of ART and a two-log reduction in HIV RNA by week 4 of ART. Virologic failure was explored at 24 weeks using the WHO recommended threshold of HIV RNA 1000 copies/ml [1] and the US Department of Health and Human Services recommended threshold of HIV RNA 200 copies/ml [2]. HIV RNA assessments above these threshold values at week 24 were considered indicative of treatment failure.

Virologic suppression was defined by an HIV RNA less than 50 copies/ml, which was the lower limit of detection for the assay in use for most of the study period.

After week 24, participants were monitored for virologic blips. A blip was defined as a transient detectable HIV RNA, not exceeding 1000 copies/ml, in an individual with previously undetectable HIV RNA that was followed by a return to undetectable HIV RNA without any change in ART regimen. The threshold for an undetectable HIV RNA level varied according to the assay in use at the time (either <50 or <20 copies/ml).

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Statistical analysis

Factors associated with each measure of virologic response to ART were explored using the χ2 test and t-test. HIV RNA changes over time were estimated across groups using linear regression with generalized estimating equations and assuming an exchangeable correlation matrix. Kaplan–Meier curves were constructed and the log-rank test was used to evaluate associations with time to HIV RNA less than 50 copies/ml. A two-sided type I error of 5% was considered statistically significant for all analyses. Analyses were performed using Stata 13.0 (StataCorp LP, College Station, Texas, USA).

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Results

Study population

During the study period, 142 152 blood samples were prospectively screened for AHI. From these, 264 Thai participants with AHI were identified, enrolled, and initiated on ART. Their median age was 27 years and 96% were men (Table 1). Study participants included 235 MSM, representing 89% of the total study population. ART was initiated during Fiebig I in 41 participants (16%), Fiebig II 75 (28%), Fiebig III 102 (39%), Fiebig IV 29 (11%), and Fiebig V 17 (6%). ART included raltegravir and maraviroc for 84 participants (32%) and regimens did not differ by Fiebig stage (P = 0.259).

Table 1

Table 1

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Virologic response to antiretroviral therapy by guideline criteria

Among 261 participants with an available HIV RNA assessment at study week 2, 17 (6.5%) had failed to achieve a one-log decline from their baseline HIV RNA at the time of ART initiation. This included eight out of 40 participants who initiated ART during Fiebig I (20.0%; Fig. 1). A lower HIV RNA at the time of ART initiation was predictive of failure to achieve a one-log decline in HIV RNA, with those failing to achieve this milestone demonstrating median HIV RNA 4.4 [interquartile range (IQR) 3.7–5.2] log10 copies/ml compared with 5.9 (5.3–6.8) log10 copies/ml among those who did achieve this milestone (P < 0.001). No difference was observed by age (P = 0.57), sex (P = 0.53), or ART regimen (P = 0.28).

Fig. 1

Fig. 1

After 4 weeks of ART, 29 out of 263 participants with available measurements (11.0%) had failed to achieve a two-log decline from their baseline HIV RNA. This included 13 out of 41 participants who initiated ART during Fiebig I (31.7%), six of whom had an initial HIV RNA less than 5000 copies/ml, which precluded a measurable two-log decline. Baseline HIV RNA was again predictive of this outcome, with those who did not achieve this milestone demonstrating median HIV RNA 4.8 (IQR 3.7–5.5) log10 copies/ml compared with 5.9 (5.4–6.9) log10 copies/ml among those who did achieve this milestone (P < 0.001). Participants receiving intensified ART with raltegravir and maraviroc were also more likely to achieve this milestone [82 of 84 participants (97.6%) compared with 152 of 179 participants (84.9%), P = 0.001].

Only three (1.1%) of 264 participants had an HIV RNA above the WHO threshold for virologic failure of 1000 copies/ml at 24 weeks. Using the lower threshold of 200 copies/ml, four participants (1.5%) were considered to have virologic failure. These included one participant who initiated ART during Fiebig II, two who initiated during Fiebig III, and one who initiated during Fiebig IV (see Figure, Supplemental Digital Content 1, http://links.lww.com/QAD/A931, for serial HIV RNA results of these participants). Three of the four participants were initially treated with a five-drug ART regimen that included maraviroc and raltegravir. One participant had intermittent adherence to therapy early on, developed genotypic resistance to efavirenz, and eventually achieved virologic suppression less than 50 copies/ml at week 60 after changing to a regimen of tenofovir disoproxil, lamivudine, and ritonavir-boosted lopinavir. Two other participants also achieved virologic suppression after similar regimen changes but without genotypic evidence of resistance. The fourth participant underwent no medication changes and withdrew consent for study participation at week 24, without achieving virologic suppression.

At week 24, an additional 14 participants had low-level viremia within the range of 51–199 copies/ml that did not satisfy criteria for virologic failure.

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Virologic response to antiretroviral therapy by plasma HIV RNA

Participants who initiated ART during Fiebig I had a lower baseline viremia at the time of ART initiation than did participants at later stages and maintained significantly lower HIV RNA levels through week 12 (Fig. 2a). From baseline to week 2, the mean change in HIV RNA for participants who initiated ART during Fiebig I was a decline of 1.41 [95% confidence interval (CI) 1.20–1.63] log10 copies/ml compared with a decline of 2.53 (95% CI 2.43–2.63) log10 copies/ml across all other Fiebig groups combined (P < 0.001). From week 2 to week 4, the slope of the HIV RNA decay decreased so that the mean decline among participants who initiated ART during Fiebig I was 0.61 (95% CI 0.45–0.77) log10 copies/ml and among participants who initiated ART during later stages 0.79 (95% CI 0.72–0.86) log10 copies/ml (P = 0.07).

Fig. 2

Fig. 2

Similarly, compared with participants who initiated ART at a higher baseline viral load, participants who initiated ART at HIV RNA 10 000 copies/ml or less maintained lower plasma HIV RNA levels through week 8 of therapy despite slower rates of HIV RNA decay (Fig. 2b). From baseline to week 2, the mean change in HIV RNA for participants who initiated ART at a lower viral load was a decline of 1.19 (95% CI 0.90–1.48) log10 copies/ml compared with a decline of 2.45 (95% CI 2.35–2.55) log10 copies/ml among participants who initiated ART at a higher viral load (P < 0.001). From week 2 to week 4, the mean HIV RNA decline among participants who initiated ART at a lower viral load was 0.31 (95% CI 0.09–0.54) log10 copies/ml compared with 0.80 (95% CI 0.73–0.86) log10 copies/ml among participants who initiated ART at a higher viral load (P < 0.001).

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Time to virologic suppression

Participants who demonstrated rapid early declines in HIV RNA had a shorter overall time to virologic suppression. Those who achieved a one-log decline in HIV RNA after 2 weeks of ART had median time to HIV RNA less than 50 copies/ml of only 8 (IQR 8–12) weeks compared with 16 (IQR 12–24) weeks among those who did not achieve this milestone (P = 0.02; Fig. 3a). Similarly, participants who achieved a two-log decline in HIV RNA after 4 weeks of ART demonstrated a shorter time to virologic suppression (12 [8–16] vs. 24 [12–24] weeks, P < 0.001; Fig. 3b).

Fig. 3

Fig. 3

Participants who initiated ART during Fiebig I demonstrated a median time to virologic suppression of 8 (IQR 4–12) weeks compared with a median 12 (IQR 8–16) weeks for all other Fiebig stages combined (P < 0.001). Similarly, participants who initiated ART at HIV RNA 10 000 copies/ml or less demonstrated a median time to suppression of 4 (IQR 2–8) weeks compared with 12 (IQR 8–16) weeks among participants who initiated ART with a higher baseline HIV RNA (P < 0.001). Participants who received raltegravir and maraviroc had a median time to suppression of 8 (IQR 4–12) weeks compared with 12 (IQR 8–20) weeks among participants who did not receive these additional medications (P < 0.001).

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Virologic blips

Virologic blips were observed in 39 participants (14.8%). Among the 244 participants who achieved a one-log decline in HIV RNA by week 2 after ART initiation, 38 (15.6%) later demonstrated virologic blips whereas one of the 17 participants (5.9%) who did not achieve this early viral load target experienced blips (P = 0.48). Similarly, among the 234 participants who achieved a two-log decline in HIV RNA by week 4 after ART initiation, 35 (15.0%) experienced blips, compared with four of 29 (13.8%) in the group that did not achieve this viral load target (P = 1.00). There was a nonsignificant trend toward fewer virologic blips among participants who started ART during Fiebig stage I as compared with all other participants (Fig. 4; P = 0.23).

Fig. 4

Fig. 4

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Discussion

Common short-term milestones for an optimal virologic response to ART initiation could not be meaningfully applied to therapy initiated during Fiebig I because of the low baseline HIV RNA in this group. Prior studies have shown that a lower baseline viral load at the time of ART initiation is associated with smaller phase 1 and phase 2 viral decay rates, potentially because of a smaller burden of productively-infected T cells [17–19]. Despite a smaller slope of HIV RNA decline, participants who initiated ART during Fiebig I consistently demonstrated lower plasma HIV RNA levels than those observed among other participants exposed to the same duration of ART. Ultimately, this group achieved the shortest time to virologic suppression among the groups examined and experienced no cases of virologic failure at 24 weeks.

In later Fiebig stages and the overall study population, achievement of early milestones for virologic response to therapy was predictive of a shorter overall time to virologic suppression. These early milestones can serve as useful prognostic markers very soon after treatment initiation, but even individuals who do not demonstrate these swift declines in HIV RNA tended to achieve virologic suppression within 24 weeks of ART initiation.

Overall, virologic failure was uncommon in this cohort when using either the WHO (1.1%) or US Department of Health and Human Services (1.5%) definitions. This is lower than the 10% rate of virologic failure at 24 weeks reported in a prior study of 102 individuals who initiated ART during symptomatic acute or early HIV infection in Boston [20]. Participants in that study received an ART regimen containing indinavir, nelfinavir, lamivudine, and stavudine, which is less potent, has more side-effects, and carries a higher pill burden than either regimen employed in this study. A selection bias because of enrollment of only symptomatic individuals in the prior study and geographic differences in HIV subtypes could also influence treatment outcomes. Recent studies of virologic response to ART initiation during chronic HIV infection have demonstrated virologic failure rates at 24 weeks of around 10–20% [21–23]. The low rate of virologic failure in the current study suggests that individuals who initiate modern regimens of ART during AHI tolerate and adhere to treatment, despite potentially complicating factors such as acute retroviral syndrome and psychologic barriers to ART adherence in the setting of recently diagnosed HIV.

The addition of raltegravir and maraviroc to a standard three-drug ART regimen reduced the time to virologic suppression in this study. This has been previously described and was not found to be associated with any differences in the measurable HIV reservoir after 24 weeks of therapy [9]. Similarly, addition of raltegravir and maraviroc to protease inhibitor-based regimens has been shown to result in rapid reduction of plasma viremia without long-term effect on HIV reservoirs when ART is initiated during primary HIV infection [24,25]. In prior studies, adherence to the intensified five-drug regimens tended to be worse and virologic failure was more common [24,25]. Interestingly, three of the four participants with virologic failure at week 24 in this study were prescribed the intensified five-drug regimen. Additional adverse effects and the inconvenience of a twice-daily dosing schedule for the additional agents may impact adherence and worsen the virologic outcomes associated with the five-drug regimen.

This study utilized a unique and well characterized cohort of individuals to describe viral dynamics after ART initiation during AHI and evaluate the usefulness of common criteria for treatment success when applied in this setting. Because virologic failure was an uncommon outcome, statistical associations between this outcome and potential predictors could not be explored. The cohort is composed predominantly of Thai MSM infected with subtype CRF01_AE virus, so findings may not be generalizable to populations in other regions, with other risk factors, or with epidemics caused by other viral subtypes. In addition, virologic outcomes within this highly monitored and structured clinical research setting may not be reproducible within the context of routine clinical care.

This study demonstrates that initiation of ART during AHI leads to rapid virologic suppression in the vast majority of cases. Individuals who initiate therapy during Fiebig I can be expected to achieve virologic suppression quickly, although routine criteria for viral load decline by two and four weeks after ART initiation may not be useful when baseline viremia is low. Individuals who initiate therapy during later stages of AHI demonstrate the same rapid decline in plasma HIV RNA as is seen when ART is initiated in chronic infection and typical criteria for virologic response to therapy may be employed by clinicians caring for these individuals.

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Acknowledgements

We thank our study participants and staff from the Thai Red Cross AIDS Research Centre, Chulalongkorn University and AFRIMS for their valuable contributions to this study. We are grateful to the Thai Government Pharmaceutical Organization (GPO), ViiV Healthcare, Gilead and Merck for providing the antiretroviral medications for this study.

T.C. designed this analysis and authored the first draft of the manuscript. N.P., E.K., J.F., D.C., S.T., P.K., and N.L. collected clinical data and assisted in data interpretation. S.P. performed statistical analyses and helped to construct figures for this manuscript. R.O. and M.R. assisted in the interpretation of the analysis. J.A. assisted with study design and interpretation and provided project oversight. All authors reviewed this manuscript, provided feedback, and approved of the manuscript in its final form.

The RV254/SEARCH 010 Study Group includes from South East Asia Research Collaboration on HIV/TRCARC/HIV-NAT: Nipat Teeratakulpisarn, Carlo Sacdalan, Duanghathai Sutthichom, Somprartthana Rattanamanee, Peeriya Prueksakaew, Sasiwimol Ubolyam, Pacharin Eamyoung and Suwanna Puttamaswin; from Chulalongkorn University: Wiriyaporn Ridtitid; from AFRIMS: Alexandra Schuetz, Nicos Karasavvas, Sandhya Vasan, Siriwat Akapirat, Yuwadee Phuang-Ngern, Surat Jongrakthaitae, Weerawan Chuenarom, Bessara Nuntapinit, Rapee Trichavaroj, Nantana Tantibul, Hathairat Savadsuk, Kirsten Smith and Tanya Wansom; from the US Military HIV Research Program: Sodsai Tovanabutra.

Disclaimer: The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense or the Department of Health and Human Services.

Sources of funding: This work was supported by cooperative agreements (W81XWH-07-2-0067, W81XWH-11-2-0174) between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of the Army. ART was supported by the Thai Government Pharmaceutical Organization (GPO), Gilead, Merck and Pfizer.

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Conflicts of interest

J.A. has served as a consultant for ViiV Healthcare, Merck and Tetralogic. The remaining authors report no relevant conflicts of interest.

Prior presentation: This work was presented, in part, at the 23rd Conference on Retroviruses and Opportunistic Infections, Boston, MA, 22–25 February 2016.

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Keywords:

acute HIV; highly active antiretroviral therapy; HIV; viral load; virologic failure

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