Crucial events occur at mucosal surfaces and within tissue compartments very rapidly following HIV acquisition. Due to the high concentration of immune cells in gut-associated lymphoid tissue (GALT), gastrointestinal sites are important targets for HIV replication and pathogenesis, resulting in substantial CD4+ T-cell depletion [1,2]. The very rapid depletion of CD4+ T cells within GALT during acute HIV infection (AHI) likely accounts for the limited efficacy of antiretroviral therapy (ART) to minimize or reverse GALT depletion [3–5]. Similarly, the central nervous system (CNS) is invaded by HIV within days of HIV infection . Recent data suggest that early ART may prevent damage and thus possibly subsequent neurocognitive impairment observed during chronic HIV infection . Whether specific antiretroviral medications protect the brain from long-term damage during early infection is unknown; however, the variable penetration of antiretroviral drugs into sanctuary sites may have clinical implications. Similarly, the variable penetration of ART into genital secretions  has implications for preventing the high rates of ongoing sexual transmission during AHI. Given limited data to guide the selection of initial ART regimens during AHI, we evaluated the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI)-sparing regimen of etravirine (ETR) in combination with darunavir boosted with ritonavir (DRV/r) started during AHI, including an evaluation of antiretroviral concentration in GALT, the CNS and genital secretions.
Although not a recommended first-line ART regimen, data suggest ETR in combination with DRV/r had comparable antiretroviral activity and potential advantages compared with standard regimens at the time of the study. ETR has activity against wild-type and many transmitted non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV variants and high rates of efficacy among heavily pretreated participants with multiple baseline NNRTI mutations [9,10], a benefit given NNRTI resistance remains the most prevalent resistance pattern in the USA and among individuals with AHI in North Carolina [11–15]. In a study of once-daily ETR with coformulated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive, chronically HIV-infected participants, 77% achieved viral suppression by week 48 . The ACTG 5142 study demonstrated equivalence of a NNRTI and a ritonavir-boosted protease inhibitor regimen versus standard ART . On the basis of the low prevalence of resistance-associated mutations with protease inhibitors and particularly DRV, protease inhibitor based regimens have been recommended for treatment during AHI and prior to availability of resistance testing results . In sum, available data demonstrated antiviral activity for a ritonavir-boosted protease inhibitor in combination with ETR comparable to standard first-line ART regimens with the potential advantage of a higher threshold for HIV resistance with both DRV and ETR.
These data in combination with advances in antiretrovirals led to the recent exploration of novel dual therapy regimens for the treatment of chronic HIV infection [19–23]. However, to our knowledge, no dual therapy regimen has been studied in the setting of acute HIV. We evaluated the safety, tolerability and activity of the dual NRTI-sparing ART regimen of DRV/r combined with ETR initiated in AHI. We evaluated viral decline and characterized pharmacokinetics in plasma and tissue compartments, including GALT, CSF and genital secretions and sought to assess the impact of early treatment with this dual regimen on neurocognitive function.
Materials and methods
ART-naive participants at least 18 years of age diagnosed with AHI within 30 days of enrolment were eligible. AHI diagnosis was the date of sample collection for the first test detecting HIV, not the date the individual was notified of the result. ART naive was defined as 14 days or less of ART prior to study entry except for postexposure prophylaxis (PEP) if HIV negative within 6 months after completing PEP. AHI was defined as negative ELISA immunoassay (EIA) and positive nucleic acid testing (NAT); positive EIA and positive NAT with a negative/indeterminate western blot; or positive EIA, positive western blot and EIA negative documentation within the preceding 30 days. Participants were referred with results suggestive of AHI from the community or from routine screening for AHI performed at the North Carolina (NC) State Laboratory of Public Health with Genetic Systems HIV-1/HIV-2 Plus 0 EIA, Bio-Rad Laboratories (Redmond, Washington, USA), Bio-Rad Genetic Systems HIV-1 Western Blot and Aptima HIV-1 RNA Qualitative Assay (Gen-Probe Inc., San Diego, California, USA) pooling of seronegative samples  until November 2013; thereafter with chemiluminescent microparticle immunoassay (CMIA) assay and the Multispot HIV-1/HIV-2 rapid test, Bio-Rad Laboratories. HIV testing at enrolment was as follows: 2009 to November 2010 with Genetic Systems HIV-1/HIV-2 Plus O EIA with Genetic Systems HIV-1 Western blot, Bio-Rad Laboratories; December 2010 to March 2012 with Abbott Architect HIV Ag/Ab Combo Assay with Bio-Rad Genetic Systems HIV-1 Western Blot and March 2012 onward with Abbott Architect HIV Ag/Ab Combo Assay and Bio-Rad Multispot HIV-1/HIV-2 Rapid Test. AHI referrals to the University of North Carolina at Chapel Hill (UNC) and Duke University were offered prompt evaluation, usually within 1–2 days [25,26]. Exclusion criteria were minimal and included pregnancy, breastfeeding, inability to commit to acceptable methods to avoid pregnancy, incarceration, recent administration of immunomodulating medications, serious acute or psychiatric illness or chronic hepatitis B infection.
In this dual-centre, single-arm, open-label pilot study, participants with AHI were administered and started darunavir 800 mg once daily, ritonavir 100 mg once daily and etravirine either as 400 mg once daily or 200 mg twice daily at enrolment. Baseline resistance testing was performed on all participants. Participants were evaluated at weeks 2, 4, 8, 12, 16, 24, 36 and 48. Virologic failure was defined as failure to achieve HIV-1 RNA less than 200 copies/ml by week 24 or 2 consecutive HIV-1 RNA levels more than 200 copies/ml at least one week apart after week 24. Adherence was assessed by self-report. Date of symptom onset consistent with AHI was documented. Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatrics Adverse Events, Version 1.0, December 2004; Clarification August 2009.
Blood samples were collected for an abbreviated pharmacokinetic analysis with samples taken predose and then at 1, 2, 3, 4 and 15–24 h after an observed dose at weeks 4 and 48, and for storage at each visit. Optional sub-studies included sample collection for pharmacokinetic analysis from genital fluids (between weeks 0–4, and weeks 12 and 48), CSF (between week 2–4, and at weeks 24 and 48), endoscopic biopsies (between weeks 4–12 and between weeks 36–48). Genital secretions were self-collected following a 48-h period of reported sexual abstinence and CSF was collected via standard lumbar puncture procedures. Endoscopic biopsies were obtained by colonoscopy from the terminal ileum; biopsy specimens weighed an average of 50 mg and were snap frozen in liquid nitrogen immediately after collection. All samples were stored at −80°C. Concentrations were quantified in matrices per previously published methods .
Neuropsychological performance was assessed at baseline (week 2 or 4), week 24 and week 48 in the following domains (measures): Premorbid/language [Wide Range Achievement Test (WRAT) 4 - Reading Subtest (Wilkinson 1993)], Learning [HVLT-R, Hopkins Verbal Learning Test–Revised (Benedict et al. 1998)], Memory (HVLT-R), Speed of Processing [Trailmaking A (Army Individual Test Battery, 1944; Reitan and Davison)], 1974, Stroop color [Stroop, 1935; Kaplan adaptation of Comalli)], Attention (WAIS-III Symbol Search (Psychological Corporatio, 1997); Stroop word (Stroop 1935); Fine motor (Grooved pegboard, Kløve 1963), Executive [Trailmaking B, Stroop interference, Letter, Category Fluency (Gladsjo et al. 1999)]. An overall summary score of neurocognitive functioning was created by averaging all tests. Participants completed the self-reported functional status. Patient's Assessment of Own Functioning Inventory (PAOFI) (Chelune, Heaton and Lehman 1986) and the Activities of Daily Living Scale (ADLS) (Lawton & Brody 1969). Best available demographically corrected normative data were utilized to create z-scores and then deficit scores for impairment ratings.
The institutional review boards at UNC and Duke University approved the study. All study participants provided written informed consent and a separate informed consent before each optional procedure.
We examined demographic and clinical characteristics of participants using descriptive statistics. Time to viral suppression was calculated as the number of days from ART initiation until the first documented HIV RNA less than 200 copies/ml and the first documented HIV RNA value less than 50 copies/ml. Exposures included baseline HIV RNA level and duration from estimated-date-of-infection [28,29] until treatment. Each exposure was dichotomized into those less than or equal to the median value and those above the median value. For the time to viral suppression analysis, participants were censored if they stopped treatment or were lost to follow-up before demonstrating viral suppression prior to week 24. Log-rank test was used to assess differences in suppression times between exposure groups. Multivariable proportional hazards regression was used to estimate hazard ratios for the association between baseline HIV RNA level and time to viral suppression. Potential confounders included CD4+ T-cell count and age. The final model was built using backwards elimination with a 10% change in estimate criteria for retaining confounding variables.
Compartment penetration ratio (matrix:plasma) was calculated by division of CSF (ng/ml), semen (ng/ml) and tissue concentrations (ng/g converted to ng/ml using a tissue density correction) with plasma concentrations (ng/ml). Samples taken within the same dosing interval were considered paired. If there were multiple plasma samples, then the sample taken closest in time to the compartment sample was chosen. All statistical analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria).
Change in neurocognitive functioning was analysed using a repeated measures analysis of variance (ANOVA) with neurocognitive performance as the dependent variable (total z-score) and time (visit) as the independent variable. Correlation between CD4+ nadir, baseline HIV RNA level and time to viral suppression with total z-score was assessed by Spearman correlation.
Between August 2009 and November 2012, 15 participants with AHI enrolled and started the study regimen. Baseline characteristics of participants are summarized in Table 1. The median age was 24 years (range 19–51). Eleven participants (74%) were African–American, three (20%) Hispanic white and one (6.7%) non-Hispanic white. The majority (n = 13; 87%) of participants were MSM, as only two (13%) female participants enrolled; no male participants self-identified as heterosexual. Among 13 MSM enrolled, 12 (92%) were less than 30 years of age; both female participants were aged more than 30 years. No potential participants were excluded from enrolment. Eleven (85%) participants were enrolled following AHI detection at the NC State Laboratory of Public Health.
Prior to starting ART, the median HIV RNA level was 1 000 000 copies/ml (range 22 858–29 807 640), and the median nadir CD4+ T-cell count was 501 cells/μl (range 268–838.) On the basis of the date of symptom onset (assumed infection to be 14 days prior based on prior analyses ,) we estimated participants initiated ART at a median of 44 days (range 23–140) after acquiring HIV [28,29], and all had seroconverted at the time of starting ART. Genotype testing revealed a mutation (E138A) associated with resistance to study treatment in only one participant at baseline. He was lost to follow-up early following entry.
The treatment regimen was well tolerated with a total of five adverse events in four participants that were attributed as possibly/definitely related to study treatment. All were Grade 1 and included nausea, rash, headache, dizziness and increase in cholesterol. All treatment-related adverse events resolved spontaneously without intervention and occurred as one-time events. No study treatment doses were held, and no participants discontinued study treatment due to an adverse event.
Forty percent (n = 6/15) of participants had a CD4+ nadir cell count less than 400 cells/μl, with a median increase in CD4+ T-cell count of 158 cells/μl (range 281–916) and 349 cells/μl (range 7–495) from baseline to week 24 and week 48, respectively. Twelve out of 15 (80%) participants suppressed to less than 200 copies/ml prior to or at week 24. Among three study-defined treatment failures at week 24, one participant was lost to follow-up (LTFU) after week 2, and two participants had low-level viremia (283 and 226 copies/ml), one of whom suppressed at week 36 and the other participant was discontinued from the trial due to poor adherence.
Overall, LTFU was minimal; 14 (93%) participants completed a study visit at or after week 36 and 12 (80%) completed a week 48 study visit. Among the 12 participants retained through week 48, nine (75%) demonstrated viral suppression less than 50 copies/ml. Among three viremic participants at week 48, two participants had low-level viremia (96 and 71 copies/ml), and the third viremic participant had prior durable HIV RNA suppression but discontinued study treatment due to preference for a one pill once-a-day regimen after week 24. The overall median time from starting ETR and DRV/r to HIV RNA suppression less than 200 copies/ml was 59 days (range 15–489) and to less than 50 copies/ml was 86 days (range 15–489).
For the optional procedures, six participants provided paired ileal biopsy samples, four participants provided seven CSF samples and six participants provided semen samples. HIV RNA was not detected in any CSF samples and HIV RNA was detected in ilieal biopsy specimens from three of six participants only at the first measurement. Median antiretroviral plasma exposures with the interquartile ranges are shown in Fig. 1. Antiretroviral exposures varied between biological matrices. DRV and ETR concentrations and area under the curve (AUC) values at 12 h were extrapolated through noncompartmental analyses for the ileum and semen (data not shown), and these agreed well with literature values . ETR exposure ranged from 4 to 25 ng/ml in CSF, 12–185 ng/ml in semen and 1317–98 293 ng/g in ileal tissue. DRV exposure ranged from 10 to 240 ng/ml in CSF, 9–1296 ng/ml in semen and 987–202 815 ng/g in ileal tissue. Of the three antiretrovirals, compared with paired plasma sample concentrations, ETR had the highest penetration into the CSF (1.6% of plasma concentrations, Table 2) and into GALT (1920% of plasma concentrations), while DRV had the highest penetration into semen (16.2% of plasma concentrations). Ileal tissue concentrations of all antiretrovirals exceeded accompanying plasma concentrations by 19.2-fold (ETR) and three-fold (DRV).
Thirteen of 15 (87%) participants had baseline neurocognitive assessments, and 11 participants had subsequent assessments at week 24 and/or 48 after ART initiation; eight participants completed assessments at all three time points. At baseline, 61% of participants were considered impaired [defined as more than two tests > 1 standard deviation (SD) below the norm], 33% were impaired at 24 weeks and 30% impaired at 48 weeks. There was a statistically significant improvement in overall neurocognitive functioning over time (F (2,17) = 4.23, P = 0.03), with the greatest improvement occurring between baseline and week 24 [baseline mean z = −0.69 (0.14), week 24 mean z = −0.40 (0.15) and week 48 mean z = −45 (0.15)] (Fig. 2). Two of the three participants who did not experience neurocognitive improvement failed to achieve virologic suppression. Self-report of current cognitive or physical problems at baseline was noted in 23%, but there was no association with overall neuropsychological performance (r = −0.22, ns). There was no correlation with CD4+ nadir and total z-score (r = 0.19, ns) for neuropsychological performance impairment, although the median CD4+ nadir was high at 501 cells/μl (range 268–838). More rapid HIV RNA suppression was significantly correlated with improved neurocognitive performance (r = −0.82, P < 0.005) (Fig. 3a). Higher baseline HIV RNA was associated with poorer neurocognitive performance at week 48 (r = −0.67, P = 0.05) (Fig. 3b).
At the time this study was initiated, ART treatment guidelines considered treatment during AHI optional due to lack of data confirming clinical benefit . In 2013, guidelines were updated to recommend the immediate initiation of ART during AHI due to expanding data on the ability of ART during AHI to preserve immune function, decrease the HIV RNA set point [30–32], reduce the size of the latent HIV reservoir [33–36] and limit viral diversity due to the suppression of viral mutations [37,38]. We sought to assess the activity of a dual, NRTI-sparing ART regimen started during AHI, and to explore whether the pharmacokinetics of this regimen might offer advantages with regards to GALT and CSF penetration.
The regimen was generally well tolerated, and despite a higher pill burden, only one participant stopped treatment due to a preference for a single tablet regimen. Viral suppression rates were comparable to recommended ART regimens at the time of the study; 80% by week 24 and 75% of those retained through week 48. Lower rates of suppression may in part reflect the impact of lost to follow-up given the small sample size. Limitations of the study include the small sample size and lack of a comparison arm, precluded by the infrequent diagnosis of acute HIV. Both prevent concluding this regimen is equivalent in efficacy to past or current standard ART; however, the findings are notable given the expansion of dual therapy for chronic HIV and its use during AHI in our study.
Time to viral suppression less than 50 copies/ml for the two-drug regimen of DRV/r and ETR in AHI (median 86 days) was shorter than that observed in an earlier study using coformulated FTC/TDF/efavirenz (median 102 days) , In comparison, chronically infected patients suppressed to less than 50 copies/ml at a median of 60 days with integrase strand transfer inhibitors (INSTIs), 137 days with NNRTI regimens and 147 days with protease inhibitor regimens . In addition, our results compare favourably with results from other studies on treatment-naive participants treated with DRV/r-containing triple drug regimens (Supplemental Figure 1, http://links.lww.com/QAD/B802) [40,41].
These results suggest that a protease inhibitor based, NRTI-sparing two-drug ART regimen started during AHI has potent activity, even in the setting of high HIV RNA typical of individuals diagnosed early. The recent FDA approval of two-drug integrase inhibitor-based ART with dolutegravir and rilpivirine, although only for patients with HIV RNA suppression, suggests the potency of current antiretroviral drugs may support treatment with NRTI-sparing regimens as a long-term strategy. Additional two-drug ART regimens have been FDA approved for ART treatment-naive participants (dolutegravir and lamivudine) and others are under evaluation (cabotegravir and rilpivirine). However, data on these dual regimens as initial therapy during AHI is not yet available, and current guidelines recommend either boosted DRV or DTG in combination with two NRTIs if started before drug resistance testing results are available .
Penetration ratios of ETR (19.2) and DRV (3) observed in GALT at least suggest these antiretrovirals could favourably minimize GALT depletion or allow early recovery in AHI. These GALT penetration ratios are consistent with previously published rectal concentrations . As expected, drug concentrations in CSF and semen were low compared with plasma and are consistent with previously published concentration ranges [27,42,43]. A limitation of this analysis is that we quantified total drug concentrations, as it has been demonstrated that unbound concentrations of efavirenz are equivalent between plasma and CSF , although DRV is chiefly unbound in CSF  However, our previous understanding of minimal protein binding potential in semen and the ileum indicates that the majority of the measured concentration of drug is available for activity against HIV in these matrices [27,46]. All of these concentrations were at least several-fold above the protein-adjusted IC50 of the virus.
In addition, our findings suggest that early initiation of ART may improve neurocognitive performance. Other studies have also demonstrated neurocognitive impairment in individuals with early or acute HIV [47,48]. Data from studies on whether ART in acute HIV improved neurocognitive performance have been inconclusive, in part due to variation in the timing of ART initiation in acute or early HIV and prevalence of substance abuse [47,48]. In our study, 61% of individuals with AHI demonstrated neurocognitive impairment at baseline, and in most, neuropsychological performance improved during 24 and 48 weeks of treatment. However, two out of three participants who met study criteria for virologic failure demonstrated persistent neurocognitive impairment. Although psychological distress of HIV infection was noted in some, there was no significant relationship to neuropsychological performance. However, higher baseline HIV RNA correlated with poorer neurocognitive outcome at week 48 and more rapid HIV RNA suppression correlated with improved neurocognitive outcome at week 48. The lack of a control group and the small sample size preclude ruling out other causes, but these data suggest that treatment during AHI may improve neurocognitive function, a plausible finding given the rapidity with which HIV virus enters the CNS following HIV infection [6,49] and persistent neurocognitive impairment observed despite viral suppression [50,51]. Accordingly, very early effective ART in AHI may improve or preserve neurocognitive function by suppressing viremia within the CNS and limiting CD4+ nadir, as the latter has been associated with the risk for neurocognitive impairment [7,48].
Among participants with AHI, this two-drug, NRTI-sparing ART regimen of DRV/r long with ETR demonstrated comparable activity to standard ART, favourable drug concentrations in GALT and improvements in neurocognitive impairment. As coformulation options expand, additional and larger studies of other dual regimens for treatment-naive patients, as well as the uptake and experience of dual regimens for maintenance therapy, are needed to fully elucidate the role of dual ART during AHI. Although this regimen in unlikely to be used given current guidelines recommending effective, coformulated options, our findings contribute to expanding data on dual ART, as well as dual ART and NRTI-sparing regimens in AHI, and tissue penetration of antiretrovirals.
We greatly appreciate the support of all study staff members, HIV care providers, staff in the UNC and Duke Infectious Diseases clinics and particularly the individuals who participated in this study. We also acknowledge and remember our very good friend and talented colleague, Kevin Robertson, who passed prior to publication of these results.
Study design was done by C.L.G, D.M.M., J.D.K., C.B.H., M.S.M., J.J.E., K.R.R., A.D.K., M.D.M.; data generation/assay performance was done by C.L.G., A.S.D., D.N., J.D.K., K.S.M., N.J.S., J.S., J.S., S.A.F., M.S.M., K.R.R., A.D.K.; drafting of the article was done by C.L.G., D.N., A.S.D., J.S., J.D.K., S.A.F., G.F., M.S.M., C.B.H., K.R.R., A.D.K., J.J.E., D.M.M.
This study is supported by the generous contributions of Janssen Scientific Affairs, LLC and the following NIH-funded programmes: the UNC Center for AIDS Research (CFAR) (P30 AI50410), the Duke CFAR (5P30 AI064518), a grant (RR00046) from the General Clinical Research Centers program of the Division of Research Resources, and in part by funding from the National Institute of Child Health and Development (T32 HD52468), and a 2K24 AI01608 award. A.S.D. is supported by the National Institute of General Medical Sciences of the NIH under Award Number T32GM086330. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Institutes of Health. Janssen Scientific Affairs, LLC provided antiretroviral medications for this study. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Conflicts of interest
C.G. has received research support from Bristol Myers Squibb, Gilead Sciences, Abbott, Janssen and ViiV Healthcare. C.H. has received grant support and/or consulting/honoraria from BMS, GSK, Merck, Tibotec Therapeutics and Gilead, and is a full-time employee at Viiv Healthcare. D.M. has consulted for Merck and Viiv Healthcare, and holds common stock in Gilead Sciences. J.E. receives research support from ViiV Healthcare, Gilead and Janssen and is a consultant to Merck, Gilead, Janssen, ViiV Healthcare. M.M. has received research support from Bristol Myers Squibb, Gilead Sciences and ViiV Healthcare. A.S.D., A.D.M.K., D.N., G. F., J.K., J.S., J.S., K.M., N.S., S.F., K.R.R declare no conflicts of interest.
1. Dandekar S. Pathogenesis of HIV in the gastrointestinal tract
. Curr HIV/AIDS Rep
2. Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells
3. Mehandru S, Poles MA, Tenner-Racz K, Jean-Pierre P, Manuelli V, Lopez P, et al. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection
. PLoS Med
4. Tincati C, Biasin M, Bandera A, Violin M, Marchetti G, Piacentini L, et al. Early initiation of highly active antiretroviral therapy fails to reverse immunovirological abnormalities in gut-associated lymphoid tissue induced by acute HIV infection
. Antivir Ther
5. Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, et al. Impact of multitargeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection
. PLoS One
6. Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, et al. Central nervous system viral invasion and inflammation during acute HIV infection
. J Infect Dis
7. Peluso MJ, Ananworanich J, Sithinamsuwan P, Slike B, Gisslen M, Zetterberg H, et alImmediate antiretroviral therapy mitigates the development of neuronal injury in acute HIV, Abstract 31.Conference on Retroviruses and Opportunistic Infections
; 2018; Boston, MA.
8. Trezza CR, Kashuba AD. Pharmacokinetics of antiretrovirals in genital secretions and anatomic sites of HIV transmission: implications for HIV prevention
. Clin Pharmacokinet
9. Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial
10. Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial
11. Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, Kiuchi M, et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update
. PLoS One
12. Yanik EL, Napravnik S, Hurt CB, Dennis A, Quinlivan EB, Sebastian J, et al. Prevalence of transmitted antiretroviral drug resistance differs between acutely and chronically HIV-infected patients
. J Acquir Immune Defic Syndr
13. Snedecor SJ, Khachatryan A, Nedrow K, Chambers R, Li C, Haider S, et al. The prevalence of transmitted resistance to first-generation nonnucleoside reverse transcriptase inhibitors and its potential economic impact in HIV-infected patients
. PLoS One
14. Gay CL, Willis SJ, Cope AB, Kuruc JD, McGee KS, Sebastian J, et al. Fixed-dose combination emtricitabine/tenofovir/efavirenz initiated during acute HIV infection; 96-week efficacy and durability
15. Levintow SN, Okeke NL, Hue S, Mkumba L, Virkud A, Napravnik S, et al. Prevalence and transmission dynamics of HIV-1 transmitted drug resistance in a Southeastern cohort
. Open Forum Infect Dis
16. Floris-Moore MA, Mollan K, Wilkin AM, Johnson MA, Kashuba AD, Wohl DA, et al. Antiretroviral activity and safety of once-daily etravirine in treatment-naive HIV-infected adults: 48-week results
. Antivir Ther
17. Mugavero MJ, May M, Ribaudo HJ, Gulick RM, Riddler SA, Haubrich R, et al. Comparative effectiveness of initial antiretroviral therapy regimens: ACTG 5095 and 5142 clinical trials relative to ART-CC cohort study
. J Acquir Immune Defic Syndr
18. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV
. Department of Health and Human Services; 2019.
19. Soriano V, Fernandez-Montero JV, Benitez-Gutierrez L, Mendoza C, Arias A, Barreiro P, et al. Dual antiretroviral therapy for HIV infection
. Expert Opin Drug Saf
20. Llibre JM, Hung CC, Brinson C, Castelli F, Girard PM, Kahl LP, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, noninferiority SWORD-1 and SWORD-2 studies
21. Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, noninferiority, phase 3 trials
2019; 393 (10167):143–155.
22. Taiwo BO, Zheng L, Stefanescu A, Nyaku A, Bezins B, Wallis CL, et al. ACTG A5353: a pilot study of dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA < 500,000 copies/mL
. Clin Infect Dis
23. Figueroa MI, Sued OG, Gun AM, Belloso W, Cecchini DM, Lopardo G, et al.DRV/R/3TC FDC for HIV-1 treatment naive patients: week 48 results of the ANDES study.Conference on Retroviruses and Opportunistic Infections
; 4–7 March 2018; Boston, MA.
24. Pilcher CD, Fiscus SA, Nguyen TQ, Foust E, Wolf L, Williams D, et al. Detection of acute infections during HIV testing in North Carolina
. N Engl J Med
25. McKellar MS, Cope AB, Gay CL, McGee KS, Kuruc JD, Kerkau MG, et al. Acute HIV-1 infection in the Southeastern United States: a cohort study
. AIDS Res Hum Retroviruses
26. Kuruc JD, Cope AB, Sampson LA, Gay CL, Ashby RM, Foust EM, et al. Ten years of screening and testing for acute HIV infection in North Carolina
. J Acquir Immune Defic Syndr
27. Brown KC, Patterson KB, Jennings SH, Malone SA, Shaheen NJ, Asher Prince HM, et al. Single- and multiple-dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and rectal tissue of HIV-negative men
. J Acquir Immune Defic Syndr
28. Gay C, Dibben O, Anderson JA, Stacey A, Mayo AJ, Norris PJ, et al. Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy
. PLoS One
29. Lindback S, Thorstensson R, Karlsson AC, von Sydow M, Flamholc L, Blaxhult A, et al. Diagnosis of primary HIV-1 infection and duration of follow-up after HIV exposure. Karolinska Institute Primary HIV Infection Study Group
2000; 14 (15):2333–2339.
30. Hogan CM, Degruttola V, Sun X, Fiscus SA, Del Rio C, Hare CB, et al. The setpoint study (ACTG A5217): effect of immediate versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individuals
. J Infect Dis
31. Hamlyn E, Ewings FM, Porter K, Cooper DA, Tambussi G, Schechter M, et al. Plasma HIV viral rebound following protocol-indicated cessation of ART commenced in primary and chronic HIV infection
. PLoS One
32. Grijsen ML, Steingrover R, Wit FW, Jurriaans S, Verbon A, Brinkman K, et al. No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial
. PLoS Med
33. Gianella S, von Wyl V, Fischer M, Niederost B, Joos B, Gunthard H, et al.Impact of early ART on proviral HIV-1 DNA and plasma viremia in acutely infected patients.17th Conference on Retroviruses and Opportunistic Infections
; 16–20 February; San Francisco, CA.
34. Hocqueloux L, Prazuck T, Avettand-Fenoel V, Lafeuillade A, Cardon B, Viard JP, et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection
35. Schmid A, Gianella S, von Wyl V, Metzner KJ, Scherrer AU, Niederost B, et al. Profound depletion of HIV-1 transcription in patients initiating antiretroviral therapy during acute infection
. PLoS One
36. Strain MC, Little SJ, Daar ES, Havlir DV, Gunthard HF, Lam RY, et al. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1
. J Infect Dis
37. Goonetilleke N, Liu MK, Salazar-Gonzalez JF, Ferrari G, Giorgi E, Ganusov VV, et al. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection
. J Exp Med
38. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF. The immune response during acute HIV-1 infection: clues for vaccine development
. Nat Rev Immunol
39. Jacobson K, Ogbuagu O. Integrase inhibitor-based regimens result in more rapid virologic suppression rates among treatment-naive human immunodeficiency virus-infected patients compared to nonnucleoside and protease inhibitor-based regimens in a real-world clinical setting: a retrospective cohort study
. Medicine (Baltimore)
40. Nishijima T, Komatsu H, Teruya K, Tanuma J, Tsukada K, Gatanaga H, et al. Once-daily darunavir/ritonavir and abacavir/lamivudine versus tenofovir/emtricitabine for treatment-naive patients with a baseline viral load of more than 100 000 copies/ml
41. Gazzard B, Duvivier C, Zagler C, Castagna A, Hill A, van Delft Y, et al. Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48-week results
42. Yilmaz A, Izadkhashti A, Price RW, Mallon PW, De Meulder M, Timmerman P, et al. Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals
. AIDS Res Hum Retroviruses
43. Tiraboschi JM, Niubo J, Ferrer E, Barrera-Castillo G, Rozas N, Maso-Serra M, et al. Etravirine concentrations in seminal plasma in HIV-infected patients
. J Antimicrob Chemother
44. Avery LB, Sacktor N, McArthur JC, Hendrix CW. Protein-free efavirenz concentrations in cerebrospinal fluid and blood plasma are equivalent: applying the law of mass action to predict protein-free drug concentration
. Antimicrob Agents Chemother
45. Croteau D, Rossi SS, Best BM, Capparelli E, Ellis RJ, Clifford DB, et al. Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration
. J Antimicrob Chemother
46. Brown KC, Patterson KB, Malone SA, Shaheen NJ, Prince HM, Dumond JB, et al. Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men
. J Infect Dis
47. Kore I, Ananworanich J, Valcour V, Fletcher JL, Chalermchai T, Paul R, et al. Neuropsychological impairment in acute HIV and the effect of immediate antiretroviral therapy
. J Acquir Immune Defic Syndr
48. Spudich S. HIV and neurocognitive dysfunction
. Curr HIV/AIDS Rep
49. Pilcher CD, Shugars DC, Fiscus SA, Miller WC, Menezes P, Giner J, et al. HIV in body fluids during primary HIV infection: implications for pathogenesis, treatment and public health
50. Peluso MJ, Meyerhoff DJ, Price RW, Peterson J, Lee E, Young AC, et al. Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection
. J Infect Dis
51. Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, et al. The prevalence and incidence of neurocognitive impairment in the HAART era