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Antiretroviral Therapy CROI 2018
New Agents/Combinations
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Joseph J. Eron MD Professor of Medicine University of North Carolina at Chapel Hill - (03/06/17)
Bictegravir
The most recently approved medication for HIV treatment is the single tablet combination of bictegravir/emtricitabine/tenofovir alafenamide or B/F/TAF. Bictegravir is a potent integrase inhibitor (INSTI), similar to dolutegravir, with activity against HIV-1 resistant to first generation INSTI and a high in vitro barrier to resistance1. In treatment naïve patients B/F/TAF has been shown to be non-inferior to dolutegravir either with TAF/FTC or in the fixed dose combination of DTG/ABC/3TC2,3. B/F/TAF is also being explored as a switch strategy. Jean-Michel Molina presented phase III data from a randomize trial that enrolled patients suppressed on DTG plus abacavir/lamivudine (ABC/3TC)4. Participants were randomized 1:1 to continue on DTG plus ABC/3TC or switch to B/F/TAF with approximately 280 participants in each arm. Virologic rebound was very uncommon; 1.1% with B/F/TAF and 0.4% with DTG plus ABC/3TC, a result which demonstrated non-inferiority. Proportion that remained suppressed to < 50 c/mL at 48 weeks was 93.6% and 95% respectively. Not surprisingly there were no substantial differences in adverse events, renal outcomes or lipids given these were all patients who were stable and tolerating DTG plus ABC/3TC prior to entering the study. While the study clearly met its goals of establishing noninferiority of B/F/TAF there were no overt or subtle difference between the two arms.
CROI: Switch to Bictegravir/F/TAF From DTG and ABC/3TC - (03/05/18)
Cissy Kityo also presented a B/F/TAF switch, this one exclusively in women5. The women entered on one of three regimens elvitegravir/cobicistat/FTC/TAF (E/C/F/TAF), E/C/F/TDF or atazanavir/ritonavir TDF/FTC. As in the study presented by Jean Michel Molina most of the participants did very well with only 2% with HIV RNA > 50 c/mL at 48 weeks and little difference in tolerability (the women came from long-term studies of the other agents. No participant on B/F/TAF (in either study) developed resistance, while one patient on E/C/F/TDF developed an M184V mutation.
CROI: Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Women - (03/06/18)
CROI: Bictegravir/FTC/TAF Single-Tablet Regimen in Adolescents: Week-24 Results - (03/06/18)
So how do these studies impact clinical care and clinical decision making? Simply, they tell us what we can now avoid with a single tablet integrase inhibitor regimen. We can avoid abacavir and we can avoid boosting agents and still get a STR with a potent integrase that is likely to have a barrier to resistance similar to dolutegravir. We avoid abacavir, I think, mainly because we cannot shake the thought that abacavir may well be a causal factor contributing to MI risk. The NA-ACCORD analysis of THE ASSOCIATION OF ABACAVIR WITH CARDIOVASCULAR OUTCOMES was finally published by Rick Elion and colleagues. Using state-of-the-art methods to control for confounding, the estimated hazard ratios for cardiovascular risk ASSOCIATED WITH ABACAVIR were in the same range as the original and follow-up D.A.D analyses 6 DTG/abacavir/3TC is also a large pill (would have been hard to believe 15 years ago that this factor would be driving choices) and there is a suggestion that some of the side effects that are being associated with integrase inhibitors, such as weight gain7 and CNS effects may be more common when DTG is combined with abacavir5,8, though not in all studies9.
Avoiding boosting makes very good sense. We should only accept the risks of drug-drug interaction when there is no clinically acceptable alternative. Now that we have a TAF-containing single tablet integrase inhibitor regimen that does not require boosting we no longer need to use cobicistat-boosted elvitegravir. B/F/TAF also has the advantage of a greater barrier to resistance. Resistance on an elvitegravir-containing first line regimen is NOT common. However, resistance to both elvitegravir and FTC can certainly emerge if there is virologic on ECFTAF or ECFTDF.
Single tablet Protease Inhibitor
I had the opportunity to present data on the single tablet protease inhibitor regimen, darunavir/cobicistat/FTC/TAF (D/C/F/TAF) studies in one of the largest (probably the largest) switch studies to date (EMERALD)10. The primary results of this study were published by Chloe Orkin (who gave a great symposium talk) and colleagues11. The overall results showed that switching from a boosted PI plus 2NRTI regimen to the STR D/C/F/TAF was non-inferior to the continued multi-pill regimens with very few virologic failures and no resistance emergence. What differentiates the EMERALD study from all other single tablet switch studies is that patients with previous virologic failure were allowed to participate. Only patients with previous failure on a darunavir regimen or those with known primary darunavir resistance mutations were excluded. In the CROI poster we looked at subsets of patients divided by previous virologic failure and by number of antiretroviral agent to which a participant was exposed (from 4 to > 7). Success rates were very similar, whether there was previous virologic failure or not and were not impacted by the number of previous antiretroviral medications to which the participants had been exposed. Baseline resistance testing in those patients with previous failure, using archive DNA testing, is planned. This single tablet regimen may be very useful in the setting where a switch in therapy is desired and treatment history is not clear or there is a past history of virologic failure on a protease inhibitor-based regimen.
CROI: Analysis of HIV Patients Switching to D/C/F/TAF by Prior ARV Treatment Experience (03/09/18)
CROI: HIV Treatment-experienced Patients Switched to D/C/F/TAF: Age, Gender, and Race Analyses (03/09/18)
CROI: Efficacy and safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in virologically-suppressed, treatment-experienced and treatment-naïve women with human immunodeficiency virus type 1 (03/08/18)
CROI: Age, Gender, and Race Analyses of D/C/F/TAF in HIV-1 Treatment-naïve Patients (03/08/18)
CROI: Pharmacokinetics of Total and Unbound Darunavir in HIV-1-infected Pregnant Women Receiving a Darunavir/Cobicistat-based Regimen (03/09/18)
MK8591
Perhaps one of the most exciting new antiretroviral agents to appear in some time is MK8591. On the surface this drug looks like a typical nucleoside reverse transcriptase inhibitor (NRTI). However, while it does compete with nucleotides for binding to the HIV-1 reverse transcriptase enzyme and can result in chain termination, once bound to the elongating HIV-1 DNA molecule it prevents translocation of the template and blocks further replication with remarkable potency12,13. Therefore, very low concentrations of this agent are able to inhibit HIV-1. This feature along with a long intracellular half-life make it possible for MK8591 to be given at long dosing intervals and also make this agent very attractive as a long-acting implantable therapy. Randolph Mathews from Merck presented data on the PK of this compound in healthy, uninfected volunteers14. He reminded us that in previous presentations (as yet unpublished) doses as low as 0.5 mg once weekly could suppress plasma HIV RNA by more than one log10 and that the intracellular half-life of EFdA-triphosphate in peripheral blood mononuclear cells was at least 120 hours. A 5 mg daily dose for 40 days in healthy uninfected volunteers was well tolerated and doses as low as 0.25 mg daily were tested for 28 days. Even with this small dose intracellular levels were in the range of concentrations that has shown activity in HIV infected persons. A phase II study using 0.25mg of MK8591 daily in combination with doravirine and 3TC in treatment naïve HIV-1 infected patients is enrolling (NCT03272347). This drug will almost certainly also be developed for prevention. In the healthy volunteer study presented by Mathews at al rectal and vaginal levels of MK8591-TP were measured. The levels achieved with each of the three doses tested (0.25, 0.75 and 5 mg daily) were above the estimated level needed to provide protection based on animal studies and TFV-DP tissue levels. Marty Markowitz and colleagues demonstrated that several different dose levels of MK8591 administered weekly to Rhesus macaques prevented SHIV infection via rectal challenge. Once weekly, once monthly or implantable formulations of MK8591 (EFdA) for prevention seem possible.
CROI: MULTIPLE DAILY DOSES OF MK-8591 AS LOW AS 0.25 MG ARE EXPECTED TO SUPPRESS HIV - (03/05/18)
CROI: Multiple Low Doses of Nucleoside MK-8591 Strong in Healthy Volunteers - Long-Acting MK-8591 /Treatment / PrEP-vaginal/rectal tissue - Mark Mascolini (03/06/18)
CROI: Low-Dose Oral MK-8591 Protects Monkeys From Rectal SHIV Infection - Mark Mascolini (03/07/18)
Does Integrase Inhibitor based therapy increase the risk of IRIS?
A critical question that has been raised by several observational studies is whether patients with advanced HIV or who present with an opportunistic infection are at greater risk of an immune reconstitution inflammatory syndrome (IRIS) if they are started on an INSTI-based therapy. The hypothesis proposed is that the rapid reduction of plasma HIV RNA by INSTI-based regimens leads to a more rapid immune recovery and increased the risk of IRIS. This question was directly addressed in an analysis from the REALITY trail in which participants were randomized to receive raltegravir plus standard ART or standard ART alone (predominantly efavirenz plus TDF/FTC)15. Diana Gibb presented the data on the 1805 participants who were randomized and followed for IRIS related death and IRIS events (including those related to specific infections)16. Median baseline CD4 cell counts were between 35 and 40 cell/mm3. IRIS events were adjudicated by a panel that was blinded to treatment assignment. The participants in the RAL intensification arm had a significantly more rapid decline in plasma HIV-1 RNA but there was no difference in IRIS related mortality, overall IRIS events or IRIS events related to specific illness, e.g. TB, cryptococcal infection etc. Rates were remarkably similar between the two arms with fatal/non-fatal IRIS occurring in 9.9% of participants in the RAL arm and 9.5% of participants in the control. TB IRIS was the most common event occurring in 5.9% and 6.0% of participants respectively. IRIS events were associated with lower pre-ART CD4, older age up to age 29 and TB infection at baseline. Participants who received enhanced prophylaxis, which was shown to improve overall mortality in this study,17 also had substantially fewer IRIS events. I think these results lay to rest the concern that using INSTI-based regimens in advance HIV infection will lead to an increase in IRIS events and clinicians should be comfortable with using INSTI-based regimens even patients who present with advance HIV-1 infection.
CROI: Impact of Raltegravir Intensification of first-line ART on IRIS in the REALITY trial (Reduction of EArly mortaLITY in HIV-infected adults and children starting ART) - (03/05/18)
Antiretroviral Interactions with TB Therapy
The developing world is moving rapidly toward INSTI first line therapy with fixed dose combinations of dolutegravir (or possibly bictegravir) with TDF or TAF and 3TC (or FTC). TDF/3TC/dolutegravir (so called TLD) was recently endorsed by PEPFAR. One critical question raised by this approach is how to manage patients with active tuberculosis infection using standard rifampin-based therapy. What dose or doses of the newer antiretrovirals like DTG, bictegravir or TAF should be used in combination with rifampin? Several presentations address this question.
Kelly Dooley presented data from a randomized study comparing standard efavirenz plus 2 NRTI therapy vs. dolutegravir 50 mg twice daily plus 2 NRTI in patients with active TB on standard treatment with INH, rifampin, pyrazinamide and ethambutol18. One hundred thirteen patients were enrolled in a 2:1 randomization and she presented 24 week data. At 24 weeks 89% of participants treated with EFV-based therapy and 81% treated with DTG-based therapy had HIV RNA < 50 c/mL. Only one participant with a very high baseline plasma HIV RNA who received DTG had a confirmed VL > 400 c/mL at week 24 (no resistance detected) and most of the difference between the two arms was related to either missing data or loss to follow-up. Importantly the PK of DTG at 50 mg twice daily were similar to the (preliminary) post TB treatment phase when participants received once daily DTG and the twice daily PK data with rifampin were also similar to historical data of once daily dolutegravir. In Botswana, where dolutegravir plus TDF/FTC is already being rolled out, they are using this strategy of twice daily DTG in patients being treated for TB. Data from the Botswana experience may be available later this year. Of note in the study presented by Kelly Dooley there was no difference in TB IRIS events between the two arms supporting the data from the REALITY study discussed above.
The question of whether a similar strategy (using twice daily dosing) can also be used with bictegravir when co-administered with rifampin was addressed in Phase I PK study presented by Joseph Custodio and colleagues19. Bictegravir is metabolized by UGT1A1 and CYP3A enzymes, which are both induced by rifampin. In this study, healthy HIV-1 uninfected volunteers were given once daily B/F/TAF, had PK measured, and then were given B/F/TAF twice daily and had the PK of bictegravir measured again. Unfortunately, rifampin co-administration reduced the trough concentration of bictegravir by approximately 80% even with doubling the dose of bictegravir. So unlike raltegravir and dolutegravir it does not appear that bictegravir will be useful in treating HIV-1 infected patient who have active TB and need rifampin.
The question of how to dose TAF in the setting of co-administration with rifamycins remains open. Rifampin affects TAF concentrations likely at least in part through induction of several transporters including P-gp. Maddalena Cerrone presented data on the impact of rifampin on the plasma and intracellular PK of TAF also in healthy volunteers when TAF/FTC was given once daily first alone and then with rifampin (abstract 28LB)20. Finally, the same volunteers were given TDF/FTC after TAF/FTC and rifampin were stopped. Blood levels of TAF were reduced with co-administration with rifampin as were intracellular levels of tenofovir-diphosphate (TFV-DP). However, the levels of TFV-DP when TAF/FTC was given with rifampin were 76% higher than when TDF/FTC was given after rifampin was stopped. Alternatively, TAF/FTC twice daily co-administered with rifampin was studied previously in healthy uninfected volunteers (Custodio et al EACS 2017). Both plasma TAF levels and intracellular TFV-DP levels were decreased compared to daily TAF/FTC though not to the same extent as seen in the work by Cerrone et al presented her at CROI. FTC levels were not affected by rifampin. When generic DTG/TAF/FTC becomes available (http://newsroom.mylan.com/2018-02-20-Mylan-Receives-Tentative-Approval-for-Combination-HIV-Treatment-DTG-FTC-TAF-Under-FDAs-PEPFAR-Program) dosing with rifampin will need to be explored further. Given the drug-drug interactions that rifampin has with both DTG and TAF - twice daily dosing during the period of co-administration with rifampin-based TB therapy may make the most sense.
CROI: INSPIRING: SAFETY AND EFFICACY OF DOLUTEGRAVIR-BASED ART IN TB/HIV COINFECTED ADULTS AT WEEK 24 - (03/05/18)
CROI: Pharmacokinetics of Bictegravir Administered Twice Daily In Combination With Rifampin - (03/06/18)
Ongoing replication during suppressive ART?
The debate over whether ongoing rounds of HIV-1 (residual) replication occur in people infected with HIV on ART who have plasma HIV RNA suppressed to below the limit of detection on standard assays continues21-24. There is no question that HIV RNA expression occurs and viral particles are released from infected cells as many patients on suppressive ART have very low levels of HIV RNA in plasma when their blood is examined by more sensitive assays (so called single copy assays)25. The debate is over whether patients on suppressive ART have continuous rounds of replication that could lead to emergence of resistance to therapy and, importantly, could replenish the persistent HIV reservoir and be a barrier to HIV cure. It is difficult to prove a negative - that is to prove beyond any doubt that no replication is occurring, but multiple groups continue to investigate this question.
Three oral presentations at CROI 2018 explored the question further. In one, Nadine Bachmann and colleagues (abstract 69LB) presenting data from the Swiss cohort which looked at determinants of cell-associated HIV DNA (CA HIV DNA) decay in a large number of long-term suppressed patients who had serial plasma HIV RNA levels measured over time26. As in a previous study published by Raj Gandhi27 there was a decline in CA HIV DNA that occurred with therapy initiation and was most pronounced in the first years post ART start. This group was able to estimate a half-life of decay. When looking at patients who had samples for more than 10 years the ½ life of decay of CA-HIV DNA was on the order of 11 years. Again, this was similar to the ½ life estimated by Gandhi et al. The Swiss group did include patients who had had blips in their plasma HIV RNA without confirmed failure. These individuals, on average, had larger CA-HIV DNA levels and slower decay - suggesting that blips may be limiting reservoir decay. Several members of the audience pointed out that the association between blips and CA DNA decay did not prove causality. An alternative explanation would essentially be the inverse causality - that patients with larger reservoirs of HIV infected cells are more likely to have release of virus that reaches a level above the limit of detection (i.e. a blip). Sequencing HIV DNA or low-level HIV RNA from these patients looking for evidence of virus evolution would be one way, perhaps, to address this question.
Mary Kearney has studied the question of ongoing HIV-1 replication by examining HIV-1 sequence evolution in painstaking studies of low level plasma HIV RNA using single genome sequencing in patients on suppressive therapy and found no evidence of ongoing HIV-1 replication14. Her team took this work one step further by examining HIV RNA and HIV DNA from lymph nodes and blood samples obtained from patients on suppressive therapy28. As in her previous work she was unable to detect sequence evolution in the blood or lymph node tissue of a small number of patients. In addition, she also demonstrated that there was overlap in HIV DNA sequences from peripheral blood cells and LN mononuclear cells - that is, no evidence of compartmentalization in the lymph nodes. She also looked at samples from two different lymph nodes from the same patient and saw overlapping sequences, without evolution, from the two sites. Finally, her group looked at lymph node samples from one patient at two different time points separated by over a year and again found overlapping sequences with no evidence of ongoing replication. During the question and answer period Dr. Kearney did acknowledge that her method was designed to detect continuous rounds of replication and that a few replication cycles in one discreet location that then stop may not be picked up by her methods. Whether other non-lymph node compartments such as gastrointestinal lymphoid tissue or the CNS might support low levels of ongoing replication remains an open question.
Thomas A Rasmussen presented a very carefully done study to examine whether intensification of an already suppressive therapy could provide evidence of ongoing replication by showing effects on measures of virus expression/replication including single copy plasma HIV RNA or accumulation of 2-LTR circles29. Forty participants on suppressive ART, that was predominantly NNRTI based, were randomized to dolutegravir or placebo for 56 days and multiple endpoints were measured. The primary endpoint was an increase in 2 LTR circles, which are formed when integration is blocked during ongoing replication; an effect that was observed in a subset of patients in 2 previous studies of raltegravir intensification30,31. Rasmussen and colleagues saw no increase in 2-LTR circles and no differences in these levels between treatment arms. They also did not see differences in plasma single copy HIV RNA levels, cell-associated HIV RNA, CA HIV DNA or markers of inflammation or T-cell activation. The results of these secondary endpoints were very similar to the work of Raj Gandhi and colleagues who studied raltegravir intensification in a placebo controlled cross over design study32,33 and also saw no effect on HIV RNA, CA RNA, CA DNA or markers of inflammation and activation. That study, however, had only infrequent measurements of 2-LTR circles leaving that question to be resolved by the Rasmussen group, whose comprehensive results argue, once again, for no evidence of ongoing replication in patients with consistent viral suppression using currently available assays.
CROI: No Evidence of Residual Virus Replication in a Randomised Controlled Trial of Dolutegravir Intensification - (03/07/18)
1. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile. Antimicrob Agents Chemother. 2016;60(12):7086-7097.
2. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063-2072.
3. Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073-2082.
4. Molina J-M, Ward D, Brar I, Mills A, Hans-JurgenStellbrink, al e. SWITCH TO BICTEGRAVIR/F/TAF FROM DTG AND ABC/3TC. CROI 2018; March 4-7, 2018; Boston, MA. Abstract 20
5. Kityo C, Hagins D, Koenig E, et al. SWITCHING TO BICTEGRAVIR/EMTRACITABINE/TENOFOVIR ALAFENIMIDE (B/F/TAF) IN WOMEN. CROI 2018; March 4-7, 2018; Boston, MA. Abstract 500
6. Elion RA, Althoff KN, Zhang J, et al. Recent abacavir use increases risk for Types 1 and 2 myocardial infarctions among adults with HIV. J Acquir Immune Defic Syndr. 2018.
7. Norwood J, Turner M, Bofill C, et al. Brief Report: Weight Gain in Persons With HIV Switched From Efavirenz-Based to Integrase Strand Transfer Inhibitor-Based Regimens. J Acquir Immune Defic Syndr. 2017;76(5):527-531.
8. Hoffmann C, Welz T, Sabranski M, et al. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med. 2017;18(1):56-63.
9. Fettiplace A, Stainsby C, Winston A, et al. Psychiatric Symptoms in Patients Receiving Dolutegravir. J Acquir Immune Defic Syndr. 2017;74(4):423-431.
10. Eron JJ, Orkin C, Molina J-M, et al. ANALYSIS OF HIV PATIENTS SWITCHING TO D/C/F/TAF BY PRIOR ARV TREATMENT EXPERIENCE. Paper presented at: CROI 2018; March 4-7, 2018; Boston, MA. Abstract 500
11. Orkin C, Molina JM, Negredo E, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. The lancet HIV. 2018;5(1):e23-e34.
12. Michailidis E, Huber AD, Ryan EM, et al. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms. J Biol Chem. 2014;289(35):24533-24548.
13. Salie ZL, Kirby KA, Michailidis E, et al. Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA). Proc Natl Acad Sci U S A. 2016;113(33):9274-9279.
14. Matthews RP, Rudd DJ, Levine V, et al. MULTIPLE DAILY DOSES OF MK-8591 AS LOW AS 0.25 MG ARE EXPECTED TO SUPPRESS HIV. Paper presented at: CROI 2018; March 4-7, 2018; Boston, MA.
15. Gibb D, Szubert AJ, Chidziva E, et al. IMPACT OF RALTEGRAVIR INTENSIFICATION OF FIRST-LINE ART ON IRIS IN THE REALITY TRIAL. CROI 2018; 2018; Boston, MA.
16. Gibb D, Szubert AJ, Chidziva E, et al. IMPACT OF RALTEGRAVIR INTENSIFICATION OF FIRST-LINE ART ON IRIS IN THE REALITY TRIAL. Paper presented at: CROI; March 4-7, 2018; Boston, MA: Abstract 23.
17. Hakim J, Musiime V, Szubert AJ, et al. Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa. N Engl J Med. 2017;377(3):233-245.
18. Dooley K, Kaplan R, Mwelase N, et al. SAFETY AND EFFICACY OF DOLUTEGRAVIR-BASED ART IN TB/HIV COINFECTED ADULTS AT WEEK 24. CROI 2018; 2018; Boston, MA.
19. Custodio JM, West SK, Collins S, et al. PHARMACOKINETICS OF BICTEGRAVIR ADMINISTERED TWICE DAILY IN COMBINATION WITH RIFAMPIN. Paper presented at: CROI 2018; Boston, MA.
20. Cerrone M, Alfarisi O, Neary M, et al. RIFAMPIN EFFECT ON TENOFOVIR ALAFENAMIDE (TAF) PLASMA INTRACELLULAR PHARMACOKINETICS. Paper presented at: CROI 2018; March 4-7, 2018; Boston, MA.
21. Van Zyl GU, Katusiime MG, Wiegand A, et al. No evidence of HIV replication in children on antiretroviral therapy. J Clin Invest. 2017;127(10):3827-3834.
22. Kearney MF, Spindler J, Shao W, et al. Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy. PLoS Pathog. 2014;10(3):e1004010.
23. Lorenzo-Redondo R, Fryer HR, Bedford T, et al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature. 2016;530(7588):51-56.
24. Rosenbloom DIS, Hill AL, Laskey SB, Siliciano RF. Re-evaluating evolution in the HIV reservoir. Nature. 2017;551(7681):E6-E9.
25. Zheng L, Bosch RJ, Chan ES, et al. Predictors of residual viraemia in patients on long-term suppressive antiretroviral therapy. Antivir Ther. 2013;18(1):39-43.
26. Bachmann N, Siebenthal Cv, Vongrad V, et al. DETERMINANTS OF HIV-1 RESERVOIR SIZE AND LONG-TERM DYNAMICS UNDER SUPPRESSIVE ART. Paper presented at: CROI 2018; March 4-7, 2018; Boston, MA.
27. Gandhi RT, McMahon DK, Bosch RJ, et al. Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation. PLoS Pathog. 2017;13(4):e1006285.
28. McManus WR, Bale MJ, Spindler J, et al. NO EVIDENCE FOR ONGOING HIV REPLICATION IN LYMPH NODES DURING SUPPRESSIVE ART. Paper presented at: CROI 2018; March 4-7, 2018; Boston, MA.
29. Rasmussen TA, McMahon J, Chang JJ, Audsley J, Solomon A, et al. NO RESIDUAL VIRUS REPLICATION IN A RANDOMISED TRIAL OF DOLUTEGRAVIR INTENSIFICATION. Paper presented at: CROI 2018; March 4-7, 2018; Boston, MA.
30. Hatano H, Strain MC, Scherzer R, et al. Increase in 2-long terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with treated HIV infection: a randomized, placebo-controlled trial. J Infect Dis. 2013;208(9):1436-1442.
31. Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16(4):460-465.
32. Gandhi RT, Coombs RW, Chan ES, et al. No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012;59(3):229-235.
33. Gandhi RT, Zheng L, Bosch RJ, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 2010;7(8).
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