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21st Conference on Retroviruses and Opportunistic Infections: Review
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March 3-6, 2014
Boston, Massachusetts
Eric S. Daar, M.D.
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at UCLA
The 21st Conference on Retroviruses and Opportunistic Infections (CROI) was a great meeting emphasizing critical issues for those investigating and caring for HIV-infected individuals. There were the usual 4,000 delegates and 1000ish presentations ranging from HIV pathogenesis, transmission, treatment and cure. Once again, too many great presentations than can be covered by any single report so I took the liberty of picking what I thought were some of the highlights. The key to reporting new data presented at meetings like this is to convey the headlines, review the data and then summarize the take home message(s). In keeping with this I have organized my summary so that each area of interest includes the "headline" followed by "study findings" and then "interpretation," acknowledging that these are all based upon my views and my views alone.
HIV PREVENTION
With the increasing recognition that the development of a highly effective preventative HIV vaccine remains elusive, increasing efforts have turned to alternative biologic means of reducing the risk of transmission. The two most promising strategies have employed antiretroviral therapy for the infected or uninfected individuals. The former is often referred to as treatment for prevention, whereas the latter as pre-exposure prophylaxis (PrEP). Treatment for prevention was proven to be effective in a large randomized controlled trial of primarily heterosexual serodiscordant couples (HPTN 052). What is not known is how this would apply to other populations, e.g. intravenous drug users and men who have sex with men (MSM). In addition, since HPTN 052 was conducted along with intensive prevention counseling including condom use, it is not known how effective this strategy would be in those who do not use condoms. PrEP has been shown to be effective when used as systemic or topical forms, but not in all studies, mostly because of poor adherence.
Headlines:
· The risk of HIV transmission amongst serodiscordant couples is very low when the infected partner is on suppressive therapy even in the absence of condom use.
· Novel strategies to improve PrEP adherence show great promise.
Study findings:
· Condomless Sex: One study characterized a select group of serodiscordant couples in the Partners Study (1). They analyzed couples where the HIV-infected partner had viral loads less than 200 copies/mL and admitted to not using condoms. They found 767 couples who fell into this category with careful follow-up for linked transmission events. After nearly 1000 condomless years of sex they were unable to document any transmission events, including in many that admitted to high risk sexual activities such as receptive anal intercourse. The authors emphasized that one must consider the confidence intervals around this estimate and that the rate could be as high as 4 per 100 condomless years of follow-up. Link to CROI webcast:
http://www.croiwebcasts.org/console/player/22072?mediaType=slideVideo&
· Tenofovir DF (TDF) vs. TDF/emtricitabine (FTC) for PrEP: One presented study attempted to define the differences in efficacy between TDF alone versus TDF combined with FTC, both of which have been shown to be efficacious in select clinical trials, but only the latter is FDA approved for this indication. This is a relevant question since there are some advantages to using one versus two drugs and there had been some earlier animal studies reporting a benefit associated with two drug regimens. The investigators performed a meta-analysis that included 4,427 pairs with transmission events occurring in 31 TDF versus 21 TDF/FTC patients with calculated incidence rates per 100 patient years being 0.70 and 0.48, respectively; hazard ratio of 0.67 (95% CI 0.39, 1.17), p=0.16 (2). While there was no significant difference between the two treatment strategies, this like other related analyses have limitations and must be considered along with other factors when choosing PrEP regimens.
· Long-acting systemic and topical PrEP: While there are many strategies being pursued to overcome the problem of poor adherence with PrEP, perhaps the greatest promise is long-acting systemic or topical therapy. One study characterized a novel integrase strand transfer inhibitor (InSTI), GSK1265744 (744) as a long-acting formulation. The drug 744 LA is being developed for intramuscular administration as infrequently as every 3 months. Previous studies showed 100% protection in pigtail macaques given 50 mg/kg as an intramuscular injection. This was tested again with follow-up challenges after dosing and found that infection rates remained low as long as there were levels of greater than 1 time the protein adjusted 90% inhibitory concentration (PAIC90), providing guidance for potential dosing frequency (3). A related study assessed activity of this drug in pigtail macaques given similar dosing with intravaginal challenges. Here they found 6 of 6 treated macaques remained uninfected compared to 0 of 6 controls (4). Another study agent was a novel nonnucleoside reverse transcriptase inhibitor (NNRTI), dapivirine dosed at 25 mg, used with or without the CCR5 antagonist maraviroc at 100 mg, or placebo in a vaginal ring form. The use of this ring resulted in good local and systemic levels of dapivirine, but low levels of maraviroc. In addition, ex vivo challenge of cervical biopsy showed that increasing levels of dapivirine was associated with decreasing infection in tissue culture (5).
Interpretation:
· The data using treatment for prevention has demonstrated astounding results from a randomized controlled trial. While this study and clinical practice continue to strongly endorse that such a strategy be complemented by the use of condoms, the current analysis suggests high levels of protection even when condoms are not used. It is important to recognize the limitations of this study and that confidence intervals suggest that risk could still be considerable. This along with the importance of condoms to prevent transmission of other sexually transmitted diseases would support continued caution for these couples.
· There is little doubt that TDF is effective as PrEP for heterosexual and intravenous drug use-associated transmission. Whether it is as effective as TDF/FTC is not known. Based upon the limitations of the data and a risk-benefit analysis the current FDA-approved treatment for PrEP, and CDC interim guidelines only endorse the two drug regimen. Novel long-acting preparations show great promise, with the injectables in early stage development and the vaginal ring moving forward into much larger efficacy and safety trials.
ANTIRETROVIRAL THERAPY
There were several very important presentations related to the treatment of antiretroviral-naïve patients. This includes updated data on prevalence of transmitted resistance and new treatment strategies. As usual, treatment studies define both efficacy and tolerability. Moreover, they focus on other important issues related to treatment, e.g. effects on lipids and bone mineral density (BMD).
Transmitted drug resistant virus
Headline:
· More than 15% of newly diagnosed MSM in key cities across the United States acquired drug resistant HIV.
Study findings:
· The National HIV Surveillance System reported new data related to transmitted drug resistant virus in MSM from Chicago, Dallas, Denver, Detroit, Los Angeles, Miami, New Orleans, New York City and Seattle (6). There was a slightly greater frequency of resistance in those with recent versus long-standing infection but even in the latter the frequency was nearly 17% overall. Transmitted resistant virus was most common to NNRTIs (~10%) followed by nucleoside reverse transcriptase inhibitors (NRTIs) at ~7%. It is important to note that surveillance data is not yet available for InSTI resistance which is still considered rare but will need to be looked at in the future as this class of drugs is being used with increasing frequency, including as first-line therapy.
Interpretation:
· Performing drug resistance testing on patients new to care and/or starting therapy for the first time is as important as ever and remains the standard of care in most developed countries. Pending more data, it is not yet considered the standard of care to perform InSTI resistance testing.
Studies of treatment-naïve patients
For treatment-naïve patients the focus was on new drugs and novel strategies. At this meeting large fully powered efficacy and safety trials compared NNRTI-sparing options and a NRTI-sparing regimen.
Headlines:
· TDF/FTC with twice daily raltegravir (RAL) was equally efficacious to the same NRTIs with atazanavir/ritonavir (ATV/r) and darunavir/ritonavir (DRV/r). Tolerability advantages were seen with RAL over the protease inhibitors (PIs), especially ATV/r, while resistance was more common with RAL.
· RAL twice daily + DRV/r once daily was noninferior to TDF/FTC + DRV/r but not in those with low CD4 cell counts.
· Abacavir/lamivudine (ABC/3TC) plus dolutegravir (DTG) continues to be superior to TDF/FTC/EFV at 96 weeks, mostly driven by superior tolerability.
· A phase 2b study of a new NNRTI, MK-1439, now known as doravirine showed good efficacy and safety at 24 weeks.
Study findings:
· The much anticipate results of ACTG A5257 were reported, including over 1800 treatment-naïve patients randomized to one of three NNRTI-sparing regimens of TDF/FTC with RAL twice daily, DRV/r or ATV/r once daily (7). The primary endpoint was to demonstrate equivalence for time to virologic failure at 96 weeks with a tolerability endpoint of time to study drug discontinuation for adverse events. As done with other recent ACTG studies, virologic failure was defined as confirmed viral load >1000 copies/mL at or after week 16 through week 24 or confirmed value greater than 200 at or after week 24. The overall efficacy was equivalent across the study arms but there were greater number of patients who stopped treatment in the ATV/r arm, largely driven by hyperbilirubinemia. Additional analyses showed that lipid profiles were excellent for all study arms but favored RAL over PIs for total and LDL cholesterol as well as triglycerides, with no difference in lipid profiles between the PIs (8). In a separate analysis, BMD was assessed showing no difference in the decline after treatment initiation with the PIs approximately 3-4%, but an attenuated reduction in the RAL-containing regimen at closer to 2% in the hip and lumbar spine (9).
· The NEAT001 Study compared the NRTI-sparing regimen of once daily DRV/r (800/100 mg) plus RAL twice-daily to a standard TDF/FTC + once-daily DRV/r regimen (10). The composite endpoint included virologic failure or treatment discontinuation with high levels of response that were noninferior between the study arms. However, when looking at response by baseline factors there was a trend towards worse outcomes in those with baseline viral load >100,000 copies/mL and a significantly worse response in those with <200 CD4 cells/uL initially randomized to the NRTI-sparing regimen.
· The 96 week follow up of the SINGLE Study showed continued better outcomes in treatment-naïve patients assigned to ABC/3TC plus DTG (80%) compared to TDF/FTC/EFV (72%). As seen as 48 weeks the difference was mostly a result of less study drug discontinuation and enhanced tolerability of ABC/3TC plus DTG compared with TDF/FTC/EFV (11). In addition, there continues to be no emergent InSTI or NRTI resistant virus in the DTG-containing study arm.
· The novel NNRTI doravirine was studied in a dose-finding phase 2b study where it was combined with TDF/FTC at doses of 25, 50, 100 and 200 mg per day compared to TDF/FTC/EFV (12). This drug has some in vitro activity against viruses resistant to other NNRTIs, e.g. those with the K103N, Y181C, G190A or E138K mutations and in early development appeared to be well tolerated. In this study 71-80% had less than 40 copies/mL of HIV present at 24 weeks compared to 64% in the TDF/FTC/EFV study arm. In addition, there appeared to be less dizziness, nightmares and effect on cholesterol with the new agent. This drug will be moving forward in development at a dose of 100 mg per day.
Interpretation:
· A5257 demonstrates the high level of efficacy of all three study regimens with distinct advantages in tolerability of RAL over the PI's, especially ATV/r which can be complicated by hyperbilirubinemia, recognizing that this is a completely reversible adverse event. In addition, there were similar effects on lipids and BMD between the two PIs, which had not been formally compared in a head-to-head fashion. There was also a better lipid profile and less effect on BMD in the RAL compared to PI-based regimens. These finding must be balanced by the fact that RAL needs to be given twice daily and when virologic failure occurs it is more likely to be with drug resistant virus on RAL than with the PIs.
· The NEAT Study showed that a NRTI-sparing regimen can be safe and effective, but it appears that those with low CD4, e.g. <200 cells/uL and possibly higher viral load, e.g. >100,000 copies/mL may be at higher risk for virologic failure than seen with dual NRTIs + DRV/r.
· The extended follow-up with ABC/3TC plus DTG illustrates its long-term safety and efficacy when compared to EFV, with difference mostly driven by increase EFV-associated side effects.
· Doravirine is in early stages of development but shows promise as a new NNRTI for first line therapy.
Studies of treatment-experienced patients
Headline:
· Those on suppressive NNRTI or PI/r-based regimens can be safely switched to TDF/FTC/cobicistat/elvitegravir (TDF/FTC/COBI/EVG).
· A novel InSTI, 744 combined with ABC/3TC is effective in suppressing plasma HIV, and once suppression is achieved it can be maintained with this drug combined with rilpivirine (RPV) given at a dose of 25 mg/daily, setting stage for studies of maintenance therapy with long acting 744 and RPV given as infrequent intramuscular injections.
· A new drug in a new class, BMS-626529 is an attachment inhibitor that showed early promise for treatment-experienced patients.
Study findings:
· Two switch studies were conducted in patients with sustained suppression on NRTIs + EFV or a PI/r to TDF/FTC/COBI/EVG. The primary rationale for such a switch would be for simplification of dosing and tolerability. The study designs were similar with one group switching from stable NNRTI-based and the other a stable PI-based regimen. All were on first or second regimens without evidence of resistance or virologic failure on TDF or FTC. They also were required to have calculated creatinine clearance of at least 70 mL/minute. The NNRTI switch study included 291 that switched and 143 that remained on their original regimen. The overwhelming majority of patients were on EFV with over 90% on their first regimen. Suppression was maintained at high levels in the switch (93%) and no change (88%) groups. It was noted that there was a significant, albeit small decrease in HDL cholesterol in those who switched, but otherwise no difference in other lipid parameters between study arms. In addition, those who switched experienced significantly lower rates of neuropsychiatric complaints at week 48 compared to those who remained on their original regimen. There was an increase in mild headache and nausea in those that switched, although it was reported that these side effects decreased with time (13). For the PI/r study there were 293 that switched and 140 that maintained their current regimen with 40% on DRV/r and 40% ATV/r-based regimens. Overall virologic suppression remained high in both arms at 48 weeks with 2 in each group experiencing protocol-defined virologic failure. There was a reduction in triglycerides and a significant decline in diarrhea and bloating amongst those that switched (14). There was also the predictable early increase in creatinine seen in those that switched therapy in both studies, the known effect of COBI on renal tubular secretion of creatinine.
· The LATTE Study enrolled treatment naive patients given the novel InSTI 744 with ABC/3TC to demonstrate efficacy and safety of 744 given at 10, 30 and 60 mg/d, for a total of approximately 180 patients (15). The reason I list this study under experienced patients is that while demonstrating 744 safety and efficacy was important, the primary goal of this study was to determine if those initially suppressed on this NRTIs + InSTI regimen could be switched to a novel 744 plus RPV combination. The main impetus for pursuing this strategy was to determine if the long-acting formulations of these drugs could ultimately be used as maintenance therapy. Viral suppression at 24 weeks was high and similar in all three doses of 744 and even higher than that seen in TDF/FTC/EFV controls. Of those suppressed that switched to 744 plus RPV over 90% maintained viral suppression after 24 weeks of maintenance therapy with good tolerability. This sets the stage for an entirely new direction in the treatment of HIV where a study will determine whether patients can be treated with monthly or even less frequent intramuscular injections.
· The only new drug in a new class presented at this meeting was a novel attachment inhibitor that binds gp120 resulting in a conformational change that prevents viral attachment to the cell. The drug known as BMS-626529 has been shown to have in vitro and in vivo activity against most strains of HIV, although there are a subset of viruses that are intrinsically resistant. Consequently, this phase 2b study targeted treatment-experienced patients that had susceptible virus at screening. Patients were randomized to receive TDF plus RAL with either the attachment inhibitor given at 400 or 800 mg twice-daily or 600 or 1200 mg once-daily, or a control arm of ATV/r. Of the nearly 200 patients assigned the experimental drug approximately 70% achieved virologic suppression, a rate very similar to the ATV/r control. In addition, the safety profile in this study appeared quite promising (16).
Interpretation:
· Select individuals on PI or NNRTI-based regimens can safely switch to TDF/FTC/COBI/EVG with sustained virologic suppression and some potential advantages regarding convenience and/or tolerability. As is always the case, the decision to switch should be made on an individual basis in settings where there are predicted to be advantages for a given patient.
· The LATTE study demonstrated short term safety and efficacy of a novel InSTI and set the stage for studies of long-acting agents.
· The new attachment inhibitor represents one of the few drugs moving forward in clinical practice that might provide options for those with limited treatment options due to resistance, tolerability or both.
BONE MINERAL DENSITY IN HIV INFECTION
Headline:
· Declines in BMD associated with initiating TDF/FTC/EFV-based regimens is attenuated by the use of Vitamin D and calcium supplementation.
· Statins can improve BMD in virologically suppressed HIV-infected patients, but it is associated with increased insulin resistance.
Study findings:
· Study ACTG A5280 was designed to determine whether vitamin D and calcium supplementation would reduce the decline in BMD observed in patients starting a TDF/FTC/EFV regimen (17). The rationale for this study included the fact that there is a predictable decline in BMD in patients starting antiretroviral therapy, and that EFV is associated with lower levels of vitamin D. The study enrolled 165 patients planning to start TDF/FTC/EFV and randomized them to receive vitamin D (4000 IU per day) plus calcium carbonate (1000 mg per day), versus placebo. It was noted that those enrolled had relatively low vitamin D intake at baseline, ~150 versus the recommended 600 IU per day. The primary endpoint was percent change in BMD at week 48 and they indeed showed that there was a 50% reduction in the BMD decline in the intervention compared to control arm. This was accompanied by a decline in markers of bone turnover. Important limitations of this study include the fact that it was limited to patients starting a single type of antiretroviral therapy, i.e. TDF/FTC/EFV, the study subjects were taking suboptimal amounts of dietary vitamin D and it is not known how much vitamin D versus calcium supplementation might have contributed to the beneficial effects of the intervention. In addition, it is not known in this setting what the clinical relevance will be of the observed attenuation in the BMD decline.
· The SATURN Study was a randomized trial of rosuvastatin at a dose of 10 mg per day compared to placebo in those on stable suppressive antiretroviral therapy with LDL <130 mg/dL and increase in CD8 T-cell activation and/or high sensitivity C-reactive protein (hsCRP). The rationale for this study was to see whether the effect statins have on bone with increases in bone morphogenetic protein 2 and reduction in inflammation would positively effect BMD (18). In fact, in the 147 enrolled patients there was a modest but significant increase in hip BMD at week 48; however, there was also a significant increase in fasting insulin and HOMA-IR. This study, along with further results described in the inflammation section below illustrate the potential benefits of statin therapy in HIV-infected individuals.
Interpretation:
· Vitamin D and calcium supplementation might have a role in reducing BMD decline when starting select antiretroviral regimens, but the clinical relevance of this effect is unknown and there remain many unanswered questions. Further analyses from the A5280 study are likely to be very informative in the future.
· Rosuvastatin has beneficial effects on bone but is associated with potentially important effects on insulin sensitivity that needs to be monitored for in clinical practice.
CURE RESEARCH
The success of antiretroviral therapy along with a few high profile anecdotes has supercharged research towards individuals being able to maintain undetectable levels of virus while off antiretroviral therapy. This can be achieved as a result of complete eradication of virus from the body or perhaps maintenance of very low levels of virus that is contained by effective immune responses. While the science is fascinating, readers should not be fooled by the hype and misleading headlines. Cured bone marrow transplants, babies and adults treated during first weeks of infection range from case reports to case series with little reason at this time to believe that we are on the brink of something bigger. Nevertheless, every meeting reports on enhanced understanding of what might be needed to achieve such viral remission as well as the obstacles in the way of success.
Headlines
· Low levels of plasma HIV RNA persist in a large number of patients treated for more than 10 years.
· More bone marrow cures- NOT!
· Another cured baby- Maybe?
Study findings
· There are many ways to demonstrate viral persistence in the body of those on suppressive antiretroviral therapy. One method is the use of an investigational and highly sensitive single copy plasma HIV RNA assay. Previous studies demonstrated that a large percentage of virologically suppressed patients will continue to have detectable plasma virus using this assay. At this meeting an analysis was performed in those with sustained viral suppression by standard HIV RNA assays at 4, 7 and 11 years of follow-up. This group observed that of the 65% of patients with detectable virus after 4 years of therapy, the majority will continue to have similar levels after 7 and even 10 years of follow-up (19).
· The only person who appears to be cured after a bone marrow transplant remains to be Timothy Brown, "The Berlin Patient" who received intensive conditioning, stem cells from patients with cells that did not express the secondary receptor required for HIV infection, CCR5, and experienced graft-versus-host disease. Recent meetings talked of two Boston patients who underwent stem cell transplants with less intensive conditioning and from donors whose cells did express CCR5. In these cases it was initially reported that 2 to 4 years after their stem cell transplants, and while on combination antiretroviral therapy they had no detectable virus using highly sensitive methods (20). Subsequently it was reported that antiretrovirals were discontinued without rebound after 2-3 months. A subsequent report noted that that both had experienced viral rebound, one at 3 and the other 8 months off therapy. At this meeting more details were reported, primarily additional studies demonstrating that they had no detectable virus using even more sensitive methods, along with 0.001% of their cells being non-donor cells and the lack of HIV-specific immunity prior to treatment interruption. In this setting, both experienced abrupt onset of very high viral load with acute retroviral syndrome, perhaps consistent with the absence of pre-existing immunity. Moreover, the virus rebound from one of the studied patient appeared to be with an isolated strain, suggesting it may have emerged from possibly a single remaining infected cell (21).
· The "Mississippi Baby" or "Mississippi Child," depending upon who you listen to was the child born to a mother found to be infected when in labor and the baby started on three drug therapy within 30 hours of birth. The baby was demonstrated to be infected by repeatedly positive virologic tests but then became undetectable for 15 months until lost to follow-up. Upon returning after approximately one year off therapy there was no detectable virus or viral-specific immune responses (22). The investigators now reported that the baby remains free of virus by multiple methods for nearly 30 months off treatment (23). While this case continues to show promise that this will translate into something special, another case was also reported. The difference, which by the way is HUGE, the "Long Beach Baby" was treated early and has little detectable virus, BUT remains on therapy (23). Let's hope that this baby experiences no viral rebound if therapy is discontinued. Let's also hope that the currently planned study to intervene in this way in larger numbers of newborns translates into a home run on the cure front. That said, it probably is premature to call this baby cured, or even maybe cured. This is particularly true in light of the observations made in the stem cell transplant patients noted above.
Interpretation:
· Data using single copy assay provide more data regarding the persistence of virally infected cells in patients on prolonged suppressive antiretroviral therapy.
· Studies of HIV-infected patients undergoing stem cell transplants continue to produce very interesting data that may further define what the critical factors were that led to the Berlin patient cure. The Boston patients illustrate some of the challenges facing cure-related research in the future.
· The Mississippi baby continues to look promising as a cure. In contrast, it is probably premature to be making any declarations of cures in a baby from Long Beach or any other city prior to treatment discontinuation. The good news is that carefully conducted studies are soon to start in order to address this critical question. Pending further data, it is not yet considered the standard of care to treat high risk newborns with the regimens used in the Mississippi and Long Beach baby cases.
CARDIOVASCULAR DISEASE AND HIV INFECTION
For many years there has been increasing data demonstrating that those with HIV infection appear to be at increased risk for cardiovascular events even in the setting of virologic suppression. Many epidemiologic studies support these observations and increasing efforts have gone into understanding the pathogenesis of these findings.
Headline:
· Systemic and arterial inflammation are associated with coronary atherosclerosis.
· The ABC link to cardiovascular disease persists with time in D:A:D.
Study findings:
· Several groups have demonstrated that compared to HIV-uninfected controls, T cell and monocyte activation remains elevated in HIV-infected patients despite sustained viral suppression. There is also increasing data linking these observations to vascular disease. One study used patients enrolled in the Multicenter AIDS Cohort Study (MACS)> that were virologically suppressed HIV-infected men or HIV-uninfected controls that underwent single assessments by cardiac CT for coronary calcification and CT angiography to characterize the type of plaque and degree of stenosis present within their coronary circulation.
Along with CT these patients had assessments of CD8 T-cell activation (CD38+/HLA-DR+) and soluble markers of monocyte activation, sCD14 and sCD163. These markers were then correlated with the CT findings after adjusting for baseline characteristics including cardiovascular risk factors and HIV parameters. This study showed that HIV-infected individuals did indeed have significantly higher levels of CD8 T-cell and monocyte activation than uninfected controls. Moreover, markers of activation were significantly associated with select types of coronary atherosclerosis (24).
· Another study used 18 fludeoxyglucose (FDG)-PET scanning to assess vascular inflammation and correlate this with high risk coronary artery plaque by CT angiography. The rationale for this research is the fact that FDG is taken up by activated macrophages that are pathologically present in atherosclerotic plaque. This study focused on the prevalence and burden of high risk coronary plaque characterized as "low attenuation" or "remodeling" which is thought to be associated with increased risk of rupture and acute coronary syndrome. They found that even in those with viral suppression, increased arterial inflammation, as measured at the aorta was associated with higher prevalence and burden of high risk coronary plaque (25). The authors acknowledged that the study was limited by small size (n=41), cross-sectional study design, and the fact that inflammation was assessed at aorta and not coronary arteries. Nevertheless, it provides early data that arterial inflammation in HIV-infected patients may be a major driver of accelerated coronary atherosclerosis.
· In approximately 2008 the very large D:A:D cohort, designed to assess relationship between HIV and antiretroviral therapy with cardiovascular endpoints reported that even after adjusting for many confounders there was an association between use of ABC and didanosine with cardiovascular events. While these observations have been supported by some studies, others have not seen such an association. As with any cohort study, a major concern is that there are unmeasured factors that might be driving the results. This includes the possibility that those with renal disease, which is a risk factor for cardiovascular events could be disproportionately given ABC to avoid the nephrotoxicity of TDF. At this year's CROI the D:A:D group provided extended follow-up of the cohort with the rationale that since 2008 there may be a trend towards investigators using ABC less in those with other cardiovascular risks, perhaps decreasing the likelihood of seeing the previously described association (26). In fact, they did see a decrease in the use of ABC amongst those with cardiovascular risk factors, consistent with the possibility that the original results did influence the thinking of patients and providers. Nevertheless, despite this trend there remained through 2011 a highly significant association between ABC use and cardiovascular endpoints.
Interpretation:
· There are increasing number of studies demonstrating that those with virologically suppressed HIV infection have persistently increased levels of systemic and vascular inflammation which appears to be associated with coronary atherosclerosis. This data supports the need for further understanding of factors that drive inflammation in these patients and consider interventions that could complement antiretroviral therapy to reduce the risk of HIV-infected patients developing atherosclerotic disease.
· While there continues to be discordance between studies with regards to the association between ABC and cardiovascular events, the results continue to be very supportive of this possibility in the D:A:D study.
NOVEL INTERVENTIONS TO TARGET INCREASED INFLAMMATION IN HIV-INFECTED INDIVIDUALS
Several explanations have been proposed to explain persistent inflammation in the setting of virologic suppression in HIV-infected individuals. A leading hypothesis is that during the first weeks of HIV infection there is massive loss of lymphoid tissue in the gastrointestinal tract that allows for bacterial translocation and resultant circulating lipopolysaccharide (LPS) and monocyte activation. This hypothesis can be tested by determining if agents that decrease intestinal bacteria and endotoxemia would decrease levels of systemic inflammation. In addition, other agents known to reduce inflammation could also be studied to assess the impact on markers of inflammation and end organ disease.
Headline:
· Several drugs with potential to influence levels of microbial translocation and gut driven inflammation showed little effect on markers of endotoxemia or inflammation.
· Statin therapy reduces systemic inflammation.
Study findings:
· Rifaximin is a nonabsorbable antibiotic that alters gastrointestinal microbiome and has potential to reduce bacterial translocation, as seen in its ability to reduce LPS levels in patients with cirrhosis. ACTG study A5286 randomized patient with virologic suppression and CD4 cells <350 cells/uL to Rifaximin 550 mg twice daily versus no therapy. After 4 weeks of treatment there was a marginal but significant reduction in CD8 T-cell activation; however, there was no effect on LPS, sCD14 or sCD163 (markers of monocyte activation), IL-6, D-dimer or sTNFr-II levels (27).
· Mesalamine is a mucosally active anti-inflammatory agent which was used in patients virologically suppressed with CD4 cells <350 cells/uL in a crossover design where 15 received active drug at 1.5 grams daily for 12 weeks and 18 placebo. After 12 weeks patients were crossed-over to the other study arm. Ultimately there was no change in CD4 or CD8 T-cell activation, sCD14, IL-6, D-dimer or effect on flow mediated dilatation, an assessment of endothelial function (28).
· Sevelamir is a phosphate binder that has been shown to decrease LPS and LDL cholesterol in patients on hemodialysis. A study evaluated whether this agent would reduce LPS levels and T cell activation in untreated HIV-infected patients. It enrolled 40 patients and administered the drug at a dose of 1600 mg three-times daily. After 8 weeks of therapy there was no significant decline in LPS, sCD14, IL-6, CRP or D-dimer, while there was an expected decrease in LDL, oxidated LDL and in Soluble Tissue Factor (29).
· Rosuvastatin is a statin that was studied in the context of the SATURN Study to assess its impact on both BMD, as described above, and systemic inflammation. Virologically suppressed patients with LDL <130 mg/dL and increased levels of CD8 T-cell activation and/or hsCRP were randomized to rosuvastatin 10 mg per day or placebo for 48 weeks. Those receiving active drug demonstrated significant declines in a variety of markers of inflammation/activation, including CD4 and CD8 T-cell activation and monocyte activation (sCD14)(30).
Interpretation:
· Multiple agents acting at the level of the intestinal lumen showed little effect on systemic inflammation or microbial translocation. This could be explained by these agents having insufficient potency or that gastrointestinal pathology may not be the lone mechanism behind persistent inflammation, activation and coagulation in virologically suppressed HIV-infected individuals.
· Statins do appear to reduce systemic inflammation, the clinically relevance of which needs to be explored in larger clinical trials.
CONCLUSIONS
Another great CROI with exciting new data related to HIV epidemiology, prevention, treatment, pathogenesis and cure. There were also some very exciting sessions related to HCV treatment that I have not addressed in my report. From a HIV clinician's perspective the most important data probably relates to new antiretroviral therapy strategies for treatment naïve and experienced patients. In addition, many exciting early findings related to the potential of new PrEP strategies, long-acting therapeutics for treatment and pilot data looking to manage the chronic inflammation and viral persistence in patients on suppressive antiretroviral therapy.
Conflicts: In the last year Eric Daar has received research support from Bristol Myers Squibb, Gilead, Merck, ViiV and was a consultant for Abbvie, Bristol Myers Squibb, Gilead, Merck, Janssen, Teva and ViiV.
References follow below after these links to studies discussed in this CROI Report by Dr Daar.
CROI: Darunavir or Atazanavir vs Raltegravir Lipid Changes are unlinked to Ritonavir Exposure: ACTG 5257 - (03/07/14)
CROI: Efficacy and Tolerability of Atazanavir, Raltegravir, or Darunavir with FTC/TDF: ACTG A5257 - (03/05/14)
CROI: First-Line Raltegravir (RAL) + Darunavir/Ritonavir (DRV/r) is Non-inferior to Tenofovir/Emtricitabine (TDF/FTC) + DRV/r: The NEAT 001/ANRS 143 Randomised Trial - (03/05/14)
CROI: GSK744 and Rilpivirine as Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results - (03/05/14)
CROI: HIV-1 Attachment Inhibitor Prodrug in Antiretroviral-Experienced Subjects: Week 24 Analysis - (03/05/14)
CROI: Dolutegravir Regimen Statistically Superior to Efavirenz/Tenofovir/Emtricitabine: 96-Week Results From the SINGLE Study (ING114467) - (03/12/14)
CROI: GSK1265744 Long-Acting Protects Macaques against Repeated High-Dose Intravaginal Challenges & Depo Provera-treated - (03/14/14)
CROI: Switch from NNRTI plus FTC/TDF to Elvitegravir/C/F/TDF Maintains HIV Suppression and is Well-Tolerated - (03/12/14)
CROI: Simplification of PI + RTV + FTC/TDF to Elvitegravir/C/F/TDF Maintains HIV Suppression and is Well-Tolerated - (03/12/14)
CROI: Rosuvastatin Improves Hip Bone Mineral Density but Worsens Insulin Resistance - (03/07/14)
CROI: Long-Acting Integrase Inhibitor GSK744 for PrEP (Once Monthly or maybe longer) - (03/05/14)
CROI: HCV Coverage at CROI - (03/10/14)
REFERENCES
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12. Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety and antiviral effect of MK-1439, a novel NNRTI (+FTC/TDF) in ART-naïve HIV-infected patients. 21st Conference on Retroviruses and Opportunistic Infections 2014, Abstract #92LB.
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19. Riddler SA, Aga E, Bosch R, et al. Pre-ART HIV-1 RNA as well as on-treatment cD8 count and CD4/CD8 ratio predict residual viremia on ART. 21st Conference on Retroviruses and Opportunistic Infections 2014, Abstract #425LB.
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27. Tenorio AR, Wilson CC, Chan ES, et al. Rifaximin has marginal impact on immune activation in immune non-responders to ART- ACTG 5286. 21st Conference on Retroviruses and Opportunistic Infections 2014, Abstract #339.
28. Dunham RM, Cohen M, Albright R, et al. Mesalamine to reduce immune activation during HIV infection: A randomized controlled trial. 21st Conference on Retroviruses and Opportunistic Infections 2014, Abstract #341.
29. Sandler NG, Zhang X, Bosch RJ, et al. Sevelamer does not decrease plasma LPS or sCD14 but does decrease soluble tissue factor and LDL. 21st Conference on Retroviruses and Opportunistic Infections 2014, Abstract #337.
30. Funderburg N, Clagett B, Jiang Y, et al. Rosuvastatin reduces immune activation and inflammation in treated HIV infection. 21st Conference on Retroviruses and Opportunistic Infections 2014, Abstract #335.
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