20th Conference on Retroviruses and Opportunistic Infections: Eradication/Cure, Prevention, Novel Strategies for administration of PrEP (delivery alternatives)
Antiretroviral Therapy/drug resistance/new drugs/Comorbidities
March 3-6, 2013
Eric S. Daar, M.D.
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at UCLA
Twenty years ago budgetary constraints led to many government-funded researchers not being able to attend the International AIDS Conference. This resulted in the establishment of the Conference on Retroviruses and Opportunistic Infections which just held its 20th annual meeting. Ironically, sequestration had again placed constraints on the travel of government investigators and threatens to further limit the ongoing progress towards curtailing the global pandemic. Despite these sad fiscal and political realities, this meeting once again proved to be a premiere environment for the sharing of high level research. In fact, despite what those who did not attend might think there was data from more than one baby presented at this meeting. In addition to the "cured baby," there were approximately 1000 scientific presentations, some of which are potentially quite impactful on the epidemic and future research.
The key to understanding new data presented at meetings is to hear the headlines, then review the data and then define 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. Since it is not possible to comment on all of the important presentations, I will summarize what I thought were highlights related to studies of HIV eradication, prevention, treatment and comorbidities.
The "Cured Baby"
By now everyone has heard about the excitement surrounding the report of a single baby that appears to have been cured of HIV infection (1). I am sure people have also read the endless analyses of what actually happened and what it may all mean. But in case you missed it, here you go.
Headline: Baby from Mississippi functionally cured of HIV by early therapy.
Study findings: A baby was born to a woman not aware of her HIV status and thus delivered without the benefit of antiretroviral therapy (ART). Since she was not taking therapy there was a high level of concern for transmission to the baby. Consequently, the child was started on combination ART with zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) at therapeutic doses. The mother was ultimately found to have CD4 cells of >600 cells/uL and plasma HIV RNA of approximately 2500 copies/mL. The baby was HIV DNA positive and then HIV RNA positive at several time points between birth and day 19 of life. Since two positive virologic tests from separate samples define neonatal infection, the diagnosis of HIV infection was made (2), and the child continued therapy, only with NVP switched to lopinavir/ritonavir (LPV/r). The child had undetectable plasma HIV RNA for months and then returned after reportedly having stopped treatment at approximately 15 months of age. Since then there has been no detectable HIV-specific antibodies, RNA, DNA or HIV-specific cellular immune responses for approximately 1 year. Voila, the baby is pronounced cured and the question emerges as to whether starting therapeutic doses of ART at birth will afford other children the same opportunity.
So what is different about this case, what happened, what didn't happen and what maybe happened? Most importantly this case represents a missed opportunity since the mother was not diagnosed with HIV during pregnancy and therefore not started on ART which is highly effective at preventing vertical transmission. Once we get past this, the difference between this patient and what is currently recommended is subtle, using therapeutic doses of a full antiretroviral regimen rather than the recommended strategy of prophylaxis with 6 weeks of therapeutic doses of ZDV and NVP given as a single dose three times during the first week of life. Something else that happened in this case which certainly occurs but not necessarily as a matter of routine was the HIV DNA test was sent at the time of delivery with a result and second sample repeated within just days of birth allowing for confirmation of infection, supporting the continued use of therapeutic doses of ART. In contrast, guidelines recommend testing be done within the first 3 weeks and then again between 1 and 2 months and 4 and 6 months, with repeat testing immediately performed upon a positive result (2). Some might ask why we would not routinely give full therapeutic doses of ART immediately upon birth, especially in a child born to a woman not on treatment. Well, it is because the data supports alternative strategies. In particular, a study was conducted in just such cases where the mother is not on treatment and not planning to breast feed and babies were randomized to receive ZDV for 6 weeks alone, versus with 3 doses of NVP within 7 days of birth or with 2 initial weeks of 3TC and nelfinavir (NFV) at therapeutic doses (3). It turned out that the latter two regimens were more efficacious in preventing vertical transmission than ZDV monotherapy, with a greater than 2-fold reduction in risk. However, there was no difference between two and three drug regimens except for increased toxicity with the latter, especially neutropenia which has been described with 3TC use in this patient population. Thus, strong data is available to support the currently recommended strategy of ZDV with a few doses of NVP. That said, what happened in this case is not rare with the most recent perinatal guidelines suggesting that clinicians can consider early initiation of therapeutic doses of combination therapy and some surveys suggest that more than half of United States physicians may actually be doing this in clinical practice (4).
Now that we are clear on what happened and how it differed from routine care we are left with the big question, what happened? The leading hypotheses are: 1) the baby was indeed infected but early treatment, plus or minus some intrinsic characteristic in newborns led to little or no establishment of a cellular reservoir of infection in resting memory cells with subsequent clearance and a true cure; 2) a cellular reservoir was established but early treatment resulted in it being extraordinarily small and either cleared or being so small that it will take more time before viral rebound occurs; 3) there was transfer of HIV-containing maternal blood, perhaps plasma and cells that were detected during the first weeks of infection and the presence of ART simply served as post-exposure prophylaxis with the baby never truly being infected; or 4) there were host or virologic factors that resulted in this child being an elite controller and that such control would have occurred without therapy. The argument made against the possibility that infection did not actually occur is that it would have required substantial transfer of maternal blood, which had a viral load of ~2500 copies/mL, to result in the baby having an initial plasma viral load of ~20,000 copies/mL. In addition, the decay of virus over the first few weeks occurred gradually and possibly even with biphasic characteristics as seen when infected individuals are started on combination ART. Based upon the estimated decay of plasma virus with a half-life on the order to 10-20 minutes one would also think that if it was simply maternal transfer of free virus clearance it would have happened much quicker. Further arguing for infection with early treatment resulting in a small reservoir and potentially a cure comes from four other children started on combination therapy during the first weeks of life who were shown to have very low levels of cellular reservoir for HIV in their blood (5).
After this case was presented it was interesting to revisit reports in the mid to late 1990s of transient infection in newborns that did not receive potent combination therapy (6). While many of these cases were shown to be related to laboratory error (7), it is conceivable that some were real and that in the current era we miss this because of delayed virologic testing in newborns and routine use of prophylaxis.
Interpretation: It is now vital to get the facts straight, clearly define the potential events that occurred, and systematically look for similar cases and design studies to pursue this strategy. Most importantly, a single case is not sufficient to change the current standard of care or to prompt the routine removal of therapy from those infected children that were treated during the early days of life, at least not outside of a clinical trial or research setting.
Other studies related to cure.
Headline: The cellular reservoir which is an obstacle to cure may be reduced by very early ART or the use of HDAC inhibitors (HDACi).
Study findings: Much of the focus on cure research is targeting latently infected resting memory cells, the cellular reservoir of infection. Several studies demonstrated that a unique intervention will be needed to address this obstacle. Besson and colleagues assessed the size of the reservoir over time in individuals on suppressive ART for as long as 10 years showing some decay with time, but very slow (8). Similar conclusions can be drawn from a study using a sensitive measure of low level viremia (down to 1 copy/mL) in patients treated for many years with fully suppressive ART (9). Once again, these values appeared to be relatively stable over time, and since plasma virus at these levels are assumed to be derived from persistently infected cells, it would appear that this population is not going away with ART and time alone. Another strategy is to treat so early that it limits the establishment of this reservoir, such as what is proposed to have happened in the case of the "cured baby." A study assessed the relationship between the size of the cellular reservoir and the timing of initiating ART. In this study patients were started on treatment when they were plasma HIV RNA+ without any antibodies, HIV RNA+ with antibodies by EIA but negative Western blot or had an indeterminate western blot. It was shown that the size of the reservoir was considerably smaller in those treated before antibodies emerged, even compared to the other groups that by all accounts also received very early therapy (10). Whether this strategy is sufficient to allow for therapy to be stopped, as in the case with the baby is not known, and frankly based upon many studies over the last 15 years of patient treated early followed by therapeutic interruption it seems unlikely that this alone will be the solution. However, when considering therapeutics to purge the cellular reservoir and/or enhance immune responses for control, the smaller the cellular reservoir the better the chance there may be for success, at least in early proof of principle experiments. Further research in this area may advance the field, but is unlikely to be clinically relevant except for the very few patients that are identified at the very earliest days of infection.
There was additional early data using HDACi, e.g. vorinostat (11) and romidepsin (12), both of which appear to result in release of latent virus from resting cells. Further studies will continue to define the optimal dose, overall safety of these and other potentially more potent HDACi, and whether this alone or perhaps supplemented by therapeutic immunizations will result in a reduction of the cellular reservoir.
Interpretation: It is great news that scientists have increasingly focused attention on the possibility of a cure. That said, the obstacles remain ENORMOUS and research is in the very earliest stages.
The only thing better than a cure is to prevent infection. No doubt that anyone reading this report is aware of the recent successes using treatment of HIV-infected individuals to prevent the spread to their partners, or the use of pre-exposure prophylaxis (PrEP) administered to uninfected individuals to protect them from infection, either as a vaginal gel for uninfected women or systemic therapy for both men and women. Everyone should be reminded of the success of PrEP in uninfected women using pre- and post-coital 1% tenofovir vaginal gel, as well as the reduced risk of infection for men who have sex with men in iPrEx, heterosexual men and women in Partners PrEP and TDF2 administered systemic antiretrovirals (tenofovir DF [TDF]/emtricitabine [FTC] in each study and also with TDF alone in TDF2). In each case the efficacy was higher amongst those with greater levels of adherence. The importance of adherence was emphasized by the FEM-PrEP study where high risk HIV-uninfected women were given TDF/FTC or placebo with the study being prematurely stopped due to the lack of any protection. Only after the study was completed was it found that despite the fact that patients claimed to take most drug, there were no detectable blood levels in a large proportion of individuals. It is felt that this extremely low level of adherence accounted for the complete lack of efficacy seen in the trial. Since these studies were reported the results of a large PrEP study has been anxiously anticipated, the VOICE Study.
Headline: Women do not take PrEP and therefore PrEP doesn't work.
Study findings: VOICE randomized more than 5000 high-risk HIV-uninfected women equally to either TDF/FTC, TDF, oral placebo, 1% tenofovir vaginal gel used daily or vaginal gel placebo (13). During the latter part of 2011 the independent Data Safety Monitoring Board stopped the TDF and vaginal gel arm for futility, meaning there was no chance that continuing the study would demonstrate that the intervention was superior to placebo. The TDF/FTC and oral placebo arms were continued and final results now reported. The bottom line is that there was no evidence of efficacy for any of the three active interventions. When adherence was assessed by patient self report using Computer Assisted Self Interview and pill count, it appeared to be in the 90% range. However, measurements of drug levels demonstrated that less than 40% of samples had detectable levels of drug in any of the intervention arms and it actually declined during the course of the study. While these results were very disappointing, they do round out the previous experience and in my view remain consistent with the fact that PrEP works if it is used appropriately. It further emphasizes how problematic it is to have good adherence with PrEP in select patient populations. The next steps are to better understand why adherence was so poor and how to move the field forward both in research and the clinic to address this important limitation.
Interpretation: Looking at all of the PrEP data thus far, it is likely that PrEP is a highly effective means of HIV prevention if used correctly. All of the studies demonstrate the importance of adherence and this being an unexpectedly high barrier to effective utilization of this strategy. Future studies need to define why adherence is so poor and how it can be enhanced. In the interim, those implementing this strategy in the clinic need to be aware of this issue and work closely with clients to assure appropriate administration of PrEP.
Novel strategies for administration of PrEP
Headline: Long acting preparations of antiretroviral agents either locally or systemically offer promise for PrEP in macaque model.
Study findings: During the same session that the VOICE Study was reported there were two very promising studies performed in macaques. One was a TDF-impregnated vaginal ring (14) and the other a long-acting injectable nanoformulation of a new integrase strand transfer inhibitor (InSTI) called GSK1265744 or "744" for short (15). Both studies demonstrated good tolerance and protection against SHIV, a virus made by combining portions of the Simian and Human Immunodeficiency Viruses in macaques against vaginal and rectal challenge, respectively. The good news is that we have new efficacious strategies for preventing HIV infection, but much left to learn as to how these should be optimally utilized.
Interpretation: Novel formulations for PrEP administration are in early stages of development but seem to be the logical next step towards overcoming the limitations of previously studied strategies. Much more to come at future meetings.
There were several very important presentations related to the treatment of antiretroviral-naïve and -experience individuals. For first-line therapy there are many options that are easy to take, well tolerated and highly efficacious. One key factor that can influence the initial choice of treatment is the presence of transmitted drug resistant virus.
Transmitted drug resistant virus
Headline: 16% of newly diagnosed patients included in recent surveillance data had transmitted drug resistant virus, a frequency that actually increased between 2007 and 2010.
Study findings: The Research Resistance Network group resented updated data from 2007 to 2010 for resistance to reverse transcriptase and protease inhibitors in newly diagnosed patients in 10 cities across the United States. There data emphasized the importance of following current treatment guidelines to routinely perform drug resistance testing prior to initiating treatment (16), with fully 16% of newly diagnosed individuals having detectable drug resistant virus (17). This was mostly to a single class (13.6%) but up to 2.1% actually having 2 class resistance. As previously seen, resistance was most commonly to nonnucleoside reverse transcriptase inhibitors (NNRTI), followed-by nucleoside reverse transcriptase inhibitors (NRTIs). Notably, there was a small but significant increase in the prevalence of detectable drug resistant virus seen over time. Transmitted InSTI resistance has thus far been limited to isolated case reports and was not assessed in the current analysis.
Interpretation: Performing drug resistance testing on patients new to care and/or starting therapy for the first time is as important as ever. With the expanded use of InSTIs, transmitted resistance to this class will likely become an issue in the future. That said, pending more data there is probably not sufficient justification for looking for InSTI resistance in treatment-naïve patients unless there is a high index of suspicion, such as known or suspected acquisition of infection from someone on drugs in this class.
Studies of treatment-naïve patients
For treatment-naïve patients the focus on new drugs was primarily looking for agents with advantages over those currently available.
Headline: Further analyses of a large study demonstrate the high level of efficacy, regardless of baseline characteristics of the new InSTI, dolutegravir (DTG), as well as early data from a large study showing efficacy and possibly improved safety of low dose of a new formulation of tenofovir, tenofovir adenamide fumarate (TAF). Early data from relatively small studies show virologic efficacy of the new NNRTI, MK-1439 and the CCR5 and CCR2 antagonist cenicriviroc.
Study findings: Detailed analyses were described for the relationship between baseline characteristics and response to the new InSTI, DTG in treatment-naïve patients. Previous reports demonstrated that this drug was as efficacious and well tolerated as raltegravir (RAL) when combined with investigator selected abacavir/lamivudine (ABC/3TC) or TDF/FTC. Moreover, DTG combined with ABC/3TC was superior to TDF/FTC/EFV, with the main differences being driven by increased toxicity in the EFV-containing regimen. The current analyses demonstrated that these differences held up regardless of baseline characteristics e.g. CD4 and viral load (18). Moreover, the data further demonstrates that unlike other studies showing that in those with high viral loads (i.e. >100,000 copies/mL) TDF/FTC was more efficacious than ABC/3TC when combined with EFV and atazanavir/ritonavir, no such difference was seen when these NRTIs were combined with DTG, acknowledging that the NRTIs were not randomized or blinded and the numbers in each treatment arm with high viral load were relatively modest.
While first-line treatment options remain excellent they continue to have some limitations, including in potential long-term toxicity. Examples of this include nephrotoxicity and loss of bone mineral density associated with TDF, the currently approved prodrug of tenofovir (TFV). In order to address this limitation, as well as potentially reduce the dose in order to facilitate coformulation with other drugs e.g. protease inhibitors (PIs), a new prodrug of TFV is being developed, tenofovir alafenamide fumarate (TAF). The properties of this drug are that it can be given at a much smaller dose than TDF and has considerably lower plasma levels of TFV with markedly higher concentration of the active form of the drug intracellular. The hope is that this form of TFV will be at least as efficacious and perhaps better tolerated due to lower blood levels. An interim analysis was presented from a head-to-head comparison of fixed dose combination TDF/FTC/Cobicistat (COBI)/elvitegravir (EVG) versus TAF/FTC/COBI/EVG (19). At 24 weeks the regimen with TAF had equivalent efficacy and some evidence of less nephrotoxicity. Although only early data there was also a significantly lower decline in bone mineral density with TAF- than the TDF-treated patients.
The investigational NNRTI, MK-1439 can be given once per day and is thought to have low potential for central nervous system toxicity. At this meeting data was presented from a small 7 day monotherapy study showing similar virologic suppression of approximately 1.3 log10 copies/mL at both 200 mg and as little as 25 mg daily (20). This would suggest that this agent can be conveniently administered, likely co-formulated and is highly efficacious. I suspect we will be hearing more about this new agent at coming meetings. Another new drug presented at this meeting was cenicriviroc, a CCR5 antagonist that also has inhibitory activity against CCR2, the latter providing the potential to reduce inflammation. Of note, the 90% inhibitory concentration for HIV is more than 20-fold lower than that needed to inhibit CCR2. The study randomized approximately 150 treatment-naïve patients without detectable CXCR4-using virus 2:2:1 to NRTIs with cenicriviroc given at 100 and 200 mg once-daily versus EFV (21). Notably, the formulation of cenicriviroc was 50 mg tablets so there were many pills used in the placebo-controlled study. The primary endpoint of <50 copies/mL at week 24 showed similar results overall with 71-76% achieving this outcome. There were differences in the number defined as "non response" favoring efavirenz at 4% than either cenicriviroc arm, which were 12 and 14%. This was balanced by the proportion with "no data available" at week 24 which favored the cenicriviroc arms at 12 and 13% compared with efavirenz at 25%. To assess CCR2 inhibition they measured change in the level of the ligand for CCR2, MCP-1 which went up in a dose-dependent fashion with approximately a 2-fold greater increase in those given the higher compared to lower dose of cenicriviroc. The study also demonstrated that cenicriviroc therapy was associated with a decrease in macrophage activation with declines in soluble CD14 (sCD14) compared to an increase seen in the EFV study arm.
Interpretation: There is little doubt that DTG is a highly active InSTI with good safety and efficacy profile in most if not all treatment-naïve patients. TAF also appears to be efficacious in comparison with TDF when combined with FTC, COBI and EVG. In addition, early data suggests that it may be associated with less renal and bone toxicity. The data is extremely preliminary but MK-1439 does appear to be a potent drug that will be worth pursuing as a potential alternative to currently licensed NNRTIs. Finally, cenicriviroc appears to be well tolerated and active, although the efficacy data was somewhat difficult to interpret with large numbers of people having no data at week 24. The study further demonstrated the effect on CCR2 inhibition, although emphasizing that the optimal dose for HIV antagonism may not be the same as that for CCR2 blockade, which depending upon the goals of therapy may need further analyses and consideration when deciding on the optimal dose to move forward with.
Studies of treatment-experienced patients
Headline: DTG may be better in InSTI-naïve, treatment-experienced patients than RAL and NRTIs are not needed as part of a regimen for highly treatment-experienced patients. In resource-limited setting those failing NRTIs plus an NNRTI respond well to LPV/r monotherapy, but viral break through often occurred with time and was effectively managed by intensification with NRTIs, despite substantial NRTI resistance present at the time of treatment initiation. Similarly, NRTIs plus LPV/r is highly efficacious and as good as LPV/r plus RAL in a population of patients failing first line NNRTI-containing therapy.
Study findings: There were four notable studies in treatment-experienced patients, two in the resource-rich and two in resource-limited settings. The first study was performed in developed countries and was called SAILING, comparing the use of the new InSTI, DTG given at 50 mg once-daily with RAL at the approved dose of 400 mg twice-daily (22). Patients were allowed to add background regimen of their choice based upon the patient's treatment history and drug resistance data. The primary endpoint was proportion with viral load <50 copies/mL after 48 weeks and showed superior outcomes in those given DTG than RAL with suppression rates of 79 and 70%, respectively. The number of subjects with virologic failure was higher in the RAL group and the proportion of subject with samples evaluable for resistance demonstrating a higher rate of InSTI and NRTI resistance in the RAL than DTG group. In fact, there has been interest in how frequent resistance may occur in DTG failures with in vitro data suggesting that it might have a higher genetic barrier to resistance. In addition, there has been no InSTI resistance yet to be selected for in treatment-naïve studies of DTG. In SAILING there were only 2 patients in the DTG group with emergent mutations in Integrase and neither conferred more than 2-fold reduction in susceptibility to DTG.
A second study of treatment-experienced patients was performed in the United States and Puerto Rico and was called OPTIONS or ACTG A5241 (23). It was designed to assess whether NRTIs are needed as part of therapy in patients with multiclass drug resistant virus. The study enrolled those who were highly treatment-experienced and performed genotypic and phenotypic drug resistance testing along with an envelope tropism assay. These results along with the treatment history were provided to experts on the study team who then recommended a regimen with at more than 2 active drugs (by phenotype score) and left it to the primary provider to select NRTIs. Nearly 60% of study subjects received a regimen of darunavir/ritonavir (DRV/r), etravirine (ETR) and RAL. They were then randomized to start the regimen with or without the pre-selected NRTIs and followed for a primary endpoint of either protocol-defined virologic failure or changing NRTIs if randomized to include them, or starting them if randomized to omit them. The pre-specified threshold for noninferiority was 15% with the final difference being 3.2% with an upper confidence interval of 12.5%, therefore meeting the criteria for noninferiority. These results suggest that in the setting of multiple other active drugs NRTIs may not be necessary. Further analyses will be needed to define whether there remains a select group that might still benefit for NRTIs, e.g. as those that may not have been able to include as many fully active agents.
In the resource-limited setting patients were studied that failed first line NRTIs plus NNRTI-based regimens. One such study was A5130 where patients had limited access to resistance or viral load testing and are known to fail such regimens with extensive NRTI resistance. They were then given LPV/r monotherapy and found to initially have good viral suppression but with time experienced increasing numbers with viral breakthrough (24). The protocol was designed to allow for NRTIs to be added in the event of failure. Interestingly, despite having extensive NRTI resistance at baseline, the majority of the failing patient resuppressed when NRTIs were added. The other study of interest was called the SECOND-LINE Study also conducted in resource limited setting and included those failing a first line regimen of NRTIs plus a NNRTI (25). The patients were randomized to NRTIs of choice with LPV/r alone or combined with RAL. Unlike what is often done in under-resourced countries more than 70% of patients selected NRTIs based upon drug resistance testing. The study overall showed virtually identical rates of suppression in both groups suggesting that either strategy might be viable, with cost favoring use of NRTIs over RAL.
Interpretation: DTG is active in InSTI-naïve patients experiencing treatment failure. Moreover, the data is consistent with the hypothesis that the genetic barrier to resistance for DTG may be higher than for other currently approved agents in this class. Further analyses of the OPTIONS Study will provide clarity as to whether there are select situations where NRTIs may still be of value in highly-treatment-experienced patients, and to better understand which patients on 3rd-plus line regimens with NRTIs can safely have drugs from this class removed. With regards to NRTIs in NNRTI-failures in low and middle income countries, most of the data suggests that NRTIs are a valuable part of therapy in this setting. Whether they need to be used up front versus only added in those who experience viral rebound on a ritonavir-boosted PI is still open to debate. The SECOND-LINE Study suggests that adding RAL to a ritonavir-boosted PI is no better and likely much more expensive that the use of NRTIs, although more data is needed regarding the extent of NRTI resistance present in this population before such conclusions can be definitively made for all such patients.
As has become the norm at HIV meetings there was a substantial amount of data related to comorbid conditions. I thought the most important data at CROI related to cardiovascular disease and HIV infection, and therefore will focus on key studies in this area. I suspect all are aware of the data demonstrating that HIV infection is associated with increased levels of soluble markers of inflammation, coagulation as well as cellular activation. ART with viral suppression appears to reduce many of these markers, but often such reversal is not complete. Recent data has used other more direct measures of coronary artery disease, e.g. coronary calcium measurements and Computed Tomography Angiography (CTA). What is particularly interesting about the latter is the ability to better characterize coronary disease and define a subset of individuals that may have higher risk plaque for rupture, the predominant mechanism behind the acute coronary syndrome. In fact, there is evidence that HIV-infected individuals have premature coronary disease compared to controls as well as increased frequency of high-risk "noncalcified" or "soft" plaque. A recent study showed that the presence of such plaque was not strongly associated traditional markers, e.g. Framingham risk score, hypertension, dyslipidemia, which do correlate with coronary calcium score, but more with levels of soluble CD163 (sCD163) and CD14 (sCD14) that are elaborated by activated monocyte/macrophages (26).
Headline: HIV is associated with increased risk for myocardial infarction, non-AIDS cancer and end-stage renal disease with data continuing to support the fact that it is an independent risk factor for cardiovascular events. New data continues to suggest that activated monocyte/macrophages may be a major determinant of this process.
Study findings: The Veterans Aging Cohort Study carefully analyzed data to assess whether myocardial infarction, non-AIDS cancer and end stage renal disease occurred at increasing frequency amongst those with HIV-infection, as well as whether these events occur at an earlier age amongst HIV-infected population (27). This study was able to adjust for other risk factors and showed that for myocardial infarction, non-AIDS cancers and renal failure compared to HIV-uninfected, infected individuals had an 81%, 37% and 55% increased risk, respectively. While this is consistent with other studies, they also found that there was no difference in adjusted mean age for these events between HIV-infected and uninfected for myocardial infarction and cancer, but those with HIV infection were younger when they were diagnosed with end stage renal disease. Although this type of analysis has limitations, it suggests that HIV is an independent risk factor for these events, but not necessarily accelerating the timeline in which these diseases occur over the course of the patient's life-time. A related analysis focusing on cardiovascular disease with aging in those with HIV in the D:A:D cohort versus those in an HIV-uninfected cohort (28). This study included data showing enhanced risk for cardiovascular events per year older that was somewhat higher than that seen in general population.
Accepting that many studies have linked HIV with cardiovascular events there has been research to better explore the pathogenesis of these findings. One explanation has been that HIV infection is associated with increased inflammation, cellular activation and coagulation, all of which is true but is at least partly ameliorated with ART and viral suppression. Nevertheless, data correlating these markers with cardiovascular events in HIV has been mixed. More recently sCD163 and sCD14, markers of monocyte/macrophage activation have been more consistently linked with this endpoint. In addition to the work by Burdo linking sCD163 with noncalcified plaque (26), Baker and colleagues at this meeting showed that markers of monocyte activation, but not T cell activation predicted progression of coronary artery calcium in HIV-infected cohort (29). Additional studies used CTA to better characterize the type of coronary disease in such patients. Post and colleagues studying HIV-infected and uninfected Multicenter AIDS Cohort Study patients cross-sectionally showed that there was increased risk of noncalcified coronary plaque in those with HIV, versus without HIV and with increasing age (30). This is particularly important in light of the fact that this type of plaque may be at greater risk for rupture and precipitating the acute coronary syndrome. Zanni et al. used another cohort and additional methods by CTA to actually further characterize plaque as being particularly vulnerable to rupture, such as showing positional remodeling, low attenuation and spotty microcalcification (31). They found in a group of 102 HIV-infected and 41 matching HIV-uninfected patient that were relatively young with low Framingham risk factors an increased risk of low attenuation and remodeling lesions without microcalcification. They further showed that IL-6, lipopolysacharide and sCD163 were associated with plaque in this patient population, but not other traditional risk factors as seen in older patients. Finally, there was related data in a cohort of HIV-infected women showing noncalcified coronary plaque in younger HIV-infected women, once again demonstrating a strong relationship between this type of plaque and monocyte/macrophage activation markers (32).
Interpretation: There is increasing evidence that HIV is associated with an increased risk of cardiovascular events. While some of this may be related to inflammation, immune activation and coagulation effects, new data increasingly has implicated monocyte/macrophage activation as a predictor of not just atherosclerosis but also the particularly high risk noncalcified plaque. Further research is needed to define which factors drive monocyte/macrophage activation in order to consider targeted therapy in the future.
Conclusions. The 20th CROI once again exceeded expectations for the amount of excellent science presented. Exciting data was presented on the cure research agenda, at least in part sparked by the very interesting baby from Mississippi, as well as on ART. There were also new insights beginning to unfold regarding the factors driving atherosclerosis in HIV-infected individuals.
Conflicts: In the last year Eric Daar has received research support from Abbott, Gilead, Merck and ViiV as well as acted as a consultant for Bristol Myers Squibb, Gilead, Merck, Janssen and ViiV.
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2. Panel of treatment of HIV-infected pregnant women and prevention of perinatal transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed March 6,, 2013.
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6. Bryson YJ, Pang S, Wei LS, Dickover R, et al. Clearance of HIV infection in a perinatally infected infant. N Engl J Med 1995; 332:833-8.
7. Frenkel LM, Mullins JI, Learn GH, et al. Genetic evaluation of suspected cases of transient HIV-1 infection of infants. Science 1998; 280:1073-7.
8. Besson G, Lalama C, Bosch R, et al. HIV-1 DNA decay patterns in blood during more than a decade of suppressive ART: Results from ACTG NWCS 360. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 172LB.
9. Riddler S, Aga E, Bosch R, et al. Prevalence and patterns of residual viremia in HIV+ patients on long-term suppressive ART. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 357.
10. Ananworanich J, Vandergeeten C, Chomchey N, et al. Early ART intervention restricts the seeding of the HIV reservoir in long lived central memory CD4 T cells. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 47.
11. Elliott J, Solomon A, Wightman F, et al. The safety and effect of multiple doses of vorinostat on HIV transcription in HIV+ patients receiving cART. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 50LB.
12. Wei, Chiang V, Fyne E, et al. Histone deacetylase inhibitor romidepsin induces HIV in CD4+ T cells from ART-suppressed subjects at concentrations achieved by clinical dosing. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 376.
13. Marrazzo J, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: Daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 26LB.
14. Smith J, Rastogi R, Teller R, et al. A tenofovir disoproxil fumarate intravaginal ring completely protects against repeated SHIV vaginal challenge in nonhuman primates. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 25LB.
15. Andrews C, Gettie A, Russell-Lodrigue K, et al. Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 24LB.
16. DHHS. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL. pdf. Section accessed March 6, 2013.
17. Kim D, Ziebell R, Saduvala N, et al. Trend in transmitted HIV-1 ARV drug resistance-associate mutations: 10 HIV surveillance areas, US, 2007-2010. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 149.
18. Brinson C, Walmsley S, Arasteh K, et al. Dolutegravir treatment response and safety by key subgroups in treatment-naïve HIV+ individuals. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 554.
19. Zolopa A, Ortiz R, Sax P, et al. Comparative study of tenofovir alafenamide vs. tenofovir disoproxil fumarate, each with elvitegravir, cobicistat, and emtricitabine, for HIV treatment. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 99LB
20. Anderson M, Gilmartin J, Robberechts M, et al. Safety and antiviral activity of MK-1439, a novel NNRTI, in treatment-naïve HIV+ patients. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 100.
21. Gathe J, Cade J, DeJesus E, et al. Week-24 primary analysis of cenicriviroc vs. efavirenz, in combination with emtricitabine/tenofovir, in treatment-naïve HIV-1+ adult with CCR5-tropic virus. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 106LB.
22. Pozniak A, Mingrone H, Shuldyakov A, et al. Dolutegravir vs raltegravir in ART-experienced, integrase0bauve subjects: 24-week interim results from SAILING (ING111762). 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 179LB.
23. Tashima K, Smeaton L, Andrade A, et al. Omitting NRTI from ARV regimens is not inferior to adding NRTI in treatment-experienced HIV+ subjects failing a protease inhibitor regimen: The ACTG OPTIONS Study. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 153LB.
24. Kumarasamy N, Aga E, Ribaudo H, et al. Lopinavir/ritonavir mono-therapy after virologic failure of 1st-line NNRTI-containing ART in resource-limited settings: Week 104 analysis of ACTG 5230. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 1112.
25. Boyd M and the SECOND-LINE Study Team. SECOND-LINE: Ritonavir-boosted lopinavir with 2-3 N(t)RTI or raltegravir in HIV+ subjects virologically failing 1st-line NNRTI/2N(t)RTI. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 180LB.
26. Burdo TH, Lo J, Abbara S, et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis 2011; 204:1227-36.
27. Althoff K, Wyatt C, Gibert C, et al. HIV+ adults are at greater risk for myocardial infarction, non-AIDS cancer, and end-stage renal disease, but events occur at similar ages compared to HIV-adults. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 59.
28. Petoumenos K, El-Sadr W, d'Arminio Monforte A, et al. Increased risk of cardiovascular disease with age in men: A comparison of D:A:D with HIV- cardiovascular disease risk equations. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 61.
29. Baker J, Huppler Hullsick K, Singh A, et al. Monocyte activation, but not T cell activation, predicts progression of coronary artery calcium in contemporary HIV cohort. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 66LB.
30. Post W, Jacobson L, Li X, et al. Age and noncalcified coronary plaque in the Multicenter AIDS Cohort Study. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 62.
31. Zanni M, Lo J, Wai B, et al. Increased coronary atherosclerotic plaque vulnerability features on computed tomography angiography among HIV+ subjects vs matched HIV- controls. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 63.
32. Fitch K, Abbara S, Burdo T, et al. Non-calcified coronary plaque and macrophage activation markers are increased in HIV+ women. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 185LB