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HIV Treatment
19th International AIDS Conference
July 22-27, 2012
Washington, D.C.
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Eric S. Daar, M.D.
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at UCLA
It was an absolute pleasure to be back in the United States for the International AIDS Conference. One cannot help but reminisce about where we were when we met in San Francisco in 1990 and compare it to where we are today. I remember well the 1990 meeting from both a personal and professional perspective. I was a fellow, yes it was a very long time ago, and abandoned my wife with a 4 week old child to attend the meeting and present data on what was at the time the first "designer" drug specifically developed to inhibit HIV replication. I presented data showing that soluble CD4, an agent that showed great promise in vitro against laboratory-adapted strains of HIV turned out to be orders of magnitude less potent against viruses derived directly from the patients (1). This data, along with disappointing clinical trial results led to the end of this therapy. However, that was then, and now is now. My wife has forgiven me for abandoning her with an infant, the infant just graduated from college, and we now have a regular Neiman Marcus of potent designer drugs developed to target different steps in the HIV life cycle. These drugs have changed the epidemic in the United States and abroad as well as the disease as we know it. My focus of reporting from this 19th International AIDS Conference will be on data related to the treatment of HIV.
Treatment Guidelines
There are numerous treatment guidelines from around the world with recommendations for when and what to start with regards to antiretroviral therapy. The Department of Health and Human Services Guidelines were update in March of 2012 with the most important change in these two key areas being an increasingly strong recommendation for treatment being offered to all patients with HIV infection, regardless of viral load and CD4 cell count (2). Just prior to this meeting the IAS-USA updated guidelines were published in JAMA (3). While there were no scientific presentations related to these guidelines, there was considerable buzz in the halls and a full symposium using case-based discussion to outline some of the changes. From my perspective, the biggest changes in the guidelines were to make a stronger recommendation for treating asymptomatic patients with CD4 cell counts greater than 500 cells/uL. In addition, they moved abacavir/lamivudine from an alternative to a preferred option for those who are HLA-B5701 negative and have plasma HIV RNA levels less than 100,000 copies/mL. Another major addition to the guidelines was discussion regarding the role of tenofovir DF/emtricitabine for pre-exposure prophylaxis. While I believe these represent the major changes in these guidelines, I strongly encourage all HIV providers to review the entire document.
When to Start Antiretroviral Therapy
The shift in guidelines towards recommending antiretroviral therapy to asymptomatic patients with high CD4 cells is primarily based upon the overall safety and tolerability of existing preferred treatment options as well as increasing concerns that ongoing viral replication is associated with inflammation and immune activation that can adversely affect multiple end organs. There are also cohort studies suggesting benefits for those with 350-500 CD4 cells/uL and in select cases even those with greater than 500 cells/uL. HPTN052 was a randomized controlled trial of serodiscordant couples where the HIV-infected individual had CD4 cells of 350-550 cells/uL. The study was designed to assess the ability of starting antiretroviral to prevent HIV transmission, which it did in dramatic fashion leading to the study being prematurely stopped by the Data Safety Monitoring Board. At this meeting more detailed information was provided regarding the differences in the occurrence of clinical events between those that started with between 350 and 550 CD4 cells/uL versus deferring treatment until symptoms developed or CD4 count was less than 250 cells/uL. Previously presented data showed that those who deferred therapy were at significantly greater risk of developing clinical progression, mostly driven by an increased risk of extrapulmonary tuberculosis. At this meeting investigators presented data on the emergence of non-clinical events such as cardiovascular, liver and renal disease based upon timing of initiation of therapy (4). This type of analysis is highly relevant in the current era where it is felt that these represent some of the key events that patients with ongoing viremia and high CD4 cells may be at increased risk for developing. It turned out that such events were relatively rare and not different between groups. This data demonstrates that studies of this kind looking at non HIV-related events in those with higher CD4 cells may require enrollment of large numbers of individuals with long-term follow-up. At the time of this analysis the median follow-up in HPTN052 was only approximately 2 years.
It has continued to be unclear as to whether there are unique benefits associated with starting antiretroviral therapy during acute or early HIV infection. Original studies focused on the possibility that early therapy may allow for preservation of host immune responses and virologic control after treatment discontinuation. More recently this endpoint is of less interest in light of the fact that current guidelines in the United States suggest that all patients should be offered antiretroviral therapy and it should not be discontinued. In addition, one of the major reasons to have people on therapy regardless of their CD4 cell count is because of increasing recognition that ongoing viremia is associated with inflammation, cellular activation and increases in markers of coagulation, all of which can be associated with end organ damage. Consequently, the interest in starting treatment during the first months of infection has shifted to the potential benefits for those on sustained virologically suppressive therapy. With this consideration, a study assessed the role of early therapy on persistent cellular activation in those on suppressive treatment that was started during primary infection (5). This study included 31 patients with acute or early HIV infection who received either a 3 or 5 drug protease-inhibitor-based regimens. They also included a cohort of 13 HIV-uninfected individuals as controls and compared levels of cellular immune activation as measured by CD8+HLA-DR+CD38+ T cells at baseline and weeks 48 and 96 of treatment. The rationale for this study is that previous analyses showed that even those with fully suppressed viral load often had higher levels of immune activation than uninfected controls. Although the numbers of patients studied were small, and there was no concurrently collected cohort of chronically HIV-infected patients available for comparison, it was noted that despite markedly higher levels of cellular activation amongst the HIV-infected individuals at baseline compared to uninfected controls, there was no difference seen after 48 and 96 weeks of treatment. Notably, there were also no differences based upon whether the patient received a 3 or 5 drug regimen. Further study is needed, but in considering ways in which we can decrease the level of residual inflammation in patients on suppressive antiretroviral therapy, starting treatment during primary infection may offer at least one strategy for further investigation.
Very Early Initiation of Combination Antiviral Therapy Results in Normalization of Markers of Immune Activation - (08/17/12)
Effect of Early versus Delayed Initiation of Antiretroviral Therapy (ART) on Clinical Outcomes in the HPTN 052 Randomized Clinical Trial - (07/26/12)
What Antiretroviral Therapy to Start
While there are currently multiple well tolerated, highly effective antiretroviral regimens for treatment naïve patients, new drugs continue to be in development that may provide important options for patients. At this meeting we saw the first phase 3 data from a large randomized, placebo-controlled trial of the new integrase strand transfer inhibitor dolutegravir. The SPRING 2 study randomized 822 treatment-naïve patients to two nucleoside reverse transcriptase inhibitors (NRTIs) with either 50 mg of dolutegravir once-daily or the currently approved integrase strand transfer inhibitor raltegravir at 400 mg twice-daily (6). The study included mostly men (~85%) and the patients had median CD4 cell count of approximately 360 cells/uL. Approximately 40% of the patients were given abacavir/lamivudine and 60% tenofovir DF/emtricitabine. The primary endpoint was the proportion with plasma HIV RNA less than 50 copies/mL at 48 weeks by the FDA SNAPSHOT analysis which is a composite of those who experienced virologic failure or who stopped or switched therapy for any reason. The response rates were very high for dolutegravir, 88% and raltegravir, 85% with adjusted difference of 2.5 (95% CI -2.2, 7.1) meeting criteria for noninferiority. Both regimens were very well tolerated with little difference between the study drugs in the frequency of adverse events and discontinuation because of adverse events, as well as little effect on lipids. There was no difference in response based upon baseline viral load or choice of NRTIs. Protocol-defined virologic failure was rare in both study arms (5-7%) with few having developed drug resistance. Amongst those with resistance data only 1 had integrase resistance in the raltegravir study arm and none in the dolutegravir group. This study clearly demonstrated that dolutegravir is a potent and well tolerated new antiretroviral agent. Like raltegravir it does not need to be pharmacologically boosted and will have relatively few drug-drug interactions. It does influence renal tubular handling of creatinine so there was an initial modest increase in creatinine and decline in calculated creatinine clearance that appears to stabilize after a few weeks with no patients discontinuing either study drug for renal toxicity. With the recent approval of elvitegravir, another integrase strand transfer inhibitor, if approved dolutegravir would offer a second once-daily option with a drug from this class. The Single Study is a large trial recently completed that compared abacavir/lamivudine plus dolutegravir to the fixed dose combination of tenofovir DF/emtricitabine/efavirenz. The key results of this study were described in a press release reporting high virologic response rates in both study arms but showing both noninferiority and superiority of dolutegravir compared to the control. Further details of this study are likely to be presented at a meeting in the very near future.
The most recently FDA-approved antiretroviral is the fixed-dose combination of tenofovir DF/emtricitabine/cobicistat/elvitegravir (Stribild®). This uses the integrase strand transfer inhibitor elvitegravir given once-daily when pharmacologically boosted by the novel boosting agent cobicistat. The latter drug is also a new agent that unlike ritonavir has no anti-HIV activity. The key registrational trials that led to this drugs approval for treatment-naïve patients were head-to-head comparisons with tenofovir DF/emtricitabine/efavirenz and with atazanavir/ritonavir plus tenofovir DF/emtricitabine. The primary endpoint for these studies was the proportion with plasma HIV RNA less than 50 copies/mL at 48 weeks. In both cases the new drug proved to be noninferior to the comparator arm with relatively similar tolerability. Follow-up data was presented based upon baseline characteristic to further characterize the activity of this new drug. For the comparison of tenofovir DF/emtricitabine/cobicistat/elvitegravir with tenofovir DF/emtricitabine/efavirenz the proportion with plasma HIV RNA less than 50 copies/mL was 84 and 79% for those with >100,000 to 400,000 copies/mL and 86 and 90% for >400,000 copies/mL, respectively (n=700) (7). Response rates for elvitegravir versus efavirenz-containing regimens amongst those with CD4 cells <200 cells/uL were also similar at 74 and 82%, respectively. There were no differences in response based upon age, sex or race. The major safety difference was an increase in creatinine during the first weeks of elvitegravir/cobicistat-containing therapy that then stabilized during follow-up. This is felt to be consistent with the effect cobicistat has on renal tubular handling of creatinine rather than an actual nephrotoxic effect. There was also the expected higher rate of neurologic symptoms seen in those given the efavirenz-based regimen.
The comparison between tenofovir DF/emtricitabine/cobicistat/elvitegravir with tenofovir DF/emtricitabine plus atazanavir/ritonavir also showed high levels of virologic suppression after 48 weeks regardless of baseline characteristics (n=708) (8). Responses were similar between cobicistat/elvitegravir and atazanavir/ritonavir-containing regimens regardless of baseline viral loads with the proportion with plasma HIV RNA less than 50 copies/mL at 48 weeks being 85 and 81% for those with viral loads of >100,000 to 400,000 and 88 and 86% for those >400,000 copies/mL at baseline, respectively. Responses were also similar for those with baseline CD4 cell count <200 cells/uL at 80% for cobicistat/elvitegravir- and 85% for atazanavir/ritonavir-containing regimens with no differences by age, sex or race. The tolerability data was also quite similar with a greater increase in triglycerides with atazanavir/ritonavir as well as higher frequency of hyperbilirubinemia with ocular icterus in this group (14%) compared to those treated with cobicistat/elvitegravir (1%). Together these studies demonstrate the efficacy and tolerability of this new fixed dose combination that includes two new drugs, elvitegravir and cobicistat. The main issues with this new drug will be the importance of potential drug-drug interactions and the effect cobicistat has on measurements of creatinine, an issue that will be of limited relevance as long as the initial changes in creatinine are ignored during the first four weeks of treatment.
The fixed-dose combination of tenofovir DF/emtricitabine/cobicistat/elvitegravir provides the option of using elvitegravir in treatment naïve patients. Cobicistat as a pharmacologic booster also provides potential opportunities for pharmacologic boosting of other drugs, such as protease inhibitors. In fact, cobicistat is being studied in this way with data submitted to the FDA on June 28th 2012 for approval as a pharmacologic booster for atazanavir and darunavir. One key study was a large placebo-controlled (n=700), randomized trial comparing tenofovir DF/emtricitabine plus atazanavir with either cobicistat or ritonavir (9). The primary endpoint was the proportion with plasma HIV RNA less than 50 copies/mL at 48 weeks using SNAPSHOT analysis. The majority of patients were men (82-83%), median CD4 was 350 cells/uL with approximately 40% having plasma HIV-1 RNA >100,000 copies/mL. Virologic suppression was excellent in both study arms, cobicistat 85% and ritonavir 87% with a difference of -2.2 (95% CI -7.4, 3.0). While noninferior efficacy is critical, it is also important to define other characteristics of this new booster. The overall safety profile for both regimens appeared quite similar for gastrointestinal adverse events and most laboratory abnormalities; however, there was a trend towards higher total cholesterol and triglycerides amongst the ritonavir-treated subjects. Both drugs were associated with modest increases in creatinine during the first weeks of therapy, with significantly greater increases seen in the cobicistat-treated patients. Importantly, as noted above this is mostly a result of the effect these drugs have on renal tubular handling of creatinine rather than actual nephrotoxicity. More data with cobicistat will be needed to completely understand important drug-drug interactions.
In addition to the newer drugs discussed above there was follow-up data on several drugs used in treatment-naïve patients. One such therapy was rilpivirine, the most recently approved nonnucleoside reverse transcriptase inhibitor (NNRTI). The two pivotal trials investigating this drug in comparison with efavirenz in treatment naïve patients were ECHO and THRIVE (n=1368). Overall, rilpivirine was shown to be noninferior to efavirenz, but there was a lower rate of virologic failure amongst those with high viral loads (>100,000 copies/mL) treated with efavirenz than rilpivirine. However, rilpivirine was better tolerated with lower frequency of central nervous system side effects and less effect on lipids. At this meeting additional data was presented related to the low level grade 1 tolerability profile of rilpivirine in the combined data from ECHO and THRIVE (10). The data focused on those events during the first 12 weeks and found results consistent with the originally reported data, with less central nervous system adverse events as well as rash and lipid abnormalities amongst the rilpivirine-treated patients. This further demonstrates the differences in even mild adverse events between the two study arms.
The five year follow-up data was reported from the MERIT ES study. This study included 611 treatment-naïve patients with undetectable CXCR4-using virus using the enhanced sensitivity phenotypic assay of Monogram Biosciences. This study compared maraviroc given 300 mg twice daily with efavirenz, both given with zidovudine/lamivudine and showed durable viral suppression with similar proportion with plasma HIV RNA less than 50 copies/mL at 5 years, 50.8 and 45.9%, respectively (11). A concern regarding this drug related to long-term side effects since it is a novel compound that actually targets the cell rather than the virus. Consequently, these patients were followed closely for adverse events with no differences in the exposure-adjusted rates of liver, cardiovascular, infections reported as serious adverse events or malignancies between the study groups.
Novel Agents and Strategies for Treatment-Naïve Patients
Preferred initial therapies in virtually all treatment guidelines include two NRTIs with a third drug in a different class. Despite this it is widely recognized that there are NRTI-associated toxicities which in certain cases may be worth avoiding. Consequently, several studies have attempted to identify safe and effective NRTI-sparing first-line regimens. Two such studies were presented at this meeting utilizing the CCR5 antagonist maraviroc with a ritonavir-boosted protease inhibitor. The first of which was a small single-arm study (n=24) that gave treatment-naïve patients with no detectable CXCR4-using virus maraviroc 150 mg once-daily with once-daily darunavir/ritonavir (12). At 24 weeks 3 of 24 experienced virologic failure and 4 of 24 by week 48. Interestingly, of the 4 patients enrolled with plasma HIV RNA >100,000 copies/mL, 3 experienced virologic failure. The second study was also relatively small (n=121) and included atazanavir/ritonavir with either tenofovir DF/emtricitabine or maraviroc given as 150 mg once-daily (13). All patients had no detectable CXCR4-using virus, were treatment naïve and were randomized 1:1 to the two regimens. Patients had relatively early stage of disease with median CD4 of approximately 350 cells/uL, but with 25-35% having baseline plasma HIV RNA greater than 100,000 copies/mL. The proportion with viral load <50 copies/mL at 96 weeks was 82% for tenofovir DF/emtricitabine and 67.8% for maraviroc-containing regimens with the majority of those with >50 copies/mL in the maraviroc study arm having a viral load of between 50 and 250 copies/mL. In addition, there was no evidence of genotypic resistance or emergence of CXCR4-using virus in any of those tested with virologic failure. There were few major differences in adverse events between the groups except increased frequency of hyperbilirubinemia and jaundice in the maraviroc group, most likely reflecting the effect tenofovir DF has on reducing atazanavir levels and the fact that these drug levels correlate with severity of this completely benign and reversible adverse event. These was also a greater change in calculated creatinine clearance from baseline to week 96 in the tenofovir DF/emtricitabine (-21.5 mL/min) than the maraviroc-containing study arm (-1.5 mL/min), the clinical relevance of which is not known. Although both of these studies are relatively small, they do suggest that the NRTI-sparing regimens may not be as effective as the preferred regimens. While the results may not influence what are considered preferred options, they do provide clinicians data for novel regimens that may be considered in select clinical situations where NRTIs may want to be avoided.
Current antiretroviral therapy has proven to be highly effective, well tolerated and generally easy to take. A major next step in drug development would be the availability of longer-acting agents that potentially could be used in combination to allow for less frequent dosing. One such strategy is to create nano-formulation of existing drugs that can be administered parenterally and then slowly released into the blood so as to have terminal half life allowing for biweekly or even monthly dosing. At this meeting the pharmacokinetics of a nano-formulation of a new integrase strand transfer inhibitor was presented. The new drug is called S/GSK1265744, also known as "744" and is similar in structure to dolutegravir. As monotherapy it induced an approximate 2.5 log10 copy/mL reduction in plasma HIV RNA and is being developed as an injectable nano-formulation for infrequent dosing. At this meeting data was presented from healthy people given between 100 and 800 mg of drug either intramuscular or subcutaneously showing an estimated half-life or 21 to 50 days, compared to the approximate 40 hours seen with oral dosing of the parent compound (14). The main adverse event associated with treatment was mild injection site reactions. This nano-formulated drug could be valuable for pre-exposure prophylaxis, post-exposure prophylaxis or even treatment, particularly if it could be paired with other long-acting agents such as some of the monoclonal antibodies in development or other nano-formulated antiretrovirals.
Antiretroviral Therapy for Treatment-Experienced Patients
Despite the observed successes with first-line therapy, there remain some patients who need new options as a result of selecting for drug resistant virus. The introduction of the integrase strand transfer inhibitor raltegravir represented a major advance in managing this patient population. The newer drug in this class, elvitegravir is also being developed for this indication. In fact, a registrational trial in treatment-experienced patients that were at least two class resistant has been completed and was presented at this meeting (15). Patients were randomized to optimized background regimen that included a ritonavir-boosted protease inhibitor and other drugs of investigators choice with either raltegravir 400 mg twice-daily or elvitegravir 150 mg once-daily (n=712). The primary endpoint was proportion with plasma HIV RNA less than 50 copies/mL after 48 weeks, which was 59% for elvitegravir and 58% for raltegravir, meeting the criteria for noninferiority, difference of 1.1 (95% CI -6.0, 8.2). The same was true for outcome at 96 weeks with 48 and 45% being less than 50 copies/mL, difference 2.6 (95%CI: -4.6, 9.9) for elvitegravir and raltegravir, respectively. Adverse events were modest and similar between study arms with the main difference being that elvitegravir was associated with somewhat more diarrhea and less transaminase elevation.
Extended follow-up from the pivotal MOTIVATE 1 and 2 trials were also presented at this meeting (16). These studies randomized treatment-experienced patients without detectable CXCR4-using virus to optimized background regimen with or without maraviroc given at a dose of 300 mg twice-daily. The primary endpoint demonstrated the antiviral activity of maraviroc in this setting and that the drug was generally well tolerated. Because this is a novel drug that actually targets the cell rather than the virus, long term safety data was felt to be particularly important. Presented at this meeting was the 5 year follow-up demonstrating durable virologic suppression and no unexpected long-term toxicity. Per 100 patient years of follow up the exposure-adjusted rate of death was 1.4, infections reported as serious adverse events 4.7, malignancies 2.4 and cardiac events 1.0. The malignancy rate, which was a concern during the early development of this class of drugs, was not different than what was seen in BENCHMRK studies of raltegravir in treatment-experienced patients. The absence of increased risk for these events is consistent with what was seen in the head-to-head comparison of maraviroc with efavirenz in the MERIT trial (11). Overall, the data from extended follow-up did not raise any significant concerns about adverse events associated with the use of this particular CCR5 antagonist.
Another group of treatment-experienced patients that consider modifying therapy do so for the opportunity to enhance convenience or tolerability. These studies tend to enroll patients on stable regimens with sustained virologic suppression. The SPIRIT study enrolled those on stable ritonavir-boosted protease inhibitor for at least 6 months. Patient could be on their first or second regimen but had to be NNRTI-naïve and not have evidence of NRTI or NNRTI resistance. Patients were randomly assigned to remain on a stable regimen or change to fixed-dose combination tenofovir DF/emtricitabine/rilpivirine (17). The study enrolled 471 patients with 93.7% and 89.9% of those who switched versus remained on their original regiment maintaining viral suppression after 24 weeks of follow-up, respectively, with a difference of 3.8 (95% CI -1.6, 9.1). There was also some evidence of less gastrointestinal intolerance as well as less fatigue, headache, depression and higher level of treatment satisfaction amongst those who switched. Finally, there was evidence of a decline in total and LDL cholesterol as well as triglycerides and a marked decline in the Total Cholesterol:HDL ratio in those that switched. This data is limited to 24 weeks of follow-up and it is assumed that great care was given by investigators to not switch those in which it was felt by treatment history were likely to have previously selected for NRTI-resistance. With these caveats, it does appear that such a switch can be done safely. Moreover, even amongst a population of patients on a stable regimen for a median of 2.6 to 2.9 years the switch was associated with some improvements in gastrointestinal tolerability and lipid profiles.
References:
1. Daar ES, Li XL, Moudgil T, Ho DD. Primary HIV-1 isolates are relatively resistant to neutralization by recombinant soluble CD4 (sCD4). VI International Conference on AIDS, San Francisco, California, 20-24 June 1990.
2. 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. 1-239. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL. pdf. Section accessed August 30 2012.
3. Thompson M, Aberg J, Hoy J, Telenti A, Benson C, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012;308: 387-402).
4. Grinsztein B, Hosseinipour M, Swindells S, et al. Effect of early versus delayed intiation of antiretroviral therapy (ART) on clinical outcomes in the HPTN 052 randomized clinical trial. XIX International AIDS Conference 2012, Washington D.C., Abst. LB Track 8.
5. Markowitz M, Evering T, Figueroa A, et al. Very early initiation of combination antiviral therapy results in normal levels of markers of immune activation. XIX International AIDS Conference 2012, Washington, D.C., Abst TUPDB0204
6. Raffi F, Rachlis A, Stellbrink JH, et al. Once-daily dolutegravir (DTG; S/GSK1349372) is non-inferior to raltegravir (RAL) in antiretroviral-naïve adults: 48 week results from SPRING-2 (ING113036). XIX International AIDS Conference 2012, Washington D.C., Abst. LB Track 8.
7. Sax P, De Jesus E, Mills A, et al. Analysis of efficacy by baseline HIV RNA: week 48 results from a phase 3 study of elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) compared to efavienz/emtricitabine/tenofovir DF in treatmnt-naive HIV-1-positive subjects. XIX International AIDS Conference 2012, Washington D.C., Abst. TUPE028.
8. De Jesus E, Rockstroh J, Henry K, et al. Analysis of efficacy by baseline viral load: phase 3 study comparing elvitegravir/cobicistat/emtricitaine/tenofovir DF (quad) versus ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF in trematne-naive HIV-1-positive subjects: week 48 results. XIX International AIDS Conference 2012, Washington D.C., Abst. TUPE043.
9. Gallant J, Koenig E, Andrade-Villanueva, et al. Cobicistat vs. Ritonavir as pharmacoenhancers in combination with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, active-controlled trial, week 48 results. XIX International AIDS Conference 2012, Washington D.C., Abst. TUAB01
10. Rashbaum B, Girard PM, Rachlis A, et al. Initial tolerability of rilpivirine (RPV, TMC278) and efavirenz (EFV) in the phase III ECHO and THRIVE tirals: profile of grade 1 events. XIX International AIDS Conference 2012, Washington D.C., Abst. TUPE024
11. Cooper DA, Heera J, Ive P, et al. Five-year efficacy and safety of maraviroc versus efavirenz, each in combination with zidovudine/lamivudine, in treatment-naïve HIV-1-infected patients: open-label extension of the randomized, double-blind merit study. XIX International AIDS Conference 2012, Washington D.C., Abst. TUPE026.
12. Taiwo B, Swindells S, Berzins B, et al. Week 48 results of the maraviroc plus darunavir/ritonavir study (MIDAS) for treatment-naive patients infected with R5-tropic HIV-1. XIX International AIDS Conference 2012, Washington D.C., Abst. TUPE099.
13. Mills A, Mildvan D, Podzamczer D, et al. Once-daily maraviroc in combination with ritnavir-boosted atazanavir in treatmnt-naive patients infected with CCR5-tropic HIV-1 (study A4001078): 96-week results. XIX International AIDS Conference 2012, Washington D.C., Abst. TUAB01.
14. Spreen W Ford SL, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inibitor SGSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. XIX International AIDS Conference 2012, Washington D.C., Abst. TUPE040.
15. Elion R, Molina JM, Arribas-Lopez JR, et al. Efficacy and safety results from a randomized, double blind, active controlled trial of elvitegravir (once-daily) vs. Raltegravir (twice-daily) in treatment-experienced HIV-positive patients: long term 96-week data. XIX International AIDS Conference 2012, Washington D.C., Abst. TUAB01
16. Gulich R, Fatkenheuer G, Burnside R, et al. Five-year safety evaluation of maraviroc in HIV-1-positive, tretment-experienced patients. XIX International AIDS Conference 2012, Washington D.C., Abst. TUPE029.
17. Palella F, Tebas P, Gazzard B, et al. SPIRIT study: switching to emtricitabine/rilpiviriine/tenofovir df (FTC/RPV/TDF) single-tablet regimen (STR) from a ritonavir-boosted protesase inhibitor and two nucleoside reerse transcriptse inhibitors (NRTIs) maintains HIV suppression and improves serum lipids in HIV-1-infected subjects. XIX International AIDS Conference 2012, Washington D.C., Abst. TUAB01
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