Coverage of the 14th Conference on Retroviruses and Opportunistic Infections (CROI)
The Conference on Retroviruses and Opportunistic Infections (CROI) is the premier domestic venue for the dissemination of data related to the clinical management of HIV infection. Smaller and more focused than most other meetings covering the care for persons living with HIV, CROI is data dense and always guaranteed to yield findings that influence how HIV infection is treated.
This February the conference was held in downtown Los Angeles, a few short miles from where the Academy Awards ceremony takes place, which was occurring as CROI opened. However, it was all business and little glamour in the conference center as attendees rushed from session to session, crisscrossing as they pursued their disparate interests.
IDCR editors and Board members were among the throngs jockeying for aisle seats with excellent views of the slide presentations. No papers directly related to the care of the HIV-infected inmate, but the major findings presented are relevant for anyone managing HIV infection. Below, our team of experts provides summaries of the data they felt would be of greatest importance to you, their correctional colleagues.
As the HIV epidemic matures and the prevalence of the infection rises, an increasing number of HIV-infected patients will receive antiretroviral HIV therapy. Unfortunately, many will harbor or develop a virus with antiretroviral drug resistance. HIV-infected men and women cycling in and out of prisons and jails may be particularly vulnerable to the development of drug resistant HIV as they may initiate, interrupt and re-initiate care during and between incarcerations. Infected inmates may also face a number of challenges to adherence with their HIV therapies including mental illness and substance abuse.
Results from a number of important clinical trials of new antiretroviral drugs were presented at CROI 2007 and offer hope for patients infected with multidrug resistant HIV. We report on two new antiretroviral agents that are relatively advanced in their clinical development, are currently available via expanded access programs, and may be of immediate clinical interest. These drugs represent two novel antiretroviral classes and have the potential to positively impact treatment outcomes as well as change the prevailing treatment paradigm of combining two nucleosides with a protease inhibitor or a non nucleoside reverse transcriptor inhibitor as the cornerstone of highly active antiretroviral therapy (HAART).
To gain entry into CD4 cells, HIV must interact with not only the CD4 receptor but with other cellular receptors including those for chemokines CCR5 and CXCR4. Maraviroc (MVC) is an entry inhibitor that is a CCR5 (R5) antagonist with in vitro activity against virus that is tropic for cells that express the R5 receptor but not cells that use CXCR4 (X4) receptors or that use both types of receptors (i.e. dual tropic HIV-1). Interim 24-week analyses of two parallel ongoing phase IIb/III double-blind, placebo-controlled studies of MVC in antiretroviral treatment-experienced, HIV-infected adults, MOTIVATE (Maraviroc Plus Optimized Background Therapy in Viremic, ART-Experienced Patients) 1 and 2, were presented.1,2 These studies were identical in design and were conducted in the U.S. and abroad. Eligible participants were triple antiretroviral class-experienced with viremia of > 5000 copies/ml, had only R5 tropic virus on baseline tropism screening, and were randomized 1:2:2 to receive placebo, twice daily MVC 300 mg or once daily MVC 300 mg. An optimized background therapy (OBT) was selected by the treating physicians to accompany the study treatment. The dose of MVC was reduced to 150 mg if the OBT contained protease inhibitors (except tipranavir) or delavirdine. Participants were further stratified by enfurvitide (T-20) use or by HIV-1 RNA value above or below 100,000 copies/ml (see Table 1).
At 24 weeks, MVC plus OBT provided superior virologic and immunologic outcomes compared to placebo plus OBT. Overall, similar results were noted for MVC once daily and twice daily dosing regimens. However, a larger proportion of patients who were found on antiretroviral resistance testing to have no active drug in OBT achieved HIV-1 RNA below 50 copies/ml in the two MVC BID arms compared to MVC QD or placebo arms in combined analysis (29% vs. 18% vs. 3% respectively in an analysis combining the results of the two trials).
No differences in the reduction in HIV-1 RNA were noted when results were stratified by receipt of enfuvirtide or by baseline HIV-1 RNA values. Adverse events were similar in all arms. Specifically, no increased risk of lymphoma or other malignancies was observed in the MVC arms compared to the placebo arm. In the subset of patients that failed treatment, patients receiving MVC were much more likely to have had shifts to X4 or dual tropic virus than those receiving placebo (see Table 1).
MCV is scheduled in April for review by the FDA for accelerated approval. It represents a welcomed addition to our antiretroviral armamentarium but its optimal role in antiretroviral therapy remains to be defined. Chemokine receptor inhibitors are the first antiretroviral drugs that target host proteins rather than viral targets. While the apparent absence of any significant sequelae among individuals with congenital deficits in chemokine receptors (e.g., CCR5-^32 homozygotes) provides some reassurance that the therapeutic use of chemokine receptor inhibits will be similarly benign, the long-term safety of CCR5 inhibition is yet to be proven. Recent reports that homozygous CCR ^32 is a strong host genetic risk factor for symptomatic laboratory-confirmed West Nile Virus infection further fuels safety concerns.3 Similarly, initial concerns regarding the emergence of X4 virus during treatment with an R5 antagonist remain. Additionally, the clinical use of MVC, in particular in treatment-experienced patients, appears to require pretreatment screening with a tropism assay because the drug will not be effective in those infected with an x4 or dual tropic virus. The expense of such assays may strain already stretched financial resources. Finally, resistance to R5 antagonists is incompletely understood.
Raltegravir, previously known as MK-0518, is an integrase inhibitor that has previously been shown to confer significant virologic benefit to antiretroviral-naive HIV-infected patients, as well as heavily treatment-experienced patients with HIV resistant to agents in each of the three original antiretroviral drug classes. The integrase enzyme is responsible for incorporating viral DNA into the host genome where, once integrated, it encodes for the production of viral proteins. As such it has been an attractive but elusive antiretroviral target. Sixteen-week data from two identical, parallel, ongoing, phase III double-blind, placebo-controlled studies, designated BENCHMRK-1 and -2, were presented at CROI 2007.4,5 Eligible participants were those failing antiretroviral therapy with triple antiretroviral class resistance and were randomized 2:1 to raltegravir 400 mg twice daily or placebo. OBT was selected by the treating physicians. Selected drugs that were investigational at the time the study was conducted (e.g. darunavir) were permitted to be part of OBT (see Table 2).
Raltegravir demonstrated superior virologic and immunologic efficacy at 16 weeks over placebo. Superior efficacy of the raltegravir arms was maintained regardless of baseline CD4 count, HIV-1 RNA values as well as predicted resistance to agents in the OBT by resistance testing. Adverse events were similar between groups (see Table 2).
Raltegravir has shown impressive efficacy in both antiretroviral naive and treatment-experienced patients. While its approval by the FDA is eagerly anticipated, its optimal role in the sequence of antiretroviral therapy remains to be well defined.
Once Daily Versus Twice a Day Lopinavir/Ritonavir and the Role of Directly Observed Therapy (DOT)
Once daily antiretroviral regimens have become de rigueur for reasons that are obvious to anyone who must take medications chronically. It is hoped that simplification of HIV therapy will improve adherence, however few studies have examined the relative efficacy of once daily and twice daily administration of the same antiretroviral agents. Once daily HIV therapy regimens also make direct observation of dosing more feasible. Certainly, no one has more experience administering antiretrovirals via directly observed therapy (DOT) than correctional facilities. Yet, again, there are limited data available regarding the role for DOT in HIV care.
AIDS Clinical Trials Group (ACTG) study A5073 aimed to compare the safety and virologic efficacy of lopinavir/ritonavir dosed at 800/200 mg once a day (n=159) versus 400/100 mg twice a day (n=161) in treatment naive patients.6 The drug was combined with emtricitabine (FTC) plus either tenofovir (used in ~ 40% of subjects) or stavudine-XR. In addition, a third arm of the study administered the once daily regimen under DOT for 24 weeks (n=82). In this study DOT consisted on the observation of ingestion of the lopinavir/ritonavir five days of the week by a health professional (e.g. doctor, nurse, pharmacist).
By 48 weeks after study entry, there was no overall difference in time to virologic failure between the self-administered once daily versus twice daily study arms with about 30% of patients in each experiencing failure by this time point. However, when stratifying response by baseline viral load, among those with a HIV-1 RNA level > 100,000 copies/mL, virologic failure was more common with self-administered once daily lopinavir/ritonavir compared to self-administered twice a day lopinavir/ritonavir.
Seventy-four percent of those assigned to DOT of once daily lopinavir/ritonavir completed the 24 week DOT program. There was 86% adherence with the DOT visits among these participants. There was a trend favoring DOT at the end of the 24 weeks in comparing the self administered once daily lopinavir/ritonavir arm to the DOT once daily lopinavir/ritonavir arm, but this did not achieve statistical significance. By week 48 (24 weeks after DOT ceased) there was no difference in the probability of virologic failure between the DOT and self-administered once daily therapy arms. Over the 48 weeks of study, there was a trend toward fewer new AIDS diagnoses and deaths among those getting their treatment via DOT, but there were too few events to make firm conclusions regarding this finding.
This trial found that once daily lopinavir/ritonavir can be most safely administered to patients with a pre-therapy viral load of less than 100,000 copies/mL. The unexpected finding of increased risk of virologic failure among those with higher viral loads assigned to once a day lopinavir/ritonavir is concerning and requires further study. Modified DOT (i.e. observation of some but not all doses) was not found to produce remarkable advantages over self-administered therapy in this community-based study, although there were intriguing trends in better virologic responses and clinical outcomes among those getting their HAART under study-defined DOT. These trends will likely spur increased efforts to study community-based DOT for HIV treatment.
Early Failure of Tenofovir, Lamivudine (3TC) and Nevirapine
HIV health care providers frequently must be creative in crafting antiretroviral regimens. While published guidelines assist clinicians in choosing appropriate therapy for patients starting HIV treatment, patients may have adverse reactions to recommended agents or other contraindications that require consideration of alternative combinations.
Investigators in France conducted a trial comparing tenofovir, lamivudine (3TC) and nevirapine versus zidovudine (ZDV), 3TC and nevirapine among treatment naive patients.7 The study was designed to enroll 250 people, but was halted after 71 were randomized as there was an excess of virologic failures in the tenofovir, 3TC and nevirapine arm. Nine of 36 participants assigned to that arm, compared to only one of 35 receiving ZDV, 3TC and nevirapine, failed. Only one of the ten patients who failed therapy had baseline resistance. Nevirapine levels were measured and found to be adequate in all failure patients. Mutations conferring resistance to nevirapine were the most commonly detected mutations observed followed by the K65R mutation, associated with tenofovir resistance and the M184V 3TC mutation.
This study serves as a cautionary tale regarding the use of untested antiretroviral regimens, particularly in treatment naive patients who are able to take more standard combinations. The reason for the early failure of tenofovir, 3TC and nevirapine remains unclear and is unexpected given the proven potency of tenofovir, 3TC and efavirenz. Further examination of these data and this regimen are needed. Until then, avoiding this particular regimen seems prudent.
Safely Dosing H2 Blockers With Atazanavir/Ritonavir
Atazanavir is a protease inhibitor that requires gastric acid to be adequately absorbed. Therefore, co-administration of proton pump inhibitors and atazanavir is contraindicated. Previous data demonstrate that H2 blockers, specifically famotidine, can be used during atazanavir therapy. According to the package insert, in treatment-naive patients atazanavir at a dose of 300 mg with ritonavir 100 mg once daily can be taken with food, without the need for separation of the dose from the H2-receptor antagonist. In treatment-experienced patients it is recommended that atazanavir/ritonavir 300/100 mg once daily be taken with food at least 2 hours before and at least 10 hours after the H2-receptor antagonist.
In a study of HIV-uninfected volunteers, atazanavir/ritonavir in standard doses along with tenofovir was administered with famotidine either simultaneously or temporally separate (10 h before and 4 h after).8 Tenofovir is commonly prescribed with ritonavir boosted atazanavir even though this nucleotide analogue reduces atazanavir levels -- an effect that is largely overcome with ritonavir boosting. In this study, atazanavir levels were adequate when famotidine 20 mg BID was given with or separate from ATV+RTV dose. Likewise, atazanavir levels were adequate when famotidine at a dose of 40 mg daily was given separate from the protease inhibitors. However, atazanavir levels were significantly reduced when famotidine at 40 mg BID was given, even when administered separately from the protease inhibitors. Therefore, twice daily dosing of this H2 blocker at the higher dose should not be administered to patients on atazanavir and should be used cautiously with this boosted protease inhibitor even at lower doses.
There were several important presentations regarding metabolic complications of HIV and its therapies. Most notable were the metabolic results of ACTG trial A5142, a large study comparing a) efavirenz plus two nucleoside analogues, b) lopinavir/ritonavir plus two nucleoside analogues and c) efavirenz and lopinavir/ritonavir without nucleosides.9 The virologic and immunologic results of the trial were presented at the International AIDS Conference last summer (see IDCR September 2006).
At CROI 2007, the relative effects of each of the three study arms on limb fat and lipids were presented and were surprising to many. Foremost, over 96 weeks, those patients assigned to efavirenz plus two nucleosides experienced an initial increase in total limb fat of approximately 8% by 48 weeks but this declined precipitously to just a 1.4% gain over baseline at 96 weeks. This is in stark contrast to those randomized to lopinavir/ritonavir and two nucleosides who experienced an increase in limb fat of almost 10% by week 48, which persisted at 96 weeks. The nucleoside-sparing regimen produced progressive limb fat gains during the study reaching 18% at week 96.
Importantly, the nucleoside agents used in the two arms containing this class of antiretrovirals was balanced between the arms with about 40% using ZDV, 30% using tenofovir and the remainder choosing stavudine-XR. Even among those taking tenofovir, a drug not thought to contribute to fat wasting, there was more lipoatrophy (>20% limb fat loss from baseline) among those assigned to take efavirenz (12%) than lopinavir/ritonavir (6%). The rise and fall of limb fat seen in the efavirenz plus two nucleoside group was similar to the changes seen in the ZDV+3TC+efavirenz arm of another study presented at CROI 2007 -- a trial of this combination versus lopinavir/ritonavir monotherapy after withdrawal of ZDV+3TC once viral suppression was achieved.10 In that study, as in A5142, the ZDV+3TC+efavirenz arm experienced an early increase in limb fat followed by a progressive decline over time. In this case, there was a net loss of fat compared to baseline in this group.
Defying predictions, increases in total cholesterol during A5142 were no different in the lopinavir/ritonavir and the efavirenz arms, rising approximately 30 mg/dL in each group. In contrast, the nucleoside sparing arm had a statistically significant greater increase of 57mg/dL at week 96. Triglycerides rose higher after the initiation of therapy in the lopinavir/ritonavir plus two nucleoside arm (46 mg/dL) compared to the efavirenz arm (19 mg/dL). And, again, the efavirenz plus lopinavir/ritonavir group saw the greatest increase (62mg/dL).
This important trial reveals that combinations of antiretrovirals can act together to produce peripheral fat wasting. In addition, the perception that metabolic toxicities belong solely within the province of protease inhibitors is demonstrated to be incorrect. Indeed, in this trial there were no differences seen between the study arms in changes of trunk fat -- an adverse effect that is typically ascribed to protease inhibitors.
Lessons From Clinical Trials of HIV/HCV Co-Infected Patients
In correctional settings, we have traditionally thought of HCV as being primarily a blood-borne infection. Data from CROI, however, challenge this notion and may have important implications for more routine testing for HCV in populations not previously thought to be at highest risk. In one study of 7223 men who have sex with men (MSM) in the U.K., increased risk for HCV infection included unprotected sex, multiple sexual partners and the presence of other sexually transmitted infections, such as gonorrhea and syphilis. HCV transmission among this cohort appeared to increase among HIV-infected individuals, perhaps due to the higher levels of HCV viremia and impaired immunological responses.11 Correctional inmates before, during or after release engage in many of the risks identified in this study and merit increased screening and risk behavior counseling.
In a plenary session by David Thomas, M.D., from Johns Hopkins University, the pros and cons of liver biopsy in HCV/HIV co-infected patients were thoroughly discussed.12 Unlike the case for HIV where surrogate markers such as viral load and CD4 cell count are the best predictors of disease progression, the extent of hepatic fibrosis is the best prognostic factor for progression of liver disease in HCV-infected patients. Liver biopsy has been the primary tool for assessing hepatic fibrosis, yet is subject to several important limitations including: 1) its invasive nature with potential for significant complications; 2) the possibility of sampling error due to a relatively small biopsy size (1/50,000th of the liver),13 the fragmentation of examined tissue, and/or the inherent heterogeneity of hepatic fibrosis14; 3) low acceptance by many patients; 4) cost considerations; and 5) lack of availability. While liver biopsy has the advantage of providing additional information on other relevant histologic findings, such as necroinflammation and steatosis, some argue that its use in patients with HIV co-infection has less merit given the accelerated rate of progression among HIV-infected patients and their high rates of liver disease-related morbidity and mortality.15,16 Nonetheless, development of noninvasive tools for staging hepatic fibrosis has been urgently needed.
Assessing liver fibrosis using non-invasive procedures has been divided into two distinct categories: 1) imaging techniques, such as elastometry (e.g., FibroScan), and serum biochemical marker tests (e.g., Fibrotest, APRI, SHASTA, FIB-4, Forns, serum hyaluronic acid).17 These tools are generally accurate in discriminating between a lack of fibrosis and advanced fibrosis, but they are less precise at distinguishing between intermediate fibrosis stages. The predictive value of these tests is particularly good for advanced hepatic fibrosis and cirrhosis. Liver fibrosis staging using elastometry seems to be particularly reliable. Assessed within 10 minutes, it is relatively low cost, can be repeated frequently without risk to the patient. It also has a positive predictive value greater than 90% for advanced fibrosis.
Despite these advances, waiting until a patient has advanced fibrosis for treatment is less than optimal in HCV/HIV co-infected patients. Instead, Thomas recommends that when chronic HCV infection is clear by the presence of HCV viremia alone, in the absence of other clinical indicators that would preclude treatment (e.g., Childs Pugh B or C cirrhosis, suggestion of autoimmune hepatitis, advanced and uncontrolled HIV infection or presence of opportunistic infection) is sufficient to warrant treatment.12 The relatively high response to pegylated interferon plus weight-based ribavirin, the faster progression of HCV-related liver disease in the HCV/HIV co-infected population, and the opportunity for assessing the HCV response at earlier time points to identify who will and will not respond to therapy all favor initiating anti-HCV therapy without the need for a liver biopsy in most cases.
In the following plenary session, Raymond Chung, MD, from Harvard University, reviewed that current HCV treatment in HIV co-infected patients.18 In addition to reviewing the three large prospective trials treating HCV among HCV/HIV co-infected patients, where sub-therapeutic ribavirin dosing was used (APRICOT,19 ACTG 5071,20 and RIBAVIC21), updated data from the PRESCO trial using weight-based ribavirin doses of 1000 to 1200 mg per day presented at CROI were also reviewed.22
The PRESCO trial demonstrated increased sustained virologic response rates (SVR, undetectable HCV viral load six months after treatment completion) (49.6%) compared to other studies. The PRESCO trial also confirmed low rates of premature discontinuation (8.2%) -- similar to trials of weight-based ribavirin and pegylated interferon in HCV mono-infected patients. The PRESCO trial answered some additional questions. First, the SVR among genotype 1 was 35.6% and 72.4% in genotypes 2 and 3. The study was also designed to address the issue of treatment duration (short vs. extended tended). Patients with genotypes 2 or 3 were randomized to receive 24 weeks (short) versus 48 weeks (extended) of treatment and patients with genotypes 1 or 4 received 48 weeks (short) versus 72 weeks (extended) of treatment. SVR rates were higher among patients assigned to received extended versus standard durations of therapy. For genotypes 2 or 3, SVR was 82% with 48 weeks versus 67% with 24 weeks. For genotypes 1 or 4, 53% had SVR with 72 weeks versus 31% with 48 weeks. Extended treatment duration did not, however, decrease the likelihood of relapse in patients with genotype 1 (33%) or genotypes 2 or 3 (17%), but did reduce relapse rates from 21% to 0% in patients with genotype 4. Extended treatment was associated with increased toxicity and drop-out.23
Further data from CROI suggested that improved outcomes can be achieved if HIV infection is optimally managed (e.g., excluding individuals receiving zidovudine or didanosine or patients with low CD4 cell counts and uncontrolled HIV RNA levels).24
In addition to this data on extended duration of treatment for HCV/HIV co-infection, a number of additional clinical pearls were gleaned from other presentations that should assist with optimizing HCV treatment. A sub-study of the RIBAVIC trial demonstrated reduced SVR among patients concomitantly receiving abacavir and ribavirin, suggesting a potential drug interaction between the two guanosine analogues.25 Though not clinically available to clinicians now, the use of transcription-mediated amplification (TMA), a very sensitive tool that has a lower limit of HCV RNA detection of 5 IU/mL, for detecting serum HCV RNA at the end of a course of HCV treatment has positive and negative predictive values exceeding 80% for relapse.26 Tools similar to this one, rather than extended treatment courses, will help individualize treatment duration.
More data supportive for dispensing with transaminase elevations as a guide for treatment evaluation were presented. Matched HCV/HIV co-infected patients with persistently normal versus elevated transaminase levels were compared. Among patients with advanced liver fibrosis (Metavir scores of F3 or F4) nearly 15% of co-infected patients had persistently normal transaminases; this finding was more frequent among women and those with genotype.4 Thus, co-infected patients with normal liver enzyme levels should not be excluded from anti-HCV therapy, as liver disease progression may occur in a significant proportion of these patients in a silent manner.
Who Gets Treated and Who Does Not
HCV therapy is becoming increasingly available in correctional facilities. A study from Johns Hopkins University looked at eligibility of HIV/HCV co-infected and HCV mono-infected injection drug users (IDUs) for HCV therapy.27 Patients studied included 180 HCV mono-infected individuals participating in a community-based Hopkins-run addiction treatment program and 183 HIV/HCV co-infected patients of the hospital's HIV clinic. All were offered free HCV therapy (see Table 3).
Eleven percent of the co-infected patients had a negative HCV RNA as did 22% of the mono-infected. More of the HIV-infected patients (40%) were deemed ineligible for HCV treatment due to having a life expectancy less than two years, active depression with suicidal ideation, allergic reaction to interferon or ribavirin, severe hepatologic abnormalities, renal insufficiency, pregnancy, or unwillingness to use birth control than the HIV-uninfected (26%). However, a similar proportion of patients (66-67%) did not start HCV therapy (see Table 3).
Therefore, HIV co-infected patients were less likely to be eligible for HCV therapy -- largely as a consequence of poor life expectancy and anemia -- but the eligible mono-infected patients were less likely to actually start HCV treatment. In both groups, the vast majority of HCV eligible patients never initiated HCV treatment. The investigators also reported that most patients (79% in the mono-infected group and 67% among the co-infected) had no or minimal fibrosis seen on liver biopsy -- perhaps suggesting that disease staging had an influence on the uptake of HCV treatment (see Table 3).
As usual, there were a number of presentations at CROI of great interest to the HIV clinician. The results of phase III trials of two new HIV therapies belonging to novel classes of antiretrovirals produced palpable excitement at the conference as clinicians recognized that a critical mass of new therapies for the patient with multi-drug resistant virus was at hand. However, for correctional clinicians unresolved issues related to the need to assess viral tropism prior to therapy initiation may temper enthusiasm for MVC. These assays are likely to carry a significant price tag and it may take weeks for a result to return. During that time as many as 8% of patients may experience a shift in viral tropism from R5 to dual/mixed virus. It is only a matter of time (measured in months) before the first correctional physicians will be prescribing these new agents and these issues will need to be addressed by the manufacturer of this important new agent.
Other clinical trial data refined our understanding of current management of HIV and HCV infections -- helping us to better tailor therapy to the individual patient. Thus, while no presentation focused specifically on the HIV epidemic in corrections, there was plenty here for correctional clinicians to learn and use.
Zelalem Temesgen, M.D. A.A.H.I.V.S., is Associate Professor of Medicine, Mayo Clinic College of Medicine; Director, HIV Clinic and Consultant, Division of Infectious Diseases, Mayo Clinic. Disclosures: Grant Support: Bristol-Myers Squibb, Abbott Laboratories, Tibotec Therapeutics, Gilead Sciences; Consulting: Abbott Laboratories, Gilead Sciences.
David A. Wohl, M.D., is Associate Professor of Medicine, Division of Infectious Diseases, AIDS Clinical Trials Unit, The University of North Carolina - Chapel Hill. Disclosures: Grant Support: Abbot Laboratories, Gilead Sciences, Roche Pharmaceuticals, National Institutes of Health; Speakers Bureau: Gilead Sciences, Abbott Laboratories, Bristol-Myers Squibb, Roche Pharmaceuticals, Boehringer-Ingelheim.
Frederick L. Altice, M.D., is Director of Clinical and Community Research, Associate Professor of Medicine, Yale University School of Medicine. Disclosures: Speakers Bureau: Bristol-Myers Squibb, Roche Pharmaceuticals, Abbott Laboratories, Glaxo SmithKline, Tibotec Therapeutics, Boehringer-Ingelheim.
This article was provided by Infectious Diseases in Corrections Report. It is a part of the publication Infectious Diseases in Corrections Report.