TBR-652 (formerly known as TAK-652) is a novel potent oral inhibitor of ligand binding to CC chemokine receptor 5 (CCR5) and is currently being developed for the treatment of HIV-1 infection. Tests of TBR-652 in clinical isolates show a protein binding-adjusted 50% inhibitory concentration (IC50) of 0.29 nM against CCR5. In addition, TBR-652 has the unique property in vitro of being a CCR2 antagonist with an IC50 of 5.9 nM. The CCR2/MCP-1 pathway seems to be active in a number of diseases, including atherosclerosis, metabolic syndrome, and insulin resistance.1 Studies in healthy volunteers have shown TBR-652 to be generally safe, with a mean half-life of 35 to 40 hours, supporting once daily dosing.2,3 This is the first evaluation of the antiviral activity and safety of TBR-652 in HIV-infected antiretroviral treatment-experienced subjects.
This was a double-blind, randomized, placebo-controlled, dose-escalating study assessing the antiviral activity, pharmacokinetics/pharmacodynamics (PK/PD), and safety and tolerability of oral once-daily TBR-652 monotherapy for 10 days in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naive subjects. The primary objectives were to evaluate the antiviral activity and safety of TBR-652 at doses of 25, 50, 75, and 150 mg versus placebo. TBR-652 PK and PD were secondary objectives. A 100-mg dose in a different formulation was tested in the same study. Because PK results indicated bioavailability that was not dose proportional,4 being closer to the 75-mg dose, this formulation is no longer under development and is not reported in the efficacy data below. It is included with the safety results to provide a complete assessment of TBR-652 safety.
HIV-positive men and women aged 18 through 65 years were eligible provided they had confirmed HIV-1 RNA levels of at least 5000 copies per milliliter and CD4+ cell counts of at least 250 cells per cubic millimeter. Virus must have been CCR5 tropic by the enhanced Trofile assay (Monogram Biosciences, South San Francisco, CA) at screening. Subjects had to have discontinued prior antiretroviral therapy at least 6 weeks before study entry. Subjects were excluded if they had CXCR4 or dual/mixed tropic virus; active Centers for Disease Control and Prevention AIDS-defining illness other than cutaneous Kaposi sarcoma that did not require treatment; history of hepatitis B or C or other active or chronic liver disease, including cirrhosis; elevated alanine aminotransferase or aspartate aminotransferase levels; recent clinically significant infection; treatment with any immunomodulator (including vaccines) or agents with anti-HIV effects within 30 days of dosing; treatment with prescription drugs, over-the-counter drugs, or supplements that could interfere with CYP 3A4 or CYP 2C8 enzymes or P-glycoprotein transporter activity within 30 days of dosing; or a history of clinically significant hepatic, metabolic, endocrine, renal, hematologic, pulmonary, gastrointestinal, or cardiovascular disorders [including electrocardiogram (ECG) abnormalities]. Women were excluded if they were pregnant or breast-feeding. All subjects of reproductive potential were required to use barrier contraception. Persons who did not meet entry criteria at screening could have been rescreened only once for eligibility. All subjects were screened for alcohol abuse or illicit drug use before dosing.
The trial was conducted in accordance with the Declaration of Helsinki. All subjects gave written informed consent before participating. Institutional review boards and independent ethics committees approved the informed consent, the protocol, and all protocol amendments before and during the trial.
Assessments and Monitoring
HIV-1 RNA levels were measured twice during screening, once at baseline, and on days 2, 3, 4, 7, 8, 10, 11, 15, 24, and 40. Samples were tested with the COBAS Amplicor polymerase chain reaction (PCR) assay (Roche Diagnostics, Branchburg, NJ); if levels were below the lower limit of quantitation (<400 copies/mL), the sample was evaluated with the ultrasensitive COBAS PCR assay (lower limit of quantitation <50 copies/mL). Viral coreceptor tropism was measured by the enhanced Trofile assay at screening and baseline, and on days 10, 24, and 40 if HIV-1 RNA levels permitted. CD4+ cell counts were evaluated at screening, baseline, and days 4, 7, 10, 15, 24, and 40.
Plasma PK was measured predose on days 1-10; then at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on days 1 and 10; and at hours 96 and 120 hours after the day 10 dose. MCP-1, hs-CRP, and IL-6 levels were measured at baseline and day 10. MCP-1 levels were measured at the central laboratory using the BD cytometric bead array (BD Biosciences, Sparks, MD).
Safety assessments included a physical examination at screening, baseline, and days 10 and 24; vital signs at screening and baseline, then daily except weekends and holidays; clinical safety laboratory evaluations (chemistry, hematology, and coagulation profile) at screening, baseline, and days 2, 4, 7, 8, 10, 24, and 40 (ICON Central Laboratories, Farmingdale, NY and CIBC, Rosario, Argentina); urinalysis at screening, baseline, and days 10 and 24; and assessment of adverse events (AEs) and concomitant medications daily except weekends and holidays, when such information was gathered retrospectively. ECG tracings were obtained at screening, baseline, and days 7, 10, and 24 and were read locally and at a central processing site (eResearch Technology, Inc, Philadelphia, PA). Women had a serum pregnancy test at screening and urine pregnancy tests at baseline and days 10 and 24. Treatment compliance was assured by direct observation of subjects each time a dose was taken, except on weekends and holidays.
Efficacy analyses included all subjects randomized to the study who took at least 1 dose of study drug and provided at least 1 valid HIV-1 RNA assessment after the first dose of study drug. Safety analyses included all subjects randomized into the study who took at least 1 dose of study drug. PK analyses included all subjects who provided adequate plasma PK samples. Subjects randomly assigned to placebo were analyzed as one group.
Demographics and baseline characteristics, including gender, age, race, height, weight, and body mass index, were summarized using descriptive statistics for each treatment group and for all randomized subjects. Plasma HIV-1 RNA level (in log10 copies/mL) at day 1 predose (baseline) and mean change from baseline thereafter were summarized and analyzed, as were plasma HIV-1 RNA level changes from baseline to nadir. At baseline, an analysis of variance model was used to compare each dose with placebo. For each change from baseline, an analysis of covariance model was used to compare each dose with placebo using the baseline value as a covariate. Subjects achieving HIV-1 RNA levels <400 copies per milliliter or <50 copies per milliliter were summarized and analyzed using a logistic regression model to compare each dose with placebo using the baseline value as a covariate. HIV-1 RNA values outside the limits of quantification were assigned the upper or lower quantitative value. All statistical tests were 1 sided, and a P value of 0.05 or less was considered statistically significant.
PK parameters were calculated using noncompartmental analysis. Differences in trough concentrations of TBR-652 on days 8, 9, and 10 were assessed using Helmert contrasts from a repeated measurement analysis of variance model to determine the time to steady state. Steady state was concluded if Helmert contrasts were not statistically significant at a 2-sided alpha level of 5%. PD analyses included nadir HIV-1 RNA change from baseline using an analysis of covariance model including baseline value as a covariate.
Treatment-emergent AEs were defined as any AEs that occurred during treatment and follow-up and were classified by the investigator as to seriousness, intensity, and relationship to study drug. Clinically notable abnormalities were defined in the statistical analysis plan as any grade 1-4 alanine aminotransferase or aspartate aminotransferase level and any other grade 3 or 4 laboratory value, vital sign, or ECG event, based on the Division of AIDS (DAIDS) toxicity grading criteria.
Subject Demographics and Baseline Characteristics
Fifty-four subjects were enrolled—52 at 9 sites in the United States and 2 at 1 site in Argentina. All patients had clade B HIV-1. The 100-mg dose group, which is excluded from the efficacy presentation but included in the safety presentation, included the 2 patients from Argentina. All subjects completed dosing except 1 subject in the 75-mg dose group who was lost to follow-up after 1 dose of TBR-652. One subject each in the other cohorts was lost to follow-up or left the study early after completing dosing. No one discontinued because of an AE. The study population was predominantly men and white, with median HIV-1 RNA levels of 4.0 to 4.6 log10 copies per milliliter and median CD4+ cell counts of 402 to 508 cells per cubic millimeter (Table 1). One subject assigned to the 50 mg/d dose group was inadvertently dosed with 25 mg/d and was therefore analyzed in the 25-mg dose group. One subject in the 150 mg/d dose group was excluded from the efficacy analysis because of dual/mixed tropic virus present at baseline. The subject in the 75 mg/d dose group who took only 1 dose was excluded from the efficacy and PK analyses.
The 10 subjects who received the 100-mg dose had significantly different PK results,4 and although the safety profile at this dose was similar to the 25-mg dose group,5 the formulation is no longer under development. These subjects are excluded from the efficacy presentation but included in the safety data.
HIV-1 RNA Changes
TBR-652 showed a potent dose-response effect on HIV-1 RNA levels, as measured by PCR, which persisted well after discontinuation of treatment (Fig. 1). The mean HIV-1 RNA reductions from baseline achieved statistical significance by day 4 for all doses, and by day 7, it reached P = 0.002 for the 25-mg one-daily (QD) dose and P < 0.001 the 50-mg, 75-mg, and 150-mg QD doses. The mean HIV-1 RNA reductions remained significant through day 15 for all TBR-652 dose groups. HIV-1 RNA reductions were still significant at day 24 in 150-mg dose group (P = 0.03). Mean changes from baseline to nadir viral load were also statistically significant for all TBR-652 dose groups and resulted in median decreases of up to 1.8 log10 copies per milliliter in the 75-mg dose group. At the 25-, 50-, 75-, and 150-mg doses, 33%, 71%, 100%, and 75% of subjects, respectively, achieved HIV-1 RNA reductions of at least 1 log10 copies per milliliter. One subject in the 25-mg dose group, 2 in the 50-mg dose group, and 3 in the 150-mg dose group achieved HIV-1 RNA levels below 400 copies per milliliter. Two subjects in the 150-mg dose group achieved levels below 50 copies per milliliter in this short-duration monotherapy study.
CD4+ Cell Counts
Mean and median changes in CD4+ cell counts were mixed (Fig. 2A). Least square mean values were significantly increased only at the 50-mg QD level on day 7 (+116 cell/mm3; P = 0.036) and day 10 (+97 cells/mm3; P = 0.020).
Maximum plasma concentrations of TBR-652 were achieved in 3-4 hours at all doses (Table 2). Helmert contrasts showed that steady-state concentrations (Css) were achieved by day 8. Log-normal (ln) transformed 24-hour area-under-the concentration-time curve (AUC0-24) and maximum plasma concentrations (Cmax) suggested a greater than dose-dependent increase in these parameters.
Inflammatory Marker Changes
A unique feature of TBR-652 as a CCR5 inhibitor is its CCR2 antagonism. Exploratory assessment of MCP-1, hs-CRP, and IL-6 levels found significant dose-dependent increases in MCP-1 (Fig. 2B). On day 10, least square mean MCP-1 levels obtained by flow cytometry were 56.3, 94.2, 34.4, and 334.3 pg per milliliter higher than at baseline in the 25, 50, 75, and 150-mg dose groups, respectively, compared with a slight decline in the placebo group. At the 50 and 150-mg doses, these results were statistically significant (P = 0.024 and P < 0.001, respectively). TBR-652 had minimal effect on hs-CRP, for which there were nonsignificant declines by day 10 (Fig. 2C). There were no changes in IL-6 levels at day 10 compared with baseline in any of the dose groups (data not shown).
TBR-652 was generally safe and well tolerated at the doses studied. The most commonly encountered treatment-emergent AEs for the subjects on active drug were gastrointestinal disorders (n = 19, 43%); general disorders (n = 11, 25%); nervous system disorders (n = 10, 23%); respiratory, thoracic, and mediastinal disorders (n = 10, 23%); infections and infestations (n = 7, 16%); and psychiatric disorders (n = 5, 11%). Most AEs in subjects on TBR-652 were mild (n = 24) or moderate (n = 5) in intensity. There was only 1 severe AE in a TBR-652-treated subject, an abscess on the shoulder, which was judged as nonserious and unrelated to study drug by the investigator, did not require treatment, and resolved without sequelae. There were no life-threatening AEs, no discontinuations because of an AE, and no deaths. No AEs were judged to be definitely related to study drug. AEs reported as possibly or probably related to study drug are listed in Table 3. Most AEs resolved without intervention. Only 4 subjects on TBR-652 required concomitant medication for an AE assessed as possibly related to study drug. These were hydrocodone plus paracetamol for abdominal pain in the 25-mg dose group, paracetamol for headache in the 50-mg dose group, ondansetron for nausea in the 100-mg dose group, and ibuprofen for a subject with headache and nausea in the 150-mg dose group. No AEs requiring treatment were considered probably related to study drug.
The only clinically notable laboratory events were a grade 3 hypophosphatemia in the 25-mg dose group that was present before dosing, a grade 4 elevated triglyceride in the 50-mg dose group in a patient who had a grade 3 triglyceride at baseline, and grades 3 and 4 amylase and lipase elevations, respectively, in a patient in the 25-mg dose group who had a history of pancreatitis (Table 3). All cases were asymptomatic except the last; this patient was diagnosed with grade 2 pancreatitis and was subsequently found to have a history of pancreatitis and alcohol consumption before initial dosing. There were no changes in vital signs, physical examinations, or ECGs at any doses that were deemed to be clinically relevant.
TBR-652 showed potent antiviral activity after 10 days of once-daily monotherapy. Nadir changes ranged from −0.7 to −1.8 log10 copies per milliliter and were greatest in the 50-, 75-, and 150-mg dose groups at −1.6, −1.8, and −1.7 log10 copies per milliliter, respectively. The fact that the median time to achieve nadir was 10-11 days indicates that a true nadir may not have been reached in the 10-day treatment. Nadir and day 11 HIV-1 RNA changes from baseline were significant at all dose levels. In addition, the antiviral effect persisted well into the posttreatment period, with HIV-1 RNA levels still significantly lower for all TBR-652 dose groups 5 days after the treatment was discontinued and significantly lower than baseline in the 150-mg dose group 2 weeks after treatment discontinuation. The numbers of subjects who achieved HIV-1 RNA reductions of at least 1 log10 copies per milliliter compare favorably with the 10-day treatment studies of maraviroc. Maraviroc doses of 50, 100, and 150 mg twice daily resulted in HIV-1 RNA declines of greater than 1 log10 copies per milliliter in 50%, 88%, and 88% of subjects at day 11, respectively,6 compared with 71%, 100%, and 75% of patients, respectively, on once-daily TBR-652. In addition, 33% of patients on 25 mg of TBR-652 also achieved a decline of at least 1 log10 copies per milliliter. The Css of TBR-652 associated with the 50% inhibitory concentration was 13.1 ng/mL, indicating that TBR-652 at doses of 50, 75, and 150 mg QD should provide strong antiviral activity in longer-duration studies.
AEs were reported in 34 subjects overall, 30 of whom were on TBR-652. Most AEs were mild, and there were no indications of a dose relationship through the 100-mg dose. The reported AEs and laboratory abnormalities did not show a dose-effect pattern. Given the generally mild AEs and the few laboratory abnormalities, no toxicity signal for TBR-652 could be found in this HIV-1-infected population, and there was no evidence of having reached a maximum-tolerated dose.
Exploratory assessments of MCP-1, hs-CRP, and IL-6 were undertaken because CCR2 antagonism with elevated MCP-1 was seen in binding studies of TBR-652 in Chinese hamster ovary cells.7 The roles of various biomarkers of inflammation, including hs-CRP and IL-6, in the inflammation processes mediated by CCR2 and its MCP-1 ligand have been investigated in the aging HIV-1-infected population, and much research is currently looking at the interrelationships of inflammation and aging with HIV infection and antiretroviral therapy.8-12 Elevations in these biomarkers have been associated with a number of inflammatory and aging-related diseases/conditions. This study found significant increases in MCP-1 at the 50- and 150-mg dose levels from 10 days of TBR-652 monotherapy; TBR-652 had little or no effect on the other measured immune parameters, including CD4+ cell counts, which was not unexpected given that this was a monotherapy trial of short duration in a generally healthy HIV-1-infected population that would be expected to have low levels of inflammation. Although the combination of CCR5 and CCR2 antagonism is unique among currently published studies for CCR5 antagonists in clinical development, there was no discernable adverse interaction of this combination receptor blockade. Both hs-CRP and IL-6 were significantly elevated in patients who died from non-AIDS causes in the Strategies for Management of Anti-Retroviral Therapy (SMART) study.9 The areas that would warrant observation in longer-duration controlled studies are potential changes in incidence of atherosclerosis,13-16 measures of weight gain and insulin resistance,17-19 rate of disease progression (especially if there are tropism shifts from CCR5 to CXCR4 virus during treatment),20 incidence of other infections,21-23 and incidence of neurologic changes in HIV-1-infected subjects.24,25 Observations of demographic effects, particularly gender and race, on aging and inflammation in HIV-positive patients also warrant study.26-28
Overall, this proof-of-concept study showed TBR-652 to be a potent, well-tolerated anti-HIV drug with potential for additional benefit through a CCR2-mediated anti-inflammatory effect. TBR-652 warrants further investigation as a potent, oral, unboosted, once-daily CCR5 receptor antagonist to be used in combination HIV-treatment regimens, especially in treatment-naive patients. Based on the biology of HIV infection, the treatment-naive population is the most appropriate one for treatment with a CCR5 antagonist because CCR5-tropic virus is more prevalent earlier in infection. The prevalence of CCR5-only virus tropism in one study was 88% of treatment-naive patients (n = 263) compared with 67% of treatment-experienced patients (n = 76).29 In the Multicenter AIDS Cohort Study (MACS), a large study of HIV natural history, 67 patients who had known HIV-1 seroconversion dates (±5 months) from before 1995 and regular study visits with blood samples that had been tested or were available for tropism testing were assessed for conversion from CCR5-tropic virus to CXCR4-tropic virus. Among these treatment-naive men, 97% had solely CCR5-tropic virus at their first visit.30 Thirty-three percent converted to dual/mixed virus, which was associated with more rapid disease progression, which included CD4+ cell counts <200 cells per cubic millimeter and AIDS-defining events. Because the prevalence of CXCR4-tropic virus increases in patient populations with more advanced disease and lower CD4+ cell counts, the utility of CCR5 antagonists in those populations becomes limited. Therefore, a larger, randomized, double-blind phase 2b study is being planned that will enroll treatment-naive patients.
Drug-drug interaction studies are underway to enable construction of a combination regimen (or regimens) with an appropriate TBR-652 dose. Given the similar efficacy of the 50 and 150 mg/d doses and the lack of any drug-related AE at the 75-mg dose, the phase 2b study will test 2 doses used in the study reported here and attempt to clarify the best dose for phase 3 study. Given the rapid reductions in HIV-1 RNA in this study, the next study will also include a positive control. In addition, the effect of CCR2 antagonism on hs-CRP, IL-6, and other biomarkers of inflammation will be further investigated, with the hopes of clarifying their usefulness in predicting inflammatory processes and reducing the risk of inflammatory disease with TBR-652 therapy. Changes in CD4+ cell counts, viral tropism, and viral resistance over time will also be assessed in the new study. It is anticipated that TBR-652 will prove a good candidate for coformulation with other once-daily antiretroviral agents, given the once-daily, low-milligram dose profile and good tolerability of TBR-652 thus far.
The authors thank the subjects and clinical study personnel for their contributions to this study; Richard Elion, MD, Whitman Walker Clinic, and Peter Ruane, MD, Light Source Medical Group, for their participation; James Saperstein, RPh, Tobira Therapeutics, for trial support and TBR-652 program development; Reynold Driz for directing clinical operations; Richard Ogden, PhD, for TBR-652 program support; study team members from ICON Clinical Research, Pharsight, KCAS, Monogram Biosciences, and eResearch Technologies; Robert Grosso, Advanced Clinical Perspectives, for program support; and Sally Snyder for assistance with manuscript preparation.
1. Deshmane SL, Kremiev S, Amini S, et al. Monocyte chemoattractant protein 1 (MCP-1): an overview. J Interferon Cytokine Res
2. Palleja S, Driz R, Wang-Smith L, et al. Pharmacokinetics (PK), safety, and tolerability of single doses of the chemokine C-C receptor 5 (CCR5) antagonist TBR-652
in healthy volunteers. Poster presented at: 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Poster WEPEB251.
3. Palleja S, Wang-Smith L, Ogden R, et al. TBR-652
, a chemokine receptor 5 (CCR5) antagonist, demonstrates good oral bioavailability and desirable pharmacokinetic (PK) and safety profiles in healthy volunteers. Poster presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-19, 2009; San Francisco, CA. Poster 925.
4. Martin D, Palleja S, Pheng L, et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652
, a chemokine receptor 5 (CCR5) antagonist, in HIV-1-infected, antiretroviral (ARV) treatment-experienced, CCR5 antagonist naive patients. Presented at: 17th Conference on Retrovireuses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Poster 598.
5. Palleja S, Cohen C, Gathe J, et al. Safety and efficacy of TBR-652
, a chemokine receptor 5 (CCR5) antagonist, in HIV-1-infected, antiretroviral (ARV) treatment-experienced, CCR5 antagonist-naïve patients. Orally presented at: 17th CROI; February 16-19, 2010; San Francisco, CA. Abstract K-111.
6. Fätkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med
7. Baba M, Takashima K, Miyake H, et al. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob Agents Chemother
8. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol
9. Kuller LH, Tracy R, Belloso W, et al. for the INSIGHT SMART Study Group. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med
10. Neuhaus J, Jacobs DR, Baker JV, et al; for the INSIGHT SMART, MESA, and CARDIA Research Groups. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis
12. Onen NF, Overton ET, Seyfried W, et al. Aging and HIV infection: a comparison between older HIV-infected persons and the general population. HIV Clin Trials
13. Medina S. Wessman D, Krause D, et al. Coronary aging in HIV-infected patients [letter]. Clin Infect Dis
14. Guaraldi G, Zona S, Alexopoulos N, et al. Coronary aging in HIV-infected patients. Clin Infect Dis
15. Ross AC, Rizk N, O'Riordan MA, et al. Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy
. Clin Infect Dis
16. Papadopoulou C, Corrigall V, Taylor R, et al. The role of the chemokines MCP-1, GRO-alpha, IL-8 and their receptors
in the adhesion of monocytic cells to human atherosclerotic plaques. Cytokine
17. Caron-Debarle M, Boccara F, Lagathu C, et al. Adipose tissue as a target of HIV-1 antiretroviral drugs. Potential consequences on metabolic regulations. Curr Pharm Des
18. Kamei N, Tobe K, Suzuki R, et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem
19. Tamura Y, Sugimoto M, Murayama T, et al. C-C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice. J Atheroscler Thromb
20. Campbell GR, Spector SA. CCL2 increases X4-tropic HIV-1 entry into resting CD4+
T cells. J Biol Chem
22. Zhao Q. Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular diseases. J Leuk Biol
23. Serbina NV, Jia T, Hohl TM, et al. Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol
24. Vivithanaporn P, Heo G, Gamble J, et al. Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study. Neurology
25. Sozzani S, Introna M, Bernasconi et al. MCP-1 and CCR2 in HIV infection: regulation of antagonist and receptor expression. J Leukoc Biol
. 1997; 62:30-33.
27. Wojna V, De La Torre T, Mayo R, et al. Increased depression and neurocognitive dysfunction in aging HIV-seropositive women despite high CD4 cell counts. Rev Antivir Ther Infect Dis
28. Sok P, Sean BR, Sandra G, et al. Determinants of health and clinical conditions on health outcomes in older adults with HIV/AIDS: the Ontario Positive Places, Healthy Spaces Study. Rev Antivir Ther Infect Dis
29. Demarest J, Bonny T, Vavro C, et al. HIV-1
Co-receptor Tropism in Treatment-Naive and Experienced Subjects. In: Proceedings of the 44th ICAAC, Washington, DC, Oct 30 to Nov 2, 2004
30. Shepherd JC, Jacobson LP, Qiao W, et al. Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the Multicenter AIDS Cohort Study. J Infect Dis