Abstract
HIV
Positive Impact of Universal ART Policy on Viral Suppression
The trend in HIV disease management is to initiate antiretroviral therapy (ART) at higher CD4 cell thresholds to limit HIV-related morbidity. “Universal ART” describes a strategy in which ART is begun in all HIV-infected persons. A study of the effects of universal ART on real-world patient outcomes was undertaken at a publicly funded clinic in San Francisco. Rates of viral suppression were compared for patients who entered the clinic with CD4 cell counts >500 cells/μL before and after the practice of universal ART was initiated. Of the 534 patients who entered the clinic, the 1-year incidence of viral suppression ranged from 9.1% to 14.1% before the universal ART approach was put in place, then rose to 52.8% afterward. The universal ART policy was associated with a sixfold increase in HIV RNA suppression 6 months after clinic entry. The authors of the study concluded that this finding “may foreshadow national trends given the March 2012 revision of national treatment guidelines to favor ART initiation for persons with CD4 cell counts of >500 cells/μL.
Source: Geng EH, Hare CB, Kahn JO, et al. The effect of a “universal antiretroviral therapy” recommendation on HIV RNA levels among HIV-infected patients entering care with a CD4 count >500/μL in a public health setting. Clin Infect Dis 2012;55:1690–1697.
Proof of Concept for a Therapeutic HIV Vaccine
Individualized therapeutic vaccines intended to induce an HIV-1-specific immune response were derived from autologous monocyte-derived dendritic cells (MD-DCs) pulsed with autologous heat-inactivated whole HIV. HIV-infected patients with CD4+ counts >450 cells/mm3 on combination antiretroviral therapy (cART) received three immunizations with either the pulsed MD-DCs or with non-pulsed MD-DCs, and their viral loads were assessed after 12 and 24 weeks of cART interruption. Vaccination was safe and well tolerated, and was associated with a decrease in the plasma viral load setpoint >1 log in 55% vs. 9% of the pulsed MD-DC versus non-pulsed MD-DC vaccine recipients at 12 weeks, and in 35% vs. 0% of the “treatment” versus “control” groups, respectively, at 24 weeks. “These data suggest that HIV-1-specific immune responses elicited by therapeutic DC vaccines could significantly change plasma viral load setpoint after cART interruption in chronic HIV-1-infected patients treated in early stages,” state the authors of the study, providing proof of concept for the ultimate objective of identifying a functional cure for HIV that could replace the current strategy of “cART for life.”
Source: Garcia F, Climent N, Guardo AC, et al. A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication. Sci Transl Med 2013;5:166ra2.
Cognitive Impairment Worse with HIV/HCV Coinfection
When administered a panel of neuropsychological (NP) tests, individuals coinfected with HIV (with controlled viral loads on antiretroviral therapy) and hepatitis C virus (HCV) scored higher for depression than non-infected control populations and had a significantly higher global deficit score (GDS) than HCV or HIV monoinfected subjects or controls. The GDS is a composite score representative of multiple domains of NP tests, including depression, attention, executive function, information processing, fine motor speed, and verbal/visual learning/memory. Specifically, HIV/HCV coinfection was linked to poorer performance on tests designed to evaluate attention working memory, executive function, fine motor function, verbal learning/memory, and visual learning/memory compared to uninfected control subjects. In HCV monoinfection, increasing viral load correlated with worsening GDS and, in particular, reduced attention, executive function, and information processing speed.
Source: Sun B, Abadjian L, REmpel H, et al. Differential cognitive impairment in HCV coinfected men with controlled HIV compared to HCV monoinfection. J Acq Immune Def Synd 2013;62:190–196.
Antidiarrheal Drug Approved for HIV/AIDS Patients
The U.S. Food and Drug Administration approved crofelemer (Fulyzaq™), an oral, delayed-release medication to relieve the symptoms of non-infectious diarrhea in adults with HIV/AIDS who are on antiretroviral therapy. Dosing is one 125-mg tablet twice a day. The most commonly reported adverse reactions are upper respiratory tract infection, bronchitis, cough, flatulence, and increased bilirubin.
Source: U.S. Food and Drug Administration.
High-Dose Flu Vaccine Boosts Seroprotection
HIV-infected persons may need immunization with a high-dose influenza vaccine rather than the standard trivalent vaccine to achieve adequate levels of influenza seroprotection due to their compromised immune status and inability to mount robust antibody responses to immunization. A randomized, double-blind, controlled trial of HIV-infected adults randomly assigned to receive either a standard dose (15 mcg antigen/strain) or high dose (60 mcg/strain) of influenza trivalent vaccine demonstrated that seroprotection rates (defined as 1:40 or greater on the hemagglutination inhibition assay) 21–28 days after vaccination were higher among the group that received the high-dose vaccine. The study did not evaluate the effectiveness of immunization in preventing clinical disease.
Source: McKittrick N, Frank I, Jacobson JM, et al. Improved immunogenicity with high-dose seasonal influenza vaccine in HIV-infected persons: A single-center, parallel, randomized trial. Ann Intern Med 2013;158:19–26.
Tenofovir-Related Proteinuria Is Reversible
Ongoing exposure to tenofovir and some protease inhibitors has been associated with proteinuria, reductions in the glomerular filtration rate, and the development of chronic and serious kidney disease. Periodic proteinuria screening for patients on an antiretroviral regimen that includes tenofovir is advisable to detect early and significant changes in the urine protein creatinine ratio (UPCR). In the absence of urinary tract infection, a UPCR >15 g/mol is indicative of proteinuria. In a study of 153 patients taking tenofovir for >1 year, all of whom had achieved viral suppression (viral load <40 copies/mL), 42 (27%) had proteinuria (mean UPCR 38 g/mol). Both longer duration of tenofovir use and concomitant protease inhibitor therapy were significantly associated with proteinuria, whereas patient age, sex, CD4 count, or treatment status at the time of initiation of tenofovir were not predictive of proteinuria. Among the patients with proteinuria, 12 of those with higher mean UPCR levels (64 vs. 28 g/mol) switched from tenofovir to an alternative nucleoside reverse transcriptase inhibitor. Over the subsequent 6 months, proteinuria decreased significantly in 11 of these 12 patients, to a mean of 14 g/mol, whereas the UPCR did not change significantly during that time among the 30 patients with proteinuria who continued taking tenofovir. The study authors speculated that “proteinuria may be an early and reversible effect of tenofovir-associated renal damage.”
Source: Kelly MD, Gibson A, Bartlett H, et al. Tenofovir-associated proteinuria. AIDS [Research Letters] 2013;27:479–485.
Assessing Standard-of-Care for AIDS-Related Lymphoma
A retrospective evaluation of treatment outcomes in patients with relapsed/refractory AIDS-related lymphoma (ARL) who underwent second-line chemotherapy with curative intent and, in some cases, autologous stem cell transplantation (ASCT) found that likelihood of a response to treatment was greater among patients with Hodgkin lymphoma than with non-Hodgkin lymphoma, and among those with relapsed rather than primary refractory disease. Furthermore, overall survival was significantly longer for patients with relapsed versus refractory disease, and for those with non-Burkitt non-Hodgkin lymphoma compared to Burkitt non-Hodgkin lymphoma. One-year survival was greater for patients who had a stem cell transplant (63.2%) versus those who did not undergo ASCT (37.2%). All of the patients included in the study were treated between 1999–2008 at sites that were part of the national AIDS Malignancy Consortium. “Long-term survival in some patients with rel/rfr ARL may be possible without transplant, although transplant remains the standard of care for chemotherapy sensitive disease,” stated the authors of the study.
Source: Bayraktar UD, Ramos JC, Petrich A, et al. Outcome of patients with relapsed/refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999–2008 and treated with curative intent in the AIDS Malignancy Consortium. Leukemia & Lymphoma 2012;53:2382–2389.
Probiotic/Prebiotic Supplementation to Improve GI Immunity
HIV infection causes damage to the gastrointestinal (GI) tract and immune activation that is only somewhat improved through antiretroviral (ARV)-mediated control of viral load. To assess the effects of probiotic/prebiotic (PP) supplementation on GI tract physiology and immune activation, a group of researchers treated SIV-infected pigtail macaques with PP therapy alone, ARV+ PP, or ARV alone; ARV achieved suppression of plasma viremia to <50 copies/mL in nearly all of the animals studied. The results indicated that genes typically expressed by antigen-presenting cells (APCs) in the GI tract were upregulated in the ARV+ PP treatment group, and that APCs were present at a significantly higher frequency in the PP-treated animals. In addition to the increased frequency and functionality of GI tract APCs with PP treatment, the researchers found enhanced reconstitution and functionality of CD4+ T cells. They reported decreased immune activation of colonic CD4+ T cells in PP-treated macaques compared to ARV-only animals, as well as a trend toward reduced plasma levels of D-dimers among PP-treated animals, which are biomarkers of inflammation associated with the clotting cascade and cardiovascular disease in ARV-treated HIV-infected patients. Furthermore, evaluation of fibrosis in lymphoid follicles revealed significantly less fibrosis in ARV+PP animals than in ARV-only animals. Based on the finding of a negative correlation between colonic fibrosis and the frequency of colonic CD4+ T cells, the study authors proposed the resolution of fibrosis in the GI tract as a potential mechanism underlying the increased frequency of CD4+ T cells in the colon of PP-treated animals.
Source: Klatt NR, Canary LA, Sun X, et al. Probiotic/prebiotic supplementation of antiretrovirals improves gatrointestinal immunity in SIV-infected macaques. J Clin Invest 2013;123:903–907.
HCV
Pivotal Interferon-Free HCV Trial
Enrollment has begun in a Phase 3 clinical trial program of HCVerso™, an interferon-free hepatitis C virus (HCV) regimen that combines the Boehringer Ingelheim Pharmaceuticals compounds faldaprevir, a once-daily protease inhibitor, BI 207127, a twice-daily non-nucleoside polymerase inhibitor, and ribavirin. The program includes two Phase 3 trials comprising about 1,000 treatment-naïve HCV genotype-1b patients, including patients who are interferon eligible or ineligible. In the first trial, patients will be randomized to one of three treatment groups: two groups (one with and one without compensated liver cirrhosis) will receive 24 weeks of BI 207127 (600 mg BID)+faldaprevir (120 QD)+ribavirin; the third group will receive 16 weeks of BI 207127 (600 mg BID)+faldaprevir (120 mg QD)+ribavirin, followed by 8 weeks of placebo. The second trial will be similar in design, except the group receiving 16 weeks of antiviral medication will be administered 8 weeks of placebo at the start of the 24-week treatment period.
Source: Boehringer Ingelheim press release: Boehringer Ingelheim enrolls first patients in pivotal phase 3 interferon-free hepatitis C trial program. January 17, 2013.
Trial Results of Oral Combination Therapy
A Phase 2a open-label study of patients with HCV genotype 1 infection without cirrhosis evaluated the effectiveness of an interferon-free, oral combination antiviral regimen, with a primary endpoint of undetectable HCV RNA from week 4–12, defined as an extended rapid virologic response. All of the patients received one of two daily doses of the Abbott drug ABT-450, an HCV NS3 protease inhibitor, combined with low-dose ritonavir, the non-nucleoside NS5B polymerase inhibitor ABT-333 (400 mg 2x/day), and ribavirin (1,000–1,200 mg/day). Patient Groups 1 and 2 were treatment naive. Group 1 received 250 mg ABT-450 and 100 mg ritonavir; Group 2 received 150 and 100 mg, respectively. Group 3 included patients with a null or partial response to previous therapy with peg-interferon and ribavirin; they received 150 mg/day ABT-450 and 100 mg ritonavir. An extended rapid virologic response was achieved by 89% (17/19) of Group 1 and 79% (11/14) of Group 2, and a sustained virologic response 12 weeks after the end of the initial 12-week treatment period was achieved in 95% and 93% of the patients in Group 1 and 2, respectively. Among Group 3 patients, 59% (10/17) had an extended rapid virologic response and 47% (8/17) had a sustained virologic response. The most common adverse events were liver-function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting.
Source: Poordad F, Lawitz E, Kowdley KV, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med 2013;368:45–53.