Abstract
HIV
Positive Results with Autologous Transplant of ZFN-Modified CD4 T-Cells: A Step Toward a Practical, Functional Cure for HIV
A genetic engineering approach designed to disrupt expression of the CCR5 gene in CD4+ T-cells to inhibit HIV entry yielded promising preliminary findings in a phase 1 study. DaleAndo and colleagues from Sangamo BioSciences (Richmond, CA), University of Pennsylvania (Philadelphia. PA), and Albert Einstein College of Medicine (Bronx, NY), presented data at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17–20, in Chicago, Illinois, to support the therapeutic potential of CCR5 modification.
This therapeutic strategy is based on previous evidence that an HIV-infected patient (the so-called “Berlin patient”) who received a hematopoietic stem cell transplant from a donor who was homozygous for a CCR5 mutation that yields a nonfunctional CCR5 receptor protein (required by HIV to gain access to CD4 cells) has survived HIV-free without the need for antiretroviral therapy for 3.5 years. The researchers used zinc finger nuclease technology to alter the CCR5 gene in subjects CD4 T-cells and then returned the cells to the patients via autologous transplantation. The six HIV-infected subjects were aviremic on highly active antiretroviral therapy (HAART) and had CD4 T-cell levels greater than 450 cells/mm3. Four weeks after a single infusion of 10 billion cells the patients began a 12-week interruption of HAART. The data presented at the conference indicate a durable increase in total CD4 T-cells associated with normalization of the CD4:CD8 ratio, and the ability of the modified cells to engraft, expand, and persist in the circulation for longer than a year. The treatment was also shown to be safe and well-tolerated.
During the period of HAART interruption, 3 of 6 subjects had 0.8 to more than 2-log reductions from their peak viral loads, and HIV-RNA became undetectable in one subject. The researchers conclude that “ZFN-mediated gene-disruption of CCR5 provides a feasible approach to HIV therapy and offers the hope of controlling HIV-infection without the need for antiretroviral medications.”
Source: Aldo D, et al. HAART treatment interruption following adoptive transfer of zinc finger nuclease (ZFN) CCR5 modified autologous CD4 T-cells (SB-728-T) to HIV-infected subjects demonstrates durable engraftment and suppression of viral load. Presented at Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 18, 2011.
Autologous CCR5-Modified CD4 T-Cells Effective in HAART Nonresponders
Another presentation at ICAAC described the use of zinc finger nuclease (ZFN) technology to introduce a mutation into the CCR5 gene in patients' CD4 T-cells, with subsequent autologous cell infusion back into the aviremic HIV-infected subjects, all of whom had CD4 counts less than 500 cells/mm3 on HAART. As in the study described above, the treatment evaluated in this phase 1 trial was shown to be safe and well-tolerated with only minor, reversible infusion-related symptoms, according to the research team from UCLA (Los Angeles, CA), Quest Clinical Research and UCSF (San Francisco, CA), and Sangamo BioSciences (Richmond, CA).
The data demonstrate increases in CD4 T-cells associated with normalization of the CD4:CD8 ratio, presence of an expanded population of CCR5 modified CD4 cells in the circulation more than 1 year after treatment, and engrafting and persistence of the transplanted CD4 cell line in rectal mucosa. A 1-log decrease in HIV-RNA observed in one subject who stopped HAART 1 year after the infusion could be evidence of an antiviral effect of the treatment. The researchers described their goal moving forward as maximizing the biallelic CCR5 modification of patients' CD4 T-cells.
Source: Mitsuyasu R, et al. Adoptive transfer of zinc finger nuclease CCR5 modified autologous CD4 T-cells (SB-728-T) to aviremic HIV-infected subjects with suboptimal CD4 counts (200–500 cells/mm3). Presented at Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 18, 2011.
New Model Proposed for Continuing HIV Replication with ART
Adding to existing hypotheses to explain how HIV avoids elimination by ART—which include the presence of resistant viral reservoirs and latent virus— Baltimore and colleagues have proposed a new model in which multiply infected cells have reduced sensitivity to ART drugs and are capable of cell-to-cell spread of HIV.
“Multiple infections of one cell may propagate at drug concentrations where infection by single particles would die out,” state the researchers. They provide experimental validation of their model through the creation of multiply infected cells by exposing a highly infection-permissive T-cell line to fluorescently labeled cell-free HIV in the presence of the drug tenofovir, a nucleotide reverse transcriptase inhibitor. At high levels of fluorescence, indicating multiple infections in a single cell, the infection was insensitive to low and intermediate concentrations of tenofovir.
Source: Sigal A, et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy [letter]. Nature 2011;477:95–98.
Effects of ART on Lipid Levels in Children
HIV-infected children on ART should be monitored for the drugs' effects on blood lipid levels, and counseled on dietary and exercise strategies, and, if needed, on pharmacotherapy to control persistent hyperlipidemia. In a study of 449 HIV-positive children, with a median follow-up of 4.5 years, ART-naïve children had normal lipid levels on average, with the exception of low high-density lipoprotein (HDL). In contrast, children on ART tended to have increased cholesterol levels, including low-density lipoprotein (LDL) and, in most cases, HDL. Protease inhibitors were associated with the greatest increases in total cholesterol and non-HDL levels. Non-nucleoside reverse transcriptase inhibitors also raised non-HDL levels, but were associated as well with clinically significant increases in HDL.
Source: Rhoads MP, et al. Effect of specific ART drugs on lipid changes and the need for lipid management in children with HIV. J Acquir Immune Defic Syndr 2011;57:404–412.
Cost-Effectiveness of Acute HIV Testing Strategies
Approximately 538,000 new infections will occur among men who have sex with men (MSM) over the next 20 years, estimate the authors of a study designed to assess the cost-effectiveness of various testing strategies to detect acute HIV infection in symptomatic MSM in the United States. The most effective method involved HIV viral load testing in MSM who present with symptoms of an influenza-like illness, however, it is a more expensive approach than expanded antibody screening (beyond annual intervals) and would cost $22,786 per quality-adjusted life years (QALY) gained. Expanding antibody screening coverage to 90% of MSM annually would reduce new infections by 2.8% and cost $12,582 per QALY gained. A combination of expanded antibody screening and symptom-based viral load testing would prevent twice as many infections compared to expanded antibody screening alone, but the cost would increase to $29,923 per QALY gained.
Source: Juusola JL, et al. The cost-effectiveness of symptom-based testing and routine screening for acute HIV infection in men who have sex with men in the USA. AIDS 2011;25:1779–1787.
Characteristics of MSM Unaware of HIV-Positive Status
Black MSM who were unaware of their HIV-positive status tended to identify themselves as gay, to have health insurance and be of moderately higher income, and to have a high perceived risk of being HIV-positive, according to a study in black and Latino MSM participated in an interview and underwent HIV testing. Importantly, among the black MSM who participated in the study, being HIV-positive unaware (18% of 1208 men) was associated with having disclosed to a current health care provider their sexuality, highlighting what the study authors describe as “missed opportunities” to diagnose HIV infection.
Furthermore, both the black and Latino HIV-unaware groups expressed the misperception that intraracial sex—black men with black men or Latino with Latino—reduces the risk of HIV transmission. Among the Latino MSM, being HIV-positive unaware (5% of the total study group) was associated with a non-gay identify and a high perceived risk of current HIV-positive status.
Source: Millett G, et al. Mistaken assumptions and missed opportunities: Correlates of undiagnosed HIV infection among black and Latino men who have sex with men. J Acuir Immune Defic Syndr 2011;58:64–71.
Factors Associated with History of HIV Testing
Nearly three quarters of high-risk, sexually active adolescents surveyed in 15 U.S. cities reported having been tested for HIV, and 89% of those tested were aware of their test results. Most of the HIV testing was performed at sites offering sexually transmitted disease (STD) testing services rather than in primary care settings.
In this study aimed at identifying factors associated with a history of HIV testing and knowledge of the results among urban youths, high risk for HIV infection was predictive of testing in general, with the exception of some partner-related factors. These factors included sex with a partner of unknown HIV status or with a partner that insisted on sex without a condom.
Source: Straub DM, et al. Correlates of HIV testing history among urban youth recruited through venue-based testing in 15 U.S. cities. Sex Trans Dis 2011;38:691–696.
Human Papilloma Virus Infection
HPV Vaccine Protects Against Anal Cancer
An adjuvanted bivalent HPV 16/18 vaccine (Cervarix, GlaxoSmithKline, Research Triangle Park, NC) evaluated in more than 4200 women provided good protection against anal HPV infection, especially among HPV-naïve women. Although anal cancer is relatively rare—affecting about 1.5 per 100,000 women annually—its incidence is increasing in some parts of the world. The fact that most cases are caused by infection with HPV 16 or 18 makes it a promising target for immunization using vaccines developed to prevent cervical HPV infection.
In the current study, young women received either the HPV vaccine or a control hepatitis A vaccine in three 0.5-mL doses: one at enrollment, one at 1 month, and one at 6 months. Four years after vaccination, the women provided anal specimens for evaluation of vaccine efficacy. Among all of the women tested, vaccine efficacy against HPV 16/18 was lower for anal infection (62.0%) compared to cervical infection (76.4%). For the cohort of women who were negative for cervical HPV16 and 18 DNA and seronegative for HPV 16 and 18 at enrollment, vaccine efficacy against anal infection was 83.6%, comparable to the 87.9% vaccine efficacy against cervical HPV 16/18.
Source: Kreimer AR, et al. Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: A nested analysis within the Costa Rica Vaccine Trial. Lancet Oncol 2011;12:862–870.
Repeat HPV Testing Increases Specificity of Cervical Cancer Screening
Compared to pap smear cytology, testing for high-risk HPV offers greater sensitivity but has reduced specificity. One effective strategy for improving the specificity of HPV testing in primary screening for cervical cancer is to perform repeat HPV testing within a short timeframe. In a study of 8000 women offered self-sampling of vaginal fluid at home, with the samples then sent for HPV analysis and typing, as a first step in cervical cancer screening, 39% selected to participate in self-sampling. If the initial sample yielded a positive test result, the women were offered a follow-up HPV test and cervical biopsy. Among the women positive for HPV on self-sampling, 89% had a follow-up examination, and 59% of this group had a positive HPV test result. HPV-related cervical lesions were found in 23% of women with an initial HPV-positive test and in 41% of women with two consecutive HPV-positive tests. The researchers concluded that short-time HPV testing increased the specificity for detection of HPV-associated cervical lesions from about 94% to nearly 98%.
Source: Gyllensten U, et al. Short-time repeat high-risk HPV testing by self-sampling for screening of cervical cancer. Br J Cancer 2011;105:694–697.