Abstract
Co-Evolution of HIV and a Broadly Neutralizing Antibody
Within an HIV-infected individual, the founder virus and strain-specific neutralizing antibodies induced in early infection may co-evolve, resulting in a mature, cross-reactive antibody capable of neutralizing a broad range of HIV isolates. Understanding this natural process of co-evolution could inform effective vaccine development efforts. Liao et al. described the evolution and structure of a broadly neutralizing antibody from an African donor who was followed from the time of infection with HIV-1. The mature antibody was able to neutralize about 55% of HIV-1 isolates. A co-crystal structure of the antibody bound to the viral envelope protein gp120 led to the identification of a novel, loop-based mechanism of CD4-binding site recognition. The researchers determined the virus and antibody gene sequences over time and showed that an early ancestor of the mature antibody bound the founder HIV-1 gp120 protein with high affinity, and that changes in the virus in and near the binding domain preceded the evolution of antibody neutralization breadth.
Source: Liao, H-C, Lynch R, Zhou R, et al. Co-evolution of a broadly neutralizing HIV-1 antibody and dounder virus. Nature 2013; doi:10.1038/nature12053.
HIV Self-Testing Is Acceptable, Feasible, and Preferred
An estimated 60% of individuals infected with HIV are unaware of their serostatus because they have not had an HIV test. The availability of oral, fluid-based, in-home HIV self-testing has the potential to increase testing rates among persons who avoid facility-based testing, for reasons that may include concerns about stigma, discrimination, lack of privacy, and long waiting times. A systematic review of seven databases and abstracts from six conferences focused on the acceptability and feasibility of HIV self-testing, and evaluated post-test linkage to counseling and treatment in the setting of a positive result. Two different self-test strategies were assessed: supervised, in which a health care professional provided counseling; and unsupervised, in which the self-test had access to phone/Internet counseling. Acceptability (range 74–96%), preference (61–91%), and partner self-testing (80–97%) were all high for both strategies. Specificity was high (99.8–100%) for both strategies; sensitivity was lower in the unsupervised (92.9–100%) vs. supervised (97.4–97.9%) approach. Data on feasibility of linkage to counseling were available for one study involving an unsupervised self-testing strategy, and 96% of individuals testing positive for HIV said they would seek post-test counseling. The results indicate that both the supervised and unsupervised self-testing strategies are feasible; however, “systems that can maintain confidentiality and operationalize linkage to care within a reasonable time frame are pertinent to its success.”
Source: Pai NP, Sharma J, Shivkumkar S, et al. Supervised and unsupervised self-testing for HIV in high- and low-risk populations: A systematic review. PLoS Med 2013; doi:10.1371/journal.pmed.1001414.
ART in Controllers
Viral replication may be a cause of the low-level viremia, elevated T-cell activation, and increased atherosclerosis seen in “controllers”—asymptomatic HIV-infected individuals able to maintain low levels of plasma RNA without ART. A prospective study designed to evaluate the effects of ART in controllers included 16 subjects with a median duration of HIV infection of 10 years. ART consisted of raltegravi plus tenofovir/emtricitabine for 24 weeks. The controllers had low pre-ART plasma RNA levels, as measured with conventional assays, but even so, ultrasensitive assays showed a significant decrease in plasma RNA levels after initiation of ART. Non-significant post-ART findings included reductions in cell-associated RNA, proviral DNA in blood, and proviral RNA/DNA in gut-associated lymphoid tissue (GALT). ART was associated with a statistically significant decrease in markers of T-cell activation/dysfunction in blood and GALT, and in HIV antibody levels. Also reported were reductions in markers of immune activation. The findings confirm that “HIV replication persists in controllers and contributes to a chronic inflammatory state. Antiretroviral therapy should be considered for these individuals.”
Source: Hatano H, Yuki S, Ferre A, et al. Prospective ART of asymptomatic HIV+ controllers. Presented at the 20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013.
Safety of Low-Glycerin Tenofovir Gel
The MTN-007 study was designed to evaluate the overall and mucosal safety of a reduced-glycerin formulation of rectal tenofovir 1% gel, as well as its acceptability and patient adherence. The glycerin concentration of the rectal tenofovir gel used in the MTN-007 study was 5% w/w mg, compared to 20% w/w for the tenofovir formulation used in the previous RMP-02/MTN-006 Phase 1 rectal study that was associated with mild to moderate gastrointestinal symptoms. In the MTN-007 study, participants were randomly assigned to one of four treatment groups: the reduced-glycerin tenofovir 1% gel, a hydroxyethyl cellulose placebo gel, a 2% nonoxynol-9 gel, or no treatment. Eight single daily doses were administered to each participant. There were no significant differences between the treatment groups in the rate of adverse events of Grade 2 or higher. Acceptability, as measured by likelihood of future product use, was 93% for the placebo gel, 87% for the tenofovir gel, and 63% for the nonoxynol-9 gel. Measures of mucosal safety including fecal calprotectin, rectal microflora, and epithelial sloughing were similar between the treatment groups, whereas nonsignificant differences were reported in histology, mucosal gene expression, protein expression, and T-cell phenotype, mainly related to nonoxynol-9 gel. The study authors concluded that “This safety profile together with evidence from the RMP-02/MTN-006 study showing that rectal use of TFV is associated with ex vivo/in vitro inhibition of HIV-1 viral replication provides a compelling rationale for progression of this product into Phase 2 development.”
Source: Mcgowan I, Hoesley C, Cranston RD, et al. A Phase 1 randomized, double blind, placebo controlled rectal safety and acceptability study of tenofovir 1% gel (MTN-007). PLoS One 2013: doi: 10.1371/journal.pone.0060147.
Pro-/Prebiotic Supplementation Improves GI Immunity
HIV infection causes damage to the gastrointestinal tract over time. Even with antiretroviral therapy and suppression of viremia, the epithelial barrier of the GI tract is often compromised, resulting in microbial translocation and immune activation. These effects are associated with inflammation and cardiovascular disease, which contribute to the increased morbidity and mortality seen in ARV-treated HIV-infected individuals. To assess the potential for symbiotic supplementation of ARV to improve GI immunity in the setting of HIV infection, Klatt et al. treated chronically SIV-infected pigtail macaques with probiotics/prebiotics (PP) for 60 days. To control viral replication, the animals also received ARV treatment over a 5-month period. Some animals received only ARV therapy. The PP treatment did not affect plasma viral load or CD4+ T cell counts in blood or the GI tract. No substantial changes in the fecal microbiome were evident either due to SIV infection or PP treatment. The symbiotic treatment was associated with an increase in the frequency and function of antigen-presenting cells (APCs) In the GI tract, enhanced reconstitution and functionality of CD4+ T cells in the GI tract, and decreased fibrosis of lymphoid follicles in the colon, suggesting that PP supplementation can improve GI tract immunity and limit the inflammatory effects of SIV infection in macaques.
Source: Klatt NR, Canary LA, Sun X, et al. Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques. J Clin Invest 2013;123:903–907.
New Trend in MSM HIV Epidemic
During the last 7 years, among men who have sex with men in San Francisco, where this group has historically comprised about 90% of the HIV epidemic, data from behavioral surveillance systems indicate a trend toward stable HIV prevalence. Contributing to this trend is increasing ART coverage resulting in improved survival, combined with decreasing HIV incidence due to ART-related viral load suppression that has been sufficient to offset ongoing sexual risk behavior. The authors describe this phenomenon as “treatment as prevention.”
Source: Raymond HF, Chen Y-H, Ick T, et al. A new trend in the HIV epidemic among men who have sex with men, San Francisco, 2004–2011. J Acquir Immune Defic Syndr 2013;62:584–589.
Promising Trends in ART Initiation and Viral Suppression in North America
Based on data gathered from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) for nearly 10,700 HIV-infected individuals, a significant trend toward increasing initiation of ART within 6 months of eligibility was documented for the period 2001–2009, rising from 51% to 72%. Other significant trends included a rise in the cumulative incidence of 1-year virologic suppression, from 55% to 81%, and from 84% to 93% among individuals in whom ART was initiated. Continuing psychosocial barriers to ART initiation included non-injection drug abuse, alcohol abuse, and mental illness.
Source: Hanna DB, Buchacz K, Gebo KA, et al. Trends and disparities in antiretroviral therapy initiation and virologic suppression among newly treatment-eligible HIV-infected individuals in North America, 2001–2009. Clin Infect Dis 2013;56:1174–1182.
Pre-ART Risk of Non-AIDS–Related Illnesses
Non-AIDS–defining illnesses pose a risk to HIV-infected patients on combination antiretroviral therapy and have been associated with low CD4 T-cell counts and increased HIV RNA levels. A team of researchers affiliated with the ATHENA national observational HIV cohort investigated the risk these illnesses pose to HIV-infected individuals not yet on cART, including more than 13,000 members of the cohort in their analysis. Based on more than 18,600 person-years of follow-up, 1.6% of the patients included in the study had one or more non-AIDS events, including cardiovascular disease, liver fibrosis/cirrhosis, and non-AIDS malignancies. The researchers found that among HIV-infected individuals not yet receiving cART, “a more severe degree of immunodeficiency rather than HIV RNA appears to be associated with an overall risk of our composite non-AIDS event endpoint.”
Source: van Sighem A, Kesselring A, Gras L, et al. Risk of non-AIDS defining events amongst HIV-infected patients not yet on antiretroviral therapy. Presented at 20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013.
Hepatitis C Virus
Vitamin A Deficiency Associated with Chronic HCV Infection
Measurement of vitamin A and vitamin D levels in treatment-naïve patients with chronic hepatitis C virus infection revealed that median serum vitamin A in the HCV-positive patients was significantly lower than in a healthy control population (256 vs. 742 ng/mL). Based on evidence indicating that vitamin A affects the expression of type I interferon receptor and enhances the ability of interferon-alpha to inhibit the replication of HCV, Bitetto et al. evaluated whether vitamin A deficiency might have a role in unresponsiveness to interferon-based anti-HCV therapy. With such therapy, sustained viral response was achieved in 122/199 patients. One of the factors predictive of nonresponse to antiviral therapy was baseline serum levels of vitamin A ≤100 ng/mL. Furthermore, combined vitamin A and vitamin D deficiency—≤100 and ≤20 ng/mL, respectively—was a strong independent predictor of nonresponse to antiviral therapy.
Source: Bitetto D, Bortolotti N, Falleti E. Vitamin A deficiency is associated with hepatitis C virus chronic infection and with unresponsiveness to interferon-based antiviral therapy. Hepatology 2013; doi: 10.1002/hep.26186.
Phase 2 Study Results for Miravirsen
Miravirsen, a microRNA-targeted, pan-HCV genotype anti-viral agent, demonstrated dose-dependent antiviral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA when administered as 4-week monotherapy (5 weekly injections). Santaris Pharma reported that the antiviral treatment extended beyond the Phase 2a study period, the therapy was safe and well tolerated, and there was no evidence of viral resistance. Miravirsen inhibits miR-122, a liver-specific microRNA required by hepatitis C virus to replicate.
Source: Santaris Pharma A/S Press Release: Research Published in the New England Journal of Medicine Demonstrates Marked and Long-Lasting Antiviral Activity Against HCV for Santaris Pharma A/S’ Miravirsen, the First MicroRNA-Targeted Drug to Enter Clinical Trials. March 27, 2013. Available at:
Tuberculosis
Role of Adherence in Drug Resistance
To assess the degree to which medication adherence affects acquired drug resistance (ADR), therapy failure, and relapse in tuberculosis, prospective studies involving adult patients with microbiologically proven pulmonary Mycobacterium tuberculosis were reviewed to compare self-administered therapy versus direct supervision by a healthcare worker of pill-taking. The study endpoints were microbiologic failure, relapse, and ADR. The review of 10 published studies found that direct supervision by a healthcare worker of medication consumption was not significantly better than self-administered therapy in terms of preventing microbiologic failure, relapse, or ADR.
Source: Pasipanodya JG, Gumbo T. A meta-analysis of self-administered versus directly observed therapy effect on microbiologic failure, relapse, and acquired drug resistance in tuberculosis patients. Clin Infect Dis 2013; doi: 10.1093/cid/cit167.
STDs
T. vaginalis-Induced Changes to the Vaginal Microbiota
To test the hypothesis that the vaginal organisms present in women with T. vaginalis infection are different from those who do not have T. vaginalis infection, Martin et al. assessed and compared the vaginal microbiota of 30 infected and 30 uninfected women. Based on sequence analysis of PCR-amplified ribosomal RNA sequences, they identified an unknown Mycoplasma-like organism. The researchers categorized the women based on Nugent scores and found that the vaginal microbiota differed between T vaginalis-infected vs. uninfected women with normal and intermediate Nugent scores, but not among those with bacterial vaginosis. The authors concluded that “T. vaginalis may alter the microbiota in a manner that is favorable to its survival and/or transmissibility,” and the newly identified Mycoplasma species contributes to this transformation. These changes may also result in an increased host inflammatory response.
Source: Martin DH, Zozaya M, Lillis RA, Myers, et al. Unique vaginal microbiota that includes an unknown Mycoplasma-like organism is associated with Trichomonas vaginalis infection. J Infect Dis 2013;doi: 10.1093/infdis/jit100.