Abstract
HIV Infection
CCR5 Gene Editing: Safe and Promising as a Therapeutic Strategy in HIV
Gene editing using zinc-finger nuclease (ZFN) technology to knock out the function of the CCR5 gene in CD4 T cells of HIV-infected patients, and then returning those autologous T cells back to the patients, giving them a population of CD4 cells that lack the CCR5 co-receptor needed for HIV infection, was shown to be safe and well-tolerated, and to have potential promise as a therapeutic strategy. Of 12 patients with chronic aviremic HIV infection who received a single dose of 10 billion autologous CD4 T cells—11–28% of which underwent ZFN modification to knock out the CCR5 gene—six of the patients interrupted their antiretroviral (ART) regimen 4 weeks after the T-cell infusion. The one serious adverse event recorded was attributed to a transfusion reaction. “The findings from this small study are notable,” according to the authors of an accompanying editorial. The results included a significant increase in the median CD4 T-cell count at week 1, with CCR5-modified CD4 cells accounting for nearly 14% of circulating CD4 cells. These modified T cells had a half-life of 48 weeks. Among the patients who underwent treatment interruption and resulting viremia, the decrease in CCR5-modified cells was significantly less than in unmodified cells, and in one of four patients evaluated, HIV RNA was undetectable at the time of treatment reinitiation. As noted in the editorial, “For this approach to become clinically useful as treatment for HIV infection, biallelic CCR5 knockout will be required. It was interesting to note that the study participant in whom the viral load fell to undetectable levels was later found to be heterozygous for the CCR5-delta32 deletion—and therefore did not require biallelic knockout.”
Sources: Tebas P, Stein D, Tang, WW, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 2014;370:901–910.
Kay MA, Walker BD. Engineering cellular resistance to HIV. N Engl J Med 2014;370:968–969.
Persistent HIV Replication in Lymphatic Tissue
Even in the presence of “viral suppression,” as defined by undetectable viral load in the peripheral blood of HIV-infected individuals on antiretroviral regimens, HIV reservoirs and viral replication can persist in lymphatic tissues. Fletcher et al. correlate persistent HIV replication in lymph node samples during treatment with five of the most commonly used antiretroviral agents to substantially lower drug concentrations in the tissue than in peripheral blood. “The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues,” state the researchers. They prospectively treated 12 HIV-infected patients with antiretroviral drugs, using genotype confirmation to determine that the virus isolated from plasma samples was sensitive to the therapeutic regimen selected. ART regimens included tenofovir dioproxil fumarate/emtricitabine in combination with efavirenz, atazanavir/ritonavir, and darunavir/ritonavir.
Source: Fletcher CV, Staskus K, Wietgrefe SW, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. PNAS 2014;111:2307–2312.
Inflammatory Cytokines and Mortality Link?
Chronic inflammation is present in HIV infection, with altered levels of inflammatory cytokines, but is there a correlation between increased levels of these cytokines and mortality in HIV-infected individuals? Fuster et al. prospectively followed a cohort of HIV-infected adults with alcohol problems for 7–9 years, with mortality as the primary outcome. They analyzed the levels of a variety of inflammatory biomarkers in peripheral blood samples. The results of individual mutivariable analyses for each biomarker point to a significant association between high levels of interleukin (IL)-6 and C-reactive protein and mortality, as well as a significant link between the overall inflammatory burden score (the number of biomarkers in the highest quartile) and mortality. In the adjusted multivariable analysis, high levels of IL-6 remained an independent risk factor for mortality.
Source: Fuster D, Cheng DM, Quinn EK, et al. Inflammatory cytokines and mortality in a cohort of HIV-infected adults with alcohol problems. AIDS 2014;doi:10.1097/QAD0000000000000184.
Assessing the Benefit of Once-Daily ART Dosing
Simpler ART regimens, with one-daily vs. twice-daily dosing and reduced pill burden, are a hallmark of newer therapies, and the hope is that they will lead to improved ART adherence and virologic outcomes. The results of a literature search of randomized controlled trials comparing once-daily vs. twice-daily ART regimens found that a higher pill burden was associated with lower adherence rates and worse virologic suppression. This association was evident in both the once-daily and twice-daily ART subgroups, but the link to adherence was not statistically significant in the once-daily subgroup; for viral suppression, the link was significant in both subgroups. The researchers found no significant difference in virologic suppression among subjects on once-daily or twice-daily regimens. In both groups, adherence decreased significantly over time; the decline in adherence was less pronounced with once-daily than twice-daily dosing. Overall, the small improvement in adherence with once-daily versus twice-daily dosing did not translate into better treatment outcomes.
Source: Nachega JB, Parienti J-J, Uthman OA, et al. Lower pill burden and once-daily dosing antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. J Clin Infect Dis 2014;doi:10.1093/cid/ciu046.
Impact of the Affordable Care Act
The recent issue of Health Affairs explored how the Affordable Care Act (ACA) could affect Americans living with HIV/AIDS, and included two articles developed with support from grants from Precision Health Economics and the Leonard D. Schaeffer Center for Health Policy and Economics at the University of Southern California, both in Los Angeles, CA. Goldman et al. used an epidemiological model of disease transmission and progression to evaluate the effects of early treatment on HIV prevention. Early treatment was defined as initiation of combination ART before CD4+ cell counts fall below 350 cells/mm3. The authors concluded that during 1996–2009 early initiation of treatment prevented 188,000 cases of HIV. Four-fifths of the cases prevented were attributed to “very early” treatment, described as cART begun when patients' CD4+ counts were >500 cells/mm3. Emphasizing the cost-effectiveness of early treatment, the researchers calculated losses in life expectancy avoided totaling $128 billion, based on a life-year valued at $150,000.
Romley et al. determined the life expectancy gains for HIV-infected individuals during the same time period, 1996 (when cART was introduced) and 2009 (when treatment guidelines in the US were revised to include earlier initiation of cART). Using the same definition of “early treatment”—CD4+ count 350–500 cells/mm3—the authors report an increase in life expectancy of 6.1 years with early treatment, and an extra 9.0 years with “very early treatment.” The combined value of added life expectancy for both the early and very early treatment groups was $80 billion. “The value of the survival gains was more than double the increase in drug manufacturers' revenues from early cART initiation,” state the authors. “Our results clarify the economic implications of adherence to treatment guidelines.”
Sources: Goldman DP, Juday T, Seekins D, Linthicum MT, and Romley JA. Early HIV treatment in the United States prevented nearly 13,500 infections per year during 1996–2009. Health Aff 2014;33:362–369.
Romley JA, Juday T, Solomon MD. Early HIV treatment led to life expectancy gains valued at $80 billion for people infected in 1996–2009. Health Aff 2014;33:370–377.
Mental Health Status and HIV Prevalence
A study of HIV infection rates among individuals receiving mental health services, in a combination of inpatient and outpatient settings, found a four times higher HIV prevalence among the study group than in the general population. Within the study population, the researchers reported a statistically significant association between HIV infection and age (HIV prevalence was highest among 40- to 49-year-olds, followed by those aged 50 years or older), race (blacks had the highest HIV prevalence), co-infection with hepatitis C virus, and identification as homosexual or bisexual, compared to heterosexual. Based on a positive association between psychiatric symptom severity and HIV infection, the authors conclude that “engaging persons with mental illness in appropriate mental health treatment may be important to HIV prevention.”
Source: Blank MB, Himelhoch SS, Balaji AB. A multisite study of the prevalence of HIV with rapid testing in mental health settings. Am J Public Health 2013;doi:10.2105/AJPH.2013.301633.
New Hypothesis to Explain CD4+ Depletion
Commenting on the article by Doitsch et al. in Nature (2014;505:509–514), Andrea Cox and Robert Siliciano, Johns Hopkins University School of Medicine (Baltimore, MD), noted that while the first paper describing AIDS identified the lack of CD4+ T cells in patients' blood, the link between HIV infection and the death of not only activated, infected CD4+ T cells, but also of uninfected ‘bystander’ CD4+ T cells, has not been clearly understood. According to the Doitsch study, most CD4+ T cells lost as a result of HIV infection die as a result of pyroptosis—following abortive HIV infection—which is a mechanism of cell death different than either apoptosis or necroptosis. During acute infection, HIV replication in actively infected CD4+ T cells results in rapid, direct cell death. Most of the CD4+ T cell death associated with HIV infection occurs during “the prolonged asymptomatic phase between the acute stage and the development of AIDS,” state Cox and Siliciano, “suggesting that the infection may promote death of quiescent (non-activated) cells.” The new hypothesis identifies pyroptosis as the mechanistic link between HIV-induced immune activation and CD4+ T cell depletion. “Pyroptosis results in lysis of the cell and release of the cytoplasmic contents into the extracellular space, and is highly inflammatory,” write Cox and Siliciano, as supported by the findings of Doitsch and colleagues of increased inflammatory cytokine levels after HIV infection. Based on these findings, new approaches to treatment could include treatments to reduce immune activation and inflammation, and the use of ART agents that target events early in the viral life cycle to block abortive infection.
Source: Cox AL, Siliciano RF. HIV: Not-so-innocent bystanders. Nature 2014:505;492–493.
HIV Transmission—Crime and Punishment
An HIV-positive man in Waterloo, Iowa, received a sentence of 2–5 years of probation for not telling his sex partner his HIV status. The suspended sentence for the 42-year-old was in lieu of up to 25 years in prison; the sentence included having to register as a sex offender. The case dates back to 2009, when the man—diagnosed with HIV 2 years previously—had unprotected sex with a man three times and was charged with criminal transmission of HIV. The partner did not become infected, but under Iowa law, the criminal charge does not require actual transmission to occur. The defense attorneys fought the HIV transmission law on Constitutional grounds, and during that time the case stalled. In November 2013, the defendant plead guilty, leading to the suspended sentence and resolution of the case.
Source: Reinitz J. Man with HIV sentenced to probation for criminal transmission. WCF Courier. February 3, 2014.
Chlamydia Infection
Link Between Persistent GI and Genital Infections
In a review of the persistence of chlamydial infections in the gastrointestinal tract, Rank and Yeruva proposed that continued shedding of chlamydia in feces from ongoing GI infection is a possible mechanism for re-infection in women cured of genital chlamydia infection. Emerging data suggesting reduced effectiveness of azithromycin in treating chlamydial GI compared to genital infections could contribute to auto-inoculation from the lower GI tract in women cured of genital infection with antibiotics.
Source: Rank RG, Yeruva L. “Hidden in plain sight:” Chlamydial gastrointestinal infection and its relevance to “persistence” in human genital infections.” J Infect Immunity 2014;doi:10.1128/IAI.01244-13.
HPV Infection
Need to Do More to Prevent HPV in Children
According to USA Today, a new report from the President's Cancer Panel concluded that only one-third of girls in the United States have received the full three doses of human papilloma virus (HPV) vaccine recommended to protect them against HPV infection and reduce their risk of developing cervical cancer. The Centers for Disease Control and Prevention (CDC) has stated that vaccination rates of at least 80% in teenage girls could prevent as many as 53,000 future cases of cervical cancer. Since 2011, the CDC has also recommended HPV immunization for boys, but the President's Cancer Panel found that only 7% of boys have been fully vaccinated. In males, HPV infection is especially linked to oral cancer. The current HPV vaccine, administered as a series of three shots several months apart, is safe and effective, and new research suggests that two doses may be just as effective. The report indicates that while the current vaccine can prevent about 70% of cases of cervical cancer, newer vaccines in development will be protective against 90% of cervical tumors. The adoption of HPV immunization in teens would benefit from stronger recommendations by physicians, with the message to patients and parents focusing on cancer prevention rather than sexual activity, and from state laws that would allow pharmacists to administer HPV shots to teens, as they do flu shots.
Source: Szabo L. Report: U.S. failing to protect kids from HPV. USA Today. February 10, 2014.
Susceptibility of HPV to Clinical Disinfectants
Two types of infectious HPV16 virions (native virus and recombinant HPV16 particles) were incubated with 11 common clinical disinfectants, and the infectivity titers of these disinfectant-treated viruses were compared to those of untreated viruses. The results showed HPV16 to be a highly resistant virus compared to other non-enveloped viruses previously studied. Both virus types were resistant to glutaraldehyde and ortho-phthalaldehyde, and were susceptible to hypochlorite and a higher concentration peracetic acid (PAA)-silver-based disinfectant. The native and recombinant viruses has similar resistance patterns, with the exception of the recombinant HPV16 being susceptible to isopropanol, the triple phenolic, and the lower concentration PAA-silver-based disinfectant. Overall, many of the commonly used clinical disinfectants, including some used for sterilization in medical and dental facilities, do not affect HPV16 infectivity.
Source: Meyers J, Ryndock E, Conway MJ, Meyers C, and Robison R. Susceptibility of high-risk human papillomavirus type 16 to clinical disinfectants. J Antimicrob Chemother 2014;doi:10.1093/jac/dku006.