Abstract
HIV Infection
Early ART “Cures” HIV in Infant
Rapid HIV testing of a mother in labor who had received no prenatal care yielded a positive result. Western blot testing confirmed the HIV-positive finding. The infant, born by spontaneous vaginal delivery, received an atypically strong antiretroviral therapy (ART) beginning at 30 h of age as prophylaxis for high-risk exposure. It comprised a three-drug regimen of zidovudine (2 mg/kg body weight every 6 h), lamivudine (4 mg/kg twice daily), and nevirapine (2 mg/kg twice daily). Repeat testing detected HIV DNA and RNA leading to a diagnosis of HIV infection, meaning that the strong ART regimen used was not “prophylactic,” but rather treating an established HIV infection, albeit one detected extremely early. ART was continued until the child was 18 months of age. At that time, plasma HIV RNA, proviral DNA in peripheral-blood mononuclear cells, and HIV antibodies were undetectable and remained so through 30 months of age, despite remaining off all anti-HIV drugs. The authors conclude that “early ART in infants may alter the establishment and long-term persistence of HIV-1 infection.”
Source: Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med 2013;doi:10.1056/NEJMoa1302976.
Proven Benefits of Early ART Initiation
A group of HIV-infected patients who initiated ART within 6 months of infection had lower CD8+ and CD4+ T-cell activation than patients who initiated ART ≥2 years after becoming infected with HIV during the period they were receiving ART. Both patient groups maintained viral suppression for at least 2 years. Early ART was also predictive of significantly lower (4.8-fold) DNA levels and cell-associated RNA levels than later ART, so smaller DNA and RNA reservoirs over the course of long-term therapy. The level of CD8+ T-cell activation among HIV-infected patients who received early ART was significantly higher than that of the HIV-negative control group.
Source: Jain V, Hartogensis W, Bacchetti P, et al. Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size. J Infect Dis 2013;208:1202–1211.
HIV Reservoirs May Be Larger Than Expected
The latent reservoirs of HIV proviruses that persist in the resting CD4+ T cells of chronically infected patients, despite ART, may be larger than initially estimated. In fact, the authors of one recent study propose that “the size of the latent reservoir—and, hence, the barrier to cure—may be up to 60-fold greater than previously estimated.” Activation of these resting CD4+ T cells can reverse the latent proviruses, but typically fewer than 1% release infectious HIV on activation in vitro. Analysis of non-induced provirus showed defects in 88.3% and intact genomes in 11.7%. The proviruses with intact genomes may have the potential to become activated, and this discovery of a larger population of replication-competent non-induced HIV proviruses led to the prediction of larger than once believed HIV reservoirs.
Sources: Ho Y-C, Shan L, Hosmane NN, et al. Replication-competent non-induced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 2013;155:540–551.
A3G Protein Inhibits Provirus Formation in “Controllers”
The term “controllers” describes a small group of chronically HIV-infected patients in whom HIV-induced immunodeficiency does not progress even in the absence of ART. Their immune systems are able to keep the virus in check and their resting memory CD4+ T cells have lower levels of HIV provirus than “non-controllers.” A comparison of resting T memory cells between controllers and ART-suppressed non-controllers showed that controllers had less provirus and more of the protein APOBEC3G (A3G), described as “a cellular factor that blocks provirus formation at multiple steps if not antagonized by HIV virion infectivity factor (Vif).” Furthermore, those resting memory T cells with the highest levels of A3G protein had the lowest levels of provirus in vivo. The authors conclude: “These results raise the hypothesis that HIV control is associated with increased cellular A3G that may be packaged into Vif-positive virions to add that mode of inhibition of provirus formation to previously described adaptive immune mechanisms for HIV control.”
Source: De Pasquale M, Kourteva Y, Allos T, D'Aquila RT. Lower HIV provirus levels are associated with more APOBEC3G protein in blood resting memory CD4+ T lymphocytes of controllers in vivo. PLos ONE 2013;doi:10.1371/journal/pone.0076002.
ZFN-Modified Autologous T-Cell Therapy Results Reported
In a presentation of results from its open-label Phase 1 clinical trial (SB-728-0902 Cohorts 1-3) in immunologic non-responders (INR), designed to assess the safety and tolerability of single infusions of an escalating dose of genetically modified autologous CD4+ T cells, Sangamo Biosciences reported that subjects had long-term increases in CD4 cell counts (as long as 3 years), and seven of nine subjects had decreased levels of HIV DNA (smaller reservoirs) at 12 months post-infusion. The patients' CD4+ cells were genetically engineered at the CCR5 gene locus using zinc finger nuclear (ZFN) technology. The median duration of HIV infection in the patient population was 21 years, and baseline CD4 T-cell counts at the start of the trial were <500 cells/μL. Immunologic non-responders tend to have lower than expected CD4 counts (<500 cells/μL) despite having well-controlled HIV infection due to ART. Subjects continued their ART regimens while receiving the CCR5-modified autologous T-cell therapy.
Source: Sangamo BioSciences. Press release: Sangamo Biosciences presents clinical data from SB-728-T HIV study demonstrating long-term immune reconstitution and reduction in the HIV DNA reservoir in subjects with long-term infection. November 4, 2013. Available at:
SIV Infection Cleared in Rhesus Macaques
Hansen et al. studied simian immunodeficiency virus (SIV)-infected rhesus macaques that had been vaccinated with rhesus cytomegalovirus (RhCMV) vectors containing a highly pathogenic strain of SIV. In a previous report, the authors had shown that about 50% of the vaccinated animals had evidence of durable aviremic control of infection. In the current study, they demonstrate substantial lymphatic and hematogenous spread of SIV, with replication-competent virus persisting at multiple sites for weeks to months. However, over time, evidence of SIV infection disappeared in the vaccinated macaques, with ultrasensitive assays to detect SIV RNA or DNA revealing no detectable plasma- or tissue-associated virus. According to the authors, these findings provide compelling evidence for “progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell–mediated immune surveillance elicited and maintained by cytomegalovirus vectors.”
Source: Hansen SG, Piatak JR M, Ventura AB, et al. Immune clearance of highly pathogenic SIV infection [Letter]. Nature 2013;502;doi:10.1038/nature12519.
HIV-Specialized Pharmacies Can Improve Adherence
Individuals with HIV infection who use HIV-specialized pharmacies (HIV-SPs) are more likely to adhere to their medication regimens. HIV-SP users are also more likely to have a significantly greater number of co-morbidities. These findings derive from two studies funded by Walgreen Co., which has established several HIV-SPs across the United States. In the first study, a retrospective review of HIV-infected patients who submitted prescriptions for ART medications and either a statin or anti-hypertension drug found that HIV-SP users had a significantly higher mean “proportion of days covered” measure than the users of traditional pharmacies for both statins and anti-hypertension medications. The second study involved a retrospective analysis of HIV patients with serious mental illness and found that among those using HIV-SPs exclusively, 32.7% were adherent, compared to 19.4% for similar patients who used only traditional pharmacies.
Source: DuChane J, Taitel M, Fensterheim L, et al. Two retrospective cohort studies exploring HIV medication and overall adherence at HIV-specialised pharmacies: implications for HIV patients with comorbid conditions and serious mental illness. The Lancet 2013;382:S3.
The Changing Picture of HIV/AIDS in the US
A report by the Kaiser Family Foundation illustrates the variation in how successful HIV prevention, treatment, and education efforts have been among different populations in the United States over the past 25–30 years. The number of new HIV diagnoses in the US each year has declined from its peak of 130,000 in the late 1980s to about 50,000, and it has remained relatively stable at that level for the past decade. Recent figures indicate that heterosexual contact accounts for 25% of new HIV diagnoses; 63% result from male-to-male sexual contact. In 2010, one-fifth of new HIV infections occurred among women, and African American women accounted for nearly two-thirds of those. Minority populations are being disproportionately affected: compared to the rate of new HIV infection in white men and women, it is 8 times higher in African American men and women and 3 times higher among Latinos. With regard to age, when the AIDS epidemic was at its peak in the late 1980s, HIV was the main cause of death of Americans ages 25–44, whereas currently it has fallen to sixth for that age group. The Foundation reported that about 82% of Americans infected with HIV have been diagnosed; however, only 1 in 4 patients undergoing treatment adhere to a therapeutic regimen closely enough to achieve viral suppression.
Source: Roethel K. Uneven gains in AIDS/HIV in different populations. SFGate. November 12, 2013. Available at:
Worldwide Progress in Combating AIDS Reported
While progress in identifying people infected with HIV around the globe and providing HIV services is accelerating in most parts of the world, global targets may not be met in others, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS). Regions of particular concern include Eastern Europe and Central Asia, where new HIV infections have risen 13% since 2006. In the Middle East and North Africa, new HIV infections have doubled since 2001. Populations that often do not have access to essential HIV services include men who have sex with men, intravenous drug users, transgender individuals, and sex workers. Funding to support prevention services targeting these at-risk populations in regions of the world with high HIV prevalence rates have been lagging in recent years. On a positive note, UNAIDS reported that in Eastern Europe in 2012, Ukraine, for the first time, had a decline in the number of new HIV cases. UNAIDS urged that more attention be paid to HIV in children and older adults, emphasizing the need for early infant diagnosis and the increasingly significant number of people aged 50 years and older who are living with HIV, estimated at 3.6 million people worldwide.
Source: UNAIDS. Press release: Ahead of World AIDS Day 2013 UNAIDS reports sustained progress in the AIDS response. November 20, 2013. Available at:
Mycobacterium tuberculosis Infection
Expanded Guidelines for Bedaquiline Use in Multidrug-Resistant TB
The Centers for Disease Control and Prevention (CDC) released provisional guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo, Johnson & Johnson) for the treatment of multidrug-resistant tuberculosis that is resistant to at least isoniazid and rifampin. The US Food and Drug Administration (FDA) approved bedaquiline, an oral diarylquinoline, in December 2012, based on the results of two Phase IIb clinical trials. In a recent report, the CDC provided provision guidelines for FDA-approved and unapproved/off-label uses of bedaquiline in specific populations that were not included in the clinical studies, including children, pregnant women, and persons with extrapulmonary multidrug-resistant tuberculosis.
Source: Mase S, Chorba T, Lobue P, Castro K. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR 2013;62:906.