HIV Persists, Continues Replicating in Lymphoid Tissue Even When Undetectable in Blood
New research indicates that HIV-1 not only persists in lymphoid tissue even after it is undetectable in blood but also continues to replicate in these viral reservoirs (Nature 2016; doi:10.1038/nature16933). These findings provide a “critical new perspective” on how HIV endures despite strong antiretroviral therapy (ART), according to a statement released by the multinational research team. HIV latency has been a perplexing problem for both researchers and clinicians. It has been unclear if this low-level persistent infection despite ART resides in a resting state in reservoir tissues or whether HIV continues replicating. To examine this issue, the investigators sequenced viral DNA from serial lymph node and blood samples collected from three HIV-infected patients before and during their first 6 months of ART. Two had only had HIV infection 3 to 4 months and had never taken ART; the third participant had had HIV infection for about 17 years, but had not taken ART for at least 1 year before the study started.
The researchers found that the virus evolved over time, suggesting that it continued to replicate. However, the investigators did not observe that the evolving HIV accrued mutations that conferred drug resistance. Indeed, HIV replication from infected cells in lymphoid tissue “sanctuary sites, where drug concentrations are not fully suppressive, can continue to replenish the viral reservoir and traffic to blood or lymphoid tissue,” according to the researchers.
The scientists also developed a mathematical model to explain how HIV evolves during ART without developing highly drug-resistant strains. This model showed that ART-sensitive HIV strains tend to predominate over ART-resistant strains when ART is at low concentrations. However, with rising drug concentrations, drug-resistant HIV strains begin to dominate. At high concentrations, HIV cannot grow.
“The study is exciting because it really changes how we think about what is happening in treated patients,” said co-author Angela McLean, a professor of mathematical biology at Oxford University, who supervised the mathematical modeling. “It helps explain why some strategies that tried to clear the reservoir have failed.”
Choice of TB Test Matters in HIV-Positive Pregnant Women
A study among HIV-positive pregnant women in India shows that choice of latent TB infection (LTBI) test matters in this immunocompromised population, with up to 20% discordance between the methods examined (Am J Respir Crit Care Med 2016 doi:10.1164/rccm. 201508-1595OC). The findings also shed light on the dynamic immune response in pregnancy and how it affects LTBI testing.
The researchers conducted the study to assess LTBI test accuracy and to determine which method best identifies women with LTBI who are most likely to develop active TB. They screened 149 pregnant, HIV-positive women in their second or third trimester of pregnancy using both a traditional tuberculin skin test (TST) and an interferon gamma release assay (IGRA). In addition, the investigators tested 103 HIV-positive women at the time of delivery. Among those tested before giving birth, 50 also were tested longitudinally, at delivery and at 3 months post-partum.
Overall, 28% of participants had positive IGRA results, compared with 10% with positive TST. There was 75% agreement between the two tests. In comparison to women who tested positive by both IGRA and TST, those positive by IGRA but negative by TST also had lower levels of interferon gamma (IFN-γ) and interleukin-2 (IL-2). In addition, the authors found that “stage of pregnancy appears to affect the IFN-γ response to [mycobacterium TB] antigens,” suggesting that “pregnant women have an impaired immune response to TB.”
TST indirectly measures type 1 helper T cell immune response, the authors explained, requiring not only IFN-γ and IL-2 but also other cytokines to stimulate a delayed hypersensitivity reaction. However, IGRAs measure only IFN-γ produced in the blood. The authors posited that lower IFN-γ and IL-2 may prevent the immune system from triggering the delayed hypersensitivity reaction, thereby causing false-negative TST results.
These findings suggest that IGRA testing may be superior to TST in identifying HIV-positive pregnant women who would benefit from isoniazid preventive therapy. The authors also called for more immunologic studies in pregnancy to improve TB prevention and management strategies in this population.
Procalcitonin Useful in Discriminating Pneumonia, Heart Failure in Emergency Department Setting
In patients with dyspnea being evaluated in emergency department settings, procalcitonin (PCT) helped discriminate for diagnosis and exclusion of pneumonia and was prognostic for 1-year mortality, adding value to mid-regional pro-atrial natriuretic peptide in this regard (Am J Med 2016;129:96–104). The findings underscore the utility of PCT in diagnosing and appropriately discriminating patients with complex symptoms due to multiple co-existing conditions, such as pneumonia and heart failure, according to the authors.
The authors evaluated pooled data from two prospective cohorts of patients who presented with dyspnea to emergency departments. In all, 453 patients had serum samples available for biomarker analysis. Although PCT results had been blinded to managing physicians during these trials, the investigators used PCT values to assess how well PCT discriminated and reclassified patients for diagnosing pneumonia, and how much prognostic value PCT held for 1-year survival.
Overall, 6.6% of patients had pneumonia alone, 47% had heart failure without pneumonia, and 6.6% had both conditions. The researchers found significantly higher PCT levels in patients with pneumonia. In addition, the area under the receiver operating characteristic curve for diagnosing pneumonia based on PCT results was 0.84. In patients for whom there was diagnostic uncertainty, a PCT value of 0.10 ng/mL had 80% sensitivity and 77% specificity for discriminating pneumonia. Adding PCT levels to variables predictive of pneumonia improved reclassification, both for up- and down-reclassifying. Elevated PCT also was predictive of 1-year mortality.
After USPSTF Recommendations, Primary Care Physicians Curbed PSA Testing; Urologists Did Not
Primary care physicians (PCP) cut back significantly on prostate-specific antigen (PSA) testing after the 2012 U.S. Preventive Services Task Force (USPSTF) recommendation against routine PSA screening in men, but urologists barely changed how often they order the test (JAMA Intern Med 2016; doi: 10.1001/jamainternmed.2015.7901). These findings might be due to opposing thoughts about the utility of PSA screening, conflicting guidelines, or differences in patient populations, according to the study authors.
The investigators examined data from the National Ambulatory Medical Care Survey in 2010 and 2012. This annual, nationally representative survey of ambulatory care in the U.S. collects information about physician office visits. The researchers looked at visits for men ages 50 to 74 who presented to PCPs or urologists for a preventive care visit. The sample of 1,222 visits extrapolated to 27 million visits, 90.8% of which occurred in PCP offices, and 9.2% in urologist offices.
In 2010, PCPs ordered PSA tests in 36.5% of these visits versus 16.4% in 2012. In contrast, urologists ordered PSA tests in 38.7% of visits in 2010 versus 34.5% in 2012. This represents a statistically significant difference in testing practices.
In assessing these findings, the authors noted that American Urological Association guidelines recommend joint decision-making for PSA testing in men ages 55 to 69 years, rather than the USPSTF’s recommendation against routine testing in all men. The authors also did not have access to actual PSA test results.
The findings emphasize “the need to continue interdisciplinary dialogue to achieve a broader consensus on prostate cancer screening,” the authors wrote.