Primecuts – This Week In The Journals

October 3, 2011

By Aviva Regev

Faculty Peer Reviewed

As we start feeling the change in season this week in New York – cooler weather, earlier sunsets, a break from that cloying humidity – it’s easy to see the city in a new light.  This week in the journals, we take a look at common diseases from a fresh perspective.

Putting an HIV patient with a low CD4 count on an immunosuppressive drug might seem like the last thing you’d want to do.  As it turns out, it may actually be a good idea in a subgroup of patients considered “immunological non-responders” (INR) to HAART therapy.  Though the viral loads of these patients are suppressed, their CD4 counts do not recover to above 200.  One theory holds that during the initial stage of infection, destruction of CD4 cells in the gut mucosa leads to release of LPS, which activates a TLR-driven immune response.  This mucosal damage is often irreversible, and the greater the degree of LPS and TLR activation, the greater the risk of a poor CD4+ recovery.  Hydroxychloroquine (HCQ), which is perhaps best known as an antimalarial but is also used in autoimmune conditions, suppresses TLR activation.  In a study of 20 HIV INRs treated with HCQ for six months, there was a positive trend in the absolute number of CD4+ cells and a significant and sustained increase in CD4+ cells as a percentage of the pool of T cells.  The authors also noted that there was a significant decrease in the LPS level and an increase in circulating T regulatory cells [1].  The clinical significance of these effects for patients with HIV is unclear; follow-up of this cohort and further investigation into a role for immunomodulation in HIV is needed.

While HAART is unarguably beneficial in treating HIV-infected patients, there are no set guidelines regarding the optimal time to initiate treatment.  Over nine thousand treatment-naïve HIV patients with CD4 counts less than 800 were observed over a decade and time to progression to AIDS or death was assessed .[2]  Each month, a new sub-cohort was defined which included only patients who had not yet intiated HAART therapy.  Therefore, a patient who initiated therapy after 1 year would be included in the first 12 sub-cohorts.  Patient with CD4 counts between 200-349/mL had the greatest benefit, with a 40% increase in time to progression, while those with CD4 counts between 350-499 had a 25% increase in progression-free survival , though that finding was non-significant.  In patients with CD4 counts of 500-799, initiation of HAART was not associated with a survival benefit.  This study supports the rationale of initiating therapy for those with CD4 cell counts below 350, but also suggests that patients with CD4 cell counts between 350 to 499 may benefit from earlier initiation as well.

Asthma is a chronic and potentially debilitating disease that affects hundreds of millions of people worldwide, and inhaled glucocorticoids are a mainstay of treatment.  Unfortunately, not all patients respond well to this approach, possibly due to genetic differences.  Tantisira et. al. screened over 500,000 single-nucleotide polymorphisms (SNPs) in 400 families with asthma and then analyzed the 100 SNPs with the greatest potential power for association with non-response to inhaled glucocorticouids [3].   Two SNPs were associated with a diminished response to inhaled glucocorticoids.  These SNPs are linked to a gene that is activated by glucocorticoids and is involved in inflammatory-cell apoptosis.  Patients who were homozygous for the mutant alleles had only about one-third the improvement in their FEV1, a commonly used marker for asthma severity, compared to patients homozygous for the wild-type allele.  In the study population, a polymorphism at these particular codons accounted for 6.6% of the variation in response to medication.  Though this offers an explanation for the lack of response, it does not suggest an alternative treatment for this unfortunate group of patients.

In other asthma news, a study presented this week at the European Respiratory Society (ERS) 2011 Annual Congress found that moderate consumption of alcohol reduces the risk of developing adult-onset asthma [4].  Among people who consumed 1-6 drinks per week, 4% developed asthma over an 8-year period, compared to 5.6% of teetotalers.   Heavy drinking also increased the risk, though not as much as abstinence.  Interestingly, exclusive beer drinkers appeared to have a slightly greater risk than those with more varied imbibing habits.

“Common things are common,” is an adage every medical student has heard countless times, but common things can have surprising interactions.  The World Health Organization (WHO) announced that it will be launching an initiative aimed at the tuberculosis-diabetes link [5].  Diabetes triples the risk of developing TB, and accounts for 8 percent of new cases, or 700,000 annually.  Though diabetes is by no means a factor in the majority of new TB cases, patients with diabetes are thought to be an easier target for iniatives aimed at TB prevention since they already have more regular contact with healthcare providers.  Moreover, diabetes is on the rise, so the population affected will only continue to increase.  The 3-fold increase in risk doesn’t compare to the 30-fold increase seen with HIV, but in some countries, diabetes is responsible for far more new TB cases: in India, 23% cases are associated with diabetes vs. 5% which are associated with HIV; in Russia, the comparison is 14% vs. 11%; and in Pakistan, 9% vs. 1.5%.  These numbers suggest that targeting the diabetic population for risk reduction might have a huge impact on the fight against TB infection worldwide.

To wrap up this week’s edition, good news for those with a serious caffeine habit, especially the ladies!  It turns out coffee consumption is inversely correlated with depression risk in women (previous studies have found similar effects in men).  A prospective, observational study of over 50,000 women with no baseline depression assessed the risk of developing depression over ten years [6].  Those who drank more than 4 cups of caffeinated coffee each day had a relative risk of developing depression of 0.8 compared to coffee abstainers.  The effect was dose-dependent, and no effect was found for decaf or other caffeinated beverages including tea and soft drinks. This may be reassuring for many coffee-dependent housestaff, though the paper did not comment on whether the mood effects differed for people who drank 4 cups because they “liked the taste” and not because they were so tired and overworked they couldn’t get through the workday without it.

Thanks for sticking it out to the end!  Here’s to starting the day with lots of coffee, having a glass of wine with dinner, and enjoying the arrival of autumn.

Aviva Regev is a 4th year medical student at NYU School of Medicine

Peer reviewed by Michael Poles, MD, section editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1.  Piconi S, Parisotto S, Rizzardini G, et al.  Hydroxychloroquine drastically reduces immune activation in HIV-infected, ART-treated, immunological non-responders.  Blood 2011; 118(12): 3263-3272.  http://bloodjournal.hematologylibrary.org/content/118/12/3263.full.pdf

2. Cole SR, Thomas JC, Porter K, Jay S, Davidian M.  Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters.  Arch Int Med 2011; 171(17): 1560-1569.  http://archinte.ama-assn.org/cgi/content/full/171/17/1560

3. Tantisira KG, Lasky-Su J, Harada M, et al.  Genomewide association between GLCCI1 and response to glucocorticoids therapy in asthma.  NEJM 2011; 365(13); 1173-1183.  http://www.nejm.org/doi/full/10.1056/NEJMoa0911353

4.  Lieberoth, S. Intake of alcohol and risk of adult-onset asthma. European Respiratory Society (ERS) 2011 Annual Congress: Abstract 319. Presented September 25, 2011. http://www.erscongress2011.org/mediacentre/news-releases/item/317-alcohol-can-reduce-asthma-risk.html

5. Maurice, J. WHO framework targets tuberculosis-diabetes link. Lancet 2011; 378: 1209-1210.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61527-4/fulltext?version=printerFriendly

6.  Lucas M, Mirzaei F, Pan A, et al.  Coffee, caffeine, and risk of depression among women.  Arch Int Med 2011; 171(7): 1571-1578.  http://archinte.ama-assn.org/cgi/reprint/171/17/1571.pdf

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