Day: 08/10/2010

Mali to rear malaria-resistant GM mosquitoes

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A laboratory in Mali will soon be rearing Africa’s first mosquitoes genetically modified to resist malaria.

The laboratory, at the Malaria Research and Training Centre, University of Bamako, was officially opened yesterday (3 August).

Its research is part of a partnership, between the University of Bamako and Keele University in the United Kingdom, which aims to develop GM mosquitoes to fight malaria.

The researchers hope that resistant mosquitoes will one day take over wild populations, eventually wiping malaria out.

Funded for three years by an £800,000 (around US$1.8 million) grant from the Wellcome Trust, the partnership has trained three Malian scientists at Keele University, and established a biosafety category 3 security laboratory at the Centre.

Mamadou Coulibaly, head of the Centre’s Genomics and Proteomics Laboratory and principal investigator on the project in Mali, said the laboratory, which was finished in mid-July, should be producing GM mosquitoes by 2011.

Paul Eggleston, professor of molecular entomology at the Centre for Applied Entomology and Parasitology at the University of Keele and head of the project in the UK, said:  “We wanted to take this technology out to Africa to get local scientists involved in what we were doing, to fully understand it, and become part of it. Ultimately, it’s [those countries] that take the final decision about whether they want to use [GM mosquitoes] or not,” he told SciDev.Net.

The production of GM mosquitoes has received approval from the University of Bamako’s Faculty of Medicine, Pharmacy and Dentistry ethics committee, said Coulibaly. Mali is also working on developing its own biosafety legislation regarding GM insects with the support of the WHO, said Eggleston.

Eggleston said they hope to test their GM mosquitoes in large outdoor field cages within three years. This will be at a field station in one of the villages outside Bamako that have a long history of working with the university, he said.

There are several projects worldwide that aim to use genetic modification to prevent mosquitoes transmitting diseases such as malaria or dengue.

Ricarda Steinbrecher, co-director of EcoNexus, a non-profit organisation that analyses developments in science and technology, and participant in the ad hoc technical expert group to the Cartagena Biosafety Protocol (AHTEG) which over the last two years has developed guidelines on the risk assessment of GM mosquitoes, said: “With GM insects — and in particular GM mosquitoes — we are faced with a number of problems that we have very little or no experience or knowledge of how to assess or deal with.

“We don’t even know, or have sufficient scientific data on, what the potential harm or negative impacts might be.

“GM insects are crucially different from GM crops. GM insects are designed to spread their engineered genes far and wide and to interact with wild populations … they will not stay put at specific locations but move into wild habitats and across national borders.

“Releases and risk assessments — and risk decisions — have thus to be a multi-national or regional concern.

“No clear or specific regulations or guidelines are yet in place for the environmental release of GM mosquitoes within any country or region. Guidelines are being worked on at international level, but concerns and uncertainties are high.

Eggleston said the team is conscious that creating GM mosquitoes in Africa was a major step and that it was important to tread cautiously.

“The risks we’re talking about [in setting up the lab] are negligible but because this is the first time this is happening in Africa we feel we need to take a ‘belt and braces’ approach,” he said.

Coulibaly added: “Ordinary Malian people think [GM mosquitoes for malaria control] are a good idea. They understand the need to control malaria. However, they do have some reservations on the possible outcomes. They need to be reassured that the laboratory will not produce mosquitoes that are more dangerous.”

JET LAG

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Jetting off for a vacation before the summer ends? The anticipation of taking a time-out and getting away from the rigors of daily life can be exhilarating… until you get to your destination feeling tired, tense, and touchy thanks to jet lag.

Crossing multiple time zones can play funny games with your circadian rhythm. If you are traveling from New York at 8 a.m. to California and it’s a five-hour flight that crosses three time zones, that means you land at 10 a.m. L.A. time. But it’s really 1 p.m. your time back in New York and starting an afternoon romp through Disneyland with the kids works out great. Consider the reverse, however: Say you leave L.A. at 5:30 a.m. to get to New York for a 1 p.m. meeting in downtown Manhattan (without the kids). If getting up that early is not normal for you, you would do well to take a nap on the flight so you’re refreshed by the time you land in New York. Or leave later in the morning from L.A. and schedule the meeting for the following day so you have time to adjust.

Adjustment. That’s the key word when it comes to jet lag, and for good reason. When your internal clock doesn’t match the external clock, it can be– and feel — like World War III in your body. The problems that arise with jet lag are a clear example of how external influences can disrupt our internal body clock.

I’ve blogged about biological clocks before. It’s a fascinating area of research that has so many applications to everyday life. Consider how much your internal clock determines the quality of your life. And if you don’t know what I mean by that, then here’s a quick summary of the role your internal clock plays:

  • Your sleep/wake cycles.
  • How refreshed you feel in the morning.
  • How easy it is for you to fall asleep at night.
  • Whether you can recover quickly from jet lag.
  • The fate of a shift worker who has to be productive at odd hours.
  • Whether you’re a lark or an owl.
  • Your mood and energy level.
  • The strength of your immune system.
  • Your ability to ward off diseases, including cancer and Alzheimer’s.

It may seem hard to believe that your body’s clock can influence diseases like cancer, but it’s true. Think of your clock as your body’s central pacemaker — a means by which the body can remain balanced and, in medical speak, in a state of homeostasis. An entire network of molecular clocks found in the different organs coordinate the body’s various physiological processes ranging from the heart beat, temperature, sleep requirement and hormone balance to behavior. All of these clocks are controlled by the master pacemaker of the hypothalamic suprachiasmatic nuclei (SCN), which synchronizes all of the body’s “peripheral” clocks with the outside world. At the molecular level, all of the clocks are based on a handful of “clock” genes and proteins that regulate each other interactively and thus generate a molecular time signal in the form of a circadian rhythm, a term that originates from the Latin for approximately (circa) and day (dies).

Research continues to emerge helping us understand our clock — or even clocks. Just last month, researchers at the Max Planck Institute for Biophysical Chemistry published a study in the Journal of Clinical Investigation demonstrating (at least for mice), that the clocks associated with individual organs in the body adapt to the new time at different speeds. So while you feel out of whack once you reach a new time zone, it’s pretty much because your body’s physiological processes are no longer coordinated. And the adrenal gland plays a key role in this process. When the researchers switched off the adrenal clock or manipulated the synthesis of the hormone corticosterone by the adrenal gland, the rodents adapted more quickly to the altered circadian rhythm. These insights could pave the way for a new approach to the hormonal treatment of the effects of jet lag and shift work.

These findings surprised even the scientists. It marks the first time that anyone has systematically studied how individual “clock” genes and the internal clocks of the different organs synchronize with the new external time in the case of jet lag.

So what can you do to prevent the jet lag from making your trip a drag? How about setting your body clock to a new time zone before the journey? By using light therapy or an alarm clock that simulates dawn and dusk with techniques to induce sleep, you can reset your circadian body clock before a journey, thus preventing jet lag from the very start. If you are planning a trip across more than two time zones and want to get accustomed to your destination’s time zone quickly, this might be an approach to take.

Let’s say you have an important business trip for which you have to fly east. Before flying, you’d go to bed and wake up earlier each day while using a light box in the morning and winding down earlier in the evening. If you’re traveling west, you would expose yourself to bright light later in the day, go to bed later and wake up a little later in the morning.

If you don’t have the time or inclination to get a light box, then consider direct sunlight as the next-best alternative. Light boxes, while producing artificial light that mimics the sun’s intensity, don’t emit ultraviolet radiation. They are designed to produce those perfect wavelengths of light (peaking in the optimal “blue” wavelength range, or 460 nanometers) and the light gets directed angularly at your eyes for the greatest effect.

If you can shift your body clock naturally prior to departing, this can be a particularly useful technique if your trip doesn’t allow for much time to adjust before kicking into high gear and demanding your top performance.

Try and switch over to your new time zone right away by going to bed and getting up at the same time you would normally, but on this new time zone. So if you usually go to bed at 10 p.m. in L.A., do the same the first night you land in New York even though your body might think it’s only 7 p.m. Then, the next morning try and go for a walk outside, exposing yourself to light and movement that can help re-set your internal clock.

And take my Traveler’s Survivor Kit with you:

  • Ear plugs
  • Eye mask
  • Favorite soothing music and head phones or a device like an iPod
  • C-shaped pillow that fits around your neck

These strategies can also be used for shift workers. But that’s another story for another day

Bon Voyage and Sweet Dreams 

Diagnosing Acute Coronary Syndromes: The Troponin Conundrum

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As the sensitivity of Tn assays rises, electrocardiographic and clinical evidence of ACS become more — not less — important in treatment decisions.

The diagnostic criteria for myocardial infarction (MI) are obtained from the triad of clinical presentation, electrocardiogram (ECG) changes, and serial cardiac enzyme or biomarker measurements. In recent years, the emphasis on biomarkers — specifically, troponin (Tn) — has increased, while ECG findings and clinical symptoms have received relatively little attention. Nonetheless, a detectable Tn level alone does not equal a diagnosis of MI.

TROPONIN AND MYOCARDIAL DAMAGE

Acute coronary syndromes (ACS) is a general term used when clinical symptoms and signs of myocardial ischemia are caused by obstruction of flow through the coronary arteries, and it typically has included both MI and unstable angina. A European Society of Cardiology and American College of Cardiology joint consensus document (published in 2000, updated in 2007) explicitly defines MI as myocardial necrosis secondary to ischemia, which can also occur in ACS without MI. Cardiac Tn is an extremely specific marker of cardiac injury; however, myocardial damage is not specific to either MI or ACS.

Several new high-sensitivity Tn (hsTn) assays are able to detect levels of Tn that would register as zero with older, conventional assays. The advantages of the hsTn assays — greater sensitivity in identifying myocardial injury and potential for earlier detection of MI — come at the cost of a reduction in specificity for the diagnosis of ACS. Indeed, in a recent report, investigators used cardiac computed tomography to confirm a mechanistic association between elevated hsTn levels and myocardial damage, not only in patients with ACS but also in those without ACS. Even with conventional Tn assays, patients can have detectable Tn levels because of etiologies other than ACS; the use of hsTn is likely to increase such false-positive findings.

We need to reassess the currently held belief that Tn is released only from irreversibly injured myocardial cells. In a recent study, marathon runners had significant elevations in Tn levels after a race. The authors postulated two alternative mechanisms for increased Tn values after heavy exertion: true myocardial injury resulting from the breakdown of myocytes, and cytosolic release of the biomarker. In the marathon study, delayed-enhancement cardiac magnetic resonance imaging supported a cytosolic release, and the authors of a recent review concluded that increased membrane permeability is a likelier mechanism than myocardial necrosis for exercise-induced Tn release. Researchers have now determined that hsTn can be detected in healthy populations and that elevated levels are associated with increased cardiovascular risk (Am Heart J 2010; 159:972).

The goal of diagnosing any medical condition is to classify patients by prognosis, pathophysiology, and response to specific therapies. An elevated Tn level in a patient with sepsis, hypertensive emergency, pulmonary embolism, hypotension, renal failure, or any of several other conditions indicates that myocardial damage or even nonthrombotic MI (the extreme end of the spectrum of demand ischemia) has occurred, producing leakage of low levels of Tn and likely indicating a poor prognosis. However, an elevated Tn level does not mean that the patient has ACS, and therefore should not necessarily lead to ACS-directed care. To distinguish ACS from nonocclusive conditions, a compatible clinical syndrome must be accompanied by a change in Tn levels — rising, falling, or both.

CONCLUSION

High-sensitivity assays will enable physicians to both confirm and exclude MI sooner than is now possible, but serial testing at 0, 4, and 8 hours remains necessary. Moreover, the tests are useful for diagnosing (“ruling in”) certain high-risk conditions (demand ischemia and MI) but not for excluding (“ruling out”) the diagnosis of unstable angina — also a high-risk situation for the patient but one in which troponin leak might not occur. Overreliance on Tn and failure to consider ECG findings and clinical presentation appropriately can lead to both over- and underdiagnosis of MI, each of which carries its own set of hazards.

— J. Stephen Bohan, MD, MS, FACP, FACEP, and Joel M. Gore, MD

Published in Journal Watch Emergency Medicine August 5, 2010

Report from the 2010 International AIDS Conference

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Prevention took center stage in Vienna, as described here by the physician-editors of Journal Watch AIDS Clinical Care.

The 18th International AIDS Conference was in beautiful (but hot) Vienna, Austria, and for the first time ever, HIV prevention truly took center stage. The biggest news by far was the CAPRISA 004 study (see JW AIDS Clin Care Jul 26 2010), which was presented in detail on the same day the results were published in Science. By demonstrating the efficacy of a tenofovir microbicide gel in preventing HIV infection, investigators gave us the first-ever clearly positive microbicide study, thus ending years of disappointing research. Almost as interesting as the results was the rapturous response of the assembled audience, with spontaneous cheers erupting as results were presented, and a standing ovation taking place at the end. A colleague of mine remarked that the reaction was similar when investigators first presented the results of BW 002, the first placebo-controlled study of AZT showing that the drug saved lives. One gets the impression that we are at a similar place in HIV prevention science, with some early positive signals but still quite far to go before we have widely effective interventions.

Below, our physician-editors offer perspective on the most clinically relevant findings described at the conference. Next year’s meeting (the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention) will take place in Rome from July 17 through 20.

— Paul E. Sax, MD

Start Antiretroviral Therapy Early with active Tuberculosis

— Abigail Zuger, MD

Initiation of antiretroviral therapy (ART) is often delayed in patients with newly diagnosed AIDS and tuberculosis (TB), to avoid immune reconstitution inflammatory syndrome (IRIS) and a tangle of possible drug interactions and adverse effects. However, results from the CAMELIA trial in Cambodia [Blanc FX et al. Abstract THLBB106] add to the growing body of evidence indicating that earlier ART is better.

A total of 661 HIV-infected, ART-naive patients with smear-positive TB and CD4 counts <200 cells/mm3 (median, 25 cells/mm3) were randomized to initiate efavirenz + d4T + 3TC either 2 weeks or 8 weeks after starting a standard four-drug regimen for TB. At 1 year, overall mortality was 34% lower in the early-ART group than in the late-ART group, and a multivariate analysis confirmed that late receipt of ART was an independent predictor of death. IRIS occurred more than twice as often in the early-ART group but was manageable in most patients. Among survivors, the virologic efficacy of ART was excellent in both groups.

These results confirm and extend the findings of two other important trials: ACTG A5164, which showed the importance of early ART during treatment for opportunistic infections other than TB (JW AIDS Clin Care Jun 22 2009), and SAPiT, which showed that integrating ART into TB treatment is better than deferring it until after TB treatment is complete (JW AIDS Clin Care Feb 24 2010). The analysis of early versus late ART in SAPiT is still pending, but one wonders whether simultaneous initiation of HIV and TB treatment could reduce early mortality rates even further.

A “CAScade” of Data on When to Start ART

— Charles B. Hicks, MD

Until findings become available from the randomized prospective clinical trial known as START, results from large cohort studies offer the best guide for when to begin ART.

A total of 9455 HIV seroconverters who enrolled in the CASCADE study between January 1996 and May 2009 were analyzed in 161 sequential nested cohorts, comparing patients who initiated ART in a given month with those who deferred ART that month [Jonsson Funk M et al. Abstract THLBB201]. Patients were grouped according to CD4 count: 0–49, 50–199, 200–349, 350–499, and 500–799 cells/mm3. Follow-up averaged about 5 years per patient (representing a total of 52,268 person-years), and the primary endpoint was a new AIDS-defining diagnosis (812 cases were identified during the study period) or death (544 patients died).

Among patients with CD4 counts <500 cells/mm3, starting ART was found to significantly reduce the risk for an AIDS-defining event or death, although the likelihood of reaching an endpoint during the first year of follow-up was very low for patients on the higher end of the spectrum (CD4 counts of 350 to 499 cells/mm3). No benefit was seen from starting ART at CD4 counts ≥500 cells/mm3.

Notably, for patients with CD4 counts of 350 to 499 cells/mm3, the number needed to treat (NNT) to prevent one case of AIDS or death within 3 years was 34; when death was the only endpoint considered, the NNT was 71. For patients with CD4 counts of 200 to 349 cells/mm3, the NNTs were 21 and 74, respectively. Such relatively low NNTs give credence to the notion of starting therapy earlier and support current recommendations for ART initiation in HIV-infected patients with CD4 counts ≤500 cells/mm3.

Treatment as Prevention

— Abigail Zuger, MD

One reason often cited for treating HIV-infected patients at higher CD4-cell counts is the theory that more people receiving treatment means more transmission events averted. Data from the shape of the HIV epidemic in Denmark, described by Susan Cowan, seem to support this idea [Abstract MOAC0103].

Of the roughly 5250 HIV-infected individuals in Denmark, about half are men who have sex with men (MSM). More than 80% of these men are taking antiretrovirals, and 86% have undetectable viral loads. Surveys have repeatedly shown that unsafe sexual practices are on the rise among HIV-infected MSM in Denmark. However, the HIV transmission rate in this population seems to be falling, from about 11 transmission events per 100 HIV-infected MSM in 1995, to 7 in 2001, to fewer than 5 now. The only logical explanation, Dr. Cowan suggested, is that the risk associated with unsafe sex in this population has declined as more and more individuals are rendered relatively noninfectious with treatment.

TMC278 (Rilpivirine) ShowS Promise and possibly problems

— Judith Feinberg, MD

A phase II study of the second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) suggested that the drug is both safe and effective in treatment-naive patients. Now, data from a pooled analysis of two manufacturer-supported phase III trials (ECHO and THRIVE) indicate that the drug is noninferior to efavirenz in this population [Cohen C et al. Abstract THLBB206].

Between the two studies, 686 patients were randomized to TMC278 (25 mg once daily) and 682 to efavirenz. Eighty percent of patients received tenofovir/FTC as the nucleoside backbone, and the rest received AZT/3TC or abacavir/3TC. The primary endpoint was the proportion of patients with viral loads <50 copies/mL at 48 weeks in an intent-to-treat, time-to-loss-of-virologic-response analysis.

Both groups had high rates of success (84.3% in the TMC278 group and 82.3% in the efavirenz group, thus demonstrating noninferiority) but for different reasons. The TMC278 group had a lower rate of discontinuation due to adverse events (2% vs. 7%), but the efavirenz group had a lower rate of virologic failure (5% vs. 9%) and also a lower rate of resistance among those who failed: NNRTI resistance mutations emerged in 54% of efavirenz recipients (most commonly, K103N) versus 63% of TMC278 recipients (most commonly, E138K, conferring resistance to etravirine), and resistance to nucleoside reverse transcriptase inhibitors (NRTIs) emerged in 32% versus 68%, respectively. In the TMC278 group, patients with baseline viral loads >100,000 copies/mL appeared to have somewhat higher rates of virologic failure than patients with baseline viral loads below that threshold — a difference that was not seen in the efavirenz group. Mean CD4-count increases were 192 cells/mm3 in the TMC278 group and 176 cells/mm3 in the efavirenz group.

On the basis of these data, the manufacturer of TMC278 has submitted a New Drug Application to the FDA and is also in the process of developing a single tablet that contains TMC278 + tenofovir/FTC. This regimen would be a reasonable alternative for treatment-naive patients who want a once-daily regimen but who cannot take efavirenz (due to concerns about central nervous system adverse effects or teratogenicity) and do not want to start a boosted protease inhibitor (PI). Whether the use of TMC278 will be limited by its somewhat higher rate of virologic failure despite meeting criteria for noninferiority awaits further analysis of the predictors of virologic failure.

NRTI-Sparing Strategies: Not Ready for Prime Time

— Paul E. Sax, MD

Current treatment guidelines recommend that initial antiretroviral regimens contain two NRTIs, but interest remains in NRTI-sparing combinations as well. Researchers evaluated the safety and efficacy of such combinations in three industry-supported, prospective, comparative trials.

  • In the SPARTAN study, patients received either raltegravir + unboosted atazanavir (at a dose of 300 mg twice daily — twice the usual dose) or ritonavir-boosted atazanavir + tenofovir/FTC [Kozal MJ et al. Abstract THLBB204].
  • In the PROGRESS study, patients received lopinavir/ritonavir + either raltegravir or tenofovir/FTC [Reynes J et al. Abstract MOAB0101].
  • In the third study, patients received ritonavir-boosted atazanavir + either maraviroc (150 mg once daily — half the usual recommended dose) or tenofovir/FTC [Mills A et al. Abstract THLBB203].

All three trials were relatively small (the largest, PROGRESS, had 206 patients) and hence can be considered pilot studies at best. In addition, although all the NRTI-sparing regimens appeared to show virologic activity comparable to that of the standard-of-care regimens, they also had limitations that would make one reluctant to choose them unless NRTIs were contraindicated.

  • In the SPARTAN study, the raltegravir + atazanavir group had a higher rate of grade 4 hyperbilirubinemia and more resistance during treatment failure than the control group. These differences prompted the study sponsors to stop the trial early.
  • In the PROGRESS study, lopinavir/r + raltegravir was associated with somewhat higher lipid levels than the control regimen. It also has the disadvantage — compared with other, preferred initial antiretroviral regimens — of being a twice-daily regimen with a relatively high pill burden.
  • In the third study, the use of boosted atazanavir + maraviroc required a pretreatment viral tropism assay that is currently expensive, has a slow turnaround time, and is not a routine part of baseline evaluations.

In the aggregate, NRTI-sparing approaches still lack a tangible benefit over the standard initial NRTI-containing therapies that treatment guidelines recommend.

572 Remains on Track

— Helmut Albrecht, MD

S/GSK1349572 (or 572, as it is often called) is a promising, once-daily, second-generation integrase inhibitor. It has shown excellent antiretroviral activity at low doses, does not require boosting, and, at least in vitro, remains active against many raltegravir-resistant isolates. Now, two industry-supported studies have validated the high expectations for this drug in raltegravir-resistant and treatment-naive patients.

In the VIKING study, 27 patients with documented raltegravir treatment failure added 572 (50 mg once daily) to their regimens in place of raltegravir — and then, on day 11, had their background regimens optimized [Eron J et al. Abstract MOAB0105]. Favorable virologic response was seen in all 18 patients who had resistance due to the N155H and Y143H mutational pathways, compared with only 3 of 9 patients who had both a mutation at the Q148 position and at least one other associated mutation. There was a strong correlation between baseline susceptibility and antiviral response.

In the SPRING-1 study, 205 treatment-naive patients were randomized to 572 (at 10, 25, or 50 mg once daily) or efavirenz, each in combination with an investigator-chosen, fixed-dose, dual-nucleoside backbone (67% tenofovir/FTC, 33% abacavir/3TC) [Arribas J et al. Abstract THLBB205]. As in all studies of integrase inhibitors to date, time to virologic suppression was significantly shorter with all doses of 572 than with efavirenz. Efficacy was independent of the nucleoside backbone, and 572 was extremely well tolerated. On the basis of these findings, the 50-mg dose was selected for upcoming phase III studies in integrase inhibitor–naive patients.

Overall, 572 has the potential to set a new standard for integrase inhibitors. Although only a relatively small number of patients received this drug together with abacavir/3TC in SPRING-1, the regimen was still effective enough to warrant further evaluation, which is gratifying since it would represent an option for a new one-pill, once-daily, fixed-dose combination. For treatment-experienced patients, the Q148 mutational pathway could be 572’s Achilles heel. To avoid the accumulation of complex Q148-associated mutation patterns — and thus preserve potential future activity of 572 — we should ensure that patients do not remain on failing raltegravir or elvitegravir regimens for longer than is absolutely necessary.

Raltegravir Resistance in a Treatment-Naive Patient

— Paul E. Sax, MD

In a small pilot study of abacavir/3TC + raltegravir, a treatment-naive patient turned out to have integrase inhibitor–resistant virus at baseline — the first time this phenomenon has been reported.

The study (SHIELD) was aimed at evaluating how raltegravir performs in initial regimens that include NRTIs other than tenofovir [Young B et al. Abstract THPE0112]. All 35 participants received abacavir/3TC + raltegravir after testing negative for both HLA-B*5701 and hepatitis B surface antigen. At week 48, the median CD4-count increase was 247 cells/mm3, and 91% of patients had achieved virologic suppression.

More important than these results, though, were the additional data obtained on a single patient who experienced virologic failure [Young B et al. Abstract TUPE0163]. This patient was known to have baseline resistance to PIs and NNRTIs. However, when his stored baseline sample was evaluated retrospectively, it also showed the major integrase mutation Q148H. Phenotype testing demonstrated a 150-fold loss of susceptibility to raltegravir.

Transmitted resistance to integrase inhibitors is likely to be rare now, given the generally infrequent occurrence of raltegravir resistance. However, clinicians should consider supplementing baseline genotype tests with an integrase genotype if the patient has evidence of resistance mutations in other drug classes and is likely to start using raltegravir.

Does the Human Papillomavirus Vaccine Prevent Cancer in Men?

— Abigail Zuger, MD

The quadrivalent human papillomavirus (HPV) vaccine has won great acclaim for the prevention of cervical cancer in women and genital warts in men. New data from a manufacturer-supported, postmarketing trial give some sense of what we can expect from the vaccine among HIV-uninfected MSM [Jessen H et al. Abstract THLBB101].

More than 4000 HIV-uninfected men (ages 16 to 26; 85% heterosexual) in 18 countries were randomized to receive three doses of vaccine or placebo. During 3 years of follow-up, vaccination led to a 90% reduction in the incidence of genital warts and other HPV-associated external genital lesions. It was also associated with an 86% reduction in the incidence of persistent HPV infection.

Anoscopy results were reported for about 400 of the 600 MSM enrolled in the trial: Anal intraepithelial neoplasia related to HPV types 6, 11, 16, and 18 was diagnosed in 2.6% of the vaccine group versus 11.5% of the placebo group — a 78% relative difference. No cases of anal cancer occurred in either group.

Whether the vaccine retains similar efficacy in an HIV-infected population, of course, awaits further study.

Published in Journal Watch HIV/AIDS Clinical Care August 9, 2010

Spinal Fluid Test Predicts Alzheimer Disease

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Patients may ask about a widely reported Archives of Neurology study that shows high accuracy in diagnosing Alzheimer disease (AD) based on protein patterns in the cerebrospinal fluid.

Researchers sought to identify biomarkers for AD without regard to clinical diagnostic information, such as cognitive testing. Measuring the spinal fluid concentrations of beta-amyloid protein 1-42 and phosphorylated tau181P protein, the researchers found that AD presented a “signature” pattern of low beta-amyloid levels and increased phosphorylated tau. The pattern was found in 90% of AD patients, 72% of those with mild cognitive impairment, and 36% of the cognitively normal.

The researchers conclude that AD apparently manifests itself earlier than previously believed and that the current diagnostic criteria for the disease should be revised.

Editorialists “strongly recommend” that the analyses be undertaken when a definitive diagnosis of AD will help counsel patients about work and driving.

Vena Cava Filters Under Scrutiny

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Some vena cava filters are prone to break apart and cause emboli themselves, according to an Archives of Internal Medicine study. Meanwhile, the FDA is expressing concern that too many devices are being left in patients after the threat of embolism has passed.

Researchers at a single institution examined some 80 patients who had received either Bard Recovery vena cava filters or a later model, the Bard G2. They found strut fractures and embolization in 25% of the Recovery recipients, and in 12% of G2 recipients. Some patients had life-threatening cardiac symptoms, including ventricular tachycardia and tamponade.

The journal’s editor expresses shock that the FDA classified the filters with other Class II devices — such as mercury thermometers. She estimates that “more than 7000 Americans may now be carrying a fractured G2 filter.”

In keeping with the researchers’ and editor’s call for more scrutiny of these devices, the FDA says it is studying the issue further.