Viral decay curve

Once you start someone on ARVs, there's a predictable decline in viral load associated with it. This article from Nature Medicine has a nice figure, showing that different cell populations actually give rise to different portions of the decay curve, and as each replication within each "compartment" of cell type gets shut off by ARVs, that population's contribution to the viral load trails off, leading to the curve. (Hopefully it'll make better sense when you look at the figure!)

http://www.nature.com/nm/journal/v9/n7/fig_tab/nm0703-853_F2.html
from (http://www.nature.com/nm/journal/v9/n7/full/nm0703-853.html)

- Christopher Hurt

Super cool HIV interactive graphic

The New England Journal published the studies of raltegravir's use/efficacy for patients with an optimized background regimen (OBR) recently, and it turns out they also had an online-only interactive graphic that would be great for teaching students and residents visiting on the service. It's online at:

http://content.nejm.org/content/vol359/issue4/images/data/339/DC2/AIDS_Interactive.shtml

Enjoy!

– Christopher Hurt, MD

Review of PPDs

We have a lot to learn regarding TB, but regarding the targeted testing for latent tuberculosis infection, here is a VERY QUICK review of what constitues a positive PPD:

>0 mm is considered a positive reaction if the patient:

• Is HIV-positive or immunocompromised AND are recent contacts to known or suspected infectious TB disease, regardless of previous treatment of LTBI
• Is HIV-positive with fibrotic changes on CXR consistent with prior TB who have received inadequate or no treatment for TB disease
• Is a child <5>

>5 mm is considered a positive reaction if the patient:

• Is HIV-positive
• Is a contact to known or suspected infectious TB case identified within the last two years
• Has fibrotic changes on CXR consistent with prior TB and have received inadequate or no treatment for TB disease
• Is Immunocompromised (receiving >15mg per day of Prednisone for one month, other immunosuppressive drugs, organ transplant recipients, persons taking TNF inhibitors)

>10 mm is considered a positive reaction if the patient:

• Is foreign-born from Asia, Africa, Carribean, Latin America, Mexico, South America, Pacific Islands, or Eastern Europe)
• Has converted their TST within two years
• Has a medical condition placing them at high-risk for TB Disease (DM, CRI, Chronic malabsorption syndrome, Leukemias and Lymphomas, Cancer of the head and neck, Silicosis, Weight loss of >10% ideal body weight, gastrectomy or intestinal bypass)
• Is an injection drug or crack cocaine user
• Is a child <4>
• Works in a mycobacterial lab

*Also, this cutoff is used per the clinicians judgement for: residents of long-term care facilities and homeless shelters, are inmates in the DOC, OR are employees in prisons/jails, long-term care facilities, hospitals/health care facilities, adult day-care centers for HIV patients, homeless shelters).

>15 mm is considered a positive reaction if the patient:

• Has NO risk factors for TB

Hope this helps!

Yvonne Carter, MD

HIV, Syphilis, and When to LP

Syphilis is a significantly prevalent STD in North Carolina, particularly in the setting of co-infection with HIV. Screening for syphilis is reviewed in the Syphilis Screening section of the blog. But, a common question that must be addressed in this circumstance is:

When is it necessary to perform an LP in to rule out Neurosyphilis in the HIV-positive patient?

The answer has many answers, but the commonly accepted answer is as follows: "All neurologically asymptomatic HIV-infected patients whose serum RPR titer is greater than or equal to 1:32 should undergo lumbar puncture regardless of syphilis stage." And, of course, any symptomatic HIV-patient with a history of syphilis should undergo LP to rule out Neurosyphilis.

This recommendation is taken from two main studies:

• Marra, et al. J Infect Dis 2004; 189: 369 - 376.
• Libois, et al. Sex Transm Dis 2006. HIV and syphilis: When to perform a lumbar puncture.

Yvonne Carter, MD

A little about Ryan White and ADAP

The AIDS Drug Assistance Program (ADAP) is funded through federal monies that are distributed under Part B (formerly Title II) of the Ryan White AIDS Care Act, which was renewed (thankfully) and "modernized" in 2006. For more information about the RWACA, see the Health Resources and Services Administration's website at http://hab.hrsa.gov, and for specifics about the individual parts (formerly "titles"), see http://hab.hrsa.gov/aboutus.htm. Our clinic receives direct funding for our nurses to follow individual at-risk patients closely by phone, under Title II/Part B. If you have someone who needs a little more attention, ask someone about how to get them onto Title II.

Below is an email sent to the division by Rhonda Stephens, the clinic's financial counselor, back in March 2008:

Each year clients are notified with 2 letters from the state ADAP program and 2 letters from the ID clinic financial counselor regarding their renewal with the ADAP program.

The letters consist of advising the clients to renew their ADAP application prior to deadline, what to bring to an appointment of renewal and whom to contact with questions.

Clients are asked to bring documentation of income which may consist of W-2, tax returns, pay check stubs, and/or benefit statements. This information is needed for everyone in the household. If client is unemployed-no letter is needed stating who is supplying their financial support. If client is employed and is not receiving a pay check stub they may return a letter from their employer stating amount of income received either monthly or annually. If this information is not returned prior to ADAP deadline, they are contacted by the ID clinic financial counselor or the ID social worker. We have made repeated contact with clients either by phone or when they were in the clinic to obtain this information.

Clients are provided with a self addressed stamped envelope which is included with the reminder letters and/or given out at clinic appointment to return requested documentation. Clients are also advised they may fax the information to the ID clinic.

Some clients have chosen to have their applications completed by an outside agency, these clients are asked to provide the ID financial counselor or ID social worker with the contact name of the person or agency completing the application so that we may stay in contact and make sure the applications are completed prior to deadline.

When clients come to their appointments, they may sign the application but many of them have failed to bring the required documentation; therefore, the application is not complete. Clients are advised that with incomplete information, the application will be delayed and they stand to have a delay in getting medication for the upcoming months. We contact the clients to remind them that their ADAP benefits will run out. Many of the clients on the list have failed to return requested documentation of income.

There are times when these clients who needed to renew their ADAP benefit were missed during their clinic appointment. These clients may not have wanted to wait to see a counselor. Transportation may have been an issue. They may have forgotten to have asked to see a counselor or they may have had other appointments they needed to attend. These clients were also contacted by phone by the counselors in hopes of capturing them prior to ADAP deadline.

We use the help of the front desk staff and the nurses to assist in capturing the clients before leaving the clinic.

– Christopher Hurt

Anal Paps for Everyone!

Although we haven't made it official, making anal Pap smear testing routine for everyone is becoming more and more important. Data from several studies in 2007 and 2008 showed (shockingly!) that heterosexuals get anal HPV just like men who have sex with men do. There are a handful of patients with whom I've dealt in-house who had abdominoperineal resection (APRs) or pelvic exenterations for advanced-stage anorectal carcinomas that could have been avoided with screening.

UCSF has sort of pioneered the "new" science of screening for cancer of the anus, and their website is I think the reference for how to do it: http://www.analcancerinfo.ucsf.edu/screening/philosophy.html . Take a quick look at their anatomy page, too, just to refresh your memory: http://www.analcancerinfo.ucsf.edu/screening/anatomy.html .

I think (and probably most of the attendings would agree) that at the very least, all sexually active men who have sex with men should have annual or every-other-year screening, a la sexually active women getting Pap smears. The British HIV Association in 2008 published guidelines for cancer screening that included a bit about anal cancer, but the USPSTF and DHHS haven't weighed in yet on things. The BHIVA's guidelines are a little wishy-washy about how to screen, and UCSF's clinic actually does anoscopy (akin to a colposcopy) on their patients, with acetic acid prep and biopsy for diagnosis - rather than cytology.

Our clinic's as-yet-unpublished chewing-gum-and-paper-clips guidelines go something like this:

• Open and nonjudgemental discussion with male and female patients about sexual risks on a routine basis, including having receptive anal sex with or without condoms
• Annual or biennial (QOY) screening with female cervical Pap kit's cytobrush inserted into the anal canal and then sent to Pathology in the supplied fixative
• If no dysplasia is identified, then likely can fall into an algorithm along the lines of female Paps, with spacing-out of tests if a couple of negative tests are obtained and patient is in a monogamous relationship
• For any dysplasia, referral to general surgery for consideration of anoscopy with biopsy for staging and additional management (just like sending to Gyn for a colpo with ASCUS, LSIL, or HSIL)

It's unclear whether or not insurance carriers will cover the Pap testing, but as with other tests we do, I think that good medicine shouldn't be impaired by the billing department. Lynda Bell and others in the clinic are working on trying to sort out those issues.

The younger guys will balk at this, and probably many women will, too. Also be aware that in the Latino community, there's a significant and well-described social desirability bias that keeps women (and sometimes men) from owning up to having anal sex. In a perfect clinic setting (which we're not), all male and female patients would be screened. Just like with your residency continuity clinics, it's difficult sometimes to work in primary and secondary prevention into visits where the patients are sick as stink or come in with specific complaints. Just do your best! :)

– Christopher Hurt

Antiretrovirals and Resistance

So this is a big topic, and I had put together a PowerPoint (with the "script" in the notes section beneath each slide) for a School of Pharmacy class in 2008 on antiretroviral resistance testing. It's at a level that I think is good for people getting acquainted with the principles of resistance tests:

http://www.unc.edu/~churt/downloads/ARV_Resistance_Hurt.ppt

This covers the basics of:

• why HIV mutates so readily
• principles of the techniques involved for resistance testing
• who needs to get a test (by the 2007/08 DHHS guidelines)
• what happens to your patient's blood sample once you order a test
• the differences among phenotypic, genotypic, and "virtual phenotype" testing
• a tangent on why certain positions (like K103N or M184V) are so significant, but other positions aren't (the answer is tertiary protein structure)

I'd welcome any questions or comments on this. The top 5 gurus for ARV resistance here (in order of who you should talk to if you have a significant, burning question) are:

1. Joe Eron
2. Joe Eron
3. Joe Eron
4. David Margolis
5. David Wohl

The thumbnail version
Basically, HIV mutates so quickly because it's crappy at proofreading itself. The reverse transcriptase (RT) has poor (but present) proofreading activity, so if it mismatches a nucleotide base-pair, it can't stop, back up, and excise the mismatch. Instead it blows through the copy, generating many, many point-mutations in the sequence of each copy. Poor fidelity in the copying process means more mutations, some of which are fatal to the protein/enzyme, rendering it useless - but others are fortuitous and confer resistance to a medication. The selection pressure of the ARVs drives natural selection in a beautifully Darwinian way. This is an important point, because without the selection pressure, the most "fit" (able to copy itself readily) version (aka "quasispecies") of HIV in the body will overgrow all others. This is usually referred to as "wild-type," meaning there's no native resistance. However, keep in mind that if a patient is infected with resistant virus at the outset (transmitted drug resistance), then that is their wild-type. Some mutations will revert back towards wild-type over time, through back-mutations, but others may persist for months-t0-years after acute infection. This is the underpinning for why the DHHS recommends now that all patients newly entering HIV care have some baseline assessment of antiretroviral resistance.

At UNC, our test of choice is the "virtual phenotype" or VIRCOtype, provided by Virco, a company with an office in the RTP but whose main offices (and labs) are in Belgium. This test combines a repository of straight-up nucleotide sequence data with one of phenotypic resistance information as lab-cultured viruses are exposed to drugs and their replication measured. Although it has some warts, it's pretty good at predicting what meds will work and which won't. It can't predict synergy, however, and that's a significant drawback.

The mutations are alphabet soup and will be for a while. Don't freak out, it's supposed to be that way – and I never feel bad about looking at one of the IAS-USA resistance cards in the clinic, since even people like Joe Eron and Amanda Corbett refer to them routinely. Realistically, you don't need to memorize any mutations. The ones that make a difference will be repeat customers and you'll come to know them by repetition. Others are less important and you have other stuff to fill your brain up with as things get going for you here. (Plus as each new med comes out of the pipeline, a new set of mutations will become apparent as more and more people get on them.)

– Christopher Hurt

Tips for calling an ID consult

General Stuff

Please try to call us with new consults before 1:00 pm, as we go down to the microbiology lab for plate rounds at 1:30, and it's helpful to be able to see their plates, etc. while we're there.

Please don't call us for oral recs on the day of discharge, if at all possible. We don't like to hold up people's exit from the hospital when we tell you they need a PICC line and 2 weeks of bug juice.

HIV Patients

In 2007, the ID division requested from all admitting services that a special HIV consult be called for any and all patients with HIV admitted to UNC, on any team. The purpose of this is to reduce the number of errors in antiretroviral medications prescribed, and so that the clinic providers know their patient is admitted. Unless there's an ID issue you need help with, we'll usually leave a brief note outlining their ARV doses, and then not actively follow the patient. If you want us to follow them, please let us know that up front.

When you call us with one of these, please tell us why they're being admitted, what their most recent CD4 count and viral load are, who their clinic provider is (and if they're not followed here, where they go), and what antiretroviral medications they're taking (if any).

Helpful ID Pearls of Wisdom

The first rule of ID is, don't catch what they have. Don't be ashamed to go dig out a green N95 mask or put on a gown to go talk to a patient, if you don't know what their diagnosis is.

If you stick yourself:

(1) stop whatever you're doing,

(2) wash your hands with soap and water,

(3) call the occupational health clinic, at 966-9119 (or after-hours, 966-7890)

There is no data supporting the use of oral antibacterials for treating a bacteremia in adults - all of them require parenteral therapy, for at least 14d (assuming it's uncomplicated - no endocarditis, indwelling lines, etc.)

Staph aureus in the urine is ALWAYS A BAD THING. It should never be considered a contaminant, and you should call us to help with a general workup for an occult bacteremia.

If you have Staph aureus in the blood, they need an echocardiogram. We're always going to ask for one if you call us with a positive Staph aureus blood culture.

Coag-negative Staph (epidermidis) should always be considered oxacillin/methicillin-resistant (ORSE/MRSE), but doesn't require contact precautions.

For fevers of unknown origin, please make sure you really have no idea where it's coming from - so make sure you have a chest film, urine and blood cultures, and sputum cultures (if appropriate) cooking before you call us.

If you're calling for antibacterial recs, please try to have an idea of what they've been on to-date, when it was started, and the most recent culture data. Microbiology labs at outside hospitals are usually pretty friendly and helpful if you call for data.

If you think your patient has necrotizing fasciitis or a deep-seated tissue infection like pyomyositis, call general surgery FIRST and THEN call us. We'll help with antibacterials, but the treatment is ALWAYS surgical. Clindamycin for the first 72h of true nec fasc may save the patient's life by shutting off bacterial toxin production. Add it if you think they're not doing so hot - and then call us.

For TB rule-outs, you don't have to get sputum samples only from the first-thing-in-the-morning sputum - you can get 3 serial samples, if they're spaced at least 8 hours apart. One bronch sample counts for 3 induced or expectorated sputa.

For questions about contact precautions, etc., we're happy to help - but the best resource is actually hospital epidemiology, whose number is 966-1636. Someone's always on-call for them, too.

New antibacterials

Linezolid is a nasty medication, and shouldn't be used willy-nilly! It can causes a reversible, isolated thrombocytopenia in up to half of patients who receive it, and whole-marrow suppression in up to 25% of those on it. It also has MAOI-like properties, so drug-drug and drug-food interactions are significant - including serotonin syndrome if co-administered with SSRIs, and hypertensive crises if taken with some foods. If you have a question about whether or not to use it for a patient, just call us.

Tigecycline makes people ridiculously nauseous, and that's by far its limiting side effect. It cannot be used for bloodstream infections, since it's static and doesn't concentrate in the blood. Great for tissue, bad for blood.

Daptomycin causes rhabomyolysis, so you need to follow CPKs on patients while on therapy. It can be used for bloodstream infections, but not pneumonias - since lung surfactant inactivates the drug. Great for blood, bad for pneumonias.