Recent Posts

June 13th, 2011

More on Generic Antiretrovirals …

In the recent post on the approval of generic Combivir — and the lack of availability of generic Epivir (lamivudine, 3TC), which was both anticipated and likely to be more useful — I speculated there were several possible causes of this surprising turn of events.

But ultimately I concluded, “In sum, the real reason there’s no generic 3TC remains a mystery.”

Last week, however, I received a fascinating email from an industry representative, who has asked that I summarize the turn of events from their perspective:

  • The Epivir patent in the US expired in May 2010.
  • A generic company was granted exclusive rights to market a generic in the US for 6 months.  (This is part of patent law.)
  • The particular company that was granted exclusivity was not been able to manufacture a product that has met approvability standards by the FDA.
  • During the period of exclusivity, furthermore, no other company can market a generic either — again, patent law in action.

Mystery solved — and thank you for the clarification.

But I hasten to add that this information was not widely known by HIV/ID specialists, and furthermore not easy to find.  One of my colleagues has likened reading rulings on patent law for generics akin to learning English as a second language, a very apt analogy.

June 9th, 2011

E. Coli, ID Doctors, and Fear of Infections

This was going to be about the shiga-toxin-producing E. coli (STEC) outbreak in Germany, and I promise to get there eventually.

But to start:  One very useful concept from psychiatry is “reaction formation.” For those of you who have forgotten your college Psych 101, here’s the definition:

A psychological defense mechanism in which one form of behavior substitutes for or conceals a diametrically opposed repressed impulse in order to protect against it.

Some examples:  the person who controls criminal impulses by becoming a cop, or someone with a fear of heights who fixes cell phone towers.

How about ID doctors?  Do some of us choose this field because we’re scared of catching nasty bugs?

Undoubtedly yes — I have one colleague who, at great personal expense, had all the windows, screens, and vents replaced in his house because he saw some bats flying around his neighborhood on a warm summer evening. He has been observed to wear a surgical mask when he looks in his patients’ ears (“just to protect you,” he lies), gets the tempura at sushi restaurants, and he wouldn’t travel to a developing country even if you gave him, for free, round-trip first-class airfare and the best suite in this resort.

He’d deny it, but I strongly suspect his choice of specialty is directly related to his fear of contagion.  (That interpretation was gratis.  You’re welcome.)

But then there are plenty of us who are relatively cavalier about infectious risks.  In one famous example, a certain sainted ID doc (initials PF) never received vaccination for hepatitis A despite having probably the highest travel/work related risk on the planet.  The result:  a fairly prolonged hospitalization from acute hepatitis A.  Boy was he sick. (Read all about it in this excellent book.)

Even more impressive, there are those who bravely volunteer for outbreak investigations, even for incredibly scary, mysterious, or untreatable diseases. Two recent examples that come to mind are SARS in China and the  extensively drug resistant (XDR) TB cases in South Africa.

With the caveat that any self-reflection is likely to be biased, even in a highly psychoanalytic milieu (my father is a psychiatrist), I consider myself as one of those ID doctor on the less-worried side of the spectrum.  I’ll take my chances with the bats (unless one actually bites me …), choose whether to eat or not to eat sushi based on taste (not because of infectious risk), and believe that most Travel Clinics cater predominantly to the worried-well — or, if you want to be less nice about it, the paranoid. Plus, I have never feared getting HIV from patients, even in the 1980s when we knew a lot less about transmission than we do today.

On the other hand, I doubt very much I’ll be raising my hand anytime soon to volunteer for on-site evaluation of an Ebola outbreak.

But getting back to this toxin-producing E. coli:  here’s one infection that I do take pretty seriously — ok, I admit it scares me — and confess to being kind of rude about it.

You don’t want me at your cookout if you plan to serve hamburgers rare, as I will undoubtedly be obnoxious about sharing my fears not just with you but all the other guests as well.  Maybe it’s because of stories like this one. Or perhaps because my wife has discussed with me a few truly harrowing examples of previously-healthy kids from her practice who ended up on dialysis.  Or that antibiotics not only don’t help, they even increase the risk of disease.  And yes, I also saw the movie “Food Inc.” (review here), which really does make you understand why ground beef in particular is so risky.

So as they investigate the source of this terrible outbreak in Germany — which appears to be non-meat related, at least based on what is known right now — do yourself a favor, and cook those burgers all the way through, and skip the sprouts.  (I know burgers taste worse cooked this way, but most people don’t like sprouts anyway.)  And take some comfort in the fact that at least in the USA, cases of STEC from the O157:H7 strain are actually down (Journal Watch summary here).  Let’s hope it stays that way.

June 4th, 2011

HIV Epidemiology and Something Even Many Smart Medical Students Don’t Know

Periodically I like to give an informal quiz to the medical students about HIV epidemiology. It’s a multiple choice question that goes something like this:

Based on the recent epidemiology of HIV in the United States, in what group are new cases of HIV infection rising the fastest?

  1. Men who have sex with men (MSM)
  2. Injection drug users (IDUs)
  3. Heterosexual women
  4. Some other group

(Correct answer:  #1.)

Now these are smart kids.  Many of them have done impressive things before starting med school, including a bunch who have even worked in the HIV field (especially global HIV).  Yet despite these brains and experience, you’d be amazed how often they choose the wrong answer, most commonly choosing #3 (a group in whom incidence is essentially flat or declining) or #2 (injection drug use HIV in the USA is, thankfully, disappearing).

On the 30th Anniversary of the first report of what is now known as AIDS, the MMWR has released its latest HIV Surveillance report.  And, as in pretty much every year for more than a decade, here are the facts:

Surveillance data show that the proportion of HIV diagnoses occurring in MSM continues to grow. HIV incidence among MSM has increased steadily since the early 1990s. In 2009, MSM accounted for 57% of all persons and 75% of men with a diagnosis of HIV infection... Syphilis and gonorrhea are endemic among MSM; outbreaks or hyperendemic sexually transmitted infections have been reported from many communities where HIV infection also is prevalent, further increasing the risk for acquiring and transmitting HIV.

I’m not sure why this isn’t more widely known (certainly we HIV/ID specialists know it), but I have a theory.  Sometimes a story has media “stickiness”, and once it’s out there, it’s hard to get rid of it.  When AIDS first hit, it was overwhelmingly a disease of MSM and IDUs; quickly it became apparent, however, that it was a sexually transmitted infection so that women were at risk too. This was a big media story — famous Life Magazine cover shown above — and somehow this has never disappeared.

It’s kind of like, “tuberculosis is making a comeback in the USA” when, in fact, TB rates are historically low.  The TB Comeback is just too sticky.  Same thing with the generalized HIV epidemic in this country which, if you take a look at this incredibly cool map, has never happened.

Take home message:  HIV prevention and testing efforts should be maximally deployed where the epidemic is still raging.  Here in the USA, that means MSM and/or communities of color.

June 2nd, 2011

Original XMRV/CFS Paper Almost, Sort-of Retracted by Science

From the pages of Science

In this week’s edition of Science Express, we are publishing two Reports that strongly support the growing view that the association between XMRV and CFS described by Lombardi et al. likely reflects contamination of laboratories and research reagents with the virus … Because the validity of the study by Lombardi et al. is now seriously in question, we are publishing this Expression of  Concern and attaching it to Science’s 23 October 2009 publication by Lombardi et al.

In the roughly year and half since this story first broke on XMRV as a possible cause of CFS, there have been literally dozens of scientific papers (published, unpublished, and presented), many editorial comments, conference proceedings — and probably thousands of blog posts (I’ve added to the traffic) and impassioned comments from people suffering from this condition.

As I’ve noted before, perhaps the best coverage in the non-medical/science press has been over here in the WSJ.

And while there is now significant “concern” about this XMRV/CFS association, there is little doubt about the need for more research on CFS.  One problem is that the XMRV debate could become a distraction in the search for other possible causes, host factors, diagnostic tests, and treatments.  Let’s hope that doesn’t happen.

May 26th, 2011

Surprise! It’s Generic Combivir!

After last week’s unveiling of the new NNRTI rilpivirine, now we have a different kind of drug approval from the FDA:

FDA granted approval for a generic formulation fixed dose combination of lamivudine and zidovudine tablets, 150 mg/300 mg, two nucleoside analogue reverse transcriptase inhibitors, indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection … FDA has determined that the generic formulation is bioequivalent and, therefore, therapeutically equivalent to the reference listed drug, Combivir Tablets…

Combivir? 

Now that’s a surprise — most HIV providers thought that the next generic antiviral would be lamivudine (3TC) on its own. Some were even expecting it last year.  After all, 3TC is incredibly safe and effective, has been used in literally millions of patients both here and abroad since its approval in 1995, and already is available as a generic all over the world.

Adding the zidovudine (AZT) part to 3TC definitely makes this generic much less appealing. Zidovudine hasn’t been a “preferred” or “recommended”  part of first-line regimens for several years due to its association with GI side effects, anemia, lipoatrophy, and the requirement for twice-daily dosing.

So why generic “Combivir” (it won’t be called that anymore) and not 3TC alone? Some thoughts:

  1. Coformulation magic.  All of us have had patients who didn’t tolerate individual drugs — efavirenz, for example — who later went on to be quite happy taking that same drug as part of a combination pill (e.g., Atripla, which has efavirenz in it).  The same thing happened when branded Combivir was approved. Suddenly, AZT was fine.  Go figure.
  2. There are a lot of pregnant women with HIV out there. Yes, most of the pregnant women with HIV are treated with Combivir.  But if the rest of the country is practicing the way we do, they are switched to something safer and better tolerated when the pregnancy ends.  So I doubt this is it.
  3. Studies suggest that everyone already on TDF/FTC, TDF/FTC/EFV,  and ABC/3TC will stay on them. Our patients love these coformulated drugs (see #1 above).  Perhaps a survey of patients, providers, payors, and other interested parties found little appetite for breaking these combinations up, which is what would be required to get generic 3TC prescribed.
  4. Some “business plan” we don’t understand. My next door neighbor is a smart guy who went to business school.  He’s not a doctor. And he says that everyone he works with knows that doctors are lousy with money issues, negotiate poorly, and are easily duped into paying top dollar for things that aren’t worth very much (electronic medical records and billing systems are his favorite examples).  So maybe we just don’t understand the finances of selling combination AZT/3TC vs 3TC alone.  Right.
  5. A deal involving companies and lawyers and back room deals. It goes something like this: The makers of branded HIV drugs have made an elaborate deal with the generic companies involving the transfer of huge sums of cash (preferably to an off-shore bank account) in exchange for not making generic 3TC. The exploitation of an obscure legal loophole would undoubtedly have been required. If it can happen with potassium … Something for the conspiracy theorists to mull over.

In sum, the real reason there’s no generic 3TC remains a mystery.

Of course the FDA could announce its availability next week, in which case this whole post is irrelevant.

May 23rd, 2011

Rilpivirine Approved — the “iPod” of NNRTIs?

From the FDA on Friday (it’s always on Friday, isn’t it):

FDA approved Edurant (rilpivirine) 25 mg tablets, a new non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV. Rilpivirine is an antiviral drug that helps to block reverse transcriptase, an enzyme necessary for HIV replication. The recommended dose of rilpivirine is one 25 mg tablet once daily taken orally with a meal.

This approval comes as little surprise, as the large ECHO and THRIVE studies clearly demonstrated that rilpivirine (RPV seems to be the preferred abbreviation) was “non-inferior” to efavirenz as initial therapy.

More controversial were the details of the aggregate study results, which demonstrated a trade-off between antiviral activity at high viral loads (which favored efavirenz) and the overall safety and tolerability (which favored rilpivirine).

So how will clinicians use the drug?

The answer may be like the debate about iPods (and CDs vs records before that, boy I am showing my age):  Audiophiles knew that the compressed sound required for iPods led to inferior sound, but the new devices were so easy to use that in most cases it didn’t really matter.  Today CDs are rapidly on their way out.

So is RPV the iPod of NNRTIs?  Both better and worse than current options?  Maybe — that would be the best case scenario.

But if the complete iPod effect is going to take place, we probably need the single-tablet formulation of TDF/FTC/RPV, which is currently under development.

May 18th, 2011

HIV Exceptionalism and the Department of Unintended Consequences

Quick question:  If there were one piece of information — clinical or lab — that you would use to determine the quality of care in an HIV program, what would it be?  (Choose one.)

  1. Rates of influenza vaccine administration
  2. Receiving PCP prophylaxis with CD4 < 200
  3. Adherence counseling before starting antiretroviral therapy
  4. Baseline toxoplasmosis serology
  5. Proportion of patients on treatment with suppressed viral load

Maybe I’m being presumptuous here, but one of these — virologic suppression — completely blows the rest of them away.  Sure, the others are worthwhile, but data linking them to improved outcomes for people with HIV are either pretty weak (adherence counseling, flu vaccine) or nonexistent (toxoplasmosis serology).

Even the use of PCP prophylaxis for CD4 < 200, which was highly effective and prolonged survival in the pre-ART era, doesn’t come close to the benefits of effective ART.  One paper even questions whether we need it, provided that the person is on fully suppressive HIV therapy.

So why bring this up under the title of “HIV Exceptionalism”?  Because a certain unnamed institution in an unnamed city (hint: begin with “B”) cannot obtain the aggregate viral load data on their own patients as part of a quality improvement initiative.

The reason?  Anything with “HIV” attached to it, you see, is privacy-protected information under Massachusetts Chapter 111, Section 70F, unless the patient provides written informed consent.  No exceptions listed.

Which means that people with HIV can’t participate in this quality improvement program — in effect, are discriminated against — due to a law that in the post HIPAA era should not even be necessary, since all medical information is now considered confidential.

The state law on HIV testing and privacy, by the way, dates back to when HIV was called “HTLV-III”, and it’s showing its age.  Fortunately, revisions to it are in the works that allow for appropriate testing, clinical care, research, and quality improvement.

Stay tuned.

May 17th, 2011

Physician Bloggers Categorized

About a year ago I linked this cartoon from “Dr. Fizzy”, and I’ve been a regular visitor to her site ever since.

Anyway, more kudos to her for this dead-on categorization of MD bloggers.

(I guess the British “spot-on” is a better choice for us docs.)

Not exactly sure where I fit in this list — yikes — but boy does she get it right here.

In fact, one could replace “The 10 Types of Physician Bloggers” with “The 10 Types of Physician Dinner Companions”, and you’d have a good description of how we MDs interface with the world in pretty much every setting.

May 12th, 2011

HPTN 052 Results — Another Win for Early HIV Therapy

The results of the HPTN Study 052 — which randomized 1,763 serodiscordant couples to early vs delayed ART to evaluate whether this reduced the risk of HIV transmission — have just been released:

Findings from the study were reviewed by an independent Data and Safety Monitoring Board (DSMB) …The DSMB concluded that initiation of ART by HIV-infected individuals substantially protected their HIV uninfected sexual partners from acquiring HIV infection, with a 96 percent reduction in risk of HIV transmission…  Among the 877 couples in the delayed ART group, 27 HIV transmissions occurred. This was in contrast to only one (1) transmission that occurred in the immediate ART group. This difference was highly statistically significant.
Full details from the study are of course not yet available, but here are some reasons why the results, if not surprising, are so important, and why this is a huge win for earlier antiretroviral therapy:
  1. The protective effect (96%) was every bit as good as that reported in non-randomized studies (such as this one).
  2. Since the study only enrolled patients who were asymptomatic with high CD4 cell counts (350-550), study subjects were generally those at the lowest risk of transmitting HIV to others — yet a significant difference in transmission was still observed.  One could have imagined the study being negative due to low event rates, and indeed the relative health of the population is at least a partial explanation for how rare transmission was even in the delayed therapy arm.
  3. Details about the one case of transmission — yes, only one! —  that occurred from someone on ART will be important, such as whether the plasma HIV RNA was undetectable, his/her level of adherence, transmission of resistant virus, etc.
  4. There were clinical benefits to early ART as well, with a significant reduction in the incidence of extrapulmonary  tuberculosis — 17 vs 3 cases in the delayed vs early ART arms respectively.
  5. Note that survival was not different — a factor likely related to #2 above, and something for us to consider when anticipating results of the START trial.

We of course await information on adverse effects, quality of life, resistance, and cost, but it’s hard to imagine that any of these factors would be of sufficient severity to negate the obvious personal and public health benefits of early ART.  In fact, I’ll go out on a limb and predict that they won’t even come close.

And I’ll also express the view that this result is far more important than the PrEP studies, since it’s always made way more sense to me to treat the person with HIV, not the other way around.  PrEP may have a small role in reducing the spread of HIV — especially in certain very high-risk individuals — but is unlikely ever to be widely adopted.

So treatment is prevention.  Now we just have to figure out how to pay for it.

May 9th, 2011

Routine Screening for Anal Cancer: Are We There Yet?

A paper recently published in AIDS evaluated the cost effectiveness of various strategies for anal cancer screening in HIV positive men-who-have-sex-with-men (MSM).

The “bottom line” (ahem):

In HIV-infected MSM, the direct use of high resolution anoscopy is the most cost-effective strategy for detecting anal intraepithelial neoplasia

Over on our Journal Watch AIDS Clinical Care site, Tim Wilkin from Cornell offers his perspective:

High-resolution anoscopy without any prior testing was the most cost-effective of 18 strategies assessed for initial anal cancer screening… This study suggests that direct use of HRA is a reasonable strategy for initial anal cancer screening in a population with a high prevalence of disease. Several other strategies were also effective at a moderate cost, including the one used in my own practice: initial anal cytology, with referral to HRA for individuals found to have atypical squamous cells (ASCUS) or greater.

We covered this area of controversy around a year ago on this site, at which time Joel Gallant admitted to an even less aggressive strategy — namely, not referring patients with ASCUS for HRA at all, but simply monitoring them with yearly pap smears.

His rationale?

My patients don’t enjoy going through HRA, biopsy, and ablation, the parallels between anal and cervical dysplasia aren’t perfect, and the protocols around anal Pap smear are written without much evidence backing them up.

As you might have guessed, I have tremendous ambivalence about what to do about anal cancer screening as of May 9, 2011 (today).  On one side:  this is a highly morbid (and potentially fatal) complication of HIV, a screening protocol, however vague, is out there, and there are advocates who strongly support screening.

On the other side are the issues cited by Joel, the lack of recommendations for anal cancer screening in published guidelines, and the fact that at one of my two practice sites, there has been no single provider who readily offers HRA.

Just speculation here, but on a national level, this last factor might be the most important driver in how often HRA is done at all.

And just like any situation where test availability drives volume, there’s something not quite right about that.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.