Pre exposure prophylaxis for HIV

A homosexual male who is an iv drug abuser walks into the office...asking ways to help him prevent contacting HIV..with his high risk behaviour!! Apart from advising on safe sex and risks of sharing needles(which are most important..and at the same time cannot be relied at all times due to non adherence)....do we have any medications to offer him??


Lets look at the iPREX study published in NEJM Dec 2010. This was a placebo-controlled, double-blind, randomized trial involving 2499 subjects(men who have sex with men) to see if a combination of Emtricitabine-Tenofivir(FTC-TDF) once daily reduced the incidence of HIV over a f/u period of 1.2 years. Of the 100 incident HIV infections during the study period, 64 occurred in the placebo group and 36 in the FTC–TDF group, with an efficacy of 44% and a 95% CI of 15 to 63. An important finding to note is that, in the FTC–TDF group, the study drug was pharmacologically detected in 51% of subjects who remained free of HIV infection but in only 9% of those who became infected. So exposure to FTC–TDF was associated with a reduction in HIV acquisition. Main issues in putting this into practice has a few concerns. Few of them are drug adherence(very poor in the study), long term outcome, side effects(quite a few in the study drug group had renal impairement which rverted to normal on discontinuation of drug!). All these issues have been nicely discussed in the letter following the study( another arrow in the Quiver.NEJM Dec 2010)
Now the trial has been extended to look for long term outcomes and ways to improve adherence. results are expected by 2013.(HIV & TB News)


An earlier study , CAPRISA 004 in which a total of 889 sexually active, HIV-uninfected women (age range, 18–40) received either 1% tenofovir gel or placebo gel, with instructions to administer the gel intravaginally within 12 hours before sex and also within 12 hours after sex. Mean follow-up was 18 months.The incidence of HIV was 5.6 /100 person-years in the tenofovir group versus 9.1 /100 person-years in the placebo group, for an incidence rate ratio (IRR) of 0.61 (95% CI, 0.40–0.94; P=0.017). Shows promise for pre exposure prophylaxis.


In this context ...FEM-PrEP trial has to be mentioned. This study evaluated if oral daily FTC-TDF prevented HIV in a group of high risk women. The study was stopped last month after an interim analysis didnt find any benefit compared to placebo.(AVAC April 2011). Full analysis of trial should be available shortly.(may be related to adherence issues!!)


VOICE trial - Vaginal and Oral Interventions to Control the Epidemic .........is an ongoing study on high risk women comparing FTC-TDF, tenofovir tablet alone , or tenofovir gel. This study might shed light into ..which of these will be more effective. By this time we will also have the long term safety and compliance outcomes on the i-PREX study.
May be 2013 might be a year the world would see a...  'HIV prevention pill'  !!!

The "aura" of migraine

Migraine can be with or without aura. What exactly comprises this aura. The prodromal  and associated  migraine symptoms may me mistaken as aura. Lets see what comprises the so called aura.  It is the migraine with aura that is related to an increased incidence of ischemic stroke, and is a contraindication for taking oral contracptives!(as risk of stroke increases 4 fold in this population)

The migraine aura is a complex of neurologic symptoms that may precede or accompany the headache phase or may occur in isolation. It usually develops over 5-20 minutes and lasts less than 60 minutes. The aura can be visual, sensory, motor, or any combination of these.

Auras most commonly consist of visual symptoms, which may be negative or positive. Negative symptoms include negative scotoma, homonymous hemianopic or quadrantic field defects, central scotomas, tunnel vision, altitudinal visual defects, or even complete blindness.The most common positive visual phenomenon is the scintillating scotoma. This consists of an arc or band of absent vision with a shimmering or glittering zigzag border. It is often combined with photopsias or visual hallucinations, which may take various shapes.Scintillating scotoma is a highly characteristic syndrome that always occurs prior to the headache phase of an attack and is pathognomonic of a classic migraine.Other positive visual phenomena include photopsia (uniform flashes of light) or simple forms of visual hallucinations. Heat waves, fractured vision, macropsia, micropsia, and achromatopsia may also occur.

Paresthesias, occurring in 40% of cases, constitute the next most common aura; they are often cheiro-oral with numbness starting in the hand, migrating to the arm, and then jumping to involve the face, lips, and tongue. As with visual auras, positive symptoms typically are followed by negative symptoms; paresthesias may be followed by numbness. Sensory aura rarely occurs in isolation and usually follows visual aura. 

Motor symptoms may occur in 18% of patients and usually are associated with sensory symptoms. Motor symptoms often are described as a sense of heaviness of the limbs before a headache but without any true weakness.Speech and language disturbances have been reported in 17-20% of patients. These disturbances are commonly associated with upper extremity heaviness or weakness.

The migrainous aura generally resolves within a few minutes and then is followed by a latent period before the onset of headache.When an aura is not followed by a headache, it is called a migraine equivalent or acephalic migraine. This is reported most commonly in patients older than 40 years who have a history of recurrent headache.
Again....all this means...that we need a more detailed history from these patients to elicit these findings!!

Headache - - Trigeminal autonomic cephalalgias!!

Lets talk some neurology, as this month Iam doing neurology! When discussing headache, we came across this entity called  'Trigeminal autonomic cephalgias' -- a group of headache disorders with pain referred to the 1st branch of trigeminal nerve associated with cranial autonomic symptoms including lacrimation, injection of the eye and rhinorrhea. They all share the same pathophysiologic etiology....which is largely unknown!!! But there is some eveidence of posterioir hypothalamus in modulating this craniofacial pain, as found out by functional imaging of brain (Lancet 2009)There are 3 types, and they vary in their frequency and duration..

1.Cluster headache - 1 to 8 attacks per day with the mean duration of each attack being 60 min.
2.Paroxsmal hemicrania -  11 to 15 attack per day with a mean duration 15 min/attack
3.SUNCT syndrome (Short lasting Unilateral neuralgiform headache with Conjuctival injection and Tearing) - roughly 20 atatcks per day with a mean duration  of 30 sec to 2 min/attack.

Well this sounds like, that someone just wanted to classify them to make it difficult for others to remember. But it turns out that differentiating these 3 on the basis of duration is important as treatment options are different!
*Indomethacin works well in paroxysmal hemicrania(PH) and SUNCT, whereas it does not help patients with Cluster headache(CH).
*Sumatriptan and Oxygen can help CH, whereas they dont help PH & SUNCT
*For prophylactic treatment for CH, PH, & SUNCT...the drug of choice are Verapamil, Indomethacin & Lamotrigine respectively.
Have a look at this article from UK which explains in detail about these 3 headaches. Especially peek at the table on page 118.(Current Neuro & neurosci report 2007). Looks like ..we may need to be more specific with timing and duration of headaches, as we do for evaluation of chest pains!

Elevated pulse pressure and white coat effect

Can we differentiate white coat effect from true hypertension in the office?
Difficult(we usually need either a 24 hr ambulatory BP monitoring or frequent home BP measurements.....both of which are cumbersome, and cant be done regularly).....but may be possible.....says Dr.Ahn from Korea, when he presented his study in the American College of Cardiology Scientific sessions earlier this month. Lets see what they found out..

They took 1087 outpatients with chronically treated hypertension, and checked home BP twice daily for 2 week, and then checked it in the office. White coat effect was defined as a difference between the physician's BP and the home BP of above 20 mm Hg systolic or 10 mm Hg diastolic BP. White-coat hypertension was found in 31% of patients. Pulse pressure of 60 mm Hg and above positively correlated with WCE by multivariate analysis. So the author concluded that... if a patient has an elevated BP reading in the clinic along with elevated pulse pressure, we can consider WCE before recommending antihypertensive agents. 


Some other interesting associations from the study : 
1. White-coat hypertension was not associated with age or gender in the study, 
2. Those with a family history of premature coronary disease were more likely to display WCE.
3. Those with diabetes or organ damage including the heart, as well as smokers, were less likely to show WCE.


The positive relationship with family history might be the result from the effects of anxiety and emotional stress, and the negative relationship with diabetes or smoking means that the WCE was relatively benign in these patients. Also pts with diabetes and organ damage may not be able to mount a stress response due to autonomic imbalance, LV dysfuction etc.


Is this important? Well.... it is...as we all know that white coat hypertension is a predecessor for chronic hypertension, as based on the findings from Italy(Hypertension 2009) ...in which thy followed nearly 1400 pts with white coat or masked hypertension , and found that 40% of patients with white coat effect progressed to develop Hypertension over a period of 10 years. So..YES...WHITE COAT HYPERTENSION needs to be identified and monitored closely. We usually dont treat WCH due to risk of hypotension...but they need to be monitored closely for development of hypertension. 

Norepinephrine or Dopamine?

It looks like...we may have a winner. Yes
Im talking about the use of vasopressors in the setting of septic shock. There have been a few clinical trials done to see if one vasopressor is better than the other in terms of mortality from septic shock. (the latest one was from SOAP 2 trial from NEJM 2010)We didnt have a clear result so far.

But  a recent meta analysis of the trials have shown that norepinephrine might be better than Dopamine. It is associated with a 9% reduction in in-hospital and 28 day mortality in patients with septic shock. Patients on Dopamine had significantly increased incidence of cardiac arrhythmias compared to norepinephrine. This is probably the reason behind the poor performance of Doapmine...as we all know that arrhythmias can hinder cardiac function. The same finding of increased cardiac arrhythmias with Dopamine was also noted in the above SOAP trial.
The above meta-analysis was done at Thomas Jefferson University.(J of Int Care Med ...March 2011)

Would be reasonable to use nor-epinephrine as the first line vasopressor for patients with septic shock. Infact according to the SOAP trial,dopamine was associated with an increased 28 day mortality in patients with cardiogenic shock, as compared to norepinephrine!

The "Duty to warn" !!

We had a young female with HIV for 10 years,who came with an infected condyloma. She has had previous MAC, vulval cancer and cervical dysplasia  in the past. She has been with her partner for last 1 year, and they are sexually active,and use protection everytime. But when enquired, she said that the partner does not know about her HIV status , and she did not want to disclose this to him .Now.......do we have to honour her wish or...do we have to let the partner know?? Lets see what Connecticut law tells us.....(beware..this may not be true for other states!)

The term “duty to warn” refers to situations in which a  physician may learn that a patient is engaging in unsafe sex without having disclosed his or her HIV-positive status to the partner.
Connecticut law permits both public health officers and physicians, under certain circumstances, to inform or warn partners that they may have been exposed to HIV.The term “partner” means an “identified spouse or sex partner of the protected individual or a person identified as having shared hypodermic needles or syringes with the protected individual.” The requirements for such a disclosure by a public health officer are that:

1.There is a reasonable belief of a significant risk of transmission to the partner.

2.The public health officer has counseled the individual regarding the need to notify a partner and reasonably believes that the individual will not disclose to the partner; and

3.The public health officer has informed the protected individual of his or her intent to make the disclosure.

A physician may only warn or inform a known partner if both the partner and the individual with HIV are under the physician’s care. A physician may also disclose confidential HIV related information to a public health officer for the purpose of warning partners, if the physician takes the same steps with respect to his or her patient as public health officers must take above.

In making such a warning, the physician or public health official shall not disclose the identity of the HIV-infected individual and, where practicable, shall make such disclosure in person.

Well...this is still an evolving area of ethics, and might change in the future. Hope this helps.....and this is a sensitive issue to be dealt.

Antihypertensives - a little pharmacology helps

I came across this article recently about some interesting facts about antihypertensive medications and their pharmacology, which I though will be useful for practising clinicians like us!
The article describes about all 4 major types of antihypertensives. But the one which stands out is the angiotension converting enzyme inhibitors----WHY?     due to their difference in pharcological actions compared  to others.Let me start with a question..
If Mr.X tolerates(no hypotension) 5mg of Lisinopril, can we increase the dose to 40mg straightaway?

Most of us would say "NO". But the author says yes....and the explanation is pretty simple, interesting and true!
Unlike the other antihypertensives(beta blockers,CCB,diuretics), ace-i do not have a linear dose-response relationship....meaning that their BP lowering effect is not proportional to the dose. In other words....the efficacy of ace-i is the same irrespective of their dosage. Again...to make it more simple...a dose of 5mg of Lisinopril will lower the BP to the same extent as 40mg of Lisinopril. So why give 40mg in place of 2.5 mg? Well...the dose correlates with the duration of action.the higher the dose...the longer the duration of action!(Brit J Pharm 1984!)
It looks like...we have the low doses of ace-i in the market mainly to be used in patients with heart failure (who might have a low BP due to their other meds) to see if they can tolerate any hypotension induced by addition of ace-i. Also, the common side effect of ace-i...COUGH ..is not dose related.So here again..the dose doesnt matter.

So the article concludes that..ace-i don't have a linear dose-response curve, and so their dose can be increased to the maximal dose without any major concerns for hypotension. But ...one aspect of ace-i that the article doesn't discuss...is hyperkalemia. Well..the risk of hyperkalemia with ace-i is dose related, and whether it would be a good idea to go for a maximal dose straightaway or to increase it gradually, in this aspect.So..bottom line-----beacuse of the risk of hyperkalemia..we may not be able to go to a maximal dose directly, and not because of risk of hypotension.
A quick word abt hyperkalemia with ace-i : the risk is quite low on its own. The risk is high in CKD(4 fold risk), hepatic disease(almost 5 fold risk), taking>15 tablets(5 to 9 fold risk), advanced age(twice likely)...
(Pharm W Sci 2009)

Finally..the above article was published in American J of Cardio vasc Drugs 2011. The graph(above) is a modified graph from the same study.