Clinical Management of HIV
PEP Regimens & Delivery
Let’s talk a little more about post exposure prophylaxis. In this lecture we’ll discuss PEP
Regimens & Delivery.
•
•
•
We will start by explaining timing for PEP initiation,
and then we’ll go over selection for PEP regimens.
We will also talk about PEP follow-up and adherence support.
Let’s remember that the first step in the approach to PEP is to determine eligibility, including
assessing whether an exposure poses a high risk of transmission, and also factoring in risks and
benefits of treatment.
The second step we talked about was to perform baseline testing, for both the exposed patient
and the source patient if possible.
Next, we’ll talk about how to select and prescribe a PEP regimen.
Optimal Timing for PEP Initiation
First off, let’s answer the question: when is the right time to start Post exposure prophylaxis?
The answer is as soon as possible.
We know that the efficacy of PEP wanes with time.
On this graph, you'll see that as time goes on, on the x axis after the exposure, that the benefits
of PEP really decrease, whereas the risks of PEP mostly stay the same over time. But the
efficacy of PEP definitely wanes with time and so the question is, at what point is it no longer
worth it?
Op#mal #me to start HIV PEP
The efficacy of PEP
wanes with 2me
benefits of PEP
risks of PEP
At what point is PEP
“no longer worth it?”
time
exposure
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Clinical Management of HIV
Just a few words on the evidence for that. We have evidence from animal models, again, from
macaques, and animal PEP studies where they studied the time to initiation of antiretroviral
therapy. These studies suggest PEP is substantially less effective beyond 24 - 36 hours.1,2
They looked at 24 hours, 48 hours, and 72 hours. They found that PEP was most efficacious if
started within 24 hours of the exposure, and that it was less effective if started 48 hours after.
And then it was least effective if started 72 hours after. But all 3 of these timings still showed
some efficacy. However, an analysis of PEP failures did not suggest a clear cut-off.3
And so the guidelines are basically the sooner the better, but we allow up to 72 hours.
Selection of PEP Regimen
Now let’s discuss how to choose a PEP regimen. The first thing to know is that all of the PEP
guidelines including the CDC and the WHO guidelines now recommend using 3 drugs, and those
3 drugs resemble the types of regimens that people take for HIV infection.
So what are some options? We normally recommend a combination of tenofovir disoproxil
fumarate, or TDF and emtricitabine, or FTC, as the backbone of the regimen, with an integrase
strand transfer inhibitor as the anchor drug. This can be either raltegravir or dolutegravir.
I put an asterisk here because there have been historic concerns about dolutegravir causing
neural tube defects in women who are taking the dolutegravir peri-conceptually, or at the time
of conception, or in the first trimester. So some guidelines still recommend raltegravir over
dolutegravir for women of childbearing age who may get pregnant. However, the WHO
recommends giving dolutegravir to pregnant women given more recent data showing that it is
actually very safe. Nonetheless, there are still some concerns and if you have the option, it may
be better to give pregnant women or women of childbearing age raltegravir instead of
dolutegravir.
So TDF/FTC with raltegravir or dolutegravir for 28 days within 72 hours is the main takeaway
here. And again, if you can start it earlier than 72 hours after exposure, that should be done, as
it is more effective the earlier it is given.
There are alternative PEP regimens.4 The alternative backbones are:
•
TDF + emtricitabine
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TDF + lamivudine
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Zidovudine (AZT) + emtricitabine
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Zidovudine (AZT) + lamivudine
And the alternative anchors are:
•
r/darunavir
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Clinical Management of HIV
•
rilpivirine
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r/lopinavir
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r/atazanavir
No need to remember any of these. What I want you to know is that there are options in case
you either cannot get the patient the first-line medications or the patient cannot take those
medications. And there are a few comments I have about these.
One thing I wanted to mention is that nevirapine, which is an older ARV is contraindicated for
post exposure prophylaxis. Nevirapine when used in high CD4 counts can lead to liver disease
or liver failure potentially. And so as you can imagine, someone who does not have HIV who's
using nevirapine for post exposure prophylaxis would have a high CD4 count and so you
wouldn't want to give nevirapine in that case.
Second, abacavir, an NRTI commonly used as a backbone in other regimens should only be used
if the patient is HLA B-5701 negative. So once we know that the patient does not have that HLA
antigen, which confers a higher risk of hypersensitivity reaction to abacavir. So again, don't use
abacavir unless you know the patient's HLA status for PEP. Typically getting that HLA status
takes a while it can take about two weeks to get those results then you're out of the window.
So, abacavir doesn't really have a role in post exposure prophylaxis, because there are many
other backbone drugs you can use that don’t require that testing, and the testing usually takes
some time to come back. So, we don’t want to do that in the setting of PEP where you want to
start the treatment immediately.
Finally, newer combination pills including the combination of elvitegravir, a newer integrase
inhibitor, plus TDF and FTC is OK.
The WHO recommendations for post exposure prophylaxis are similar to what we just
discussed. Regimens should be three drugs.5
The first-line regimen for adults and adolescents is the same as the CDC, which is TDF/FTC plus
dolutegravir.
In children aged 10 or younger, we give AZT+3TC as the backbone although there are several
alternatives to this, including ABC+3TC, TDF+3TC/FTC.
And you can see that the recommended third drug is the same for kids as for adults:
dolutegravir, while raltegravir is an alternative.6
Ok, let’s ask and answer another question. How long do we give PEP for?
I mentioned already that we're going to do 28 days.
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Those are the recommendations, but where do we get this data? So, this comes from again, a
macaque study of 24 macaques which were inoculated with SIV intravenously. They were given
tenofovir alone subcutaneously for PEP and that was initiated 24 hours post inoculation. So
within that 72 hour window. And PEP was administered for 3, 10 or 28 days.
Dura#on of PEP
N = 24 macaques
inoculated with SIV
intravenously
24
PMPA for PEP
ini+ated 24 hours
post-inocula+on
PEP administered for
3, 10, or 28 days
Tsai et al., 1998
And here you can see on the graph the rates of seroconversion based on the number of days
the animals were given PEP. 50% of the macaques converted to SIV if they were only given
three days of post exposure prophylaxis.
If they were given 10 days of PEP, there was a 25% seroconversion rate.
Here you can see with 28 days of PEP there weren’t any seroconversions. This is some of the
evidence that determined the duration of PEP.
So, based on what is seen in animal models, the takeaway here is that 28 days is best. Much
better than 10 days. Much better than three days. And so not surprisingly, both the CDC and
WHO guidelines recommend four weeks of therapy.7
We've selected a PEP regimen, we're going to give this person PEP for 28 days. Now, let’s go
back to our approach to PEP to understand what the next steps should be.
So far, we’ve determined eligibility, including
1. Assessing the risk of transmission and
2. Considering other factors, including risks & benefits
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Clinical Management of HIV
We’ve performed baseline tests, and we’ve selected & prescribed a PEP regimen, including the
timing and duration of PEP.
PEP Follow-up and Adherence Support
The final step is to determine a follow-up & adherence support plan. And there are several
different reasons for needing a follow-up plan. First, the scheduled follow up visits are
necessary so that you can re-test the patient for HIV following initiation of PEP. This should
happen at 6 weeks, then 3 months, and then again at 6 months. This is necessary because you
really need to know as soon as possible if the patient does end up acquiring HIV.
Lab Monitoring and Follow-up
Re-test for HIV following ini2a2on of PEP
Baseline Tes1ng
HIV Ag/Ab
See prior
Crea+nine
Aminotransferases
Hepa++s C Ab
Baseline
Hepa++s B sAg,
cAb, sAb
STI Screen
Pregnancy Test
HIV Ag/Ab
HIV Ag/Ab
6 weeks
3 months
HIV Ag/Ab
6 months
USPHS, 2013
When you are seeing a patient at these follow-up visits, it’s also important to screen them for:
•
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any side effects of the medication,
and also for any flu-like symptoms that could be symptoms of acute HIV infection.
Finally, it is important to take steps to support adherence to the regimen once you’ve outlined
your follow-up plan because adherence can be very low.
In one systematic review and meta-analysis of 97 studies, there was only a 56% completion rate
of PEP. That was 65% for non-occupational exposures, 67% MSM, 40% for sexual assault
exposures, and really, really, low for adolescents, only 36%.
Adherence support could include adherence counseling, adherence support groups, peer
educators or peer navigators, or other systems. These may be most important for adolescents
because their rates are lower as compared to adults and pediatric patients.
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Summary
In summary, the choice of drug regimen for PEP is similar to first-line regimens for HIV; namely,
TDF with FTC, plus either raltegravir or dolutegravir.
Consider raltegravir in women of childbearing age.
PEP should be given as soon as possible after exposure and should continue for 28 days.
A follow-up plan is essential for follow-up testing, side effect and other symptom monitoring,
and adherence counseling and support.
References
1. Tsai, C. C., et al. (1995). Prevention of SIV infection in macaques by (R)-9-(2phosphonylmethoxypropyl)adenine. Science (New York, N.Y.), 270(5239), 1197–1199.
https://doi.org/10.1126/science.270.5239.1197
2. Shih, C. C., et al. (1991). Postexposure prophylaxis with zidovudine suppresses human
immunodeficiency virus type 1 infection in SCID-hu mice in a time-dependent manner.
The Journal of Infectious Diseases, 163(3), 625–627.
https://doi.org/10.1093/infdis/163.3.625
3. Office of Enterprise Communication. (2001). Mobility and mortality weekly report June
29, 2001 (Report No. RR-11). U.S. Center for Disease
Control. https://www.cdc.gov/media/mmwrnews/2001/n010629.htm
4. USPHS Working Group on Occupational Postexposure Prophylaxis. (2013). Updated U.S.
Public Health Service Guidelines for the Management of Occupational Exposures to
Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis.
Retrieved from https://npin.cdc.gov/publication/updated-us-public-health-serviceguidelines-management-occupational-exposures-human
5. World Health Organization. (2021). Consolidated Guidelines on Prevention, Testing,
Treatment, Service Delivery and Monitoring: Recommendations for a Public Health
Approach. [Section 3.3, p.87-90]
6. Ford, N., et al. for the World Health Organization Postexposure Prophylaxis Guideline
Development Group. (2015). World Health Organization guidelines on postexposure
prophylaxis for HIV: Recommendations for a public health approach. Clinical Infectious
Diseases 60(suppl_3), S161–S164, https://doi.org/10.1093/cid/civ068
7. Cardo, et al. (1997). A case-control study of HIV seroconversion in health care workers
after percutaneous exposure. Centers for Disease Control and Prevention Needlestick
Surveillance Group. The New England Journal of Medicine, 337(21), 1485–1490.
https://doi.org/10.1056/NEJM199711203372101
8. Ford, N. et al. (2014). Adherence to HIV postexposure prophylaxis: A systematic review
and meta-analysis. AIDS (London, England), 28(18), 2721–2727.
https://doi.org/10.1097/QAD.0000000000000505
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9. National Clinician Consultation Center. (2016). PEP Guidelines. Retrieved from
https://nccc.ucsf.edu/clinical-resources/pep-resources/pep-guidelines/
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