A 26 year old female diagnosed with HIV for several years was urgently brought to the OR for a c/s for NRFHT. The patient was being treated by quadruple anti viral therapy for her HIV. She was also on bactrim presumably as a prophylactic against PCP +/- toxoplasmosis. After successful spinal anesthesia, the patient was laid down and oxygen applied. I discarded of all sharps, and then went to dispose of the remaining packaging. As I did so, my index finger received a superficial puncture from a needle that had not been visible in the remaining packaging. I discovered that it was the needle used for the local anesthetic injection prior to the spinal injection. The cap had fallen off exposing the needle.
HIV is a Lentivirus that belongs to a group of retroviruses. Reverse transcriptase is an enzyme that enables retroviruses such as HIV to transcribe their own RNA into DNA. This DNA can then been incorporated into the host genome to produce large quantities of new HIV RNA. HIV attacks the cells containing antigens CD4 (T-helper lymphocytes and macrophages) on their surface and then destroys them, which leads to immunodeficiency, increased incidence of opportunistic infections, and malignancies.
According to the International Health Care Worker Safety Center (IHCWSC), approximately 295,000 hospital-based healthcare workers experience occupational percutaneous injuries annually. Other studies put the risk of needle stick injuries at 83% annually. There are more than 20 blood borne pathogens that might be transmitted from a contaminated sharp, but the ones most commonly affecting health care workers (HCW) are HCV, HBV, and HIV.
List of potential pathogens transmitted after needle stick injury
- Human T lymphotrophic retroviruses (HTLV I and II)
- Hepatitis D virus (HDV or delta agent, which is activated in the presence of HBV)
- Hepatitis G virus (GB virus or GBV-C)
- Cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
- Parvovirus B19
- Transfusion-transmitted virus (TTV)
- West Nile virus (WNV)
- Malarial parasites
- Prion agents
- Blastomycosis
- Cryptococossis
- Diptheria
- Ebola
- Leptosprirosis
- Mycobacterium tuberculosis
- Toxoplasmosis
The biggest concern after a needle stick in the health care setting is typically related to hepatitis B, hepatitis C and HIV. Fortunately, today, virtually everyone working in the US health care system has been vaccinated against HBV. There is no vaccine for hepatitis C, but it can be cured with medication. Unfortunately, the medication used to cure Hepatitis C is extremely expensive. HIV is not curable, but can be managed effectively with expensive pharmacotherapy.
Fortunately, for me the source patient was HCV negative and I have immunity to HBV (although the patient was also negative for HBV). My immediate focus was determining my probability for seroconversion to HIV positive. I finished the case about 60 min after the percutaneous puncture, and went to the ER. I received one dose in the ER of two reverse transcriptase inhibitors (emtricitabine and tenofovir) and one integrase inhibitor (Raltegravir) as part of the standard PEP regimen.
Contacting HIV after a needle stick injury is rare fortunately. From 1981 through 2006, the CDC documented only 57 cases of HIV transmission in HCWs following occupational exposure and identified an additional "possible" 140 cases. There are no high quality human studies to provide us any guidance on understanding the probability of seroconversion after a needle stick. The commonly cited risk of 0.3% transmission was from a study done in the late 80's and 90's where HAART therapy was non existent, thus creating a higher risk study population vs. today. In 1997, Cardo and colleagues identified four factors associated with increased risk for seroconversion:
- Deep injury (Odds Ratio=15)
- Injury with a device visibly contaminated with source patient blood (Odds ratio=6.2)
- Injury from a needle that was in blood vessel (Odds ratio=4.3).
- Exposure to a source patient who died of AIDS two months following the occupational exposure (Odds ratio=5.6)
While the amount of blood contaminating a needle after a needle stick injury is an important consideration, so is the viral load of a source patient. The viral load is greater during early HIV infection, before the immune system has had a chance to mount a response. Pilcher et al. estimated that viral load reaches its peak at 17 days after seroconversion in blood [2]. Likewise, in late stage AIDS, viral load will increase as the viral replication overwhelms the host patient's immune defenses. The viral load varies from patient to patient but has a large effect on the conversion rates, where it is as low as 0.01% with viral loads less than 1,700 copies / mL, but closer to 0.3% when the viral load is greater than 38,000 copies / mL. This may explain the rate of seroconversion that occurs with a blood transfusion from an HIV infected blood source of 95%. While this is high, why is it not 100%? You are receiving 300 to 350 mL of blood after all. I suspect that it relates to the viral load of the source blood. The next highest risk activity to result in HIV infection is the birth process at 13 to 45%. In decreasing risk, you then have needle sharing for IV drug use, unprotected receptive anal intercourse (0.5%), needle stick injury (0.3%), and exposure of mucous membranes to contaminated blood (0.09%). Of course, the probablities listed are averages from studies. After a needle stick injury, the risk for serconversion in that one event could be wildly different from that quoted due to all of the unknowns. However, the good news is that it is low.
During acute HIV infection, the viral doubling time is approximately 10 hours and approximately 19 newly infected cells will develop from each HIV infected cell. Therefore, within 48 hours of infection, there will be more than 1.3 x 10^6 HIV infected cells. HIV is also readily incorporated into the DNA of resting lymphocytes, where it exists in a non duplicating state. This is important because this DNA is not susceptible to anti retroviral therapy. This relates to the recommendations of what actions to take after a needle stick injury from an HIV infected patient. The CDC currently recommends that after a needle stick injury from a known HIV infected patient to start triple drug pharmacotherapy within two hours of the accident and not greater than 72 hours after the injury. It is recommeneded to continue this therapy for 28 days. This recommendation is based on a variety of studies. The only human study we have relates to post exposure treatment mentioned above with ZDV [1]. In this case-control study, there was an 79% reduction in seroconversion when the HCW took zidovudine. Animal models are also illuminating. therese studies when therapy was begun immediately or within a few hours and continued for days to weeks it was effective in reducing rates of seroconversion. Pharmacotherapy was ineffective if begun after 72 hours. In animals treated with chemoprophylaxis within 24 hours of inoculation infection was prevented. However, if there was a delay of 48 hours, 1/2 of the animals became infected and half again became infected if the delay was 72 hours. Others studies have found a similar result. Likewise, therapy lasting only three days in animals resulted in 100% rate of seroconversion whereas, therapy lasting 10 days resulted in a seroconversion rate of 50%, whereas a 28 day course of chemoprophylaxis prevented infection in all animals tested. In Africa there have been several retrospective studies tracking HCWs exposed to HIV and using PEP. The PEP regimens were typically based on zidovudine, plus one or two additional medications. In these small studies there were zero cases of seroconversion despite a large number of those exposed failing to complete their PEP regimen.
Currently the CDC is recommending triple drug regimen for PEP. This is based on two concepts. 1) it is likely that the effectiveness of PEP is related to the host's immunological response and ability to clear the HIV virus from the body, indicating that PEP is more a treatment than a prophylactic, and 2) in more robust studies looking at vertical transmission in pregnancy there is a study showing that rates of transmission are 20%,10%, 3.8% and 1.2% if mothers received no therapy, ZDV mono therapy, two drug therapy, and triple therapy respectively.
Understanding cases of post exposure prophylaxis (PEP) failure is also illuminating. There have been 24 cases of reported failure that can be verified in the literature as of 2014. In these cases, 75% of the patients used single agent zidovudine as their PEP. There has been only six cases of failure with multiple agent prophylaxis regimens. There are also cases of failure of PEP in HCW only to discover after further testing that the HCW was infected by another source outside of work after the completion of PEP or that PEP was not continued. (as Hard as that is to believe-I mean who gets exposed to HIV at work, starts PEP, and then contracts HIV in the community?)
The take home message on PEP is this: If it is to be effective, the number of drugs you take is probably less important than making sure the full 28 day course is completed. If a triple drug regimen is stopped early due to side effects/toxicity, then clearly mono therapy or dual therapy would be more effective if tolerated the full 28 days. This fact is born out in studies showing that triple drug therapy is cause for a greater number of side effects and issues with toxicity. However, the issues related to toxicity have been greatly diminished with newer medications (see below). However, the newer medications are also extremely expensive which can also be a barrier to full treatment.
The first line PEP regimen is Truvada + Isentress. Truvada (Gilead) is a combination of emtricitabine and tenofovir. These medications are in the class if HIV drugs known as NRTIs or nucleoside reverse transriptase inhibitors. They block HIV's ability to convert its RNA into DNA.
Insetress (Raltegravir) is an integrase inhibitor. After HIV has successfully used its own enzyme reverse transcriptase to make make a copy of its RNA into DNA, raltegravir inhibits this DNA's ability to integrate into the host's DNA.
There are now a large number of different anti-HIV medications available. What exactly one should use for PEP may depend on a number of factors and may require consultation with an infectious disease specialist. However, if the source patient has an undetectable viral load, PEP is not necessary. An undetectable viral load means that a real time PCR is unable to detect any virus free in the blood. The PCR test today can detect down to a threshold of 20 copies of RNA / mL of blood. Another issue to consider is the cost. Truvada costs around $1500 for a 28 day regimen. raltegravir is another $1200 or so. No studies have been done to show that using a triple drug regimen is better than single drug PEP. The only evidence we have in humans for PEP comes from a case control study with zidovudine where HIV serconversion was decreased by 79% [1]. In my case, I looked at the factors that increase risk. I was stuck fairly superficially (not deep) with a small gauge (25g) needle with no evidence of visible blood on the needle after a SQ injection of local anesthetic (i.e. needle was not placed directly into a blood vessel). The patient's viral load was detectable (at the time of exposure we had no lab value as such), but she was taking four different medications for HIV. Since she was also pregnant, I presumed that she was likely fairly compliant as she was likely motivated by her unborn child to reduce the chance of perinatal transmission of HIV. I also considered that I began therapy (truvada + isentress) early after exposure (2 hrs). Because I was financially responsible for the PEP regiment thereafter and discovering that GILEAD offered a free 28 day supply of truvada, I opted for this. It is recommended with newer tests that you can test for HIV after four weeks. I tested negative at 4 weeks. At 12 weeks, I will test again. However, if the first test is negative, there is a 95% chance the second test will also be negative.
Patients coming to surgery requiring anesthesia who are on antiviral therapy for HIV should be evaluated for toxicity from this therapy. Fortunately, newer agents used today are far less toxic than their older counter parts. Nevertheless, potential toxicity exists for many of these agents and include problems such as:
- dyslipidemia
- hyperglycemia
- insulin resistance
- osteopenia/osteoporosis
- anemia, neutropenia and thrombocytopenia
- lactic acidosis
- hepatic toxicity
- peripheral neuropathy
- rionavir/darunavir (protease inhibitors) can enhance the affect of opoiods and ketamine due to inhibition of liver enzyme CYP 3A4.
- Saquinavir/ritonavir/darunavir (protease inhibitor) may inhibit midazolam metabolism and oral administration is particularly problematic; IV midazolam should be used with caution.
- Ca2+ channel blockers (amlodipine, diltiazem) may be enhanced due to enzyme inhibition from darunavir (protease inhibitor)
- Lidocaine and other amide local anesthetics (bupivacaine) may have increased blood levels due to enzyme inhibition since they are metabolized by CYP 3A4 if given to someone on darunavir or ritonavir.
- Neuromuscular blocker effects may be prolonged due to inhibition of metabolism.
- Aprepitant is metabolized by CYP 3A4 therefore, darunavir could increase aprepitant concentrations.
- Dexamethasone is a CYP 3A4 inducer and therefore, at high doses over a long period of time can reduce the effectiveness of both darunavir and ritonavir in treatment of HIV. This should not be a problem with a single preoperative dose for PONV prophylaxis however.
- Dexmedetomidine undergoes extensive hepatic metabolism and therefore, theoretically both darunavir and ritonavir could decrease dexmedetomidine blood concentrations requiring a larger dose.
- Ergotamine is metabolized by CYP 3A4 and darunavir/ritonavir may lead to toxic levels if multiple doses are given. This could lead to a life threatening event due to the narrow therapeutic window of ergotamine.
- Labetaolol
HCW are at high risk today to exposure to a number of infectious agents. Needlevstick injuries continue to occur in HCW despite universal precautions. HIV represents only one of these. HIV infection continues to quietly cause a large number of infecctions worldwide and is an ongoing epidemic despite receiving little press. Although HIV can now be managed with medications, life with HIV significantly altered and complex when considering the complexity of the drug regimens, ability of the virus to become resistant, ongoing potential to infect others around you, expense of lifelong medications and infectious disease consultation, etc etc. Therefore, needle stick injuries in the HCW produce a large degree of anxiety. However, it is clear that the risk for seroconversion overall is low and is largely dependent degree of virus in the source patient's blood, amount of blood on the source needle, and degree of injury from the needle itself. The risk of seroconversion can be further modified by determining the need for PEP within two hours of exposure, taking an appropriate regimen based on risk profile of exposure, and continuing the prescribed regimen for the full course (likely 28 days). Testing for HIV should be done at time point zero, 4 weeks, and again at 12 weeks to determine if serovconversion occurred. In most cases of seroconversion, patients will experience full like symptoms associated with viral replication and the immune system's response to the virus. HCW who experience a work related needle injury of low risk, and take the prescribed PEP as recommended have a very low risk of seroconversion, but unfortunately, the probability is not quantified due to lack of studies.
1. Bell, DM. et al. NEJM. 1997; 337:21:1485-1490.
2. Pilcher CD, Joaki G, Hoffman IF, et al. AIDS 2007;21(13):1723-30.
1. Bell, DM. et al. NEJM. 1997; 337:21:1485-1490.
2. Pilcher CD, Joaki G, Hoffman IF, et al. AIDS 2007;21(13):1723-30.
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