- Email: [email protected]
Refractive surgery in the HIV-positive U.S. Military Natural History Study Cohort: complications and risk factors
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ARTICLE
Refractive surgery in the HIV-Positive U.S. Military Natural History Study Cohort: Complications and risk factors Carter S. Tisdale, MD, Grant A. Justin, MD, Xun Wang, MS, Xiuping Chu, MS, Darrel K. Carlton, MD, MSPH, Jason F. Okulicz, MD, Christina Schofield, MD, Ryan C. Maves, MD, Brian K. Agan, MD, Gary L. Legault, MD, Infectious Disease Clinical Research Program HIV Working Group
Purpose: This study sought to assess the frequency of refractive surgery complications in human immunodeficiency virus-positive (HIVC) individuals and related risk factors.
Settings: Multiple centers in the United States. Design: Prospective observational cohort study. Methods: The U.S. Military HIV Natural History Study is a prospective observational cohort study of HIVC servicemembers and beneficiaries. Participants were selected who had Current Procedural Terminology codes for laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and other refractive surgeries. The frequency of complications was determined using International Classification of Diseases-9 codes. Covariates included age, sex, antiretroviral therapy, time since HIV diagnosis, history of acquired immune deficiency syndrome (AIDS), and CD4 (T lymphocytes) count and viral load. Statistical analysis was completed using univariate (c2 and Wilcoxon-Mann-Whitney tests) and multivariate analyses.
Results: Seventy-nine of 2073 participants had refractive surgery. Fifty-three patients underwent PRK, 23 LASIK, two radial keratotomy (RK), and one astigmatic correction. Complications occurred in 6 (7.6%) of 79 participants, including 5 patients who underwent PRK and one after RK, occurring between 8 and 217 days after surgery. Five ulcers and one unspecified keratitis were noted. In the univariate analysis, type of surgery (P Z .02) and history of AIDS (P Z .02) were risk factors for complications. In logistic regression analysis, no variables were found to be risk factors for complications. Conclusion: Complications were infrequent among HIVC participants after refractive surgery. Point estimates suggest that PRK might have more complications than LASIK and that advanced HIV, reflected by previous AIDS, might be associated with an increased risk for complications. Further study will be required to confirm these findings. J Cataract Refract Surg 2019; -:-–- Published by Elsevier Inc. on behalf of ASCRS and ESCRS.
Supplemental material available at www.jcrsjournal.org.
I
n the 1980s and early 1990s, human immunodeficiency virus (HIV) infection was largely considered a fatal disease. The emergence of improved disease recognition,
access to care, and effective treatment with effective combination antiretroviral therapy (ART) have significantly decreased the number of HIV-related deaths as well as
Submitted: May 15, 2019 | Final revision submitted: June 20, 2019 | Accepted: June 21, 2019 From the 563rd Operations Support Squadron (Tisdal), Nellis Air Force Base, Las Vegas, Nevada, the Department of Ophthalmology (Justin, Carlton, Legault), Brooke Army Medical Center, San Antonio, Texas, the Department of Surgery (Justin, Carlton, Legault), Uniformed Services University of the Health Science, Bethesda, Maryland, the Infectious Disease Clinical Research Program (Wang, Chu, Okulicz, Agan), Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, The Henry M. Jackson Foundation for the Advancement of Military Medicine (Wang, Chu, Agan), Bethesda, Maryland, the Infectious Disease Service (Okulicz), Brooke Army Medical Center, Fort Sam Houston, Texas, the Division of Infectious Diseases (Schofield), Madigan Army Medical Center, Joint Base Lewis-McChord, Washington, and the Division of Infectious Diseases (Maves), Naval Medical Center San Diego, California, USA. Presented at the ASCRSASOA Society of Military Ophthalmology Symposium, San Diego, California, USA, May 2019. This study was conducted by the Infectious Disease Clinical Research Program, a United States Department of Defense program executed by the Uniformed Services University of the Health Sciences through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Inter-Agency Agreement Y1-AI-5072. Disclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, Naval Medical Center San Diego, Madigan Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Air Force, the Department of the Army, the Department of the Navy, Department of Defense, the Uniformed Services University of the Health Sciences, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. or any other agency of the U.S. Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. The investigators have adhered to the policies for protection of human subjects as prescribed in 45CRF46. Camille Estupigan provided editorial assistance during preparation of this manuscript. Corresponding author: Grant A. Justin, MD, Brooke Army Medical Center, San Antonio, TX, USA. Email: [email protected] Published by Elsevier Inc. on behalf of ASCRS and ESCRS.
0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2019.06.017
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increased the total life expectancy of HIV-positive (HIVC) patients.1,A Given improved survival, HIVC patients are now more likely to pursue common elective procedures, such as refractive surgery to improve visual acuity. However, the U.S. Food and Drug Administration (FDA) currently states that patients with HIV or other immunodeficiency states are not good candidates for refractive surgery.B A recent published guideline by the American Academy of Ophthalmology (AAO)2 lists uncontrolled autoimmune or other immune-mediated disease as an absolute contraindication to refractive surgery, whereas controlled disease is only relatively contraindicated. The current body of literature is limited on the outcomes of elective refractive surgery in the HIVC population.3,4 The objectives of this study were to first evaluate the type of refractive surgery performed and then characterize the participants by the following: antiretroviral therapy use, time since HIV diagnosis, presence of AIDS, CD4 (T-lymphocyte) count, HIV-1 viral load, and select comorbidities (diabetes mellitus type 2 and smoking). Secondly, we studied both the incidence of and risk factors for postoperative complications of refractive surgery.
PARTICIPANTS AND METHODS Started in 1986, the U.S. Military HIV Natural History Study (NHS) is a large, continuous enrollment cohort study of HIVC active duty U.S. servicemembers, their family members, and retirees from the Department of Defense.5,6 Active duty service members are routinely screened for HIV infection, approximately every 2 years, and negative test dates are collected in addition to positive dates. Participants have study visits approximately every 6 months including coordinator and physician interviews, centralized Department of Defense electronic medical record review, and laboratory assays. The study was approved by the Institutional Review Board of the Uniformed Services University of the Health Sciences and participating sites; all participants provide written informed consent. Figure 1 shows the selection of participants for this study. Inclusion criteria consisting of (1) HIVC status between 1997 and 2016; (2) a history of refractive surgery demonstrated by one of the following Current Procedural Terminology (CPT) codes: 65760/S0800 (laser in situ keratomileusis [LASIK]), 66999/S0810 (photorefractive keratectomy [PRK]), 65771 (radial keratotomy [RK]), 65772/65775 (astigmatism correction), 65765 (keratophakia), 65767 (epikeratoplasty), S0812 (phototherapeutic keratectomy), 0402T (collagen cross-linking), 65785 (implantation of intrastromal corneal ring); and (3) a refractive International Classification of Disease (ICD)-9 code (367.0 – 367.9). Complications were defined by ICD-9 codes: corneal ulcer (370.00 – 370.07), interstitial keratitis (370.50 – 370.59), unspecified keratitis (370.9), corneal abrasion (918.1), corneal haze (371.89), or diffuse lamellar keratitis (370.8) within 1 year after refractive surgery. Patients were excluded from this study for any one of the following: (1) a history of refractive surgery before the diagnosis of HIV infection; (2) a history of an ICD-9 code of a surgical complication (corneal ulcer [370.00 – 370.07], interstitial keratitis [370.50 – 370.59], unspecified keratitis [370.9], corneal abrasion [918.1], corneal haze [371.89], or diffuse lamellar keratitis [370.8]) within 1 year before refractive surgery; or (3) absence of a refractive Current Procedural Terminology code. The outcome studied was the proportion of post-refractive surgical complication(s) after refractive surgery. Volume - Issue - - 2019
Demographic and clinical data were extracted from the study database for analysis including age, sex, race, time since HIV diagnosis, history of AIDS (Centers for Disease Control and Prevention 1993 revised classification system7), antiretroviral therapy (ART) by medication class, CD4 count and HIV viral load at time of ophthalmic diagnosis, total number of ophthalmic diagnoses, diabetes mellitus type 2, hypertension, hyperlipidemia, and smoking. Baseline was defined as earliest documented HIVC test date; ART was defined as in previous NHS studies (Supplemental Table 1, available at http://jcrsjournal.org).8 Most patients were taking two or more nucleoside reverse transcriptase inhibitors and either a nonnucleoside reverse transcriptase inhibitor, unboosted versus boosted protease inhibitor, or an integrase inhibitor. Statistical Analysis All events occurred in HIVC participants. Events were defined as either time of refractive surgery or in controls as censorship date (death, lost to follow-up, or the last study visit). Statistical analysis was completed using chi-square or Wilcoxon-Mann-Whitney tests. Further multivariate analysis was completed using logistic regression. All tests were two-sided, and a P value less than 0.05 was considered statistically significant. Statistical analyses were performed using SAS software (version 9.4, SAS Institute, Inc.).
RESULTS Baseline Characteristics
In the NHS cohort, 79 of 2073 participants met inclusion criteria. Of the participants, 53 underwent PRK, 23 LASIK, 2 RK, and 1 astigmatic correction. Table 1A shows the baseline demographic characteristics, Table 1B shows the baseline HIV-related and medical history parameters, and Supplemental Table 2 (available at http://jcrsjournal.org) shows the indications for surgery. Compared with the HIVC participants who did not undergo refractive surgery, a greater proportion of refractive surgery patients in the cohort were active duty (P Z .0005) and enlisted (P ! .0001). A significant difference in Armed Service branch representation existed (P Z .021). Reflecting the overall trend toward more elective refractive surgery within this population and the general population, an increasing number of refractive surgeries were noted in successive calendar intervals within the cohort (Figure 2) (P Z .014 for increasing trend). Nearly twothirds (50) of the 79 patients undergoing refractive surgery were on treatment with ART at the time of surgery and 49 patients had a viral load less than 400 copies/mL; the median CD4 count was 624 cells/mL and only one patient had less than 200 cells/mL. Complications and Risk Factors
Six (7.6%) of the 79 participants undergoing refractive surgery experienced postoperative complications. No complications were observed in patients undergoing LASIK. Complications within 1 year of surgery occurred in only one RK patient (44 days). However, 5 patients (9.6%) who underwent PRK had complications within 1 year (at 8, 13, 127, 134, and 217 days). Of the 6 complications, three were an unspecified corneal ulcer, one was a marginal corneal ulcer, one a perforated corneal ulcer, and one an unspecified keratitis. In the univariate analysis, the type of surgery performed (P Z .0206) and a previous history of
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Figure 1. Flow chart of study participant selection (CPT Z Current Procedural Terminology; HIVC Z human immunodeficiency virus-positive; ICD Z International Classification of Disease).
AIDS at time of the procedure (P Z .0219) were risk factors for complications (Supplemental Table 3, available at http://jcrsjournal.org). Of the 6 patients who had complications, three were on ART at the time of surgery and 4 had a detectable viral load greater than 400 copies/ mL (1735, 2547, 12 600, and 36 269); however, none had a CD4 counts less than 200 cells/mL at time of surgery (median 658.0 cell/uL, range 349.0 to 691.0 cell/uL). Of those who were on ART, in addition to two nucleoside reverse transcriptase inhibitors, one was on an unboosted protease inhibitor, one a boosted protease inhibitor, and another a nonnucleoside reverse transcriptase inhibitor. Using logistic regression analysis, no covariates were found to be risk factors for complications; however, the sample size was small (Supplemental Table 4, available at http://jcrsjournal.org). DISCUSSION This study represents the first published cohort of HIVC patients who underwent refractive surgery, to the authors’ knowledge. In 1999, Hovanesian et al.3 reported on a case of bilateral bacterial keratitis after a LASIK procedure in an HIVC patient. Unquantified anecdotal reports of postoperative keratitis, delayed wound healing, and dry eye after refractive surgery in HIVC patients have also been reported.4 The lack of published data on postsurgical outcomes in this population has led to inconsistency between published recommendations and actual practice patterns. The FDA established a list of contraindications to PRK in the 1990s, and later published a similar list of contraindications to LASIK. At present, the FDA states that patients who have HIV or are in other immunodeficiency states are not good candidates for refractive
surgery.B Cobo-Soriano et al.9 suggested that controlled systemic disease need not be an absolute contraindication to LASIK. A recent published guideline by the AAO2 lists uncontrolled autoimmune or other immune-mediated disease as an absolute contraindication to refractive surgery, whereas controlled disease is only relatively contraindicated. In actual practice, there is no universal approach to refractive surgery in the HIV population. A 2010 webbased survey of 285 refractive surgeons4 found that 50.2% of respondents consider persons with HIV acceptable candidates for elective refractive surgery, but 88% felt that patients with current AIDS were not appropriate candidates. In our study of HIVC active duty, retirees, and dependents, we found an overall proportion of post-refractive surgical complications of 7.6%. The proportion of complications was 9.4% in those who underwent PRK, whereas no complications were observed in the LASIK patients; PRK was more than twice as common as LASIK in this population, reflecting military practice. Corneal ulcer accounted for 5 of the 6 total complications. Although it was originally thought that PRK predisposes patients to an increased risk for infectious keratitis, large studies have demonstrated similar rates between LASIK and PRK. Wroblewski et al.8 reported 5 cases (0.019%) of post-procedural infectious keratitis out of 25 337 PRK procedures performed at 6 institutions within the Army and Navy database between 1995 and 2004. Llovet et al.10 reported 72 cases (0.035% rate) of post-procedural infectious keratitis out of 204 586 LASIK procedures at a single institution in Spain between 2002 and 2008. Despite the similar complication rates, it has been suggested that PRK poses an increased risk for post-procedural infectious keratitis because of the breakdown of the barrier function of the Volume - Issue - - 2019
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Table 1A. Baseline demographic characteristics of the human immunodeficiency virus-positive participants who had refractive surgery. No Refractive Surgery (n Z 1994)
Overall (N Z 2073)
Parameter Age (y) at surgery or censor Sex Male Female Race/ethnicity White African American Hispanic/Other Marital status Single Married Missing data Rank Officer/Warrant Enlisted N/A (eg, dependent) Duty status Active duty Retired Dependent Other (eg, civilian, end of service) Service Air Force Army Marines Navy Other (eg, public health service, foreign military)
N (%)
Median (IQR)
N (%)
40.8 (18.3)
Median (IQR)
Refractive Surgery (n Z 79)
N (%)
41.2 (18.6)
Median (IQR) 31.2 (12.1)
1904 (91.8) 169 (8.2)
1831 (91.8) 163 (8.2)
73 (92.4) 6 (7.6)
786 (37.9) 932 (45.0) 355 (17.1)
755 (37.9) 898 (45.0) 341 (17.1)
31 (39.2) 34 (43.0) 14 (17.7)
1059 (51.1) 866 (41.8) 148 (7.1)
1022 (51.3) 826 (41.4) 146 (7.3)
37 (46.8) 40 (50.6) 2 (2.5)
188 (9.1) 1503 (72.5) 382 (18.4)
173 (8.7) 1441 (72.3) 380 (19.1)
15 (19.0) 62 (78.5) 2 (2.5)
1068 (51.5) 887 (42.8) 87 (4.2) 30 (1.4)
1008 (50.6) 869 (43.6) 86 (4.3) 30 (1.5)
60 (75.9) 18 (22.8) 1 (1.3) 0 (0.0)
448 (21.6) 562 (27.1) 147 (7.1) 856 (41.3) 60 (2.9)
441 (22.1) 537 (26.9) 139 (7.0) 817 (41.0) 60 (3.0)
7 (8.9) 25 (31.6) 8 (10.1) 39 (49.4) 0 (0.0)
P Value !.0001 .8535
.9406
.1179
!.0001
.0005
.0211
IQR Z interquartile range; N/A Z not applicable
corneal epithelium.11 On the other hand, a break in the epithelial barrier during LASIK has been reported to predispose patients to keratitis.10 It appears from the data collected in our study that PRK in HIVC patients might be a risk factor for ulcers, although whether they were specifically infectious is difficult to discern because of the use of ICD-9 codes. In addition, it is critical to recognize that three of the 5 PRK complications occurred late after the surgery (at 127, 134, and 217 days). It is possible that these are unrelated to the refractive surgery, or that the disruption of the epithelial barrier at the time of surgery might predispose these patients to later complications. A previous study12 found that atypical organisms such as mycobacteria and fungi have a later mean onset of presentation; however, unfortunately, the specific culture data were not available in our complications. Finally, the small sample size limits the precision of the point estimates, so it should be interpreted cautiously. We found that a history of AIDS was a potential risk factor for complication after refractive surgery. To our knowledge, there are no previous studies that address post-refractive surgical complications in the HIV population, nor are there published guidelines that suggest an ideal Volume - Issue - - 2019
preoperative CD4 count. In cataract surgery, there are very few studies discussing surgical complications in this patient populace and no published guidelines.13,14 A report of abdominal and plastic surgeries among HIVC patients also found that a lower CD4 count (!200 cells/mL) and viral load (O10 000 copies/mL) were associated with an increased risk for complications,15 and some surgical guidelines have reinforced this.16 In orthopedic trauma, a CD4 count less than 300 cells/mL was associated with the development of postoperative infection.17 However, in patients with HIV, the surgical risk assessment should be individualized and discussed with the patient.18,C It seems prudent that surgeons who are considering operating on patients with HIV should review CD4 counts and viral load to help inform the approach to follow-up. The surgeon could consider that if the CD4 count is less than 200 cells/mL and the viral load more than 10 000 copies/mL, then defer surgery and recommend that the patient start ART therapy; however, further studies and guidelines are required in ophthalmic surgery. In addition, poor ART compliance could signal poor postoperative compliance with topical medications. This is also a potential area of future study in HIVC patients.
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Table 1B. Baseline HIV-related characteristics and medical history of the HIV-positive participants who had refractive surgery. Overall (N Z 2073)
Parameter Age HIV dx Year HIV dx Before 1997 1997–2000 2001–2005 2006–2010 2011–2016 CD4 at HIV dx (cells/mL) VL at HIV dx (log10 copies/mL) HIV dx to surgery or censor Age ART started ART initiation era 1996–2000 2001–2008 2009–2017 No ART started record Time from ART to surgery or censor CD4 at ART (cells/mL) VL at ART (log10 copies/mL) History of AIDS No Yes Year of surgery or censor Before 1997 1997–2000 2001–2005 2006–2010 2011–2016 CD4 at surgery or censor (cells/mL) VL at surgery or censor ART status at surgery or censor Yes No ART medication by class at surgery or censor Boosted PI Integrase inhibitor NNRTI Other Three or more NRTI Unboosted PI DM type 2 at baseline Yes No Hypertension at baseline Yes No Hyperlipidemia at baseline Yes No Tobacco smoking at baseline Yes No
N (%)
Median (IQR)
No Refractive Surgery (n Z 1994)
N (%)
28.8 (11.1) 749 (36.1) 315 (15.2) 380 (18.3) 422 (20.4) 207 (10.0)
Median (IQR)
N (%)
29.0 (10.9) 734 (36.8) 306 (15.3) 360 (18.1) 400 (20.1) 194 (9.7)
475 (285) 4.4 (1.1) 9.1 (11.5) 33.1 (12.3) 804 (38.8) 469 (22.6) 532 (25.7) 268 (12.9)
Refractive Surgery (n Z 79)
P Value
25.5 (8.5)
.0004 .0040
505 (235) 4.5 (0.9) 4.1 (5.6) 28.7 (10.4)
.5711 .5371 !.0001 .0002 .0184
3.2 (5.4) 421 (214) 4.5 (1.1)
!.0001 .0085 .7251 .3568
15 (19.0) 9 (11.4) 20 (25.3) 22 (27.8) 13 (16.5) 475 (289) 4.4 (1.1) 9.3 (11.7) 33.2 (12.3)
786 (39.4) 446 (22.4) 504 (25.3) 258 (12.9) 7.1 (10.0) 355 (227) 4.5 (1.2)
Median (IQR)
18 (22.8) 23 (29.1) 28 (35.4) 10 (12.7) 7.3 (10.3) 352 (225) 4.5 (1.2)
1976 (95.3) 97 (4.7)
1899 (95.2) 95 (4.8)
77 (97.5) 2 (2.5)
52 (2.5) 163 (7.9) 258 (12.4) 381 (18.4) 1219 (58.8)
52 (2.6) 156 (7.8) 241 (12.1) 361 (18.1) 1184 (59.4)
0 (0.0) 7 (8.9) 17 (21.5) 20 (25.3) 35 (44.3)
.0129
627 (389) 1.6 (1.3)
627 (391) 1.5 (1.3)
624 (298) 1.7 (2.1)
1659 (80.0) 414 (20.0)
1609 (80.7) 385 (19.3)
50 (63.3) 29 (36.7)
282 (17.0) 475 (28.6) 669 (40.3) 52 (3.1) 31 (1.9) 150 (9.0)
279 (17.3) 467 (29.0) 636 (39.5) 52 (3.2) 31 (1.9) 144 (8.9)
3 (6.0) 8 (16.0) 33 (66.0) 0 (0.0) 0 (0.0) 6 (12.0)
201 (9.7) 1872 (90.3)
197 (9.9) 1797 (90.1)
4 (5.1) 75 (94.9)
670 (32.3) 1403 (67.7)
648 (32.5) 1346 (67.5)
22 (27.8) 57 (72.2)
1040 (50.2) 1033 (49.8)
1006 (50.5) 988 (49.5)
34 (43.0) 45 (57.0)
1209 (78.6) 329 (21.4)
1159 (78.9) 310 (21.1)
50 (72.5) 19 (27.5)
NR NR NR
NR
.1559
.3862
.1962
.2028
AIDS Z acquired immune deficiency syndrome; ART Z antiretroviral therapy; CD4 Z T lymphocytes; DM Z diabetes mellitus; dx Z diagnosis; HIV Z human immunodeficiency virus; IQR Z interquartile range; NNRTI Z non-nucleoside reverse transcriptase inhibitor; NR Z P value not reported because of differing follow-ups between groups; NRTI Z nucleoside reverse transcriptase inhibitor; PI Z protease inhibitor; VL Z viral load
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population, although larger studies will be required to fully evaluate this. Advanced HIV infection, reflected by a previous diagnosis of AIDS, as well as active viremia and the absence of ART, might be associated with an increased risk for complications. Further study using larger cohorts or metaanalysis will be required to better understand the risk factors for complications of refractive surgery in HIVC patients.
WHAT WAS KNOWN There is limited literature on refractive surgery in human immunodeficiency virus-positive (HIVC) patients. Figure 2. Incidence of refractive surgery (CI Z confidence interval).
One of the lingering concerns of refractive surgeons operating on patients with HIV infection has been the risk for viral transmission during the procedure. However, despite concerns in the pre-ART era, HIV transmission from patients to operating surgeons is extremely rare. Hagen et al.19 concluded that, based on experimentation with the similarly structured pseudorabies virus, excimer laser ablation of the cornea of an HIV-infected patient is unlikely to transmit the virus to the surgeon. In another study by Taravella et al.,20 only DNA fragments of an attenuated varicella-zoster virus were found to have survived excimer laser ablation. Both of these studies reinforce the low risk; however, a website-based survey of refractive surgeons operating on HIV patients4 revealed that 51% were concerned about virus transmission to the surgeon or operating room staff and 40% were concerned about virus transmission to other patients. Standard precautions to prevent occupational exposure to HIV and other infectious pathogens in the healthcare setting and during surgery have proven highly effective with only one confirmed healthcare worker–HIV transmission event from 2000 to 2013.21 These data reinforce the necessity for ongoing and further education of providers and staff regarding the utility of standard precautions and low risk for HIV transmission. And although additional studies to fully characterize HIV transmission risks in various surgical settings such as ophthalmology are also required, the increasing trend of refractive surgeries in our study suggests that attitudes might be shifting in a positive way. The key limitations of this study are related to the patient population and number of procedures performed. The NHS participants were mostly male, young and previously healthy, and active duty with open access to healthcare and medications. These limitations might impact the generalizability. The overall number of participants was small, so findings should be interpreted cautiously. In conclusion, complications occurred infrequently in HIVC patients with virologic suppression on ART after refractive surgery. Many patients living with HIV infection might be appropriate candidates for refractive surgery. PRK might predispose to more complications than LASIK in this Volume - Issue - - 2019
WHAT THIS PAPER ADDS This study evaluated a cohort of HIVC patients who underwent refractive surgery to assess the rate of complications and related risk factors. No HIVC patients who underwent laser in situ keratomileusis had a complication. Further analysis is required in larger cohorts to better understand whether the type of refractive surgical procedure is a risk factor for complications. A history of acquired immune deficiency syndrome (AIDS) was a risk factor for complications in univariate analysis. It is critical that ophthalmologists evaluate antiretroviral therapy status, CD4 (T lymphocytes) count and viral load, and history of AIDS before operating on an HIVC patient.
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10. Llovet F, de Rojas V, Interlandi E, Martín C, Cobo-Soriano R, OrtegaUsobiaga J, Baviera J. Infectious keratitis in 204 586 LASIK procedures. Ophthalmology 2010; 117:232–238 11. Donnenfeld ED, O’Brien TP, Solomon R, Perry HD, Speaker MG, Wittpenn J. Infectious keratitis after photorefractive keratectomy. Ophthalmology 2003; 110:743–747 12. Karp CL, Tuli SS, Yoo SH, Vroman DT, Alfonso EC, Huang AH, Pflugfelder SC, Culbertson WW. Infectious keratitis after LASIK. Ophthalmology 2003; 110:503–510 13. Accorinti M, Cecere M, Scala A, Pirraglia MP. Cataract surgery in HIV seropositive patients: long-term follow-up. Ocul Immunol Inflamm 2019; 27:435–446 14. Chew GWM, Teoh SCB, Agrawal R. Analysis and outcomes of cataract surgery in patients with acquired immunodeficiency syndrome. Ocul Immunol Inflamm 2017; 25:535–539 15. Deneve JL, Shantha JG, Page AJ, Wyrzykowski AD, Rozycki GS, Feliciano DV. CD4 count is predictive of outcome in HIV-positive patients undergoing abdominal operations. Am J Surg 2010; 200:694–699 16. Davison SP, Reisman NR, Pellegrino ED, Larson EE, Dermody M, Hutchison PJ. Perioperative guidelines for elective surgery in the human immunodeficiency virus-positive patient. Plast Reconstr Surg 2008; 121:1831–1840 17. Guild GN, Moore TJ, Barnes W, Hermann C. CD4 count is associated with postoperative infection in patients with orthopaedic trauma who are HIV positive. Clin Orthop Relat Res 2012; 470:1507–1512 18. Madiba TE, Muckart DJ, Thomson SR. Human immunodeficiency disease: how should it affect surgical decision making? World J Surg 2009; 33:899–909 19. Hagen KB, Kettering JD, Aprecio RM, Beltran F, Maloney RK. Lack of virus transmission by the excimer laser plume. Am J Ophthalmol 1997; 124:206–211 20. Taravella MJ, Weinberg A, Blackburn P, May M. Do intact viral particles survive excimer laser ablation? Arch Ophthalmol 1997; 115:1028–1030 21. Joyce MP, Kuhar D, Brooks JT. Notes from the field: occupationally acquired HIV infection among health care workers – United States, 1985-2013. MMWR Morb Mortal Wkly Rep 2015; 63:1245–1246
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OTHER CITED MATERIAL A. World Health Organization. HIV/AIDS. Available at: www.who.int/en/ news-room/fact-sheets/detail/hiv-aids B. U.S. Food and Drug Administration. When is LASIK not for me? Available at: https://www.fda.gov/medicaldevices/productsandmedicalprocedures/ surgeryandlifesupport/lasik/ucm061366.htm. Accessed August 15, 2019 C. New York State Department of Health AIDS Institute. Clinical Guidelines Program, Medical Care Criteria Committee, January 2012. Perioperative Management. Available at: https://www.hivguidelines.org/hiv-care/perioperativemanagement/. Accessed August 15, 2019
Disclosures: None of the authors has a financial or proprietary interest in any material or method mentioned. Members of the Infectious Disease Clinical Research Program HIV Working Group include the following: United States California: Naval Medical Center San Diego (S. Cammarata, N. Kirkland, CAPT R. Maves, CAPT [Ret.] G. Utz); Hawaii: Tripler Army Medical Center, Honolulu (COL M. Price); Maryland: National Institute of Allergy and Infectious Diseases, Bethesda (J. Powers, COL [Ret.] E. Tramont), Uniformed Services University of the Health Sciences, Bethesda (B. Agan; X. Chu, W. Horton, H. Hsieh, A. Noiman, E. Parmelee, D. Tribble, X. Wang, S. Won), Walter Reed National Military Medical Center, Bethesda (I. Barahona, LTC J. Blaylock, C. Decker, A. Ganesan, COL R. Ressner, D. Wallace), and Walter Reed Army Institute of Research, Silver Spring (S. Peel); Texas: Brooke Army Medical Center, Fort Sam Houston (S. De Leon, S. Merritt, T. Merritt, Lt Col J. Okulicz, T. Sjoberg); Virginia: Naval Medical Center Portsmouth, Portsmouth (S. Banks, CAPT K. Kronmann, T. Lalani, R. Tant, T. Warkentien); Washington: Madigan Army Medical Center, Joint Base LewisMcChord (C. Baker, S. Chambers, R. Colombo, COL T. Ferguson, LTC A. Kunz, C. Schofield, M. Stein)
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ARTICLE
Refractive surgery in the HIV-Positive U.S. Military Natural History Study Cohort: Complications and risk factors Carter S. Tisdale, MD, Grant A. Justin, MD, Xun Wang, MS, Xiuping Chu, MS, Darrel K. Carlton, MD, MSPH, Jason F. Okulicz, MD, Christina Schofield, MD, Ryan C. Maves, MD, Brian K. Agan, MD, Gary L. Legault, MD, Infectious Disease Clinical Research Program HIV Working Group
Purpose: This study sought to assess the frequency of refractive surgery complications in human immunodeficiency virus-positive (HIVC) individuals and related risk factors.
Settings: Multiple centers in the United States. Design: Prospective observational cohort study. Methods: The U.S. Military HIV Natural History Study is a prospective observational cohort study of HIVC servicemembers and beneficiaries. Participants were selected who had Current Procedural Terminology codes for laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and other refractive surgeries. The frequency of complications was determined using International Classification of Diseases-9 codes. Covariates included age, sex, antiretroviral therapy, time since HIV diagnosis, history of acquired immune deficiency syndrome (AIDS), and CD4 (T lymphocytes) count and viral load. Statistical analysis was completed using univariate (c2 and Wilcoxon-Mann-Whitney tests) and multivariate analyses.
Results: Seventy-nine of 2073 participants had refractive surgery. Fifty-three patients underwent PRK, 23 LASIK, two radial keratotomy (RK), and one astigmatic correction. Complications occurred in 6 (7.6%) of 79 participants, including 5 patients who underwent PRK and one after RK, occurring between 8 and 217 days after surgery. Five ulcers and one unspecified keratitis were noted. In the univariate analysis, type of surgery (P Z .02) and history of AIDS (P Z .02) were risk factors for complications. In logistic regression analysis, no variables were found to be risk factors for complications. Conclusion: Complications were infrequent among HIVC participants after refractive surgery. Point estimates suggest that PRK might have more complications than LASIK and that advanced HIV, reflected by previous AIDS, might be associated with an increased risk for complications. Further study will be required to confirm these findings. J Cataract Refract Surg 2019; -:-–- Published by Elsevier Inc. on behalf of ASCRS and ESCRS.
Supplemental material available at www.jcrsjournal.org.
I
n the 1980s and early 1990s, human immunodeficiency virus (HIV) infection was largely considered a fatal disease. The emergence of improved disease recognition,
access to care, and effective treatment with effective combination antiretroviral therapy (ART) have significantly decreased the number of HIV-related deaths as well as
Submitted: May 15, 2019 | Final revision submitted: June 20, 2019 | Accepted: June 21, 2019 From the 563rd Operations Support Squadron (Tisdal), Nellis Air Force Base, Las Vegas, Nevada, the Department of Ophthalmology (Justin, Carlton, Legault), Brooke Army Medical Center, San Antonio, Texas, the Department of Surgery (Justin, Carlton, Legault), Uniformed Services University of the Health Science, Bethesda, Maryland, the Infectious Disease Clinical Research Program (Wang, Chu, Okulicz, Agan), Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, The Henry M. Jackson Foundation for the Advancement of Military Medicine (Wang, Chu, Agan), Bethesda, Maryland, the Infectious Disease Service (Okulicz), Brooke Army Medical Center, Fort Sam Houston, Texas, the Division of Infectious Diseases (Schofield), Madigan Army Medical Center, Joint Base Lewis-McChord, Washington, and the Division of Infectious Diseases (Maves), Naval Medical Center San Diego, California, USA. Presented at the ASCRSASOA Society of Military Ophthalmology Symposium, San Diego, California, USA, May 2019. This study was conducted by the Infectious Disease Clinical Research Program, a United States Department of Defense program executed by the Uniformed Services University of the Health Sciences through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Inter-Agency Agreement Y1-AI-5072. Disclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, Naval Medical Center San Diego, Madigan Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Air Force, the Department of the Army, the Department of the Navy, Department of Defense, the Uniformed Services University of the Health Sciences, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. or any other agency of the U.S. Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. The investigators have adhered to the policies for protection of human subjects as prescribed in 45CRF46. Camille Estupigan provided editorial assistance during preparation of this manuscript. Corresponding author: Grant A. Justin, MD, Brooke Army Medical Center, San Antonio, TX, USA. Email: [email protected] Published by Elsevier Inc. on behalf of ASCRS and ESCRS.
0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2019.06.017
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increased the total life expectancy of HIV-positive (HIVC) patients.1,A Given improved survival, HIVC patients are now more likely to pursue common elective procedures, such as refractive surgery to improve visual acuity. However, the U.S. Food and Drug Administration (FDA) currently states that patients with HIV or other immunodeficiency states are not good candidates for refractive surgery.B A recent published guideline by the American Academy of Ophthalmology (AAO)2 lists uncontrolled autoimmune or other immune-mediated disease as an absolute contraindication to refractive surgery, whereas controlled disease is only relatively contraindicated. The current body of literature is limited on the outcomes of elective refractive surgery in the HIVC population.3,4 The objectives of this study were to first evaluate the type of refractive surgery performed and then characterize the participants by the following: antiretroviral therapy use, time since HIV diagnosis, presence of AIDS, CD4 (T-lymphocyte) count, HIV-1 viral load, and select comorbidities (diabetes mellitus type 2 and smoking). Secondly, we studied both the incidence of and risk factors for postoperative complications of refractive surgery.
PARTICIPANTS AND METHODS Started in 1986, the U.S. Military HIV Natural History Study (NHS) is a large, continuous enrollment cohort study of HIVC active duty U.S. servicemembers, their family members, and retirees from the Department of Defense.5,6 Active duty service members are routinely screened for HIV infection, approximately every 2 years, and negative test dates are collected in addition to positive dates. Participants have study visits approximately every 6 months including coordinator and physician interviews, centralized Department of Defense electronic medical record review, and laboratory assays. The study was approved by the Institutional Review Board of the Uniformed Services University of the Health Sciences and participating sites; all participants provide written informed consent. Figure 1 shows the selection of participants for this study. Inclusion criteria consisting of (1) HIVC status between 1997 and 2016; (2) a history of refractive surgery demonstrated by one of the following Current Procedural Terminology (CPT) codes: 65760/S0800 (laser in situ keratomileusis [LASIK]), 66999/S0810 (photorefractive keratectomy [PRK]), 65771 (radial keratotomy [RK]), 65772/65775 (astigmatism correction), 65765 (keratophakia), 65767 (epikeratoplasty), S0812 (phototherapeutic keratectomy), 0402T (collagen cross-linking), 65785 (implantation of intrastromal corneal ring); and (3) a refractive International Classification of Disease (ICD)-9 code (367.0 – 367.9). Complications were defined by ICD-9 codes: corneal ulcer (370.00 – 370.07), interstitial keratitis (370.50 – 370.59), unspecified keratitis (370.9), corneal abrasion (918.1), corneal haze (371.89), or diffuse lamellar keratitis (370.8) within 1 year after refractive surgery. Patients were excluded from this study for any one of the following: (1) a history of refractive surgery before the diagnosis of HIV infection; (2) a history of an ICD-9 code of a surgical complication (corneal ulcer [370.00 – 370.07], interstitial keratitis [370.50 – 370.59], unspecified keratitis [370.9], corneal abrasion [918.1], corneal haze [371.89], or diffuse lamellar keratitis [370.8]) within 1 year before refractive surgery; or (3) absence of a refractive Current Procedural Terminology code. The outcome studied was the proportion of post-refractive surgical complication(s) after refractive surgery. Volume - Issue - - 2019
Demographic and clinical data were extracted from the study database for analysis including age, sex, race, time since HIV diagnosis, history of AIDS (Centers for Disease Control and Prevention 1993 revised classification system7), antiretroviral therapy (ART) by medication class, CD4 count and HIV viral load at time of ophthalmic diagnosis, total number of ophthalmic diagnoses, diabetes mellitus type 2, hypertension, hyperlipidemia, and smoking. Baseline was defined as earliest documented HIVC test date; ART was defined as in previous NHS studies (Supplemental Table 1, available at http://jcrsjournal.org).8 Most patients were taking two or more nucleoside reverse transcriptase inhibitors and either a nonnucleoside reverse transcriptase inhibitor, unboosted versus boosted protease inhibitor, or an integrase inhibitor. Statistical Analysis All events occurred in HIVC participants. Events were defined as either time of refractive surgery or in controls as censorship date (death, lost to follow-up, or the last study visit). Statistical analysis was completed using chi-square or Wilcoxon-Mann-Whitney tests. Further multivariate analysis was completed using logistic regression. All tests were two-sided, and a P value less than 0.05 was considered statistically significant. Statistical analyses were performed using SAS software (version 9.4, SAS Institute, Inc.).
RESULTS Baseline Characteristics
In the NHS cohort, 79 of 2073 participants met inclusion criteria. Of the participants, 53 underwent PRK, 23 LASIK, 2 RK, and 1 astigmatic correction. Table 1A shows the baseline demographic characteristics, Table 1B shows the baseline HIV-related and medical history parameters, and Supplemental Table 2 (available at http://jcrsjournal.org) shows the indications for surgery. Compared with the HIVC participants who did not undergo refractive surgery, a greater proportion of refractive surgery patients in the cohort were active duty (P Z .0005) and enlisted (P ! .0001). A significant difference in Armed Service branch representation existed (P Z .021). Reflecting the overall trend toward more elective refractive surgery within this population and the general population, an increasing number of refractive surgeries were noted in successive calendar intervals within the cohort (Figure 2) (P Z .014 for increasing trend). Nearly twothirds (50) of the 79 patients undergoing refractive surgery were on treatment with ART at the time of surgery and 49 patients had a viral load less than 400 copies/mL; the median CD4 count was 624 cells/mL and only one patient had less than 200 cells/mL. Complications and Risk Factors
Six (7.6%) of the 79 participants undergoing refractive surgery experienced postoperative complications. No complications were observed in patients undergoing LASIK. Complications within 1 year of surgery occurred in only one RK patient (44 days). However, 5 patients (9.6%) who underwent PRK had complications within 1 year (at 8, 13, 127, 134, and 217 days). Of the 6 complications, three were an unspecified corneal ulcer, one was a marginal corneal ulcer, one a perforated corneal ulcer, and one an unspecified keratitis. In the univariate analysis, the type of surgery performed (P Z .0206) and a previous history of
REFRACTIVE SURGERY IN THE HIV+ U.S. MILITARY
3
Figure 1. Flow chart of study participant selection (CPT Z Current Procedural Terminology; HIVC Z human immunodeficiency virus-positive; ICD Z International Classification of Disease).
AIDS at time of the procedure (P Z .0219) were risk factors for complications (Supplemental Table 3, available at http://jcrsjournal.org). Of the 6 patients who had complications, three were on ART at the time of surgery and 4 had a detectable viral load greater than 400 copies/ mL (1735, 2547, 12 600, and 36 269); however, none had a CD4 counts less than 200 cells/mL at time of surgery (median 658.0 cell/uL, range 349.0 to 691.0 cell/uL). Of those who were on ART, in addition to two nucleoside reverse transcriptase inhibitors, one was on an unboosted protease inhibitor, one a boosted protease inhibitor, and another a nonnucleoside reverse transcriptase inhibitor. Using logistic regression analysis, no covariates were found to be risk factors for complications; however, the sample size was small (Supplemental Table 4, available at http://jcrsjournal.org). DISCUSSION This study represents the first published cohort of HIVC patients who underwent refractive surgery, to the authors’ knowledge. In 1999, Hovanesian et al.3 reported on a case of bilateral bacterial keratitis after a LASIK procedure in an HIVC patient. Unquantified anecdotal reports of postoperative keratitis, delayed wound healing, and dry eye after refractive surgery in HIVC patients have also been reported.4 The lack of published data on postsurgical outcomes in this population has led to inconsistency between published recommendations and actual practice patterns. The FDA established a list of contraindications to PRK in the 1990s, and later published a similar list of contraindications to LASIK. At present, the FDA states that patients who have HIV or are in other immunodeficiency states are not good candidates for refractive
surgery.B Cobo-Soriano et al.9 suggested that controlled systemic disease need not be an absolute contraindication to LASIK. A recent published guideline by the AAO2 lists uncontrolled autoimmune or other immune-mediated disease as an absolute contraindication to refractive surgery, whereas controlled disease is only relatively contraindicated. In actual practice, there is no universal approach to refractive surgery in the HIV population. A 2010 webbased survey of 285 refractive surgeons4 found that 50.2% of respondents consider persons with HIV acceptable candidates for elective refractive surgery, but 88% felt that patients with current AIDS were not appropriate candidates. In our study of HIVC active duty, retirees, and dependents, we found an overall proportion of post-refractive surgical complications of 7.6%. The proportion of complications was 9.4% in those who underwent PRK, whereas no complications were observed in the LASIK patients; PRK was more than twice as common as LASIK in this population, reflecting military practice. Corneal ulcer accounted for 5 of the 6 total complications. Although it was originally thought that PRK predisposes patients to an increased risk for infectious keratitis, large studies have demonstrated similar rates between LASIK and PRK. Wroblewski et al.8 reported 5 cases (0.019%) of post-procedural infectious keratitis out of 25 337 PRK procedures performed at 6 institutions within the Army and Navy database between 1995 and 2004. Llovet et al.10 reported 72 cases (0.035% rate) of post-procedural infectious keratitis out of 204 586 LASIK procedures at a single institution in Spain between 2002 and 2008. Despite the similar complication rates, it has been suggested that PRK poses an increased risk for post-procedural infectious keratitis because of the breakdown of the barrier function of the Volume - Issue - - 2019
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REFRACTIVE SURGERY IN THE HIV+ U.S. MILITARY
Table 1A. Baseline demographic characteristics of the human immunodeficiency virus-positive participants who had refractive surgery. No Refractive Surgery (n Z 1994)
Overall (N Z 2073)
Parameter Age (y) at surgery or censor Sex Male Female Race/ethnicity White African American Hispanic/Other Marital status Single Married Missing data Rank Officer/Warrant Enlisted N/A (eg, dependent) Duty status Active duty Retired Dependent Other (eg, civilian, end of service) Service Air Force Army Marines Navy Other (eg, public health service, foreign military)
N (%)
Median (IQR)
N (%)
40.8 (18.3)
Median (IQR)
Refractive Surgery (n Z 79)
N (%)
41.2 (18.6)
Median (IQR) 31.2 (12.1)
1904 (91.8) 169 (8.2)
1831 (91.8) 163 (8.2)
73 (92.4) 6 (7.6)
786 (37.9) 932 (45.0) 355 (17.1)
755 (37.9) 898 (45.0) 341 (17.1)
31 (39.2) 34 (43.0) 14 (17.7)
1059 (51.1) 866 (41.8) 148 (7.1)
1022 (51.3) 826 (41.4) 146 (7.3)
37 (46.8) 40 (50.6) 2 (2.5)
188 (9.1) 1503 (72.5) 382 (18.4)
173 (8.7) 1441 (72.3) 380 (19.1)
15 (19.0) 62 (78.5) 2 (2.5)
1068 (51.5) 887 (42.8) 87 (4.2) 30 (1.4)
1008 (50.6) 869 (43.6) 86 (4.3) 30 (1.5)
60 (75.9) 18 (22.8) 1 (1.3) 0 (0.0)
448 (21.6) 562 (27.1) 147 (7.1) 856 (41.3) 60 (2.9)
441 (22.1) 537 (26.9) 139 (7.0) 817 (41.0) 60 (3.0)
7 (8.9) 25 (31.6) 8 (10.1) 39 (49.4) 0 (0.0)
P Value !.0001 .8535
.9406
.1179
!.0001
.0005
.0211
IQR Z interquartile range; N/A Z not applicable
corneal epithelium.11 On the other hand, a break in the epithelial barrier during LASIK has been reported to predispose patients to keratitis.10 It appears from the data collected in our study that PRK in HIVC patients might be a risk factor for ulcers, although whether they were specifically infectious is difficult to discern because of the use of ICD-9 codes. In addition, it is critical to recognize that three of the 5 PRK complications occurred late after the surgery (at 127, 134, and 217 days). It is possible that these are unrelated to the refractive surgery, or that the disruption of the epithelial barrier at the time of surgery might predispose these patients to later complications. A previous study12 found that atypical organisms such as mycobacteria and fungi have a later mean onset of presentation; however, unfortunately, the specific culture data were not available in our complications. Finally, the small sample size limits the precision of the point estimates, so it should be interpreted cautiously. We found that a history of AIDS was a potential risk factor for complication after refractive surgery. To our knowledge, there are no previous studies that address post-refractive surgical complications in the HIV population, nor are there published guidelines that suggest an ideal Volume - Issue - - 2019
preoperative CD4 count. In cataract surgery, there are very few studies discussing surgical complications in this patient populace and no published guidelines.13,14 A report of abdominal and plastic surgeries among HIVC patients also found that a lower CD4 count (!200 cells/mL) and viral load (O10 000 copies/mL) were associated with an increased risk for complications,15 and some surgical guidelines have reinforced this.16 In orthopedic trauma, a CD4 count less than 300 cells/mL was associated with the development of postoperative infection.17 However, in patients with HIV, the surgical risk assessment should be individualized and discussed with the patient.18,C It seems prudent that surgeons who are considering operating on patients with HIV should review CD4 counts and viral load to help inform the approach to follow-up. The surgeon could consider that if the CD4 count is less than 200 cells/mL and the viral load more than 10 000 copies/mL, then defer surgery and recommend that the patient start ART therapy; however, further studies and guidelines are required in ophthalmic surgery. In addition, poor ART compliance could signal poor postoperative compliance with topical medications. This is also a potential area of future study in HIVC patients.
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Table 1B. Baseline HIV-related characteristics and medical history of the HIV-positive participants who had refractive surgery. Overall (N Z 2073)
Parameter Age HIV dx Year HIV dx Before 1997 1997–2000 2001–2005 2006–2010 2011–2016 CD4 at HIV dx (cells/mL) VL at HIV dx (log10 copies/mL) HIV dx to surgery or censor Age ART started ART initiation era 1996–2000 2001–2008 2009–2017 No ART started record Time from ART to surgery or censor CD4 at ART (cells/mL) VL at ART (log10 copies/mL) History of AIDS No Yes Year of surgery or censor Before 1997 1997–2000 2001–2005 2006–2010 2011–2016 CD4 at surgery or censor (cells/mL) VL at surgery or censor ART status at surgery or censor Yes No ART medication by class at surgery or censor Boosted PI Integrase inhibitor NNRTI Other Three or more NRTI Unboosted PI DM type 2 at baseline Yes No Hypertension at baseline Yes No Hyperlipidemia at baseline Yes No Tobacco smoking at baseline Yes No
N (%)
Median (IQR)
No Refractive Surgery (n Z 1994)
N (%)
28.8 (11.1) 749 (36.1) 315 (15.2) 380 (18.3) 422 (20.4) 207 (10.0)
Median (IQR)
N (%)
29.0 (10.9) 734 (36.8) 306 (15.3) 360 (18.1) 400 (20.1) 194 (9.7)
475 (285) 4.4 (1.1) 9.1 (11.5) 33.1 (12.3) 804 (38.8) 469 (22.6) 532 (25.7) 268 (12.9)
Refractive Surgery (n Z 79)
P Value
25.5 (8.5)
.0004 .0040
505 (235) 4.5 (0.9) 4.1 (5.6) 28.7 (10.4)
.5711 .5371 !.0001 .0002 .0184
3.2 (5.4) 421 (214) 4.5 (1.1)
!.0001 .0085 .7251 .3568
15 (19.0) 9 (11.4) 20 (25.3) 22 (27.8) 13 (16.5) 475 (289) 4.4 (1.1) 9.3 (11.7) 33.2 (12.3)
786 (39.4) 446 (22.4) 504 (25.3) 258 (12.9) 7.1 (10.0) 355 (227) 4.5 (1.2)
Median (IQR)
18 (22.8) 23 (29.1) 28 (35.4) 10 (12.7) 7.3 (10.3) 352 (225) 4.5 (1.2)
1976 (95.3) 97 (4.7)
1899 (95.2) 95 (4.8)
77 (97.5) 2 (2.5)
52 (2.5) 163 (7.9) 258 (12.4) 381 (18.4) 1219 (58.8)
52 (2.6) 156 (7.8) 241 (12.1) 361 (18.1) 1184 (59.4)
0 (0.0) 7 (8.9) 17 (21.5) 20 (25.3) 35 (44.3)
.0129
627 (389) 1.6 (1.3)
627 (391) 1.5 (1.3)
624 (298) 1.7 (2.1)
1659 (80.0) 414 (20.0)
1609 (80.7) 385 (19.3)
50 (63.3) 29 (36.7)
282 (17.0) 475 (28.6) 669 (40.3) 52 (3.1) 31 (1.9) 150 (9.0)
279 (17.3) 467 (29.0) 636 (39.5) 52 (3.2) 31 (1.9) 144 (8.9)
3 (6.0) 8 (16.0) 33 (66.0) 0 (0.0) 0 (0.0) 6 (12.0)
201 (9.7) 1872 (90.3)
197 (9.9) 1797 (90.1)
4 (5.1) 75 (94.9)
670 (32.3) 1403 (67.7)
648 (32.5) 1346 (67.5)
22 (27.8) 57 (72.2)
1040 (50.2) 1033 (49.8)
1006 (50.5) 988 (49.5)
34 (43.0) 45 (57.0)
1209 (78.6) 329 (21.4)
1159 (78.9) 310 (21.1)
50 (72.5) 19 (27.5)
NR NR NR
NR
.1559
.3862
.1962
.2028
AIDS Z acquired immune deficiency syndrome; ART Z antiretroviral therapy; CD4 Z T lymphocytes; DM Z diabetes mellitus; dx Z diagnosis; HIV Z human immunodeficiency virus; IQR Z interquartile range; NNRTI Z non-nucleoside reverse transcriptase inhibitor; NR Z P value not reported because of differing follow-ups between groups; NRTI Z nucleoside reverse transcriptase inhibitor; PI Z protease inhibitor; VL Z viral load
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population, although larger studies will be required to fully evaluate this. Advanced HIV infection, reflected by a previous diagnosis of AIDS, as well as active viremia and the absence of ART, might be associated with an increased risk for complications. Further study using larger cohorts or metaanalysis will be required to better understand the risk factors for complications of refractive surgery in HIVC patients.
WHAT WAS KNOWN There is limited literature on refractive surgery in human immunodeficiency virus-positive (HIVC) patients. Figure 2. Incidence of refractive surgery (CI Z confidence interval).
One of the lingering concerns of refractive surgeons operating on patients with HIV infection has been the risk for viral transmission during the procedure. However, despite concerns in the pre-ART era, HIV transmission from patients to operating surgeons is extremely rare. Hagen et al.19 concluded that, based on experimentation with the similarly structured pseudorabies virus, excimer laser ablation of the cornea of an HIV-infected patient is unlikely to transmit the virus to the surgeon. In another study by Taravella et al.,20 only DNA fragments of an attenuated varicella-zoster virus were found to have survived excimer laser ablation. Both of these studies reinforce the low risk; however, a website-based survey of refractive surgeons operating on HIV patients4 revealed that 51% were concerned about virus transmission to the surgeon or operating room staff and 40% were concerned about virus transmission to other patients. Standard precautions to prevent occupational exposure to HIV and other infectious pathogens in the healthcare setting and during surgery have proven highly effective with only one confirmed healthcare worker–HIV transmission event from 2000 to 2013.21 These data reinforce the necessity for ongoing and further education of providers and staff regarding the utility of standard precautions and low risk for HIV transmission. And although additional studies to fully characterize HIV transmission risks in various surgical settings such as ophthalmology are also required, the increasing trend of refractive surgeries in our study suggests that attitudes might be shifting in a positive way. The key limitations of this study are related to the patient population and number of procedures performed. The NHS participants were mostly male, young and previously healthy, and active duty with open access to healthcare and medications. These limitations might impact the generalizability. The overall number of participants was small, so findings should be interpreted cautiously. In conclusion, complications occurred infrequently in HIVC patients with virologic suppression on ART after refractive surgery. Many patients living with HIV infection might be appropriate candidates for refractive surgery. PRK might predispose to more complications than LASIK in this Volume - Issue - - 2019
WHAT THIS PAPER ADDS This study evaluated a cohort of HIVC patients who underwent refractive surgery to assess the rate of complications and related risk factors. No HIVC patients who underwent laser in situ keratomileusis had a complication. Further analysis is required in larger cohorts to better understand whether the type of refractive surgical procedure is a risk factor for complications. A history of acquired immune deficiency syndrome (AIDS) was a risk factor for complications in univariate analysis. It is critical that ophthalmologists evaluate antiretroviral therapy status, CD4 (T lymphocytes) count and viral load, and history of AIDS before operating on an HIVC patient.
REFERENCES 1. Marcus J, Chao C, Leyden WA, Xu L, Quesenberry CP Jr, Klein DB, Towner WJ, Horberg MA, Silverberg MJ. Narrowing the gap between HIV-infected and HIV-uninfected individuals with access to care. J Acquir Immune Defic Syndr 2016; 73:39–46 2. Chuck RS, Jacobs DS, Lee JK, Afshari NA, Vitale S, Shen TT, Keenan JD. American Academy of Ophthalmology Preferred Practice Pattern Refractive Management/Intervention Panel. Refractive Errors & Refractive Surgery Preferred Practice Pattern. Ophthalmology 2018; 125:P1–P104 3. Hovanesian JA, Faktorovich EG, Hoffbauer JD, Shah SS, Maloney RK. Bilateral bacterial keratitis after laser in situ keratomileusis in a patient with human immunodeficiency virus infection. Arch Ophthalmol 1999; 117:968–970 4. Aref AA, Scott IU, Zerfoss EL, Kunselman AR. Refractive surgical practices in persons with human immunodeficiency virus positivity or acquired immune deficiency syndrome. J Cataract Refract Surg 2010; 36:153–160 5. Marconi VC, Grandits GA, Weintrob AC, Chun H, Landrum ML, Ganesan A, Okulicz JF, Crum-Cianflone N, O’Connell RJ, Lifson A, Wortmann GW, Agan BK, Infectious Disease Clinical Research Program HIV Working Group (IDCRP). Outcomes of highly active antiretroviral therapy in the context of universal access to healthcare: the U.S. Military HIV Natural History Study. AIDS Res Ther 2010; 7:14 6. Guest JL, Weintrob AC, Rimland D, Rentsch C, Bradley WP, Agan BK, Marconi VC, I D C R P H I V Working Group. A Comparison of HAART Outcomes between the US Military HIV Natural History Study (NHS) and HIV Atlanta Veterans Affairs Cohort Study (HAVACS). PLoS ONE 2013; 8:e62273 7. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992; 41:1–19 8. Wroblewski KJ, Pasternak JF, Bower KS, Schallhorn SC, Hubickey WJ, Harrison CE, Torres MF, Barnes SD. Infectious keratitis after photorefractive keratectomy in the United States Army and Navy. Ophthalmology 2006; 113:520–525 9. Cobo-Soriano R, Beltran J, Baviera J. LASIK outcomes in patients with underlying systemic contraindications. Ophthalmology 2006; 113:1118.e1– 1118.e8
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10. Llovet F, de Rojas V, Interlandi E, Martín C, Cobo-Soriano R, OrtegaUsobiaga J, Baviera J. Infectious keratitis in 204 586 LASIK procedures. Ophthalmology 2010; 117:232–238 11. Donnenfeld ED, O’Brien TP, Solomon R, Perry HD, Speaker MG, Wittpenn J. Infectious keratitis after photorefractive keratectomy. Ophthalmology 2003; 110:743–747 12. Karp CL, Tuli SS, Yoo SH, Vroman DT, Alfonso EC, Huang AH, Pflugfelder SC, Culbertson WW. Infectious keratitis after LASIK. Ophthalmology 2003; 110:503–510 13. Accorinti M, Cecere M, Scala A, Pirraglia MP. Cataract surgery in HIV seropositive patients: long-term follow-up. Ocul Immunol Inflamm 2019; 27:435–446 14. Chew GWM, Teoh SCB, Agrawal R. Analysis and outcomes of cataract surgery in patients with acquired immunodeficiency syndrome. Ocul Immunol Inflamm 2017; 25:535–539 15. Deneve JL, Shantha JG, Page AJ, Wyrzykowski AD, Rozycki GS, Feliciano DV. CD4 count is predictive of outcome in HIV-positive patients undergoing abdominal operations. Am J Surg 2010; 200:694–699 16. Davison SP, Reisman NR, Pellegrino ED, Larson EE, Dermody M, Hutchison PJ. Perioperative guidelines for elective surgery in the human immunodeficiency virus-positive patient. Plast Reconstr Surg 2008; 121:1831–1840 17. Guild GN, Moore TJ, Barnes W, Hermann C. CD4 count is associated with postoperative infection in patients with orthopaedic trauma who are HIV positive. Clin Orthop Relat Res 2012; 470:1507–1512 18. Madiba TE, Muckart DJ, Thomson SR. Human immunodeficiency disease: how should it affect surgical decision making? World J Surg 2009; 33:899–909 19. Hagen KB, Kettering JD, Aprecio RM, Beltran F, Maloney RK. Lack of virus transmission by the excimer laser plume. Am J Ophthalmol 1997; 124:206–211 20. Taravella MJ, Weinberg A, Blackburn P, May M. Do intact viral particles survive excimer laser ablation? Arch Ophthalmol 1997; 115:1028–1030 21. Joyce MP, Kuhar D, Brooks JT. Notes from the field: occupationally acquired HIV infection among health care workers – United States, 1985-2013. MMWR Morb Mortal Wkly Rep 2015; 63:1245–1246
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OTHER CITED MATERIAL A. World Health Organization. HIV/AIDS. Available at: www.who.int/en/ news-room/fact-sheets/detail/hiv-aids B. U.S. Food and Drug Administration. When is LASIK not for me? Available at: https://www.fda.gov/medicaldevices/productsandmedicalprocedures/ surgeryandlifesupport/lasik/ucm061366.htm. Accessed August 15, 2019 C. New York State Department of Health AIDS Institute. Clinical Guidelines Program, Medical Care Criteria Committee, January 2012. Perioperative Management. Available at: https://www.hivguidelines.org/hiv-care/perioperativemanagement/. Accessed August 15, 2019
Disclosures: None of the authors has a financial or proprietary interest in any material or method mentioned. Members of the Infectious Disease Clinical Research Program HIV Working Group include the following: United States California: Naval Medical Center San Diego (S. Cammarata, N. Kirkland, CAPT R. Maves, CAPT [Ret.] G. Utz); Hawaii: Tripler Army Medical Center, Honolulu (COL M. Price); Maryland: National Institute of Allergy and Infectious Diseases, Bethesda (J. Powers, COL [Ret.] E. Tramont), Uniformed Services University of the Health Sciences, Bethesda (B. Agan; X. Chu, W. Horton, H. Hsieh, A. Noiman, E. Parmelee, D. Tribble, X. Wang, S. Won), Walter Reed National Military Medical Center, Bethesda (I. Barahona, LTC J. Blaylock, C. Decker, A. Ganesan, COL R. Ressner, D. Wallace), and Walter Reed Army Institute of Research, Silver Spring (S. Peel); Texas: Brooke Army Medical Center, Fort Sam Houston (S. De Leon, S. Merritt, T. Merritt, Lt Col J. Okulicz, T. Sjoberg); Virginia: Naval Medical Center Portsmouth, Portsmouth (S. Banks, CAPT K. Kronmann, T. Lalani, R. Tant, T. Warkentien); Washington: Madigan Army Medical Center, Joint Base LewisMcChord (C. Baker, S. Chambers, R. Colombo, COL T. Ferguson, LTC A. Kunz, C. Schofield, M. Stein)
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