HIV Reports
The Association of Uncontrolled HIV Infection and Other Sexually Transmitted Infections in Metropolitan Atlanta Youth Pamela S. Brownstein, MD,* Scott E. Gillespie, MS,† Traci Leong, PhD,‡ Ann Chahroudi, MD, PhD,§¶ Rana Chakraborty, MD, PhD,§¶ and Andres F. Camacho-Gonzalez, MD, MSc§¶ Background: Half of the 19 million sexually transmitted infections (STIs) and 26% of HIV infections annually in the United States occur in youth aged 13–24 years. STIs are a risk factor for HIV acquisition and transmission, but data are lacking on HIV treatment as an intervention to reduce STIs. Methods: A single-centered, retrospective analysis of HIV-infected sexually active adolescents and young adults from January 2009 to December 2011 was performed to compare STI incidence among patients with controlled and uncontrolled HIV and to identify associated risk factors. Results: Of 205 enrolled subjects, 59% were male and 92% African American with mean age of 21 years (2.1 SD). Sixty-six percent were horizontally infected, and 19% met the definition of controlled HIV. Forty-seven percent were men who have sex with men, 76% reported condom use, 27% prior sexual abuse, 58% drug use and 50% claimed >5 lifetime sexual partners. Sixty-seven percent contracted a co-STI for a cumulative incidence rate of 35 STIs per 100 person-years. Subjects with uncontrolled HIV had a significantly higher STI incidence than did subjects with controlled infection (42.7 vs. 19.7 per 100 person-years, P < 0.001). Uncontrolled individuals had more STIs (P = 0.01), sexual partners (P = 0.008) and horizontal acquisition (P = 0.001). In an adjusted logistic model, having ≥1 STI was associated with older age (P = 0.033), >5 sexual partners (6–10 partners, P = 0.001; >10, P < 0.001) and no condom use (P = 0.025). Subjects with uncontrolled infection had 2.8 times [95% confidence interval (CI): 1.16–6.94] the odds of ≥1 STI relative to controlled HIV. Conclusions: Uncontrolled HIV increases the incidence of co-STIs among adolescents and young adults. Interventions to improve antiretroviral compliance and reduce risk behaviors are urgently needed. Key Words: HIV, adolescents, sexually transmitted infections (Pediatr Infect Dis J 2015;34:e119–e124)
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he Centers for Disease Control and Prevention estimates that there are 37,350 people between the ages of 13 and 24 years living with HIV in the United States. Incidence data report about 9000 new cases each year in this population, representing almost one third of all new HIV infections in the United States.1 Similarly, Accepted November 20, 2014. From the *Department of Pediatrics, Children’s Healthcare of Atlanta, Georgia; †Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; ‡Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia; §Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Georgia; and ¶Ponce Family and Youth Clinic, Grady Infectious Diseases Program, Grady Health Systems, Atlanta, Georgia. A.F. C.-G. has received research support from Bristol-Myers Squibb. R.C. has received research support from Gilead. The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Andres F. Camacho-Gonzalez, MD, MSc, Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory U niversity School of Medicine, 2015 Uppergate Dr. Suite 500, Atlanta, GA 30322. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-e119 DOI: 10.1097/INF.0000000000000632
of the most 20 million new sexually transmitted infections (STIs) in the United States, half occur in adolescents and young adults (AYAs), despite AYAs representing only 25% of the sexually active population.2 According to the 2013 Youth Risk and Behavior Survey, 46.8% of American teens have had sex at least once, and 34.0% are currently sexually active, with only 59.1% using a condom during their most recent intercourse.3 This pattern of high-risk behavior is no different in HIV-infected AYAs.4,5 HIV and other STIs may interact synergistically, so that breached mucosal barriers with recruitment and activation of immune cells at local sites of infection and inflammation from an STI could enhance the transmission and dissemination of HIV. In addition, HIV alters the natural course of co-STIs, with secondary immunosuppression leading to increased severity or atypical clinical manifestations of the latter.6 It is imperative to diagnose and treat HIV infection not only to reduce individual morbidity and mortality but also to prevent secondary transmission.7 Treatment as prevention has been widely adopted in recent US guidelines on HIV management in AYAs and is reflected nationwide in initiating combination antiretroviral therapy (cART) at higher thresholds for CD4+ T-cell number irrespective of plasma HIV viral load.8 Linkage to and retention in medical care are essential for adherence to cART but has been challenging to successfully implement in HIV-infected AYAs. In the state of Georgia, for example, estimates from 2012 show that approximately 82% of patients know their HIV diagnosis, but only 44% are linked to care.9 African-American men who have sex with men between the ages of 13 and 24 years are the least likely to be linked.10 One method to improve linkage to and retention in care has been establishing medical homes to provide comprehensive care, including client tracking, patient education and case management.11 Although researchers have evaluated the impact of virologic control in reducing secondary HIV transmission, there have been only a few published studies with conflicting results evaluating the impact of HIV infection on the transmission of other STIs. Mullins and colleagues5 demonstrated that young women with HIV not on cART were more likely to acquire trichomonas than did the HIVinfected women receiving cART, but other studies have failed to show an association between cART status and STI acquisition.6,12 Others have shown that teens receiving cART continue to engage in high-risk sexual behaviors including unprotected sex with multiple partners.4,13 Although these studies evaluated whether or not a patient was on cART, none have examined the impact of effective HIV treatment on prevention of STI acquisition. In this study, we hypothesized that virologically controlled HIV-infected AYAs in metropolitan Atlanta have a lower incidence of co-STIs compared with the uncontrolled HIV infection and that virologic control may be associated with decreasing rates of coSTIs in this group.
METHODS Patient Population We undertook a retrospective chart review of patients attending the Ponce Family and Youth Clinic in Atlanta, GA, from
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The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
January 1, 2009, to December 31, 2011. All HIV-infected, sexually active (by self-report) patients aged 13–24 years who presented for HIV care during this time period were included, regardless of when they presented initially for HIV care (before or during the time period studied). All patients with a minimum of 1 clinic visit during the study period were included. The Institutional Review Boards of both Emory University and Grady Health System approved this study. Information was obtained from existing outpatient clinical and laboratory records. Data were collected on self-reported demographic information, social history and sexual behaviors. Condom, drug and alcohol use were considered positive if patient reported its use at least once during the study period. STI diagnostic data were collected from both physical examination and laboratory findings. HIV-related values were collected from laboratory data.
Definitions Controlled HIV The primary definition of virologically controlled HIV infection included patients with mean HIV-1 RNA level of less than 500 copies/mL of plasma and mean CD4+ T-cell counts greater than 200 cells/μL of peripheral blood over the 3-year study period. We chose an HIV-1 RNA level of less than 500 copies/mL to account for potential viral blips during the study period that may not necessarily reflect true virologic failure. To be considered controlled, patients had to meet both virologic and immunologic criteria for all known data points collected during the study period. Individuals failing to meet these criteria were identified as uncontrolled. The mean was calculated if the patient had at least 2 CD4+ T-cell count or viral load tests performed during the study period. A secondary definition of virologically controlled disease included patients who had undetectable HIV-1 RNA levels for at least 6 months from the event (STI). This definition was used to account for those patients who, despite virologic control, did not immune-reconstitute in the time period studied.
Sexually Transmitted infection Recorded STIs and associated inclusion definitions were 1. Gonorrhea: determined by a positive culture (throat, rectum or penile discharge) or positive nucleic acid test from urine, throat or rectum. 2. Chlamydia: determined by positive nucleic acid testing from urine, cervical or rectal specimens. 3. Syphilis: determined by positive screening with rapid plasma reagin circle card test and confirmatory testing with a treponemal test. 4. Herpes simplex virus (HSV): positive clinical diagnosis documented in the chart or a positive direct fluorescent antibody or culture for HSV. 5. Trichomonas: positive wet mount or urine analysis showing trichomonads. 6. Lymphogranuloma venereum: positive serology for Chlamydia trachomatis serovars L1, L2 and L3 with associated compatible clinical symptoms (large inguinal adenopathy and painful/ bloody stools). 5. Chancroid: clinical manifestations compatible with chancroid (painful genital ulcer with suppurative inguinal adenopathy). 6. Human papillomavirus (HPV): positive clinical diagnosis of warts documented in the chart or a positive cytologic report from cervix or rectum that mentioned the presence of HPV.
Statistical Analyses All statistical analyses were performed using SAS 9.3 (Cary, NC), and statistical significance was assessed at 0.05 unless otherwise
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noted. Before the analysis, the normality of age, CD4+ T-cell counts, viral load and age at first sexual encounter was assessed using the Anderson–Darling test for normality and by visual inspection of the histograms. Only viral load failed to meet the assumption of normality and is presented with the median, 25th and 75th percentiles. Discrete variables are represented by frequency counts, Agresti–Coull proportions and confidence intervals (CIs) when appropriate.14 Descriptive statistics were calculated for all variables of interest in the overall sample and by controlled versus uncontrolled disease. Comparisons between variables were made using t tests and χ2 test of independence. In cases of nonnormality, nonparametric procedures, such as the Mann–Whitney and Kolmogorov– Smirnov tests, were used. An exact form of the Pearson χ2 test was implemented when frequency counts were low (10 partners OR: 4.54, 95% CI: 1.96–10.50) and the lack of barrier contraception use (OR: 2.34, 95% CI: 1.11– 4.91; Table 3). In addition, an individual with uncontrolled HIV infection had 2.84 times (95% CI: 1.16–6.94) the odds of having © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Uncontrolled HIV and STIs
TABLE 1. Overall Patient Characteristics and Proportions with 95% CIs* Characteristic Gender, n % (95% CI) Age (years), mean ± SD† Race, n % (95% CI)
Mode of HIV transmission, n % (95% CI) CD4 T-cell counts, mean ± SD HIV-1 RNA level, median (25–75%) Undetectable HIV-1 RNA level in 6 months, n % (95% CI) cART, n % (95% CI) Well-controlled disease, n % (95% CI) Age at first sexual encounter (years), mean ± SD Sexual preference, n % (95% CI) Partners, n % (95% CI) Barrier contraceptive use, n % (95% CI) Hormonal contraceptive use, n % (95% CI)‡ Pregnancy, n % (95% CI)‡ History of sexual abuse, n % (95% CI) Prostitution, n % (95% CI) Drugs, n % (95% CI) Alcohol, n % (95% CI) School, n % (95% CI) Education, n % (95% CI) Working, n % (95% CI) Living, n % (95% CI)
Contract STI during study, n % (95% CI) Number of STIs, n % (95% CI)
Level
n = 205
Proportion (95% CI)†
Male Female — Caucasian African American Hispanic Other Vertical Horizontal — — Yes No Yes No Yes No — Homosexual Heterosexual Bisexual 0–5 6–10 >10 Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Some high school Completed high school Some college/college Yes No Family Friends Homeless Other Yes No 0 1–2 >2
122 83 21.0 ± 2.1 5 191 5 4 67 132 373.7 ± 208.5 7700 (1416–27,890) 72 133 124 81 38 167 15.2 ± 2.6 68 109 26 91 33 53 143 44 62 20 42 35 46 127 8 88 118 83 98 100 85 106 88 40 71 80 88 135 24 9 33 138 67 67 111 27
59.3 (52.7–66.0) 40.7 (34.0–47.3) — 3.3 (0.9–5.8) 92.3 (88.7–95.9) 3.3 (0.9–5.8) 2.9 (0.6–5.1) 34.0 (27.5–40.5) 66.0 (59.5–72.5) — — 35.4 (28.9–41.9) 64.6 (58.1–71.1) 60.3 (53.7–66.9) 39.7 (33.1–46.3) 19.1 (13.8–24.5) 80.9 (75.5–86.2) — 33.5 (27.1–39.9) 53.1 (46.3–59.9) 13.4 (8.8–18.0) 51.4 (44.1–58.7) 19.2 (13.6–25.1) 30.4 (23.7–37.1) 75.9 (69.9–82.0) 24.1 (18.0–30.1) 74.4 (65.2–83.6) 25.6 (16.4–34.8) 54.3 (43.5–65.2) 45.7 (34.8–56.5) 27.1 (20.6–33.7) 72.9 (66.3–79.4) 10.0 (4.1–15.9) 90.0 (84.1–95.9) 58.5 (51.8–65.3) 41.5 (34.7–48.2) 49.5 (42.6–56.4) 50.5 (43.6–57.4) 44.6 (37.6–51.6) 55.4 (48.4–62.4) 44.3 (37.5–51.2) 20.7 (15.1–26.3) 36.0 (29.4–42.6) 47.7 (40.2–55.1) 52.3 (44.9–59.8) 66.8 (60.4–73.3) 12.7 (8.1–17.2) 5.4 (2.3–8.5) 17.1 (11.9–22.2) 67.0 (60.6–73.4) 33.0 (26.6–39.4) 33.0 (26.6–39.4) 54.1 (47.3–60.8) 13.9 (9.2–18.6)
*Outcomes labeled as “Unknown” were counted as missing data. Thus, not all counts will sum to n = 205. †Agresti–Coull proportions and CIs. ‡Hormonal contraceptive use and pregnancy were calculated only for the female subpopulation (n = 84). SD indicates standard deviation.
one or more STIs when compared with a subject with controlled HIV infection (Table 3). Although mode of transmission was a significant univariate predictor, it was removed from the multivariable model because of its high association with the other predictors, thus violating the multicollinearity assumption.
DISCUSSION Previous work has established increased susceptibility to HIV acquisition, as well as an increased risk of secondary © 2015 Wolters Kluwer Health, Inc. All rights reserved.
HIV transmission in individuals with co-STIs.6 There is an urgent need to better characterize sexual behavior in at-risk HIV-infected youth given the alarming rise in sexually active HIV-infected AYAs. This increase is secondary to 2 overlapping phenomena: many AYAs who were perinatally HIV-infected are now sexually active and there continues to be an increasing population of horizontally infected AYAs.15,16 Understanding sexual behavior in HIV-infected youth becomes increasingly important as we emphasize a public health approach to HIV and STI prevention. www.pidj.com | e121
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The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
TABLE 2. Patient Characteristics by Uncontrolled Versus Controlled Disease Status and P Values Characteristic
Level
Uncontrolled HIV, n = 167
Controlled HIV, n = 38
P Value
Gender, n (%)
Male Female — Caucasian African American Hispanic Other Vertical Horizontal — — Yes No Yes No —
102 (83.6) 65 (78.3 21.0 ± 2.1 3 (60.0) 157 (82.2) 4 (80.0) 3 (75.0) 46 (68.7) 116 (87.9) 329.0 ± 187.2 11,724 (4778–35,420) 41 (56.9) 126 (94.7) 95 (76.6) 72 (88.9) 15.1 ± 2.5
20 (16.4) 18 (21.7 20.7 ± 2.3 2 (40.0) 34 (17.8) 1 (20.0) 1 (25.0) 21 (31.3) 16 (12.1) 569.9 ± 184.1 0 (0–20.0) 31 (43.1) 7 (5.3) 29 (23.4) 9 (11.1) 15.5 ± 3.1
0.338
Homosexual Heterosexual Bisexual 0–5 6–10 >10 Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Some High School Completed High School Some College/College Yes No Family Friends Homeless Other Yes No 0 1–2 >2
61 (89.7) 83 (76.1) 21 (80.8) 67 (73.6) 27 (81.8) 50 (94.3) 117 (81.8) 37 (84.1) 50 (80.7) 14 (70.0) 37 (88.1) 25 (71.4) 38 (82.6) 101 (79.5) 8 (100.0) 63 (71.6) 99 (83.9) 66 (79.5) 85 (86.7) 76 (76.0) 65 (76.5) 90 (84.9) 76 (86.4) 32 (80.0) 54 (76.1) 67 (83.8) 72 (81.8) 106 (78.5) 20 (83.3) 8 (88.9) 29 (87.9) 120 (87.0) 47 (70.2) 47 (70.2) 95 (85.6) 25 (92.6)
7 (10.3) 26 (23.9) 5 (19.2) 24 (26.4) 6 (18.2) 3 (5.7) 26 (18.2) 7 (15.9) 12 (19.3) 6 (30.0) 5 (11.9) 10 (28.6) 8 (17.4) 26 (20.5) 0 (0) 25 (28.4) 19 (16.1) 17 (20.5) 13 (13.3) 24 (24.0) 20 (23.5) 16 (15.1) 12 (13.6) 8 (20.0) 17 (23.9) 13 (16.2) 16 (18.2) 29 (21.5) 4 (16.7) 1 (11.1) 4 (12.1) 18 (13.0) 20 (29.8) 20 (29.8) 16 (14.4) 2 (7.4)
Age (years), mean ± SD Race, n (%)
Mode of HIV transmission, n (%) CD4+ T-cell counts, mean ± SD HIV-1 RNA level, median (25–75%) Undetectable HIV-1 RNA level in last 6 months, n (%) cART, n (%) Age at first sexual encounter (years), mean ± SD Sexual preference, n (%) Partners, n (%) Barrier contraceptive, n (%) Hormonal contraceptive, n (%) Pregnancy, n (%) History of sexual abuse, n (%) Prostitution, n (%) Drugs, n (%) Alcohol, n (%) School, n (%) Education, n (%) Working, n (%) Living, n (%)
Contract STI during study, n (%) Number of STIs, n (%)
0.439 0.736
0.001 < 0.001 < 0.001 < 0.001 0.029 0.468 0.085 0.008 0.824 0.358 0.086 0.675 0.107 0.425 0.053 0.139 0.246 0.741 0.610
0.004 0.010
SD indicates standard deviation.
Overall, 67% of our HIV-infected cohort contracted an STI during the study period, for an overall cumulative incidence rate of 35 STIs per 100 person-years. Few studies have examined co-STI incidence in HIV-infected individuals. A study by Mullins and colleagues5 looking at STIs in HIV-infected and HIV-uninfected AYAs showed differences in rates of co-STIs based on gender and type of co-STI. A smaller study from the United Kingdom of perinatally HIV-infected AYAs showed a frequency of STIs of 11.5% over a 6-year period with an incidence rate of 5.4 per 100 person-years.17 These rates are substantially less than the rates reported in our study even when only perinatally HIV-infected AYAs were considered (16%, with a cumulative incidence rate of 18.5 STIs per 100 person years, data not shown).
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Associated factors for STI acquisition included older age, a higher number of sexual partners and nonuse of barrier contraceptive methods. The association between older age and a higher risk of STI acquisition has been previously described and may be related to an increasing number of sexual partners as the adolescent ages.18,19 An important discrepancy was noted between the high rates of STIs and the fairly high use of barrier protection reported by study participants. Other studies have documented similar or higher rates of reported condom use. The Longitudinal Epidemiological Study to Gain Insight into HIV/AIDS in Children and Youth reported 80% condom use in their cohort,18 and similar numbers were noted in the Pediatric Spectrum of HIV Disease Study.20 However, DiClemente and colleagues21 point out that condom use may be overestimated among AYAs, either © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Uncontrolled HIV and STIs
FIGURE 1. STIs contracted by controlled versus uncontrolled disease status. TABLE 3. Ordinal Logistic Regression Model ORs and 95% Confidence Limits Controlling for Disease Status Parameter Number of partners Controlled Barrier Age
Level
OR
95% Confidence Limits
P Value
>10 6–10 Uncontrolled disease No —
4.54 4.05 2.84 2.34 1.20
1.96–10.50 1.73–9.47 1.16–6.94 1.11–4.91 1.01–1.42
The Association of Uncontrolled HIV Infection and Other Sexually Transmitted Infections in Metropolitan Atlanta Youth Pamela S. Brownstein, MD,* Scott E. Gillespie, MS,† Traci Leong, PhD,‡ Ann Chahroudi, MD, PhD,§¶ Rana Chakraborty, MD, PhD,§¶ and Andres F. Camacho-Gonzalez, MD, MSc§¶ Background: Half of the 19 million sexually transmitted infections (STIs) and 26% of HIV infections annually in the United States occur in youth aged 13–24 years. STIs are a risk factor for HIV acquisition and transmission, but data are lacking on HIV treatment as an intervention to reduce STIs. Methods: A single-centered, retrospective analysis of HIV-infected sexually active adolescents and young adults from January 2009 to December 2011 was performed to compare STI incidence among patients with controlled and uncontrolled HIV and to identify associated risk factors. Results: Of 205 enrolled subjects, 59% were male and 92% African American with mean age of 21 years (2.1 SD). Sixty-six percent were horizontally infected, and 19% met the definition of controlled HIV. Forty-seven percent were men who have sex with men, 76% reported condom use, 27% prior sexual abuse, 58% drug use and 50% claimed >5 lifetime sexual partners. Sixty-seven percent contracted a co-STI for a cumulative incidence rate of 35 STIs per 100 person-years. Subjects with uncontrolled HIV had a significantly higher STI incidence than did subjects with controlled infection (42.7 vs. 19.7 per 100 person-years, P < 0.001). Uncontrolled individuals had more STIs (P = 0.01), sexual partners (P = 0.008) and horizontal acquisition (P = 0.001). In an adjusted logistic model, having ≥1 STI was associated with older age (P = 0.033), >5 sexual partners (6–10 partners, P = 0.001; >10, P < 0.001) and no condom use (P = 0.025). Subjects with uncontrolled infection had 2.8 times [95% confidence interval (CI): 1.16–6.94] the odds of ≥1 STI relative to controlled HIV. Conclusions: Uncontrolled HIV increases the incidence of co-STIs among adolescents and young adults. Interventions to improve antiretroviral compliance and reduce risk behaviors are urgently needed. Key Words: HIV, adolescents, sexually transmitted infections (Pediatr Infect Dis J 2015;34:e119–e124)
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he Centers for Disease Control and Prevention estimates that there are 37,350 people between the ages of 13 and 24 years living with HIV in the United States. Incidence data report about 9000 new cases each year in this population, representing almost one third of all new HIV infections in the United States.1 Similarly, Accepted November 20, 2014. From the *Department of Pediatrics, Children’s Healthcare of Atlanta, Georgia; †Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; ‡Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia; §Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Georgia; and ¶Ponce Family and Youth Clinic, Grady Infectious Diseases Program, Grady Health Systems, Atlanta, Georgia. A.F. C.-G. has received research support from Bristol-Myers Squibb. R.C. has received research support from Gilead. The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Andres F. Camacho-Gonzalez, MD, MSc, Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory U niversity School of Medicine, 2015 Uppergate Dr. Suite 500, Atlanta, GA 30322. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-e119 DOI: 10.1097/INF.0000000000000632
of the most 20 million new sexually transmitted infections (STIs) in the United States, half occur in adolescents and young adults (AYAs), despite AYAs representing only 25% of the sexually active population.2 According to the 2013 Youth Risk and Behavior Survey, 46.8% of American teens have had sex at least once, and 34.0% are currently sexually active, with only 59.1% using a condom during their most recent intercourse.3 This pattern of high-risk behavior is no different in HIV-infected AYAs.4,5 HIV and other STIs may interact synergistically, so that breached mucosal barriers with recruitment and activation of immune cells at local sites of infection and inflammation from an STI could enhance the transmission and dissemination of HIV. In addition, HIV alters the natural course of co-STIs, with secondary immunosuppression leading to increased severity or atypical clinical manifestations of the latter.6 It is imperative to diagnose and treat HIV infection not only to reduce individual morbidity and mortality but also to prevent secondary transmission.7 Treatment as prevention has been widely adopted in recent US guidelines on HIV management in AYAs and is reflected nationwide in initiating combination antiretroviral therapy (cART) at higher thresholds for CD4+ T-cell number irrespective of plasma HIV viral load.8 Linkage to and retention in medical care are essential for adherence to cART but has been challenging to successfully implement in HIV-infected AYAs. In the state of Georgia, for example, estimates from 2012 show that approximately 82% of patients know their HIV diagnosis, but only 44% are linked to care.9 African-American men who have sex with men between the ages of 13 and 24 years are the least likely to be linked.10 One method to improve linkage to and retention in care has been establishing medical homes to provide comprehensive care, including client tracking, patient education and case management.11 Although researchers have evaluated the impact of virologic control in reducing secondary HIV transmission, there have been only a few published studies with conflicting results evaluating the impact of HIV infection on the transmission of other STIs. Mullins and colleagues5 demonstrated that young women with HIV not on cART were more likely to acquire trichomonas than did the HIVinfected women receiving cART, but other studies have failed to show an association between cART status and STI acquisition.6,12 Others have shown that teens receiving cART continue to engage in high-risk sexual behaviors including unprotected sex with multiple partners.4,13 Although these studies evaluated whether or not a patient was on cART, none have examined the impact of effective HIV treatment on prevention of STI acquisition. In this study, we hypothesized that virologically controlled HIV-infected AYAs in metropolitan Atlanta have a lower incidence of co-STIs compared with the uncontrolled HIV infection and that virologic control may be associated with decreasing rates of coSTIs in this group.
METHODS Patient Population We undertook a retrospective chart review of patients attending the Ponce Family and Youth Clinic in Atlanta, GA, from
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
www.pidj.com | e119
Brownstein et al
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
January 1, 2009, to December 31, 2011. All HIV-infected, sexually active (by self-report) patients aged 13–24 years who presented for HIV care during this time period were included, regardless of when they presented initially for HIV care (before or during the time period studied). All patients with a minimum of 1 clinic visit during the study period were included. The Institutional Review Boards of both Emory University and Grady Health System approved this study. Information was obtained from existing outpatient clinical and laboratory records. Data were collected on self-reported demographic information, social history and sexual behaviors. Condom, drug and alcohol use were considered positive if patient reported its use at least once during the study period. STI diagnostic data were collected from both physical examination and laboratory findings. HIV-related values were collected from laboratory data.
Definitions Controlled HIV The primary definition of virologically controlled HIV infection included patients with mean HIV-1 RNA level of less than 500 copies/mL of plasma and mean CD4+ T-cell counts greater than 200 cells/μL of peripheral blood over the 3-year study period. We chose an HIV-1 RNA level of less than 500 copies/mL to account for potential viral blips during the study period that may not necessarily reflect true virologic failure. To be considered controlled, patients had to meet both virologic and immunologic criteria for all known data points collected during the study period. Individuals failing to meet these criteria were identified as uncontrolled. The mean was calculated if the patient had at least 2 CD4+ T-cell count or viral load tests performed during the study period. A secondary definition of virologically controlled disease included patients who had undetectable HIV-1 RNA levels for at least 6 months from the event (STI). This definition was used to account for those patients who, despite virologic control, did not immune-reconstitute in the time period studied.
Sexually Transmitted infection Recorded STIs and associated inclusion definitions were 1. Gonorrhea: determined by a positive culture (throat, rectum or penile discharge) or positive nucleic acid test from urine, throat or rectum. 2. Chlamydia: determined by positive nucleic acid testing from urine, cervical or rectal specimens. 3. Syphilis: determined by positive screening with rapid plasma reagin circle card test and confirmatory testing with a treponemal test. 4. Herpes simplex virus (HSV): positive clinical diagnosis documented in the chart or a positive direct fluorescent antibody or culture for HSV. 5. Trichomonas: positive wet mount or urine analysis showing trichomonads. 6. Lymphogranuloma venereum: positive serology for Chlamydia trachomatis serovars L1, L2 and L3 with associated compatible clinical symptoms (large inguinal adenopathy and painful/ bloody stools). 5. Chancroid: clinical manifestations compatible with chancroid (painful genital ulcer with suppurative inguinal adenopathy). 6. Human papillomavirus (HPV): positive clinical diagnosis of warts documented in the chart or a positive cytologic report from cervix or rectum that mentioned the presence of HPV.
Statistical Analyses All statistical analyses were performed using SAS 9.3 (Cary, NC), and statistical significance was assessed at 0.05 unless otherwise
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noted. Before the analysis, the normality of age, CD4+ T-cell counts, viral load and age at first sexual encounter was assessed using the Anderson–Darling test for normality and by visual inspection of the histograms. Only viral load failed to meet the assumption of normality and is presented with the median, 25th and 75th percentiles. Discrete variables are represented by frequency counts, Agresti–Coull proportions and confidence intervals (CIs) when appropriate.14 Descriptive statistics were calculated for all variables of interest in the overall sample and by controlled versus uncontrolled disease. Comparisons between variables were made using t tests and χ2 test of independence. In cases of nonnormality, nonparametric procedures, such as the Mann–Whitney and Kolmogorov– Smirnov tests, were used. An exact form of the Pearson χ2 test was implemented when frequency counts were low (10 partners OR: 4.54, 95% CI: 1.96–10.50) and the lack of barrier contraception use (OR: 2.34, 95% CI: 1.11– 4.91; Table 3). In addition, an individual with uncontrolled HIV infection had 2.84 times (95% CI: 1.16–6.94) the odds of having © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Uncontrolled HIV and STIs
TABLE 1. Overall Patient Characteristics and Proportions with 95% CIs* Characteristic Gender, n % (95% CI) Age (years), mean ± SD† Race, n % (95% CI)
Mode of HIV transmission, n % (95% CI) CD4 T-cell counts, mean ± SD HIV-1 RNA level, median (25–75%) Undetectable HIV-1 RNA level in 6 months, n % (95% CI) cART, n % (95% CI) Well-controlled disease, n % (95% CI) Age at first sexual encounter (years), mean ± SD Sexual preference, n % (95% CI) Partners, n % (95% CI) Barrier contraceptive use, n % (95% CI) Hormonal contraceptive use, n % (95% CI)‡ Pregnancy, n % (95% CI)‡ History of sexual abuse, n % (95% CI) Prostitution, n % (95% CI) Drugs, n % (95% CI) Alcohol, n % (95% CI) School, n % (95% CI) Education, n % (95% CI) Working, n % (95% CI) Living, n % (95% CI)
Contract STI during study, n % (95% CI) Number of STIs, n % (95% CI)
Level
n = 205
Proportion (95% CI)†
Male Female — Caucasian African American Hispanic Other Vertical Horizontal — — Yes No Yes No Yes No — Homosexual Heterosexual Bisexual 0–5 6–10 >10 Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Some high school Completed high school Some college/college Yes No Family Friends Homeless Other Yes No 0 1–2 >2
122 83 21.0 ± 2.1 5 191 5 4 67 132 373.7 ± 208.5 7700 (1416–27,890) 72 133 124 81 38 167 15.2 ± 2.6 68 109 26 91 33 53 143 44 62 20 42 35 46 127 8 88 118 83 98 100 85 106 88 40 71 80 88 135 24 9 33 138 67 67 111 27
59.3 (52.7–66.0) 40.7 (34.0–47.3) — 3.3 (0.9–5.8) 92.3 (88.7–95.9) 3.3 (0.9–5.8) 2.9 (0.6–5.1) 34.0 (27.5–40.5) 66.0 (59.5–72.5) — — 35.4 (28.9–41.9) 64.6 (58.1–71.1) 60.3 (53.7–66.9) 39.7 (33.1–46.3) 19.1 (13.8–24.5) 80.9 (75.5–86.2) — 33.5 (27.1–39.9) 53.1 (46.3–59.9) 13.4 (8.8–18.0) 51.4 (44.1–58.7) 19.2 (13.6–25.1) 30.4 (23.7–37.1) 75.9 (69.9–82.0) 24.1 (18.0–30.1) 74.4 (65.2–83.6) 25.6 (16.4–34.8) 54.3 (43.5–65.2) 45.7 (34.8–56.5) 27.1 (20.6–33.7) 72.9 (66.3–79.4) 10.0 (4.1–15.9) 90.0 (84.1–95.9) 58.5 (51.8–65.3) 41.5 (34.7–48.2) 49.5 (42.6–56.4) 50.5 (43.6–57.4) 44.6 (37.6–51.6) 55.4 (48.4–62.4) 44.3 (37.5–51.2) 20.7 (15.1–26.3) 36.0 (29.4–42.6) 47.7 (40.2–55.1) 52.3 (44.9–59.8) 66.8 (60.4–73.3) 12.7 (8.1–17.2) 5.4 (2.3–8.5) 17.1 (11.9–22.2) 67.0 (60.6–73.4) 33.0 (26.6–39.4) 33.0 (26.6–39.4) 54.1 (47.3–60.8) 13.9 (9.2–18.6)
*Outcomes labeled as “Unknown” were counted as missing data. Thus, not all counts will sum to n = 205. †Agresti–Coull proportions and CIs. ‡Hormonal contraceptive use and pregnancy were calculated only for the female subpopulation (n = 84). SD indicates standard deviation.
one or more STIs when compared with a subject with controlled HIV infection (Table 3). Although mode of transmission was a significant univariate predictor, it was removed from the multivariable model because of its high association with the other predictors, thus violating the multicollinearity assumption.
DISCUSSION Previous work has established increased susceptibility to HIV acquisition, as well as an increased risk of secondary © 2015 Wolters Kluwer Health, Inc. All rights reserved.
HIV transmission in individuals with co-STIs.6 There is an urgent need to better characterize sexual behavior in at-risk HIV-infected youth given the alarming rise in sexually active HIV-infected AYAs. This increase is secondary to 2 overlapping phenomena: many AYAs who were perinatally HIV-infected are now sexually active and there continues to be an increasing population of horizontally infected AYAs.15,16 Understanding sexual behavior in HIV-infected youth becomes increasingly important as we emphasize a public health approach to HIV and STI prevention. www.pidj.com | e121
Brownstein et al
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
TABLE 2. Patient Characteristics by Uncontrolled Versus Controlled Disease Status and P Values Characteristic
Level
Uncontrolled HIV, n = 167
Controlled HIV, n = 38
P Value
Gender, n (%)
Male Female — Caucasian African American Hispanic Other Vertical Horizontal — — Yes No Yes No —
102 (83.6) 65 (78.3 21.0 ± 2.1 3 (60.0) 157 (82.2) 4 (80.0) 3 (75.0) 46 (68.7) 116 (87.9) 329.0 ± 187.2 11,724 (4778–35,420) 41 (56.9) 126 (94.7) 95 (76.6) 72 (88.9) 15.1 ± 2.5
20 (16.4) 18 (21.7 20.7 ± 2.3 2 (40.0) 34 (17.8) 1 (20.0) 1 (25.0) 21 (31.3) 16 (12.1) 569.9 ± 184.1 0 (0–20.0) 31 (43.1) 7 (5.3) 29 (23.4) 9 (11.1) 15.5 ± 3.1
0.338
Homosexual Heterosexual Bisexual 0–5 6–10 >10 Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Some High School Completed High School Some College/College Yes No Family Friends Homeless Other Yes No 0 1–2 >2
61 (89.7) 83 (76.1) 21 (80.8) 67 (73.6) 27 (81.8) 50 (94.3) 117 (81.8) 37 (84.1) 50 (80.7) 14 (70.0) 37 (88.1) 25 (71.4) 38 (82.6) 101 (79.5) 8 (100.0) 63 (71.6) 99 (83.9) 66 (79.5) 85 (86.7) 76 (76.0) 65 (76.5) 90 (84.9) 76 (86.4) 32 (80.0) 54 (76.1) 67 (83.8) 72 (81.8) 106 (78.5) 20 (83.3) 8 (88.9) 29 (87.9) 120 (87.0) 47 (70.2) 47 (70.2) 95 (85.6) 25 (92.6)
7 (10.3) 26 (23.9) 5 (19.2) 24 (26.4) 6 (18.2) 3 (5.7) 26 (18.2) 7 (15.9) 12 (19.3) 6 (30.0) 5 (11.9) 10 (28.6) 8 (17.4) 26 (20.5) 0 (0) 25 (28.4) 19 (16.1) 17 (20.5) 13 (13.3) 24 (24.0) 20 (23.5) 16 (15.1) 12 (13.6) 8 (20.0) 17 (23.9) 13 (16.2) 16 (18.2) 29 (21.5) 4 (16.7) 1 (11.1) 4 (12.1) 18 (13.0) 20 (29.8) 20 (29.8) 16 (14.4) 2 (7.4)
Age (years), mean ± SD Race, n (%)
Mode of HIV transmission, n (%) CD4+ T-cell counts, mean ± SD HIV-1 RNA level, median (25–75%) Undetectable HIV-1 RNA level in last 6 months, n (%) cART, n (%) Age at first sexual encounter (years), mean ± SD Sexual preference, n (%) Partners, n (%) Barrier contraceptive, n (%) Hormonal contraceptive, n (%) Pregnancy, n (%) History of sexual abuse, n (%) Prostitution, n (%) Drugs, n (%) Alcohol, n (%) School, n (%) Education, n (%) Working, n (%) Living, n (%)
Contract STI during study, n (%) Number of STIs, n (%)
0.439 0.736
0.001 < 0.001 < 0.001 < 0.001 0.029 0.468 0.085 0.008 0.824 0.358 0.086 0.675 0.107 0.425 0.053 0.139 0.246 0.741 0.610
0.004 0.010
SD indicates standard deviation.
Overall, 67% of our HIV-infected cohort contracted an STI during the study period, for an overall cumulative incidence rate of 35 STIs per 100 person-years. Few studies have examined co-STI incidence in HIV-infected individuals. A study by Mullins and colleagues5 looking at STIs in HIV-infected and HIV-uninfected AYAs showed differences in rates of co-STIs based on gender and type of co-STI. A smaller study from the United Kingdom of perinatally HIV-infected AYAs showed a frequency of STIs of 11.5% over a 6-year period with an incidence rate of 5.4 per 100 person-years.17 These rates are substantially less than the rates reported in our study even when only perinatally HIV-infected AYAs were considered (16%, with a cumulative incidence rate of 18.5 STIs per 100 person years, data not shown).
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Associated factors for STI acquisition included older age, a higher number of sexual partners and nonuse of barrier contraceptive methods. The association between older age and a higher risk of STI acquisition has been previously described and may be related to an increasing number of sexual partners as the adolescent ages.18,19 An important discrepancy was noted between the high rates of STIs and the fairly high use of barrier protection reported by study participants. Other studies have documented similar or higher rates of reported condom use. The Longitudinal Epidemiological Study to Gain Insight into HIV/AIDS in Children and Youth reported 80% condom use in their cohort,18 and similar numbers were noted in the Pediatric Spectrum of HIV Disease Study.20 However, DiClemente and colleagues21 point out that condom use may be overestimated among AYAs, either © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Uncontrolled HIV and STIs
FIGURE 1. STIs contracted by controlled versus uncontrolled disease status. TABLE 3. Ordinal Logistic Regression Model ORs and 95% Confidence Limits Controlling for Disease Status Parameter Number of partners Controlled Barrier Age
Level
OR
95% Confidence Limits
P Value
>10 6–10 Uncontrolled disease No —
4.54 4.05 2.84 2.34 1.20
1.96–10.50 1.73–9.47 1.16–6.94 1.11–4.91 1.01–1.42
