Josiah D. Rich

A prospective study of adherence and viral load in a large multi-center cohort of HIV-infected women

Objectives: To examine the relationship between antiretroviral adherence and viral load, and to determine the predictors of adherence over time in HIV-infected women. Design: Prospective observational study. Methods: One-hundred sixty-one HIV-infected women who were taking antiretroviral therapy for a median of 3.0 years were recruited from the HIV Epidemiology Research Study, a multicenter cohort study of HIV infection in women. Antiretroviral adherence (percent of doses taken as prescribed) was measured over a 6-month period using MEMS caps. At baseline and follow-up, CD4 lymphocyte count and viral load were measured, and a standardized interview was administered to elicit medication history and drug use behaviors. To examine changes in adherence over time, the mean adherence to all antiretroviral agents was calculated for each monitored month. Results: Adherence varied significantly over time (P < 0.001), ranging from a mean of 64% in month 1 to 45% in month 6. Nearly one-fourth of the participants had a 10% or greater decrease in adherence between consecutive months. Virologic failure occurred in 17% of women with adherence of ⩾ 88%, 28% of those with 45–87% adherence, 43% of those with 13–44% adherence, and 71% of those with ⩽ 12% adherence. In multivariate analysis, factors predicting lower adherence included active drug use, alcohol use, more frequent antiretroviral dosing, shorter duration of antiretroviral use, younger age, and lower initial CD4 lymphocyte count. Conclusions: Antiretroviral adherence is not stable over time. Interventions aimed at monitoring and improving long-term adherence in women are urgently needed.

Prevalence and Incidence of HIV, Hepatitis B Virus, and Hepatitis C Virus Infections Among Males in Rhode Island Prisons

OBJECTIVES We evaluated prevalence and intraprison incidence of HIV, hepatitis B virus, and hepatitis C virus infections among male prison inmates. METHODS We observed intake prevalence for 4269 sentenced inmates at the Rhode Island Adult Correctional Institute between 1998 and 2000 and incidence among 446 continuously incarcerated inmates (incarcerated for 12 months or more). RESULTS HIV, hepatitis B virus, and hepatitis C virus prevalences were 1.8%, 20.2%, and 23.1%, respectively. Infections were significantly associated with injection drug use (odds ratio = 10.1, 7.9, and 32.4). Incidence per 100 person-years was 0 for HIV, 2.7 for HBV, and 0.4 for HCV. CONCLUSIONS High infection prevalence among inmates represents a significant community health issue. General disease prevention efforts must include prevention within correctional facilities. The high observed intraprison incidence of HBV underscores the need to vaccinate prison populations.

Successful linkage of medical care and community services for HIV-positive offenders being released from prison.

Human immunodeficiency virus (HIV) infection is more prevalent among the incarcerated than the general population. For many offenders, incarceration is the only time that they may access primary care. Project Bridge is a federally funded demonstration project that provides intensive case management for HIV-positive exoffenders being released from the Rhode Island state prison to the community. The program is based on collaboration between colocated medical and social work staff. The primary goal of the program is to increase continuity of medical care through social stabilization; it follows a harm reduction philosophy in addressing substance use. Program participants are provided with assistance in accessing a variety of medical and social services. The treatment plan may include the following: mental illness triage and referral, substance abuse assessment and treatment, appointments for HIV and other medical conditions, and referral for assistance to community programs that address basic survival needs. In the first 3 years of this program, 97 offenders were enrolled. Injection drug use was reported by 80% of those enrolled. There were 90% followed for 18 months, 7% moved out of state or died, and 3% were lost to follow-up. Reincarceration happened to 48% at least once. Of those expressing a need, 75% were linked with specialty medical care in the community, and 100% received HIV-related medical services. Of those expressing a need for substance abuse treatment, 67% were successful in keeping appointments for substance abuse treatment within the community. Project Bridge has demonstrated that it is possible to maintain HIV-positive ex-offenders in medical care through the provision of ongoing case management services following prison release. Ex-offenders will access HIV-related health care after release when given adequate support.

Overcoming Barriers to Prevention, Care, and Treatment of Hepatitis C in Illicit Drug Users

Injection drug use accounts for most of the incident infections with hepatitis C virus (HCV) in the United States and other developed countries. HCV infection is a complex and challenging medical condition in injection drug users (IDUs). Elements of care for hepatitis C in illicit drug users include prevention counseling and education; screening for transmission risk behavior; testing for HCV and human immunodeficiency virus infection; vaccination against hepatitis A and B viruses; evaluation for comorbidities; coordination of substance-abuse treatment services, psychiatric care, and social support; evaluation of liver disease; and interferon-based treatment for HCV infection. Caring for patients who use illicit drugs presents challenges to the health-care team that require patience, experience, and an understanding of the dynamics of substance use and addiction. Nonetheless, programs are successfully integrating hepatitis C care for IDUs into health-care settings, including primary care, methadone treatment and other substance-abuse treatment programs, infectious disease clinics, and clinics in correctional facilities.

Blood-borne and sexual transmission of human herpesvirus 8 in women with or at risk for human immunodeficiency virus infection

BACKGROUND Human herpesvirus 8 (HHV-8), the causal agent of Kaposis sarcoma, is transmitted sexually among homosexual men, but little is known of its transmission among women. Although HHV-8 has been detected in blood, there has been no clear evidence of blood-borne transmission. METHODS We identified risk factors for HHV-8 infection in 1295 women in Baltimore, Detroit, New York, and Providence, Rhode Island, who reported high-risk sexual behavior or drug use. HHV-8 serologic studies were performed with two enzyme-linked immunosorbent assays. RESULTS In univariate analyses, HHV-8 was associated with black race, Hispanic ethnic background, a lower level of education, and infection with syphilis, the human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). The risk of seropositivity for HHV-8 increased with the frequency of injection-drug use (P<0.001); HHV-8 seroprevalence among the women who used drugs daily was three times that among women who never injected drugs. Among the women with a low risk of sexual transmission, HHV-8 seroprevalence was 0 percent in those who had never injected drugs and 36 percent in those who had injected drugs (P<0.001). However, injection-drug use was linked less strongly to HHV-8 infection than to infection with HBV or HCV. In a multivariate analysis, independent predictors of HHV-8 seropositivity included HIV infection (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.2), syphilis infection (odds ratio, 1.8; 95 percent confidence interval, 1.1 to 2.8), and daily injection-drug use (odds ratio, 3.2; 95 percent confidence interval, 1.4 to 7.6). CONCLUSIONS Both injection-drug use and correlates of sexual activity were risk factors for HHV-8 infection in the women studied. The independent association of HHV-8 infection with injection-drug use suggests that HHV-8 is transmitted through needle sharing, albeit less efficiently than HBV, HCV, or HIV.

Public Health and the Epidemic of Incarceration

An unprecedented number of Americans have been incarcerated in the past generation. In addition, arrests are concentrated in low-income, predominantly nonwhite communities where people are more likely to be medically underserved. As a result, rates of physical and mental illnesses are far higher among prison and jail inmates than among the general public. We review the health profiles of the incarcerated; health care in correctional facilities; and incarcerations repercussions for public health in the communities to which inmates return upon release. The review concludes with recommendations that public health and medical practitioners capitalize on the public health opportunities provided by correctional settings to reach medically underserved communities, while simultaneously advocating for fundamental system change to reduce unnecessary incarceration.

Incidence and prevalence of hepatitis C in prisons and other closed settings: Results of a systematic review and meta‐analysis

People detained in prisons and other closed settings are at elevated risk of infection with hepatitis C virus (HCV). We undertook a systematic review and meta‐analysis with the aim of determining the rate of incident HCV infection and the prevalence of anti‐HCV among detainees in closed settings. We systematically searched databases of peer‐reviewed literature and widely distributed a call for unpublished data. We calculated summary estimates of incidence and prevalence among general population detainees and detainees with a history of injection drug use (IDU), and explored heterogeneity through stratification and meta‐regression. The summary prevalence estimates were used to estimate the number of anti‐HCV positive prisoners globally. HCV incidence among general detainees was 1.4 per 100 person‐years (py; 95% confidence interval [CI]: 0.1, 2.7; k = 4), and 16.4 per 100 py (95% CI: 0.8, 32.1; k = 3) among detainees with a history of IDU. The summary prevalence estimate of anti‐HCV in general detainees was 26% (95% CI: 23%, 29%; k = 93), and in detainees with a history of IDU, 64% (95% CI: 58%, 70%; k = 51). The regions of highest prevalence were Central Asia (38%; 95% CI 32%, 43%; k = 1) and Australasia (35%; 95% CI: 28%, 43%; k = 9). We estimate that 2.2 million (range: 1.4‐2.9 million) detainees globally are anti‐HCV positive, with the largest populations in North America (668,500; range: 553,500‐784,000) and East and Southeast Asia (638,000; range: 332,000‐970,000). Conclusion: HCV is a significant concern in detained populations, with one in four detainees anti‐HCV‐positive. Epidemiological data on the extent of HCV infection in detained populations is lacking in many countries. Greater attention towards prevention, diagnosis, and treatment of HCV infection among detained populations is urgently required. (Hepatology 2013;58:1215–1224)

Buprenorphine and Buprenorphine/Naloxone Diversion, Misuse, and Illicit Use: An International Review

The diversion, misuse, and non-medically supervised use of buprenorphine and buprenorphine/naloxone by opioid users are reviewed. Buprenorphine and buprenorphine/naloxone are used globally as opioid analgesics and in the treatment of opioid dependency. Diversion of buprenorphine and buprenorphine/naloxone represents a complex medical and social issue, and has been widely documented in various geographical regions throughout the world. We first discuss the clinical properties of buprenorphine and its abuse potential. Second, we discuss its diversion and illicit use on an international level, as well as motivations for those activities. Third, we examine the medical risks and benefits of buprenorphines non-medically supervised use and misuse. These risks and benefits include the effect of buprenorphines use on HIV risk and the risk of its concomitant use with other medications and drugs of abuse. Finally, we discuss the implications of diversion, misuse, and non-medically supervised use (including potential measures to address issues of diversion); and potential areas for further research.

Misdiagnosis of HIV infection by HIV-1 plasma viral load testing: a case series.

The current standard of care for patients infected with HIV includes plasma viral load tests to monitor the effectiveness of antiretroviral regimens (1, 2). The assays approved for this use detect cell-free plasma viral RNA by using various amplification techniques (2). Access to these sensitive techniques and the trend toward earlier and more aggressive treatment approaches have led to the use of these assays as primary tools for the diagnosis of acute HIV infection (3, 4). Plasma viral load tests for HIV-1 were neither developed nor evaluated for the diagnosis of HIV infection; therefore, their diagnostic specificity is not well delineated when applied to persons who are negative for HIV antibody (5). We report two cases of false-positive results obtained by using branched-chain DNA assay (Chiron Quantiplex, Emeryville, California) and one case of a false-positive result obtained by using HIV reverse transcriptase polymerase chain reaction (RT-PCR) (Roche Amplicor Monitor, Basel, Switzerland) plasma viral load assay. These three cases demonstrate the potential problems of using HIV-1 plasma viral load tests for diagnosis of HIV infection. Case One A previously healthy 12-year-old boy, whose HIV-infected mother is cared for at one of our institutions, presented for evaluation of a positive plasma viral load of 1254 copies/mL determined by using the branched-chain DNA assay (Chiron Quantiplex) for HIV-1 RNA. The patients mother had received a diagnosis of HIV infection around the time of his birth, and the patient had tested negative for HIV-1 by enzyme-linked immunosorbent assay (ELISA) several times in the years after his birth. Although the patient reported no risk factors for HIV infection, he underwent plasma viral load testing after his primary care physician noted a skin lesion that was interpreted as herpes zoster. At our institution, the patient subsequently had a negative result on HIV-1 ELISA, a normal CD4 cell count and CD4:CD8 ratio, and a negative plasma viral load (also determined by using the branched-chain DNA assay). His skin lesion was diagnosed as impetigo, and he remains in excellent health 3 months after his initial presentation. Case Two A previously healthy, pregnant 40-year-old woman presented for an HIV test. Her male sexual partner, with whom she had recently had repeated unprotected vaginal intercourse, had been given a diagnosis of HIV infection 1 week before her office visit. The patient tested negative for HIV-1 antibody on the oral mucosal transudate (OraSure, Epitope, Inc., Beaverton, Oregon) HIV-1 oral specimen collection device but continued to be concerned about her HIV status. One week after her initial presentation, she underwent a plasma viral load test (Chiron Quantiplex) for HIV-1 RNA that yielded a positive value of 1574 copies/mL. The patient was told that she was probably infected with HIV. During the next 3 months, she had a negative result on an HIV-1 ELISA, a normal CD4 cell count and CD4:CD8 ratio, and three HIV-1 plasma viral load tests (all done by using branched-chain DNA assay) that showed an undetectable viral load. When the patient delivered a healthy baby 7 months after her initial presentation, another HIV-1 ELISA yielded negative results. Case Three A 20-year-old healthy woman was referred for further evaluation by her primary care physician when she had a positive result on HIV-1 ELISA and an indeterminate result on a Western blot test. The patients only risk factor was heterosexual intercourse, but she stated that her partner had used condoms consistently during the previous year. During a 4-month period after her indeterminate result on the Western blot test, she had a positive result on ELISA and an indeterminate result on a Western blot test on separate occasions. Five months later, both ELISA and a Western blot test yielded negative results, but the patient had a plasma viral load of 1300 copies/mL (determined by using RT-PCR assay [Roche Amplicor Monitor]). She was subsequently counseled that she was probably infected with HIV. Nearly 6 months after her initial indeterminate HIV test result, she was tested by a third laboratory and was negative for HIV-1 antibodies on both ELISA and Western blot test. She had a normal CD4 cell count and CD4:CD8 ratio and a plasma viral load that was undetectable on RT-PCR assay (Roche Amplicor Monitor). She remains healthy 8 months after her initial presentation. Discussion These three cases, which were observed in one region during a 2-month period, are probably examples of false-positive results on HIV-1 plasma viral load tests. Only one other case of a false-positive HIV-1 plasma viral load has been fully documented; that test had been performed by using RT-PCR, and the result was thought to be related to the administration of an HIV-1 vaccine (6). The patients described here had normal CD4 cell counts and CD4:CD8 ratios, low plasma viral loads, and subsequent negative results on HIV-1 ELISA and plasma viral load tests. To our knowledge, the lowest reported plasma viral load during seroconversion is more than 17 times higher than the highest viral load detected in our three patients (7). Although transient HIV infection has been reported in infants, it is unlikely in two of our patients because they had not recently been exposed to HIV (8, 9). Other potential explanations of false-positive HIV-1 plasma viral load include laboratory error, cross-contamination, and mix-up of specimens. From the patients perspective, false-positive results on an HIV test are potentially devastating, regardless of the cause. Further clinical experience is required to determine whether specific clinical circumstances correlate with an increased incidence of false-positive HIV-1 plasma viral load results. The current standard diagnostic protocol for HIV infection is based on detection of HIV-1-specific antibodies. The combination of screening ELISA followed by a confirmatory Western blot assay has been more than 99% accurate in detecting HIV infection (10, 11). This protocol has a relatively low rate of false-positive results (approximately 0.0006%) but can have negative or indeterminate results during the 3 to 4 weeks before seroconversion (12-14). Although host antibody responses may be undetectable during this acute infection period, the viral load in plasma is usually very high and initial viremia usually occurs in 4 to 11 days (4, 7, 15, 16). The occurrence of high levels of viremia during primary HIV infection has led some physicians to use plasma viral load assays as diagnostic tests to detect early HIV infection. However, plasma viral load assays are designed for monitoring the effectiveness of antiretroviral therapies and for measuring the quantity of virus in patients with confirmed HIV infection, not for the diagnosis of HIV infection. Their performance in patients who are not infected with HIV is unknown (1, 2). The first case illustrates the importance of following the most recent testing protocol for the diagnosis of HIV infection. The patients pediatrician requested a plasma viral load assay because the patient, whose mother has asymptomatic HIV infection, presented with a skin rash thought to be consistent with herpes zoster. In this case, because primary HIV infection was not suspected, an HIV-1 ELISA should have been ordered and, if reactive, followed by a Western blot assay. In the second case, a plasma viral load assay was ordered despite a negative result on an oral mucosal transudate test (OraSure) because the patient was pregnant and was at substantial risk for recent exposure to HIV. However, on the basis of current knowledge about viral replication during primary HIV infection, the patients plasma viral load would probably have been much higher if she had been infected with HIV in the previous 2 weeks (15). In the third case and in other cases described in the literature, plasma viral load testing was used to further analyze an indeterminate result on an HIV-1 Western blot assay (3). To minimize the occurrence of false-positive results, testing protocols for the diagnosis of HIV infection should include tests that complement each other. The HIV-1 ELISA assay, which has excellent diagnostic sensitivity, remains an important, inexpensive screening tool. Because of its high specificity, the HIV-1 Western blot assay is a reliable confirmatory test after reactive ELISA. Only patients who have a high pretest probability of a positive result should be evaluated for primary HIV infection by using plasma viral load testing. Such patients include those who are at high risk for recent exposure to HIV and present with indeterminate or negative results on Western blot tests and especially those with an appropriate accompanying clinical syndrome (4). A patient with a high HIV-1 plasma viral load is most likely in the process of seroconversion; although it is theoretically possible that a patient with an undetectable or low plasma viral load may have recently been infected with HIV, that possibility is much less likely. It is important to consider the pretest likelihood of acute infection when counseling patients with negative results on serologic testing and a low plasma viral load. Physicians should explain that the patient may not be infected with HIV-1 but should take precautions to avoid infecting others until follow-up testing provides a definite result. If HIV-1 plasma viral load testing is used in the diagnosis of primary HIV infection before the development of serum antibodies, low positive plasma viral load results should be interpreted with caution and the patients true disease status should be confirmed with repeated plasma viral load testing and follow-up serologic testing.

Laboratory testing for infection with the human immunodeficiency virus: established and novel approaches

The enzyme-linked immunosorbent assay (ELISA) and the Western blot are the primary tests for the diagnosis and confirmation of human immunodeficiency virus (HIV) infection. The ELISA, an inexpensive screening test for antibodies to HIV-1, is both sensitive and specific. The HIV-1 Western blot is a reliable confirmatory test following a repeatedly reactive ELISA. False-positive HIV-1 results with this sequence of tests are extremely rare but can occur, and test results that are inconsistent with clinical or other laboratory information should be questioned, repeated, or supplemented. The US Food and Drug Administration has also approved rapid and more accessible testing methods. Oral mucosal transudate and urine testing are noninvasive testing methods; rapid and home sample collection kits offer easier access to testing.