David P. Paar

Response to Lamivudine-Zidovudine plus Abacavir Twice Daily in Antiretroviral-Naive, Incarcerated Patients with HIV Infection Taking Directly Observed Treatment

Prison inmates with human immunodeficiency virus (HIV) infection can be difficult to treat because of the complexity and intrusiveness of many combination antiretroviral therapy regimens. NZTA4007, a 24-week open-label, single-arm clinical trial involving 108 antiretroviral therapy-naive, incarcerated, HIV-infected persons, was conducted to evaluate a compact regimen (4 tablets per day) consisting of 1 lamivudine-zidovudine (150 mg/300 mg) combination tablet (COM) and one 300-mg abacavir tablet administered twice daily under directly observed treatment conditions. In the intent-to-treat observed analysis, the plasma HIV type 1 (HIV-1) RNA level remained at < or =400 copies/mL in 85% of the patients and at < 50 copies/mL in 75% of the patients. Median change from baseline was -2.41 log(10) copies/mL for the HIV-1 RNA level and +111 cells/mm(3) for the CD4 cell count. The overall adherence to prescribed doses was 94% for patients who remained enrolled in the study. COM-abacavir given twice daily was generally well tolerated, and adverse events prompted only 4 patients to withdraw from the study.

Enrollment in Outpatient Care Among Newly Released Prison Inmates with HIV Infection

Objectives. Although many prisoners infected with human immunodeficiency virus (HIV) initiate and adhere to treatment regimens while incarcerated, the benefits of in-prison therapy are frequently lost after community reentry. Little information is available on the percentage of released inmates who establish community-based HIV outpatient treatment in a timely fashion. We sought to determine the proportion of HIV-infected Texas prison inmates who enrolled in an HIV clinic within 90 days after release and to identify variables associated with timely linkage to clinical care. Methods. This was a retrospective cohort study of 1,750 HIV-infected inmates who were released from the Texas Department of Criminal Justice (TDCJ) and returned to Harris County between January 2004 and December 2007. We obtained demographic and clinical data from centralized databases maintained by TDCJ and the Harris County Health District, and used logistic regression analysis to identify factors associated with linkage to post-release outpatient care. Results. Only 20% of released inmates enrolled in an HIV clinic within 30 days of release, and only 28% did so within 90 days. Released inmates ≥30 years of age were more likely than their younger counterparts to have enrolled in care at the 30- and 90-day time points. Inmates diagnosed with schizophrenia were more likely to have initiated care within 30 days. Inmates who received antiretroviral therapy while incarcerated and those who received enhanced discharge planning were more likely to begin care at both time points. Conclusions. A large proportion of HIV-infected inmates fail to establish outpatient care after their release from the Texas prison system. Implementation of intensive discharge planning programs may be necessary to ensure continuity of HIV care among newly released inmates.

Low‐level plasma HIVs in patients on prolonged suppressive highly active antiretroviral therapy are produced mostly by cells other than CD4 T‐cells

The cellular source(s) and the clinical significance of persistent low‐level viremia, below 50 HIV RNA copies per ml of plasma, achieved in many patients with high adherence to highly active antiretroviral therapy (HAART) remain unclear. Also, it is not clear if residual plasma HIVs during HAART can become predominant populations in the rebounding plasma viral loads after therapy interruption. Since, different HIV quasispecies tend to compartmentalize in various cell types and tissue locations in patients during chronic infection, the phylogenetic relationships between HIV sequences amplified from residual plasma viruses and CD4 T cells of five patients on long‐term suppressive therapy were examined. Three of these patients stopped therapy voluntarily for 3 weeks, but only one of them demonstrated viral load rebound in plasma. In phylogenetic analyses, the residual plasma viruses were found to be distinct genetically from the majority of CD4 T cell‐associated virus populations in four of five patients. The compartmental analyses revealed that in all patients, plasma‐ and CD4 T cell‐derived viral sequences were compartmentalized separately. Interestingly, the plasma sequences obtained before and after HAART‐off in two patients were produced apparently from the same compartment, which was different from the circulating CD4 T cell‐compartment. These results suggest the possibility that residual plasma viruses in patients on long‐term suppressive HAART may be produced persistently from a cellular source yet to be identified, and are capable of spreading quickly in vivo, accounting for the rapid rebound of viral loads in plasma after therapy interruption. J. Med. Virol. 81:9–15, 2009.

Predictors of Reincarceration and Disease Progression Among Released HIV-Infected Inmates

We conducted a retrospective cohort study to determine the 3-year reincarceration rate of all HIV-infected inmates (n = 1917) released from the Texas prison system between January 2004 and March 2006. We also analyzed postrelease changes in HIV clinical status in the subgroup of inmates who were subsequently reincarcerated and had either CD4 lymphocyte counts (n = 119) or plasma HIV RNA levels (n = 122) recorded in their electronic medical record at both release and reincarceration. Multivariable analyses were performed to assess predictors of reincarceration and clinical changes in HIV status. Only 20% of all HIV-infected inmates were reincarcerated within 3 years of release. Female inmates (hazard ratio [HR] 0.63; 95% confidence interval [CI], 0.47, 0.84) and inmates taking antiretroviral therapy at the time of release (HR 0.31; 95% CI, 0.25, 0.39) were at decreased risk of reincarceration. African Americans (HR 1.58; 95% CI, 1.22, 2.05), inmates with a major psychiatric disorder (HR 1.82; 95% CI, 1.41, 2.34), and inmates released on parole (HR 2.86; 95% CI, 2.31, 3.55) were at increased risk of reincarceration. A subgroup of reincarcerated inmates had a mean decrease in CD4 cell count of 79.4 lymphocytes per microliter (p < 0.0003) and a mean increase in viral load of 1.5 log(10) copies per milliliter (p < 0.0001) in the period between release and reincarceration. Our findings, although substantially limited by selection bias, highlight the importance of developing discharge planning programs to improve linkage to community-based HIV care and reduce recidivism among released HIV-infected inmates.

Psychiatric disorders, HIV infection and HIV/hepatitis co-infection in the correctional setting

Abstract Psychiatric disorders such as bipolar disorder, schizophrenia and depression have long been associated with risk behaviors for HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV). The US prison population is reported to have elevated rates of HIV, hepatitis and most psychiatric disorders. This study examined the association of six major psychiatric disorders with HIV mono-infection, HIV/HCV co-infection and HIV/HBV co-infection in one of the nations largest prison populations. The study population consisted of 370,511 Texas Department of Criminal Justice inmates who were incarcerated for any duration between January 1, 2003 and July 1, 2006. Information on medical conditions and sociodemographic factors was obtained from an institution-wide electronic medical information system. Offenders diagnosed with HIV mono-infection, HIV/HCV, HIV/HBV and all HIV combined exhibited elevated rates of major depression, bipolar disorder, schizophrenia, schizoaffective disorder, non-schizophrenic psychotic disorder and any psychiatric disorder. In comparison to offenders with HIV mono-infection, those with HIV/HCV co-infection had an elevated prevalence of any psychiatric disorder. This cross-sectional studys finding of positive associations between psychiatric disease and both HIV infection and hepatitis co-infection among Texas prison inmates holds both clinical and public health relevance. It will be important for future investigations to examine the extent to which psychiatric disorders serve as a barrier to medical care, communication with clinicians and adherence to prescribed medical regimens among both HIV-mono-infected and HIV/hepatitis-co-infected inmates.

CD4 lymphocytes in the blood of HIV+ individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion

The mechanism(s) by which human immunodeficiency virus (HIV) causes depletion of CD4 lymphocytes remains unknown. Evidence has been reported for a mechanism involving HIV binding to (and signaling) resting CD4 lymphocytes in lymphoid tissues, resulting in up‐regulation of lymph node homing receptors and enhanced homing after these cells enter the blood, and induction of apoptosis in many of these cells during the homing process, caused by secondary signaling through homing receptors. Supportive evidence for this as a major pathogenic mechanism requires demonstration that CD4 lymphocytes in HIV+ individuals do migrate to lymph nodes at enhanced rates. Studies herein show that freshly isolated CD4 lymphocytes labeled with 111Indium and intravenously reinfused back into HIV+ human donors do home to peripheral lymph nodes at rates two times faster than normal. They also home at enhanced rates to iliac and vertebral bone marrow. In contrast, two hepatitis B virus‐infected subjects displayed less than normal rates of blood CD4 lymphocyte migration to peripheral lymph nodes and bone marrow. Furthermore, the increased CD4 lymphocyte homing rates in HIV+ subjects returned to normal levels after effective, highly active antiretroviral therapy treatment, showing that the enhanced homing correlated with active HIV replication. This is the first direct demonstration of where and how fast CD4 lymphocytes in the blood traffic to tissues in normal and HIV‐infected humans. The results support the theory that the disappearance of CD4 lymphocytes from the blood of HIV+ patients is a result of their enhanced migration out of the blood (homing) and dying in extravascular tissues.

Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine

ObjectivesTo compare the efficacy and safety of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. DesignTwo multicenter, open-label, randomized 24-week studies. MethodsAdults HIV-1 infection, HIV-1 RNA greater than 10 000 copies/ml, and no prior lamivudine or protease inhibitor therapy were eligible. In a pilot study (Study A), patients received indinavir at 800 mg every 8 h, 1000 mg every 12 h, or 1200 mg every 12 h. In a subsequent study (Study B), patients received indinavir at 800 mg every 8 h or 1200 mg every 12 h. All subjects received zidovudine (300 mg) and lamivudine (150 mg) every 12 h. An intent-to-treat analysis was used. ResultsIn Study A, which enrolled 88 patients, neither HIV-1 RNA nor CD4 cell responses differed significantly between treatment groups at 24 weeks when corrected for multiple comparisons. Study B enrolled 433 patients, but was prematurely discontinued when interim analysis suggested greater efficacy of three-times-daily indinavir. Of the first 87 patients reaching week 24, HIV-1 RNA was less than 400 copies/ml in 91% receiving three-times-daily versus 64% receiving two-times-daily indinavir (P < 0.01). ConclusionThree-times-daily indinavir appears more efficacious than two-times-daily dosing when administered with zidovudine and lamivudine. Two-times-daily indinavir dosing should only be considered in situations characterized by favorable pharmacokinetic drug–drug interactions.

HCV-related mortality among male prison inmates in Texas, 1994-2003

PURPOSE The prevalence of hepatitis C virus (HCV) infection is high among adult incarcerated populations, but HCV-related mortality data are lacking. The study purpose was to assess HCV-related mortality over time and across racial/ethnic categories from 1994 through 2003 among male prisoners in the Texas Department of Criminal Justice (TDCJ). METHODS TDCJ decedent data were linked with Texas Vital Statistics multiple-cause-of-death data. Crude annual HCV death rates, age- and race-adjusted summary rates, and average annual percent changes were estimated. The proportion of deaths due to chronic liver disease/cirrhosis, liver cancer, hepatitis B, and HIV for which HCV was identified as an intervening or contributing cause of death was calculated. RESULTS Among Texas male prisoners, HCV death rates were high and increased over the 10-year study period by an average 21% annually, with the largest increase occurring among Hispanic prisoners. HCV was identified as an intervening or contributing cause of death in 15% of chronic liver disease/cirrhosis deaths, 33% of liver cancer deaths, 81% of hepatitis B deaths, and 7% of HIV deaths. CONCLUSIONS Because HCV-related deaths among Texas male prisoners are high and increasing, particularly among Hispanics, targeted prevention, screening, and treatment of HCV infections should be among the priorities of U.S. correctional healthcare systems.

Chronic Liver Disease Mortality Among Male Prison Inmates in Texas, 1989–2003

OBJECTIVES:Alcohol abuse and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the major etiologic factors for chronic liver disease/cirrhosis (CLD) in the United States. These CLD risk factors are highly prevalent in US adult incarcerated populations, but CLD-related mortality data from these populations are lacking. The primary objective of this study was to assess CLD-related mortality over time and across categories of race–ethnicity from 1989 through 2003 among male inmates in the Texas state prison system. The secondary objective was to examine patterns of recorded underlying, intervening, and contributing causes of death for CLD-related deaths.METHODS:Prisoner decedent data were linked with Texas Vital Statistics multiple-cause-of-death data. Deaths were considered CLD-related if CLD or common sequelae were recorded as the underlying, intervening, or contributing causes of death. CLD-related crude annual death rates, 5-year average annual death rates, and average annual percentage changes were estimated.RESULTS:Among male Texas prisoners from 1989 to 2003, CLD-related deaths accounted for 16% of deaths (688/4,316). CLD-related crude annual death rates were high and increased over the study period by an average of 4.5% annually, with similar rate increases across categories of race–ethnicity. CLD-related average annual death rates were higher among Hispanic prisoners than among black prisoners in each 5-year period, and were higher than those for white prisoners in the 1994–1998 and 1999–2003 periods. HBV or HCV was identified as a causal factor in more than a third (34%) of CLD-related deaths.CONCLUSIONS:From 1989 to 2003, CLD-related death rates among male Texas prisoners were high and increased over time, particularly among Hispanics. Targeted prevention, screening, and treatment of CLD risk factors, especially HCV, and early detection and treatment of CLD should be considered as priorities of the US prison healthcare systems.

Immunotherapy of CMV Infections

Immunotherapy has not only become the accepted standard for some CMV infections, but also remains an area of active investigation for the treatment and prophylaxis of CMV infections. Polyclonal immunoglobulin administration has improved the survival of CMV pneumonitis in BMT recipients, and monoclonal anti-CMV antibodies, notably MSL-109, appear to increase the time to relapse of CMV retinitis in patients with AIDS. The adoptive transfer of CMV-specific CD8 cells is under investigation as another CMV prophylactic strategy in BMT recipients, and it is hopeful that this methodology can be applied to the therapy of established CMV infections.