Timothy P. Flanigan

Highly Active Antiretroviral Therapy Decreases Mortality and Morbidity in Patients with Advanced HIV Disease

The introduction of combination antiretroviral therapy for HIV infection revolutionized treatment of AIDS and HIV disease. Such treatment, which usually includes two nucleoside analogue inhibitors of HIV reverse transcriptase and at least one HIV protease inhibitor or non-nucleoside inhibitor of HIV reverse transcriptase, is called highly active antiretroviral therapy (HAART). Early cohort and registry-based studies showed a lower incidence of AIDS and decreased rates of AIDS-related mortality after the introduction of HAART in late 1995 in the United States (1-3), France (4), Australia (5), Germany (6), and Switzerland (7). However, ecologic studiesthose that measured use of HAART and mortality in groups rather than in individual patientsmay be subject to confounding by calendar period changes in other unmeasured variables. In addition, many studies that directly measured the effects of HAART on survival of patients with AIDS did not provide specific evidence of such effects in the patients with the most advanced cases (8-10), with the exception of small cohorts of patients with cytomegalovirus (CMV) retinitis (11) and progressive multifocal leukoencephalopathy (12). We therefore studied the effect of HAART in a large multicenter trial of blood transfusion in patients with advanced HIV disease who were also anemic, an indicator of poor prognosis (13, 14). Because the study spanned the period before and after the introduction of HAART, we could directly assess the effect of HAART status on subsequent death or opportunistic events. In addition, because our person-year analysis was controlled for calendar time, our estimates of the magnitude of the effect of HAART on mortality and morbidity are less likely to be confounded by changes in patient mix or medical practice compared with previously published studies. Methods Patients and Study Design The Viral Activation Transfusion Study (VATS) was a multicenter, randomized, double-blind clinical trial of leukoreduced versus nonleukoreduced red blood cell transfusion in HIV-infected patients who required a first transfusion for anemia. Details of the study design have been published elsewhere (15, 16). In brief, we enrolled patients who were HIV seropositive, were CMV seropositive or had a history of documented CMV disease, had an expected survival of at least 1 month, and required red blood cell transfusion for anemia. Data on clinical end points and prescribed medications were obtained by interview and medical record review at baseline and every 3 months thereafter. Ophthalmologic examinations to detect CMV retinitis were done at baseline and every 6 months thereafter. In patients who did not return for follow-up visits, vital status was ascertained by review of the medical record, a search for a death certificate, and tracing by using public databases. Of 528 patients, 58 were excluded before death or end of the study, including 29 for whom no follow-up information on opportunistic events was available and 3 for whom follow-up for death but not for opportunistic events was complete. The CD4+ lymphocyte count and plasma HIV RNA level were measured by using frozen blood specimens at the central study laboratory, as described elsewhere (15). The study protocol was approved by the institutional review boards of the 11 participating medical centers, and informed consent was obtained from all participants. Definitions of HAART and End Points The VATS did not dictate the choice of antiretroviral therapy for enrolled patients, except that prescription of new antiretroviral drugs was discouraged during the 2 weeks after the first two transfusion episodes. Highly active antiretroviral therapy was defined as prescription of at least three antiretroviral medications with activity against HIV, at least one of which was an HIV protease inhibitor or a non-nucleoside HIV reverse transcriptase inhibitor. Medication history collected at each quarterly visit included the names and start and stop dates of any HIV antiretroviral medications taken since the previous visit or in the 30 days before entry into the study. Patients taking no HIV antiretroviral medications and those taking HIV antiretroviral medications that did not fulfill our definition of HAART were classified as before HAART until the day that they began HAART. Once a patient initiated HAART, all of his or her subsequent follow-up time remained designated as after HAART even if they discontinued HAART, to approximate an intention-to-treat analysis. We made this conservative decision to avoid overestimating the effect of HAART, which would occur if patients who stopped HAART because of intolerance subsequently contributed outcomes to the before HAART person-years. Adherence to prescribed medications was not measured. End points of the current study were death, opportunistic events, and recurrent transfusions. Opportunistic events were defined a priori and confirmed by expert reviewers; they included clinical diagnoses corresponding to the Centers for Disease Control and Preventions AIDS-defining conditions (17), with some modifications. Presumptive diagnoses of central nervous system toxoplasmosis were allowed according to the Centers for Disease Control and Preventions definition. For CMV retinitis, progression of disease requiring initiation of or a change in anti-CMV medication counted as a clinical event. For analysis, end points were grouped as follows: CMV opportunistic events; non-CMV opportunistic events; all opportunistic events; death; and any end point, including death and all opportunistic events. We analyzed recurrent red blood cell transfusion (that is, occurring after the enrollment transfusion event) as a separate end point. Statistical Analysis We used a person-years approach to analyze event rates. The denominator for these rates was not the individual patient but was person-years of observation time, defined as study follow-up time for each patient classified as before or after initiation of HAART and summed over all patients. For example, patients who started HAART during the study contributed observation time to both the post-HAART and pre-HAART categories, in effect serving as their own controls. Patients who began HAART before study entry and those who never began HAART during the study period contributed only post-HAART or pre-HAART observation time, respectively. Observation time for a patient extended from the date of study entry to death or the end of follow-up. Because some patients had no follow-up information for opportunistic events and a few had less follow-up for opportunistic events than for mortality, the total observation time for opportunistic events was shorter than that for overall survival. Events were assigned to the time period during which they occurred, and incidence was reported as the number of events per person-year of observation time. A single patient could contribute multiple events (except for the mortality analysis) to the same or to different time periods. The association between HAART use and incidence rates was expressed as a rate ratio. Confidence intervals and P values were calculated from a Poisson regression model using generalized estimating equations with exchangeable correlation structure to adjust for correlated observations across time within the same patient (18, 19). All P values are two sided. Because the use of HAART increased dramatically over the 4 years of the study, the comparison of post-HAART and pre-HAART data is confounded with calendar time. In addition, the mixture of HIV risk groups, prevalence of prophylaxis against opportunistic infections, diagnostic testing accuracy, and physician experience may have changed over time. To evaluate and control for these and other calendar time effects, each patients observation time was further categorized as four 1-year calendar time periods, starting in July 1995. Similarly, a patients time since entering the study was divided into five study time periods (0 to 6, 7 to 12, 13 to 18, 19 to 24, or >24 months from randomization). The Poisson regression generalized estimating equations method was then used to calculate the rate ratios associated with CD4 T-cell count, plasma HIV RNA level, calendar time, and time on study and to adjust the comparisons of post-HAART and pre-HAART data for these covariates, both in pairs and combined with patient characteristics. Results Participants The VATS enrolled patients with anemia and HIV infection who received a first red blood cell transfusion between August 1995 and July 1998. Patients were followed until death or their last scheduled quarterly visit before 30 June 1999. Of 531 patients enrolled in VATS, we excluded 3 patients for whom no data on medication were available; thus, the sample for analysis in this study was 528 patients. Table 1 shows the baseline characteristics of the study sample. Most patients were 30 to 49 years of age and male, and equal proportions of patients were of white and nonwhite ethnicity. Half of the patients were men who reported sex with other men as their only HIV risk factor; 19% each were injection drug users or sexually active heterosexuals without other risk factors for HIV; and 12% had multiple or other risk factors. At baseline, the median CD4+ lymphocyte count was 0.015 109 cells/L, and 69% of patients had a CD4+ lymphocyte count less than 0.050 109 cells/L. The median HIV RNA level was 4.8 log10 copies/mL, and only 8% of patients had plasma levels of HIV RNA levels less than 200 copies/mL. Table 1. Baseline Characteristics of 528 Patients in the Viral Activation Transfusion Study At baseline, most patients had previously taken antiretroviral medication; more than half had taken such medication for 12 months or longer. The proportion of patients taking prophylaxis or treatment of Pneumocystis carinii pneumonia and Mycobacterium avium complex infection decreased from 95% and 49%, respectively, in 19951996 to 82% and 44% in 19

Cryptosporidium Infection and CD4 Counts

Excerpt Cryptosporidiumis a coccidian parasite that infects the gastrointestinal tract in humans and can cause severe enteritis and malabsorption. Cryptosporidiosis is selflimited in immunocompeten...

Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: influence of the menstrual cycle.

A cholera vaccine containing killed vibrios and cholera toxin B subunit (CTB) was used to compare mucosal immunization routes for induction of systemic and mucosal Ab. Four groups of women were given three monthly immunizations by the rectal immunization (Rimm) route, nasal immunization (Nimm) route, or vaginal immunization route during either the follicular (V-FPimm) or luteal (V-LPimm) menstrual cycle phase. Nimm was performed with 10-fold less vaccine to determine if administration of less Ag by this route can, as in rodents, produce mucosal Ab responses comparable to those induced by higher dose Rimm or vaginal immunization. Concentrations of Ab induced in sera and secretions were measured by ELISA. None of these routes produced durable salivary Ab responses. Nimm induced greatest levels of CTB-specific IgG in sera. Rimm failed to generate CTB-specific IgA in genital tract secretions. Nimm, V-FPimm, and V-LPimm all produced cervical CTB-specific IgA responses comparable in magnitude and frequency. However, only V-FPimm induced cervical IgA2-restricted Ab to the bacterial LPS vaccine component. V-FPimm, but not V-LPimm, also induced CTB-specific IgA in rectal secretions. Nimm was superior to V-FPimm for producing rectal CTB-specific IgA, but the greatest amounts of CTB-specific IgA and LPS-specific IgA, IgG, and IgM Ab were found in rectal secretions of Rimm women. These data suggest that in women, Nimm alone could induce specific Ab in serum, the genital tract, and rectum. However, induction of genital tract and rectal Ab responses of the magnitude generated by local V-FPimm or Rimm will likely require administration of comparably high nasal vaccine dosages.

Marriage, monogamy and HIV: a profile of HIV-infected women in south India

A retrospective study was conducted on 134 HIV-infected females evaluated at an HIV/AIDS centre in south India to characterize their socio-demographics, HIV risk factors and initial clinical presentations. The mean age was 29 years; 81% were housewives; 95% were currently or previously married; 89% reported heterosexual sex as their only HIV risk factor; and 88% reported a history of monogamy. The majority were of reproductive age, thus the potential for vertical transmission of HIV and devastating impacts on families is alarming. Nearly half of these women initially presented asymptomatically implying that partner recruitment can enable early HIV detection. Single partner heterosexual sex with their husband was the only HIV risk factor for the majority of women. HIV prevention and intervention strategies need to focus on married, monogamous Indian women whose self-perception of HIV risk may be low, but whose risk is inextricably linked to the behaviour of their husbands.

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.

Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA.

ObjectivesTo determine the frequency of cervicovaginal lavage and plasma HIV-1 RNA levels that are below detectable levels (< 400 copies/ml) among women on highly active antiretroviral therapy (HAART), non-HAART and on no therapy. To compare the effect of initiating HAART on the timing of HIV-1 RNA suppression in the blood plasma and genital tract among antiretroviral-naïve women. MethodsData were obtained from 205 HIV-infected women with paired plasma and cervicovaginal lavage viral load measurements. Seven antiretroviral-naïve women starting HAART had viral load measurements performed daily for one week, at 2 weeks and at 1 month after initiating therapy. Viral load quantification was carried out by nucleic acid sequence-based amplification assay. The lower limit of detection was 400 copies/ml. ResultsPlasma and cervicovaginal HIV-1 RNA was detectable in 71 and 26% of the women, respectively. Among women with plasma viral loads less than 400, 400–9999, and 10 000 copies/ml or over, genital tract HIV-1 RNA was detected in 3, 17 and 48%, respectively (P < 0.001). Fifty-one per cent of the women with CD4 cell counts of less than 200/mm3 had detectable cervicovaginal viral loads compared with 18% among women with CD4 cell counts of 200/mm3 or over (P < 0.001). Cervicovaginal HIV-1 RNA was less than 400 copies/ml in 85% of those on HAART, 69% of those on non-HAART and 69% of those on no therapy (P < 0.045). In seven antiretroviral-naïve women initiating HAART, cervicovaginal HIV-1 RNA decreased by 0.7–2.1 log10 within 1–14 days of starting therapy. ConclusionThe cervicovaginal HIV-1 RNA level was positively correlated with plasma HIV-1 RNA and negatively with the CD4 cell count. The use of HAART was significantly associated with below-detectable levels of HIV-1 RNA in both plasma and the genital tract. HIV-1 RNA suppression in the genital tract may occur rapidly after initiating therapy.

Human Immunodeficiency Virus in Correctional Facilities: A Review

It is estimated that up to one-fourth of the people living with human immunodeficiency virus (HIV) infection in the United States pass through a correctional facility each year. The majority of persons who enter a correctional facility today will return home in the near future. Most inmates with HIV infection acquire it in the outside community; prison does not seem to be an amplifying reservoir. How correctional health services deal with the HIV-infected person has important implications to the overall care of HIV-infected people in the community. Routine HIV testing is well accepted. Combination antiretroviral therapy has been associated with a reduction in mortality in prisons. A link between area HIV specialists and correctional health care providers is an important partnership for ensuring that HIV-infected patients have optimal care both inside prison and after release.

Natural History of Human Immunodeficiency Virus Disease in Southern India

There are few reports of the natural history of human immunodeficiency virus (HIV) infection from Asia. In a retrospective analysis of 594 patients (72.9% male; baseline CD4 cell count, 216 cells/microL) receiving care at YRG Center for AIDS Research and Education, a tertiary HIV referral center in southern India, the mean duration of survival from serodiagnosis was 92 months. Ninety-three percent of the patients acquired infection through heterosexual contact. The most common acquired immune deficiency syndrome-defining illnesses were pulmonary tuberculosis (49%; median duration of survival, 45 months), Pneumocystis carinii pneumonia (6%; median duration of survival, 24 months), cryptococcal meningitis (5%; median duration of survival, 22 months), and central nervous system toxoplasmosis (3%; median duration of survival, 28 months). Persons with a CD4 lymphocyte count of <200 cells/microL were 19 times (95% confidence interval [CI], 5.56-64.77) more likely to die than were those with CD4 cell count of >350 cells/microL. Patients who had > or =1 opportunistic infection were 2.6 times more likely to die (95% CI, 0.95-7.09) than were those who did not have an opportunistic infection. Antiretroviral therapy for patients with low CD4 lymphocyte counts improved the odds of survival (odds ratio, 5.37; 95% CI, 1.82-15.83).

Human Immunodeficiency Virus Infection, AIDS, and Smoking Cessation: The Time is Now

Treatments for persons who are infected with human immunodeficiency virus (HIV) or who have developed AIDS have advanced to the point where death is no longer the inevitable outcome of diagnosis. Combination antiretroviral therapy has made HIV infection less of a terminal condition and more of a medically manageable chronic disease. Thus, efforts to improve the health status and quality of life of HIV-infected persons have become one of the highest treatment priorities for the next decade. Cigarette smoking is highly prevalent among HIV-infected persons, and quitting smoking would greatly improve the health status of these individuals. However, to date, no studies have evaluated the efficacy of a smoking-cessation intervention specifically tailored to this population. This article reviews the evidence and rationale for advancing smoking-cessation treatments specifically tailored to the needs of HIV-infected persons and provides recommendations for future treatment studies.

Hiv Treatment Outcomes Among Hiv-infected, Opioid-dependent Patients Receiving Buprenorphine/naloxone Treatment within Hiv Clinical Care Settings: Results From a Multisite Study

Background:Having opioid dependence and HIV infection are associated with poor HIV-related treatment outcomes. Methods:HIV-infected, opioid-dependent subjects (N = 295) recruited from 10 clinical sites initiated buprenorphine/naloxone (BUP/NX) and were assessed at baseline and quarterly for 12 months. Primary outcomes included receiving antiretroviral therapy (ART), HIV-1 RNA suppression, and mean changes in CD4 lymphocyte count. Analyses were stratified for the 119 subjects not on ART at baseline. Generalized estimating equations were deployed to examine time-dependent correlates for each outcome. Results:At baseline, subjects on ART (N = 176) were more likely than those not on ART (N = 119) to be older, heterosexual, have lower alcohol addiction severity scores, and lower HIV-1 RNA levels; they were less likely to be homeless and report sexual risk behaviors. Subjects initiating BUP/NX (N = 295) were significantly more likely to initiate or remain on ART and improve CD4 counts over time compared with baseline; however, these improvements were not significantly improved by longer retention on BUP/NX. Retention on BUP/NX for three or more quarters was, however, significantly associated with increased likelihood of initiating ART (β = 1.34 [1.18, 1.53]) and achieve viral suppression (β = 1.25 [1.10, 1.42]) for the 64 of 119 (54%) subjects not on ART at baseline compared with the 55 subjects not retained on BUP/NX. In longitudinal analyses, being on ART was positively associated with increasing time of observation from baseline and higher mental health quality of life scores (β = 1.25 [1.06, 1.46]) and negatively associated with being homo- or bisexual (β = 0.55 [0.35, 0.97]), homeless (β = 0.58 [0.34, 0.98]), and increasing levels of alcohol addiction severity (β = 0.17 [0.03, 0.88]). The strongest correlate of achieving viral suppression was being on ART (β = 10.27 [5.79, 18.23]). Female gender (β = 1.91 [1.07, 3.41]), Hispanic ethnicity (β = 2.82 [1.44, 5.49]), and increased general health quality of life (β = 1.02 [1.00,1.04]) were also independently correlated with viral suppression. Improvements in CD4 lymphocyte count were significantly associated with being on ART and increased over time. Conclusions:Initiating BUP/NX in HIV clinical care settings is feasible and correlated with initiation of ART and improved CD4 lymphocyte counts. Longer retention on BPN/NX was not associated with improved prescription of ART, viral suppression, or CD4 lymphocyte counts for the overall sample in which the majority was already prescribed ART at baseline. Among those retained on BUP/NX, HIV treatment outcomes did not worsen and were sustained. Increasing time on BUP/NX, however, was especially important for improving HIV treatment outcomes for those not on ART at baseline, the group at highest risk for clinical deterioration. Retaining subjects on BUP/NX is an important goal for sustaining HIV treatment outcomes for those on ART and improving them for those who are not. Comorbid substance use disorders (especially alcohol), mental health problems, and quality-of-life indicators independently contributed to HIV treatment outcomes among HIV-infected persons with opioid dependence, suggesting the need for multidisciplinary treatment strategies for this population.