Bacterial infections in AIDS patients.

Bacterial infections cause a substantial burden of disease in the HIV-infected population. Like the opportunistic infections associated with AIDS, they are often usually severe. Unlike many AIDS-related opportunistic infections, however, many can be eradicated by therapy with the appropriate antibiotic, although some, like Salmonella sepsis, require prolonged suppressive therapy to prevent recurrences. Most importantly, the possibility of a bacterial infection should be kept in mind when evaluating any acutely ill HIV-infected patient, as therapy of bacterial disease is often curative while untreated infection can lead to severe morbidity and premature death.

Survival differences in patients with AIDS.

To define the clinical, demographic, and behavioral variables that may influence survival in patients with AIDS, we studied 526 patients with AIDS diagnosed through September 1987 who were cared for at a single medical center. A diversity of racial and ethnic backgrounds, ages, both men and women, and all risk behaviors except hemophilia were well represented. The initial AIDS defining diagnosis was the most powerful predictor of survival. The median survival was 12.8 months for patients presenting with Kaposi's sarcoma (p less than 0.001), 10.9 months for patients presenting with Pneumocystis carinii pneumonia (p less than 0.001), and 4.8 months for patients presenting with other infections or neoplasms (p less than 0.02). For the entire series, male sex and younger age were associated with more favorable survival (p less than 0.025). For those presenting with Pneumocystis carinii pneumonia, in addition to younger age (p less than 0.025), black race (p less than 0.025) and the combination of male sex and intravenous drug use (p less than 0.005) were associated with a more favorable survival. Within a setting of comparable clinical care, survival from the point of diagnosis of AIDS is associated most strongly with the initial AIDS diagnosis, but differences in age, gender, race, and risk behavior also exert an influence on survival.

Cervical and vaginal squamous cell abnormalities in women infected with human immunodeficiency virus.

We sought to determine whether women infected with human immunodeficiency virus (HIV) had cervicovaginal cellular changes suggesting lower genital tract neoplasia or human papillomavirus (HPV) infection at a rate different from that in women without HIV infection. In a blinded fashion, cytological preparations of cervicovaginal smears from women infected with the HIV were analyzed and compared to preparations from women at high risk for but not infected with HIV. Eleven of 35 (31%) HIV-infected subjects had evidence of squamous abnormalities compared with 1 of 23 (4%) non-HIV-infected women (p = 0.019). Nine of 35 (26%) HIV-infected women had cytohistological evidence of human papillomavirus (HPV) infection compared to 1 of 23 (4%) non-HIV-infected women (p = 0.072). We conclude that HIV-infected women have a high prevalence of cervical and vaginal cytological abnormalities and evidence of genital HPV infection. Further study is necessary to determine whether there is an increased risk for cervicovaginal neoplastic disorders in women infected with HIV.

Cervical cytologic abnormalities and papillomavirus in women infected with human immunodeficiency virus.

We investigated the relationship of human papillomavirus (HPV) infection of the female genital tract, cervical cytology, and human immunodeficiency virus (HIV) infection in 67 women. Forty-eight women had a history of intravenous drug use, 18 were heterosexual partners of HIV-infected intravenous drug users, and one was a transfusion recipient. Patients received a Pap smear, cervicovaginal lavage for HPV determination by Southern blot, HIV serum antibody by enzyme immunoassay with Western blot confirmation, and thorough screening for other sexually transmitted diseases. Seventeen of the 35 (49%) women seropositive for HIV had HPV infection, compared with 8 of 32 (25%) seronegative women (p less than 0.05). Fourteen of 35 (40%) HIV-positive women had squamous intraepithelial lesions (SIL) on cervical cytology, compared with three of 32 (9%) HIV-negative women (p less than 0.01). Of 22 women with symptomatic HIV infection, 11 (50%) had SIL on cytology; 10 of these 11 were HPV-positive. Among 13 asymptomatic HIV-positive women, only three (23%) had such cytological lesions. Our findings strongly suggest that HIV-induced immunosuppression exacerbates HPV-mediated cervical cytologic abnormalities.

National AIDS incidence trends and the extent of zidovudine therapy in selected demographic and transmission groups.

After mid-1987 fewer than the expected number of cases of AIDS were reported in the United States in some demographic and transmission groups but not in others. Gay men (regardless of intravenous drug use), adults with hemophilia, and transfusion recipients exhibited fewer cases than expected based on previously reliable models. These favorable trends could not be explained by assuming earlier cessation of human immunodeficiency virus (HIV) infection. Favorable AIDS incidence trends were not found in heterosexual intravenous drug users or in persons infected through heterosexual contact. White gay men from New York City, Los Angeles, and San Francisco experienced markedly favorable trends, whereas little changes was observed for nonwhite gay men from nonurban areas. AIDS incidence trends were quantitatively consistent with the fraction of AIDS-free persons with severe immunodeficiency who received zidovudine in three cohorts. Gay men in San Francisco used zidovudine more frequently than did adults with hemophilia, while little was used by intravenous drug users in New York City. Data describing the initial national distribution of zidovudine (March 31-September 18, 1987) indicated relatively high use by patients with severe immunodeficiency in those groups, such as urban white gay men, that subsequently experienced fewer cases of AIDS than expected. Available data suggest that zidovudine, perhaps in combination with other therapies, has been one factor contributing to favorable AIDS incidence trends in some groups. Broader application of therapy might further retard the incidence of AIDS, especially in intravenous drug users, persons infected through heterosexual contact, minorities, women, and persons diagnosed outside major metropolitan areas.

Impact of immunosuppression on health care use by men in the Multicenter AIDS Cohort Study (MACS).

The effects of human immunodeficiency virus type 1 (HIV-1) serostatus, AIDS, and level of immunosuppression on health service use were examined in the Multicenter AIDS Cohort Study. Data on self-reported hospitalizations, outpatient medical services (non-emergency room) and emergency room care during the preceding 6 months were collected for 3,447 homosexual/bisexual men returning for their 14th and/or 15th semiannual visits in Chicago, Baltimore, Los Angeles, and Pittsburgh. AIDS-free seropositive men with CD4+ cells < 200/microliters were more likely to be hospitalized [odds ratio (OR) = 2.3, 95% confidence limits (CL) = 1.4, 3.8] and use outpatient medical care (OR = 7.9, 95% CL = 4.9, 12.6), compared with seronegative men. Increased outpatient care was initiated at the earliest stages of HIV-1 infection, even when CD4+ cells were > 500/microliter. Dramatic increases in outpatient care for each level of immunosuppression were observed. HIV-1-related symptoms were associated with increased hospitalizations (OR = 4.8, 95% CL = 3.2, 7.3), use of outpatient medical services (OR = 3.3, 95% CL = 1.9, 5.6), and emergency room care (OR = 3.1, 95% CL = 2.1, 4.6). Persons with AIDS and < or = 50 CD4+ cells/microliter most likely to be hospitalized (OR = 8.1; 95% CL = 4.4, 14.9). No significant difference (p > 0.05) in emergency room use was observed according to HIV-1 serostatus, AIDS, or immunosuppression, after adjusting for insurance and clinical symptoms. To the extent that CD4+ cell counts are used as one of the criteria for an AIDS diagnosis and such a diagnosis broadens available benefits to persons with HIV disease, the pattern of health care services described here will be important for health care providers and planners.

Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy.

The eradication of human immunodeficiency virus 1 (HIV-1) from infected persons is the ultimate goal of HIV therapeutic interventions. Great strides have been made in developing potent antiretroviral regimens that greatly suppress HIV-1 replication. Despite these therapeutic advances, major obstacles remain to eradicating HIV-1. Reservoirs of HIV-1 have been identified that represent major impediments to eradication. Conceptually, there are 2 types of sanctuaries for HIV-1, cellular and anatomical. Cellular sanctuaries may include latent CD4+ T cells containing integrated HIV-1 provirus; macrophages, which may express HIV-1 for prolonged periods; and follicular dendritic cells, which may hold infectious HIV-1 on their surfaces for indeterminate lengths of time. The key anatomical reservoir for HIV-1 appears to be the central nervous system. An understanding of the nature of HIV within these reservoirs is critical to devising strategies to hasten viral eradication.

Studies in subjects with long-term nonprogressive human immunodeficiency virus infection.

BACKGROUND: In a small percentage of persons infected with human immunodeficiency virus type 1 (HIV-1), there is no progression of disease and CD4+ T-cell counts remain stable for many years. Studies of the histopathological, virologic, and immunologic characteristics of these persons may provide insight into the pathogenic mechanisms that lead to HIV disease and the protective mechanisms that prevent progression to overt disease. METHODS AND RESULTS: We studied 15 subjects with long-term nonprogressive HIV infection and 18 subjects with progressive HIV disease. Nonprogressive infection was defined as seven or more years of documented HIV infection, with more than 600 CD4+ T cells per cubic millimeter, no antiretroviral therapy, and no HIV-related disease. Lymph nodes from the subjects with nonprogressive infection had significantly fewer of the hyperplastic features, and none of the involuted features, characteristic of nodes from subjects with progressive disease. Plasma levels of HIV-1 RNA and the viral burden in peripheral-blood mononuclear cells were both significantly lower in the subjects with nonprogressive infection than in those with progressive disease (P = 0.003 and P = 0.015, respectively). HIV could not be isolated from the plasma of the former, who also had significantly higher titers of neutralizing antibodies than the latter. There was viral replication, however, in the subjects with nonprogressive infection, and virus was consistently cultured from mononuclear cells from the lymph nodes. In the lymph nodes virus "trapping" varied with the degree of formation of germinal centers, and few cells expressing virus were found by in situ hybridization. HIV-specific cytotoxic activity was detected in all seven subjects with nonprogressive infection who were tested. CONCLUSIONS: In persons who remain free of disease for many years despite HIV infection the viral load is low, but viral replication persists. Lymph-node architecture and immune function appear to remain intact.

Predictors for failure of Pneumocystis carinii pneumonia prophylaxis. Multicenter AIDS Cohort Study.

OBJECTIVE: To identify clinical and epidemiological factors associated with failure of Pneumocystis carinii pneumonia (PCP) prophylaxis in those receiving primary and secondary prophylaxis. DESIGN: Longitudinal cohort study of participants infected with human immunodeficiency virus type 1 in the Multicenter AIDS Cohort Study who used PCP prophylaxis regimens after their T-helper lymphocyte counts had decreased to less than 0.200 x 10(9)/L (200/microL). MAIN OUTCOME MEASURE: Occurrence or recurrence of PCP. RESULTS: A total of 476 participants reported taking one or more of the following regimens: trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, and/or aerosolized pentamidine--367 as primary prophylaxis and 109 as secondary prophylaxis after a previous episode of PCP. A total of 92 (20%) developed PCP despite prophylaxis. The mean failure rates per person-year of follow-up were 16.0% for those receiving primary prophylaxis and 12.1% for those receiving secondary prophylaxis (P = .19). Median times to death after initiation of primary or secondary prophylaxis were 2.0 and 1.2 years, respectively. The main predictor for failure of PCP prophylaxis was profound T-helper lymphocytopenia; 86% of failures occurred after T-helper cell counts decreased to less than 0.075 x 10(9)/L and 76% occurred after counts decreased to less than 0.050 x 10(9)/L. In multivariate time-dependent analysis, when compared with counts between 0.100 x 10(9)/L and 0.200 x 10(9)/L, the risk ratio for failure with counts less than 0.050 x 10(9)/L was 2.90 (P < .001). Once T-helper cell counts were considered, fever was the only other health status indicator that predicted subsequent PCP (ie, a time-dependent risk ratio of 2.22; P = .01). Use of TMP-SMX as the prophylaxis regimen was protective but did not eliminate failure (ie, a time-dependent risk ratio of 0.55; P = .03). CONCLUSIONS: These findings strongly support identifying improved methods of PCP prophylaxis once T-helper cell counts decrease to less than 0.075 x 10(9)/L or 0.100 x 10(9)/L. Given this severe degree of immunosuppression, an inherently more effective regimen against P carinii is required.

Epidemiologic patterns of upper respiratory illness and Pneumocystis carinii pneumonia in homosexual men.

The relationship between self-reported upper respiratory illness symptoms (URI) and human immunodeficiency virus Type 1 (HIV-1) was examined in homosexual men using semiannual visits from 1984 to 1988. Temporal and geographic patterns of Pneumocystis carinii pneumonia (PCP) diagnosis in these men during the same time period are also described. URI, including acute sinusitis, was reported more often by 916 HIV-1-seropositive participants than by 2,161 seronegative participants (32.21 versus 28.86% p less than 0.001). For 387 seropositive subjects who progressed to acquired immunodeficiency syndrome (AIDS), the proportion reporting URI peaked one visit pre-AIDS at a level significantly higher than matched control subjects (0.45 versus 0.28, p less than or equal to 0.001). The peak was higher for those with PCP as an initial diagnosis. Reported URI peaked in winter and troughed in summer, and PCP diagnosis rates peaked and troughed 4 months later, respectively. Cities with the highest reported rates of URI also had the highest proportions of AIDS cases with PCP as an initial diagnosis. No temporal or geographic patterns were observed for other HIV-1-related symptoms or non-PCP AIDS diagnoses. These patterns suggest the possibility of a person-to-person transmission of P. carinii similar to that of other respiratory pathogens, which would imply a need to consider stricter methods to prevent nosocomial transmission of this pathogen in inpatient and outpatient settings. Further investigation of these issues is needed.

Changes in survival after acquired immunodeficiency syndrome (AIDS): 1984-1991.

In a prospective cohort of 2,647 human immunodeficiency virus type 1 (HIV-1) seropositive homosexual men enrolled in Baltimore, Chicago, Los Angeles, and Pittsburgh, 891 developed clinical acquired immunodeficiency syndrome (AIDS) between June 1984 and January 1992. Cox proportional hazards models were used to examine temporal trends in survival after AIDS for specific diagnoses, controlling for level of immunosuppression at diagnosis, age, race, and geographic location. Median survival time following AIDS onset increased from 11.6 months in 1984-1985 to 19.5 months in 1988-1989; for those diagnosed in 1990-1991, the median survival time dropped to 17.2 months. Trends in improved survival were diagnosis-specific. Survival after Pneumocystis carinii pneumonia consistently improved from 1984 to 1991 (p < 0.001). Compared with men diagnosed in 1984-1985, those diagnosed with P. carinii pneumonia in 1990-1991 had one-tenth the hazard of dying. For men with > or = 100 helper T-lymphocytes (CD4+ cells) when diagnosed with Kaposi's sarcoma, the relative hazards (95% confidence intervals) of dying after Kaposi's sarcoma were 0.8 (0.42-1.60) in 1986-1987, 0.7 (0.34-1.58) in 1988-1989, and 0.6 (0.19-1.61) in 1990-1991 compared with those diagnosed before 1986. Men with < 100 CD4+ cells when diagnosed with Kaposi's sarcoma did not demonstrate a consistent change in their subsequent survival. After a nonsignificant (p > 0.05) initial improvement in prognosis, there has not been a significant improvement in survival for men who presented with other opportunistic infections. Observed increases in overall survival probably relate to improved treatment of patients who develop P. carinii pneumonia. Limited improvement in survival following other AIDS diagnoses indicates the need for developing effective treatment against these diseases.

Trends in the incidence of outcomes defining acquired immunodeficiency syndrome (AIDS) in the Multicenter AIDS Cohort Study: 1985-1991.

Incidence of clinical outcomes defining acquired immunodeficiency syndrome (AIDS) may be expected to change as a consequence of progressive immunosuppression and use of chemoprophylaxis before the onset of AIDS. Using Poisson regression methods, we examined trends in the incidence of initial and secondary AIDS-defining illnesses from 1985 to 1991 among 2,627 homosexual men participating in the Multicenter AIDS Cohort Study who were seropositive for human immunodeficiency virus type 1. The incidence of Pneumocystis carinii pneumonia rose steeply until 1987 but has declined since then (p < 0.001), while the other AIDS-defining conditions have showed significant (p < or = 0.039) upward trends. Trends for Kaposi's sarcoma, lymphoma, neurologic disease, and cytomegalovirus/herpes simplex virus infections were explained by progressive immunosuppression, but residual downward and upward trends were present for P. carinii pneumonia and other opportunistic infections (bacterial, fungal, and protozoal infections and wasting syndrome). Despite selection bias, those receiving P. carinii pneumonia chemoprophylaxis showed a significantly lower incidence of P. carinii pneumonia (relative risk = 0.32, 95% confidence interval 0.16-0.63), and the time trends of P. carinii pneumonia were explained by progressive immunosuppression and use of prophylaxis. No significant effects on all other diagnoses were seen in those selected to receive antiretroviral therapy. Secondary diagnoses showed a strongly significant (p < 0.001) increase in non-P. carinii pneumonia and non-Kaposi's sarcoma among those with initial diagnoses of Kaposi's sarcoma. Overall, the trend observed in the incidence of other opportunistic infections underscores the need for developing and testing new strategies to curtail or delay the onset of these diseases.

Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators.

CONTEXT: Time to development of acquired immunodeficiency syndrome (AIDS) and time to death have been extended with the increased use of combination therapy and protease inhibitors. Cohort studies following up persons with human immunodeficiency virus (HIV) infection in periods characterized by different therapies offer the opportunity to estimate therapy effectiveness at the population level. OBJECTIVE: To assess the effectiveness of self-reported, long-term potent antiretroviral therapy in a cohort of 536 men whose duration of HIV infection was known (seroconverters). DESIGN: Cohort study. The cohort was compared for time to development of AIDS and time to death in 1984 to 1990, 1990 to 1993, 1993 to July 1995, and July 1995 to July 1997 when the major treatments were no therapy, monotherapy, combined therapy, and potent antiretroviral therapy, respectively. Survival analysis methods with time zero set as the date of seroconversion and incorporating staggered entries into each period were used. Mean CD4 cell change, stratified by infection duration, was determined for each period using a random effects model. SETTING: The Multicenter AIDS Cohort Study (MACS) in 4 urban areas (Baltimore, Md; Chicago, III; Los Angeles, Calif; and Pittsburgh, Pa). PARTICIPANTS: A total of 5622 men who were 18 years or older were enrolled into MACS. Of the 5622, there were 2191 HIV-positive individuals at enrollment. Of the 3431 men who were HIV-negative, 536 were observed to seroconvert and were followed up for up to 13 years. The group of 536 who seroconverted constituted the study population. MAIN OUTCOME MEASURES: Time from seroconversion to development of AIDS and to death and change in CD4 cell count. RESULTS: A total of 231 seroconverters developed AIDS, and 200 men died. Using 1990 to 1993 as the reference period, the relative hazard of AIDS was 1.04 (95% confidence interval [CI], 0.73-1.48) during 1993 to July 1995 and 0.35 (95% CI, 0.20-0.61) during July 1995 to July 1997. Relative hazards of death were 0.87 (95% CI, 0.58-1.31) and 0.62 (95% CI, 0.38-1.01 ) for the same periods. The relative time (the factor by which times are contracted or expanded) to development of AIDS was 0.97 (95% CI, 0.86-1.09) for 1993 to July 1995 and 1.63 (95% CI, 1.40-1.89) for July 1995 to July 1997. Relative survival time for 1993 to July 1995 was 1.01 (95% CI, 0.91-1.12) and for July 1995 to July 1997 was 1.21 (95% CI, 1.07-1.36) relative to 1990 to 1993. The rate of CD4 cell count decline in July 1995 to July 1997 was significantly lower (P<.05) compared with the previous 2 periods. CONCLUSIONS: In the calendar period when potent antiretroviral therapy was introduced, the time to development of AIDS and time to death were extended, and rate of CD4 cell count decline was arrested.

Reversibility of the pathological changes in the follicular dendritic cell network with treatment of HIV-1 infection.

Over the course of HIV-1 infection, the lymphoid follicles where the humoral immune response is generated initially increase in size and number and then progressively involute. In advanced disease, the network of the processes of follicular dendritic cells (FDCs) that serve as antigen repositories and anatomical substrate for B and T cells and antigen to interact is destroyed, contributing to the breakdown of the immune system. Because destruction of FDCs is associated with deposition of HIV-1, and much of the virus can be cleared from the network with antiretroviral therapy, we investigated the reversibility of damage. We measured the immunohistochemically stainable FDC compartment by quantitative image analysis, and we documented changes in this compartment at different stages of disease. We show that treatment, initiated even at advanced stages of HIV-1 disease, can slowly reverse pathological changes in the FDC network.