Cefazolin versus Nafcillin for Methicillin-Sensitive Staphylococcus aureus Bloodstream Infection in a California Tertiary Medical Center.

Recent observational studies have suggested possible reductions in mortality in patients receiving cefazolin versus antistaphylococcal penicillins. We examined 90-day mortality in patients receiving cefazolin compared to nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infection (BSI). We identified persons with MSSA BSI admitted to San Francisco General Hospital from January 2008 to July 2013 through a hospital-wide infection surveillance system and confirmed 90-day mortality using U.S. national vital registries. We included persons receiving cefazolin or nafcillin as the predominant intravenous antimicrobial agent; all participants received inpatient Infectious Diseases service consultation. We estimated the association between receipt of cefazolin and 90-day risk of death by multivariate logistic regression, including a propensity score for receiving cefazolin as the second predictor. Of 230 MSSA BSI cases, 30 received nafcillin and 70 received cefazolin as the predominant antimicrobial; 10 died within 90 days, 5 from each group. Unadjusted analysis showed substantial but not statistically significant reduced odds of death in those receiving cefazolin (odds ratio, 0.38; 95% confidence interval [CI], 0.10 to 1.44). Multivariate analysis with propensity scores found a similar adjusted odds ratio (0.40; 95% CI, 0.09 to 1.74; P = 0.22). We found a large reduction in 90-day mortality in those receiving cefazolin compared to nafcillin for MSSA BSI, but this finding was not statistically significant. The magnitude of effect seen in this and other studies justifies further study.

A model-based estimate of the mean incubation period for AIDS in homosexual men.

Because of the difficulty in identifying the date of exposure to type 1 of the human immunodeficiency virus (HIV-1) infection in persons other than transfusion recipients, studies of the incubation periods for acquired immunodeficiency syndrome (AIDS) have been limited. When data from a cohort of 84 homosexual and bisexual men that provided the information to determine the years of conversion of sera infected with HIV-1 were analyzed, a model for the proportion likely to develop AIDS and the incubation period for AIDS in homosexual men could be derived. The maximum likelihood estimate for the proportion of infected homosexual men developing AIDS is 0.99 (90% confidence interval ranging from 0.38 to 1). Furthermore, the maximum likelihood estimate for the mean incubation period for AIDS in homosexual men is 7.8 years (90% confidence interval ranging from 4.2 years to 15.0 years), which is close to the estimate of 8.2 years for adults developing transfusion-associated AIDS.

Antiretroviral regimens for patients with HIV who fail first-line antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy has reduced the morbidity and mortality of patients with HIV/AIDS. A common first-line ART regimen includes a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs). If treatment failure occurs, a change to second-line therapy is necessary. OBJECTIVES: This meta-analysis aimed to assess the optimum antiretroviral regimen for patients with HIV who fail first-line therapy (ART-naive) with d4T+3TC+NVP; d4T+3TC+EFV; ZDV+3TC+NVP; and ZDV+3TC+EFV. SEARCH STRATEGY: Electronic databases and conference proceedings were searched with relevant search terms without limits to language. SELECTION CRITERIA: Randomised controlled trials of HIV-infected adult patients administered second-line ART after virologic failure of a first-line regimen were included. The primary outcome measure included the proportion of patients achieving undetectable plasma HIV RNA concentration (viral load). Secondary outcome measures included change in mean CD4 cell count, clinical resolution of symptoms, rate of adverse events, rate of change in therapy for failure, rate of change in therapy for toxicity, and mortality. DATA COLLECTION AND ANALYSIS: Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form. MAIN RESULTS: Twenty-one records were identified in total, 6 of which were duplicates. None of the records met inclusion criteria. AUTHORS' CONCLUSIONS: There is insufficient evidence to evaluate second-line therapies in patients with HIV who fail first-line treatment with d4T+3TC+NVP; d4T+3TC+EFV; ZDV+3TC+NVP; and ZDV+3TC+EFV. Current recommendations are based on available resources and results from individualised treatment decisions based on resistance testing and clinician choice.

Antiretroviral post-exposure prophylaxis (PEP) for occupational HIV exposure.

BACKGROUND: Populations such as healthcare workers (HCWs), injection drug users (IDUs), and people engaging in unprotected sex are all at risk of being infected with the human immunodeficiency virus (HIV). Animal models show that after initial exposure, HIV replicates within dendritic cells of the skin and mucosa before spreading through lymphatic vessels and developing into a systemic infection (CDC 2001). This delay in systemic spread leaves a "window of opportunity" for post-exposure prophylaxis (PEP) using antiretroviral drugs designed to block replication of HIV (CDC 2001). PEP aims to inhibit the replication of the initial inoculum of virus and thereby prevent establishment of chronic HIV infection. OBJECTIVES: To evaluate the effects of antiretroviral PEP post-occupational exposure to HIV. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AIDSearch, and the Database of Abstracts of Reviews of Effectiveness were searched from 1985 to January 2005 to identify controlled trials. There were no language restrictions. Because no controlled clinical trials were retrieved, the search was repeated on 31 May 2005 in MEDLINE, AIDSearch and EMBASE using a search strategy to identify analytic observational studies. Handsearches of the reference lists of all pertinent reviews and studies found were also undertaken. Experts in the field of HIV prevention were contacted. SELECTION CRITERIA: Types of studies: All controlled trials (including randomized clinical trials and controlled clinical trials). If no controlled trials were found, analytic studies (e.g. cohort and case-control studies) were considered. Descriptive studies (i.e. studies with no comparison groups) were excluded. Types of participants included:HCWs exposed to any known or potentially HIV contaminated product;anyone exposed to a needlestick contaminated by known or potentially HIV-infected blood or other bodily fluid in an occupational setting; andanyone exposed through the mucous membranes to an HIV-infected or potentially infected substance in occupational setting.Excluded: Sex workers (PEP post-sexual exposure is addressed in another Cochrane review (Martín 2005)). Types of interventions: Any intervention that administered single or combinations of antiretrovirals as PEP to people exposed to HIV through percutaneous injuries and/or occupational mucous membrane exposures when the HIV status of the source patient was positive or unknown. Studies comparing two types of PEP regimens were considered, as were studies comparing PEP with no intervention. Types of outcome measures:Incidence of HIV infection in those given PEP versus those given placebo or a different PEP regimen; Adherence to PEP; Complications of PEPTypes of outcome measures: Incidence of HIV infection in those given PEP versus those given placebo or a different PEP regimen; Adherence to PEP; Complications of PEP DATA COLLECTION AND ANALYSIS: Data concerning outcomes, details of the interventions, and other study characteristics were extracted by two independent authors (TY and JA) using a standardized data extraction form (Table 04). A third author (GK) resolved disagreements. The following information was gathered from each included study: location of study, date, publication status, demographics (e.g. age, gender, occupation, risk behavior, etc.) of participants/exposure modality, form of PEP used, duration of use, and outcomes. Odds ratios with a 95% confidence interval (CI) were used as the measure of effect. A meta-analysis was performed for adverse events where two-drug regimens were compared with three-drug regimens. Due to overlap between Puro 2000 and Puro 2005, the former was not included in the combined analysis. MAIN RESULTS: Effect of PEP on HIV seroconversionNo randomized controlled trials were identified. Only one case-control study was included. HIV transmission was significantly associated with deep injury (OR 15, 95% CI 6.0 to 41), visible blood on the device (OR 6.2, 95% CI 2.2 to 21), procedures involving a needle placed in the source patient's blood vessel (OR 4.3, 95% CI 1.7 to 12), and terminal illness in the source patient (OR 5.6, 95% CI 2.0 to 16). After controlling for these risk factors, no differences were detected in the rates at which cases and controls were offered post-exposure prophylaxis with zidovudine. However, cases had significantly lower odds of having taken zidovudine after exposure compared to controls (OR 0.19, 95%CI 0.06 to 0.52). No studies were found that evaluated the effect of two or more antiretroviral drugs for occupational PEP. Adherence to and complications with PEPEight reports from observational comparative studies confirmed findings that adverse events were higher with a three-drug regimen, especially one containing indinavir. However, discontinuation rates were not significantly different. AUTHORS' CONCLUSIONS: The use of occupational PEP is based on limited direct evidence of effect. However, it is highly unlikely that a definitive placebo-controlled trial will ever be conducted, and, therefore, on the basis of results from a single case-control study, a four-week regimen of PEP should be initiated as soon as possible after exposure, depending on the risk of seroconversion. There is no direct evidence to support the use of multi-drug antiretroviral regimens following occupational exposure to HIV. However, due to the success of combination therapies in treating HIV-infected individuals, a combination of antiretroviral drugs should be used for PEP. Healthcare workers should be counseled about expected adverse events and the strategies for managing these. They should also be advised that PEP is not 100% effective in preventing HIV seroconversion. A randomized controlled clinical trial is neither ethical nor practical. Due to the low risk of HIV seroconversion, a very large sample size would be required to have enough power to show an effect. More rigorous evaluation of adverse events, especially in the developing world, are required. Seeing that current practice is partly based on results from individual primary animal studies, we recommend a formal systematic review of all relevant animal studies.

Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults.

BACKGROUND: A favourable regimen for people infected with HIV/AIDS is one that provides optimal efficacy, durability of antiretroviral activity, tolerability, and has low adverse effects and drug-drug interactions. The combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), and two nucleoside reverse transcriptase inhibitors, stavudine (d4T) and lamivudine (3TC), is widely used as first-line therapy, especially in low-resource countries. Analysis of the efficacy, durability and tolerability of the regimen is thus important to clinicians, consumers and policy-makers living in both rich and poor countries. OBJECTIVES: To examine the efficacy of the stavudine, lamivudine and nevirapine regimen for the treatment of HIV infection and AIDS in adults. SEARCH STRATEGY: We used the comprehensive search strategy developed specifically by the Cochrane HIV/AIDS Review Group to identify HIV/AIDS randomised controlled trials, and searched the following electronic databases: MEDLINE (searched July 2004); Embase (searched October 2004); and CENTRAL (July 2004). This search was supplemented with a search of AIDSearch (April 2005) to identify relevant conference abstracts, as well as searching reference lists of all eligible articles. The search was not limited by language or publication status. SELECTION CRITERIA: Randomised controlled trials of the stavudine, lamivudine and nevirapine regimen, compared with any other regimens for treating HIV/AIDS, in antiretroviral treatment-naive or antiretroviral treatment-experienced adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the methodological quality of the trials and extracted data. MAIN RESULTS: Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ. AUTHORS' CONCLUSIONS: The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.

Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV.

BACKGROUND: Cryptococcal disease is an opportunistic infection that causes significant morbidity and mortality in adults with HIV. Primary prophylaxis with antifungal interventions may decrease cryptococcal disease incidence and associated mortality. OBJECTIVES: To assess the efficacy of antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. SEARCH STRATEGY: We searched the following databases: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), ClinicalTrials.gov, Database of Abstracts of Reviews of Effectiveness (DARE), Latin American and Caribbean Literature on the Health Sciences (LILACS), and the Cochrane Controlled Trials Register (CCTR). We reviewed abstracts from the following relevant conferences: International AIDS Conference, International AIDS Society Conference on HIV Pathogenesis and Treatment, and Conference on Retroviruses and Opportunistic Infections. We searched reference lists for all primary and other pertinent articles identified. We attempted to contact experts in the field, particularly primary authors of included studies, to better ensure completeness of included studies. We also approached pharmaceutical companies for any available and relevant unpublished data. The time period searched was from 1980 to August 2004. We placed no language restrictions on the search. Key words used include: meningitis, cryptococcal, cryptococcus, cryptococcosis, acquired immunodeficiency syndrome, human immunodeficiency virus, prophylaxis, chemoprevention, antifungal agents, and the Cochrane screen for randomized controlled trials. SELECTION CRITERIA: Randomized controlled trials using antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV were selected. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality. Trial authors, experts, and pharmaceutical companies were contacted for additional and/or missing information. Data were abstracted by two reviewers. Data were pooled, where appropriate, to yield summary estimates. MAIN RESULTS: Five studies (N=1316) were identified. All study patients had CD4 cell counts <300 cells/microl, and the majority of patients had CD4 cell counts <150 cells/microl. When all five studies are analyzed as a single group (N=1316), the incidence of cryptococcal disease was decreased in those taking primary prophylaxis (RR 0.21, 95% CI 0.09, 0.46) compared to those taking placebo. However, there was no significant difference in overall mortality observed (RR 1.01, 95% CI 0.71, 1.44). When the three studies using itraconazole as the intervention were analyzed together (N=798), the incidence of cryptococcal disease was decreased in those taking itraconazole for primary prophylaxis (RR 0.12, 95% CI 0.03, 0.51) compared to those taking placebo; however, there was no significant difference in overall mortality (RR 1.12, 95% CI 0.70, 1.80). When the two studies using fluconazole as the intervention were analyzed together (N=518), the incidence of cryptococcal disease was decreased in those taking fluconazole for primary prophylaxis (RR 0.25, 95% CI 0.07, 0.87) compared to those taking placebo; however, there was no significant difference in overall mortality (RR 0.59, 95% CI 0.14, 2.62). AUTHORS' CONCLUSIONS: Antifungal primary prophylaxis with either itraconazole or fluconazole is effective in reducing the incidence of cryptococcal disease in adults with advanced HIV disease. However, neither of these interventions has a clear effect on overall mortality. Further research is needed to better understand these interventions and the populations in which they may be most effective.

Evaluation of AIDS prevention and control programs.

PIP: To date, no full-scale community-based trials of acquired immunodeficiency syndrome (AIDS) prevention interventions with appropriate controls have been conducted and the true effect of such programs on the community-wide incidence of human immunodeficiency virus (HIV) infection cannot be measures. A review of the literature indicates, however, that some AIDS prevention programs are building in an evaluation component, including baseline studies and needs assessments, pre- and post-test measures of knowledge, attitude, and behavioral changes, and biomedical indicators of program-related effects such as HIV serostatus. The literature from the period July 1988-June 1989 reveals a trend toward interventions targeted at high-risk populations such as racial and ethnic minorities, prostitutes, prison inmates, substance abusers, and adolescents. Evaluations of programs aimed at specific populations commonly measure the impact of one or more types of interventions on the knowledge and practice of behaviors known to reduce the risk of HIV transmission. Programs that give participants the skills needed for the initiation and maintenance of risk-reduction behaviors appear to be more effective than programs emphasizing cognitive or affective learning alone. The literature confirms the benefits of use of indigenous health communicators in program planning and implementation and of a multi-faceted (e.g., mass media, community, and individual-level interventions) strategy.^ieng

Effect of the revised AIDS case definition on AIDS reporting in San Francisco: evidence of increased reporting in intravenous drug users.

To examine the effect of the revision of the US national AIDS case definition in September 1987, we compared demographic and clinical information for AIDS patients diagnosed and reported to the San Francisco Department of Public Health between 1 September 1987 and 31 October 1989. Of the 3167 patients diagnosed and reported during the study period, 584 (18%) met the revised case definition only, increasing AIDS case reporting in San Francisco by 23%. One hundred and thirty-four of these 584 patients (23%) subsequently developed diagnoses meeting the old definition. After adjusting for this proportion, the revised case definition increased reporting by 17%. The mean time between initial diagnosis with a disease meeting the revised definition and subsequent development of a disease meeting the old definition was 18.5 months. Patients who met the revised case definition only were slightly older and more likely to be Black, female, and intravenous drug users (IVDUs) than those meeting the old case definition. The majority of patients who met the revised case definition only had initial diagnoses of HIV wasting syndrome (26%), HIV encephalopathy (21%), and presumptive Pneumocystis carinii pneumonia (19%). The revised AIDS case definition has significantly increased the reporting of severe morbidity associated with HIV infection, particularly among IVDUs.

The epidemiology of AIDS in Asian and Pacific Islander populations in San Francisco.

To evaluate the epidemiology of HIV infection in Asian and Pacific Islander populations in San Francisco, we compared cases of AIDS reported in Asians and Pacific Islanders with those reported in other racial and ethnic groups. The incidence of AIDS in Asians and Pacific Islanders was significantly lower than in Whites, Blacks, Latinos and American Indians and Alaska natives. AIDS cases among Asians and Pacific Islanders have increased 177% since 1985 compared with 54% in other racial and ethnic groups, with the greatest increase in homosexual and bisexual men and transfusion recipients. Among Asian and Pacific Islander ethnic groups, the incidence of AIDS was 168 cases per 100,000 in Polynesians, 141 per 100,000 in Japanese, 92 per 100,000 in 100 Filipinos, 72 per 100,000 in southeast Asians, and 21 per 100,000 in Chinese. We conclude that AIDS cases are disproportionately increasing in Asians and Pacific Islanders in San Francisco.

PIP: In Asia and in people of Asian and Pacific Islander ancestry in the United States, AIDS is a rare disease. San Francisco, with the highest incidence of AIDS in the United States, also has the highest percentage (21%) of Asians and Pacific Islanders. To understand the potential for AIDS in this select population, trends over time and the demographics of reported AIDS cases among the select population in San Francisco were analyzed. Records were reviewed of AIDS cases reported to the San Francisco Department of Health, which had a substantiated 98% report rate. As of March 31,1988, 83 (1.8%) of the 4689 cases and 42 (1.5%) of the 2831 deaths reported were among the select population. The incidence of AIDS among the select population (58.5/100,000) was significantly lower than among whites (1108.8/100,000), blacks (368.9/100,000), and latinos (421.0/100,000). Among the select population, however, AIDS increased more rapidly since 1985 than among the whites, blacks, or latinos. Of the 83 cases reported, 69 were homosexual or bisexual men without intravenous drug use, 3 homosexual or bisexual men with histories of intravenous drug use, 6 were transfusion recipients, 3 were heterosexual intravenous drug users, 1 was a heterosexual contact of a person at risk for AIDS, and 1 was a hemophiliac. Comparison of transmission categories of the select population with those of the other racial and ethnic groups showed a significantly greater (P 0.001) number of transfusion recipients and a significantly lower (P 0.02) number of homosexual and bisexual intravenous drug users. The greatest increase in cases among the select population was in homosexual and bisexual men without histories of intravenous drug use, which was greater than the increase among nonAsian or Pacific Islander homosexual and bisexual men (P 0.10). These findings support the theory that HIV entered the select population communities later than it did nonAsian or Pacific Islander communities.

Survival following diagnosis of Kaposi's sarcoma for AIDS patients in San Francisco.

To evaluate survival for AIDS patients diagnosed with Kaposi's sarcoma (KS), we calculated survival for 1,015 patients reported in San Francisco between July 1981 and December 31, 1987, representing 22% of total patients reported. These patients had a definitive initial diagnosis of KS, and developed no other diseases within 3 months of diagnosis. Patients were followed prospectively through December 31, 1988. All patients evaluated in this study were men. Survival was evaluated for subgroups based on age, race and ethnicity, year of diagnosis, and transmission category. The median survival for patients diagnosed with KS alone was 17.0 months, with a 5-year survival rate of 8.7%. Poorer prognosis was found for patients with older age at diagnosis and with later year of diagnosis. Proportional hazards analysis indicated that age (p less than 0.001) and year of diagnosis (p less than 0.05) were significant independent predictors of survival, while race or ethnicity and risk group were not.

The epidemiology of AIDS-related Kaposi's sarcoma in San Francisco.

To clarify further the epidemiology of AIDS-related Kaposi's sarcoma (KS) in San Francisco, we reviewed AIDS cases reported to the San Francisco Department of Public Health through August 31, 1990. Of the 7,119 patients reported, 2,346 (33%) had been diagnosed as having KS: 1,716 (73%) as their presenting clinical manifestation of AIDS and 648 (27%) as a later manifestation. Of these 2,364 KS patients, 2,075 (88%) were homosexual or bisexual men without histories of intravenous drug use, and 273 (12%) were homosexual or bisexual intravenous drug users. From 1981 to August 1989, the proportion of AIDS patients presenting with KS declined from 55 to 19% (p less than 0.001). However, the number of patients being diagnosed with KS has increased along with the overall number of AIDS patients, but this increase was less than the increase in number of patients with other opportunistic infections and malignancies. KS patients were less likely than patients without KS to be reported through an active surveillance system and less likely to be found through retrospective reviews of medical records, death certificates, and obituaries. We conclude that the proportion of AIDS patients with KS is continuing to decline in San Francisco and that this decline is not an artifact of the AIDS surveillance system.

Impact of AIDS on mortality in San Francisco, 1979-1986.

We used death certificate data for San Francisco residents from 1979 to 1986 to calculate the number of deaths and years of potential life lost before age 65 (YPLL) for leading causes of death. Acquired immune deficiency syndrome (AIDS)-related deaths were defined as including cytomegalovirus infection (ICD-9 078.5); cryptococcal infection (ICD-9 117.5); Pneumocystis carinii pneumonia (ICD-9 136.3); other malignant neoplasms of the skin, site unspecified (ICD-9 173.9); deficiency of cell-mediated immunity (ICD-9 279.1); and unspecified immunity deficiency (ICD-9 279.3). These deaths increased from 5 (0.1% of all deaths) in 1979 to 534 (6.6%) in 1986. Of the 1,225 deaths caused by AIDS-related diseases during this period, 1,032 (84%) occurred in men aged 20-49 years. AIDS-related deaths increased between 1979 and 1986 from 0 to 44 (25% of all deaths), 0 to 257 (44%), and 0 to 150 (35%) in men aged 20-29 years, 30-39 years, and 40-49 years, respectively. In 1986, AIDS-related diseases were the third leading cause of deaths and the leading cause of YPLL among male San Francisco residents.

Kaposi's sarcoma among homosexual and bisexual men enrolled in the San Francisco City Clinic Cohort Study.

The changing epidemiology of Kaposi's sarcoma (KS) and possible explanations for this change were analyzed using data from a well-characterized cohort of homosexual and bisexual men. Among 1,341 men with AIDS, the proportion presenting with KS declined from 79% in 1981 to 25% in 1989. For 250 men whose date of HIV seroconversion could be well characterized, persons presenting with KS had a shorter interval from HIV seroconversion to AIDS diagnosis than other AIDS patients without KS (mean = 77 vs. 86 months). Among 182 men who were interviewed prior to a diagnosis of AIDS, men with and without KS did not significantly differ with respect to number of sex partners, a history of certain sexually transmitted or enteric diseases, use of certain recreational drugs (including nitrite inhalants), or participation in certain specific sexual practices. The decline in KS may at least partly be due to a shorter latency period from infection to disease. Although cofactors for the development of KS may exist, many previously hypothesized agents were not supported by this analysis.

Relationship between AIDS latency period and AIDS survival time in homosexual and bisexual men.

We identified 277 homosexual and bisexual men diagnosed with acquired immune deficiency syndrome (AIDS) whose estimated human immunodeficiency virus (HIV) seroconversion dates, ranging from 1977-85, could be well approximated. These men were from a cohort of 6,705 homosexual and bisexual men originally recruited for studies of sexually transmitted hepatitis B in San Francisco in 1978-80. We compared the time from HIV seroconversion to the initial disease diagnostic of AIDS (AIDS latency period) with the time from first AIDS diagnosis to death (AIDS survival time) and found no significant overall correlation between latency period and survival time. Both Kaplan-Meier and Cox proportional hazard stepwise analyses found the initial AIDS diagnosis to be significantly associated with latency period, with individuals first diagnosed with Kaposi's sarcoma (KS) having a shorter latency but longer survival than those first diagnosed with Pneumocystis carinii pneumonia (PCP) or other AIDS diagnoses. Individuals with KS tended to be diagnosed earlier in the epidemic compared to those with PCP and other non-KS diagnoses. The AIDS survival time was significantly associated with the initial AIDS diagnosis but not with the estimated year of seroconversion, the year of first AIDS diagnosis, age at seroconversion, or racial/ethnic group. The information presented here on the relationship between the AIDS latency period and survival times suggests a model for the pathogenesis of HIV infection in which there is continual deterioration of the immune system. The wider use of antiviral and prophylactic therapies both preceding and following a diagnosis of AIDS may change this model as both latency and survival times are improved.

Phase I study of low-dose zidovudine and acyclovir in asymptomatic human immunodeficiency virus seropositive individuals.

PURPOSE: The combination of zidovudine and acyclovir has shown in vitro antiretroviral activity and led to short-term improvement in patients with symptomatic human immunodeficiency disease (HIV) disease. We performed a phase I study of zidovudine (500 mg/day) plus acyclovir (2 or 4 g/day) in asymptomatic HIV-seropositive men to investigate pharmacokinetics, safety, tolerance, and immunologic effects of the combination. SUBJECTS AND METHODS: Fifty HIV-seropositive homosexual or bisexual men from the San Francisco City Clinic Cohort Study were recruited for the study; of these, 20 met the eligibility criteria. Treatment with zidovudine and acyclovir was open label. Pharmacokinetic, virologic, immunologic, and clinical data were collected periodically over a 24-week period. RESULTS: Pharmacokinetic analysis showed no drug interaction. The combination was generally well tolerated, and hematologic parameters remained stable through 24 weeks. There were no significant changes in total lymphocytes, T4 lymphocytes, overall skin test reactivity, or ability to culture virus from peripheral blood. CONCLUSION: This combination of agents is safe in this population for at least six months. Conclusions about long-term tolerance and efficacy await the results of larger trials with longer follow-up.

Fatiguing illness among employees in three large state office buildings, California, 1993: was there an outbreak?

UNLABELLED: The objective was to determine if a cluster of chronic fatigue syndrome (CFS)-like illness had occurred among employees in two large state office buildings in northern California, and to identify risk factors for and features of fatiguing illness in this population. DESIGN: case-control study. POPULATION AND SETTING: Over 3300 current employees in two state office buildings and employees in a comparable "control" building. Information was collected on demographic and occupational variables, the occurrence of fatiguing illness for at least one month in the previous year, and the presence of 36 symptoms. A total of 3312 (82%) of 4035 employees returned questionnaires. Overall, 618 (18.7%) persons reported fatigue lasting at least one month; including 382 (11.5%) with fatigue of at least six months' duration and 75 (2.3%) with symptoms compatible with a CFS-like illness. Independent risk factors for fatigue lasting one month or longer were found to be Native American ethnicity (OR 2.4, CI 1.1,5.3), Hispanic ethnicity (OR 1.7, CI 1.3,2.3), female sex (OR 1.5, CI 1.2,1.9), gross household incomes of less than $50,000 (OR 1.3, CI 1.1,1.6), and less than a college education (OR 1.3, CI 1.1,1.6). Similar risks were observed for persons who reported fatigue lasting six months or longer. Female sex (OR 3.2, CI 1.7, 6.4) was the only independent risk factor found for those persons classified as having a CFS-like illness. Case prevalence rates for all three categories of fatigue, as determined by multivariate analysis, were not significantly different among buildings. Despite finding a substantial number of employees with fatiguing illness in the two state office buildings, the prevalence was not significantly different than that for a comparable control building. Previously unidentified risk factors for fatigue of at least one month and at least six months identified in this population included Hispanic ethnicity, not having completed college, and income below $50,000.

Public health, communicable diseases, and managed care: Will managed care improve or weaken communicable disease control?

BACKGROUND: Several changes can be anticipated in the practice of communicable disease control as a result of the health care delivery system's transition from a predominantly fee-for-service system to a predominantly managed care system. These changes will clearly involve clinical services provided by public health agencies, such as immunizations and diagnosis and treatment of tuberculosis and sexually transmitted diseases, as well as those that do not involve direct patient care, such as public health surveillance, disease investigation, outbreak control, contact tracing, public health laboratory services, and health education. METHODS: In this paper I review the potential impact of managed care on each of these areas of communicable disease control and suggest strategies for minimizing adverse effects and maximizing potential areas of cooperation. RESULTS: Examples of successful strategies include California's Medi-Cal managed care expansion, which allows local public health agencies to bill managed care organizations for the sexually transmitted disease, immunization, and confidential HIV services they provide to managed care beneficiaries. A different strategy is illustrated by the Pacific Business Group on Health, an employer-based purchasing group, that uses purchasing power to standardize the clinical preventive services benefit across all plans with which it contracts and to promote immunization goals. CONCLUSION: This analysis and these examples suggest that the emergence of managed care as the predominant form of health care financing and delivery in the United States offers an important opportunity for public health.

Research in the Veterans Health Administration: the report of the Research Realignment Advisory Committee.

In 1995 the Under Secretary for Health of the Department of Veterans Affairs constituted the Research Realignment Advisory Committee and charged it with reviewing the VA's research program. After meeting in 1995 and 1996, the committee identified 12 findings, which fall into four broad categories: allocation of research resources among VA research programs, acquisition and protection of resources, stability and maintenance of infrastructure, and outreach and communications. The most far-reaching recommendation was to establish designated research areas so that VA research could be focused more sharply on the specific needs of veterans while maintaining a research base for relatively less common conditions and needs integral to the VA's mission. The second major issue was that research funding should be increased (because it had fallen in inflation-adjusted dollars while the cost of doing research continued to rise). The third major area dealt with operational issues about how research was administered in the newly created system of geographically defined "veterans integrated service networks" and at the medical centers and how research monies flowed to medical centers. The final major area had to do with career development, for the committee considered the recruitment and retention of outstanding junior investigators to be a core function of VA research. The committee's recommendations, some of which have already been implemented, form the basis for strengthening the VA's research enterprise and for fully integrating it within the new structure of health care delivery in the VA.

Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection.

BACKGROUND: Combination antiretroviral therapy administered to HIV-infected individuals has been shown to improve immunologic function and delay the progression of HIV infection. However, because patient adherence to complicated combination-therapy antiretroviral regimens is difficult and because of concerns regarding cumulative toxicity of antiretroviral drugs, regimens that utilize fewer antiretroviral agents are desirable. OBJECTIVES: To compare the use three- or four- versus two-drug antiretroviral maintenance regimens following successful induction therapy for HIV infection. SEARCH STRATEGY: The following electronic databases were searched for relevant randomized trials or reviews: 1. MEDLINE for the years 1982-1999 using the search terms human immunodeficiency virus, antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, AIDS, anti-HIV agents, HIV infection and HIV seropositivity 2. AIDSLINE for the years 1982-1999 using the search terms antiretroviral therapy, maintenance therapy, zidovudine, lamidvudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, anti-HIV agents 3. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register in the Cochrane Library, Issue 2, 1999. 4. The specialist register of trials maintained by the Cochrane Collaborative Review Group on HIV Infection and AIDS 5. AIDSTRIALS, a specialist registry of current and completed trials maintained by the U.S. National Library of Medicine The abstracts of relevant conferences, including the International Conferences on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Infectious Disease Society of America annual meeting and the Interscience Conference on Antimicrobial Agents and Chemotherapy, as indexed by AIDSLINE, were also reviewed. All reference lists of all review articles and primary articles identified were searched. SELECTION CRITERIA: Randomized controlled trials in which HIV-infected adults who had successfully completed three- or four-drug antiretroviral induction therapy were randomized to maintenance therapy with three or four drugs or maintenance therapy with two drugs. Successful induction therapy was defined by a plasma viral load of less than 500 copies/ml. DATA COLLECTION AND ANALYSIS: Two reviewers assessed eligibility and trial quality. Attempts were made to contact the authors of the included abstract. Data on the number of patients experiencing loss of viral suppression were abstracted by two reviewers. The data were pooled, where appropriate, to yield odds ratios, using random effects models. MAIN RESULTS: Four trials were identified including three published studies and one abstract. Compared to three- or four-drug maintenance therapy, maintenance therapies including fewer drugs were associated with a higher risk of virologic failure (loss of HIV suppression to non-detectable levels). Combining the results of all four studies yielded an odds ratio of 5.55 (95% confidence interval, 3.14 - 9.80). Similar results were obtained when the one abstract was excluded (odds ratio, 5.48; 95% confidence interval, 2.82 - 10.65). Performing subgroup analyses of studies using the same induction and maintenance regimens gave similar results. Maintenance regimens of zidovudine and lamivudine compared to maintenance regimens with zidovuine, lamivudine and indinavir, were associated with significantly higher rates of virologic failure (odds ratio, 4.57; 95% confidence interval, 1.80 - 11.58). Similarly, maintenance regimens that discontinued one or more protease inhibitor after including them in induction therapy were also associated with a significantly higher risk of virologic failure (odds ratio, 6.15; 95% confidence interval, 3.40 -11.10). (ABSTRACT TRUNCATED)

Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection.

BACKGROUND: Combination antiretroviral therapy administered to HIV-infected individuals has been shown to decrease viral replication, improve immunologic function and delay the progression of HIV infection. However, because patient adherence to complicated combination-therapy antiretroviral regimens is difficult and because of concerns regarding the cumulative toxicity of antiretroviral drugs, regimens that utilize fewer antiretroviral agents are desirable. OBJECTIVES: To compare the use three- or four- versus two-drug antiretroviral maintenance regimens following successful initial therapy for HIV infection. SEARCH STRATEGY: The following electronic databases were searched for relevant randomized trials or reviews: 1. MEDLINE for the years 1982-May 2003 using the search terms human immunodeficiency virus, antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, AIDS, anti-HIV agents, HIV infection and HIV seropositivity. 2. AIDSLINE for the years 1982- May 2003 using the search terms antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, anti-HIV agents. 3. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register in the Cochrane Library, through May 2003. 4. AIDSTRIALS, a specialist registry of current and completed trials maintained by the U.S. National Library of Medicine through May 2003. The abstracts of relevant conferences, including the International Conferences on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Infectious Disease Society of America annual meeting and the Interscience Conference on Antimicrobial Agents and Chemotherapy, as indexed by AIDSLINE, were also reviewed. Reference lists of all review articles and primary articles identified were also searched. SELECTION CRITERIA: Randomized controlled trials in which HIV-infected adults who had successfully completed initial three- or four-drug antiretroviral therapy were randomized to maintenance therapy with three or four drugs or maintenance therapy with two drugs. Successful initial therapy was defined by a plasma viral load of less than 500 copies/ml. DATA COLLECTION AND ANALYSIS: Two reviewers assessed eligibility and trial quality. Attempts were made to contact the authors of the included abstract. Data on the number of patients experiencing loss of viral suppression were abstracted by two reviewers. The data were pooled, where appropriate, to yield odds ratios, using random effects models. MAIN RESULTS: Four trials were identified including three published studies and one abstract. Compared to three- or four-drug maintenance therapy, maintenance therapies including fewer drugs were associated with a higher risk of virologic failure (loss of HIV suppression to non-detectable levels). Combining the results of all four studies yielded an odds ratio of 5.55 (95% confidence interval, 3.14 - 9.80). Similar results were obtained when the one abstract was excluded (odds ratio, 5.48; 95% confidence interval, 2.82 - 10.65). Performing subgroup analyses of studies using similar induction and maintenance regimens gave similar results. Maintenance regimens of zidovudine and lamivudine compared to maintenance regimens with zidovudine, lamivudine and indinavir, were associated with significantly higher rates of virologic failure (odds ratio, 4.57; 95% confidence interval, 1.80 - 11.58). Similarly, maintenance regimens that discontinued one or more protease inhibitor after including them in induction therapy were also associated with a significantly higher risk of virologic failure (odds ratio, 6.15; 95% confidence interval, 3.40 -11.10). REVIEWER'S CONCLUSIONS: Although it is desirable to reduce the number of antiretroviral drugs given in combination therapy for reasons of compliance and toxicity, maintenance regimens with fewer drugs are associated with significantly increased resistance and risk of loss of viral suppression. Successful initial therapy, as evidenced by suppression of viral load, should not be modified in the maintenance phase unless clinically necessary.