This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >/=18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy. These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel. This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.

Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

This paper attempts to summarize current knowledge about immune responses to vaccines that correlate with protection. Although the immune system is redundant, almost all current vaccines work through antibodies in serum or on mucosa that block infection or bacteremia/viremia and thus provide a correlate of protection. The functional characteristics of antibodies, as well as quantity, are important. Antibody may be highly correlated with protection or synergistic with other functions. Immune memory is a critical correlate: effector memory for short-incubation diseases and central memory for long-incubation diseases. Cellular immunity acts to kill or suppress intracellular pathogens and may also synergize with antibody. For some vaccines, we have no true correlates, but only useful surrogates, for an unknown protective response.

Correlates of Protection Induced by Vaccination

Cytomegalovirus establishes a lifelong latent infection following primary infection that can periodically reactivate with shedding of infectious virus. Primary infection, reactivation and reinfection during pregnancy can all lead to in utero transmission to the developing fetus. Congenital CMV infections are a major cause of permanent hearing loss and neurological impairment. In this literature review, we found that CMV infection was relatively common among women of reproductive age, with seroprevalence ranging from 45 to 100%. CMV seroprevalence tended to be highest in South America, Africa and Asia and lowest in Western Europe and United States. Within the United States, CMV seroprevalence showed substantial geographic variation as well, differing by as much as 30 percentage points between states, though differences might be explained by variation in the types of populations sampled. Worldwide, seroprevalence among non-whites tended to be 20-30 percentage points higher than that of whites (summary prevalence ratio (PR) = 1.59, 95% confidence interval (CI) = 1.57-1.61). Females generally had higher seroprevalences than males, although in most studies the differences were small (summary PR = 1.13, 95% CI = 1.11-1.14). Persons of lower socioeconomic status were more likely to be CMV seropositive (summary PR = 1.33, 95% CI = 1.32-1.35). Despite high seroprevalences in some populations, a substantial percentage of women of reproductive age are CMV seronegative and thus at risk of primary CMV infection during pregnancy. Future vaccine or educational campaigns to prevent primary infection in pregnant women may need to be tailored to suit the needs of different populations.

Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection.

Hepatitis B vaccination is the most effective measure to prevent hepatitis B virus (HBV) infection and its consequences, including cirrhosis of the liver, liver cancer, liver failure, and death. In adults, ongoing HBV transmission occurs primarily among unvaccinated persons with behavioral risks for HBV transmission (e.g., heterosexuals with multiple sex partners, injection-drug users [IDUs], and men who have sex with men [MSM]) and among household contacts and sex partners of persons with chronic HBV infection. This report, the second of a two-part statement from the Advisory Committee on Immunization Practices (ACIP), provides updated recommendations to increase hepatitis B vaccination of adults at risk for HBV infection. The first part of the ACIP statement, which provided recommendations for immunization of infants, children, and adolescents, was published previously (CDC. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices [ACIP]. Part 1: immunization of infants, children, and adolescents. MMWR 2005;54[No. RR-16]:1-33). In settings in which a high proportion of adults have risks for HBV infection (e.g., sexually transmitted disease/human immunodeficiency virus testing and treatment facilities, drug-abuse treatment and prevention settings, health-care settings targeting services to IDUs, health-care settings targeting services to MSM, and correctional facilities), ACIP recommends universal hepatitis B vaccination for all unvaccinated adults. In other primary care and specialty medical settings in which adults at risk for HBV infection receive care, health-care providers should inform all patients about the health benefits of vaccination, including risks for HBV infection and persons for whom vaccination is recommended, and vaccinate adults who report risks for HBV infection and any adults requesting protection from HBV infection. To promote vaccination in all settings, health-care providers should implement standing orders to identify adults recommended for hepatitis B vaccination and administer vaccination as part of routine clinical services, not require acknowledgment of an HBV infection risk factor for adults to receive vaccine, and use available reimbursement mechanisms to remove financial barriers to hepatitis B vaccination.

A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults.

In this review of the acquired immunodeficiency syndrome (AIDS) the authors have evaluated a total of 352 homosexual patients with AIDS or generalized lymphadenopathy managed at the University of California San Francisco (UCSF) between 1979 and 1984. Of an initial unselected group of 318 patients 124 (39%) were neurologically symptomatic and 1/3 already had their neurological complaints at the time of presentation. An additional 210 AIDS patients with neurological symptoms have been reported in the literature. Thus a total of 366 neurologically symptomatic patients with AIDS or lymphadenopathy are reviewed. Central nervous system (CNS) complications encountered in 315 patients included the following viral syndromes: subacute encephalitis (54) atypical aseptic meningitis (21) herpes simplex encephalitis (9) progressive multifocal leukoencephalopathy (6) viral myelitis (3) and varicella-zoster encephalitis (1). Non-viral infections were caused by Toxoplasma gondii (103) Cryptococcus neoformans (41) Candida albicans (6) Mycobacteria (6) Treponema pallidum (2) coccidiodomycosis (1) Mycobacterium tuberculosis (1) Aspergillus fumigatus (1) and Escherichia coli (1). Neoplasms included primary CNS lymphoma (15) systemic lymphoma with CNS involvement (12) and metastatic Kaposis sarcoma (3). Cerebrovascular complications were seen in 4 patients with hemorrhage and 5 with infarction. 5 patients in the UCSF series had multiple intracranial pathologies including 2 cases of simultaneous Toxoplasma gondii infections and primary CNS lymphoma 2 cases of coexistent Toxoplasma gondii and viral infections and 1 case of combined Toxoplasma gondii and atypical mycobacterial infection. Cranial or peripheral nerve complications seen in 51 patients included cranial nerve syndromes secondary to chronic inflammatory polyneuropathy (5) lymphoma (5) and Bells palsy (5). Peripheral nerve syndromes included chronic inflammatory polyneuropathy (5) distal symmetrical neuropathy (13) herpes zoster radiculitis (6) persistent myaligias (2) myopathy (2) and polymyositis (1). In light of the protean behavior of AIDS and the problems related to the clinical and radiological and serological diagnosis of the unusual and varied associated nervous system diseases patients with AIDS and neurological complaints require a rigorous and detailed evaluation. The authors experience suggests that biopsy of all CNS space-occupying lesions should be performed for tissue diagnosis prior to the institution of other therapies. (authors)

Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature.

To study the duration of antibody persistence and protection provided by the hepatitis B vaccine, we followed 773 homosexual men for five years after completion of vaccination. Among the 635 participants in whom antibody levels above 9.9 sample ratio units (SRU) developed after vaccination, 15 percent lost antibody altogether, and in another 27 percent, antibody levels declined below 10 SRU within five years. The extent of the maximal antibody response strongly predicted the persistence of protective antibody. Hepatitis B infection occurred in 55 men; 8 of these infections were clinically important (characterized by the presence of the hepatitis B surface antigen and elevation of liver-enzyme levels), and two of the patients became hepatitis B virus carriers. The long-term risk of hepatitis B infection was inversely related to the maximal antibody response to vaccine. Most severe infections occurred among those who responded poorly or had no response to the vaccination. The risk of late infection with hepatitis B in those with an initially adequate vaccine response increased markedly when antibody levels decreased below 10 SRU, but only 1 of 34 late infections resulted in viremia and liver inflammation. A second series of vaccinations induced a moderate antibody response in 50 percent of the subjects who initially had no response or a poor response; however, the persistence of antibody was poor. Both antibody loss and the risk of severe disease should be considered when booster-dose strategies for the hepatitis B vaccine are being designed.

https://www.nejm.org/doi/pdf/10.1056/NEJM198607243150401?listPDF=true

Long-Term Immunogenicity and Efficacy of Hepatitis B Vaccine in Homosexual Men

A randomized, double-blind, vaccine/placebo trial of the Merck 20-micrograms hepatitis B virus (HBV) vaccine was done among 1402 homosexual men attending venereal disease clinics in five American cities. Vaccination was followed by only minimal side effects. Two doses of vaccine induced antibody in 80% of vaccine recipients. A booster dose 6 months after the first dose induced antibody in 85% of recipients and markedly increased the proportion of recipients who produced high antibody titers. The incidence of HBV events was markedly less in the vaccine recipients compared to that in the placebo recipients (p = 0.0004). Between month 3 and 15 after the first dose, 56 more significant HBV events (hepatitis, or hepatitis B surface antigen positive, or both) occurred in the placebo group while only 11 occurred in the vaccine group. Ten of the 11 HBV events in the vaccine recipients occurred in hypo- or nonresponders to the vaccine. This vaccine appears to be safe, immunogenic, and efficacious in preventing infection with hepatitis B virus.

The prevention of hepatitis B with vaccine. Report of the centers for disease control multi-center efficacy trial among homosexual men.

A cohort of 6875 homosexual men initially seen at the San Francisco City Clinic between 1978 and 1980 were studied to determine the incidence and prevalence of the acquired immunodeficiency syndrome related conditions and infection with the human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). By December 1984 2.4% of the men had the syndrome; mortality attributable to the syndrome in 1984 was 600/100000. For each man with the syndrome in a representative sample of 474 cohort members seen in 1984 7.5 men had generalized lymphadenopathy 1.1 had other prodromal findings and 0.8 had hematologic abnormalities. Prevalence of serum antibodies to HTLV-III/LAV measured by an enzyme-linked immunosorbent assay increased from 4.5% in 1978 to 67.4% in 1984. Of 31 persons who were seropositive and without the syndrome between 1978 and 1980 2 developed the syndrome and 8 developed related conditions during a median follow-up of 61 months. Over a 6-year period 2/3 of cohort members were infected with HTLV-III/LAV and almost 1/3 developed elated conditions. (authors)

The acquired immunodeficiency syndrome in a cohort of homosexual men. A six-year follow-up study.

Levels of cytomegalovirus antibody (IgG and IgM) were measured and urine viral cultures were done in 237 homosexual men over a mean period of 14.1 months. The initial prevalence of cytomegalovirus IgG antibody was 86.9%. By the 9th month of follow-up, 71% of serosusceptible men had become infected with cytomegalovirus. During the study period cytomegaloviruria was noted in 32% of seropositive men. Cytomegalovirus IgM antibody was intermittently present in the serum of 95% of IgG-seropositive men, suggesting that frequent reactivation of latent infection or reexposure to exogenous virus had occurred. Of seven sexual practices investigated, only passive anal-genital intercourse correlated with the acquisition of cytomegalovirus infection (p = 0.008).

Erwin H. Braff

Papers

Long-Term Immunogenicity and Efficacy of Hepatitis B Vaccine in Homosexual Men

The prevention of hepatitis B with vaccine. Report of the centers for disease control multi-center efficacy trial among homosexual men.

The acquired immunodeficiency syndrome in a cohort of homosexual men. A six-year follow-up study.

Cytomegalovirus Infections in Homosexual Men: An Epidemiological Study