Paul M. O'Malley

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

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.

The Prevention of Hepatitis B with Vaccine: Report of the Centers for Disease Control Multi-Center Efficacy Trial Among 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.

Long-term HIV-1 infection without immunologic progression.

Objective:To identify and describe a subgroup of men infected with HIV for 10–15 years without immunologic progression, and to evaluate the effect of sexually transmitted diseases (STD) and recreational drug use on delayed HIV disease progression. Design: Inception cohort study. Setting: Municipal STD clinic. Participants:A total of 588 men with well documented dates of HIV seroconversion and 197 HIV-seronegative controls. Main outcome measures:AIDS, CD4+ count, rate of CD4+ cell loss, CD8+ count, β2-microglobulin, complete blood count, p24 antigen and HIV-related symptoms. Results:Of 588 men, 69% had developed AIDS by 14 years after HIV seroconversion (95% confidence interval, 64–73%). Of 539 men with HIV seroconversion dates prior to 1983, 42 men (8%) were healthy long-term HIV-positives (HLP), HIV-infected > 10 years without AIDS and with CD4+ counts >500 × 106/l. When compared with progressors (men with HIV seroconversion prior to 1983 but with AIDS or CD4+ counts <200 × 106/l, HLP had a significantly slower rate of CD4+ decline (6 versus 85x106/l cells/year), and less abnormal immunologic, hematologic and clinical parameters. However, when compared with HIV-uninfected controls, HLP demonstrated lower CD4+ counts and mild hematologic abnormalities. There were no consistent differences between HLP and progressors in prior exposure to recreational drugs or STD. Conclusion:There are individuals with long-term HIV infection who appear clinically and immunologically healthy 10–15 years after HIV seroconversion, with stable CD4+ counts. Lack of exposure to STD or recreational drugs does not appear to explain the delayed course of disease progression in HLP.

Combination Antiretroviral Therapy and Recent Declines in AIDS Incidence and Mortality

The reasons for recent declines in AIDS incidence and mortality may include advances in treatment, but these may be confounded by earlier declines in the incidence of human immunodeficiency virus (HIV) infection. To determine whether the declines in AIDS and mortality may, in part, stem from wider use of combination antiretroviral therapy, 622 HIV-positive men with well-characterized dates of seroconversion were followed. In this group, combination therapy came into widespread use in only 1996. In a Cox proportional hazards model, the 1996 calendar period was significantly associated with slower progression to AIDS (relative hazard [RH]=0. 19, 95% confidence interval [CI], 0.05-0.69, P=.01) and death (RH=0. 45, 95% CI, 0.21-0.95, P=.04). Declines in incidence of HIV infection, changes in HIV virulence, and end-point underreporting cannot fully explain the decline in AIDS and death in 1996. The introduction of combination antiretroviral therapy as the standard of care may already have had measurable effects.

Course of HIV-I infection in a cohort of homosexual and bisexual men: An 11 year follow up study

OBJECTIVE--To characterise the natural history of sexually transmitted HIV-I infection in homosexual and bisexual men. DESIGN--Cohort study. SETTING--San Francisco municipal sexually transmitted disease clinic. PATIENTS--Cohort included 6705 homosexual and bisexual men originally recruited from 1978 to 1980 for studies of sexually transmitted hepatitis B. This analysis is of 489 cohort members who were either HIV-I seropositive on entry into the cohort (n = 312) or seroconverted during the study period and had less than or equal to 24 months between the dates of their last seronegative and first seropositive specimens (n = 177). A subset of 442 of these men was examined in 1988 or 1989 or had been reported to have developed AIDS. MAIN OUTCOME MEASURES--Development of clinical signs and symptoms of HIV-I infection, including AIDS, AIDS related complex, asymptomatic generalised lymphadenopathy, and no signs or symptoms of infection. MEASUREMENTS AND MAIN RESULTS--Of the 422 men examined in 1988 or 1989 or reported as having AIDS, 341 had been infected from 1977 to 1980; 49% (167) of these men had died of AIDS, 10% (34) were alive with AIDS, 19% (65) had AIDS related complex, 3% (10) had asymptomatic generalised lymphadenopathy, and 19% (34) had no clinical signs or symptoms of HIV-I infection. Cumulative risk of AIDS by duration of HIV-I infection was analysed for all 489 men by the Kaplan-Meier method. Of these 489 men, 226 (46%) had been diagnosed as having AIDS. We estimated that 13% of cohort members will have developed AIDS within five years of seroconversion, 51% within 10 years, and 54% within 11.1 years. CONCLUSION--Our analysis confirming the importance of duration of infection to clinical state and the high risk of AIDS after infection underscores the importance of continuing efforts both to prevent transmission of HIV-I and to develop further treatments to slow or stall the progression of HIV-I infection to AIDS.

The Acquired Immunodeficiency Syndrome in a Cohort of Homosexual Men: A Six-Year Follow-up Study

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 600/100 000. 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, two thirds of cohort members were infected with HTLV-III/LAV and almost one third developed related conditions.

Risk factors for human immunodeficiency virus (HIV) infections in homosexual men.

To clarify risk factors for infection with the human immunodeficiency virus (HIV) we selected at random 785 homosexual men who had participated in studies of hepatitis B in San Francisco in 1978-80 for a follow-up study of the acquired immunodeficiency syndrome. Although most had not been contacted in over five years, 492 (63 per cent) were located and enrolled. The 240 (67 per cent) who had developed antibodies to HIV, as measured by an enzyme-linked immunosorbent assay (ELISA), were compared with 119 who had remained seronegative. In multivariate analyses, receptive anal intercourse with ejaculation by nonsteady sexual partners, many sexual partners per month, and other indicators of high levels of sexual activity were highly associated with seroconversions. None of the sexual practices that we studied appeared to offer protection against HIV infection.

HIV seroconversion in two homosexual men after receptive oral intercourse with ejaculation: implications for counseling concerning safe sexual practices.

Seroconversion for HIV antibody occurred in two homosexual men who reported no anal intercourse for greater than or equal to 5 years and multiple episodes of receptive oral intercourse with ejaculation. Neither man reported intravenous drug use or receipt of blood products. The last antibody-negative specimen was also negative by the polymerase chain reaction and p24 antigen assays. All sexually active persons should be clearly counselled that receptive oral intercourse with ejaculation carries a potential risk of HIV transmission.

Persistent Infection with Human T-Lymphotropic Virus Type III/Lymphadenopathy-Associated Virus in Apparently Healthy Homosexual Men

A group of 14 apparently health homosexual men with serologic evidence of human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) infection were studied to determine the duration of their seropositivity, their immunologic status, and the frequency of isolation of HTLV-III/LAV from their peripheral blood. The men were selected from a larger sample of patients who attended a clinic for treatment of sexually transmitted diseases in San Francisco because they did not have acquired immunodeficiency syndrome (AIDS), signs or symptoms suggestive of the prodrome of AIDS, or laboratory evidence of anemia or leukopenia. 4 or more serum samples were available from previous clinic visits. The men ranged in age from 26-41 years, and had a median number of sexual partners in the last year of 23. The estimated duration of seropositivity ranged from 4-69 months (median, 33 months). 11 of the 14 had T-helper: T-suppressor cell ratios below 1 (the lower limit of normal), and low ratios were significantly correlated with duration of seropositivity. HTLV-III/LAV was isolated in peripheral blood samples from 8 of 12 men tested. Culture-positive and culture-negative men did not differ significantly in terms of age, presence of a palpable lymph node, T helper:T-suppressor cell ratio, or duration of seropositivity. These findings suggest that some seropositive men may remain asymptomatic for at least 5 years. However, the isolation of HTLV-III/LAV from the peripheral blood of most of these men indicates persistent infection may be common among asymptomatic seropositive men at risk for AIDS. It should be assumed that these men have the potential to transmit HTLV-III/LAV infection.

Impact of HIV infection on mortality and accuracy of AIDS reporting on death certificates.

To assess the impact of HIV infection on mortality and the accuracy of AIDS reporting on death certificates, we analyzed data from 6704 homosexual and bisexual men in the San Francisco City Clinic cohort. Identification of AIDS cases and deaths in the cohort was determined through multiple sources, including the national AIDS surveillance registry and the National Death Index. Through 1990, 1518 deaths had been reported in the cohort and 1292 death certificates obtained. Of the 1292 death certificates, 1162 were for known AIDS cases, but 9% of the AIDS cases did not have HIV infection or AIDS noted on the death certificate. Only 0.7% of the decedents had AIDS listed as a cause of death and had not been reported to AIDS surveillance. AIDS and HIV infection was the leading cause of death in the cohort, with the highest proportionate mortality ratio (85%) and standardized mortality ratio (153 in 1987), and the largest number of years of potential life lost (32,008 years). The devastating impact of HIV infection on mortality is increasing and will require continued efforts to prevent and treat HIV infection.