Thinh N. Le

Higher socioeconomic status is associated with slower progression of HIV infection independent of access to health care

In order to identify socioeconomic characteristics associated with slower progression of HIV infection, we conducted a nested case-control study within a cohort of 729 homosexual men. The study compared non-progressors (defined as subjects who, at a follow-up visit during the period October 1989-December 1990, had been HIV positive for at least 5 years, had a CD4 count > 0.5 x 10(9)/l, had a Karnofsky score of 100%, were at Centers for Disease Control (CDC) Stage III or less, and had never received zidovudine or prophylaxis against Pneumocystis carinii pneumonia) with rapid progressors (defined as those who had developed AIDS other than Kaposis sarcoma within 6 years of seroconversion, or within 5 years of enrollment if already seropositive). Rapidly progressing subjects were matched to non-progressing subjects on the basis of date of enrollment if seroprevalent and date of seroconversion if seroincident. Socioeconomic data were taken from the questionnaire obtained at enrollment into the cohort during 1982-84. There were 41 subjects in each group. A significantly higher proportion of the non-progressors had annual incomes above

Progression to AIDS and predictors of AIDS in seroprevalent and seroincident cohorts of homosexual men.

10,000, at enrollment (85 vs 62%; p = 0.019). Similarly, a greater proportion of the non-progressors were more likely to have finished secondary school (100 vs 84%; p = 0.020) than rapid progressors. A higher proportion of non-progressors reported employment in management and professional positions (35 vs 15%). The non-progressing group also had a significantly higher socioeconomic index based on self-reported occupation (45.1 vs 38.3; p = 0.035). The association with higher income persisted even after adjustment for baseline CD4 count and symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for a sexually transmitted cofactor for AIDS-related Kaposi's sarcoma in a cohort of homosexual men.

As part of an ongoing prospective study of seropositive homosexual men in Vancouver, Canada, a seroprevalent cohort of 246 subjects (i.e. duration of infection unknown) and a seroincident cohort of 102 subjects (i.e. duration of infection known) were followed a median of 63 and 45 months, respectively. Follow-up with validation utilizing record linkage with the Canadian Federal Centre for AIDS registry revealed 58 and nine cases of AIDS in the seroprevalent and seroincident cohorts, respectively, through July 1988. These data yield product limit estimates of the cumulative progression rates to AIDS at 60 months of 23.0% for the seroprevalent cohort, 13.0% for the seroincident cohort, and 21.0% for the combined groups. Univariate analyses revealed the following to be statistically and clinically significant predictors of AIDS progression: low CD4 counts, low CD4/CD8 ratios, elevated immune complexes, elevated immunoglobulin G (IgG) and immunoglobulin A (IgA) levels, and low platelet counts. Cox regression revealed that elevated IgA levels, low CD4 counts, elevated immune complexes, two or more symptoms, and more than 20 male sexual partners in high-risk areas in the 5 years prior to enrollment were independent predictors of progression to AIDS over the subsequent 5 years. A multivariate risk function based on the latter five variables delineated low-, medium- and high-risk groups whose 5-year progression rates to AIDS were 6.7, 15.6 and 64.4%, respectively. The high-risk group contained 75% of all subjects who progressed to AIDS. Only 6% of the high-risk group would have qualified for zidovudine therapy under current guidelines at the beginning of the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

The changing spectrum of AIDS index diseases in Canada

We examined factors associated with the subsequent development of AIDS-related Kaposis sarcoma in a cohort of 353 homosexual men infected with human immunodeficiency virus (HIV). Cumulative incidence curves for the development of Kaposis sarcoma and opportunistic infection were stratified over a wide range of variables at enrollment, including those related to demographics, sexual behavior, illicit drug use, and medical history. We found no strong associations between any of these variables and the development of opportunistic infection, but two were related to Kaposis sarcoma: use of nitrite inhalants (relative risk, 2.3; 95% confidence interval, 1.0-5.0) and high numbers of sexual contacts during the period 1978-1982 in the AIDS epidemic centers of San Francisco, Los Angeles, and/or New York (relative risk, 3.5; 95% confidence interval, 1.6-7.6). The latter variables remained independently associated with risk of Kaposis sarcoma even after multivariate adjustment for a number of classical HIV risk factors. These results are consistent with the hypothesis that Kaposis sarcoma is caused by a sexually transmitted cofactor that has remained more prevalent in the original epidemic centers. The effect of nitrites could be due to an independent biological mechanism or to enhancement of transmission of the cofactor. (Epidemiology 1992;3:203-209)

Susceptibility to AIDS progression appears early in HIV infection.

ObjectiveTo describe the changing spectrum of AIDS index diseases in Canada over a 10-year period from 1981 to 1991. DesignA descriptive, population-based study. SettingCanada. PatientsAll cases of AIDS in Canada reported by the Division of HIV/AIDS Epidemiology of the Department of National Health and Welfare. Main outcome measuresAge-standardized rates of initial AIDS manifestations (1987 Centers for Disease Control and Prevention case definition), by year of diagnosis among adults in Canada. ResultsA total of 6641 adult AIDS cases were examined. The rate of Pneumocystis carinii pneumonia (PCP) peaked in 1989 with a rate of 3.18 per 100000, declining to 2.74 per 100000 in 1991 (P= 0.894). Similarly, the rate of Kaposis sarcoma (KS) stabilized during this interval from 1.06 per 100 000 in 1987 to 1.14 per 100000 in 1991 (P=0.189). In contrast, the rates of all other AIDS-defining illnesses increased from 1.48 per 100 000 in 1987 to 3.43 per 100000 in 1991 (P= 0.001). For these other AIDS index diseases, significant rate increases were observed for esophageal candidiasis, cytomegalovirus (CMV) diseases, wasting syndrome, toxoplasmosis, and Mycobacterium avium complex (MAC) disease. ConclusionsOur study shows a leveling and decline in incidence of KS and PCP, respectively, and a concomitant increase of other diagnoses, especially esophageal candidiasis, CMV, wasting syndrome, toxoplasmosis, and MAC disease in Canada. These findings highlight the importance of developing specific strategies to prevent emerging AIDS index diseases and serve as a cautionary note to practicing clinicians, indicating the relative widening of the spectrum of HIV index diseases.

HIV-1 and the aetiology of AIDS

To investigate whether predictors of AIDS progression are operative very early in the natural history of HIV infection, we conducted a nested case-control study within a cohort of 119 subjects who seroconverted while under observation in a prospective study of homosexual men. For each of the 18 cases who have progressed to AIDS, we randomly Selected three controls who had seroconverted within 3 months of the case but who have remained AIDS-free. Cases and controls were compared with regard to laboratory and clinical parameters obtained at the time of the earliest HIV-positive result. The median duration between the estimated date of seroconversion and this first positive result was 4 months for cases and 6 months for controls. Cases exhibited lower CD4 counts (657 versus 774 × 106/I; P = 0.037), lower CD4:CD8 ratios (0.98 versus 1.39; P = 0.003), higher immune complex levels (C1q binding: 25 versus 15%; P = 0.002), lower hemaglobin concentrations (14.8 versus 15.2 g/l; P = 0.011), higher immunoglobulin (lg) A levels (272 versus 184mg/dl; P = 0.003), and higher lgG levels (1530 versus 1300mg/dl; P = 0.037) than controls. Cases exhibited higher CD8 counts of marginal statistical significance (732 versus 597 × 1.06/I; P = 0.059). No differences were observed with respect to lgM levels, total lymphocyte or white blood cell counts, or the frequency of generalized lymphadenopathy. A total of 27.8% of cases but only 11.5% of controls reported one or more symptoms during the 6-month period preceding the first positive visit (P = 0.027). We conclude that laboratory and clinical abnormalities which are predictive of more rapid progression to AIDS may appear very early in HIV infection. This suggests that some of the factors responsible for more rapid disease progression are present in the host prior to or shortly after infection occurs.

Application of the World Health Organization system for HIV infection in a cohort of homosexual men in developing a prognostically meaningful staging system.

The belief that HIV-1 infection causes AIDs has been questioned, and the suggestion made that to know the correct cause of AIDS the incidence of disease in patients with and without risk behaviours and with and without antibody to HIV-1 must be known. We describe findings in such a cohort. In 715 homosexual men followed for a median of 8.6 years, all 136 AIDS cases occurred in the 365 individuals with pre-existing HIV-1 antibody. Most men negative for HIV-1 antibody reported risk behaviours but none developed any AIDS illnesses. CD4 counts fell in anti-HIV-1-positive men but remained stable in antibody-negative men, whether or not risk behaviours were present. The hypothesis that AIDS in homosexual men is caused not by HIV-1 infection but by drugs and sexual activity is rejected by these data. HIV-1 has an integral role in the pathogenesis of AIDS.

Low Hiv-1 proviral Dna burden detected by negative polymerase chain reaction in seropositive individuals correlates with slower disease progression

ObjectiveValidation of a modified version of the recently proposed World Health Organization (WHO) staging system for HIV infection and disease in a cohort of homosexual men. MethodsFive hundred and thirty HIV-positive men followed for a median of 51 months (range, 1–98 months) were eligible for analysis. Subjects were classified into stages at their first seropositive visit and at all subsequent visits. ResultsAs of 1 April 1991, 136 subjects (26%) had progressed to stage IV of the modified WHO system on the basis of their CD4 lymphocyte counts, and 78 subjects (15%) had died. Kaplan-Meier estimates for progression to stage IV from stages I, II and III were 52.8 ± 7.5% over 6.6 years, 58.1 ± 7.1% over 5.9 years and 66.5 ± 9.7% over 5.7 years (log-rank P = 0.0001). Estimated median times to stage IV were 6.4, 5.3 and 3.8 years from stages I, II and III, respectively. Estimated median times to death were 10.9, 8.2, 6.3 and 1.7 years from stages I to IV, respectively. Results remained unchanged when CD4 lymphocyte count was replaced with lymphocyte count in the laboratory axis of the staging system. ConclusionsThe proposed staging scheme, based on the WHO system, provides a prognostically meaningful classification for HIV infection in a cohort of homosexual men. Furthermore, the use of absolute lymphocyte count as a valid alternative for CD4 lymphocyte count has implications for the applicability of this system in many parts of the world where diagnostic resources are limited.

Canadian multicenter azidothymidine trial : AZT pharmacokinetics

During 1989, 316 members of a cohort of homosexual men were tested for HIV-specific DNA by the polymerase chain reaction (PCR) using a pair of gag-region primers. Of 125 HIV-seronegative subjects, 123 (98.4%) were PCR-negative while 158 (82.7%) of 191 HIV-seropositive subjects were PCR-positive. Fewer of the 33 subjects who were seropositive and PCR-negative were at Centers for Disease Control (CDC) stage IV than the seropositive, PCR-positive subjects (6 versus 25%; P = 0.030). The seropositive, PCR-negative group had higher median CD4 counts (640 versus 490 ± 106 cells/I; P = 0.006), higher CD4: CD8 ratios (0.92 versus 0.64; P = 0.004), lower immunoglobulin (Ig) G levels (1290 versus 1645 mg/dl; P = 0.002), lower IgA levels (168 versus 251 mg/dl; P < 0.001), and lower C1q binding activity (8 versus 14%; P = 0.010) than the seropositive, PCR-positive subjects. The median rate of CD4 cell decline in the 3 years preceding the PCR sample was less marked in the seropositive, PCR-negative group than the seropositive, PCR-positive group (—58 versus — 77 ± 106 cells/I per year; P = 0.028). To control for duration of infection, we restricted the analysis to the subgroups of 11 seropositive, PCR-negative subjects and 34 seropositive, PCR-positive subjects who had seroconverted earlier in the cohort study. Both subgroups had similar durations of infection, yet the same pattern of differences persisted. Moreover, despite a median of 51 months since seroconversion, the seropositive, PCR-negative subgroup had CD4 counts and antecedent rates of CD4 cell decline that were similar to those of the 123 seronegative, PCR-negative homosexual controls who were not infected with HIV. We conclude that PCR can identify a group of HIV-infected people with very low levels of proviral DNA who demonstrate slower progression of the effects of HIV.

Oral corticosteroids in patients with mild Pneumocystis carinii pneumonia and the acquired immune deficiency syndrome (AIDS)

Summary:The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early, asymptomatic human immunodeficiency virus (HlV)-infected individuals. The study design was a multicenter, prospective, descriptive single-dose pharmacokinetic study. Each of 66 fasting, male, HIV-infected homosexuals older than 18 years of age and in CDC classifications II, III, and IVC2 received a single 400-mg oral dose of AZT with subsequent pharmacokinetic measurements performed during an 8-h period for AZT and its major metabolite, glucuronylazidothymidine (GAZT). Results were obtained in 65 patients (36 smokers, 29 nonsmokers), of whom 3 were noted to have hepatic dysfunction. In those with normal hepatic function, the following parameters were described: AZT, area under the curve (AUC) ± SD, 9.9 ± 5.7 μ.M.h, maximum concentration (Cmax) ± SD, 7.3 ± 4.7 μ.M; time to maximum concentration (Tmax) ± SD, 0.93 ± 0.42 h, and half-life (t1/2) ± SD, 1.0 ± 0.8 h. Corresponding values for GAZT were: AUC ± SD 35.7 ± 10.3 μM.h, Cmax ± SD 21.3 ± 7.3 μ.M, Tmax ± SD 1.2 ± 0.50 h, t1/2 ± SD 0.98 ± 0.62 h, No significant differences were found in comparisons of study site, CDC classification of disease, smokers versus nonsmokers, and in patients with hepatic dysfunction, although a higher AUC and earlier Cmax for AZT was noted in the latter group. It is concluded that AZT pharmacokinetics are similar in patients with early asymptomtic HIV disease when compared with previous reports in patients with later disease. This study finds no difference in pharmacokinetics of AZT in smokers versus nonsmokers and suggests a trend to a decreased presystemic elimination in patients with hepatic dysfunction.