Neil M. H. Graham

Dementia in AIDS patients Incidence and risk factors

We determined incidence and future projections of dementia after AIDS onset in 492 homosexual men with AIDS in the Baltimore/Los Angeles sites of the Multicenter AIDS Cohort Study, 64 of whom developed dementia. We studied various risk factors for dementia, including demographic and clinical features, medical history, markers of immune status before AIDS, and zidovudine use. During the first 2 years after AIDS, HIV dementia developed at an annual rate of 7%. Overall, 15% of the cohort followed through death developed dementia. The median survival after dementia was 6.0 months. Using a proportional hazards model, risk factors for more rapid development of dementia were lower hemoglobin (relative hazard, 0.59 per additional 2 g/dl;p = 0.0005) and body mass index (relative hazard, 0.64 per additional 5 kg/m2; p = 0.05) 1 to 6 months before AIDS, more constitutional symptoms 7 to 12 months before AIDS (relative hazard, 1.68 per additional symptom, p = 0.005), and older age at AIDS onset (relative hazard, 1.60 per decade older; p = 0.009). In a multivariate model, pre-AIDS hemoglobin remained the most significant predictor of dementia. There were no significant risks defined from demographic characteristics, specific AIDS-defining illnesses, zidovudine use before AIDS, or CD4+ lymphocyte count before AIDS. We project that 12 months after the first AIDS diagnosis, 7.1% of survivors will have dementia. The observed association between anemia, low weight, constitutional symptoms, and dementia suggests a role for cytokines inducing both systemic and neurologic disease.

Potential factors affecting adherence with HIV therapy

A greatly increased level and duration of suppression of HIV replication has become possible with the use of protease inhibitors in combination with nucleoside analogues as antiretroviral therapy [1,2]. The long-term effectiveness of protease inhibitors, and other antiretroviral medications, is dependent upon strict adherence to the prescribed regimen, since HIV resistance to these drugs can develop with subtherapeutic doses [3,4]. Consequences of poor adherence include not only diminished outcome for the patient, but also the public health threat of multidrug-resistant HIV, and widespread transmission of drug-resistant virus, similar to that seen with multidrug-resistant tuberculosis [5].

The Effects on Survival of Early Treatment of Human Immunodeficiency Virus Infection

BACKGROUND Zidovudine has been shown to prolong survival in patients with the acquired immunodeficiency syndrome (AIDS) and, in persons with human immunodeficiency virus (HIV) infection but not AIDS, to delay the progression to AIDS. However, it is still uncertain whether treatment before the development of AIDS prolongs survival. METHODS We analyzed data from a cohort of 2162 high-risk men who were already seropositive for HIV type 1 (HIV-1) and 406 men who seroconverted from October 1986 through April 1991. There were 306 deaths. The probabilities of death were compared among men at similar stages of disease who began zidovudine therapy before the diagnosis of AIDS and among those who did not. Relative risks of death were calculated for each of five initial disease states on the basis of CD4+ cell counts and clinical symptoms and signs appearing over follow-up periods of 6, 12, 18, and 24 months. Adjustments were also made for the use of prophylaxis against Pneumocystis carinii pneumonia (PCP). RESULTS After we controlled for CD4+ cell count and symptoms, the use of zidovudine with or without PCP prophylaxis before the development of AIDS significantly reduced mortality in all follow-up periods. The relative risks of death were 0.43 (95 percent confidence interval, 0.23 to 0.78) at 6 months, 0.54 (95 percent confidence interval, 0.38 to 0.78) at 12 months, 0.59 (95 percent confidence interval, 0.44 to 0.79) at 18 months, and 0.67 (95 percent confidence interval, 0.52 to 0.86) at 24 months. After we adjusted for the effects of PCP prophylaxis, zidovudine alone significantly reduced mortality at 6, 12, and 18 months (relative risks, 0.45, 0.59, and 0.70, respectively), but not at 24 months (relative risk, 0.81). Among zidovudine users, those who also used PCP prophylaxis before the development of AIDS had significantly lower mortality at 18 and 24 months than those who did not (relative risks, 0.62 and 0.60, respectively). CONCLUSIONS The results of this study support the hypothesis that in HIV-1 infection, early treatment with zidovudine and PCP prophylaxis improves survival in addition to slowing the progression to AIDS.

Association between serum vitamin A and E levels and HIV-1 disease progression

Objective:To examine the associations between serum vitamin A and E levels and risk of progression to three key outcomes in HIV-1 infection: first AIDS diagnosis, CD4+ cell decline to < 200 cells × 106/l, and mortality. Design:Non-concurrent prospective study. Methods:Serum levels of vitamins A and E were measured at the enrollment visit of 311 HIV-seroprevalent homo-/bisexual men participating in the Baltimore/Washington DC site of the Multicenter AIDS Cohort Study. Cox proportional hazards models were used to estimate the relative hazard of progression to each outcome over the subsequent 9 years, adjusting for several independent covariates. Results:Men in the highest quartile of serum vitamin E levels (≥ 23.5 µmol/l) showed a 34% decrease in risk of progression to AIDS compared with those in the lowest quartile [relative hazard (RH), 0.66; 95% confidence interval (CI), 0.41–1.06)]. This effect was statistically significant when comparing the highest quartile of serum vitamin E to the remainder of the cohort (RH, 0.67; 95% CI, 0.45–0.98). Associations between serum vitamin A levels and risk of progression to AIDS were less clear, but vitamin A levels were uniformly in the normal to high range (median = 2.44 µmol/l). Similar trends were observed for each vitamin with mortality as the outcome, but neither vitamin was associated with CD4+ cell decline to < 200 cells × 106/l. Men who reported current use of multivitamin or single vitamin E supplements had significantly higher serum tocopherol levels than those who were not taking supplements (P = 0.0001). Serum retinol levels were unrelated to intake of multivitamin or single vitamin A supplements. Conclusions:These data suggest that high serum levels of vitamin E may be associated with slower HIV-1 disease progression, but no relationship was observed between retinol levels and disease progression in this vitamin A-replete population.

A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy

Objective To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response. Design A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States. Participants A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor. Interventions Randomization was to antiretroviral therapy guided by PRT or SOC. Main outcome measures The percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of ‘active’ (less than fourfold resistance) antiretroviral agents used (secondary). Results At week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P = 0.036, ITT observed;P = 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P = 0.005 for 400 copies/ml;P = 0.049 for 50 copies/ml assay detection limit). Significantly more subjects in the PRT arm were treated with two or more ‘active’ antiretroviral agents than in the SOC arm (P = 0.003). Conclusion Antiretroviral treatment guided prospectively by PRT led to the increased use of ‘active’ antiretroviral agents and was associated with a significantly better virological response.

Weight Loss Prior to Clinical Aids as a Predictor of Survival

In this analysis the aim was to determine the independent effect of moderate to severe weight loss prior to an AIDS diagnosis on survival after AIDS. The study was conducted as part of the Multicenter AIDS Cohort Study (MACS), a longitudinal study of HIV-1-seropositive gay or bisexual men. Measured weight and self-reported weight loss data were collected semiannually from 1984 through 1993. The study population included 962 HIV-1-seropositive men who developed clinical AIDS during the follow-up period. Median survival after AIDS was significantly lower for men with measured weight loss of > or = 4.5 kg 3-9 months and 3-15 months prior to AIDS, or who had lost > 10% of their baseline body weight compared with men with less weight loss or weight gain. Men with self-reported unintentional weight loss of > or = 4.5 kg 3-9 months prior to AIDS had significantly poorer survival (median = 1.05 years vs. 1.48 years; p = 0.0001) compared with men not reporting weight loss. After adjusting for potential confounding factors, men in the high measured weight loss group 3-9 months prior to AIDS still had significantly poorer survival [relative hazard (RH) = 1.36; p = 0.02]. Similar trends were seen for the two longer intervals prior to AIDS (RH = 1.38, p = 0.01; and RH = 1.50, p = 0.02, respectively). Men who self-reported weight loss > or = 4.5 kg 3-9 months prior to AIDS also had significantly poorer survival after AIDS (RH = 1.43; p = 0.002) in multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of zidovudine and Pneumocystis carinii pneumonia prophylaxis on progression of HIV-1 infection to AIDS

Although used widely, the effectiveness of zidovudine therapy and primary prophylaxis for Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals, has not been assessed in a large cohort. We have done an observational study between October, 1986, and October, 1990, of a cohort of 2145 HIV-1-seropositive men and 371 who seroconverted during the study. A Markov chain transitional analysis was used to examine the effect of zidovudine and PCP prophylaxis on the probability of progression of HIV-1 infection to AIDS (after 6, 12, 18, and 24 months) after follow-up visits categorised into one of six disease states. The six starting states were based on CD4+ lymphocyte counts and the presence of HIV-related symptoms. Use of pre-AIDS zidovudine and PCP prophylaxis was associated with significant reductions in rates of progression to AIDS at 6, 12, 18, and 24 months for participants starting with less than 350 CD4+ lymphocytes/microliter. For those starting with 350 or more CD4+ lymphocytes/microliter, non-significant protective trends were seen during 12, 18, and 24 month intervals. In multivariate log-linear models virtually all the treatment effect was due to zidovudine. However, after adjusting for the effects of zidovudine, PCP prophylaxis reduced significantly the probability of progression to a first episode of PCP during 6, 12, 18, and 24 month intervals. This study suggests that early primary PCP prophylaxis is effective in preventing first episodes of PCP, and that the efficacy of zidovudine demonstrated in clinical trials can be translated to the population level.

HIV-1 Coreceptor Use in Triple-Class Treatment–Experienced Patients: Baseline Prevalence, Correlates, and Relationship to Enfuvirtide Response

OBJECTIVE We wished to assess, in heavily treatment-experienced patients, the prevalence of and baseline characteristics associated with HIV-1 coreceptor use and their relationship to responses to enfuvirtide treatment. METHODS Samples were obtained from participants in phase 3 studies of enfuvirtide. Multiple logistic regression and analysis of covariance were performed on data for baseline coreceptor use, virological and immunological response, and changes in coreceptor use during treatment. RESULTS Baseline envelopes were phenotyped for 724 patients; 50% harbored R5 strains, 48% harbored dual/mixed (D/M) strains, and 2% harbored X4 strains. D/M strains were associated with significantly lower CD4(+) cell counts but comparable viral loads, compared with R5 strains (P=.0005). Virological and immunological responses to enfuvirtide-based treatment showed no correlation with baseline coreceptor use. Changes in virus tropism from D/M to R5 strains during treatment were common, particularly in patients who received enfuvirtide (27%, vs. 14% who received no enfuvirtide; P<.05). CONCLUSION At baseline, D/M strains were associated with lower CD4(+) cell counts but similar viral loads, compared with R5 strains, and were common across CD4(+) cell count strata. The comparable virological and immunological responses and bias toward shifts from D/M to R5 strains in patients who received enfuvirtide support its use in triple-class treatment-experienced patients and its study as a therapeutic partner for coreceptor-binding inhibitors.

Health services use by urban women with or at risk for HIV-1 infection: the HIV Epidemiology Research Study (HERS).

OBJECTIVE To characterize health services use by urban women with or at risk for HIV-1 infection enrolled in a prospective multicenter study. METHODS 1310 women 16 to 55 years of age who were at risk for HIV-1 infection were recruited between April 1993 and January 1995 at four urban centers (Baltimore, Maryland; The Bronx, New York; Detroit, Michigan; and Providence, Rhode Island). HIV-1-seropositive women without AIDS-defining illness were oversampled in a ratio of 2:1 in comparison with HIV-1-seronegative women. At a baseline study visit, the women received physical and laboratory examinations, including CD4+ counts, and were interviewed regarding HIV risk behavior, health services use, and clinical data. RESULTS 863 women were HIV-1-seropositive and 430 were HIV-1-seronegative. Fifty-two percent of the women reported injection drug use (IDU) since 1985, and 48% acquired HIV through sexual contact. Seventy-seven percent were African American, 23% were white, and 16% were Hispanic. The median age was 35 years. HIV-seronegative women were significantly less likely to have health insurance (19%) than were HIV-seropositive women (30%; p < .001). Among the HIV-seropositive women, 68% had CD4+ cell counts of <500/microl, and 64% were asymptomatic. Sixty-four percent of the HIV-seronegative women had had an outpatient hospital visit in the past 6 months, as had 86% of HIV-seropositive women (p < 0.001). Hospitalization in the past 6 months was also higher in HIV-seropositive women (22% vs. 12%; p < .001). Despite heavy use of health services, only 49% of women with CD4+ counts of <200/microl reported current use of antiretroviral therapy, and only 58% reported current use of Pneumocystis carinii pneumonia (PCP) prophylaxis. Among HIV-seropositive women, and after adjusting for CD4+ count, HIV symptoms, race, and study site, IDUs were significantly less likely to have a regular doctor and a recent outpatient visit and more likely to be hospitalized and use the emergency department (ED) than were non-IDUs. In multivariate analyses of HIV-seropositive persons, African American women had similar access to care and use of antiretroviral therapy and PCP prophylaxis than did white women but were less likely to have an outpatient department visit in the previous 6 months and to be taking PCP and opportunistic infection (OI) prophylaxis. Health services access and use of HIV-related therapies did not significantly differ between Hispanic and white women with HIV infection. CONCLUSION Although both HIV-seropositive and HIV-seronegative women had high levels of use of medical services, current use of antiretrovirals and OI prophylaxis was low throughout, and IDUs used HIV-related primary health services less and were more likely to receive emergency or episodic care. IDU and African American race were independently associated with decreased use of medical services.

Antibody Responses to Haemophilus influenzae Type b Vaccines in Men with Human Immunodeficiency Virus Infection

BACKGROUND Persons with human immunodeficiency virus (HIV) infection are at increased risk for serious infections caused by Haemophilus influenzae, yet there are few data on their antibody responses to the H. influenzae type b vaccines. METHODS We evaluated antibody responses in 248 men who were randomly assigned to receive a single dose of either the H. influenzae type b polysaccharide (PRP) vaccine or the polysaccharide-mutant diphtheria toxoid conjugate vaccine (PRP-CRM). The subjects were stratified into four groups: seronegative men (67 subjects), men with asymptomatic HIV infection (79), men with symptomatic HIV infection (47), and men with the acquired immunodeficiency syndrome (AIDS) (55). RESULTS Before immunization, the subjects with AIDS had the lowest PRP-antibody titers; 40 percent had titers below the putative protective level (less than 0.15 micrograms per milliliter). In the seronegative subjects, those with asymptomatic HIV infection, and those with symptomatic HIV infection, the PRP-CRM vaccine led to a threefold greater increase in geometric mean antibody titers than did the PRP vaccine (P less than 0.01). However, the subjects with AIDS had a greater antibody response to the PRP vaccine. The antibody response of HIV-seropositive men to the PRP-CRM vaccine correlated significantly with the number of CD4 lymphocytes (r = 0.47, P less than 0.0001, as compared with r = -0.01 for the PRP vaccine). In these HIV-infected men, both vaccines elicited the dominant anti-PRP idiotype described previously in populations not infected with HIV. CONCLUSIONS Immunization with the PRP-CRM conjugate vaccine early in the course of HIV infection is likely to confer protection against disease caused by H. influenzae type b.