Daniel W. Fitzgerald

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.

BACKGROUND Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. METHODS We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. FINDINGS In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men. INTERPRETATION This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.

Early Versus Standard Antiretroviral Therapy for HIV Infected Adults in Haiti

BACKGROUND For adults with human immunodeficiency virus (HIV) infection who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter and who live in areas with limited resources, the optimal time to initiate antiretroviral therapy remains uncertain. METHODS We conducted a randomized, open-label trial of early initiation of antiretroviral therapy, as compared with the standard timing for initiation of therapy, among HIV-infected adults in Haiti who had a confirmed CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter at baseline and no history of an acquired immunodeficiency syndrome (AIDS) illness. The primary study end point was survival. The early-treatment group began taking zidovudine, lamivudine, and efavirenz therapy within 2 weeks after enrollment. The standard-treatment group started the same regimen of antiretroviral therapy when their CD4+ T-cell count fell to 200 per cubic millimeter or less or when clinical AIDS developed. Participants in both groups underwent monthly follow-up assessments and received isoniazid and trimethoprim-sulfamethoxazole prophylaxis with nutritional support. RESULTS Between 2005 and 2008, a total of 816 participants--408 per group--were enrolled and were followed for a median of 21 months. The CD4+ T-cell count at enrollment was approximately 280 per cubic millimeter in both groups. There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P=0.001). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P=0.01). CONCLUSIONS Early initiation of antiretroviral therapy decreased the rates of death and incident tuberculosis. Access to antiretroviral therapy should be expanded to include all HIV-infected adults who have CD4+ T-cell counts of less than 350 per cubic millimeter, including those who live in areas with limited resources. (ClinicalTrials.gov number, NCT00120510.)

Time from HIV seroconversion to death: a collaborative analysis of eight studies in six low and middle-income countries before highly active antiretroviral therapy.

Objectives:To estimate survival patterns after HIV infection in adults in low and middle-income countries. Design:An analysis of pooled data from eight different studies in six countries. Methods:HIV seroconverters were included from eight studies (three population-based, two occupational, and three clinic cohorts) if they were at least 15 years of age, and had no more than 4 years between the last HIV-negative and subsequent HIV-positive test. Four strata were defined: East African cohorts; South African miners cohort; Thai cohorts; Haitian clinic cohort. Kaplan–Meier functions were used to estimate survival patterns, and Weibull distributions were used to model and extend survival estimates. Analyses examined the effect of site, age, and sex on survival. Results:From 3823 eligible seroconverters, 1079 deaths were observed in 19 671 person-years of follow-up. Survival times varied by age and by study site. Adjusting to age 25–29 years at seroconversion, the median survival was longer in South African miners: 11.6 years [95% confidence interval (CI) 9.8–13.7] and East African cohorts: 11.1 years (95% CI 8.7–14.2) than in Haiti: 8.3 years (95% CI 3.2–21.4) and Thailand: 7.5 years (95% CI 5.4–10.4). Survival was similar for men and women, after adjustment for age at seroconversion and site. Conclusion:Without antiretroviral therapy, overall survival after HIV infection in African cohorts was similar to survival in high-income countries, with a similar pattern of faster progression at older ages at seroconversion. Survival appears to be significantly worse in Thailand where other, unmeasured factors may affect progression.

Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial

BACKGROUND Patients with HIV-1 infection respond well to treatment for active tuberculosis, but whether such patients are at increased risk of disease recurrence after complete cure is uncertain. We did a randomised trial in Port au Prince, Haiti, to determine whether recurrent tuberculosis after curative tuberculosis treatment is more common in HIV-1-infected individuals than HIV-1-uninfected individuals, and to determine whether post-treatment isoniazid prophylaxis decreases the risk of recurrent tuberculosis. METHODS Patients older than 18 years who were diagnosed with a first episode of tuberculosis at the national HIV testing centre in Haiti, and who successfully completed a 6-month rifampicin-containing regimen for active pulmonary tuberculosis, were randomly assigned 1 year of post-treatment isoniazid prophylaxis or placebo. The primary outcome measure was rate of recurrent tuberculosis after at least 24 months. An intention-to-treat analysis was used. FINDINGS Of 354 patients with active pulmonary tuberculosis, 274 successfully completed treatment, and 233 were randomised. Of 142 HIV-1-positive patients, 68 were assigned isoniazid and 74 placebo. Of 91 HIV-1-negative individuals, 51 were assigned isoniazid and 40 placebo. The rate of recurrent tuberculosis was 4.8 per 100 person-years in HIV-1-infected individuals and 0.4 per 100 person-years in uninfected individuals (relative risk 10.7 [95% CI 1.4-81.6]). Among HIV-1-positive patients receiving isoniazid, the tuberculosis recurrence rate was 1.4 per 100 person-years, and among HIV-1-positive patients receiving placebo, it was 7.8 per 100 person-years (0.18 [0.04-0.83]). Among HIV-1-positive individuals, all cases of recurrent tuberculosis occurred in individuals with a history of HIV-1-related symptoms before initial tuberculosis diagnosis. INTERPRETATION The rate of recurrent tuberculosis is higher in HIV-1-positive individuals than in HIV-1-negative individuals, and is strongly associated with a history of symptomatic HIV-1 disease before initial tuberculosis diagnosis. Post-treatment isoniazid prophylaxis decreases the risk of recurrence in HIV-1-positive individuals, and should be considered for HIV-1-positive individuals with a history of HIV-1-related symptoms at the time of tuberculosis diagnosis.

Prospective, multi-centre clinic-based evaluation of four rapid diagnostic tests for syphilis

Objectives: To evaluate prospectively four rapid, point-of-care serological tests for syphilis in prenatal or high risk populations in four countries. Methods: Tests were performed on consecutive clinic attenders, using whole blood in the clinic, and whole blood and serum in the laboratory. The sensitivity and specificity of each test was evaluated, using a standard treponemal test (Treponema pallidum haemagglutination assay (TPHA) or fluorescent treponemal antibody, absorbed (FTA-ABS) as gold standard. Non-treponemal tests (rapid plasma reagin (RPR) or venereal diseases research laboratory (VDRL) tests) were also performed on all subjects at three sites. Results: The specificity of each rapid test was >95% at each site. Sensitivities varied from 64–100% and, in most cases, were lower when whole blood was used rather than serum. Conclusions: Rapid serological tests for syphilis are an acceptable alternative to conventional laboratory tests. Since they do not require equipment or electricity, they could increase coverage of syphilis screening, and enable treatment to be given at the first clinic visit.

Improved methods and assumptions for estimation of the HIV/AIDS epidemic and its impact: Recommendations of the UNAIDS Reference Group on estimates, modelling and projections

UNAIDS and WHO produce biannual country-specific estimates of HIV/AIDS and its impact. These estimates are based on methods and assumptions that reflect the best understanding of HIV epidemiology and demography at the time. Where significant advances are made in epidemiological and demographic research, the methods and assumptions must evolve to match these advances. UNAIDS established an Epidemiology Reference Group in 1999 to advise them and other organisations on HIV epidemiology and methods for making estimates and projections of HIV/AIDS. During the meeting of the reference group in 2001, four priority areas were identified where methods and assumptions should be reviewed and perhaps modified: a) models of the HIV epidemic, b) survival of adults with HIV-1 in low and middle income countries, c) survival of children with HIV-1 in low and middle income countries, and d) methods to estimate numbers of AIDS orphans. Research and literature reviews were carried out by Reference Group members and invited specialists, prior to meetings held during 2001-2. Recommendations reflecting the consensus of the meeting participants on the four priority areas were determined at each meeting. These recommendations were followed in UNAIDS and WHO development of country-specific estimates of HIV/AIDS and its impact for end of 2001.UNAIDS and WHO produce biannual country-specific estimates of HIV/AIDS and its impact. These estimates are based on methods and assumptions that reflect the best understanding of HIV epidemiology and demography at the time. Where significant advances are made in epidemiological and demographic research, the methods and assumptions must evolve to match these advances. UNAIDS established an Epidemiology Reference Group in 1999 to advise them and other organisations on HIV epidemiology and methods for making estimates and projections of HIV/AIDS. During the meeting of the reference group in 2001, four priority areas were identified where methods and assumptions should be reviewed and perhaps modified: a) models of the HIV epidemic, b) survival of adults with HIV-1 in low and middle income countries, c) survival of children with HIV-1 in low and middle income countries, and d) methods to estimate numbers of AIDS orphans. Research and literature reviews were carried out by Reference Group members and invited specialists, prior to meetings held during 2001-2. Recommendations reflecting the consensus of the meeting participants on the four priority areas were determined at each meeting. These recommendations were followed in UNAIDS and WHO development of country-specific estimates of HIV/AIDS and its impact for end of 2001.

Examining the Relationship between Urogenital Schistosomiasis and HIV Infection

Background Urogenital schistosomiasis, caused by infection with Schistosoma haematobium, is widespread and causes substantial morbidity on the African continent. The infection has been suggested as an unrecognized risk factor for incident HIV infection. Current guidelines recommend preventive chemotherapy, using praziquantel as a public health tool, to avert morbidity due to schistosomiasis. In individuals of reproductive age, urogenital schistosomiasis remains highly prevalent and, likely, underdiagnosed. This comprehensive literature review was undertaken to examine the evidence for a cause-effect relationship between urogenital schistosomiasis and HIV/AIDS. The review aims to support discussions of urogenital schistosomiasis as a neglected yet urgent public health challenge. Methodology/Principal Findings We conducted a systematic search of the literature including online databases, clinical guidelines, and current medical textbooks. We describe plausible local and systemic mechanisms by which Schistosoma haematobium infection could increase the risk of HIV acquisition in both women and men. We also detail the effects of S. haematobium infection on the progression and transmissibility of HIV in co-infected individuals. We briefly summarize available evidence on the immunomodulatory effects of chronic schistosomiasis and the implications this might have for populations at high risk of both schistosomiasis and HIV. Conclusions/Significance Studies support the hypothesis that urogenital schistosomiasis in women and men constitutes a significant risk factor for HIV acquisition due both to local genital tract and global immunological effects. In those who become HIV-infected, schistosomal co-infection may accelerate HIV disease progression and facilitate viral transmission to sexual partners. Establishing effective prevention strategies using praziquantel, including better definition of treatment age, duration, and frequency of treatment for urogenital schistosomiasis, is an important public health priority. Our findings call attention to this pressing yet neglected public health issue and the potential added benefit of scaling up coverage of schistosomal treatment for populations in whom HIV infection is prevalent.

A Multi-centre Evaluation of Nine Rapid Point of Care Syphilis Tests Using Archived Sera

Objectives: To evaluate nine rapid syphilis tests at eight geographically diverse laboratory sites for their performance and operational characteristics. Methods: Tests were compared “head to head” using locally assembled panels of 100 archived (50 positive and 50 negative) sera at each site using as reference standards the Treponema pallidum haemagglutination or the T pallidum particle agglutination test. In addition inter-site variation, result stability, test reproducibility and test operational characteristics were assessed. Results: All nine tests gave good performance relative to the reference standard with sensitivities ranging from 84.5–97.7% and specificities from 84.5–98%. Result stability was variable if result reading was delayed past the recommended period. All the tests were found to be easy to use, especially the lateral flow tests. Conclusions: All the tests evaluated have acceptable performance characteristics and could make an impact on the control of syphilis. Tests that can use whole blood and do not require refrigeration were selected for further evaluation in field settings.

Urogenital Schistosomiasis in Women of Reproductive Age in Tanzania's Lake Victoria Region

We conducted a community-based study of 457 women aged 18-50 years living in eight rural villages in northwest Tanzania. The prevalence of female urogenital schistosomiasis (FUS) was 5% overall but ranged from 0% to 11%. FUS was associated with human immunodeficiency virus (HIV) infection (odds ratio [OR] = 4.0, 95% confidence interval [CI] = 1.2-13.5) and younger age (OR = 5.5 and 95% CI = 1.2-26.3 for ages < 25 years and OR = 8.2 and 95% CI = 1.7-38.4 for ages 25-29 years compared with age > 35 years). Overall HIV prevalence was 5.9% but was 17% among women with FUS. We observed significant geographical clustering of schistosomiasis: northern villages near Lake Victoria had more Schistosoma mansoni infections (P < 0.0001), and southern villages farther from the lake had more S. haematobium (P = 0.002). Our data support the postulate that FUS may be a risk factor for HIV infection and may contribute to the extremely high rates of HIV among young women in sub-Saharan Africa.

HIV infection in Haiti : natural history and disease progression

ObjectiveA study was conducted to define the natural history and disease progression of HIV infection in a developing country. DesignA prospective longitudinal cohort study. MethodsForty-two patients with documented dates of HIV seroconversion were followed in Port-au-Prince, Haiti. Patients were seen at 3 month intervals or when ill. Patients were treated for bacterial, mycobacterial, parasitic, and fungal infections, but antiretroviral therapy was not available. Patients were followed until death or until 1 January 2000; median follow-up was 66 months. ResultsBy Kaplan–Meier analyses, the median time to symptomatic HIV disease (CDC category B or C) was 3.0 years [95% confidence interval (CI) 2.3–5.0 years]. The median time to AIDS (CDC category C) was 5.2 years (95% CI 4.7–6.5 years), and the median time to death was 7.4 years (95% CI 6.2–10.2 years). Community-acquired infections, including respiratory tract infections, acute diarrhea, and skin infections were common in the pre-AIDS period. AIDS-defining illnesses included tuberculosis, wasting syndrome, cryptosporidiosis, cyclosporiasis, candida esophagitis, toxoplasmosis, and cryptococcal meningitis. Rapid progression to death was associated with anemia at the time of seroconversion hazards ratio (HR) 4.1 (95% CI 1.1–15.0), age greater than 35 years at seroconversion HR 4.4 (95% CI 1.1–16.6), and lymphopenia at seroconversion HR 11.0 (95% CI 2.3–53.0). ConclusionThis report documents rapid disease progression from HIV seroconversion until death among patients living in a developing country. Interventions, including nutritional support and prophylaxis of common community-acquired infections during the pre-AIDS period may slow disease progression and prolong life for HIV-infected individuals in less-developed countries.