Charles van der Horst

Diagnosis and Management of Increased Intracranial Pressure in Patients with AIDS and Cryptococcal Meningitis

This study was undertaken to characterize the laboratory and clinical course of patients with AIDS and cryptococcal meningitis who had normal or elevated cerebrospinal fluid (CSF) pressure. Data were obtained retrospectively from a randomized multicenter quasifactorial phase III study comparing amphotericin B with or without flucytosine in primary treatment of cryptococcal meningitis. CSF pressure was measured before treatment and at 2 weeks. Repeated lumbar punctures were done to drain CSF and to reduce pressure. Patients with the highest baseline opening pressures (> or = 250 mm H2O) were distinguished by higher titers of cryptococcal capsular polysaccharide antigen in CSF; more frequently positive India ink smears of CSF; and more frequent headache, meningismus, papilledema, hearing loss, and pathological reflexes. After receiving antifungal therapy, those patients whose CSF pressure was reduced by >10 mm or did not change had more frequent clinical response at 2 weeks than did those whose pressure increased >10 mm (P /=250 mm H2O be treated with large-volume CSF drainage.

Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both

BACKGROUND Although trimethoprim-sulfamethoxazole is the drug of choice for the prevention of Pneumocystis carinii pneumonia, many patients cannot tolerate it and must switch to an alternative agent. METHODS We conducted a multicenter, open-label, randomized trial comparing daily atovaquone (1500-mg suspension) with daily dapsone (100 mg) for the prevention of P. carinii pneumonia among patients infected with the human immunodeficiency virus who could not tolerate trimethoprim-sulfamethoxazole. The median follow-up period was 27 months. RESULTS Of 1057 patients enrolled, 298 had a history of P. carinii pneumonia. P. carinii pneumonia developed in 122 of 536 patients assigned to atovaquone (15.7 cases per 100 person-years), as compared with 135 of 521 in the dapsone group (18.4 cases per 100 person-years; relative risk for atovaquone vs. dapsone, 0.85; 95 percent confidence interval, 0.67 to 1.09; P=0.20). The relative risk of death was 1.07 (95 percent confidence interval, 0.89 to 1.30; P=0.45), and the relative risk of discontinuation of the assigned medication because of adverse events was 0.94 (95 percent confidence interval, 0.74 to 1.19; P=0.59). Among the 546 patients who were receiving dapsone at base line, the relative risk of discontinuation because of adverse events was 3.78 for atovaquone as compared with dapsone (95 percent confidence interval, 2.37 to 6.01; P<0.001); among those not receiving dapsone at base line, it was 0.42 (95 percent confidence interval, 0.30 to 0.58; P<0.001). CONCLUSIONS Among patients who cannot tolerate trimethoprim-sulfamethoxazole, atovaquone and dapsone are similarly effective for the prevention of P. carinii pneumonia. Our results support the continuation of dapsone prophylaxis among patients who are already receiving it. However, among those not receiving dapsone, atovaquone is better tolerated and may be the preferred choice for prophylaxis against P. carinii pneumonia.

Microalbuminuria in HIV infection.

Objective:Microalbuminuria is associated with increased risk of cardiovascular disease and mortality. The objective of the study was to evaluate if HIV infection was an independent risk factor for microalbuminuria. Design:Cross sectional. Methods:The relationship between HIV infection and microalbuminuria was assessed using subjects enrolled in the study of Fat Redistribution and Metabolic Change in HIV Infection, which consists of HIV-positive and control men and women. Participants with proteinuria (dipstick ≥ 1+) were excluded. Results:Microalbuminuria (urinary albumin/creatinine ratio, ACR > 30 mg/g) was present in 11% of HIV infected, and 2% of control participants (P < 0.001); a fivefold odds after multivariate adjustment (odds ratio, 5.11; 95% confidence interval, 1.97–13.31; P=0.0008). Several cardiovascular risk factors were associated with higher ACR in HIV participants: insulin resistance (HOMA > 4; 32%, P < 0.0001), systolic blood pressure (21%, P = 0.01 for 120–140 versus < 120 mmHg, and 43%, P = 0.06 for > 140 versus < 120 mmHg), and family history of hypertension (17%, P = 0.03). Higher CD4 cell count was associated with lower albumin/creatinine ratio (−24%, P = 0.009 for 200–400 versus < 200 cells/ml and −26%, P = 0.005 for > 400 versus < 200 cells/ml). Conclusion:HIV infection had a strong and independent association with microalbuminuria, the severity of which was predicted by markers of insulin resistance, hypertension, and advanced HIV infection. These associations warrant further investigation, as the increased prevalence of microalbuminuria in HIV infection may be a harbinger of future risk of cardiovascular and kidney diseases.

Modifications of a large HIV prevention clinical trial to fit changing realities: a case study of the Breastfeeding, Antiretroviral, and Nutrition (BAN) protocol in Lilongwe, Malawi.

In order to evaluate strategies to reduce HIV transmission through breast milk and optimize both maternal and infant health among HIV-infected women and their infants, we designed and implemented a large, randomized clinical trial in Lilongwe, Malawi. The development of protocols for large, randomized clinical trials is a complicated and lengthy process often requiring alterations to the original research design. Many factors lead to delays and changes, including study site-specific priorities, new scientific information becoming available, the involvement of national and international human subject committees and monitoring boards, and alterations in medical practice and guidance at local, national, and international levels. When planning and implementing a clinical study in a resource-limited setting, additional factors must be taken into account, including local customs and program needs, language and socio-cultural barriers, high background rates of malnutrition and endemic diseases, extreme poverty, lack of personnel, and limited infrastructure. Investigators must be prepared to modify the protocol as necessary in order to ensure participant safety and successful implementation of study procedures. This paper describes the process of designing, implementing, and subsequently modifying the Breastfeeding, Antiretrovirals, and Nutrition, (BAN) Study, a large, on-going, randomized breastfeeding intervention trial of HIV-infected women and their infants conducted at a single-site in Lilongwe, Malawi. We highlight some of the successes, challenges, and lessons learned at different stages during the conduct of the trial.

A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV

Background: Once daily (QD) dosing facilitates regimen simplification and adherence to antiretroviral therapy. Emtricitabine (FTC) QD is a newly approved nucleoside reverse transcriptase inhibitor compared in this study to twice daily lamivudine (3TC BID). Methods: Controlled, open label equivalence trial of 440 HIV-1-infected patients with plasma HIV-1 RNA stably suppressed on a regimen of 3TC 150 mg BID, stavudine or zidovudine, and a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Patients were randomized to continue their current regimen or replace 3TC with FTC 200 mg QD. If HIV-1 RNA levels were ⩽ £ 400 copies/ml at 48 weeks in Protocol 303, patients could continue on FTC in Protocol 350. The primary analysis was based on virologic failure and response defined by plasma HIV-1 RNA suppression below 400 copies/ml. Results: At baseline, the mean CD4 cell count was 525 (FTC) and 533 × 106 cells/l (3TC). At week 48 in Protocol 303, the probability of virologic failure was low, 7% (FTC) and 8% (3TC), and the probability of sustained viral suppression at week 48 was equivalent between treatment arms at both the 50 and 400 copies/ml thresholds. The mean increase in CD4+ T-cell percentage was 2.5% (FTC) and 1.7% (3TC). In Protocol 350, the probability of virologic failure was 11% after 4 years on FTC-containing highly active antiretroviral therapy (HAART). Conclusion: In stably suppressed patients, 200 mg emtricitabine QD was equivalent to 150 mg lamivudine BID. Emtricitabine-containing HAART was associated with a high rate of sustained virologic suppression during 4 years of follow-up.

Cytomegalovirus viremia, mortality, and end-organ disease among patients with AIDS receiving potent antiretroviral therapies.

Objective:To determine the association of cytomegalovirus (CMV) viremia with CMV disease and death in patients with AIDS. Design and setting:Prospective, observational cohort study conducted at a university hospital. Methods:A cohort of 190 subjects with AIDS who were CMV seropositive and had no history or evidence of CMV disease were longitudinally evaluated for signs and symptoms of CMV disease and CMV viremia with plasma CMV DNA polymerase chain reaction (PCR) and whole blood CMV hybrid capture. Results:A total of 187 subjects had at least 1 study visit following entry. At baseline, the median CD4+ cell count and plasma HIV RNA level were 110/μL (range = 3-620/μL) and 47,973 copies/mL (<30- >750,000 copies/mL), respectively. Highly active antiretroviral therapy (HAART) use increased from 87.5% during the 1st study year to 98.5% by the end of the study. During a median follow-up of 334 days, 16% (30) of the subjects died and 2 (6%) developed CMV disease. No deaths were attributable to CMV disease; 4 subjects who died developed CMV prior to death. Baseline HIV viral load and final CD4+ cell count were significantly and independently associated with mortality. Detectable plasma CMV DNA PCR was an independent predictor of death even after adjusting for HIV RNA level and CD4+ cell count prior to death (P = 0.038). In contrast, whole blood CMV hybrid capture did not predict mortality. The CMV assays neither collectively nor individually were found to be associated with the few cases of CMV disease. Conclusions:In patients with AIDS and seropositive for CMV, detection of CMV viremia with plasma CMV DNA PCR was predictive of death and provided additional prognostic information on the risk of all cause-mortality beyond that obtained with CD4+ cell count and HIV viral load testing alone. Detection of CMV viremia by plasma with CMV DNA PCR in patients with AIDS, particularly those with low CD4+ cell counts, provides additional rationale for optimization of antiretroviral therapy and consideration for preemptive anti-CMV therapy.

Diverse and High Prevalence of Human Papillomavirus Associated with a Significant High Rate of Cervical Dysplasia in Human Immunodeficiency Virus–Infected Women in Johannesburg, South Africa

OBJECTIVE To evaluate the epidemiology of the human papillomavirus (HPV) type and correlate it with the Papanicolaou smears in human immunodeficiency virus-seropositive women in Johannesburg, South Africa. STUDY DESIGN In a cohort of 148 women, HPV DNA testing was performed with the Roche HPV genotyping test (Branchburg, New Jersey, U.S.A). Papanicolaou smears were performed by standard cytology utilizing 2001 Bethesda reporting guidelines. RESULTS The average age and CD4 count of the participants was 35 years and 255 cells per mm3, respectively. Fifty-four percent had abnormal Papanicolaou smears; 66% of the abnormal cytology was low grade changes, with 33% assessed as having high grade changes. HPV DNA was found in 95% of the 148 subjects assessed, with 83% having 1 or more HPV oncogenic types. Common oncogenic types were 16, 35, 53 and 18. When HPV results were stratified by CD4, there was a significant risk of an oncogenic HPV type in women with CD4 <200. Significant odds ratios for high grade lesions were seen in HPV types 16, 35, 51, 66, 69 and 73. CONCLUSION The results of HPV typing illustrate the diverse range of oncogenic HPV and high prevalence of oncogenic type. These results highlight the need for improved access to Papanicolaou smear screening for this population.

Thoughts of death and suicidal ideation in nonpsychiatric human immunodeficiency virus seropositive individuals

The present study examines the prevalence of death thoughts and suicidality in HIV infection. Subjects (n = 246) were examined for psychiatric morbidity and suicidality. Compared to high risk HIV seronegatives, HIV seropositives (HIV +) had significantly increased frequency and severity of both suicidal ideation and death thoughts. Two-thirds of seropositives had suicidal ideation at some point; half of the seropositives reported suicide plans and one quarter suicide attempts; and third of seropositives reported current suicidal ideation. Suicidal ideation did not increase with advancing disease. The high prevalence of suicidal ideation suggests inclusion of its assessment in HIV treatment regardless of stage.

Low Absolute Neutrophil Counts in African Infants

Infants of African origin have a lower normal range of absolute neutrophil counts than white infants; this fact, however, remains under appreciated by clinical researchers in the United States. During the initial stages of a clinical trial in Malawi, the authors noted an unexpectedly high number of infants with absolute neutrophil counts that would be classifiable as neutropenic using the National Institutes of Health’s Division of AIDS toxicity tables. The authors argue that the relevant Division of AIDS table does not take into account the available evidence of low absolute neutrophil counts in African infants and that a systematic collection of data from many African settings might help establish the absolute neutrophil count cutpoints to be used for defining neutropenia in African populations.

Survival in Women Exposed to Single-Dose Nevirapine for Prevention of Mother-to-Child Transmission of HIV: A Stochastic Model

BACKGROUND Single-dose nevirapine (sdNVP)-based regimens reduce mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) but result in resistance to NVP and may reduce the ability of highly active antiretroviral therapy (HAART) used for prevention of MTCT (PMTCT). The impact that sdNVP has on survival in the era of increasing access to HAART is unknown. METHODS We developed a stochastic simulation model to predict survival and sdNVP-attributable mortality in sub-Saharan African women exposed to different PMTCT regimens. RESULTS Our model predicts that mortality attributable to exposure to sdNVP is low--1.1% (interquartile range [IQR], 0.6%-1.5%) and 3.5% (IQR, 3.1%-3.9%) at 5 and 10 years after PMTCT therapy--when all eligible women receive HAART after PMTCT therapy. Predictions were robust to univariate sensitivity analysis. In the worst-case multivariate sensitivity analysis, the increased mortality attributable to sdNVP was 10.4% (IQR, 10.0%-10.8%) at 10 years after PMTCT therapy. CONCLUSIONS Concern has been expressed that widespread use of sdNVP for PMTCT in resource-poor settings will compromise the effectiveness of HAART in HIV-infected women. Although our model does not address other important outcomes of PMTCT regimens, such as transmission of resistant virus, it provides strong arguments that sdNVP for PMTCT should not be delayed because of fear of compromising the survival of women after PMTCT therapy.