Bienvenido G. Yangco

Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS

The effects of dronabinol on appetite and weight were evaluated in 139 patients with AIDS-related anorexia and > or = 2.3 kg weight loss in a multi-institutional study. Patients were randomized to receive 2.5 mg dronabinol twice daily or placebo. Patients rated appetite, mood, and nausea by using a 100-mm visual analogue scale 3 days weekly. Efficacy was evaluable in 88 patients. Dronabinol was associated with increased appetite above baseline (38% vs 8% for placebo, P = 0.015), improvement in mood (10% vs -2%, P = 0.06), and decreased nausea (20% vs 7%; P = 0.05). Weight was stable in dronabinol patients, while placebo recipients had a mean loss of 0.4 kg (P = 0.14). Of the dronabinol patients, 22% gained > or = 2 kg, compared with 10.5% of placebo recipients (P = 0.11). Side effects were mostly mild to moderate in severity (euphoria, dizziness, thinking abnormalities); there was no difference in discontinued therapy between dronabinol (8.3%) and placebo (4.5%) recipients. Dronabinol was found to be safe and effective for anorexia associated with weight loss in patients with AIDS.

Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia

We studied the effects of long-term (12 months) dronabinol in 94 late-stage acquired immunodeficiency syndrome (AIDS) patients (mean CD4 count of 45/mm3) who previously participated in a 6-week study (placebo versus dronabinol). All patients received dronabinol orally-2.5 mg twice daily (90%) or 2.5 mg once daily (10%). Appetite was measured using a visual analogue scale for hunger (VASH). Dronabinol was associated with consistent improvement in mean appetite. Patients previously treated with dronabinol continued to show improvement in VASH (percent change from baseline of 6-week trial: 48.6-76.1% at each month), whereas those previously treated with placebo exhibited substantial improvement in mean appetite, particularly during the initial 4 months of treatment (48.5-69.9%). Thereafter, dronabinol was associated with a VASH change at least twice baseline. Patients tended toward stable body weight for at least 7 months. Adverse events were primarily related to known central nervous system effects of dronabinol. These data support long-term, safe use of dronabinol for anorexia associated with weight loss in patients with AIDS.

Once-Daily versus Twice-Daily Lopinavir/Ritonavir in Antiretroviral-Naive HIV-Positive Patients: A 48-Week Randomized Clinical Trial

The safety, pharmacokinetics, and antiviral activity of lopinavir, a human immunodeficiency virus (HIV) protease inhibitor, coformulated with ritonavir as a pharmacokinetic enhancer were evaluated in 38 antiretroviral-naive patients randomized 1:1 to receive open-label lopinavir/ritonavir at a dose of 800/200 mg once daily or 400/100 mg twice daily, each in combination with stavudine and lamivudine twice daily, for 48 weeks. Over the course of 48 weeks, median predose concentrations of lopinavir exceeded the protein-binding corrected concentration required to inhibit replication of wild-type HIV by 50% in vitro by 40- and 84-fold in the once- and twice-daily groups, respectively. Predose concentrations of lopinavir were more variable in the once-daily group (mean +/- SD, 3.62+/-3.38 microg/mL for the once-daily group and 7.13+/-2.93 microg/mL for the twice-daily group). At week 48, in an intent-to-treat (missing = failure) analysis, 74% of patients in the once-daily group and 79% of patients in the twice-daily group had HIV RNA levels of <50 copies/mL (P=.70). Study drug-related discontinuations occurred in 1 patient in each treatment group. Genotypic resistance testing of 4 patients with HIV RNA levels >400 copies/mL between weeks 24 and 48 demonstrated no protease inhibitor-resistance mutations.

A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection : selection of thymidine analog regimen therapy (START I)

BackgroundNo clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. ObjectiveTo compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DesignRandomized, open-label, multi-center. SettingFifteen HIV clinical research centers. PatientsTwo-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts ⩾ 200 × 106/l and HIV-1 RNA ⩾ 10 000 copies/ml (bDNA assay), modified to 5000 copies/ml. Interventiond4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MeasurementsPrimary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA ⩽ 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. ResultsFor HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, −0.204 to 0.036;P = 0.213], with 49% and 47% respectively achieving ⩽ 50 copies/ml at 48 weeks (90% CI, −0.134 to 0.096;P = 0.834). Median change in CD4 cell counts at 48 weeks was + 227 × 106/l and + 198 × 106/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 × 106/l versus 110 × 106/l;P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. ConclusionsThese results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection.

PURPOSE Weight loss is a strong predictor of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. Men with acquired immunodeficiency syndrome (AIDS) lose body cell mass. Hypogonadism is also common. This study tested the efficacy of a testosterone transscrotal patch (6 mg/day) in improving body cell mass and treating hypogonadism in these patients. SUBJECTS AND METHODS This multicenter, randomized, double-blinded, placebo-controlled trial was conducted from August 1995 to October 1996 in 133 men, 18 years of age and older, who had AIDS, 5% to 20% weight loss, and either a low morning serum total testosterone level (<400 ng/dL) or a low free testosterone level (<16 pg/mL). Outcomes included weight, body cell mass as measured using bioelectrical impedance analysis, quality of life, and morning measurements of serum testosterone and dihydrotestosterone levels, lymphocyte subsets, and HIV quantification. RESULTS There were no significant differences in baseline weight, CD4 cell counts, or HIV serum viral quantification between treatment arms. Morning total and free testosterone levels increased in those treated with testosterone, but not with placebo. Following 12 weeks of treatment there were no differences (testosterone-placebo) in mean weight change (-0.3 kg [95% confidence interval (CI): -1.4 to 0.8]) or body cell mass (-0.2 kg [95% CI: -1.0 to 0.6]) in the two groups. There were also no changes in quality of life in either group. CONCLUSION Hypogonadal men with AIDS and weight loss can achieve adequate morning serum sex hormone levels using a transscrotal testosterone patch. However, this system of replacement does not improve weight, body cell mass, or quality of life.

Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection

BACKGROUND Most individuals infected with HIV-1 show disease progression despite both cellular and humoral immune responses. We investigated whether immunisation of patients who had symptomless HIV-1 infection with an envelope subcomponent vaccine (MNrgp120) to augment immune response can slow progression of HIV-1 disease. METHODS In a randomised, double-blind, placebo-controlled trial, carried out in university infectious disease clinics and community infectious disease practices, we enrolled 573 HIV-infected patients with CD4 counts above 600 cells/microL (0.6 x 10(9)/L). Patients received 600 micrograms vaccine or placebo by intramuscular injection monthly for 6 months then every alternate month throughout the study. The primary endpoint was the rate of decline in CD4 count; secondary endpoints were HIV-1 RNA concentrations in plasma and minor clinical events associated with HIV. Analysis was by intention to treat. FINDINGS At baseline, the study participants had a mean CD4 count of 775 cells/microL (SD 172) and 89% of participants had detectable HIV RNA (> 200 copies/mL). These RNA-positive individuals had a median viral load of 9250 copies/mL (IQR 2670-26960). Analysis after 15 months of follow-up of the 568 subjects who had at least one CD4 count done after randomisation showed no difference between the 287 vaccine recipients and 281 placebo recipients in rate of decline of CD4 count (yearly decrease 53.8 [SE 7.6] vs 42.3 [7.6] cells/microL; ratio of mean gradients 1.27 [95% CI 0.63-2.55]) or in plasma HIV-1 RNA concentrations (p > or = 0.63). The study was designed with power to detect a vaccine-induced reduction in rate of decline in CD4 count of 60%; these results exclude with 95% confidence a reduction of 40% or more. More vaccine-treated patients than placebo recipients showed a 50% decrease in CD4 count (11 vs 5; relative risk 2.15 [95% CI 0.76-6.12], p = 0.13). The frequencies of HIV-related minor clinical events were similar in the two groups. Pain at the injection site was the only adverse event that occurred more frequently in vaccine-treated group. INTERPRETATION Postinfection immunisation of symptom-free HIV-infected patients with MNrgp120 vaccine did not alter HIV-1 disease progression as measured by immunological, virological, and clinical endpoints over a 15-month period.

Efficacy Testing of Recombinant Human Immunodeficiency Virus (HIV) gp160 as a Therapeutic Vaccine in Early-Stage HIV-1-Infected Volunteers

A phase II efficacy trial was conducted with recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein gp160 (rgp160) in 608 HIV-infected, asymptomatic volunteers with CD4+ cell counts >400 cells/mm3. During a 5-year study, volunteers received a 6-shot primary series of immunizations with either rgp160 or placebo over 6 months, followed by booster immunizations every 2 months. Repeated vaccination with rgp160 was safe and persistently immunogenic. Adequate follow-up and acquisition of endpoints allowed for definitive interpretation of the trial results. There was no evidence that rgp160 has efficacy as a therapeutic vaccine in early-stage HIV infection, as measured at primary endpoints (50% decline in CD4+ cell count or disease progression to Walter Reed stage 4, 5, or 6) or secondary endpoints. A transient improvement was seen in the secondary CD4 endpoint for the vaccination compared with the placebo arm, but this did not translate into improved clinical outcome.

Rapidly Progressive Herpetic Retinal Necrosis: A Blinding Disease Characteristic of Advanced AIDS

Eleven patients with rapidly progressive herpetic retinal necrosis (RPHRN) complicating AIDS were investigated retrospectively to study the disease spectrum, systemic involvement, and therapy. The mean CD4 cell count was 24/microL. There was a characteristic disease pattern with rapid progression, 82% bilaterality, relative resistance to intravenous antiviral therapy, and 70% retinal detachment. Varicella-zoster virus was the probable cause in 10 patients (detected by polymerase chain reaction in two eyes investigated), and herpes simplex virus was the probable cause in one. Cutaneous zoster occurred previously in 73% but was not concurrent. Seventy-three percent had central nervous system disease, possibly virus-related. RPHRN may be a local herpetic recrudescence in an immune-privileged site with transneural spread. Only four of 20 affected eyes retained useful vision. Poor ocular bioavailability, retinal ischemia, acquired drug resistance, and strain pathogenicity may underlie treatment failure. Acyclovir therapy appears relatively ineffective. Combined intravenous and intravitreal therapy with foscarnet and ganciclovir may be the best current management. Research advances are needed urgently.

Discontinuation of Chemoprophylaxis against Pneumocystis carinii Pneumonia in Patients with HIV Infection

Highly active antiretroviral therapy (HAART) has substantially affected the care and the disease course of HIV-infected patients. In the HIV Outpatient Study (HOPS), a study of ambulatory HIV-infected patients in HIV clinics across the United States, we have observed several phenomena related to the use of HAART. Mortality and morbidity rates have declined remarkably and substantially in this population with the advent of more effective antiretroviral therapies (1), but the typical patient must take an average of 13 pills per day to maintain a good virologic and immunologic result (2). Meanwhile, as CD4+ lymphocyte counts have increased in treated patients, the incidence of Pneumocystis carinii pneumonia (PCP) has declined dramatically (1, 3). Given the low incidence of PCP, the occasional toxicity of PCP chemoprophylaxis, and the numerous pills that ambulatory HIV patients receive, many HIV clinicians have begun cautiously discontinuing PCP prophylaxisnormally trimethoprim-sulfamethoxazole given three or more times per weekamong patients who have sustained immunologic and virologic responses to HAART. In this study, we sought to determine whether discontinuing PCP prophylaxis in HOPS patients who had sustained CD4+ cell counts greater than 200 cells/mm3 changed the rates of development of PCP compared with patients who continued PCP prophylaxis. Methods The methods used in HOPS, a dynamic cohort study, have been described elsewhere (1, 4). This continuously recruiting study now includes prospective, electronically collected summaries of physicianpatient interactions and the course of disease for more than 4800 HIV-infected ambulatory patients seen in more than 82 000 outpatient visits since 1992. Our analysis included persons who visited a HOPS site from June 1995 through December 1998. Our study sites were 10 HIV clinics, of which 8 were private and 2 were public, in 8 U.S. cities: Tampa, Florida; Washington, D.C.; Denver, Colorado; Portland, Oregon; Oakland, California; Chicago, Illinois; Stony Brook, New York; and Philadelphia, Pennsylvania. Of the 12 HOPS physicians, 11 are board-certified in internal medicine and infectious diseases; these physicians routinely care for hundreds of HIV-infected patients every year and thus are experienced HIV caregivers. Information in five general categories is abstracted from each patient visit by trained study staff and is electronically entered in a common data collection system that spans the time of observation. Data are collected centrally, and they are reviewed and corrected before being added to the database. The five categories of information are demographic characteristics and risk behaviors for HIV infection; symptoms; diagnosed diseases (definitive and presumptive); prescribed medications, including dosage and duration; and laboratory values, including CD4+ lymphocyte counts and viral loads (HIV RNA copies/mL of plasma). In this analysis, we assessed patients whose CD4+ cell counts increased from 200 cells/mm3 or less to greater than 200 cells/mm3 after antiretroviral therapy (HAART was being given in more than 80% of patients by 1998 [1]) and who were nonrandomly chosen by their clinicians to discontinue or continue PCP prophylaxis. The observation periods for all patients who had two consecutive cell counts greater than (that is, sustained higher than) 200 CD4+ cells/mm3 started when they first had a CD4+ cell count greater than 200 cells/mm3. We compared the demographic (age, sex, race or ethnicity, geographic site, HIV risk group, education level, and insurance or payment source), clinical (previous PCP, other opportunistic infections, and AIDS diagnosis), immunologic (CD4+ cell count, including lowest and highest), and most recent virologic (copies of HIV RNA [viral load]) characteristics of patients who either discontinued or continued PCP prophylaxis. Data collected in the HOPS were analyzed by using SAS software, version 6.0 (SAS Institute, Inc., Cary, North Carolina), and EpiInfo, version 6.04 (Centers for Disease Control and Prevention, Atlanta, Georgia). We calculated, by using an exact binomial test, the upper confidence limits for (zero) PCP incidence in patients who discontinued and those who continued prophylaxis. The characteristics of those who discontinued PCP prophylaxis were compared with the characteristics of those who continued it by using the chi-square test or Wilcoxon rank-sum test, as appropriate. The HOPS as a whole and this substudy are funded entirely by the Centers for Disease Control and Prevention. Results Of patients who maintained CD4+ lymphocyte counts greater than 200 cells/mm3, 146 who discontinued PCP prophylaxis were followed for a mean of 18.2 months (221.4 total person-years) and 345 who continued PCP prophylaxis were followed for a mean of 14.0 months (402.5 total person-years) (Table 1). Patients and their physicians were more likely to discontinue PCP prophylaxis in succeeding calendar years of the study (data not shown). Neither patients who discontinued nor those who continued PCP prophylaxis acquired definitive or presumptive PCP (upper 95% exact binomial confidence limits, 2.3/100 person-years for patients who discontinued prophylaxis and 1.3/100 person-years for patients who continued prophylaxis). Table 1. Demographic and Clinical Characteristics of Patients Who Discontinued and Those Who Continued Pneumocystis carinii Pneumonia Chemoprophylaxis Toxoplasmosis did not occur in either group. Bacterial infections, such as pneumonia, sinusitis, bronchitis, and urinary tract infections, occurred somewhat less often in patients who discontinued PCP prophylaxis (18.6%) than in those who continued PCP prophylaxis (28.3%), but the difference was not significant (Yates-corrected chi-square test, P=0.14). Compared with patients who continued PCP prophylaxis, more of those who discontinued prophylaxis were white than belonged to any other racial or ethnic groups, and fewer of these patients had had a previous episode of PCP (Table 1). The median patient age did not significantly differ between the group that discontinued PCP prophylaxis and the group that continued PCP prophylaxis (median, 39.2 years compared with 39.9 years; Wilcoxon test, P=0.2). We also analyzed the insurance (payer) status of patients; no significant differences were seen in care between the two groups, whether their care was compensated by the patient, private insurance, public insurance, or assistance such as Medicare and Medicaid (data not shown). Of patients discontinuing PCP prophylaxis, 75% were receiving protease inhibitor-based antiretroviral therapy at the time of discontinuation, but this percentage did not differ from rates of protease inhibitor use in the HOPS cohort in the same years (1). According to laboratory data, patients who discontinued PCP prophylaxis had a significantly higher CD4+ cell nadir (lowest recorded CD4+ cell count), a higher acme (highest recorded CD4+ cell count), a longer period during which CD4+ cell counts were greater than 200 cells/mm3, and a lower (most recent) viral load. In addition, more (51.9%) patients who discontinued PCP prophylaxis had 400 or fewer copies of HIV-1 RNA per mL (undetectable) than patients who continued PCP prophylaxis (Table 2). Table 2. Virologic and Immunologic Characteristics of Patients Who Discontinued and Those Who Continued Pneumocystis carinii Pneumonia Chemoprophylaxis We also analyzed patterns of discontinuing PCP prophylaxis at the 10 study sites and found that the percentage of patients who discontinued such prophylaxis ranged from 8.3% to 46.9% of all potentially eligible patients (those with CD4+ counts>200 cells/mm3). Of the 146 patients who discontinued PCP prophylaxis, only 6 (4%) patients did so because of chemoprophylactic agent toxicity (trimethoprim-sulfamethoxazole) or potential drug interactions. Discussion Our study suggests that discontinuing PCP prophylaxis may be appropriate for selected HIV-infected ambulatory patients who have sustained clinical, immunologic, and virologic improvement with antiretroviral therapy. In more than 2655 person-months of observation, PCP did not develop in any of the 146 U.S. patients who discontinued prophylaxis; this result corresponds with results of European studies of 78 HIV-infected patients in the Netherlands (5), 235 patients in three separate studies in Spain (6-8), 40 patients in France (9), and 262 patients in Switzerland (10). In those observational studies (5, 7-10) and the single randomized trial (6), a total of 615 patients discontinued PCP prophylaxis after their CD4+ cell counts increased to more than 200 cells/mm3; after follow-up of more than 5888 person-months, PCP had not developed in any patient. On the basis of these results, recent guidelines for opportunistic infection prevention suggest that providers consider discontinuation of PCP prophylaxis in HIV-infected patients with sustained CD4+ cell counts greater than 200 cells/mm3 (11). It is evident that HOPS physicians were careful in selecting patients for discontinuation of PCP prophylaxis. In general, patients who discontinued PCP prophylaxis had higher CD4+ cell counts before and after antiretroviral therapy, had maintained CD4+ cell counts greater than 200 cells/mm3 for a longer period, had significantly lower recent viral loads, and had fewer previous episodes of PCP compared with patients who continued PCP prophylaxis. These clinical, immunologic, and virologic factors may be important in deciding to discontinue PCP prophylaxis in an HIV-infected patient. Although we did not examine whether adherence to antiretroviral therapy might be improved by discontinuation of PCP prophylaxis, an approximately contemporaneous, anonymous survey of 504 HOPS patients showed statistically significant greater adherence to all medicines in patients who did not receive prophylaxis against opportunistic infections (80%) than in those who did (75%) (P=0.027) (2). Aside fro

A Matter of Perspective: Comparison of the Characteristics of Persons with HIV Infection in the United States from the HIV Outpatient Study, Medical Monitoring Project, and National HIV Surveillance System

Comparative analyses of the characteristics of persons living with HIV infection (PLWH) in the United States (US) captured in surveillance and other observational databases are few. To explore potential joint data use to guide HIV treatment and prevention in the US, we examined three CDC-funded data sources in 2012: the HIV Outpatient Study (HOPS), a multisite longitudinal cohort; the Medical Monitoring Project (MMP), a probability sample of PLWH receiving medical care; and the National HIV Surveillance System (NHSS), a surveillance system of all PLWH. Overall, data from 1,697 HOPS, 4,901 MMP, and 865,102 NHSS PLWH were analyzed. Compared with the MMP population, HOPS participants were more likely to be older, non-Hispanic/Latino white, not using injection drugs, insured, diagnosed with HIV before 2009, prescribed antiretroviral therapy, and to have most recent CD4+ T-lymphocyte cell count ≥500 cells/mm3 and most recent viral load test<2 00 copies/mL. The MMP population was demographically similar to all PLWH in NHSS, except it tended to be slightly older, HIV diagnosed more recently, and to have AIDS. Our comparative results provide an essential first step for combined epidemiologic data analyses to inform HIV care and prevention for PLWH in the US.