Beverly Alston

Guidelines for preventing opportunistic infections among HIV-infected persons - 2002

Introduction In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV) (1-3). These guidelines, which are intended for clinicians and health-care providers and their HIV-infected patients, were revised in 1997 (4) and again in 1999 (5), and have been published in MMWR (1, 4, 5), Clinical Infectious Diseases (2, 6, 7), Annals of Internal Medicine (3, 8), American Family Physician (9, 10), and Pediatrics (11); accompanying editorials have appeared in JAMA (12, 13). Response to these guidelines (e.g., a substantial number of requests for reprints, website contacts, and observations from health-care providers) demonstrates that they have served as a valuable reference for HIV health-care providers. Because the 1995, 1997, and 1999 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the relative importance of each recommendation. Since acquired immunodeficiency syndrome (AIDS) was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life for HIV-infected persons in the industrialized world. During the first decade of the epidemic, this improvement occurred because of improved recognition of opportunistic disease processes, improved therapy for acute and chronic complications, and introduction of chemoprophylaxis against key opportunistic pathogens. The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAART) as well as continuing progress in preventing and treating OIs. HAART has reduced the incidence of OIs and extended life substantially (14-16). HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy (14-16). However, certain patients are not ready or able to take HAART, and others have tried HAART regimens but therapy failed. Such patients will benefit from prophylaxis against OIs (15). In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART (15). Clearly, since HAART was introduced in the United States in 1995, chemoprophylaxis for OIs need not be lifelong. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by CD4+ T lymphocyte counts for patients who are receiving HAART. Thus, a strategy of stopping primary or secondary prophylaxis for certain patients whose immunity has improved as a consequence of HAART is logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care, and potentially facilitate adherence to antiretroviral regimens. In 1999, the USPHS/IDSA guidelines reported that stopping primary or secondary prophylaxis for certain pathogens was safe if HAART has led to an increase in CD4+ T lymphocyte counts above specified threshold levels. Recommendations were made for only those pathogens for which adequate clinical data were available. Data generated since 1999 continue to support these recommendations and allow additional recommendations to be made concerning the safety of stopping primary or secondary prophylaxis for other pathogens. For recommendations regarding discontinuing chemoprophylaxis, readers will note that criteria vary by such factors as duration of CD4+ T lymphocyte count increase, and, in the case of secondary prophylaxis, duration of treatment of the initial episode of disease. These differences reflect the criteria used in specific studies. Therefore, certain inconsistencies in the format of these criteria are unavoidable. Although considerable data are now available concerning discontinuing primary and secondary OI prophylaxis, essentially no data are available regarding restarting prophylaxis when the CD4+ T lymphocyte count decreases again to levels at which the patient is likely to again be at risk for OIs. For primary prophylaxis, whether to use the same threshold at which prophylaxis can be stopped (derived from data in studies addressing prophylaxis discontinuation) or to use the threshold below which initial prophylaxis is recommended, is unknown. Therefore, in this revision of the guidelines, in certain cases, ranges are provided for restarting primary or secondary prophylaxis. For prophylaxis against Pneumocystis carinii pneumonia (PCP), the indicated threshold for restarting both primary and secondary prophylaxis is 200 cells/L. For all these recommendations, the Roman numeral ratings reflect the lack of data available to assist in making these decisions (Box). Table. System Used to Rate the Strength of Recommendations and Quality of Supporting Evidence During the development of these revised guidelines, working group members reviewed published manuscripts as well as abstracts and material presented at professional meetings. Periodic teleconferences were held to develop the revisions. Major Changes in These Recommendations Major changes in the guidelines since 1999 include the following: Higher level ratings have been provided for discontinuing primary prophylaxis for PCP and Mycobacterium avium complex (MAC) when CD4+ T lymphocytes have increased to >200 cells/L and >100 cells/L, respectively, for 3 months in response to HAART (AI), and a new recommendation to discontinue primary toxoplasmosis prophylaxis has been provided when the CD4+ T lymphocyte count has increased to >200 cells/L for 3 months (AI). Secondary PCP prophylaxis should be discontinued among patients whose CD4+ T lymphocyte counts have increased to >200 cells/L for 3 months as a consequence of HAART (BII). Secondary prophylaxis for disseminated MAC can be discontinued among patients with a sustained (e.g., 6-month) increase in CD4+ count to >100 cells/L in response to HAART, if they have completed 12 months of MAC therapy and have no symptoms or signs attributable to MAC (CIII). Secondary prophylaxis for toxoplasmosis and cryptococcosis can be discontinued among patients with a sustained increase in CD4+ counts (e.g. 6 months) to >200 cells/L and >100200 cells/L, respectively, in response to HAART, if they have completed their initial therapy and have no symptoms or signs attributable to these pathogens (CIII). The importance of screening all HIV-infected persons for hepatitis C virus (HCV) is emphasized (BIII). Additional information concerning transmission of human herpesvirus 8 infection (HHV-8) is provided. New information regarding drug interactions is provided, chiefly related to rifamycins and antiretroviral drugs. Revised recommendations for vaccinating HIV-infected adults and HIV-exposed or infected children are provided. Using the Information in This Report For each of the 19 diseases covered in this report, specific recommendations are provided that address 1) preventing exposure to opportunistic pathogens, 2) preventing first episodes of disease, and 3) preventing disease recurrences. Recommendations are rated by a revised version of the IDSA rating system (17). In this system, the letters AE signify the strength of the recommendation for or against a preventive measure, and Roman numerals IIII indicate the quality of evidence supporting the recommendation (Box). Because of their length and complexity, tables in this report are grouped together and follow the references. Tables appear in the following order: Table 1 Dosages for prophylaxis to prevent first episode of opportunistic disease among infected adults and adolescents; Table 1. Prophylaxis to Prevent First Episode of Opportunistic Disease among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV) Table 2 Dosages for prophylaxis to prevent recurrence of opportunistic disease among HIV-infected adults and adolescents; Table 2. Prophylaxis to Prevent Recurrence of Opportunistic Disease, after Chemotherapy for Acute Disease, among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV) Table 3 Effects of food on drugs used to treat OIs; Table 3. Effects of Food on Drugs Used to Prevent Opportunistic Infections Table 4 Effects of medications on drugs used to treat OIs; Table 4. Effects of Medications on Drugs Used to Prevent Opportunistic Infections Table 5 Effects of OI medications on drugs commonly administered to HIV-infected persons; Table 5. Effects of Opportunistic Infection Medications on Antiretroviral Drugs Commonly Administered to Persons Infected with Human Immunodeficiency Virus (HIV) Table 6 Adverse effects of drugs used to prevent OIs; Table 6. Adverse Effects of Drugs Used in Preventing Opportunistic Infections Table 7 Dosages of drugs for preventing OIs for persons with renal insufficiency; Table 7. Dosing of Drugs for Primary Prevention of or Maintenance Therapy for Opportunistic Infections Related to Renal Insufficiency Table 8 Costs of agents recommended for preventing OIs among adults with HIV infection; Table 8. Wholesale Acquisition Costs of Agents Recommended for Preventing Opportunistic Infections among Adults Infected with Human Immunodeficiency Virus Table 9 Immunologic categories for HIV-infected children; Table 9. Immunologic Categories for Human Immunodeficiency Virus-Infected Children, Based on Age-Specific CD4+ T Lymphocyte Counts and Percentage of Total Lymphocytes Table 10 Immunization schedule for HIV-infected children; Table 10. Recommended Immunization Schedule for Human Immunodeficiency Virus (HIV)-Infected Children Table 11 Dosages for prophylaxis to prevent first episode of opportunistic disease among HIV-infected infants and children; Table 11. Prophylaxis to Prevent First Episode of Opportunistic Disease among Infants and Children Infected with Human Immunodeficiency Virus Tabl

Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047.

Objective Lipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug–drug interactions. Design Randomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA. Methods Three groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1–4 and 15–18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4–18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1–14 with pravastatin 40 mg daily added from days 15–18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry. Results Fifty-six subjects completed both pharmacokinetic study days. In arms 1–3, the median estimated area under the curves (AUC)0−−24 for the statins were: pravastatin (arm 1, n = 13), 151 and 75 nguu.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P = 0.005); simvastatin (arm 2, n = 14), 17 and 548 nguu.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P < 0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 nguu.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P < 0.001). In arm 4, the median estimated AUC0−−8 for NFV (24 319 versus 26 760 nguu.h/ml;P = 0.58) and its active M8 metabolite (15 565 versus 14 571 nguu.h/m;P = 0.63) were not statistically different from day 14 to day 18 (without or with pravastatin). Conclusions Simvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use.

Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study.

Efavirenz (EFV) is associated with hyperlipidemia when used in combination with other antiretroviral drugs. EFV is a mixed inducer/inhibitor of cytochrome P450 (CYP) 3A4 isozyme and may interact with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are primarily metabolized via CYP3A4. To assess the drug-drug interaction of EFV used in combination with simvastatin (SIM), atorvastatin (ATR), or pravastatin (PRA), an open-label trial was conducted in 52 healthy adult HIV-seronegative subjects across AIDS Clinical Trials Group sites in the United States. Subjects received 40 mg of SIM, 10 mg of ATR, or 40 mg of PRA daily on days 0 through 3 and days 15 through 18. EFV was administered daily at a dose of 600 mg on days 4 through 18. SIM, ATR, and PRA concentrations were determined before and after EFV, and EFV concentrations were determined before and after statins. EFV reduced SIM acid exposure (area under the curve at 0 to 24 hours [AUC0-24h]) by 58% (Wilcoxon signed rank test, P = 0.003) and active HMG-CoA reductase inhibitory activity by 60% (P < 0.001). EFV reduced ATR exposure by 43% (P < 0.001) and the total active ATR exposure by 34% (P = 0.005). EFV administration resulted in a 40% decrease in PRA exposure (P = 0.005). SIM, ATR, and PRA had no effect on non-steady-state EFV concentrations. In conclusion, EFV, when administered with SIM, ATR, or PRA, can result in significant induction of statin metabolism. The reduced inhibition of HMG-CoA reductase activity during coadministration of EFV may result in diminished antilipid efficacy at usual doses of SIM, ATR, and PRA.

Weekly Fluconazole for the Prevention of Mucosal Candidiasis in Women with HIV Infection: A Randomized, Double-Blind, Placebo-Controlled Trial

The demographic characteristics of the human immunodeficiency virus (HIV) epidemic in the United States have changed markedly in recent years. In 1994, 18% of new cases of acquired immunodeficiency syndrome (AIDS) occurred in women [1]; AIDS is now the third leading cause of death in women of reproductive age [2]. Candidiasis is a frequent complication of HIV infection [3-5]. The risk for oropharyngeal and esophageal candidiasis increases as the immune system becomes more suppressed. Vaginal candidiasis is also common in HIV-infected women [6, 7]. Because few HIV-infected women have been enrolled in clinical trials of therapy for and prophylaxis of fungal infections, few data have been recorded on the natural history, prevention, and treatment of mucosal candidiasis in women. Fluconazole, a broad-spectrum systemic antifungal agent, has been used effectively for the treatment of candidiasis in patients with HIV infection or AIDS and may result in a more rapid clinical and mycologic response than other azoles [8]. Although several regimens of fluconazole have been shown to prevent candidiasis (including recurrent episodes in persons with HIV infection), routine prophylaxis with fluconazole has not been recommended because of cost; the possible emergence of resistant Candida species; and drug interactions with non-sedating antihistamines, warfarin, phenytoin, oral hypoglycemic agents, rifampin or rifabutin, and hydrochlorothiazide [9-11]. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) initiated this study in HIV-infected women to evaluate the effectiveness and safety of weekly fluconazole for the prevention of mucosal candidiasis and to detect alterations in vaginal colonization by Candida species [12]. A substudy was also done to investigate in vitro resistance to Candida organisms. Methods Study Sample Patients were enrolled in the Womens Fungal Study (CPCRA 010) at 14 sites that were participating in the CPCRA [12]. The CPCRA is a consortium of community-based sites that provide primary health care to patients who are infected with HIV. Potentially eligible patients were identified by physicians who were participating in the consortium. Female patients with HIV infection who were 13 years of age or older were eligible if their CD4+ cell count did not exceed 300 cells/mm3 or 20% of their total lymphocyte count. Patients were excluded if they had a history of Candida esophagitis, were receiving systemic antifungal agents, had a known intolerance of azoles, or were pregnant or lactating. The protocol was approved by the internal review board at each site. Informed consent was obtained from all patients before they were assigned to a study group. Study Design In this double-blind trial, patients were randomly assigned to receive weekly fluconazole or placebo using a permuted block scheme with randomly mixed block sizes of two and four. Randomization was stratified by CPCRA site and was done through the CPCRA statistical center. The target sample size (400 patients) and study duration (18 months) were chosen to ensure that there would be 80% power to detect a 50% difference in the rate of episodes of candidiasis between groups with a two-sided P value of 0.05. We extended the follow-up period to obtain more information on clinical and in vitro resistance. Treatment Regimens Fluconazole was provided in 100-mg capsules; patients received 200 mg of fluconazole per week or placebo. This dosage was used because pharmacologic studies by Houang and colleagues [13] indicated that therapeutic concentrations of fluconazole greater than the median minimal inhibitory concentration (MIC) of Candida albicans were found in vaginal secretions and tissues for 96 hours after a fluconazole dose of 150 mg. Open-label daily fluconazole for prophylaxis was permitted after two episodes of oropharyngeal or vaginal candidiasis or one episode of esophageal candidiasis (that is, prophylaxis failure). The relative severity of the candidiasis was considered in defining prophylaxis failure. Therapy with the study drug was continued during episodes of oropharyngeal and vaginal candidiasis but not during episodes of esophageal candidiasis. Ongoing use of systemic antifungal agents required withdrawal of the study drug. Topical antifungal agents were recommended for the treatment of oropharyngeal and vaginal candidiasis; fluconazole was recommended for esophageal candidiasis. End Points Episodes of candidiasis were reviewed by a committee that was blinded to treatment group. Several major clinical end points were specified: 1) first episode of confirmed vaginal candidiasis, confirmed oropharyngeal candidiasis, or confirmed or probable esophageal candidiasis; 2) prophylaxis failure, defined as the first episode of confirmed or probable esophageal candidiasis or the second episode of confirmed vaginal or oropharyngeal candidiasis; and 3) confirmed or probable clinical resistance to fluconazole. Esophageal candidiasis was confirmed by histologic or cytologic evidence on microscopy or evidence of candidiasis on gross endoscopic inspection or at autopsy. Patients were considered to have had a probable episode of esophageal candidiasis if they had recent onset of dysphagia or odynophagia and had either a confirmed diagnosis of oropharyngeal candidiasis or a response to antifungal therapy. Oropharyngeal or vaginal candidiasis was confirmed by a positive culture for Candida species in the presence of two or more clinical signs or symptoms. Patients were considered to have had a probable episode of mucosal candidiasis if 1) the culture was positive and they had one clinical sign or symptom [other than white exudates for oropharyngeal candidiasis], 2) a potassium hydroxide preparation was positive and they had two or more clinical signs or symptoms, or 3) they responded to antifungal therapy and had two or more signs or symptoms. Confirmation of clinical resistance to fluconazole required all of the following: 1) confirmed or probable esophageal candidiasis, confirmed vaginal candidiasis, or confirmed oropharyngeal candidiasis; 2) no response to a previous course of antifungal therapy and the need for high-dose therapy with systemic azoles or intravenous amphotericin B; and 3) no other identifiable cause of the symptoms. The patients were considered to have had probable clinical resistance if the first two criteria were met but other causes for the symptoms could not be ruled out. Adverse events were graded on a five-point scale (I through V). We recorded events that were at least grade IV, that were not caused by the progression of HIV infection, and that led to discontinuation of treatment while patients were receiving the study medication and for 8 weeks thereafter. Follow-up The trial ended on 30 November 1995, which was 22 months after the last patient was randomly assigned. The median length of follow-up was 29 months. Every 3 months, we ascertained symptoms of candidiasis, collected a vaginal specimen for yeast culture, and documented concomitant treatments and new HIV-related diagnoses. Liver function tests were done and CD4+ cell counts were measured every 6 months. Substudy of in Vitro Resistance to Fluconazole A substudy examining in vitro resistance to fluconazole (CPCRA 029) was started 1 year after the primary study began. After patients were enrolled, vaginal specimens that were obtained at scheduled follow-up visits every 3 months were analyzed for susceptibility to five antifungal agents. Isolates that had been obtained for other end points of the primary study were also analyzed. We used microtiter methods for in vitro susceptibility testing in accordance with National Committee for Clinical Laboratory Standards [14]. In vitro resistance to fluconazole was defined as an MIC of 16 g/mL or less at 48 hours. Statistical Analysis Participating investigators were blinded to interim results. Treatment groups were compared according to each patients original assignment (intention-to-treat analysis); the comparison groups consisted of patients who received weekly fluconazole and patients who received placebo until prophylaxis failure, at which time daily fluconazole could be prescribed at the clinicians discretion. Analyses were stratified by CPCRA site in accordance with the randomization method. Baseline comparability was assessed using the Mantel-Haenszel chi-square or stratified analysis of variance [15, 16]. For clinical end points and adverse events, time-to-event methods (including Kaplan-Meier estimation, log-rank tests, and proportional hazards regression models) were used to compare treatment groups [17-19]. We also compared two-sided P values and 95% CIs for relative risks (RRs) of fluconazole with those of placebo. Natural history analyses could be done because our control group received placebo. For such analyses, a proportional hazards regression model was used to investigate the independent influence of the following baseline variables on risk for candidiasis: ethnic group, injection drug use, CD4+ cell count, history of mucosal candidiasis, presence of AIDS, prophylaxis for Pneumocystis carinii pneumonia, antiretroviral treatment, and result of vaginal yeast culture at baseline. Vaginal specimens were collected every 3 months and analyzed for colonization by Candida species using a model for longitudinal binary data; findings are summarized with relative odds estimates for fluconazole compared with placebo [20]. All analyses were done using SAS software (SAS Institute, Cary, North Carolina). The National Institute of Allergies and Infectious Diseases (NIAID) supported the clinical sites and statistical center responsible for gathering and analyzing the data. Staff members from NIAID were also part of the protocol team but had no role in the decision to publish the results of the study. Results Study Sample Between May 1992 and January 1994, 323 patients were enrolled in CPCRA 010; 162 were randomly ass

The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial.

ObjectiveEfficacy and safety of adefovir dipivoxil (adefovir) added to background antiretroviral therapy in advanced HIV disease. DesignRandomized, double-blind, placebo-controlled multicenter trial. SettingFifteen clinical trial units providing HIV primary care. ParticipantsAdults with CD4 cell count ⩽ 100 × 106/l, or 101–200 × 106/l with prior nadir ⩽ 50 × 106/l. InterventionsOral adefovir or placebo 120 mg once daily. Main outcome measuresSurvival, cytomegalovirus (CMV) disease, plasma HIV-RNA, CD4 cell count, grade 4 drug toxicity, permanent drug discontinuation due to toxicity. ResultsAmong the 253 patients assigned adefovir and the 252 assigned placebo, respectively, 17 and 16 died (P = 0.88), and four and eight experienced CMV disease (P = 0.25). Mean change in log10 plasma HIV-RNA in the adefovir and placebo groups, respectively, was 0.09 and −0.03 copies/ml at 6 months (P = 0.22) and 0.06 and −0.02 at 12 months (P = 0.87). Changes in CD4 cell counts were not different between groups. At 12 months the cumulative percent with proximal renal tubular dysfunction (PRTD) was 17% in the adefovir group and 0.4% in the placebo group (P < 0.0001, log rank test). Median time to resolution of PRTD was 15 weeks among patients assigned adefovir, and 16% of patients did not resolve completely 41 weeks after onset. More drug discontinuations occurred in the adefovir group than in the placebo group. ConclusionsNo virologic or immunologic benefit was observed when adefovir was added to background antiretroviral therapy in advanced HIV disease, and adefovir was associated with considerable nephrotoxicity. This study does not support the use of adefovir for treatment of advanced HIV disease in pretreated patients.

A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals

Objective:Evaluate safety and efficacy of oral ganciclovir (GCV) for preventing cytomegalovirus (CMV) disease in HIV-infected persons at high risk for CMV disease. Design:Double-blind, placebo-controlled, randomized clinical trial in primary care clinics and private practice offices specializing in the care of people with HIV. Interventions were oral GCV (1000 mg three times/day) or placebo. Protocol amendment allowed switch to open-label oral GCV. Main outcome measures were confirmed CMV retinal or gastrointestinal mucosal disease, and death. The study enrolled 994 people co-infected with CMV and HIV, with at least one CD4 count recorded < 100 × 106 cells/l. Results:At study completion (15 months median follow-up), CMV event rates in the oral GCV and control groups were 13.1 and 14.6 per 100 person years, respectively, a hazard ratio (HR) of 0.92 [95% confidence interval (CI), 0.65–1.27; P = 0.6]. At protocol amendment event rates were 12.7 and 15.0, respectively (HR, 0.85; 95% CI, 0.56–1.30; P = 0.45). At study completion, event rates for death were 26.6 and 32.0 (HR, 0.84; P = 0.09), and at protocol amendment were 18.9 and 19.6 (HR, 0.95; P = 0.78), respectively. At protocol amendment for the CMV endpoint, the oral GCV treatment effect was associated with baseline use of didanosine (ddI). For patients taking ddI at randomization, HR was 7.48 (P = 0.02). For patients not taking ddI, HR was 0.62 (P = 0.04). These HR were statistically different (P = 0.0006). Conclusions:In our study, 3 g/day oral GCV did not significantly reduce CMV disease incidence, but there was a suggestion of a death-rate reduction. Furthermore, results suggest that oral GVC decreased risk of CMV disease in patients not prescribed ddI, and increased risk in those prescribed ddI. For the CMV endpoint, our study differs markedly from the only similar study, although for the death endpoint, a combined analysis of studies indicated significant reduction in death rate.

Changes in Weight and Lean Body Mass during Highly Active Antiretroviral Therapy

BACKGROUND Few studies have prospectively evaluated the impact of highly active antiretroviral therapy (HAART) on body weight and lean body mass (LBM) or explored the impact of baseline immunologic or virological changes on these parameters. METHODS Adult AIDS Clinical Trials Group (ACTG) protocol 892 was a prospective, 48-week, multisite observational study of body composition conducted during 1997-2000 among 224 antiretroviral-naive and antiretroviral-experienced subjects coenrolled into various adult ACTG antiretroviral studies. Assessments included human immunodeficiency virus type 1 (HIV-1) RNA load (by polymerase chain reaction); T lymphocyte subset analysis; Karnofsky score; height (baseline only); weight, LBM, and fat (by bioelectrical impedance analysis); and functional performance (by questionnaire). RESULTS Overall, only modest median increases in body weight (1.9 kg) and LBM (0.6 kg) occurred after 16 weeks of therapy. Significantly greater median increases in body weight (2.1 vs. 0.5 kg; P=.045) occurred in subjects who achieved virological suppression (HIV-1 RNA load, <500 copies/mL) at week 16 than in subjects who did not. Subjects who were antiretroviral naive at baseline gained more weight (median increase in body weight, 2.6 vs. 0.0 kg; P<.001) and LBM (1.0 vs. 0.1 kg; P=.002) after 16 weeks of treatment than did subjects who were antiretroviral experienced. Subjects with lower baseline CD4 cell counts (<200 cells/mm3) and subjects with higher baseline HIV-1 RNA loads (> or =100,000 copies/mL) were more likely to show increases in LBM of >1.5 kg (P=.013 and P=.005, respectively). CONCLUSIONS HAART had modestly favorable effects on body composition, particularly in patients with greater pretreatment immunocompromise and virological compromise. The difference between antiretroviral-naive and antiretroviral-experienced subjects with regard to the ability to achieve increased body weight and LBM requires more study.

Pharmacokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers : ACTG study A5108

Background:Nelfinavir, an HIV protease inhibitor with numerous drug–drug interactions, is associated with dyslipidemia. Pravastatin is the preferred statin prescribed for HIV-associated dyslipidemia. Objective:To examine the effect of nelfinavir on pravastatin pharmacokinetics. Design:Open-label study in healthy HIV-seronegative adults conducted at the AIDS Clinical Trials Group sites in the United States. Methods:Subjects received pravastatin 40 mg daily and underwent intensive sampling for pharmacokinetics on day 3. Subjects took only nelfinavir 1250 mg twice daily on days 4–12. On days 13–15, subjects continued nelfinavir and reinitiated pravastatin. Plasma samples were collected over 24 h for the calculation of pravastatin area under the concentration–time curve for 0–24 h on days 3 and 16. Results:Data from 14 subjects with complete pharmacokinetic samples were available for analysis. The median within-subject percentage change in pravastatin AUC was a decrease of 46.5%. Pravastatin maximum plasma concentrations were also lower when pravastatin was administered with nelfinavir. Median values for the maximum plasma concentrations were 27.9 and 12.4 ng/ml for days 3 and 16, respectively, and the median within-subject decrease was 40.1%. Conclusions:Coadministration of pravastatin and nelfinavir led to a substantial reduction in pravastatin plasma concentrations. Higher doses of pravastatin may need to be prescribed in order to achieve optimal lipid-lowering activity.

Sustained Long-term Antiviral Maintenance Therapy in HCV/HIV Coinfected Patients (SLAM-C)

Background:Hepatitis C virus (HCV)/HIV coinfection treatment is suboptimal with low sustained viral response rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated interferon maintenance therapy was performed by the National Institutes of Health-funded AIDS Clinical Trials Group network. Methods:HCV treatment-naive and nonresponding interferon-experienced subjects with confirmed HCV and HIV, CD4 >200 cells per cubic millimeter, and at least stage 1 fibrosis were enrolled and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg per week (PEG) + weight-based ribavirin to determine response status. Nonresponder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist. Results:Three hundred thirty subjects were enrolled; median age was 48 years; 43% white, 37% black, non-Hispanic; 83% male; CD4+ 498 cells per cubic millimeter; 32% were interferon experienced; 74% had entry HIV RNA <50 copies per milliliter. early virologic responder was observed in 55.9% and 42.5% achieved complete Early Viral Response (cEVR). A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm. Conclusions:Lack of fibrotic progression in the control arm was unexpected and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression, and use of antiretroviral regimens that may be less toxic than prior generations of therapy.

Absence of Sustained Hyperlactatemia in Hiv-infected Patients With Risk Factors for Mitochondrial Toxicity

BackgroundThe prevalence of asymptomatic hyperlactatemia among HIV-infected individuals has been reported to be 4% to 36%. This variability may reflect differences in the definition of and risk factors for hyperlactatemia and/or techniques for venous lactate collection. MethodsWe examined the prevalence of elevated venous lactate collected in accordance with Adult AIDS Clinical Trials Group (AACTG) guidelines among HIV-infected and nucleoside analogue–treated subjects with risk factors associated with hyperlactatemia. Sustained hyperlactatemia was defined as 2 consecutive levels ≥1.5 but ≤4 times the upper limit of normal (ULN) within 30 days. ResultsEighty-three subjects were enrolled. Two thirds had ≥2 risk factors, with 11% having >4 risk factors. The median entry venous lactate level was 1.2 mmol/L (range: 0.7–5.1 mmol/L). Two subjects had a lactate level >1.5 times the ULN: 1 with a value of 2.1 times the ULN at entry and a week 2 level of 1.2 times the ULN and a second subject with a week 2 value of 1.9 times the ULN but an entry level of 1.4 times the ULN. The latter subject developed symptomatic lactic acidosis 3 weeks following study discontinuation. ConclusionsSustained asymptomatic hyperlactatemia among subjects with risk factors associated with hyperlactatemia was not observed when venous lactate was measured in a standardized fashion. One case of hyperlactatemia that evolved into symptomatic lactic acidosis was diagnosed soon after the completion of the study, however. Our findings indicate that asymptomatic hyperlactatemia is either very rare or an artifact of collection technique.