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CPCRA Protocol Specific Articles

  CPCRA 001 TOXO

Jacobson MA, Besch CL, Child C, Hafner R, Matts JP, Muth K, et al. Primary
prophylaxis with pyrimethamine for toxoplasmic encephalitis in patients with advanced HIV disease: Results of a randomized trial. J Infect Dis 1994;169:384-394.
This article is available as a PDF File

In a placebo-controlled study of clindamycin and pyrimethamine for prophylaxis of toxoplasmic encephalitis (TE), researchers found a significantly higher death rate among patients receiving pyrimethamine. There was insufficient power to compare the treatment arms with respect to prevention of TE because the event rate was too low; however, in observational analyses within each treatment group there was a difference in the event rate between patients receiving aerosolized pentamidine or trimethoprim-sulfamethoxazole for PCP prophylaxis. An additional TE prophylaxis may be unnecessary for patients receiving trimethoprim-sulfamethoxazole. Further research is necessary to define the dose and frequency of trimethoprim-sulfamethoxazole in preventing PCP and to identify the best TE prophylaxis regimen for patients who are TMS- intolerant.

Jacobson MA, Besch CL, Child C, Hafner R, Matts JP, Muth K, et al. Toxicity of clindamycin as prophylaxis for AIDS-associated toxoplasmic encephalitis. Lancet 1992;339(8789):333-334.
This article is available as a PDF File

In a placebo-controlled study of clindamycin and pyrimethamine for prophylaxis of toxoplasmic encephalitis (TE), researchers found that patients treated with clindamycin were more likely to experience an adverse effect that necessitated withdrawal of the study drug than those who received placebo. Therefore, the clindamycin arm was terminated prematurely, although the study continued in order to evaluate the efficacy of pyrimethamine for TE prophylaxis. The findings of this trial suggested that clindamycin, which has been identified as a candidate for TE prophylaxis, would be poorly tolerated as TE prophylaxis.

Jacobson MA, Besch CL, Child C, Hafner R, Muth K, Deyton L. Clinical Programs for Clinical Research on AIDS: Description of a randomized prospective study of clindamycin versus pyrimethamine for prevention of toxoplasma gondii infection. Eur J Clin Microbiol Infect Dis 1991;10(3):195-198.
This article is available as a PDF File

The CPCRA initiated a randomized, placebo-controlled study of clindamycin and pyrimethamine for prophylaxis of toxoplasmic encephalitis in patients who are coinfected with toxoplasma gondii and HIV. The study was designed to determine whether antimicrobial prophylaxis was superior to careful monitoring of at-risk patients and to evaluate the safety and efficacy of the two best candidate agents for preventing toxoplasmic encephalitis.

  CPCRA 002-DDI/DDC

Goldman AI, Carlin BP, Crane LR, Launer C, Korvick JA, Deyton L, et al. Response of CD4 lymphocytes and clinical consequences of treatment using ddI or ddC in patients with advanced HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 1996;11(2):161-169.
This article is available as a PDF File

The value of CD4+ lymphocyte counts as a surrogate marker in persons with advanced HIV-infection during antiretroviral treatment was assessed using longitudinal models and data from the CPCRA ddI/ddC trial of HIV-infected patients. A CD4 + cell count response was not a good surrogate marker in this study.

Fleming TR, Neaton JD, Goldman A, DeMets DL, Launer C, Korvick J, et al. Insights from monitoring the CPCRA didanosine/zalcitabine trial. J Acquir Immune Defic Syndr Hum Retrovirol 1995;10(Suppl.2)S9-S18.
This article is available as a PDF File

The design, conduct, and analysis of clinical trials that evaluate the safety and efficacy of treatment interventions in patients with HIV infection provide many scientific challenges. The results of this study provided important insights into how a data a safety monitoring board can reduce the risk of inappropriate early study termination. The trial also provided valuable insights into how treatment effects should be assessed, revealing inconsistencies between effects on the CD4 surrogate end point and effects on primary clinical efficacy end points and showing the incompleteness of the standardly employed definition of AIDS progression. Finally, the results of this ddI/ddC trial are used to examine the role of covariate adjustment.

Abrams DI, Goldman AI, Launer C, Korvick JA, Neaton JD, Crane LR, et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. N Engl J Med 1994;330(10):657-662.
This article is available as a PDF File

The CPCRA multicenter, open-label trial compared didanosine and zalcitabine monotherapy in HIV-infected patients with CD4+ cell counts <300 mm3 or AIDS who could not tolerate zidovudine treatment or who have had disease progression despite it. The study found that zalcitabine was as efficacious as didanosine in delaying disease progression, including death, and suggested to clinicians that zalcitabine can be used as an alternative second-line therapy. The toxicity profiles of didanosine and zalcitabine should be an important consideration in choosing the appropriate antiretroviral therapy for individual patients.

  CPCRA 003-ODB

Torres RA, Neaton J, Wentworth D, Barr MR, Abrams D, Sherer R, et al. Acyclovir use and survival among human immunodeficiency virus-infected patients with CD4 cell counts of<500/mm3. Clin Infect Dis 1998;26:85-90.
This article is available as a PDF File

The study analyzes the effects of acyclovir use on survival and disease progression in a large cohort of HIV-infected persons enrolled in an observational study. This is the largest reported observational multicenter cohort of HIV-infected patients followed prospectively over time, where the effect of acyclovir use on mortality has been analyzed. Overall, 31% of the patients enrolled in cohort reported taking acyclovir at some time during followup, and 15% reported taking the drug at baseline. Increased mortality rated were associated with acyclovir use, irrespective of previous history of herpes simplex or zoster, or previous AIDS diagnosis. If acyclovir use does confer a survival benefit to HIV-positive persons, that benefit is likely to be small and will only be reliably detected through a well-planned, adequately powered, randomized and controlled prospective clinical trial with long-term follow-up and retention of study participants.

Burns DN, Hillman D, Neaton JD, Sherer R, Mitchell T, Capps L, et al. Cigarette
smoking, bacterial pneumonia and other clinical outcomes in HIV-1 Infection. JAIDS 1996;13(4):374-383.
This article is available as a PDF File

Cigarette smoking has been associated with impaired immune defenses and an increased risk of certain infectious and neoplastic diseases in HIV-1 seronegative populations. Differences in clinical outcomes between never, former, and current cigarette smokers were assessed using proportional hazard regression analysis. After adjustment for CD4+ cell count, prior disease progression, use of antiretroviral therapy, and other covariates, there was no difference between current smokers and never smokers in the overall risk of opportunistic diseases or death. However, current smokers were more likely to develop bacterial pneumonia, oral candidiasis, and AIDS dementia complex. In addition, current smokers were less likely to develop Kaposi's sarcoma and several other non-respiratory tract diseases. If confirmed by other studies, these findings have important clinical implications.

  CPCRA 004/ACTG 177-TB/PPD+

Gordin FM, Cohn D, Matts JP, Chaisson RE, O'Brien RJ. Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: Is it different than in HIV-negative persons?. Clin Infect Dis August 15, 2004;39(4):561-565.
This article is available as a PDF File

Background. In 2000, results of a multinational trial demonstrated that a 2-month course of rifampin and pyrazinamide (RZ) was as effective as isoniazid (INH) in reducing tuberculosis in human immunodeficiency virus (HIV) infected individuals with latent tuberculosis infection (LTBI). After the release of new guidelines, the Centers for Disease Control and Prevention received reports of severe hepatotoxicity associated with the use of the RZ regimen for the treatment of LTBI in the general population. To better understand the occurrence of hepatotoxicity in an HIV-infected population, we conducted a more detailed analysis of the liver function test results obtained in the multinational trial of RZ.
Methods. At study entry, patients were required to have a bilirubin level of =2.5 mg/dL and both an aspartate aminotransferase (AST) level and an alkaline phosphatase level of =5 times the upper limit of normal. Patients with acute hepatitis were excluded. At months 1 and 2 of the study, all patients had bilirubin and AST levels measured.
Results. There was no difference between the RZ and INH groups with regard to AST level or bilirubin level at baseline. An increase in the AST level of =40 U/L was associated with the use of INH and older age; and an increase in the bilirubin level of =0.5 mg/dL was associated with the use of RZ, male sex, and nonwhite race (P <.05). An absolute AST level of >250 U/L occurred in 12 of 745 INH recipients and in 15 of 721 RZ recipients (P = .56), and an absolute bilirubin level of >2.5 mg/dL occurred in 5 of 743 INH recipients and 13 of 718 RZ recipients (P = .06).
Conclusions. These data demonstrate very little liver injury associated with either INH or RZ in the HIV- infected subjects, leaving unclear the reasons for serious RZ-related liver damage in the general population.

Gordin F, Chaisson RE, Matts JP, Miller C, de Lourdes Garcia M, Hafner R, et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: An international randomized trial. JAMA 2000;283(11):1445-1450.
This article is available as a PDF File

This paper describes a randomized open-label controlled trial that studied HIV-positive persons with a positive tuberculin skin test in outpatient clinics in the United States, Mexico, Haiti, and Brazil. The study compared a 2-month regimen of daily rifampin-and-pryazinamide with a 12-month regimen of daily isoniazid in preventing tuberculosis in HIV-infected persons. The primary endpoint was culture proven tuberculosis. Secondary endpoints were proven or probable tuberculosis, adverse events and death. There were no significant differences in rates for confirmed or probable tuberculosis, HIV progression, death, or overall adverse events. Neither regimen appeared to lead to the development of drug-resistant tuberculosis. The study concluded that, for preventing tuberculosis in HIV-infected patients, a regimen of rifampin-and-pyrazinamide, given daily for 2 months, is similar in safety and efficacy to a 12-month regimen of daily isoniazid. This shorter regimen offers practical advantages both to patients and to tuberculosis control programs.

  CPCRA 005-TB Anergic

Gordin FM, Matts JP, Miller C, Brown LS, Hafner R, John SL, et al. A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. N Engl J Med 1997;337(5):315-20.
This article is available as a PDF File

This study evaluated the effectiveness of providing isoniazid prophylaxis to anergic, HIV-infected persons with risk factors for tuberculosis. Due to the low incidence of tuberculosis in our study, we observed no significant benefit associated with isoniazid use. This cohort was highly representative of groups perceived to be at risk for tuberculosis in the United States and, without a more accurate method to detect latent tuberculosis, it would not be possible to identify individuals who are likely to benefit from prophylaxis. The results of this study, therefore, do not support the use of isoniazid preventive therapy for HIV-infected, anergic individuals in the United States as had been suggested by the CDC other than in specific high-risk situations, such as individuals who are recent close contacts of active cases of tuberculosis.

  CPCRA 006-PCP-TMS

El-Sadr WM, Luskin-Hawk R, Yurik TM, Walker J, Abrams D, John SL, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in Human Immunodeficiency Virus-infected persons. Clin Infect Dis 1999;29:775-783.
This article is available as a PDF File

We enrolled 2,625 human immunodeficiency virus-infected patients into a randomized trial to assess the efficacy and tolerability of daily vs. thrice-weekly trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis carinii pneumonia (PCP). Overall estimates for efficacy end points favored daily trimethoprim-sulfamethoxazole, although rates of intolerance were higher among patients receiving that dose. Daily trimethoprim-sulfamethoxazole may offer advantages as a first choice for PCP prophylaxis; thrice-weekly dosing is an appropriate option for patients intolerant of the daily dose.

  CPCRA 007-NuCombo

Saravolatz LD, Winslow DL, Collins G, Hodges JS, Pettinelli C, Stein DS, et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immune deficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. N Engl J Med 1996;335(15):1099-1106.
This article is available as a PDF File

In patients with advanced HIV infection, combination therapy with zidovudine and either didanosine or zalcitabine was studied and found not to be superior to zidovudine therapy alone. However, these combinations may be more effective than zidovudine monotherapy in patients with little or no previous zidovudine treatment.

  CPCRA 008-TB Booster

Webster CT, Gordin FM, Matts JP, Korvick JA, Miller C, Muth K, et al. Two-stage tuberculin skin testing in individuals with human immunodeficiency virus infection. Am J Respir Crit Care Med 1995;151: 805-808.
This article is available as a PDF File

The investigators in this CPCRA study estimated the occurrence of the booster effect in a population infected with the human immunodeficiency virus (HIV) and assessed the relationship between the booster effect, T-lymphocyte CD4+ cell counts, tuberculosis (Tb) risk categories, and HIV exposure categories. The major conclusions and impact on clinical practice showed the following: 1) the booster effect occurs in a small percentage (2.7%) of HIV-infected patients; 2) age, race, CD4 cell count, IDU, anergy status, Tb risk factors, and HIV exposure categories were NOT predictive of boosting; and 3) the two-stage procedure is probably of limited value in the diagnosis of latent tuberculosis infection in HIV-infected persons.

  CPCRA 009/ACTG 196 - MAC Prophylaxis

Benson CA, Williams PL, Cohn DL, Becker S, Hojczyk P, Nevin T, et al. Clarithromycin or rifabutin alone or the combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS. A randomized, double-blind, placebo-controlled trial. J Infect Dis 2000;181:1289-97.
This article is available as a PDF File

The efficacy and safety of clarithromycin, rifabutin, and the combination for prevention of Mycobacterium avium complex (MAC) disease were compared in a randomized, double-blinded, placebo-controlled trial in 1178 patients with AIDS and < 100 CD4+ T cells/µL. Clarithromycin reduced the risk of MAC disease by 44% and the combination by 57% compared with rifabutin. The combination was not more effective than clarithromycin. There were no differences in survival in the three arms. From patients who failed prophylaxis with clarithromycin or the combination, 29% and 27% of MAC isolates, were resistant to clarithromycin, respectively. Dose-limiting adverse effects occurred in 16% of those on clarithromycin, 18% on rifabutin, and 31% on the combination. This study supports the recommendation for use of clarithromycin as a first-line agent for the prevention of MAC disease in patients with HIV infection and advanced immunosuppression, but not the use of combination therapy for prophylaxis.

  CPCRA 010-Women's Fungal

Vazquez JA, Peng G, Sobel JD, Steele-Moore L, Schuman P, Holloway W, Neaton JD. Evolution of antifungal susceptibility among Candida species isolates recovered from Human Immunodeficiency Virus-infected women receiving fluconazole prophylaxis. Clin Infect Dis 2001; 33:1069-1075.
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The effect of fluconazole on the susceptibility of Candida isolates recovered from women infected with human immunodeficiency virus (HIV) was evaluated in a randomized, double-blind, placebo-controlled trial. Women with CD4+ cell counts of <300 cells/mm3 received either fluconazole (200 mg/week) or placebo as prophylaxis. The antifungal susceptibility of specimens was evaluated. One patient who received fluconazole and 2 patients assigned to placebo had Candida Albicans isolates recovered that were resistant to fluconazole (MIC, >64 µg/mL). Eleven patients assigned fluconazole and 4 patients assigned placebo has non-albicans Candida strains (all Candida glabrata) recovered that were resistant to fluconazole. There was significant azole cross-resistance among the non-albicans Candida species isolates. Although the rate of azole resistance did not significantly increase after fluconazole prophylaxis, there was a trend toward more in vitro azole resistance in C. glabrata isolates from patients assigned fluconazole. Moreover, the majority of resistant vaginal isolates of Candida species were recovered after initiation of open-label fluconazole use.

Vazquez JA, Sobel JD, Peng G, Steele-Moore L, Schuman P, Holloway W, et al. Evolution of vaginal Candida species recovered from Human Immunodeficiency Virus-infected women receiving fluconazole prophylaxis: The emergence of Candida glabrata? Clin Infect Dis 1999;28:1025-31.
This article is available as a PDF File

The effect of fluconazole prophylaxis on the vaginal flora of 323 HIV-infected women was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. The effect of fluconazole prophylaxis can be attributed to the reduction in vaginal C. albicans colonization; however, C. glabrata colonization rapidly supervened.

Capps, L.; Peng, G.; Doyle; El-Sadr, W.; Neaton, JD. Sexually transmitted infections in women infected with the human immunodeficiency virus. Sex Transm Dis 1998;25(8):443-447.
This article is available as a PDF File

Twenty-five percent of 323 HIV-infected women developed new STIs while participating in a trial. Prevention efforts should be emphasized among high-risk HIV-infected patients.

Schuman P, Capps L, Peng G, Vazquez J, El-Sadr W, Goldman AI, et al. Weekly
fluconazole for the prevention of mucosal candidiasis in women with HIV infection. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997;126(9):689-696.
This article is available as a PDF File

In patients with HIV infection, mucosal candidiasis is a frequent complication. Weekly fluconazole (200 mg) appears safe and effective in preventing oropharyngeal and vaginal candidiasis. This regimen has a useful role in the management of HIV-infected women at risk for recurrent mucosal candidiasis.

  CPCRA 017-TB Registry

Gordin FM, Nelson ET, Matts JP, Cohn DL, Ernst J, Benator D, et al. The impact of human immunodeficiency virus on drug-resistant tuberculosis. Am J Respir Crit Care Med 1996;154(5):1478-1483.
This article is available as a PDF File

In order to examine the relationship of HIV infection to drug-resistant tuberculosis in other selected regions of the United States, a registry of cases of culture-proven tuberculosis was established. Results of this study showed that HIV infection is associated with increased rates of resistance to antituberculosis drugs in the New York City area. In areas outside of New York City, HIV-infected U.S.-born persons have higher rates of drug resistant tuberculosis than non-HIV infected U.S.-born persons. MDR tuberculosis is occurring predominantly in the New York City area and is highly correlated with HIV infection.

  CPCRA 018-TB/HCWs

Zahnow K, Matts JP, Hillman D, Finley E, Brown Jr LS, Torres RA, et al. Rates of tuberculosis infection in healthcare workers providing services to HIV-infected populations. Infect Control Hosp Epidemiol 1998;19:829-835.
This article is available as a PDF File

The objective of the study was to determine the relationship of demographic and occupational factors to tuberculosis infection rates in health care workers (HCWs) providing services to HIV-infected individuals. Neither the percentage of patients seen who were HIV-infected, nor the amount of contact with HIV-infected patients was related to the rate of tuberculosis infection. These data provide some reassurance that caring for HIV-infected patients is not in and of itself related to an increased prevalence of tuberculosis infection among HCWs. The risk of tuberculosis infection appears to be related to the prevalence of the disease in the individual community.

  CPCRA 019/ACTG 222-TB Treatment

El-Sadr WM, Perlman DC, Matts JP, Nelson ET, Cohn DL, Salomon N, et al. Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Clin Infect Dis 1998;26:1148-1158.
This article is available as a PDF File

The rise of tuberculosis (TB), including drug-resistant TB, among HIV-infected patients underscores the importance of identifying new agents and regimens that improve treatment outcomes. This study examined the response to a largely intermittent four-drug regimen (isoniazid, rifampin, pyrazinamide, ethambutol) and whether adding a quinolone, levofloxacin, would improve 8-week culture response to therapy in HIV-related pulmonary TB. The study results provide strong evidence that a four-drug largely intermittent induction regimen is highly efficacious in the initial treatment of HIV-related pulmonary TB. Both regimens were comparably well tolerated. There was no added benefit noted with the addition of levofloxacin in this population.

Perlman DC, El-Sadr WM, Nelson ET, Matts JP, Telzak EE, Salomon N, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. Clin Infect Dis 1997;25:242-246.
This article is available as a PDF File

This paper evaluates the effect of HIV disease stage on chest radiograph (CXR) findings among patients with HIV-related pulmonary tuberculosis. The study demonstrates associations of certain CXR findings with HIV disease stage. Knowledge of immunosuppression level is important when evaluating CXR in HIV-infected patients which may reflect variations in pathophysiology at different degrees of immunosuppression.

Perlman DC, El-Sadr WM, Heifets LB, Nelson ET, Matts JP, Chirgwin K, et al. Susceptibility to levofloxacin of Mycobacterium tuberculosis isolates from patients with HIV-related tuberculosis and characterization of a strain with levofloxacin monoresistance. AIDS 1997;11:1473-1478.
This article is available as a PDF File

This paper reports on the susceptibility to levofloxacin on Mycobacterium tuberculosis isolates from patients with HIV related TB. One isolate, obtained from a patient who had been treated with levofloxacin for chronic bronchiectasis, was resistant with an MIC = 16 Fg/mL and was demonstrated to have a unique point mutation in gyrA. 134/135 isolates (99%) were susceptible with an MIC # 1.0 Fg/mL. Clinical TB isolates were generally susceptible to levofloxacin. However, the occurrence of resistance highlights the need for circumspection in the use of fluoroquinolones in the setting of potential TB and for monitoring of fluoroquinolone resistance rates.

  CPCRA 022-Acupuncture

Shlay JC, Chaloner K, Max MB, Flaws B, Reichelderfer P, Wentworth D, et al. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: A randomized controlled trial. JAMA 1998;280:1590-1595.
This article is available as a PDF File

In a randomized, placebo-controlled trial with patients enrolling into one of three options: a standardized acupuncture regimen (SAR) versus control points (CP), amitriptyline (75 mg) versus placebo, or both using 2x2 factorial design, patients received treatment for 14 weeks and rated their pain daily in a diary. Of 250 patients enrolled, 239 were in the acupuncture comparison and 136 were in the amitriptyline comparison. For both the acupuncture and amitriptyline comparison, change in pain score was not significantly different between the two groups. This is the largest reported randomized, placebo-controlled clinical trial of symptomatic treatment of HIV-related peripheral neuropathy. Neither this SAR nor amitriptyline was effective in relieving pain. Additional clinical trials in HIV-associated neuropathies are needed.

  CPCRA 023-CMV

Brosgart CL, Louis TA, Hillman DW, Craig CP, Alston B, Fisher E, et al. A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals. AIDS 1998;12(3):269-277.
This article is available as a PDF File

The safety and efficacy of oral ganciclovir for preventing CMV disease in persons with severe immunosuppression were evaluated. The major findings were as follows: 1) oral ganciclovir did not prevent CMV retinal or gastrointestinal mucosal disease; 2) oral ganciclovir did not prevent death; 3) oral ganciclovir did not prevent CMV disease or death; 4) oral ganciclovir was significantly associated with more reportable adverse experiences; 5) oral ganciclovir was significantly associated with more grade 3 or higher neutropenia events; and 6) a subgroup analysis suggested a possible ddI-oral ganciclovir interaction that requires further research.

  CPCRA 026/ACTG 238-MDRTB

Telzak EE, Chirgwin KD, Nelson ET, Matts JP, Sepkowitz KA, Benson CA, et al. Predictors for multidrug-resistant tuberculosis among HIV-infected patients and response to specific drug regimens. Int J Tuberc Lung Dis 1999;3(4):337-43.
This article is available as a PDF File

Mortality associated with HIV-related multidrug-resistant tuberculosis (MDRTB) is reduced with effective early therapy. Identifying predictors of, and effective regimens for, MDRTB is critical. Patients were prospectively evaluated for MDRTB. The conclusions reached showed that a history of treatment for tuberculosis was the only predictor for MDRTB among a cohort of HIV-infected patients with tuberculosis. In addition, this prospective study supports the results of prior retrospective studies that effective treatment impacts on mortality. Current second-line treatment, including high dose levofloxacin, appears to be well tolerated.

  CPCRA 027-MAC Treatment

Cohn DL, Fisher EJ, Peng GT, Hodges SJ, Chesnut J, Child CC, et al. A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: Excess mortality associated with high-dose clarithromycin. Clin Infect Dis 1999;29:125-33.
This article is available as a PDF File

The optimal regimen for treatment of Mycobacterium avium complex (MAC) disease has not been established. Eighty-vie AIDS patients with disseminated MAC disease were randomized to receive a three-drug regimen of clarithromycin, rifabutin of clofazimine, and ethambutol. Two dosages of clarithromycin were compared. The Data and Safety Monitoring Board recommended discontinuation of the clarithromycin dosage comparison and continuation of the rifabutin vs. clofazimine comparison. Bacteriologic outcomes were similar among treatment groups. In treating MAC disease in AIDS patients, the maximum dose of clarithromycin should be 500 mg. b.i.d.

  CPCRA 030-Fluconazole/Methadone-pk

Cobb MN, Desai J, Brown Jr LS, Zannikos PN, Rainey PM. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther 1998;63:655-62.
This article is available as a PDF File

This paper describes a study which evaluated the pharmacokinetics of methadone in the presence of fluconazole therapy in patients on methadone maintenance. The study demonstrated that methadone concentrations were increased, although renal clearance was not affected. Despite the exposure to higher methadone, fluconazole-treated patients did not exhibit signs or symptoms of narcotic overdose.

  CPCRA 034/ACTG 277-PCP-INT2

El-Sadr WM, Murphy RL, Yurik TM, Luskin-Hawk R, Cheung TW, Balfour HH, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med 1998;339:1889-1895.
This article is available as a PDF File

This paper describes a multicenter, open-label, randomized trial comparing daily atovaquone with daily dapsone for the prevention of P. carinii pneumonia among patients infected with HIV who could not tolerate trimethoprim-sulfamethoxazole. P. carinii pneumonia developed in 122 of 536 patients assigned to atovaquone, as compared with 135 of 521 in the dapsone group. The rates of P. carinii pneumonia were similar in the two treatment groups. It was concluded that, among patients who cannot tolerate trimethoprim-sulfamethoxazole, atovaquone and dapsone are similarly effective for the prevention of P. carinii pneumonia. The 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.

  CPCRA 038-Nutrition

Williams SB, Bartsch G, Muurahainen N, Collins G, Raghavan SS, Wheeler D. Protein intake is positively associated with body cell mass in weight-stable HIV-infected men. J Nutrition 2003; 133:1143-1146.
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Gibert CL, Wheeler DA, Collins D, Madans M, Muurahainen N, Raghavan SS, et al.
Randomized, controlled trial of caloric supplements in HIV infection. JAIDS, 1999;22:253-259.
This article is available as a PDF File

The objective of the study was to compare the efficacy of three nutritional regimens in the prevention of weight loss. The design was a three-arm randomized, controlled trial with primary outcome measure percent change in weight over 4 months. There were no significant differences among the three regimens in the percent change in weight and body cell mass. The study concluded that caloric supplements do not promote increases in average weight or body cell mass in weight-stable, HIV-infected adults beyond that offered by a multivitamin and mineral supplement.

Muurahainen N, Mulligan K. Clinical trials update in Human Immunodeficiency Virus wasting. Semin Oncol 1998;25(6)104-111.
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The major acquired immunodeficiency syndrome (AIDS) clinical trials groups in the Division of AIDS of the NIH have been investigating weight loss and wasting in persons with the human immunodeficiency virus (HIV) and AIDS. This article reviews multicenter trials concerning HIV-related malnutrition and wasting conducted by the AIDS clinical trials groups. CPCRA trials will examine the effects of caloric supplements and triglycerides, or the use of megestrol acetate, oxandrolone, and progressive resistance training, on weight loss in patients with HIV-associated wasting. Planned ACTG trials will study the effects of the combination of megestrol acetate and testosterone, the testosterone derivative nandrolone decanoate, or highly active antiretroviral therapy on weight loss. Results from these studies may also have relevance to clinical oncologists who are treating patients with cancer-related cachexia.

  CPCRA 039 - bis-POM

Fisher EJ, Chaloner K, Cohn DL, Bjorling Grant L, Alston B, Brosgart CL, Schmetter B, El-Sadr WM, Sampson J. 2000. The safety and efficacy of adefovir dipivoxil in persons with advanced HIV disease: a randomized, prospective trial. AIDS 2001; 15:1695-1700.
This article is available as a PDF File

Objective: Efficacy and safety of adefovir dipivoxil (adefovir) added to background antiretroviral therapy in advanced HIV disease.
Design: Randomized, double blind, placebo-controlled trial. Setting: Multicenter clinical trials program. Participants: Adults with CD4+ cell count 100/µL, or 101-200/µL with prior nadir 50/µL. Interventions: Oral adefovir or placebo 120 mg daily. Primary outcome measures: Survival, cytomegalovirus (CMV) disease.
Results: Among the 253 patients assigned adefovir and the 252 assigned placebo, respectively, 17 and 16 died (relative risk=1. 05; 95% CI: 0.53 to 2.09; p-value=0.88), and 4 and 8 experienced confirmed CMV disease (relative risk=0.49; 95% CI: 0.15 to 1.64; p-value=0. At 12 months the cumulative percent with nephrotoxicity was 17% in the adefovir group and 0.4% in the placebo group (log rank p-value<0.0001). Among patients assigned adefovir, median time to resolution of PRTD was 15 weeks, and 16% of patients did not resolve. There were no differences in grade 4 toxicities; significantly more drug discontinuations occurred in the adefovir group.
Conclusions: Evaluation of clinical endpoints was inconclusive due to low event rates. A significantly higher rate of nephrotoxicity was observed in patients assigned adefovir. This study does not support the use of adefovir 120 mg daily for to prolong survival or prevent CMV disease in patients with advanced HIV disease.

  CPCRA 042 - NvR

Loutfy M, Walmsley S, Mullin C, Perez G, Neaton J. CD4+ increase predicts clinical benefit in patients with advanced HIV with persistent viremia after one year of combination antiretroviral therapy. J Infect Dis 2005(15 October);192:1407-1411.
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The relationship between 12-month CD4+ cell count response and clinical outcome (AIDS-defining event or death) in a subset of 228 patients with human immunodeficiency virus load >400 copies/mL despite receiving combination antiretroviral therapy as part of a larger randomized trial was defined by use of Cox models. The 12-month CD4+ cell count responses were divided into 5 categories, ranging from decrease or no change (19% of patients) to a >100-cell/mm3 increase (27% of patients). There was a lower risk of clinical progression for each incremental increase in CD4+ cell count response. A 25-cell/mm3 increase in CD4+ cell count was associated with a 21% reduction in the risk of an AIDS-defining event or death (P<.0001).

MacArthur RD, Perez G, Walmsley S, Baxter JD, Mullin CM, Neaton JD. Comparison of prognostic importance of latest CD4+ cell count and HIV RNA levels in patients with advanced HIV infection on highly active antiretroviral therapy. HIV Clin Trials 2005;6(3):127-135.
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The comparative prognostic importance of latest plasma HIV RNA levels (viral loads) and CD4+ cell counts among patients prescribed highly active antiretroviral therapy (HAART) has not been well characterized. Method: We assessed the prognostic value of latest CD4+ cell counts and latest viral loads for progression to AIDS or death and explored their interaction among 432 HIV-infected persons with advance HIV who were prescribed a protease inhibitor (PI) as their first HAART regimen. Results: Pre-HAART median CD4+ cell count and viral load were 41 cells/mm3 and 126,331 copies/mL, respectively. After 12 months of HAART, the median CD4+ cell count was 154 cells/ mm3; 39% of patients had a viral load of 400 copies/mL or lower. Over a median follow-up of 33 months, 109 (25%) of the 432 patientsw experienced an AIDS event or died. The hazard ratio for AIDS or death for those with latest CD4+ cell count <50 cells/mm3 versus >200 cells/mm3 was 13.9 (95% CI 6.5 to 29.7) without adjustment for latest viral load measurements and 9.5 (95% CI 4.0 to 22.5) after adjustment for latest viral load. In contrast, the hazard ratio for AIDS or death for those with viral load >100,000 versus <400 copies/mL was 4.2 (95% CI 2.3 to 7.7) without adjustment for latest CD4+ level and 1.2 (95% CI 0.6 to 2.4) with adjustment for latest CD4+ cell count. Conclusion: We conclude that when latest CD4+ cell count and viral load are considered separately, both are significantly related to AIDS or death; when these markers are jointly considered, the association of viral load with AIDS or death is substantially diminished. Latest CD4+ levels are more strongly related to AIDS or death than latest viral load levels in patients on HAART.

Perez G, MacArthur R, Walmsley S, Baxter J, Mullin C, Neaton J. A multinational randomized clinical trial comparing nelfinavir and ritonavir in 775 patients (CPCRA 042/CTN 102). HIV Clin Trials 2004;5(1):7-18.
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Purpose: To compare the long-term clinical efficacy and toxicity of initial strategies of nelfinavir (NFV) or ritonavir (RTV) in patients with CD4+ cells below 200/mm3.
Method: This was an open-label randomized multicenter trial (CPCRA, CTC). Patients were naïve to protease inhibitor use except for hard gel saquinavir. Patients who were intolerant to their assigned therapy were allowed to switch arms (later RTV-intolerant patients could switch to indinavir). The primary objective was to compare the regimens for AIDS-defining conditions and death (AIDS/death) using intent-to-treat analysis. Hazard ratios (HR) for NFV and RTV were estimated using Cox’s proportional hazards models. Kaplan-Meier life table summaries were also used to compare the two groups.
Results: There were 775 patients who were randomized beginning in January 1997 and followed through December 2001. At entry, mean CD4+ cell count was 58 cells/mm3 and the HIV RNA level averaged 4.9 log copies/mL. After a median follow-up of 52 months, rates of AIDS/death were 12.7 and 11.0 per 100 person years for the NFV and RTV groups, respectively (HR=1.16;95% Cl, 0.92-1.46; p=.21). Discontinuations occurred earlier in the RTV group (p=.0001).
Conclusion: There are moderate differences in efficacy and large differences in tolerability between a strategy of initial NFV or RTV in patients with advanced disease. Finding the right balance between potency and tolerability remains a challenge. Key words: clinical endpoints, protease inhibitors, tolerability.

  CPCRA 046 - GART

Baxter JD, Merigan TC, Wentworth DN, Neaton JD, Hoover ML, Hoetelmans RMW, et al. Both baseline HIV-1 drug resistance and antiretroviral drug levels are associated with short-term virological responses to salvage therapy. AIDS 2002; 16:1131-1138.
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To determine the impact of HIV-1 drug resistance at baseline and antiretroviral drug levels (DL) during follow-up on virologic response to the next antiretroviral regimen. Conclusions: In salvage therapy, both the number of active drugs and the DL for each drug in the new regimen determine the antiviral response.

Weinstein MC, Goldie SJ, Losina E, Cohen CJ, Baxter JD, Zhang H, et al. Use of genotypic resistance testing to guide HIV therapy: Clinical impact and cost-effectiveness. Ann Intern Med 2001; 134:440-450.
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To assess the cost-effectiveness of genotyping resistance testing for patients acquiring drug resistance through failed treatment (secondary resistance) and those infected with resistant virus (primary resistance). Conclusions: Genotypic antiretroviral resistance testing following antiretroviral failure is cost-effective. Primary resistance testing also seems to be reasonably cost-effective and will become more so as the prevalence of primary resistance increases.

Winters MA, Baxter JD, Mayers DL, Wentworth DN, Hoover ML, Neaton JD, et al.
Frequency of antiretroviral drug resistance mutations in HIV-1 strains from patients failing triple drug regimens. Antiviral Therapy 2000, 5(1):57-63.
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This paper describes a prospective randomized controlled trial (CPCRA 046) that determined the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. 153 HIV-infected adults with a three-fold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy were studied. Randomization was either to a GART group, where genotype interpretation and suggested regimens (the GART report) were provided to clinicians, or to a No-GART group, where treatment choices were made without such input. The primary endpoint was change in plasma HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. The average baseline CD4 cell count was 230 cells/mm3 and the median plasma HIV-1 RNA was 28,085 copies/mL. The number of drugs prescribed to which the patients' HIV-1 appeared susceptible (active drugs) was significantly greater in the GART compared with the No-GART group. The results showed that, in patients failing triple drug therapy, GART with expert advice was superior to No-GART as measured by short-term viral load responses.

Baxter JD, Mayers DL, Wentworth DN, Neaton JD, Hoover ML, Winters MA, et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. AIDS 2000 14(9)F83-F93.
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This paper describes the CPCRA 046 GART study, a randomized controlled trial to determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a proteasse inhibitor and two nucleoside reverse transcriptase inhibitors. The study included 153 HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. The average baselinee CD4 cell count was 230x106 cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the no-GART patients (treatment difference: -0.53 log, 95% confidence interval), -0.77 to -0.29; P=0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. Conclusion: In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

DeGruttola V, Dix L, D'Aquila R, Holder D, Phillips A, Ait-Khaled M, Baxter J, et al. The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standardized data analysis plan. Antiviral Therapy 2000; 5:41-48.
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To assess the relation between resistance to antiretroviral drugs for treatment of HIV-1 infection and virological response to therapy, results from 12 different studies were re-analysed according to a standard data analysis plan. These studies included nine clinical trials and three observational cohorts. The primary end-point in our analyses was virological failure by week 24. Baseline factors that were investigated as predictors of virological failure were plasma HIV-1 RNA, the number and type of new antiretroviral drugs in the regimen, and viral susceptibility to the drugs in the regimen, determined by genotyping or phenotyping methods. These analyses confirmed the importance of both genotypic and phenotypic drug resistance as predictors of virological failure, whether these factors were analysed separately or adjusted for other baseline confounding factors, In most of the re-analysed studies, the odds of virological failure were reduced by about twofold for each additional drug in the regimen to which the patient's virus was sensitive by genotyping methods, and by about two-to threefold for each additional drug that was sensitive by phenotyping.

  CPCRA 048 - CR-MAC

El-Sadr WM, Burman WJ, Bjorling Grant L, Matts JP, Hafner R, Crane L, et al. Discontinuation of prophylaxis against Mycobacterium avium complex in HIV-infected patients who have a response to antiretroviral therapy. N Engl J Med 2000;342(15):1085-1092.
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This paper describes a multicenter, double-blind, randomized trial comparing azithromycin with placebo among patients whose CD4+ cell count increased from <50 to >100 cell/mm3 with antiretroviral therapy. The primary endpoint of the trial was disseminated MAC or bacterial pneumonia. A total of 520 patients were enrolled in the study; 65% had a prior AIDS-defining illness; the results showed that there were no episodes of disseminated MAC in either treatment group. In addition, there was no difference in the rates of disseminated MAC or bacterial pneumonia in the azithromycin or placebo arms of the study. The study demonstrated that deferral or withdrawal of azithromycin prophylaxis is safe among HIV-infected patients who have experienced CD4+ cell rebound to >100 cells/mm3 due to antiretroviral therapy. This policy can simplify treatment regimens, decrease adverse events, decrease risk of antimicrobial resistance and may improve adherence to other therapies.

  CPCRA 058 - FIRST

MacArthur RD, Novak RM, Peng G, Chen L, Xiang Y, Huppler Hullsiek K, Kozal MJ, Van den Berg-Wolf M, Henely C, , Schmetter B, Dehlinger M. Long-Term Clinical and Immunologic Outcomes Are Similar in HIV-Infected Persons Randomized to NNRTI vs PI vs NNRTI+PI-based Antiretroviral Regimens as Initial Therapy: Results of the CPCRA 058 FIRST Study. The Lancet December 16, 2006;368:2125-2135.
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Editorial: Abgrall S. Initial strategy for antiretroviral-naïve patients. The Lancet December 16, 2006;368:2107-2109.
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Background: Long-term data from randomized trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes. Methods: Between 1999 and 2002, 1397 antiretroviral-treatment-naïve patients, presenting at 18 clinical trial units with 80 research sites in the SUA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI[; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n-463), or a three-class strategy (PI plus NNRTI; n-464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison and average change in CD4 cell count at or after 32 months for the three-class versus combines two-class comparison. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00000922. Findings: 1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1•02 (95% CI 0•79-1•31, 1•07 (0•80-1.41), 0•95 (0•66-1•37), and 0•66 (0•56-0•78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0•62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1•15 (0•91-1•45) and 0•87 (0•75-1•00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0•38 for interaction), and for participants with baseline HIV RNA concentrations less than 100000 copies per mL and 1000000 copies per mL or more (p=0•26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-classs strategies (HR 1•58; p<0•0001). Interpretation: Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naïve patients with HIV.

Novak RM, Chen L, MacArthur RD, Baxter JD, Huppler Hullsiek K, Peng G, Xiang Y, Henely C, Schmetter B, Uy J, van den Berg-Wolf M, Kozal M, and the Terry Beirn Community Programs for Clinical Research on AIDS 058 Study Team. Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy. Clin Infect Dis 2005: 40:468-474.
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MacArthur RD, Chen L, Peng G, Novak RM, van den Berg-Wolf M, Kozal M, Besch L, Yurik T, Schmetter B, Henley C, Dehlinger M and the CPCRA 058 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. Efficacy and safety of abacavir plus lamivudine versus didanosine plus stavudine when combined with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or both in HIV-1 positive antiretroviral-naive persons. HIV Clin Trials 2004; 5(6):361-370.
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Purpose: The combination of abacavir + lamivudine (ABC+3TC) versus didanosine + stavudine (ddI+d4T), each combined with other classes of antiretrovirals (ARVs) in ARV-naïve patients, was compared for the combined endpoint of time to plasma HIV RNA >50 copoies/mL (at or after the 8-month visit) or death (primary endpoint) in a nested substudy of an ongoing multicenter randomized trial.
Method: The substudy enrolled 182 patients; mean HIV RNA and CD4+ cell counts at baseline were 5.1 log10 copies/mL and 212 cells/mm3, respectively. Results: After a median follow-up of 28 months, rates of primary endpoint were 57.2 and 67.8 per 100 person-years for the ABC+3TC and ddI+d4T groups (hazard ratio [HR] = 0.81, 95% confidence interval [CI] 0.58-1.14, p = .23).
Conclusion: There was a trend for treatments containing ABC+3TC to be better than treatments containing ddI+d4T with respect to HIV RNA decreases, CD4+ cell count increases, and tolerability.

MacArthur RD, Chen L, Mayers DL, Besch CL, Novak R, van den Berg-Wolf M, et al. The rationale and design of the CPCRA (Terry Beirn Community Programs for Clinical Research on AIDS) 058 FIRST (Flexible Initial Retrovirus Suppressive Therapies) Trial. Control Clin Trials 2001; 22: 176-190.
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The CPCRA 058 FIRST (Flexible Initial Retrovirus Suppressive Therapies) trial is a large, long-term randomized, prospective comparison of three different antiretroviral strategies in highly active antiretroviral therapy-naïve, HIV-1-infected persons. The trial was designed as a flexible framework upon which other studies could be added to answer more limited, but still important, questions. This article presents the study design, discusses the challenges we have faced in implementing the trial, and describes our preliminary experiences.

  CPCRA 059 - IL-2

Markowitz N, Bebchuk J, Abrams D. Nadir CD4+ t-cell count predicts response to subcutaneous recombinant interleukin-2. Clin Infect Dis. Clin Infect Dis 2003;37:e115-120.
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Community Program for Clinical Research on AIDS 059 was a multicenter study conducted among human immunodeficiency virus (HIV)-infected individuals with CD4+ cell counts >300 cells/mm3 who were randomly assigned to receive antiretroviral therapy with or without intermittent subcutaneously administered recombinant interleukin-2 (rIL-2). To identify factors associated with a response to IL-2, a secondary analysis was performed that included the subset of rIL-2 recipients who were able to complete all 3 initial treatment cycles. Predictors of a change in CD4+ cell count between baseline and month after the start of treatment cycle 3 were examined in a multivariate model that included sex, race, body surface area, rIL-2 dose, HIV load, and both baseline and nadir CD4+ cell count. The combination of race and sex (P = .027) and the nadir CD4+ cell count (P = .05) were significant predictors of mean CD4+ cell count response. Baseline CD4+ cell count had no significant effect. The strong association between nadir CD4+ cell count and CD4+ cell count response suggest that immunologic losses resulting from HIV-mediated CD4+ cell depletion may be irreversible. l

Abrams DI, Bebchuk JD, Denning ET, Davey RT, Fox L, Lane HC, Sampson J, Verheggen R, Zeh D, Markowitz NP. A randomized open-label study of the impact of two doses of subcutaneous recombinant IL-2 on viral burden in patients with HIV-1 infection and CD4+ cell counts 300/mm3: CPCRA 059 . J Acquir Immune Defic Syndr 2002; 29:221-231.
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Summary: The effect of intermittent courses of recombinant interleukin-2 (rIL-2) on HIV-1 load in patients receiving combination antiretroviral therapy remains uncertain. CPCRA 059 was an open-label, randomized, multicenter trial in which 511 patients with HIV-1 infection and CD4+ cell counts of >300/mm3 who were receiving antiretroviral therapy were assigned to receive no rIL-2 (255 patients [controls]) or subcutaneous rIL-2 in dosages of 4.5 MIU (130) or 7.5 MIU (126) twice daily for 5-day courses every 8 weeks to maintain CD4+ cell counts that were twice the baseline value or >1,000/ mm3. The primary objective of this study was to compare the effects of the two doses of rIL-2 and no rIL-2 on viral load and CD4+ cell counts over 12 months. There was no difference in the following viral load measurements between the rIL-2 treatment groups and the control treatment group: percentage of patients with viral loads of <50 copies/mL at 12 months (p = .55), time to viral load of >5 copies/mL for patients who had baseline viral loads of <50 copies/mL (p = .35), and change in viral load from baseline for patients who had viral loads of >50 copies/mL at baseline (p = .63). At each follow-up visit, the change in CD4+ cell count from baseline was significantly greater in the rIL-2 treatment groups than in the control treatment group, with a mean difference of 251/mm3 at month 12 (95% confidence interval, 207-295; P < .0001). no unanticipated adverse experiences were seen in this trial, to our knowledge the largest randomized evaluation of rIL-2 treatment conducted to date.

  CPCRA 061 - Metabolic

El-Sadr WM, Mullin CM, Carr A, Gibert C, Rappoport C, Visnegarala F, Grunfeld C, Raghavan SS. Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral-naïve cohort. HIV Medicine 2005;6:114-121.
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Objectives. With the use of potent antiretroviral therapy in patients with HIV disease, changes in lipid parameters and glucose homeostasis have been onte. Hover, these effects have been difficult to interpret because of the varied demographic and treatment characteristics of the cohorts and the complexity of difrentiating the effect of HIV disease from that of the drugs used in its treatment. This study was designed to explore these issues.
Methods. Demographic information and fasting blood samples were collected from 419 antiretroviral-naïve HIV-1-infected patients.
Conclusions. Both HIV disease and demographic characteristics were found to influence lipid values and glucose homeostasis in the absence of antiretroviral treatment. More advanced HIV disease was associated with less favourable lipid and glucose homeostatic profiles. The independent association between HIV RNA levels and various lipid parameters suggests that viral replication had a direct effect on lipid levels. Interpretation of the effects of various HIV treatment regimen and drugs on metabolic parameters must take into account the stage of HIV disease and the demographic characteristics of the population studied.

Shlay JC, Visnegarwala F, Bartsch G, Wang J, Peng G, El-Sadr WM, Gibert C, Kotler D, Grunfeld C, and Raghavan S for the Terry Beirn Community Programs for Clinical Research on AIDS. Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine. J Acquir Immune Defic Syndr 2005; 38(2):147-155.
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Summary: Comparisons of body composition and metabolic changes among antiretroviral-naïve patients randomly assigned to didanosine and stavudine- (ddI+d4T vs. abacavir and lamivudine- (ABC+3TC) containing regimens were assessed in a nested substudy of an ongoing multicenter randomized trial. At baseline and every 4 months, body cell mass and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. The rates of change (unit/mo) estimated using the slopes of regression lines and overall mean changes from baseline were compare by study assignment. Among 9 patients enrolled, 46 received ddI+d4T- and 50 received ABC+3TC-containing regimens with a median follow-up of 32.4 months. For both study arms, an overall increase in the rates of change was seen for body cell mass. For ddI+d4T, after an initial increase, the rates of change declined for regional fat and total body fat compared with an increase for ABC+3TC, with the 2 arms being significantly different (P < 0.05). For high-density lipoprotein cholesterol rates of change, ddI+d4T decreased, while ABC+3TC increased. For both arms, low-density lipoprotein cholesterol decreased, while triglycerides increased. Early and sustained increases in insulin and insulin resistance were seen only for ddI+d4T. In this prospective study, metabolic and body composition changes varied according to whether subject received ddI+d4T or ABC+3TC. .

Visnegarwala F, Raghavan SS, Mullin CM, Bartsch G, Wang J, Kotler D, Gibert CL, Shlay J, Grunfeld C, Carr A, El-Sadr W. Sex differences in the associations of HIV disease characteristics and body composition in antiretroviral-naive persons. Am J Clin Nu. 2005; 82(4):850-856.
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Background: Data on associations of body composition with HIV disease characteristics are limited.
Objective: We compared sex-specific associations between HIV disease characteristics and body composition in an racially-ethnically diverse cohort of antiretroviral-naive patients.
Design: The study was a cross-sectional analysis of participants enrolled in a metabolic substudy of a multicenter trial. Regional fat was measured, and total body fat (TBF) was derived by using the Durnin-Womersley formula (DWF) and bioelectrical impedance analysis (BIA). Body cell mass (BCM) was measured by BIA.
Results: Among 422 participants, 22% were women, 60% were African American, and 36% had prior AIDS-defining illnesses. Mean (±SD) age was 38.2 ± 9.6 y, CD4+ count was 215 ± 184 cells/mm3, and HIV RNA log10 was 5.0 ± 0.8 copies/mL. On multivariate analysis, women with AIDS-defining illness had significantly (P < 0.005) lower regional body fat and TBF (BIA: –9.5 kg; DWF: –7.3 kg) but nonsignificantly lower BCM (–1.3 kg) than did women without such illnesses, whereas men with AIDS-defining illness had significantly (P < 0.005) lower BCM (–1.7 kg) but nonsignificantly lower TBF (BIA: –1.3 kg; DWF: –1.83 kg) than did men without such illnesses (P < 0.05 for sex differences in TBF). Significant negative associations of HIV RNA with BCM (–0.9 kg/log RNA; P = 0.03), TBF by BIA (–1.4 kg/log RNA; P = 0.05) and by DWF (–1.6 kg/log RNA; P = 0.01), and regional fat were observed in men only.
Conclusions: The effect of prior AIDS illness on body fat differed significantly between the sexes: women with prior AIDS-defining illness had significantly less fat than did women without such illnesses. An independent effect of HIV viremia on BCM and fat was seen in men. These distinctions may be due to inherent biological differences between the sexes.

Wang J, Bartsch G, Raghavan SS, Yurik T, Peng G, Chen L, LeSueur D, Shlay J for the Terry Beirn Community Programs for Clinical Research on AIDS. Reliability of circumferences and skinfold measurements by 19 observers trained in groups. Int J Body Composition Res 2004; 2(1):31-36.
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Background: Waist circumference (WC) is now accepted as a practical measure of adipose tissue distribution. Four body sites for WC measurements are commonly used, as follows: immediately below the lowest ribs (WC1), the narrowest waist (WC2, and midpoint between the lowest rib and the iliac crest (WC3), and immediately above the iliac crest (WC4). Objective: We sought to compare the magnitude and reliability of WC measured at these 4 sites in males and females. Design: WC was measured at each site 1 time in all subjects [49 males and 62 females, aged 7-83 y, with a body mass index (in kg/m2) of 9-43] and 3 times in a subgroup (n = 93) by one experienced observer using a heavy-duty inelastic tape. Body fat was measured in a subgroup (n = 74) with the use of dual-energy X-ray absorptiometry.
Results: The mean values of WC were WC2<WCX1<WC3<WC4 (P < 0.01) in females and WC2<wc1, WC3, and WC4 (P < 0.01) in males. For all 4 sites, measurement reproducibility was high, with intraclass correlation (r) values > 0.99. WC values were significantly correlated with fatness; correlations with trunk fat were higher than correlations with total body fat in both sexes.
Conclusions: WC values at the 4 commonly used anatomic sites differ in magnitude depending on sex, are highly reproducible, and are correlated with total body and trunk adiposity in a sex-dependent manner. These observations have implications for the use of WC measurements in clinical practice and patient-oriented research.

  CPCRA 062 - Adherence

Mannheimer SB, Morse E, Matts JP, Andrews L, Child C, Schmetter B, Friedland GH. Sustained benefit From a Long-Term Antiretroviral Adherence Intervention. J Acqir Immune Defic Syndr December 1, 2006;43:S41-S47.
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Objective: To assess the efficacy of 2 adherence interventions, medication managers (MM) and medication alarms (ALR), among antiretroviral (ARV)-naïve persons with HIV initiating ARV therapy.

Methods: A multicenter, randomized, adherence intervention clinical trial was conducted among participants coenrolled in an HIV ARV strategy study for ARV-naive individuals. Sites were assigned by cluster randomization using s 2x2 factorial design to administer MM, ALR, MM+ALR, or neither (control). MM participants received individualized, structured, long-term adherence support from trained MMs. ALR participants received individually programmed ALR alarms for use throughout the study.

Results: The 928 participants, followed a median of 30 months, included 22% women and 75% nonwhites; the median baseline CD4 count was 155 cells/mm3. First virologic failure was 13% lower in all MM versus no-MM groups (P=0.13) and 28% lower in MM versus non-MM subgroups randomized to 2-class ARV arms in the parent ARV study (P=0.01). MM (vs. no-MM) participants had significantly better CD4 cells count (P=0.01) and adherence (P<0.001) outcomes. ALR (vs. no-ALR) participants had worse virologic outcomes.

Conclusion: This large randomized clinical trial demonstrated that interpersonal structured adherence support was associated with improved long-term medication adherence and virologic and immunologic HIV outcomes.

Key Words: adherence, alarm, antiretroviral therapy, behavior, HIV, intervention study.

Mannheimer SB, Matts J, Telzak E, Chesney M, Child C, Wu AW, Friedland G. Quality of life in HIV-infected individuals receiving antiretroviral therapy is related to adherence. AIDS Care, January 2005; 17(01):10-22
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This ssesses changes in quality of life (QoL) over time among HIV-infected individuals receiving antiretroviral therapy (ART) and evaluates how this relates to ART adherence. Prospective, longitudinal data were examined from 1050 participants in two large, randomized, multi-centre antiretroviral clinical trials. QoL was assessed by the SF-12; adherence by the terry Beirn Community Programs for Clinical Research on AIDS Antiretroviral Medication Self-report. Participants included 20% women, 53% African Americans, 16% Latinos; mean age was 39 years; mean baseline CD4+ cell count 230 cells/mm3; 89% were ART-naïve at entry. Baseline physical and mental health summary QoL scores were 45.4 and 42.9, comparable to scores reported in other advanced HIV populations. Significant improvements in mean QoL scores were seen for the group as a whole after 1 to 4 months on new ART regimens, and persisted for 12 months. Participants reporting 100% ART adherence achieved significantly higher QoL scores at 12 months compared to those with poorer adherence, particularly if 100% adherence was consistent (p <0.001). Those with at least 80% ART adherence had smaller gains in QoL at 12 months when compared to baseline, while those with <80% adherence had worsening of QoL. In this analysis, ART adherence was associated with improved QoL, particularly if adherence was sustained.

  CPCRA 064 - MDR-HIV

Lawrence J, Huppler Hullsiek K, Thackeray LM, Abrams DI, Crane LR, Mayers DL, Jones MC, Saldanha JM, Schmetter BS, Baxter JD. Disadvantages of structured treatment interruption persists in patients with multidrug-resistant HIV-1: Final results of the the CPCRA 064 study. J Acquir Immune Defic Syndr October 1, 2006;43(2):169-178.
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Background: We report the final results of Community Programs for Clinical Research on AIDS (CPCRA-064) study, a multicenter, prospective, randomized, controlled trial that determines the long-term clinical impact of structured treatment interruption (STI) in patients with multidrug-resistant (MDR) HIV-1.

Methods and Results: Two hundred seventy-four patients on stable antiretroviral therapy with MDR HIV-1 treatment failure were randomized to a 4-month STI, followed by an optimized antiretroviral regimen (STI arm, n=140) or an immediate change to an optimized antiretroviral regimen (control arm, n=134). Main outcome measures were progression of disease or death and changes from baseline in HIV RNA levels (log copies/mL) and CD4 cell counts (cells/mm3). The median baseline HIV RnA level was 5.0 log copies/mL, the median CD4 count was 147 cells/mm3, and the nadir CD4 count was 32 cells/mm3. The median follow-up was 37 months. After the STI period, there were no differences in HIV RNA level responses between treatment arms. Differences in CD4 count responses always favored the control arm, with an advantage of 84 cells from 0 to 4 months (P<0.0001), 50 cells from 4 to 12 months (P<0.0001), 45 cells from 12 to 24 months (P=0.006), and 43 cells after 24 months (P=0.07). Rates in the STI and control arms for first progression-of-disease event or death were 17.5 and 14.3, respectively (hazard ratio=1.28; P=0.22).

Conclusion: STI before changing regimens in patients with MDR HIV-1 treatment failure has a prolonged negative impact on CD4 cell count recovery and does not confer progression of disease or virologic benefits. Key Words: HIV Infection, salvage therapy, treatment failure, treatment interruption.

Lawrence J, Mayers D, Huppler Hullsiek K, Gollins G, Abrams D, Reisler R, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med, 2003; 349(9):837-46.
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Prescribed interruptions in antiretroviral therapy--so-called "drug holidays"--may hasten disease progression in a subset of HIV-infected individuals, namely those whose treatment has been rendered significantly less effective by the development of resistance to multiple anti-HIV drugs (MDR-HIV).

  CPCRA 065 - SMART

A Large, Simple Trial Comparing Two Strategies for Management of Anti-Retroviral Therapy (The SMART Study).

El-Sadr WM, Lundren JD Neaton JD, Gordin F, Abrams D, Arduino, RC, Babiker A, Burman W, Clumeck N. Cohen, CJ, Cohn D, Cooper D, Darbyshire, J, Emery S, Fätkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Ramos Mejia JM, Markowitz N, Neuhaus J, Phillips, A, Rappport C. CD4+ Count-Guided Interruption of Antiretroviral Treatment. NEJM 2006;355(22):2283-2296.

Background. Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV).

Methods. We randomly assigned persons infected with HIV who had a CD4+ count of more than 350 cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease.

Results. A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies of less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1).

Conclusions. Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy

Editorial: Currier JS, Baden LR. Getting Smarter – The Toxicity of Undertreated HIV Infection. NEJM 2006;25(22)2359-2361. .