Judith S. Currier

A CONTROLLED TRIAL OF TWO NUCLEOSIDE ANALOGUES PLUS INDINAVIR IN PERSONS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND CD4 CELL COUNTS OF 200 PER CUBIC MILLIMETER OR LESS

BACKGROUND The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. METHODS A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. RESULTS The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. CONCLUSIONS Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.

The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response

OBJECTIVE To correlate self-reported antiretroviral adherence with virologic suppression. DESIGN Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. SETTING Five university-affiliated HIV clinics. PATIENTS A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6) cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. INTERVENTION Individualized, unrestricted antiretroviral therapy. MEASUREMENTS Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. RESULTS Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4 cells/l in those reporting 100% adherence (P = 0.02). CONCLUSION Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.

Joint effects of HIV-1 RNA levels and CD4 lymphocyte cells on the risk of specific opportunistic infections

OBJECTIVES To evaluate the predictive value of baseline plasma HIV-1 RNA levels and CD4 lymphocyte counts and early changes in these markers after initiating antiretroviral therapy on the risk of development of specific opportunistic infections (OIs). DESIGN Patient data from four antiretroviral therapy studies were combined for a retrospective analysis. The analysis included 842 participants from the virology substudies of these trials who had baseline measurements for both HIV-1 RNA levels and CD4 cell counts. METHODS Cox proportional hazards models were used to assess the joint effects of baseline CD4 cell count and HIV-1 RNA level and early treatment-associated changes in these values on the risk of development of Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV), or Mycobacterium avium complex (MAC). The effects of potential confounders such as prior prophylaxis and previous OIs were also addressed. RESULTS Baseline CD4 cell counts and HIV-1 RNA measurements showed significant associations with the risk of PCP, CMV, and MAC. Patients with higher levels of HIV-1 RNA were estimated to have three to six times the risk of these OIs than those with lower levels. Reductions in viral load were linked to significantly reduced risks of PCP, CMV, and MAC. Early decreases in RNA were generally more predictive of risk than were early increases in CD4 cell counts. CONCLUSIONS Baseline viral load and reductions in viral load during therapy appeared to influence the risk of these OIs independently of the CD4 cell count. Future guidelines for the initiation of prophylaxis for these OIs may be improved by incorporating information on viral load.

Alternative Regimens for the Prophylaxis of Mycobacterium avium Complex in Acquired Immune Deficiency Syndrome (AIDS)

Azithromycin, clarithromycin, and rifabutin are all FDA-approved for prophylaxis against Mycobacterium avium complex (MAC) in patients with advanced HIV infection. Recently, results of two large, randomized, controlled trials were reported that may alter the way these compounds are used in preventing MAC. Results have shown that both azithromycin (1,200 mg once weekly) and clarithromycin (500 mg twice daily) are more efficacious than rifabutin in preventing MAC. Combination prophylaxis with a macrolide and rifabutin improves the efficacy of azithromycin but not that of clarithromycin. Additionally, combination therapy has been associated with increased toxicity, resulting in more adverse events. While both azithromycin and clarithromycin are very effective, the once-weekly administration and fewer drug interactions offer an advantage to azithromycin prophylaxis over clarithromycin in most settings.

A study of discontinuing maintenance therapy in human immunodeficiency virus-infected subjects with disseminated Mycobacterium avium complex: AIDS clinical trial group 393 study team

The present nonrandomized prospective study evaluated whether antimycobacterial therapy for disseminated Mycobacterium avium complex (MAC) could be withdrawn from human immunodeficiency virus-infected subjects who experienced immunologic recovery while receiving highly active antiretroviral therapy (HAART). Eligible subjects had received macrolide-based therapy for least 12 months, were asymptomatic for MAC, had received HAART for at least 16 weeks, and had CD4+ T cell counts >100 cells/microL. Forty-eight subjects were enrolled, with a median CD4+ T cell count of 240 cells/microL at the time of discontinuation of MAC therapy. Forty-seven subjects remained MAC free, whereas 1 subject developed localized MAC osteomyelitis. The median duration of follow-up while not receiving therapy was 77 weeks, and the incidence of MAC infection was 1.44/100 person-years (95% confidence interval, 0.04-8.01). Withdrawal of anti-MAC therapy appears to be safe in patients who have been treated with a macrolide-based regimen for at least 1 year and have an immunologic response on HAART.

Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine

ObjectivesTo compare the efficacy and safety of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. DesignTwo multicenter, open-label, randomized 24-week studies. MethodsAdults HIV-1 infection, HIV-1 RNA greater than 10 000 copies/ml, and no prior lamivudine or protease inhibitor therapy were eligible. In a pilot study (Study A), patients received indinavir at 800 mg every 8 h, 1000 mg every 12 h, or 1200 mg every 12 h. In a subsequent study (Study B), patients received indinavir at 800 mg every 8 h or 1200 mg every 12 h. All subjects received zidovudine (300 mg) and lamivudine (150 mg) every 12 h. An intent-to-treat analysis was used. ResultsIn Study A, which enrolled 88 patients, neither HIV-1 RNA nor CD4 cell responses differed significantly between treatment groups at 24 weeks when corrected for multiple comparisons. Study B enrolled 433 patients, but was prematurely discontinued when interim analysis suggested greater efficacy of three-times-daily indinavir. Of the first 87 patients reaching week 24, HIV-1 RNA was less than 400 copies/ml in 91% receiving three-times-daily versus 64% receiving two-times-daily indinavir (P < 0.01). ConclusionThree-times-daily indinavir appears more efficacious than two-times-daily dosing when administered with zidovudine and lamivudine. Two-times-daily indinavir dosing should only be considered in situations characterized by favorable pharmacokinetic drug–drug interactions.

A Randomized Study of the Utility of Human Immunodeficiency Virus RNA Measurement for the Management of Antiretroviral Therapy

To compare frequent measurement with infrequent measurement of human immunodeficiency virus (HIV) RNA levels in the management of antiretroviral therapy, we conducted a clinical strategy study of 206 HIV-infected patients who had <500 CD4 cells/mm(3). Patients were randomized (1.5:1) to undergo frequent monitoring (at baseline and every 2 months) or infrequent monitoring (at baseline and twice yearly), with CD4 cell counts determined every 2 months. Patients received unrestricted antiretroviral therapy. In the primary analysis (at month 6), the frequent group had a mean HIV RNA reduction (+/- standard deviation) of 0.93+/-0.79 log(10) copies/mL, versus 0.48+/-0.83 log(10) copies/mL for the infrequent group (P=.0002). A trend (P=.1) toward improved survival was seen in the frequent group. Given this improved virological response, more frequent HIV RNA measurement than is recommended in published guidelines (every 3-4 months) may be appropriate.

Indinavir, Nevirapine, Stavudine, and Lamivudine for Human Immunodeficiency Virus–Infected, Amprenavir-Experienced Subjects: AIDS Clinical Trials Group Protocol 373

This prospective, multicenter, open-label study was designed to determine the antiretroviral activity and safety of a 4-drug regimen: 1000 mg indinavir every 8 h with 200 mg nevirapine, 40 mg stavudine, and 150 mg lamivudine, each given twice daily in amprenavir-experienced subjects. The primary end points of the study were the human immunodeficiency virus (HIV) RNA level and CD4 cell count responses. Fifty-six subjects were enrolled and were changed from amprenavir-containing regimens to the 4-drug regimen. Overall, at week 48, 33 (59%) of 56 subjects had HIV RNA levels <500 copies/mL (intent-to-treat analysis, where missing values equal > or =500 copies/mL) and CD4 cell counts increased by 94 cells/mm(3) from baseline. Subjects who had previously taken amprenavir combination therapy were more likely to experience virologic failure than those who had taken amprenavir monotherapy (odds ratio, 7.7; P=.0012). In this study, most subjects who had taken amprenavir-based regimens and who changed to a 4-drug regimen achieved subsequent durable virologic suppression.

Summaries for patients. Nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1.

What is the problem and what is known about it so far? Some of the most effective combination antiretroviral regimens for the treatment of HIV infection include efavirenz. However, some people, including women considering becoming pregnant and patients with severe psychiatric disease, are not good candidates to receive efavirenz because it can cause birth defects and may be linked to suicidal ideation and suicide. Why did the researchers do this particular study? To better understand the efficacy and safety of 3 HIV regimens that do not include efavirenz in people with HIV infection. Who was studied? More than 1800 adults with HIV infection at 57 sites in the United States and Puerto Rico who had never received antiretroviral drugs and had sufficient virus levels in their blood to monitor viral response and whose virus was not resistant to the drugs being tested. How was the study done? Every patient received emtricitabine, 200 mg/d, plus tenofovir disoproxil fumarate, 300 mg/d. In addition, each patient was randomly assigned to receive either atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d. What did the researchers find? All 3 regimens performed similarly in suppressing the amount of HIV in the blood and restoring immune function. They differed somewhat in how well they were tolerated. What were the limitations of the study? The doctors and patients knew what drugs patients were receiving, which may have influenced their decision to switch from atazanavir when patients had symptoms and signs of liver function abnormality. What are the implications of the study? Patients and doctors seem to have several good options for the initial treatment of HIV infection with regimens that do not contain efavirenz.