Opt in or opt out: what is optimal for prenatal screening for HIV infection?
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Canada↗
Biomedical subjects
Sharon Walmsley
Publications and source records attributed to Sharon Walmsley.
Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America.
BACKGROUND: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. METHODS: Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. RESULTS: A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group. CONCLUSIONS: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.
Adult↗
Use of complementary and alternative medicine by HIV-infected outpatients in Ontario, Canada.
Little is known about complementary and alternative medicine (CAM) use in Canadian patients with HIV. We sought to determine the prevalence of CAM use by patients attending HIV outpatient clinics in Ontario, Canada, and to compare the characteristics of users and nonusers. Impact of CAM definition on reported utilization rates was also assessed, specifically in relation to the inclusion and exclusion of vitamins, minerals, and multivitamins in CAM definition. In-person interviews were conducted between 1999 and 2001 with 104 HIV-positive outpatients enrolled in the HIV Ontario Observational Database project (HOOD) and attending HIV outpatient clinics in Ontario. Self-reported CAM utilization and demographic data were collected. Clinical data were obtained from medical chart review. Seventy-seven percent of participants reported current CAM use. Inclusion of vitamins and minerals (CAMVIT) increased this estimate to 89%. Nearly all patients used CAM in conjunction with antiretroviral medications. Out of pocket costs ranged from CAD$0 to more than CAD$250 per month. Most patients reported CAM use was beneficial and had improved their overall health. Female gender, HIV risk group, number of prescriptions, and overall number of drugs used were associated with CAM use. CAM use in Canadian patients with HIV is extremely common, with higher use among women. The definition of CAM has a substantial impact both on reported prevalence rates and on predictors of CAM use.
Adult↗
Value of CT in assessing probable severe acute respiratory syndrome.
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Adult↗
Individualized therapy for the treatment-experienced patient.
Treatment failure is still common in HIV-infected patients despite the use of multidrug antiretroviral therapy. In the absence of maximal suppression of viral replication during antiretroviral therapy, the selection for and accumulation of drug-resistant mutations is inevitable. This is reflected by a detectable viral load; in this setting, the therapy is changed in an attempt to better control viral replication. Strategies used when selecting salvage therapy include resistance testing to help guide the choice of regimen, exploiting pharmacokinetic interactions by boosting protease inhibitor trough levels, and counseling the patient on adherence. Salvage regimens should include as many new agents to which no or minimal resistance is anticipated as are available and an agent in a class that has not been previously used. The selection of salvage therapy remains complex and needs to be individualized.
Anti-HIV Agents↗
A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis.
Valganciclovir, an oral prodrug of the anti-cytomegalovirus (CMV) agent ganciclovir, was evaluated in a single-arm open-label safety study. AIDS patients (median CD4 lymphocyte count of 140 cells/microL) with treated CMV retinitis (N = 212) received 900-mg once-daily valganciclovir maintenance therapy with courses of 900-mg twice-daily valganciclovir induction therapy as needed to treat progression. After a median treatment duration of 372 days, the adverse event profile was similar to that reported for intravenous (IV) and oral ganciclovir. Adverse event rates of note were diarrhea (35%), nausea (23%), fever (18%), neutropenia (absolute neutrophil count <500 cells/microL) (10%), and anemia (hemoglobin <8.0 g/dL) (12%). Consistent with prior treatment studies of oral ganciclovir, IV catheter-related adverse events were uncommon (6%) and lower than previously reported for IV ganciclovir. The mortality rate was 0.072 deaths per patient-year. Progression of CMV retinitis occurred in 17% of patients during the study treatment period, usually in association with a low CD4 cell count. Other than a higher than expected frequency of oral candidiasis (17%), no clinical toxicities or laboratory abnormalities occurred during treatment with valganciclovir that have not been observed during treatment with ganciclovir.
AIDS-Related Opportunistic Infections↗
Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection.
BACKGROUND: Lopinavir is a newly developed inhibitor of human immunodeficiency virus (HIV) protease that, when formulated with ritonavir, yields mean trough plasma lopinavir concentrations that are at least 75 times as high as that needed to inhibit replication of wild-type HIV by 50 percent. METHODS: We conducted a double-blind trial in which 653 HIV-infected adults who had not received antiretroviral therapy for more than 14 days were randomly assigned to receive either lopinavir-ritonavir (400 mg of lopinavir plus 100 mg of ritonavir twice daily) with nelfinavir placebo or nelfinavir (750 mg three times daily) with lopinavir-ritonavir placebo. All patients also received open-label stavudine and lamivudine. The primary efficacy end points were the presence of fewer than 400 HIV RNA copies per milliliter of plasma at week 24 and the time to the loss of virologic response through week 48. RESULTS: At week 48, greater proportions of patients treated with lopinavir-ritonavir than of patients treated with nelfinavir had fewer than 400 copies of HIV RNA per milliliter (75 percent vs. 63 percent, P<0.001) and fewer than 50 copies per milliliter (67 percent vs. 52 percent, P<0.001). The time to the loss of virologic response was greater in the lopinavir-ritonavir group than in the nelfinavir group (hazard ratio, 2.0; 95 percent confidence interval, 1.5 to 2.7; P<0.001). The estimated proportion of patients with a persistent virologic response through week 48 was 84 percent for patients receiving lopinavir-ritonavir and 66 percent for those receiving nelfinavir. Both regimens were well tolerated, with the rate of discontinuation related to the study drugs at 3.4 percent among patients receiving lopinavir-ritonavir and 3.7 percent among patients receiving nelfinavir. Among patients with more than 400 copies of HIV RNA per milliliter at some point from week 24 through week 48, resistance mutations in HIV protease were demonstrated in viral isolates from 25 of 76 nelfinavir-treated patients (33 percent) and none of 37 patients treated with lopinavir-ritonavir (P<0.001). CONCLUSIONS: For the initial treatment of HIV-infected adults, a combination regimen that includes lopinavir-ritonavir is well tolerated and has antiviral activity superior to that of a nelfinavir-containing regimen.
Adult↗
A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis.
BACKGROUND: Valganciclovir is an orally administered prodrug that is rapidly hydrolyzed to ganciclovir. We compared the effects of oral valganciclovir with those of intravenous ganciclovir as induction therapy for newly diagnosed cytomegalovirus retinitis in 160 patients with the acquired immunodeficiency syndrome (AIDS). METHODS: The primary end point was photographically determined progression of cytomegalovirus retinitis within four weeks after the initiation of treatment. Secondary end points included the achievement of a prospectively defined satisfactory response to induction therapy and the time to progression of cytomegalovirus retinitis. After four weeks, all patients received valganciclovir as maintenance therapy. RESULTS: Eighty patients were randomly assigned to each treatment group. Of the patients who could be evaluated, 7 of 70 assigned to intravenous ganciclovir (10.0 percent) and 7 of 71 assigned to oral valganciclovir (9.9 percent) had progression of cytomegalovirus retinitis during the first four weeks (difference in proportions, 0.1 percentage point; 95 percent confidence interval, -9.7 to 10.0). Forty-seven of 61 patients (77.0 percent) assigned to intravenous ganciclovir and 46 of 64 (71.9 percent) assigned to valganciclovir had a satisfactory response to induction therapy (difference in proportions, 5.2 percentage points; 95 percent confidence interval, -20.4 to 10.1). The median times to progression of retinitis were 125 days in the group assigned to intravenous ganciclovir and 160 days in the group assigned to oral valganciclovir. The mean values for the area under the curve for the ganciclovir dosage interval were similar at both induction doses and maintenance doses. The frequency and severity of adverse events were similar in the two treatment groups. CONCLUSIONS: Orally administered valganciclovir appears to be as effective as intravenous ganciclovir for induction treatment and is convenient and effective for the long-term management of cytomegalovirus retinitis in patients with AIDS.
AIDS-Related Opportunistic Infections↗
CD36 deficiency induced by antiretroviral therapy.
BACKGROUND: The molecular basis of lipodystrophy, a syndrome associated with HIV antiretroviral (ARV) therapy, remains unknown. OBJECTIVES: To examine whether ARV therapy might inhibit the expression of CD36, which is known to play an important role in fatty acid and glucose metabolism, and if this might contribute to the metabolic alterations associated with lipodystrophy. DESIGN: The effects of ARV therapy on CD36 levels was examined in vivo in a prospective cohort of individuals treated with ARV therapy and in vitro in assays of human cell lines exposed to ARV drugs. METHODS: Monocyte CD36 levels were assessed by flow cytometry at baseline and after 7 days of therapy in five healthy volunteers and 10 treatment-naive HIV-1-infected individuals. ARV therapy included protease inhibitors (ritonavir, nelfinavir or lopinavir/ritonavir). In addition, human cell lines (THP-1 and C32) were assessed for CD36 levels pre and post-ritonavir treatment. RESULTS: Three of four healthy controls (one withdrew because of adverse effects) and 6 of 10 HIV-1-infected individuals had a 50 to > 90% decrease in monocyte CD36 levels after 7 days of therapy. One of ten HIV-infected subjects had a 30% decrease, and the remaining individuals had no change or an increase in CD36 levels. CD36 levels decreased significantly in human cell lines treated with ritonavir but not in those treated with zidovudine. CONCLUSIONS: ARV therapy resulted in a marked decrease in CD36 in approximately 70% of our participants. Sustained ARV therapy-induced CD36 deficiency may contribute to insulin resistance and other metabolic complications of lipodystrophy.
Anti-HIV Agents↗
Can structured treatment interruptions (STIs) be used as a strategy to decrease total drug requirements and toxicity in HIV infection?
Structured treatment interruptions (STIs) are a new strategy under investigation in clinical trials involving a number of different HIV-infected populations. These populations include patients with prolonged HIV RNA suppression who were treated in either seroconversion or later in disease, and patients with virologic failure despite HAART, prior to the initiation of a salvage regimen. The goals of STI vary in each of these groups. Until the results of clinical trials are available, the use of STIs must be considered experimental. There are a number of potential risks, including the loss of a significant number of CD4 cells with the development of opportunistic infections, rebound of HIV RNA, emergence of drug resistance, and reseeding of viral reservoirs. However, STIs also hold the promise for decreasing antiretroviral drug burden and toxicity, and improving quality of life. Given that much of the world's population infected with HIV does not have access to continuous HAART, the development of strategies that could decrease overall drug burden and cost is important. This paper provides an update of the recently published and presented studies on the use of STIs in various populations of HIV-infected patients. In particular, it discusses what is known and unknown about the relative risks and benefits of this approach, and what studies are ongoing. Lastly, it identifies how the use of STIs could decrease drug burden and toxicity in patients receiving therapy.
Anti-HIV Agents↗