Mark Holodniy

Adherence to protease inhibitors, Hiv-1 viral load, and development of drug resistance in an indigent population

ObjectiveTo examine the relationship between adherence, viral suppression and antiretroviral resistance in HIV-infected homeless and marginally housed people on protease inhibitor (PI) therapy. Design and settingA cross-sectional analysis of subjects in an observational prospective cohort systematically sampled from free meal lines, homeless shelters and low-income, single-room occupancy (SRO) hotels. ParticipantsThirty-four HIV-infected people with a median of 12 months of PI therapy. Main outcomesAdherence measured by periodic unannounced pill counts, electronic medication monitoring, and self-report; HIV RNA viral load; and HIV-1 genotypic changes associated with drug resistance. ResultsMedian adherence was 89, 73, and 67% by self-report, pill count, and electronic medication monitor, respectively. Thirty-eight per cent of the population had over 90% adherence by pill count. Depending on the measure, adherence explained 36–65% of the variation in concurrent HIV RNA levels. The three adherence measures were closely related. Of 20 genotyped patients who received a new reverse transcriptase inhibitor (RTI) when starting a PI, three had primary protease gene substitutions. Of 12 genotyped patients who received a PI without a new RTI, six had primary protease gene substitutions (P < 0.03). ConclusionA substantial proportion of homeless and marginally housed individuals had good adherence to PI therapy. A strong relationship was found between independent methods of measuring adherence and concurrent viral suppression. PI resistance was more closely related to the failure to change RTI when starting a PI than to the level of adherence.

High levels of adherence do not prevent accumulation of HIV drug resistance mutations.

Objectives: To assess the relationship between development of antiretroviral drug resistance and adherence by measured treatment duration, virologic suppression, and the rate of accumulating new drug resistance mutations at different levels of adherence. Methods: Adherence was measured with unannounced pill counts performed at the participants usual place of residence in a prospective cohort of HIV-positive urban poor individuals. Two genotypic resistance tests separated by 6 months (G1 and G2) were obtained in individuals on a stable regimen and with detectable viremia (> 50 copies/ml). The primary resistance outcome was the number of new HIV antiretroviral drug resistance mutations occurring over the 6 months between G1 and G2. Results: High levels of adherence were closely associated with greater time on treatment (P < 0.0001) and viral suppression (P < 0.0001) in 148 individuals. In a subset of 57 patients with a plasma viral load > 50 copies/ml on stable therapy, the accumulation of new drug resistance mutations was positively associated with the duration of prior treatment (P = 0.03) and pill count adherence (P = 0.002). Assuming fully suppressed individuals (< 50 copies/ml) do not develop resistance, it was estimated that 23% of all drug resistance occurs in the top quintile of adherence (92–100%), and over 50% of all drug resistance mutations occur in the top two quintiles of adherence (79–100%). Conclusion: Increasing rates of viral suppression at high levels of adherence is balanced by increasing rates of drug resistance among viremic patients. Exceptionally high levels of adherence will not prevent population levels of drug resistance.

The Impact of Active Herpes Simplex Virus Infection on Human Immunodeficiency Virus Load

The effect of a concurrent herpes simplex virus (HSV) infection on human immunodeficiency virus type 1 (HIV-1) load was evaluated. Sixteen subjects were identified with an active HSV infection and had pre-outbreak, acute-phase, and post-outbreak plasma (n = 16) and peripheral blood mononuclear cell (PBMC) (n = 8) samples for evaluation. All subjects were treated for an acute HSV outbreak with acyclovir for 10 days, followed by chronic prophylaxis. HIV-1 plasma RNA levels were determined by branched DNA, and intracellular HIV gag mRNA copy numbers were determined by quantitative reverse transcriptase-polymerase chain reaction ELISA. Plasma virus load increased a median of 3.4-fold during the acute outbreak (range, 0- to 10-fold; P = .002), while post-outbreak levels (30-45 days after the appearance of lesions) remained above pre-outbreak, baseline levels in some subjects. Intracellular HIV gag mRNA increased during the outbreak as well. Thus, an acute HSV episode can result in increased HIV transcription and plasma virus load.

Effect of Home Testing of International Normalized Ratio on Clinical Events

BACKGROUND Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes. METHODS We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death). RESULTS The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001). CONCLUSIONS As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.).

Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4

The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervico-vaginal mucosa being the main portal of entry in women. The cervico-vaginal mucosa is naturally colonized with commensal bacteria, primarily lactobacilli. To address the urgent need for female-controlled approaches to block the heterosexual transmission of HIV, we have engineered natural human vaginal isolates of Lactobacillus jensenii to secrete two-domain CD4 (2D CD4) proteins. The secreted 2D CD4 recognized a conformation-dependent anti-CD4 antibody and bound HIV type 1 (HIV-1) gp120, suggesting that the expressed proteins adopted a native conformation. Single-cycle infection assays using HIV-1HxB2 carrying a luciferase reporter gene demonstrated that Lactobacillus-derived 2D CD4 inhibited HIV-1 entry into target cells in a dose-dependent manner. Importantly, coincubation of the engineered bacteria with recombinant HIV-1HxB2 reporter virus led to a significant decrease in virus infectivity of HeLa cells expressing CD4–CXCR4–CCR5. Engineered lactobacilli also caused a modest, but statistically significant, decrease in infectivity of a primary isolate, HIV-1JR-FL. This represents an important first step toward the development of engineered commensal bacteria within the vaginal microflora to inhibit heterosexual transmission of HIV.

New Protease Inhibitors for the Treatment of Chronic Hepatitis C: A Cost-Effectiveness Analysis

BACKGROUND Chronic hepatitis C virus is difficult to treat and affects approximately 3 million Americans. Protease inhibitors increase the effectiveness of standard therapy, but they are costly. A genetic assay may identify patients most likely to benefit from this treatment advance. OBJECTIVE To assess the cost-effectiveness of new protease inhibitors and an interleukin (IL)-28B genotyping assay for treating chronic hepatitis C virus. DESIGN Decision-analytic Markov model. DATA SOURCES Published literature and expert opinion. TARGET POPULATION Treatment-naive patients with chronic, genotype 1 hepatitis C virus monoinfection. TIME HORIZON Lifetime. PERSPECTIVE Societal. INTERVENTION Strategies are defined by the use of IL-28B genotyping and type of treatment (standard therapy [pegylated interferon with ribavirin]; triple therapy [standard therapy and a protease inhibitor]). Interleukin-28B-guided triple therapy stratifies patients with CC genotypes to standard therapy and those with non-CC types to triple therapy. OUTCOME MEASURES Discounted costs (in 2010 U.S. dollars) and quality-adjusted life-years (QALYs); incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS For patients with mild and advanced fibrosis, universal triple therapy reduced the lifetime risk for hepatocellular carcinoma by 38% and 28%, respectively, and increased quality-adjusted life expectancy by 3% and 8%, respectively, compared with standard therapy. Gains from IL-28B-guided triple therapy were smaller. If the protease inhibitor costs

Detection and Qualification of Human Immunodeficiency Virus RNA in Patient Serum by Use of the Polymerase Chain Reaction

1100 per week, universal triple therapy costs

Integrating Tobacco Cessation Into Mental Health Care for Posttraumatic Stress Disorder: A Randomized Controlled Trial

102,600 per QALY (mild fibrosis) or

Long-Term Persistence of Zoster Vaccine Efficacy

51,500 per QALY (advanced fibrosis) compared with IL-28B-guided triple therapy and

Recombinant Soluble CD4 Therapy in Patients with the Acquired Immunodeficiency Syndrome (AIDS) and AIDS-Related Complex: A Phase I-II Escalating Dosage Trial

70,100 per QALY (mild fibrosis) and