Comparisons of anemia, thrombocytopenia, and neutropenia at initiation of HIV antiretroviral therapy in Africa, Asia, and the Americas

SummaryBackgroundHematological abnormalities are common manifestations of advanced HIV-1 infection that could affect the outcomes of highly-active antiretroviral therapy (HAART). Although most HIV-1-infected individuals live in resource-constrained countries, there is little information about the frequency of hematological abnormalities such as anemia, neutropenia, and thrombocytopenia among individuals with advanced HIV-1 disease.MethodsThis study compared the prevalence of pre-antiretroviral therapy hematological abnormalities among 1571 participants in a randomized trial of antiretroviral efficacy in Africa, Asia, South America, the Caribbean, and the USA. Potential covariates for anemia, neutropenia, and thrombocytopenia were identified in univariate analyses and evaluated in separate multivariable models for each hematological condition.ResultsThe frequencies of neutropenia (absolute neutrophil count ≤1.3×109/l), anemia (hemoglobin ≤10g/dl), and thrombocytopenia (platelets ≤125×109/l) at initiation of antiretroviral therapy were 14%, 12%, and 7%, respectively, and varied by country (p<0.0001 for each). In multivariable models, anemia was associated with gender, platelet count, and country; neutropenia was associated with CD4+ lymphocyte and platelet counts; and thrombocytopenia was associated with country, gender, and chronic hepatitis B infection.ConclusionsDifferences in the frequency of pretreatment hematological abnormalities could have important implications for the choice of antiretroviral regimen in resource-constrained settings

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Background: Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and Findings: 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007). Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen

Validation of the GenoType® MTBDRplus Ver 2.0 assay for detection of rifampicin and isoniazid resistance in Mycobacterium tuberculosis complex isolates at UZCHS-CTRC TB research laboratory

Background: Multidrug-resistant tuberculosis (MDR-TB) is a public health concern globally. MDR-TB is defined as resistance to rifampicin (RIF) and isoniazid (INH), the two-major anti-TB first-line TB treatment drugs. Rapid identification of MDR-TB can contribute significantly to the control of TB. The GenoType® MTBDRplus Ver 2.0 assay is a molecular assay used to detect genetic mutations that result in RIF and INH resistance. The aim of this study was to validate the performance of the GenoType® MTBDRplus Ver 2.0 assay for the detection of INH and RIF resistance. Methods: Fifty-five stored Mycobacterium tuberculosis isolates were tested using both the mycobacterial growth indicator tube (MGIT), antimicrobial susceptibility testing (AST), and the GenoType® MTBDRplus Ver 2.0 assay. The MGIT AST was done according to the BBL MGIT AST SIRE system with RIF and INH final critical concentrations of 1.0 μg/ml and 0.1 μg/ml, respectively. The GenoType® MTBDRplus assay (Hain Lifescience, Germany) was performed following the manufacturer's instructions. Results: The GenoType® MTBDRplus Ver 2.0 assay had a sensitivity, specificity, positive predictive value, and negative predictive value of 100% for INH and RIF resistance. The intra-assay precision for the assay was 100%. Conclusion: The GenoType® MTBDRplus Ver 2.0 assay's sensitivity and specificity show that the assay is highly accurate for the detection of RIF and INH resistance and thus can be used as an alternate platform due to its shorter results turnaround time

Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.

BackgroundAntiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and findings1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p&lt;0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).ConclusionEFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial registrationwww.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary

Primary and secondary time-to-event outcomes for the comparison of atazanavir plus didanosine-EC and emtricitabine to efavirenz plus lamivudine-zidovudine using data collected through 22 May 2008.

a<p>Also known as relative risk. Estimated from Cox regression model stratified by both country and RNA stratum and including randomized treatment group as sole covariate.</p>b<p><i>p</i>-Value calculated from stratified log-rank test between arms.</p>c<p>The five most common causes of death were infection (six deaths), liver disease (three deaths), malignancy (two deaths), suicide (two deaths), and unknown cause (two deaths).</p>d<p>Disease progression diagnoses are in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s007" target="_blank">Table S2</a>; grade 3 and 4 laboratory events in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s008" target="_blank">Table S3</a>; and signs and symptoms in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s009" target="_blank">Table S4</a>.</p>e<p>All events meeting these criteria are reported; some participants met criteria for multiple endpoints.</p>f<p>Confirmed plasma HIV RNA≥1,000 copies/ml at study week 16 or later.</p>g<p>Elevated bilirubin concentration not included.</p>h<p>Change in any component of initial randomized antiretroviral regimen.</p>i<p>The following antiretroviral substitutions were prespecified and were not included in this endpoint: TDF for DDI, stavudine or TDF for ZDV, or nevirapine for EFV.</p>j<p>CD4+ lymphocytes <100/µl at week 48 or later.</p

Subgroup analysis for primary efficacy and safety endpoints by randomly assigned antiretroviral treatment.

<p>Subgroup analyses were conducted for the baseline covariates self-reported sex and race/ethnicity and the countries in which the participating research sites were located. The relative risk and 95% CIs are provided for all participants (overall) and for each subgroup. <i>p</i>-Value represents interaction test between baseline covariate and randomized treatment group. Comparisons between ATV plus DDI and FTC and EFV plus 3TC-ZDV are in red. Comparisons between EFV plus FTC-TDF and EFV plus 3TC-ZDV are in green. (A) Treatment failure (efficacy) composite endpoint. (B) Safety events composite endpoint.</p

Primary and secondary time-to-event outcomes for comparison of efavirenz plus emtricitabine-tenofovir-DF to efavirenz plus lamivudine-zidovudine using data collected through 31-May-2010.

a<p>Also known as relative risk. Estimated from Cox regression model stratified by both country and RNA stratum and including randomized treatment group as sole covariate.</p>b<p><i>p</i>-Value calculated from stratified log-rank test between arms. Not applicable (NA) because no formal hypothesis testing was performed based on DSMB recommendations.</p>c<p>The five most common causes of death were infection (17 deaths) and unknown cause (five deaths) followed by suicide, trauma, and stroke (three deaths each).</p>d<p>Disease progression diagnoses are in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s012" target="_blank">Table S7</a>; grade 3 and 4 laboratory adverse events in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s013" target="_blank">Table S8</a>; and signs and symptoms in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s014" target="_blank">Table S9</a>.</p>e<p>All events meeting these criteria are reported; some participants met criteria for multiple endpoints.</p>f<p>Confirmed plasma HIV RNA≥1,000 copies/ml at study week 16 or later.</p>g<p>Change in any component of initial randomized antiretroviral regimen.</p>h<p>The following antiretroviral substitutions were prespecified and were not included in this endpoint: stavudine or TDF for ZDV, nevirapine for EFV, or didansoine for TDF.</p>i<p>CD4+ lymphocytes <100/µl at week 48 or later.</p

Efficacy and safety of randomized study treatment over time.

<p>(A–H) black circles, EFV plus 3TC-ZDV; red triangles, ATV plus DDI-EC and FTC; green squares, EFV plus FTC-TDF. (A–B) Estimated cumulative probability of antiretroviral regimen failure defined by the protocol-specified primary efficacy endpoint: comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (A) and EFV plus FTC-TDF (B). (C–D) Proportion of participants with plasma HIV-1 RNA less than 400 copies/ml for comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (C) and EFV plus FTC-TDF (D). These comparisons included all randomized study participants according to assigned study treatment. The analysis that counted missing values as greater than 400 copies/ml (open symbols) is truncated at the maximum potential duration of study follow-up for participants who entered the study at the end of the enrollment period (144 wk). (E–F) Median change in CD4+ lymphocyte count from screening value over time for comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (E) and EFV plus FTC-TDF (F). (G–H) Estimated cumulative probability a safety endpoint over time for comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (G) and EFV plus FTC-TDF (H). For (A–D, G and H), bars represent the 95% CI for the estimate. For (E–F), bars represent the interquartile range. (A–H) The number of evaluable participants at each time point is provided for each randomized treatment assignment.</p