Rapid CD4 decline after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy in a resource-limited setting

<p>Abstract</p> <p>Background</p> <p>Non-nucleoside reverse transcriptase inhibitor (NNRTI) with stavudine and lamivudine is widely used as the first-line antiretroviral therapy (ART) in resource-limited settings. Lipodystrophy is common and options for switching ART regimen are limited; this situation can lead to patients' poor adherence and antiretroviral resistance. Treatment interruption (TI) in patients with high CD4 cell counts, lipodystrophy, and limited options may be an alternative in resource-limited settings. This study aimed to determine time to resume ART after TI and predictors for early resumption of ART in a resource-limited setting.</p> <p>Methods</p> <p>A prospective study was conducted in January 2005 to December 2006 and enrolled HIV-infected patients with HIV-1 RNA <50 copies/mL, CD4 > 350 cells/mm³, and willing to interrupt ART. CD4 cell count, HIV-1 RNA, lipid profile, and lipodystrophy were assessed at baseline and every 3 months. ART was resumed when CD4 declined to <250 cells/mm³or developed HIV-related symptoms. Patients were grouped based on ART regimens [NNRTI or protease inhibitor (PI)] prior to TI.</p> <p>Results</p> <p>There were 99 patients, 85 in NNRTI group and 14 in PI group. Mean age was 40.6 years; 46% were males. Median duration of ART was 47 months. Median nadir CD4 and baseline CD4 were 151 and 535 cells/mm³, respectively. Median CD4 change at 3 months after TI were -259 (NNRTI) and -105 (PI) cells/mm³(p = 0.038). At 13-month median follow-up, there was no AIDS-defining illness; 38% (NNRTI) and 29% (PI) of patients developed HIV-related symptoms. ART was resumed in 51% (NNRTI) and 36% (PI) of patients (p = 0.022). By Kaplan-Meier analysis, median time to resume ART was 5.5 (NNRTI) and 14.2 (PI) months (log rank test, p = 0.026). By Cox's regression analysis, NNRTI-based ART (HR 4.9; 95%CI, 1.5–16.3), nadir CD4 <100 cells/mm³(HR 2.7; 95%CI 1.4–5.3) and baseline CD4 <500 cells/mm³(HR 1.6; 95%CI, 1.2–3.1) were predictors for early ART resumption.</p> <p>Conclusion</p> <p>TI of NNRTI-based ART leads to rapid CD4 decline and high probability of early ART resumption and should be avoided. It is necessary to scale-up the options for HIV-infected patients with lipodystrophy in resource-limited settings.</p

Treatment outcomes and plasma level of ritonavir-boosted lopinavir monotherapy among HIV-infected patients who had NRTI and NNRTI failure

<p>Abstract</p> <p>Background</p> <p>Different strategies of ritonavir-boosted lopinavir monotherapy have been explored; however, data regarding salvage therapy among HIV-infected patients who failed nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) is still limited.</p> <p>Methods</p> <p>A prospective study was conducted among HIV-infected patients who failed NNRTI-based antiretroviral therapy with M184V, TAMs, and NNRTI mutations, and were naïve to protease inhibitor. LPV/r at 400/100 mg and lamivudine 150 mg were given twice daily. CD4 and HIV-1 RNA were monitored at week 0, 12, 24, and 48. LPV Cmin was assayed for the first 14 patients using HPLC.</p> <p>Results</p> <p>There were 40 patients with a mean age of 37 years and 70% were male. Median (IQR) baseline CD4 was 123 (37-245) cells/mm³and median (IQR) HIV-1 RNA was 55,800 (9,670-100,000) copies/mL. By intend-to-treat analysis, 30 (75%) and 24 (60%) patients achieved HIV-1 RNA at <400 and <50 copies/mL, respectively. In as-treated analysis, the corresponding rates were 29 (83%) and 23 (67%), respectively. Low-level viral rebound was found in 6 (15%) patients at week 48. Medians CD4 at week 12, 24, 36 and 48 were 249, 283, 307, and 351 cells/mm³and significantly changed from baseline (all, <it>P </it>< 0.05). At 6 and 12 weeks, median (min-max) LPV Cmin was 6.52 (1.62-11.64) mg/L and 5.79 (0.75-16.31) mg/L, respectively. There were increments of mean total cholesterol and triglyceride at 48 weeks from baseline (<it>P </it>< 0.05).</p> <p>Conclusion</p> <p>LPV/r monotherapy with recycled lamivudine can maintain virological suppression in a substantial proportion of patients failing NNRTI-based regimen and provides adequate plasma concentrations of LPV although the incidence of low-level viremia is relatively high.</p

PS-SiZer map to investigate significant features of body-weight profile changes in HIV infected patients in the IeDEA Collaboration

Objectives: We extend the method of Significant Zero Crossings of Derivatives (SiZer) to address within-subject correlations of repeatedly collected longitudinal biomarker data and the computational aspects of the methodology when analyzing massive biomarker databases. SiZer is a powerful visualization tool for exploring structures in curves by mapping areas where the first derivative is increasing, decreasing or does not change (plateau) thus exploring changes and normalization of biomarkers in the presence of therapy. Methods: We propose a penalized spline SiZer (PS-SiZer) which can be expressed as a linear mixed model of the longitudinal biomarker process to account for irregularly collected data and within-subject correlations. Through simulations we show how sensitive PS-SiZer is in detecting existing features in longitudinal data versus existing versions of SiZer. In a real-world data analysis PS-SiZer maps are used to map areas where the first derivative of weight change after antiretroviral therapy (ART) start is significantly increasing, decreasing or does not change, thus exploring the durability of weight increase after the start of therapy. We use weight data repeatedly collected from persons living with HIV initiating ART in five regions in the International Epidemiologic Databases to Evaluate AIDS (IeDEA) worldwide collaboration and compare the durability of weight gain between ART regimens containing and not containing the drug stavudine (d4T), which has been associated with shorter durability of weight gain. Results: Through simulations we show that the PS-SiZer is more accurate in detecting relevant features in longitudinal data than existing SiZer variants such as the local linear smoother (LL) SiZer and the SiZer with smoothing splines (SS-SiZer). In the illustration we include data from 185,010 persons living with HIV who started ART with a d4T (53.1%) versus non-d4T (46.9%) containing regimen. The largest difference in durability of weight gain identified by the SiZer maps was observed in Southern Africa where weight gain in patients treated with d4T-containing regimens lasted 59.9 weeks compared to 133.8 weeks for those with non-d4T-containing regimens. In the other regions, persons receiving d4T-containing regimens experienced weight gains lasting 38-62 weeks versus 55-93 weeks in those receiving non-d4T-based regimens. Discussion: PS-SiZer, a SiZer variant, can handle irregularly collected longitudinal data and within-subject correlations and is sensitive in detecting even subtle features in biomarker curves

Cryptococcus neoformans meningitis in a diabetic patient - the perils of an overzealous immune response: a case report

Uncontrolled diabetics are prone to infections due to numerous factors as the glucose-rich blood serves as an excellent media for growth. Cryptococcus neoformans is an opportunistic fungus that is an important cause of CNS infections among immunocompromised patients, but it has only sporadically been reported in non-HIV-positive persons. The presence of elevated pro-inflammatory cytokines and abnormalities in numerous systemic indicators of inflammation in diabetics makes it conceivable that diabetics mount an exaggerated immune response to C. neoformans (paradoxical to their defective immune state) leading to grave outcomes. We present a fatal case of C. neoformans meningitis in a diabetic patient which emphasizes the perils of an overzealous immune response

Revealing geographical and population heterogeneity in HIV incidence, undiagnosed hiv prevalence and time to diagnosis to improve prevention and care : Estimates for France

Funding Information: LM, DC and VS thank INSEE and Réeseau Quetelet for kindly providing national and subnational statistics on population size (Donnéees harmoniséees des recensements de la population: Tabulation sur mesure, INSEE [producteur], ADISP-CMH [diffuseur]). LM, DC and VS also thank Christophe Godéereaux for optimizing the code written in C and Eric Janssen (OFDT) for sharing his estimates on drug use in France before publication as well as providing additional estimates. This work was supported by ANRS throughout the project ANRS 95017 INDIC and the framework of HIVERA JTC 2014. The sponsor had no role in the study. Publisher Copyright: © 2018 The Authors.To close gaps in HIV prevention and care, knowledge about locations and populations most affected by HIV is essential. Here, we provide subnational and sub-population estimates of three key HIV epidemiological indicators, which have been unavailable for most settings. Methods: We used surveillance data on newly diagnosed HIV cases from 2004 to 2014 and back-calculation modelling to estimate in France, at national and subnational levels, by exposure group and country of birth: the numbers of new HIV infections, the times to diagnosis, the numbers of undiagnosed HIV infections. The denominators used for rate calculations at national and subnational levels were based on population size (aged 18 to 64) estimates produced by the French National Institute of Statistics and Economic Studies and the latest national surveys on sexual behaviour and drug use. Results: We estimated that, in 2014, national HIV incidence was 0.17& (95% confidence intervals (CI): 0.16 to 0.18) or 6607 (95% CI: 6057 to 7196) adults, undiagnosed HIV prevalence was 0.64& (95% CI: 0.57 to 0.70) or 24,197 (95% CI: 22,296 to 25,944) adults and median time to diagnosis over the 2011 to 2014 period was 3.3 years (interquartile range: 1.2 to 5.7). Three mainland regions, including the Paris region, out of the 27 French regions accounted for 56% of the total number of new and undiagnosed infections. Incidence and undiagnosed prevalence rates were 2-to 10-fold higher than the national rates in three overseas regions and in the Paris region (p-values < 0.001). Rates of incidence and undiagnosed prevalence were higher than the national rates for the following populations (p-values < 0.001): born-abroad men who have sex with men (MSM) (respectively, 108-and 78-fold), French-born MSM (62-and 44-fold), born-abroad persons who inject drugs (14-and 18-fold), sub-Saharan African-born heterosexuals (women 15-and 15-fold, men 11-and 13-fold). Importantly, affected populations varied from one region to another, and in regions apparently less impacted by HIV, some populations could be as impacted as those living in most impacted regions. Conclusions: In France, some regions and populations have been most impacted by HIV. Subnational and sub-population estimates of key indicators are not only essential to adapt, design implement and evaluate tailored HIV interventions in France, but also elsewhere where similar heterogeneity is likely to exist.publishersversionPeer reviewe

Emergence of HIV-1 drug resistance mutations among antiretroviral-naïve HIV-1-infected patients after rapid scaling up of antiretroviral therapy in Thailand

<p>Abstract</p> <p>Background</p> <p>After rapid scaling up of antiretroviral therapy in HIV-1-infected patients, the data of primary HIV-1 drug resistance in Thailand is still limited. This study aims to determine the prevalence and associated factors of primary HIV-1 drug resistance in Thailand.</p> <p>Methods</p> <p>A prospective observational study was conducted among antiretroviral-naïve HIV-1-infected Thai patients from 2007 to 2010. HIV-1 subtypes and mutations were assayed by sequencing a region of HIV-1 pol gene. Surveillance drug resistance mutations recommended by the World Health Organization for surveillance of transmitted HIV-1 drug resistance in 2009 were used in all analyses. Primary HIV-1 drug resistance was defined as the presence of one or more surveillance drug resistance mutations.</p> <p>Results</p> <p>Of 466 patients with a mean age of 38.8 years, 58.6% were males. Risks of HIV-1 infection included heterosexual (77.7%), homosexual (16.7%), and intravenous drug use (5.6%). Median (IQR) CD4 cell count and HIV-1 RNA were 176 (42-317) cells/mm³and 68,600 (19,515-220,330) copies/mL, respectively. HIV-1 subtypes were CRF01_AE (86.9%), B (8.6) and other recombinants (4.5%). The prevalence of primary HIV-1 drug resistance was 4.9%; most of these (73.9%) had surveillance drug resistance mutations to only one class of antiretroviral drugs. The prevalence of patients with NRTI, NNRTI, and PI surveillance drug resistance mutations was 1.9%, 2.8% and 1.7%, respectively. From logistic regression analysis, there was no factor significantly associated with primary HIV-1 drug resistance. There was a trend toward higher prevalence in females [odds ratio 2.18; 95% confidence interval 0.896-5.304; p = 0.086].</p> <p>Conclusions</p> <p>There is a significant emergence of primary HIV-1 drug resistance in Thailand after rapid scaling up of antiretroviral therapy. Although HIV-1 genotyping prior to antiretroviral therapy initiation is not routinely recommended in Thailand, our results raise concerns about the risk of early treatment failure in patients with primary HIV-1 drug resistance. Interventions to prevent the transmission of HIV-1 drug resistance and continuation of surveillance for primary HIV-1 drug resistance in Thailand are indicated.</p

Expert review on global real-world vaccine effectiveness against SARS-CoV-2

Introduction COVID-19 vaccines have been highly effective in reducing morbidity and mortality during the pandemic. While primary series vaccination rates are generally high in Southeast Asian (SEA) countries, various factors have limited the rollout and impact of booster doses. Areas covered We reviewed 79 studies in the International Vaccine Access Center (IVAC) VIEW-hub platform on vaccine effectiveness (VE) after primary immunizations with two-dose schedules. VE data were reported for SARS-CoV-2 infection, COVID-19-related hospitalizations and deaths, and stratified across variants of concern, age, study design and prior SARS-CoV-2 infection for mRNA vaccines (BNT162b2, mRNA-1273, and combinations of both), vector vaccines (AstraZeneca, AZD1222 [ChAdOx1 nCoV-19] ‘Vaxzevria’), and inactivated virus vaccines (CoronaVac). Expert opinion The most-studied COVID-19 vaccines provide consistently high (>90%) protection against serious clinical outcomes like hospitalizations and deaths, regardless of variant. Additionally, this protection appears equivalent for mRNA vaccines and vector vaccines like AZD1222, as supported by our analysis of Asian and relevant international data, and by insights from SEA experts. Given the continued impact of COVID-19 hospitalizations and deaths on health-care systems worldwide, encouraging vaccination strategies that reduce this burden is more relevant than attempting to prevent broader but milder infections with specific variants, including Omicron

Tuberculosis in antiretroviral treatment programs in lower income countries: availability and use of diagnostics and screening.

In resource-constrained settings, tuberculosis (TB) is a common opportunistic infection and cause of death in HIV-infected persons. TB may be present at the start of antiretroviral therapy (ART), but it is often under-diagnosed. We describe approaches to TB diagnosis and screening of TB in ART programs in low- and middle-income countries