Cortical stimulation leads to shortened myelin sheaths and increased axonal branching in spared axons after cervical spinal cord injury.

Neural activity and learning lead to myelin sheath plasticity in the intact central nervous system (CNS), but this plasticity has not been well-studied after CNS injury. In the context of spinal cord injury (SCI), demyelination occurs at the lesion site and natural remyelination of surviving axons can take months. To determine if neural activity modulates myelin and axon plasticity in the injured, adult CNS, we electrically stimulated the contralesional motor cortex at 10 Hz to drive neural activity in the corticospinal tract of rats with sub-chronic spinal contusion injuries. We quantified myelin and axonal characteristics by tracing corticospinal axons rostral to and at the lesion epicenter and identifying nodes of Ranvier by immunohistochemistry. Three weeks of daily stimulation induced very short myelin sheaths, axon branching, and thinner axons outside of the lesion zone, where remodeling has not previously been reported. Surprisingly, remodeling was particularly robust rostral to the injury which suggests that electrical stimulation can promote white matter plasticity even in areas not directly demyelinated by the contusion. Stimulation did not alter myelin or axons at the lesion site, which suggests that neuronal activity does not contribute to myelin remodeling near the injury in the sub-chronic period. These data are the first to demonstrate wide-scale remodeling of nodal and myelin structures of a mature, long-tract motor pathway in response to electrical stimulation. This finding suggests that neuromodulation promotes white matter plasticity in intact regions of pathways after injury and raises intriguing questions regarding the interplay between axonal and myelin plasticity.

Fluorescein diacetate and rapid molecular testing for the early identification of rifampicin resistance in Mali.

BACKGROUND: Non-conversion on auramine smear microscopy indicates a lack of treatment response, possibly associated with initial rifampicin-resistant tuberculosis (RR-TB). However, dead bacteria still stain positive and may be detected. Fluorescein diacetate smear microscopy (FDA) shows live mycobacteria only. Therefore, we studied the potential of 2-month (2M) FDA for the identification of initial RR-TB.METHODS: Between 2015 and 2018, we enrolled new smear-positive pulmonary TB patients from five local centres in Bamako, Mali. After baseline screening, sputum samples were collected at 1M, 2M, 5M and 18M. We used rpoB sequencing to identify initial RR-TB.RESULTS: Of 1359 patients enrolled, 1019 (75%) had rpoB sequencing results. Twenty-six (2.6%, 95%CI: 1.7-3.7) had mutations conferring rifampicin resistance. Most frequent rpoB mutations were located at the codons Asp435Val (42.4%) and Ser450Leu (34.7%). Among patients with initial RR-TB, 72.2% were FDA-negative at 2M (P = 0.2). The positive and negative predictive value of 5M FDA for culture-based failure was respectively 20.0% and 94.7%.CONCLUSION: FDA did not identify the majority of patients with initial RR-TB or culture-based failure. As the full spectrum of mutations identified on sequencing was identified using Xpert, our data support its rapid universal implementation in Mali.

Diabetes Mellitus among new tuberculosis patients in Bamako, Mali.

INTRODUCTION: Diabetes Mellitus (DM) increases worldwide, mostly in low- and middle-income countries. In Mali, the prevalence in the adult population is estimated at 1.8%, but tuberculosis (TB) patients are not systematically screened. The goal of our study was to determine the prevalence of DM among newly diagnosed TB patients. METHODS: We conducted a cross sectional study and a pilot prospective cohort study in four health centers in Bamako. All patients underwent fasting capillary-blood glucose (FCBG) test at Day 0, and repeated after one-week of TB treatment. Venous FBG test was performed for discrepancies between the two FCBG results. Thereafter, FCBG was performed for pilot study at month-2 (M2) and M5 of TB treatment. RESULTS: Two hundred and one patients were enrolled in this study. Impaired fasting blood glucose was identified in 17 (8.5%), of whom 11 (5.5%) had DM (VFBG >7 mmol/L). Among patients with DM, seven (63.6%) had successful TB treatment outcome, versus 142 (74.7%) of those without DM (p = 0.64), and (OR: 1.69, 95%CI 0.47-6.02). CONCLUSION: The prevalence of DM among TB patients in Bamako exceeds that of the general population and screening at TB diagnosis suffices to identify those with DM. Systematic screening of both diseases will allow better treatment.

Second-line antiretroviral therapy failure and characterization of HIV-1 drug resistance patterns in children in Mali.

INTRODUCTION: In recent years, children born to HIV-infected mothers have been receiving antiretroviral treatment (ART) with limited or no virologic monitoring, which increases the likelihood of development and accumulation of drug resistance mutations, which itself may limit the effectiveness of future ART. The objective of this study was to evaluate the prevalence of resistance mutations in children infected with HIV-1 experiencing virological failure to second-line ART in the Pediatric Department of Gabriel Touré Hospital in Mali. METHODS: Children aged from 5 to 18 infected with HIV-1 on second-line antiretroviral therapy and whose viral load was greater than 1000 copies/mL after observance reinforcement were enrolled. The protease and reverse transcriptase genes were sequenced with ViroSeq®. The results were interpreted according to the last version of the Stanford algorithm in 2018. The study was approved by the Ethics Committee of the Faculty of Medicine and Dentistry, University of Sciences, Techniques and Technologies of Bamako (Mali). RESULTS: Of 216 children, 33 (15.3%) who had a viral load (VL)>1000 copies/mL in second line were recruited and included in the study. The median plasma viral load was 77,000 copies/mL [IQR (28,000-290,000)] and the median CD4 cell count was 310 cells/mm3 [IQR (152-412)]. The median age was 12 years; 48.5% of patients were treated with a combination of stavudine/lamivudine/nevirapine (Triomune®) for first-line treatment and 60.6% with abacavir/lamivudine/lopinavir/ritonavir for the second-line ART. The median treatment duration was 8.5 years [range, 3-13]. Of the 33 children whose treatment failed, the predominant HIV-1 subtype was CRF02_AG (66.7%). The prevalence of resistance to ART classes was 60.61% (20/33) to nucleoside reverse transcriptase inhibitors (NRTIs), 54.51% (18/33) to nonnucleoside reverse transcriptase inhibitors (NNRTIs), and 51.52% (17/33) to protease inhibitors (PIs). Of the patients studied, 90.9% were exposed to lopinavir/ritonavir (LPV/r) but only 15.2% (5/33) developed resistance to LPV/r. CONCLUSIONS: This study demonstrated that LPV/r remains active in most patients after second-line ART failure. In children whose second-line ART fails, particular attention should be paid to their ART and adherence history when considering the next treatment option.

Clinical characteristics of non-tuberculous mycobacterial pulmonary infections in Bamako, Mali.

The global spread of non-tuberculous mycobacteria (NTM) may be due to HIV/AIDS and other environmental factors. The symptoms of NTM and tuberculosis (TB) disease are indistinguishable, but their treatments are different. Lack of research on the epidemiology of NTM infections has led to underestimation of its prevalence within TB endemic countries. This study was designed to determine the prevalence and clinical characteristics of pulmonary NTM in Bamako. A cross-sectional study which include 439 suspected cases of pulmonary TB. From 2006 to 2013 a total of 332 (76%) were confirmed to have sputum culture positive for mycobacteria. The prevalence of NTM infection was 9.3% of our study population and 12.3% of culture positive patients. The seroprevalence of HIV in NTM group was 17.1%. Patients who weighed <55 kg and had TB symptoms other than cough were also significantly more likely to have disease due to NTM as compared to those with TB disease who were significantly more likely to have cough and weigh more than 55 kg (OR 0.05 (CI 0.02-0.13) and OR 0.32 (CI 0.11-0.93) respectively). NTM disease burden in Bamako was substantial and diagnostic algorithms for pulmonary disease in TB endemic countries should consider the impact of NTM.

Performance of microscopic observation drug susceptibility for the rapid diagnosis of tuberculosis and detection of drug resistance in Bamako, Mali.

OBJECTIVES: In Mali early detection and treatment of multidrug-resistant tuberculosis (MDR-TB) are still challenging due to the cost, time and/or complexity associated with regular tests. Microscopic Observation Drug Susceptibility (MODS) is a low-cost assay validated by WHO in 2010. It is a liquid-culture-based assay to detect the 'cording' characteristic of Mycobacterium tuberculosis complex and to assess susceptibility to both isoniazid and rifampicin defining multidrug-resistant tuberculosis (MDR-TB). In this study we aimed to evaluate the performance of MODS as diagnostic tool compared with a validated method-Mycobacteria Growth Indicator Tube/Antimicrobial Susceptibility Testing/Streptomycin, Isoniazid, Rifampicin and Ethambutol (MGIT/AST/SIRE). METHODS AND RESULTS: Between January 2010 and October 2015 we included 98 patients with suspected TB in an observational cohort study. The sensitivity and specificity of MODS assay for detecting TB were respectively 94.12% and 85.71% compared with the reference MGIT/7H11 culture, with a Cohen κ coefficient of 0.78 (95% CI 0.517-1.043). The median time to culture positivity for MODS assay and MGIT (plus interquartile range, IQR) was respectively 8 days (IQR 5-11) and 6 days (IQR 5-6). In detecting patients with MDR-TB, the sensitivity and specificity of MODS assay were respectively 100% and 95.92%. The positive predictive value and negative predictive value were, respectively, 66.7% and 100%. The median turnaround times for obtaining MDR-TB results using MODS assay and MGIT/AST/SIRE was respectively 9 days and 35 days. Hence, the MODS assay rapidly identifies MDR-TB in Mali compared with the MGIT/AST/SIRE. CONCLUSION: As an easy, simple, fast and affordable method, the MODS assay could significantly improve the management of TB.

Establishing Reference Ranges of Hematological Parameters from Malian Healthy Adults.

INTRODUCTION: Measurement of immuno-hematological parameters has been historically helpful in the diagnosis and treatment monitoring of many infectious diseases and cancers. However, these parameters have not yet been established in many developing countries where patient care strongly relies on such low-cost tests. This study describes the immuno-hematological parameter ranges for Malian healthy adults. METHODS: A cross sectional study was conducted from August 2004 to May 2013. We included 213 healthy volunteers (173 male and 40 female), aged between 18-59 years. Median, 2.5 and 97.5 percentile ranges for each immuno-hematological parameter are presented. RESULTS: In our study population, the hematological parameters' ranges were mostly different to the universal established ranges. We found in our population a Median white blood cell (WBC) count of 5200 cells/µL [3237.5-11900], Red Blood Cell (RBC) count of 4.94 10^6 [3.56-6.17], hemoglobin (Hb) of 14.2 g/dL [12.2-17.38], platelet count (Plt) of 275 10^3/µL [145.4-614.4], lymphocytes 2050/µL [1200-3800], neutrophils 2200/µL [1040-6220]; monocytes 200/µL [100-660]; eosinophils 131/µL [0-1026]; CD4 902 cells/µL [444-1669] and CD8 485 cells/µL [0-1272]. We found significant gender differences in RBC, Hb level and MPV. However, RBC and Hb were higher in males median values compared to females (median values) (p<0.001), whereas the Mean platelet volume lower values (MPV) in males than females (P<0.047). The hemoglobin level for some West African countries (Mali, Burkina Faso, Togo, and Nigeria) ranged from 13.5 to 15.1 g/dL for males and 12 to 13 g/dL for females. However in East and Southern Africa, the values were anywhere from 14.1 to 16.1 for males and 11.2 to 14.4 for females. CONCLUSION: Our data may help physicians to better define hematological abnormalities in patients. They may also be used to define new "normal hematological values" in Malian population or in the whole West African population.

Tuberculosis drug resistance in Bamako, Mali, from 2006 to 2014.

BACKGROUND: Although Drug resistance tuberculosis is not a new phenomenon, Mali remains one of the "blank" countries without systematic data. METHODS: Between 2006 and 2014, we enrolled pulmonary TB patients from local TB diagnostics centers and a university referral hospital in several observational cohort studies. These consecutive patients had first line drug susceptibility testing (DST) performed on their isolates. A subset of MDR was subsequently tested for second line drug resistance. RESULTS: A total of 1186 mycobacterial cultures were performed on samples from 522 patients, including 1105 sputa and 81 blood samples, yielding one or more Mycobacterium tuberculosis complex (Mtbc) positive cultures for 343 patients. Phenotypic DST was performed on 337 (98.3%) unique Mtbc isolates, of which 127 (37.7%) were resistant to at least one drug, including 75 (22.3%) with multidrug resistance (MDR). The overall prevalence of MDR-TB was 3.4% among new patients and 66.3% among retreatment patients. Second line DST was available for 38 (50.7%) of MDR patients and seven (18.4%) had resistance to either fluoroquinolones or second-line injectable drugs. CONCLUSION: The drug resistance levels, including MDR, found in this study are relatively high, likely related to the selected referral population. While worrisome, the numbers remained stable over the study period. These findings prompt a nationwide drug resistance survey, as well as continuous surveillance of all retreatment patients, which will provide more accurate results on countrywide drug resistance rates and ensure that MDR patients access appropriate second line treatment.

Is there any relationship between hearing threshold levels and CD4 cell count of human immunodeficiency virus infected adults?

Background The role of viral load level and/or CD4 (Cluster of differentiation 4) cell count in the aetiopathogenesis of hearing loss in HIV infection is unclear. Therefore, we investigated the relationship between CD4 cell counts, viral load and hearing threshold of HIV (Human immunodeficiency virus) infected adults. METHODS: This cohort audiometric study involved consecutive HIV-infected and HIV-uninfected adults as controls. Clinical data relating to hearing loss, HIV status, and highly -active antiretroviral therapy (HAART) were obtained. Audiornetric evaluation was performed. The most recent CD4 cell counts and RNA viral load-of HIV-infected participants were obtained from clinic records. RESULTS: There were 299(66.7%) HIV-infected adults and 149(33.3%) controls with mean age of 39.64± 12.45 years and 39.60±12.45 years respectively (p=0.98). In both groups, there were more participants with left hearing loss. Mild to profound hearing loss was found in 65.9% HIV- infected participants and 53.7% controls. Majority (86.3%) of the HIV-infected participants were on HAART. The mean CD4 cell count was 654.58±289.15 in 41 HIV-infected participants not on HAART and 523.95±300.17 in 258 participants on HAART (p=0.01). Majority,- 197 (62%) HIV- infected participants with hearing loss had CD4 cell count ≤200 cells/mm3. Higher viral load significantly correlated with low CD4 cell counts (p<0.0 1; r=0. 18) and low CD4 cell count significantly correlated with high hearing threshold (p

Impact of HIV type 1 subtype on drug resistance mutations in Nigerian patients failing first-line therapy.

A diverse array of non-subtype B HIV-1 viruses circulates in Africa and dominates the global pandemic. It is important to understand how drug resistance mutations in non-B subtypes may develop differently from the patterns described in subtype B. HIV-1 reverse transcriptase and protease sequences from 338 patients with treatment failure to first-line ART regimens were evaluated. Multivariate logistic regression was used to examine the effect of subtype on each mutation controlling for regimen, time on therapy, and total mutations. The distribution of HIV-1 subtypes included CRF02_AG (45.0%), G (37.9%), CRF06_cpx (4.4%), A (3.6%), and other subtypes or recombinant sequences (9.2%). The most common NRTI mutations were M184V (89.1%) and thymidine analog mutations (TAMs). The most common NNRTI mutations were Y181C (49.7%), K103N (36.4%), G190A (26.3%), and A98G (19.5%). Multivariate analysis showed that CRF02_AG was less likely to have the M41L mutation compared to other subtypes [adjusted odds ratio (AOR) = 0.35; p = 0.022]. Subtype A patients showed a 42.5-fold increased risk (AOR = 42.5, p = 0.001) for the L210W mutation. Among NNRTI mutations, subtype G patients had an increased risk for A98G (AOR = 2.40, p = 0.036) and V106I (AOR = 6.15, p = 0.010), whereas subtype CRF02_AG patients had an increased risk for V90I (AOR = 3.16; p = 0.003) and a decreased risk for A98G (AOR = 0.48, p = 0.019). Five RT mutations were found to vary significantly between different non-B West African subtypes. Further study to understand the clinical impact of subtype-specific diversity on drug resistance will be critically important to the continued success of ART scale-up in resource-limited settings.

Pharmacokinetics, protein-binding-adjusted inhibitory quotients for atazanavir/ritonavir 300/100 mg in treatment-naïve HIV-infected patients.

OBJECTIVES: Studies have shown the importance of having a high protein-binding-adjusted inhibitory quotient (IQ) for protease inhibitors (PIs) boosted with ritonavir. The objective of this study was to explore the virological response when combination atazanavir/ritonavir was administered to treatment-nai¨ve patients. METHODS: Protein-binding-adjusted IQs were calculated in 100 treatment-nai¨ve patients initiating therapy with atazanavir 300 mg/ritonavir 100 mg plus two nucleoside reverse transcriptase inhibitors. RESULTS: The median atazanavir trough level was 635 ng/mL [interquartile range (IQR) 342-1000] and the median atazanavir protein-binding-adjusted IQ was 45 (IQR 24-71). Eighty-four per cent of patients had a successful virological response, and those who failed did not develop resistance. The IQ for boosted atazanavir is high, resulting in rare treatment failure without resistance mutations. CONCLUSIONS: This study showed that the protein-binding-adjusted IQ of atazanavir is close to those measured for lopinavir and darunavir used once daily in first-line treatment. Finally the selection of resistance in the case of virological failure (plasma viral load 4400 HIV-1 RNA copies/mL) to atazanavir/ritonavir used in first-line therapy seems uncommon, as it is for all boosted PIs.

Mycobacterium tuberculosis and Mycobacterium africanum in stools from children attending an immunization clinic in Ibadan, Nigeria.

BACKGROUND: Tuberculosis is a major cause of childhood morbidity and mortality in Nigeria. Diagnosis of childhood tuberculosis is a global challenge making early treatment a mirage. In this study we investigated the stools of children for the presence of mycobacteria. METHODS: Stool samples from children aged 3 days to 3 years who presented for postnatal immunization at a large university-based clinic in Nigeria, were subjected to Ziehl-Neelsen staining. Samples with acid-fast bacilli were further processed using mycobacterial culture, spoligotyping, and deletion typing. RESULTS: One hundred and ninety-two stool samples from different children were collected and processed. Thirty (15.6%) had acid-fast bacilli. Of these, eight had Mycobacterium tuberculosis and one had Mycobacterium africanum. CONCLUSIONS: Approximately 5% (9/192) of apparently well children had evidence of potentially serious tuberculosis infection. The usefulness of stool specimens for diagnosing pediatric tuberculosis warrants further investigation.

Chiari I malformation and idiopathic growth hormone deficiency in siblings.

INTRODUCTION: The authors report a case of three brothers. Two of these siblings presented with congenital growth hormone deficiency and Chiari I malformation. The third and younger brother has been found not to have growth hormone deficiency or the Chiari I malformation. RESULTS: Sparse cases of these two clinical occurrences have been reported. Further, the posterior cranial fossa has been determined to be altered in patients with Chiari I malformation and growth hormone deficiency. CONCLUSION: Our current case reports strengthen the association between these two pathological entities and are, to our knowledge, the first description of both defects in siblings.

Safety, pharmacokinetics, and efficacy of (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine with efavirenz and stavudine in antiretroviral-naïve human immunodeficiency virus-infected patients.

Racivir [RCV; (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine], a 50:50 racemic mixture of the two beta nucleoside enantiomers, is currently in development for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. RCV was administered once a day orally for 14 days at doses of 200, 400, or 600 mg in combination with stavudine and efavirenz to HIV-1-infected treatment-naïve male volunteers in a phase Ib/IIa study. Six volunteers at each dose were monitored for a total of 35 days for tolerance, pharmacokinetics, and plasma HIV RNA levels. RCV in combination with stavudine and efavirenz was well tolerated at all doses tested. Pharmacokinetic parameters were dose proportional, and the maximum concentration of drug in serum at all doses exceeded the 90% effective concentration for wild-type HIV-1. Viral loads dropped as expected in all dosage groups, with mean reductions from 1.13 to 1.42 log10 by day 4 and 2.02 to 2.43 log10 by day 14. HIV RNA levels remained suppressed for more than 2 weeks in the absence of any additional therapy, with mean viral loads ranging from 2.1 to 2.6 log10 below baseline through day 28. By day 35, HIV RNA levels began to increase but still remained >1 log10 below baseline levels.

Extended antiretroviral treatment interruption in HIV-infected patients with long-term suppression of plasma HIV RNA.

OBJECTIVES: Evaluation of extended treatment interruption (TI) in chronic HIV infection among patients successfully treated with antiretroviral therapy. METHODS: An observational analysis of 25 patients in a prospectively followed cohort with chronic HIV infection, viral loads <500 HIV-1 RNA copies/mL for at least 6 months, and an interruption in therapy of >/=28 days duration was carried out. Follow up was divided into 3-month time periods for analysis. The effects of time period, stratification group and stratification group by time period interactions on CD4 counts were tested using a mixed model. Univariate comparisons among patient characteristics and responses were performed using Fisher's exact test or the Wilcoxon rank sum test. RESULTS: At initiation of TI, the median CD4 count was 799 cells/microL. TI duration was a median of 7.1 months. HIV RNA rebounded to a median maximum level of 75 000 copies/mL. Maximum viral rebound was significantly greater in patients who were male, had lipodystrophy and had zenith HIV RNA prior to TI of >/=50 000 copies/mL. Lower CD4 cell counts were observed during TI in patients with lipodystrophy, zenith HIV RNA >/=50 000 copies/mL, history of AIDS, HIV infection >/=5 years and presuppression CD4 count

The results of compression forces applied to the isolated human calvaria.

Data for the force necessary to fracture the isolated calvaria (skull cap) are not available in the extant literature. Twenty dry adult calvaria were tested to failure quasistatically at the vertex using a 15-kN load cell. The forces necessary to fracture or cause diastasis of calvarial sutures were then documented and gross examination of the specimens made. Failure forces had a mean measurement of 2772 N. Initial fractures did not cross suture lines. Prior to complete destruction of the calvaria there were 7 specimens in which all sutures of the calvaria became diastatic, 6 specimens in which the calvaria became diastatic along only the coronal sutures, 2 specimens in which the calvaria became diastatic along only the sagittal suture and 5 specimens in which there were diagonal linear parietal bone fractures. Our hopes are that these data may contribute to the structural design of more safer protective devices for use in our society, assist in predicting injury and aid in the construction of treatment paradigms.

Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study.

BACKGROUND: The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS: In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS: Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION: Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.

Switch studies: a review.

Many physicians and patients wish to switch from successful protease inhibitor (PI)-based regimens to alternative regimens, usually composed of a nonnucleoside reverse transcriptase inhibitor (NNRTI) or abacavir plus two nucleoside reverse transcriptase inhibitors (NRTIs). This reflects a desire to avoid or reverse the metabolic changes observed during long-term PI-based antiretroviral therapy; to alleviate PI-associated adverse effects; and to improve adherence by simplifying the regimen. Data from a number of randomized and cohort PI switch studies are reviewed. Overall, the results of these studies are mixed, perhaps because of limitations in study design, patient number and duration of follow-up. In most studies, the frequency of virological failure is reduced by switching to a NNRTI regimen. Switching to an abacavir-based regimen is associated with two-fold higher risk of virological failure if mutations in the reverse transcriptase gene pre-exist. Improvements in metabolic and lipid abnormalities have not been uniform but favourable lipid changes have been reported, particularly after switching to nevirapine. Resolution of lipodystrophy symptoms has not been demonstrated objectively, perhaps because of insufficient follow-up and/or the role of NRTIs in this syndrome.

Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials.

Our objective was to evaluate valaciclovir for anogenital herpes in HIV-infected individuals using 2 controlled trials conducted before highly active antiretroviral therapy (HAART) was used. In Study 1, 1062 patients (CD4+ > or = 100 cells/mm(3)) received suppressive valaciclovir or aciclovir for one year and were assessed monthly. In Study 2, 467 patients were treated episodically for > or =5 days with valaciclovir or aciclovir and evaluated daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpes. Hazard ratios [95% confidence interval (CI)] for time to recurrence for valaciclovir 500 mg twice daily and 1000 mg once daily vs aciclovir were 0.73[0.50, 1.06], P=0.10, and 1.31[0.94, 1.82], P=0.11. Valaciclovir 500 mg twice daily was superior to 1000 mg once daily, P=0.001. Valaciclovir 1000 mg twice daily was comparable to aciclovir on herpes episode duration (hazard ratio 0.92[0.75, 1.14]). Adverse events were similar among treatments. In conclusion, valaciclovir is a safe, effective, convenient alternative to aciclovir for HSV infection in HIV-infected individuals.

Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile.

BACKGROUND: Protease inhibitor-containing antiretroviral therapy for the treatment of HIV-1 infection is associated with elevated triglyceride and low-density lipoprotein (LDL)-cholesterol levels which may expose patients to an increased risk of coronary artery disease (CAD). We report the lipid and lipoprotein profiles of a representative subset of treatment-naive patients included in the Atlantic Study. This study compares patients treated with stavudine and didanosine plus the random addition of either the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), the protease inhibitor indinavir or the nucleoside reverse transcriptase inhibitor lamivudine. METHODS: Lipids and lipoproteins were quantified from prospectively collected and cryopreserved plasma samples obtained at weeks 0, 6 and 24. RESULTS: We observed a striking increase in high-density lipoprotein (HDL)-cholesterol (49%), apolipoprotein AI (19%), lipoprotein AI (38%) and HDL particle size (3%) in the NVP-treated patients (n = 34) at week 24. Much less pronounced changes in these parameters were seen to a similar extent both in patients receiving lamivudine (n = 39) and indinavir (n = 41). LDL-cholesterol also increased significantly both in the NVP and indinavir arms, but only in the NVP arm was this offset by a significant reduction (14%) in total over HDL-cholesterol ratio. Using a multivariate linear regression model, adjusting for CD4 cell count and plasma HIV RNA both at baseline and during treatment, randomization to the NVP-containing arm remained significant in explaining the observed changes in HDL-cholesterol and other HDL-related parameters. CONCLUSIONS: In HIV-1 infected patients treated with a regimen of stavudine, didanosine and NVP we found changes in lipids and lipoproteins which are associated with a sharp decrease in risk for CAD in other settings. If confirmed in larger studies, these findings both may influence the initial choice of therapy for HIV-1 infection, and might lead to novel approaches targeted at raising HDL-cholesterol for CAD prevention.