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Lenacapavir is the first capsid inhibitor, its use is currently approved for multidrug resistant HIV-1 infection. We report that, despite an initial efficacy of a LEN-containing regimen in patients with multi-drug resistant HIV-2 viruses, virological suppression was not achieved after a year and most patients selected capsid drug-resistance associated mutations., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Because NRTIs can have fetal toxicities, we evaluated a perinatal NRTI-sparing strategy to prevent perinatal HIV transmission. Our primary objective was to determine the proportion maintaining a viral load (VL) of <50 copies/mL up to delivery on darunavir/ritonavir monotherapy, without requiring treatment intensification., Methods: In a one-arm, multicentre Phase 2 clinical trial, eligible patients in the first trimester of pregnancy on ART with plasma VL < 50 copies/mL received maintenance monotherapy with darunavir/ritonavir, 600/100 mg twice daily. VL was monitored monthly. ART was intensified in the case of VL > 50 copies/mL. Neonates received nevirapine prophylaxis for 14 days., Results: Of 89 patients switching to darunavir/ritonavir monotherapy, 4 miscarried before 22 weeks' gestation, 2 changed treatment for elevated liver enzymes without virological failure, and 83 were evaluable for the main outcome. Six had virological failure confirmed on a repeat sample (median VL = 193 copies/mL; range 78-644), including two before switching to monotherapy. In these six cases, ART was intensified with tenofovir disoproxil fumarate/emtricitabine. The success rate was 75/83, 90.4% (95% CI, 81.9%-95.7%) considering two patients with VL missing at delivery as failures, and 77/83, 92.8% (95% CI, 84.9%-97.3%) when considering them as successes since both had undetectable VL on darunavir/ritonavir throughout pregnancy. In ITT, the last available VL before delivery was <50 copies/mL in all of the patients. There was no case of perinatal HIV transmission., Conclusions: Darunavir/ritonavir maintenance monotherapy required intensification in nearly 10% of cases. This limits its widespread use, thus other regimens should be evaluated in order to limit exposure to antiretrovirals, particularly NRTIs, during pregnancy., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: In a 4 days/week (4/7 days) maintenance strategy (ANRS-170 QUATUOR trial), the virological impact of an intermittent strategy was assessed by ultrasensitive virological analyses of reservoirs and resistance., Methods: HIV-1 total DNA, ultra-sensitive plasma viral load (USpVL) and semen VL were measured in the first 121 participants. Sanger and ultra-deep sequencing (UDS) were performed on the HIV-1 genome (Illumina technology) according to the ANRS consensus. A generalized estimation equation with a Poisson distribution was used to compare changes in the proportion of residual viraemia, detectable semen HIV RNA and HIV DNA within and between the two groups over time., Results: The proportion of participants with residual viraemia at Day 0 (D0) and Week 48 (W48) was 16.7% and 25.0% in the 4/7 days group and 22.4% and 29.7% in the 7/7 days group, respectively (+8.3% versus +7.3%, P = 0.971). The proportion of detectable DNA (>40 copies/106 cells) at D0 and W48 was 53.7% and 57.4% in the 4/7 days group and 56.1% and 51.8% in the 7/7 days group, respectively (+3.7% versus -4.3%, P = 0.358). Semen HIV RNA was detectable (≥100 copies/mL) in 2.2% of participants at D0 and 4.5% at W48 in the 4/7 days group versus 6.1% and 9.1% in the 7/7 days group, respectively (+2.3% versus +3.0%, P = 0.743). Emerging resistance at failure was more frequent in the 4/7 days group detected by Sanger sequencing: 3/6 participants versus 1/4 in the 7/7 days group, and similar with the UDS assay: 5/6 versus 4/4, respectively., Conclusions: These findings support the potency of a 4/7 days maintenance strategy on virological suppression at the reservoirs and emergent resistance level, including minority variants., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Whether integrase strand transfer inhibitors (INSTIs) can decrease HIV-1 DNA levels more rapidly than boosted PIs during primary HIV-1 infection (PHI) is unknown. We hypothesized that once-daily dolutegravir/tenofovir/emtricitabine could reduce the viral reservoir through rapid viral replication control further than once-daily darunavir/cobicistat/tenofovir/emtricitabine., Methods: The OPTIPRIM2-ANRS 169 study was a randomized (1:1), open-label, multicentre trial in adults with ≤5 or ≤3 HIV antibodies detected, respectively, by western blot or immunoblot in the last 10 days. The primary endpoint was total HIV-1 DNA levels in PBMCs at Week 48 (W48) adjusted for baseline levels. The main secondary endpoint was HIV-1 RNA level decrease., Results: Between April 2017 and August 2018, 101 patients were included from 31 hospitals. Most patients were men (93%), the median age was 36 years and 17% were Fiebig stage ≤3. The median (IQR) plasma HIV-1 RNA and DNA levels were, respectively, 5.8 (5.0-6.6) and 3.87 (3.52-4.15) log10 copies/million PBMCs. The median (IQR) decreases in HIV-1 DNA levels at W48 were -1.48 (-1.74 to -1.06) and -1.39 (-1.55 to -0.98) log10 copies/million PBMCs in the dolutegravir and darunavir/cobicistat groups, respectively (P = 0.52). Plasma HIV-1 RNA levels were <50 copies/mL in 24% versus 0% of patients in the dolutegravir and darunavir/cobicistat groups at W4, 55% versus 2% at W8, 67% versus 17% at W12, and 94% versus 90% at W48, respectively., Conclusions: Dolutegravir-based and darunavir-based regimens initiated during PHI strongly and similarly decreased the blood reservoir size. Considering the rapid viral suppression during a period of high HIV-1 transmission risk, dolutegravir-based regimens are a major first-line option., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Using data from the COHERE collaboration, we investigated whether primary prophylaxis for pneumocystis pneumonia (PcP) might be withheld in all patients on antiretroviral therapy (ART) with suppressed plasma human immunodeficiency virus (HIV) RNA (≤400 copies/mL), irrespective of CD4 count., Methods: We implemented an established causal inference approach whereby observational data are used to emulate a randomized trial. Patients taking PcP prophylaxis were eligible for the emulated trial if their CD4 count was ≤200 cells/µL in line with existing recommendations. We compared the following 2 strategies for stopping prophylaxis: (1) when CD4 count was >200 cells/µL for >3 months or (2) when the patient was virologically suppressed (2 consecutive HIV RNA ≤400 copies/mL). Patients were artificially censored if they did not comply with these stopping rules. We estimated the risk of primary PcP in patients on ART, using the hazard ratio (HR) to compare the stopping strategies by fitting a pooled logistic model, including inverse probability weights to adjust for the selection bias introduced by the artificial censoring., Results: A total of 4813 patients (10 324 person-years) complied with eligibility conditions for the emulated trial. With primary PcP diagnosis as an endpoint, the adjusted HR (aHR) indicated a slightly lower, but not statistically significant, different risk for the strategy based on viral suppression alone compared with the existing guidelines (aHR, .8; 95% confidence interval, .6-1.1; P = .2)., Conclusions: This study suggests that primary PcP prophylaxis might be safely withheld in confirmed virologically suppressed patients on ART, regardless of their CD4 count., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: An increased risk of cardiovascular disease (CVD) was reported in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), without identifying factors associated with atherosclerotic CVD (ASCVD) events., Methods: HIV-HCV coinfected patients were enrolled in the Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS) CO13 HEPAVIH nationwide cohort. Primary outcome was total ASCVD events. Secondary outcomes were coronary and/or cerebral ASCVD events, and peripheral artery disease (PAD) ASCVD events. Incidences were estimated using the Aalen-Johansen method. Factors associated with ASCVD were identified using cause-specific Cox proportional hazards models., Results: At baseline, median age of the study population (N = 1213) was 45.4 (interquartile range [IQR] 42.1-49.0) years and 70.3% were men. After a median follow-up of 5.1 (IQR 3.9-7.0) years, the incidence was 6.98 (95% confidence interval [CI], 5.19-9.38) per 1000 person-years for total ASCVD events, 4.01 (2.78-6.00) for coronary and/or cerebral events, and 3.17 (2.05-4.92) for PAD ASCVD events. Aging (hazard ratio [HR] 1.06; 95% CI, 1.01-1.12), prior CVD (HR 8.48; 95% CI, 3.14-22.91), high total cholesterol (HR 1.43; 95% CI, 1.11-1.83), high-density lipoprotein cholesterol (HR 0.22; 95% CI, 0.08-0.63), statin use (HR 3.31; 95% CI, 1.31-8.38), and high alcohol intake (HR 3.18; 95% CI, 1.35-7.52) were independently associated with total ASCVD events, whereas undetectable baseline viral load (HR 0.41, 95% CI, 0.18-0.96) was associated with coronary and/or cerebral events., Conclusions: HIV-HCV coinfected patients experienced a high incidence of ASCVD events. Some traditional cardiovascular risk factors were the main determinants of ASCVD. Controlling cholesterol abnormalities and maintaining undetectable HIV RNA are essential to control cardiovascular risk., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Relations between different measures of human immunodeficiency virus-related immunosuppression and chronic kidney disease (CKD) remain unknown., Methods: Immunosuppression measures included baseline, current, time-lagged and nadir CD4, years and percentage of follow-up (%FU) with CD4 ≤200 cells/μL, and CD4 recovery. CKD was defined as confirmed estimated glomerular filtration rate <60 mL/minute/1.73 m2., Results: Of 33 791 persons, 2226 developed CKD. Univariably, all immunosuppression measures predicted CKD. Multivariably, the strongest predictor was %FU CD4 ≤200 cells/μL (0 vs >25%; incidence rate ratio [IRR], 0.77 [95% confidence interval [CI], .68-.88]), with highest effect in those at low D:A:D CKD risk (IRR, 0.45 [95% CI, .24-.80]) vs 0.80 [95% CI, .70-.93])., Conclusions: Longer immunosuppression duration most strongly predicts CKD and affects persons at low CKD risk more., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: This work aimed to study the prevalence and risk factors associated with well-being and career satisfaction among French internal medicine physicians and residents., Methods: A total of 1689 French internal medicine physicians or trainees were surveyed to evaluate their workload, well-being and career satisfaction during February 2018., Results: The response rate was 620/1689 (37%). The mean age of the participants was 37 years (±12); 49% of the participants were female, 27% worked in the Paris area, 74% worked in a university hospital and 49% were residents. Sixty-six per cent of the responders were satisfied with their work, and 66% would choose the internal medicine specialty again. However, 71% of the responders worked more than 50 hours a week, 21% worked more than 60 hours a week and 70% believed that they did not have enough time for personal/family activities. Twenty-five per cent of the responders had at least one sign of burnout (19% of the physicians in practice and 32% of the residents). Compared with the graduate physicians in practice, the residents worked more hours a week, had more activities at night, spent more time on administrative tasks, had a worse global appreciation of their work and felt that their work was less meaningful. In multivariate analysis, the factors associated with global satisfaction at work were autonomy and meaningful work., Conclusions: French internal medicine physicians have a high rate of career satisfaction. However, residents have a higher workload, less time for personal/family activities and feel that their work is less meaningful., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: It is unclear whether use of contemporary protease inhibitors pose a similar risk of chronic kidney disease (CKD) as use of older protease inhibitors., Methods: Participants in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study were followed up until the earliest occurrence of CKD, the last visit plus 6 months, or 1 February 2016. Adjusted Poisson regression was used to assess associations between CKD and the use of ritonavir-boosted atazanavir (ATV/r) or ritonavir-boosted darunavir (DRV/r)., Results: The incidence of CKD (10.0/1000 person-years of follow-up; 95% confidence interval, 9.5-10.4/1000 person-years of follow-up) increased gradually with increasing exposure to ATV/r, but the relation was less clear for DRV/r. After adjustment, only exposure to ATV/r (adjusted incidence rate ratio, 1.4; 95% confidence interval, 1.2-1.6), but not exposure to DRV/r (1.0; .8-1.3), remained significantly associated with CKD., Conclusion: While DRV/r use was not significantly associated with CKD an increasing incidence with longer ATV/r use was confirmed., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: We aimed to determine the consequences of delayed human immunodeficiency virus type 1 (HIV-1) infection diagnosis by comparing long-term outcomes depending on the time of combination antiretroviral therapy (cART) initiation in patients diagnosed during primary HIV infection (PHI)., Methods: We selected patients from the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) PRIMO cohort, treated for ≥36 months, with sustained HIV RNA <50 copies/mL: 77 treated within 1 month following PHI diagnosis (immediate ART) and 73 treated >12 months after infection (deferred ART). We measured inflammatory biomarkers from PHI through the last visit on cART, and CD4+ and CD8+ T-cell activation and plasma ultrasensitive HIV RNA at the last visit. Inflammation/activation levels were compared with those of uninfected controls. We modeled CD4+ count, CD4:CD8 ratio, and HIV DNA dynamics on cART., Results: The decrease of HIV DNA levels was more marked in the immediate than deferred ART group, leading to a sustained mean difference of -0.6 log10 copies/106 peripheral blood mononuclear cells. Immediate ART led to improved CD4+ T-cell counts and CD4:CD8 ratios over the first 4 years of cART. At the last visit (median, 82 months), there was no difference between groups in CD4+ counts, CD4:CD8 ratio, ultrasensitive HIV RNA, or inflammation/activation marker levels. Long-term suppressive cART failed to normalize inflammation levels, which were not associated with immunovirological markers., Conclusions: Antiretroviral therapy initiated during PHI promotes long-term reduction of HIV reservoir size. In patients with sustained virologic suppression, inflammation may be driven by non-HIV-related factors.

Background: The OPTIPRIM-ANRS 147 trial compared intensive combination ART (darunavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection with standard tritherapy with darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine. From month 6 to 18, the percentage of viral load values <50 copies/mL was lower in the pentatherapy arm than in the tritherapy arm. Here we compared antiretroviral drug concentrations between the two arms., Methods: Plasma samples were collected from 50 patients at various times after drug administration. A Bayesian approach based on published population pharmacokinetic models was used to estimate residual drug concentrations (Ctrough) and exposures (AUC) in each patient. A mixed linear regression model was then used to compare the AUC and Ctrough values of each drug used in both groups., Results: Published models adequately described our data and could be used to predict Ctrough and AUC. No significant difference in tenofovir disoproxil fumarate, emtricitabine and ritonavir parameters was found between the two arms. However, darunavir Ctrough and AUC were significantly lower in the pentatherapy arm than in the tritherapy arm (P = 0.03 and P = 0.04, respectively)., Conclusions: Adding maraviroc and raltegravir to darunavir-based tritherapy decreased darunavir concentrations. Compliance issues, maraviroc-darunavir interaction and raltegravir-darunavir interaction were suspected and may affect the kinetics of viral decay during pentatherapy. A specific pharmacokinetic interaction study is needed to explore the interactions between darunavir and maraviroc and raltegravir.

Background: While the association between renal impairment and cardiovascular disease (CVD) is well established in the general population, the association remains poorly understood in human immunodeficiency virus (HIV)-positive individuals., Methods: Individuals with ≥2 estimated glomerular filtration rate (eGFR) measurements after 1 February 2004 were followed until CVD, death, last visit plus 6 months, or 1 February 2015. CVD was defined as the occurrence of centrally validated myocardial infarction, stroke, invasive cardiovascular procedures, or sudden cardiac death., Results: During a median follow-up duration of 8.0 years (interquartile range, 5.4-8.9 years) 1357 of 35 357 individuals developed CVD (incidence rate, 5.2 cases/1000 person-years [95% confidence interval {CI}, 5.0-5.5]). Confirmed baseline eGFR and CVD were closely related with 1.8% of individuals (95% CI, 1.6%-2.0%) with an eGFR > 90 mL/minute/1.73 m(2) estimated to develop CVD at 5 years, increasing to 21.1% (95% CI, 6.6%-35.6%) among those with an eGFR ≤ 30 mL/minute/1.73 m(2) The strong univariate relationship between low current eGFR and CVD was primarily explained by increasing age in adjusted analyses, although all eGFRs ≤ 80 mL/minute/1.73 m(2) remained associated with 30%-40% increased CVD rates, and particularly high CVD rates among individuals with an eGFR ≤ 30 mL/minute/1.73 m(2) (incidence rate ratio, 3.08 [95% CI, 2.04-4.65])., Conclusions: Among HIV-positive individuals in a large contemporary cohort, a strong relation between confirmed impaired eGFR and CVD was observed. This finding highlights the need for renal preventive measures and intensified monitoring for emerging CVD, particularly in older individuals with continuously low eGFRs., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients with cirrhosis have long been considered to be difficult to treat, and real-life efficacy and tolerance data with all-oral direct-acting antiviral (DAA) combinations in these patients are scarce., Methods: Cirrhotic HIV/HCV-coinfected patients enrolled in the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) CO13 HEPAVIH cohort initiating an all-oral DAA regimen were consecutively included. A negative HCV RNA result at 12 weeks of follow-up or thereafter was assumed as a sustained virologic response (SVR12). Adjusted exact logistic regression was used to study factors associated with treatment outcome., Results: We included 189 patients who initiated an all-oral DAA regimen with the following characteristics: median age 53.2 years; 74.6% male; Centers for Disease Control and Prevention classification A/B/C: 37%/31%/32%; Child-Pugh class A/B/C: 91%/8%/1%; 87% with HIV RNA <50 copies/mL; 99% on antiretrovirals; median CD4 count: 489 cells/µL; HCV treatment naive 29%; HCV genotype 1/2/3/4: 58%/4%/17%/21%. Sofosbuvir (SOF) + daclatasvir ± ribavirin (RBV) was used in 123 patients, SOF + RBV in 30, SOF + simeprevir in 11, and SOF + ledipasvir in 23. An SVR12 was reported in 93.1% of the patients (95% confidence interval, 88.5%-96.3%). In adjusted analyses, no difference was found between 12 or 24 weeks of treatment, in patients receiving RBV or not, and in treatment-naive vs experienced patients. Premature stop of DAA was reported for 8 patients. One patient died during treatment (unknown cause), and 12 other patients developed liver-related events., Conclusions: In this prospective real-life cohort, all-oral DAA regimens were well tolerated and associated with a high virologic efficacy in cirrhotic HIV/HCV-coinfected patients. This should not alleviate the surveillance for liver-related events in these patients., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Retreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population., Methods: HIV type 1-infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were excluded. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32-56 weeks according to virological response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24)., Results: Sixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% confidence interval, 68%-88%). SVR24 was not influenced by baseline fibrosis stage, IL28B genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematological (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two patients died during the study. No HIV breakthrough was observed., Conclusions: Despite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experienced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)-positive persons with initially normal renal function is unknown., Methods: D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥ 90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤ 70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤ 60 mL/min (a value indicative of moderately severe chronic kidney disease [CKD]) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥ 3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression., Results: Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤ 70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up [95% confidence interval {CI}, 4.35-5.22]) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up [95% CI, 1.10-1.56]) during a median follow-up duration of 4.5 years (interquartile range [IQR], 2.7-6.1 years). A current eGFR of 60-70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio [aIRR], 1.72 [95% CI, 1.38-2.14]) but not other ARVs compared with a current eGFR of ≥ 90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year [95% CI, 1.12-1.25]) and ritonavir-boosted atazanavir use (aIRR, 1.19/year [95% CI, 1.09-1.32]) were independent predictors of a confirmed eGFR of ≤ 70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year [95% CI, 1.05-1.17] and 1.22/year [95% CI, 1.16-1.28], respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs., Conclusions: Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.

Background: Liver diseases are the leading causes of death in human immunodeficiency virus (HIV)-positive persons since the widespread use of combination antiretroviral treatment (cART). Most of these deaths are due to hepatitis C (HCV) or B (HBV) virus coinfections. Little is known about other causes. Prolonged exposure to some antiretroviral drugs might increase hepatic mortality., Methods: All patients in the Data Collection on Adverse Events of Anti-HIV Drugs study without HCV or HBV coinfection were prospectively followed from date of entry until death or last follow-up. In patients with liver-related death, clinical charts were reviewed using a structured questionnaire., Results: We followed 22 910 participants without hepatitis virus coinfection for 114 478 person-years. There were 12 liver-related deaths (incidence, 0.10/1000 person-years); 7 due to severe alcohol use and 5 due to established ART-related toxicity. The rate of ART-related deaths in treatment-experienced persons was 0.04/1000 person-years (95% confidence interval, .01, .10)., Conclusions: We found a low incidence of liver-related deaths in HIV-infected persons without HCV or HBV coinfection. Liver-related mortality because of ART-related toxicity was rare.

Background: once-daily combinations of efavirenz and two nucleoside analogues are recommended for the treatment of HIV infection. Long-term efficacy and safety data are scarce for the combination of efavirenz, emtricitabine and didanosine., Methods: the ALIZE ANRS 099 trial enrolled 355 adults with plasma HIV RNA levels of <400 copies/mL under a protease inhibitor-based regimen, who were randomized to remain on this regimen or to switch to a once-daily regimen of emtricitabine, didanosine and efavirenz for 48 weeks. An extended 4 year follow-up was available for the 178 patients who switched to the efavirenz-containing regimen, and assessed plasma HIV RNA levels, CD4 cell counts, safety and tolerability., Results: after a median follow-up of 42 months, 121 patients (68%) remained on an efavirenz-based regimen, and 62% and 57% had plasma HIV RNA levels of <400 and <50 copies/mL, respectively, in an intent-to-continue analysis with missing data and treatment discontinuation considered as failure. There was a significant increase in CD4 cell count of 41 cells/mm(3). Drug-related adverse events were the main reason for treatment discontinuation in 26 patients (15%), and 15 were reported during the first year of therapy (58%). There was no emergence of clinically defined lipodystrophy, and lipid and glucose profiles were favourable with a significant increase from baseline of high-density lipoprotein cholesterol levels (median increase 12 mg/dL, P < 10(-4))., Conclusions: a once-daily regimen of emtricitabine, didanosine and efavirenz provided a durable antiretroviral response and was well tolerated through 4 years of therapy.

Background: Current guidelines suggest that primary prophylaxis for Pneumocystis jiroveci pneumonia (PcP) can be safely stopped in human immunodeficiency virus (HIV)-infected patients who are receiving combined antiretroviral therapy (cART) and who have a CD4 cell count >200 cells/microL. There are few data regarding the incidence of PcP or safety of stopping prophylaxis in virologically suppressed patients with CD4 cell counts of 101-200 cells/microL., Methods: The Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) included data from 23,412 patients from 12 European cohorts who started taking cART after 1997. Poisson regression was used to model incidence rate ratios (IRRs) of primary PcP., Results: There were 253 PcP cases during 107,016 person-years of follow-up (PYFU). Prophylaxis significantly reduced the incidence of PcP among patients with current CD4 cell counts 100 cells/microL (adjusted IRR, 0.41; 95% confidence interval [CI], 0.27-0.60) but not significantly among those with current CD4 cell counts of 101-200 cells/microL (adjusted IRR, 0.63; 95% CI, 0.34-1.17). The incidence of PcP among patients who had a current CD4 cell count of 100-200 cells/microL, who had a viral load <400 copies/mL, and who were receiving prophylaxis was 2.1 cases per 1000 PYFU (95% CI, 0.8-4.3 cases per 1000 PYFU; 7 events occurred during 3363 PYFU), whereas 1.2 cases per 1000 PYFU (95% CI, 0.2-4.5 cases per 1000 PYFU; 2 events occurred during 1614 PYFU) occurred among persons who were not receiving prophylaxis (adjusted IRR, 1.65; 95% CI, 0.33-8.15). Among patients who discontinued PcP prophylaxis after starting cART, the incidence of primary PcP was 0 cases per 1000 PYFU (95% CI, 0.0-2.7 cases per 1000 PYFU; 0 events occurred during 1363 PYFU) for patients who had a current CD4 cell count of 101-200 cells/microL and who were receiving cART., Conclusions: The incidence of primary PcP among patients who had virologically suppressed HIV infection, were receiving cART, and who had CD4 cell counts >100 cells/microL was low irrespective of prophylaxis use. Discontinuation of prophylaxis may be safe in patients with CD4 counts of 101-200 cells/microL and suppressed viral load.

Background: Our aim was to study the in vivo viral genetic pathways for resistance to raltegravir, in antiretroviral-experienced patients with virological failure (VF) on raltegravir-containing regimens., Methods: We set up a prospective study including antiretroviral-experienced patients receiving raltegravir-based regimens. Integrase (IN) genotypic resistance analysis was performed at baseline. IN was also sequenced at follow-up points in the case of VF, i.e. plasma HIV-1 RNA>400 copies/mL at month 3 and/or >50 copies/mL at month 6. For phenotyping, the IN region was recombined with an IN-deleted HXB2-based HIV-1 backbone. A titrated amount of IN recombinant viruses was used for antiviral testing against raltegravir and elvitegravir., Results: Among 51 patients, 11 (21.6%) had VF. Four different patterns of IN mutations were observed: (i) emergence of Q148H/R with secondary mutations (n=5 patients); (ii) emergence of N155H, then replaced by a pattern including Y143C/H/R (n=3); (iii) selection of S230N (n=1); and (iv) no evidence of selection of IN mutations (n=2). The median raltegravir and elvitegravir fold changes (FCs) were 244 (154-647) and 793 (339-892), respectively, for the Q148H/R pattern, while the median raltegravir and elvitegravir FCs were 21 (6-52) and 3 (2-3), respectively, with Y143C/H/R. The median plasma raltegravir Cmin was lower in patients with selection of the N155H mutation followed by Y143C/H/R compared with patients with Q148H/R and with patients without emerging mutations or without VF., Conclusions: Diverse genetic profiles can be associated with VF on raltegravir-containing regimens, including the dynamics of replacement of mutational profiles. Pharmacokinetic parameters could be involved in this genetic evolution.

Background: Little is known about the causes of death in human immunodeficiency virus (HIV)-infected women in the era of combination antiretroviral therapy (ART)., Methods: In the French nationwide Mortalité 2000 and 2005 surveys, physicians reported causes of deaths in HIV-infected adults in 2000 and 2005, using a standardized questionnaire. We used multivariate logistic regression models to study the association between gender and AIDS-defining causes of death, adjusting for other characteristics., Results: Of the 1013 HIV-infected adults who died in 2005, 247 (24%) were women. Half of women were infected through heterosexual contacts, compared with 25% men. In 2005, the proportion of AIDS-defining causes of death was higher in women than in men (43 vs 34%; P = 0.01), whereas it had been the same in 2000 (47% in women and men). In 2005, women died less frequently than men from respiratory malignancies (lung, ear/nose/throat) and cardiovascular disease (9% of all causes of death in women compared with 16% in men; P = 0.004), and suicides or accidents (4 vs 9%; P = 0.02). Socio-economic precariousness, younger age, less alcohol and tobacco consumption and lack of prior ART explained the higher proportion of deaths from AIDS in women compared with men., Conclusions: The higher proportion of AIDS-related deaths in women is probably explained by two factors: (i) some HIV-infected women, especially migrants in poor socio-economic conditions, may not have access to optimal care; and (ii) a lower prevalence of risk factors for respiratory, cardiovascular and violent deaths means that the risk of dying from non-AIDS causes may be lower in women.

Background: Human immunodeficiency virus (HIV)-infected patients are at higher risk of malignancies. In addition to traditional determinants, a specific deleterious effect of HIV and immunodeficiency is speculated. We aimed at studying the association between immunological and virological characteristics of HIV-infected patients in care and the risk of acquired immunodeficiency syndrome (AIDS)-defining and non-AIDS-defining malignancies., Methods: Patients consecutively enrolled in the hospital-based Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort were included if the duration of follow-up was >3 months during the period 1998-2006. Multivariate modeling used an extended Cox proportional hazards model for time-dependent covariates and delayed entry., Results: The 4194 patients included in the study developed 251 first malignancies during 22,389 person-years. A higher incidence of AIDS-defining malignancies (107 cases) was independently associated with (1) both longer and current exposures to a plasma HIV RNA level >500 copies/mL (hazard ratio [HR], 1.27 per year [P<.001] and 3.30 [P<.001], respectively) and (2) both longer and current exposure to a CD4(+) cell count <200 cells/mm(3) (HR, 1.36 per year [P<.001] and 6.33 [P<.001], respectively). A higher incidence of non-AIDS-defining malignancies (144 cases) was independently associated with longer and current exposure to a CD4(+) cell count <500 cells/mm(3) (HR, 1.13 per year [P=.01] and 2.07 [P<.001], respectively) and male sex (HR, 1.69; P=.02) but not with plasma HIV RNA level (P=.49 and P=.10 for cumulative and current exposures, respectively)., Conclusions: Uncontrolled plasma HIV RNA level was independently associated with a higher likelihood of developing AIDS-defining malignancies, whereas immunosuppression was associated with a higher risk of developing any type of malignancies. Antiretroviral treatment should aim at reaching and maintaining a CD4(+) count >500 cells/mm(3) to prevent the occurrence of malignancy, this should be integrated to malignancy-prevention policies.

Background: The goal of the current study was to describe the distribution and characteristics of malignancy related deaths among human immunodeficiency virus (HIV)-infected patients with use of data obtained from a national survey conducted in France in 2005 and to compare with results obtained from a similar survey conducted in 2000., Method: The underlying cause of death was documented using a standardized questionnaire fulfilled in French hospital wards and networks that were involved in the treatment of HIV-infected patients., Results: Among the 1042 deaths reported in 2005 (964 were reported in 2000), 344 were cancer related (34%), which represented a significant increase from 2000 (29% of deaths were cancer related) (P=.02); 134 of the cancer-related deaths were AIDS related and 210 were not AIDS related. Among the cancer-related causes of death, the proportion of hepatitis-related cancers (6% in 2000 vs. 11% in 2005) and non-AIDS/hepatitis-related cancers (38% in 2000 vs 50% in 2005) significantly increased from 2000 to 2005 (P=.03 and P=.01, respectively), compared with the proportion of cancer that was AIDS related and adjusting for age and sex. Among cases involving AIDS, the proportion of non-Hodgkin lymphoma-associated deaths did not change statistically significantly between 2000 and 2005 (11% and 10% of deaths, respectively)., Conclusions: In this study, an increasing proportion of lethal non-AIDS-related cancers was demonstrated from 2000 to 2005; meanwhile, the proportion of lethal AIDS-related cancers remained stable among HIV-infected patients. Thus, cancer prophylaxis, early diagnosis, and improved management should be included in the routine long-term follow-up of HIV-infected patients.

Background: Treatment initiation at the time of primary human immunodeficiency virus (HIV) type 1 (HIV-1) infection has become less frequent in recent years., Methods: In the French prospective PRIMO Cohort, in which patients are enrolled at the time of primary HIV-1 infection, 30% of the 552 patients recruited during 1996-2004 did not start receiving antiretroviral treatment during the first 3 months after diagnosis. We analyzed the patients' clinical and immunological outcomes and examined potential predictors of disease progression. Progression was defined as the occurrence of an acquired immunodeficiency syndrome (AIDS)-related clinical event or a CD4 cell count <350 cells/mm3., Results: Fifty-six (34%) of the untreated patients experienced immunological progression during a median duration of follow-up of 24 months, and 1 of these patients had an AIDS-related event. The estimated risks of progression were 25%, 34%, and 42% at 1, 2, and 3 years after enrollment, respectively. Compared with patients who did not have progression, those with progression had significantly lower CD4 cell counts at diagnosis (455 vs. 738 cells/mm3), higher plasma HIV RNA levels (4.9 vs. 4.5 log10 copies/mL), and higher HIV DNA levels (3.3 vs. 3.0 log(10) copies/10(6) peripheral blood mononuclear cells [PBMCs]). All 3 parameters were significantly associated with progression in univariate analysis. In multivariate analysis, only the CD4 cell count and HIV DNA level were independently predictive of disease progression (relative hazard for CD4 cell count, 1.84 per decrease of 100 cells/mm3; relative hazard for HIV DNA level, 2.73 per increase of 1 log(10) copies/10(6) PBMCs)., Conclusions: Both a low initial CD4 cell count and a high HIV DNA level are predictive of rapid progression of untreated primary HIV-1 infection. Affected patients may therefore benefit from close clinical and laboratory monitoring and/or early administration of treatment.

Background: High grade non-Hodgkin lymphoma (NHL) remains the most common Acquired Immune Deficiency Syndrome (AIDS)-associated neoplasia and an important cause of mortality in people living with human immunodeficiency virus (HIV) infection in industrialized countries in the era of highly active antiretroviral therapy (HAART)., Method: A case-control study was implemented in a large cohort of HIV-infected patients. Case patients had newly diagnosed NHL, and control subjects were matched for CD4(+) cell count, calendar period, sex, and length of follow-up., Results: Variables associated with a decreased risk of NHL were the use of HAART during follow-up for at least 6 months (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.21-0.98), receipt of a diagnosis of AIDS before the censoring date (OR, 0.37; 95% CI, 0.18-0.76), and undetectable level of HIV RNA during follow-up (OR, 0.34; 95% CI, 0.15-0.77). The use of antiherpetic drug for at least 6 months was associated with a nonsignificant decreased risk of NHL (OR, 0.40; 95% CI, 0.11-1.44; P=.16). In multivariate analysis, variables significantly associated with a decreased risk of NHL were the use of HAART for at least 6 months during follow-up (OR, 0.37; 95% CI, 0.16-0.87) and receipt of an AIDS-related diagnosis before the censoring date (OR, 0.44; 95% CI, 0.21-0.93). Age, transmission group, hepatitis B and C coinfections, CD4(+) and CD8(+) cell count nadir, and previous history of herpes virus infection were not associated with an increased risk for NHL., Conclusion: The use of HAART for at least 6 months was associated with a decreased risk of NHL, whereas uncontrolled HIV RNA load may be associated with an increased risk. The role of antiherpetic drugs needs further investigation.

Background: We assessed a once-daily combination to simplify therapy in patients infected with human immunodeficiency virus type 1 (HIV-1)., Methods: A total of 355 adults with plasma HIV-1 RNA levels <400 copies/mL were randomly assigned to either switch to once-daily emtricitabine, didanosine, and efavirenz (n=178) or maintain their protease inhibitor (PI)-based regimens (n=177). The primary end point was sustained suppression of plasma HIV-1 RNA levels to <400 copies/mL., Results: At week 48, the proportion of patients meeting the end point was 87.6% in the PI group and 90.5% in the once-daily group, with a treatment difference of -2.9% (upper bound of the 1-tailed 95% confidence interval, 2.6%). The proportion of patients with HIV-1 RNA levels <50 copies/mL was higher in the once-daily group (87%) than in the PI group (79%) (P<.05). Resistance mutations to efavirenz and emtricitabine were detected in all patients in the once-daily group who experienced virologic failure while receiving study medication. The proportion of patients discontinuing study medication because of adverse events was similar between the once-daily group (9%) and the PI group (10%) (P=.8)., Conclusions: Substituting a convenient once-daily combination of emtricitabine, didanosine, and efavirenz for a PI-based regimen was well tolerated and associated with sustained virologic suppression.

Background: In the era of highly active antiretroviral therapy (HAART) mortality has decreased substantially among human immunodeficiency virus (HIV)-infected people with access to HAART, but there are concerns regarding co-morbidities and adverse effects of HAART, which may impair vital prognosis. The Mortality 2000 study examined the causes of death in HIV-infected adults at a national level in France in the year 2000., Methods: All French hospital wards known to be involved in the management of HIV infection were asked to notify prospectively the deaths that occurred in 2000 among HIV-infected adults. The causes of death were documented using a standardized questionnaire., Results: The 185 participating wards notified 964 deaths. The main underlying causes of death were AIDS-related (47%, non-Hodgkin's lymphoma: 23%), viral hepatitis (11%, hepatitis C: 9%, hepatitis B: 2%), cancer not related to AIDS or hepatitis (11%), cardiovascular disease (7%), bacterial infections (6%), suicide (4%), and adverse effect of antiretroviral treatments (1%). Among AIDS-related deaths, HIV infection had been diagnosed recently in 20%. Smoking was recorded in 72% of cancer-related deaths and alcohol consumption in 54% of hepatitis-related deaths. Among non-HIV related deaths between 25 and 64 years, the proportion of infectious diseases (including HCV and HBV-related deaths) was higher in HIV-infected adults than in the general population., Conclusions: Improved strategies for detecting HIV infection before AIDS-defining complications occur are needed in the era of HAART. The prevention of non-AIDS related cancers, especially lung cancer, the management of non-Hodgkin's lymphoma, and of viral hepatitis are also important priorities.

Risk factors associated with the occurrence of protease inhibitor (PI)-related severe and serious adverse drug reactions (SADRs) were analyzed in a prospective cohort of 1155 patients who initiated PI-containing therapy. During a total follow-up of 2037 patient-years, 169 SADRs were reported, yielding a rate of 8 incidents per 100 patient-years (95% confidence interval [CI], 6.8-8.6). The most frequent SADRs were elevated transaminase levels (in 49 events); renal colic (27); abnormal hematological findings (23); and metabolic (18), neuromuscular (7), pancreatic (6), cutaneous (6), cardiovascular (5), and psychiatric disorders (5). Among baseline characteristics, plasma human immunodeficiency virus RNA levels of >or=5 log(10) copies/mL (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2), elevated aspartate aminotransferase levels (HR, 1.1 for each 20 IU of elevation; 95% CI, 1.1-1.2), creatinine clearance levels of <70 mL/min (HR, 2.1; 95% CI, 1.2-3.7), test results positive for hepatitis C virus antibodies or hepatitis B surface antigenemia (HR, 2.6; 95% CI, 1.8-3.7), and receipt of indinavir (HR, 1.7; 95% CI, 1.2-2.4) were independently predictive of a SADR. SADRs were frequent in the first 4 months after initiation of highly active antiretroviral therapy but continued to occur after that time period.

A case-control study was undertaken to determine risk factors for lactic acidosis in human immunodeficiency virus-infected patients treated with nucleoside reverse-transcriptase inhibitors (NRTIs). From May 1996 to June 2000, 9 patients with lactic acidosis (defined as a plasma lactic acid level of >5 mM and plasma pH of <7.38) were identified. Control patients were randomly selected from among a large cohort of patients who initiated a dual NRTI regimen in 1996 or after. Two factors were associated with an increased risk of lactic acidosis: first, a creatinine clearance of <70 mL/min before lactic acidosis (OR, 15.8 [range, 3.0-86.5], P<10(-4)), and, second, a low nadir CD4+ T lymphocyte count before the inception of NRTI therapy (OR, 8.4 [range, 1.2-infinity], P=.03). The total cumulative exposure to NRTIs was not associated with an increased risk of lactic acidosis, nor was the cumulative exposure to any of the 4 NRTIs studied. According to these results, monitoring of creatinine clearance, especially in patients with a low nadir CD4+ T lymphocyte count, could lead to modifications in antiretroviral therapy in order to diminish the risk of occurrence of lactic acidosis.

A randomized, open-label trial was performed to study virological and intracellular interactions between stavudine and ribavirin in 30 patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Patients were randomized to receive either interferon and ribavirin or no treatment for HCV infection for 3 months. Intracellular peripheral blood mononuclear cells' stavudine-triphosphate (TP) concentrations were assessed. Plasma HIV RNA levels did not change significantly between baseline and month 3. There was a nonstatistically significant trend for a lower median residual concentration of intracellular stavudine-TP in the treated group, compared with the control group. The same trend was also observed for peak concentrations. Coprescription of ribavirin and stavudine has no short-term impact on plasma HIV RNA level in HIV-HCV-coinfected patients treated with stavudine as a part of their antiretroviral treatment; this coprescription can be safely used, although an in vivo interaction between ribavirin and stavudine is possible.

We performed a retrospective study to evaluate, under routine circumstances, the tolerance and immunovirological changes associated with antiretroviral regimens that contain nevirapine in 137 patients (88% were antiretroviral experienced). During a mean follow-up of 11 months, 33% of patients reported side effects attributed to nevirapine, and 21% discontinued treatment because of poor tolerance. Administration of antihistamines or corticosteroids at the initiation of treatment was not protective against adverse events (relative risk, 0.82; 95% confidence interval, 0.49-1.38). The proportion of patients with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) coinfection who had alanine aminotransferase levels of >100 IU/L increased from 19.4% at baseline to 42.9% at month 12 of follow-up (P=.02). We noticed a significant increase of the proportion of patients with total cholesterol levels of >5.5 mM (P=.02). We have shown that there is a high level of discontinuation of nevirapine therapy in clinical practice and that side effects were not prevented by administration of antihistamines or corticosteroids. Coinfection with HCV or HBV increased the risk of hepatotoxicity, which lead to the cautious use of nevirapine for such patients.

In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension (1500 mg orally twice daily) plus either pyrimethamine (75 mg per day after a 200-mg loading dose) or sulfadiazine (1500 mg 4 times daily) as treatment for acute disease (for 6 weeks) and as maintenance therapy (for 42 weeks) for toxoplasmic encephalitis (TE) in patients infected with human immunodeficiency virus. Twenty-one (75%) of 28 patients receiving pyrimethamine (95% lower confidence interval [CI], 58%) and 9 (82%) of 11 patients receiving sulfadiazine (95% lower CI, 53%) responded to treatment for acute disease. Of 20 patients in the maintenance phase, only 1 experienced relapse. Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events, 9 because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. Although gastrointestinal side effects were frequent, atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis.

The role of nucleoside analogues (NAs) in lipodystrophy (LD) syndrome in human immunodeficiency virus (HIV)-infected patients remains controversial. We studied the prevalence of LD in previously untreated patients randomized to receive different NA combinations (in the ALBI-ANRS 070 trial) for 6 months. At month 30 of follow-up, 37 (31%) of 120 patients had >/=1 morphologic change, and 21 (57%) of 37 had isolated peripheral lipoatrophy; corresponding values for the patients who received only NAs throughout follow-up were 20 (30%) of 66 and 14 (67%) of 21, respectively. In multivariate analysis, factors associated with presence of LD at month 30 were initial assignment to the group receiving stavudine and didanosine (odds ratio [OR], 6.7; P=.02), age (OR for being 10 years older, 3.6; P=.002), and HIV RNA level at month 30 (OR, 0.4; P=.007). No difference was observed in cholesterol and glucose levels as a function of any pattern of antiretroviral exposure. Exposure to stavudine and didanosine was associated with LD syndrome (predominantly lipoatrophy).

The objective of this study was to estimate the prevalence of and risk factors for clinical lipodystrophy (LD) and metabolic disorders in human immunodeficiency virus (HIV) type 1-infected patients. A cross-sectional survey of the Aquitaine Cohort was performed in January 1999. The clinical diagnosis of LD was categorized as fat wasting (FW), peripheral fat accumulation (FA), and mixed syndromes (MS). Of the 581 patients studied, 61% were treated with protease inhibitors. The overall prevalence of LD was 38% (95% confidence interval [CI], 32-42): prevalence of FW was 16% (95% CI, 13-18); of FA, 12% (95% CI, 10-15); and of MS, 10% (95% CI, 8-13). The prevalences of metabolic abnormalities were 49% (95% CI, 44-53) for lipid disorders and 20% (95% CI, 17-23), for glucose disorders. Factors associated with LD were age (for FW and MS), male sex (for FW), AIDS stage (for MS), body mass index (for FW and FA), waist-to-hip ratio (for FA and MS), and duration of antiretroviral treatment (for FW).

The safety and efficacy of a once-daily regimen that combines emtricitabine, didanosine, and efavirenz was studied among 40 previously untreated human immunodeficiency virus (HIV)-infected patients. The median plasma HIV RNA level was 4.77 log(10) copies/mL at baseline and decreased by a median of 3.5 log(10) copies/mL at 24 weeks, with 98% and 93% of patients achieving plasma HIV RNA levels <400 and <50 copies/mL, respectively. The median CD4 cell count was 373 cells/microL at baseline and increased by a median of 159 cells/microL at week 24. The most common treatment-related adverse events were mild to moderate central nervous system symptoms (73% of patients), diarrhea (33%), rashes (10%), and biochemical abnormalities. Adverse reactions led to permanent drug discontinuation in only 1 patient. The once-daily combination therapy of emtricitabine, didanosine, and efavirenz was safe and demonstrated strong antiviral and immunologic effects that lasted for the 24-week period of the study.

Although drug-induced rash is frequent in human immunodeficiency virus (HIV)-infected patients, rash due to pyrimethamine has not been described previously. In a randomized, double-blind, placebo-controlled study of pyrimethamine as primary prophylaxis for toxoplasmic encephalitis, the incidence of rash (per hundred patient-years) was 8.1 in the pyrimethamine group versus 1.5 in the placebo group (P < .0002). The 1-year incidence of toxoplasmic encephalitis after occurrence of rash was 37%, as compared with 9.6% in the pyrimethamine group without rash, with a 3.7 times higher risk for patients with pyrimethamine-induced rash (P = .001); the incidence was 13% in the placebo group. At the time of toxoplasmic encephalitis, pyrimethamine was successfully readministered to 80% of patients who discontinued it because of rash. Thus, pyrimethamine, when used for prophylaxis, does induce rash in HIV-infected patients. These patients are at higher risk for toxoplasmic encephalitis and should be carefully monitored for it.

Pyrimethamine (50 mg) with folinic acid (15 mg) given three times weekly was assessed as primary prophylaxis for toxoplasmic encephalitis (TE) in 554 human immunodeficiency virus-infected patients seropositive for Toxoplasma gondii and with < 200 CD4 cells/mm3. At 1 year, the incidence of TE was similar in pyrimethamine, 12%, and placebo, 13%, groups (relative risk [RR], 0.9; 95% confidence interval [CI], 0.6-1.4), and the survival rate was also similar, 85% and 80%, respectively (RR, 0.9; 95% CI, 0.7-1.2). Rash was the only adverse event that appeared significantly more frequently in the pyrimethamine arm (7% vs. 1%). In the on-treatment analysis, the incidence of TE was lower in the pyrimethamine arm, 4%, than in the placebo arm, 12% (P < .006). Thus, pyrimethamine cannot be recommended as a first-line regimen for primary prophylaxis of TE if the patient can take cotrimoxazole. However, it should be considered for patients who are intolerant to cotrimoxazole, especially in high-risk patients with < 100 CD4 cells/mm3.