Jean-Philippe Chave

Cognitive dysfunction in HIV patients despite long-standing suppression of viremia.

Objective:To determine the prevalence of cognitive complaints and HIV-associated neurocognitive disorders (HANDs) in a cohort of aviremic HIV-positive patients. To evaluate the relevance of the HIV dementia scale to detect HANDs. Design:Assessment of HANDs with neuropsychological tests. Methods:Two hundred HIV-infected patients with undetectable HIV-1 RNA concentrations in the plasma, no history of major opportunistic infection of the central nervous system in the past 3 years, no current use of intravenous drugs, and no major depression answered a questionnaire designed to elicit cognitive complaints. Cognitive functions of 50 complaining and 50 noncomplaining HIV-positive patients were assessed. Results:Patients had undetectable HIV-1 RNA concentrations for a median time of 48 months (range 3.2–136.6). The prevalence of cognitive complaints was 27%. The prevalence of HANDs was 84% among patients with cognitive complaints (asymptomatic neurocognitive impairment 24%, mild neurocognitive disorders 52%, and HIV-associated dementia 8%) and 64% among noncomplainers (asymptomatic neurocognitive impairment 60%, mild neurocognitive disorders 4%, and HIV-associated dementia 0%; P < 0.001). A score of 14 points or less on the HIV dementia scale yielded a positive predictive value of HANDs of 92% in complainers and 82% in noncomplainers. Conclusion:The prevalence of HANDs is high even in long-standing aviremic HIV-positive patients. However, HANDs without functional repercussion in daily life (asymptomatic neurocognitive impairment) is the most frequent subtype observed. In this population, the HIV dementia scale with a cutoff of 14 points or less seems to provide a useful tool to screen for the presence of HANDs.

Premature atherosclerosis in HIV-infected individuals : focus on protease inhibitor therapy

ObjectiveLipid disorders associated with the use of protease inhibitors may contribute to the premature development of atherosclerosis. The purpose of the present study was to determine whether the administration of a protease inhibitor-containing regimen to middle-aged (30–50 years) HIV-infected individuals for 6 months or longer is associated with an increased prevalence of atherosclerosis. MethodsHigh-resolution B-mode ultrasound imaging was used to visualize the femoral and carotid arteries of 68 HIV-negative and 168 HIV-infected individuals, including 136 patients who had received protease inhibitors for 26.8 ± 8.9 months (mean ± SD). Atherogenic plaques were defined as a thickening of the intima–media ⩾ 1200 mm. ResultsThe proportion of participants with one or more plaques was higher in the HIV-infected group in comparison with the HIV-negative group (55 versus 38%;P = 0.02), and so was the prevalence of cigarette smoking (61 versus 46%;P = 0.03) and hyperlipidaemia (56 versus 24%;P < 0.001). The presence of plaque was independently associated with age, male gender, plasma low-density lipoprotein cholesterol levels and smoking. In univariate logistic regression analysis, an association was also found with HIV infection. Among HIV-infected subjects protease inhibitor therapy was not associated with the presence of plaque. ConclusionsA large proportion of the middle-aged HIV-infected individuals examined during this study had one or more atherosclerotic plaques within the femoral or carotid arteries. The presence of peripheral atherosclerosis within this population is not associated with the use of protease inhibitors, but rather with ‘classic’ cardiovascular risk factors such as smoking and hyperlipidaemia, which are amenable to interventions.

Acute Hiv infection: impact on the spread of Hiv and transmission of drug resistance

ObjectiveTo assess the impact of primary HIV infection (PHI) on the spread of HIV and the temporal trends in transmission of HIV drug resistance between 1996 and 1999 in Switzerland. MethodsSequencing of the genes for reverse transcriptase (RT) and protease was performed for 197 individuals with documented PHI. Phylogenetic analyses were confronted with epidemiological data. ResultsSignificant clustering was demonstrated for 29% of the RT sequences. All these cases occurred closely together in place and time; contact tracing demonstrated transmission at the time of PHI in 30% of them. Genotypic drug resistance was detected in 8.6% of PHI individuals in 1996, 14.6% in 1997, 8.8% in 1998 and 5.0% in 1999. Drug-resistant variants were identified in 11.3% of individuals infected by homosexual contacts, 6.1% by heterosexual contacts, 13% of intravenous drug users and more frequently in men (10.4%) than women (2.6%). Potential factors involved in the recent decrease of transmission of drug-resistant variants include increase of HIV non-B subtypes from 23% in 1996 to 35% in 1999 (only one non-B subtype had resistance mutations) and a steady increase of patients with undetectable viraemia as documented in Swiss HIV Cohort Study (10% in 1996 vs 53% in 1999). ConclusionsPhylogenetic and epidemiological analyses underline the impact of PHI in the spread of HIV. Moreover, this study indicates that drug resistance transmission may have decreased recently in Switzerland through the increased frequency of infection with HIV non-B subtypes and the steady increase of patients with undetectable viraemia.

Hyperlactatemia and Antiretroviral Therapy: The Swiss HIV Cohort Study

The prevalence, clinical presentation, and risk factors for hyperlactatemia among patients receiving antiretroviral therapy was determined during a 1-month period for patients in the Swiss HIV Cohort Study. Overall, 73 (8.3%) of 880 patients presented an increase in serum lactate of >1.1 times the upper normal limit (UNL). For 9 patients (1%), lactate elevation was moderate or severe (>2.2 times the UNL). Patients who presented with hyperlactatemia were more likely to be receiving stavudine with or without didanosine (odds ratio, 2.7; 95% confidence interval, 1.5-4.8), as compared with patients who received zidovudine-based regimens. The risk increased with increasing time receiving stavudine with or without didanosine. The association between hyperlactatemia and stavudine with or without didanosine was not biased by these medications being more recently available and, therefore, being given preferentially to patients who had prolonged use of nucleoside analog reverse-transcriptase inhibitors. Hyperlactatemia was associated with lipoatrophy, hyperlipidemia, and hyperglycemia. Age, sex, or stage of infection with human immunodeficiency virus were not predictive of hyperlactatemia. Determination of lactate levels may prove useful in the screening for mitochondrial toxicity.

Impact of drug resistance mutations on virologic response to salvage therapy

OBJECTIVE To assess the prognostic significance of drug-associated mutations in the protease and reverse transcriptase (RT) genes on virological response to salvage therapy. PATIENTS All patients from four centres of the Swiss HIV Cohort Study who were switched, between February and October 1997, to nelfinavir plus other antiretroviral drugs following failure of highly active antiretroviral therapy (HIV-1 RNA >1000 copies/ml after > 3 months). METHODS Direct sequencing of RT and protease genes derived from plasma RNA was performed in 62 patients before salvage therapy. Baseline predictors (drug-resistance mutations, drug exposure, clinical and biological parameters) of virological response after 4-12 weeks of therapy were assessed by linear regression analyses. RESULTS Patients had been treated with RT inhibitors and protease inhibitors for a median duration of 35.6 and 12.2 months, respectively. Baseline median CD4 cell count was 113 x 10(6)/l and HIV-1 RNA 5.16 log10 copies/ml. The median decrease of HIV-1 RNA was 0.38 log10; 32% of the patients showed > 1 log10 decrease. At baseline, 90% of the patients had RT inhibitor-resistance mutations with a median number per patient of four (range, 0-7). Primary and secondary protease inhibitor-resistance mutations were detected in 69% and 89% of the patients, respectively. The median number of total protease inhibitor-resistance mutations per patient was four (range, 0-9). In univariate analysis, virological response to salvage therapy was associated with number of RT inhibitors, primary and secondary protease inhibitor-resistance mutations, history of protease inhibitor use (duration and number), but not with clinical stage, HIV-1 RNA level or CD4 cell count. After adjustment for all variables, the number of RT inhibitor plus protease inhibitor-resistance mutations was the only independent predictor. CONCLUSIONS In patients with advanced HIV infection, the virological response to salvage therapy containing nelfinavir is best predicted by the number of baseline RT inhibitor plus protease inhibitor-resistance mutations.

A controlled study of inhaled pentamidine for primary prevention of Pneumocystis carinii pneumonia

BACKGROUND Current recommendations for prophylaxis of Pneumocystis carinii pneumonia (PCP) are based on data from patients who have had at least one episode of PCP (secondary prevention). We designed a study to determine the efficacy and side effects of inhaled pentamidine in the primary prevention of PCP. METHODS Two hundred twenty-three patients sero-positive for human immunodeficiency virus (HIV) who had the acquired immunodeficiency syndrome (AIDS) but not PCP, who had advanced AIDS-related complex, or who had less than 0.2 x 10(9) CD4-positive lymphocytes per liter received either 300 mg of pentamidine isethionate or 300 mg of sodium isethionate every 28 days by inhaler. The proportion of patients surviving without PCP was analyzed with the log-rank test as a function of time spent in the trial, according to the intention to treat with either placebo or pentamidine. RESULTS The third of five planned interim analyses showed a significant difference in the occurrence of PCP, with 8 cases in pentamidine group and 23 in the placebo group (nominal P value = 0.0021). There were no deaths within 60 days of the diagnosis of PCP and no significant differences in survival between groups. Approximately 53 inhalations were needed to prevent one episode of pneumonia. Thirty-eight of 114 patients given pentamidine (33 percent) and 7 of 109 given placebo (6 percent) had moderate-to-severe coughing during inhalations (two-tailed P less than 0.00001), which caused 4 patients given pentamidine (3.5 percent) to discontinue taking it. CONCLUSIONS A dose of 300 mg of aerosolized pentamidine given every four weeks was well tolerated and 60 to 70 percent effective in preventing a first episode of PCP in patients with HIV infection.

Abnormalities of body fat distribution in HIV-infected persons treated with antiretroviral drugs: The Swiss HIV Cohort Study.

We prospectively assessed the 1-month prevalence of abnormal body fat distribution in HIV-infected individuals. Of 1,359 patients treated with antiretroviral drugs, 578 (43%) had signs of abnormal fat distribution. Peripheral fat loss was observed in 382 patients (28%), whereas 412 (30%) had signs of fat accumulation. The presence of lipodystrophy (peripheral fat loss with or without fat accumulation) was found to be independently associated with increasing age (less than 35 years of age as a reference group: 35 to 41 years of age, OR = 1.5 [95% CI, 1.1-2.3]; and older than 41 years of age, OR = 2.4 [95% CI, 1.7-3.5]), current use of stavudine (OR = 2.4 [95% CI, 1.8-3.3]), current use of abacavir (OR = 2.1 [95% CI, 1.3-3.4]), and elevated lactate level (OR = 1.6 [95% CI, 1.1-2.4]). The prevalence of lipodystrophy was higher among patients who had received stavudine for a longer period (no stavudine in the current combination as a reference group: <6 months, OR = 1.1 [95% CI, 0.6-1.8]; 6-24 months, OR = 2.4 [95% CI, 1.7-3.5]; and >24 months, OR = 3.2 [95% CI, 2.4-4.3]). This study confirms the association between the use of stavudine and lipodystrophy.

TOXOPLASMA ENCEPHALITIS IN PATIENTS WITH THE ACQUIRED IMMUNODEFICIENCY SYNDROME

Among 504 cases of AIDS diagnosed between 1983 and 1990, there were 86 patients (17%) with toxoplasma encephalitis (TE). All were symptomatic at the time of diagnosis. General signs such as fever, neck stiffness, or headache were present in 87.2%, and 75.6% had focal signs. The primary means of diagnosis was computerized tomographic scanning, revealing 169 lesions of which 80% were immediately contrast-enhancing. All patients had IgG antibodies against Toxoplasma gondii either before (74 of 75 evaluable patients) or at the time of diagnosis of TE (73 of 75). Elevated antibody titers were present in 44% of evaluable patients, compared to 11% of patients with AIDS and other opportunistic infections. Initial treatment was pyrimethamine plus sulfonamides in 65 patients, and pyrimethamine plus clindamycin in 12 patients, with other combinations or no treatment accounting for the remainder. Life-table analysis of the time to discontinuation of treatment because of suspected side effects suggested that sulfadiazine was significantly more toxic, with 48% of patients experiencing an interruption in treatment after 30 days, than pyrimethamine (12%) or clindamycin (24%). The 30-day mortality rate was 12%, and median survival was 310 days after diagnosis, 530 in patients treated with zidovudine and 190 days in those not so treated. Of 82 evaluable patients, 16 relapsed once and 4 of these more than once. The risk of relapse was 27% 1 year after diagnosis of a first episode of TE.

Prevalence of comedications and effect of potential drug-drug interactions in the Swiss HIV Cohort Study.

BACKGROUND Potential drug-drug interactions (PDDIs) might expand with new combination antiretroviral therapies (ART) and polypharmacy related to increasing age and comorbidities. We investigated the prevalence of comedications and PDDIs within a large HIV cohort, and their effect on ART efficacy and tolerability. METHODS All medications were prospectively recorded in 1,497 ART-treated patients and screened for PDDIs using a customized version of the Liverpool drug interactions database. RESULTS Overall, 68% (1,013/1,497) of patients had a comedication and 40% (599/1,497) had > or = 1 PDDI. Among patients with comedication, 2% (21/1,013) had red-flag interactions (contraindicated) and 59% (597/1,013) had orange-flag interactions (potential dose adjustment and/or close monitoring required). The latter involved mainly central nervous system drugs (49%), cardiovascular drugs (34%) and methadone (19%). In the multivariate analysis, factors associated with having a comedication were advanced age, female gender, obesity and HCV infection. Independent risk factors for PDDIs were regimens combining protease inhibitors and non-nucleoside reverse transcriptase inhibitors (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.44-6.48), > or = 2 comedications (OR 1.89, 95% CI 1.32-2.70), current illicit drug use (OR 2.00, 95% CI 1.29-3.10) and patients with HCV infection (OR 1.74, 95% CI 1.19-2.56). Viral response was similar in patients with and without PDDIs (84.5% versus 86.4%; P=0.386). During follow-up, ART was modified in 134 patients with comedication regardless of the presence of PDDIs (P=0.524). CONCLUSIONS PDDIs increase with complex ART and comorbidities. No adverse effect was noted on ART efficacy or tolerability; however, most PDDIs affected comedication but were manageable through dose adjustment or monitoring.

Time of initiation of antiretroviral therapy: impact on HIV-1 viraemia.

ObjectiveThe current recommendation that patients infected with HIV-1 be treated early is based on little evidence. We examined whether the early initiation of antiretroviral treatment affects residual HIV-1 viraemia. MethodsViraemia was measured using an assay with a detection limit of 3 HIV-1 RNA copies/ml in drug-naïve patients who started antiretroviral therapy at the time of primary HIV-1 infection (PHI) (n = 10), during chronic infection without immune suppression (CD4 cell counts ⩾ 500/mm3; median 577) (n = 10), or after immune suppression developed (CD4 cell counts < 500/mm3; median 113) (n = 21). ResultsIn 249 samples collected 24 to 120 weeks after treatment initiation, the mean proportion of samples with HIV-1 RNA levels of less than 3 copies/ml was 75% for PHI patients compared with 32 and 8% for immunocompetent and immunosuppressed chronically infected patients, respectively. Fifty per cent of PHI patients, but none of the chronically infected patients, had persistently fewer than 3 HIV-1 RNA copies/ml. PHI patients had lower residual HIV-1 RNA levels than chronically infected patients, and immunocompetent patients had lower residual HIV-1 RNA levels than immunosuppressed patients (all pairwise, P  < 0.001). The mean residual HIV-1 RNA level was independently associated with the initiation of therapy during PHI and baseline CD4 cell counts (P  < 0.001 for both associations). ConclusionViraemia levels are associated with clinical progression and predict virological treatment failure. The initiation of antiretroviral therapy at the time of PHI and while CD4 cell counts are high results in lower residual viraemia. These results support early antiretroviral therapy in HIV-1-infected patients.