A case of a 15 year old girl with retroviral rebound syndrome after discontinuation of highly active antiretroviral treatment (HAART) due to side effects is presented. The patient was transmitted with HIV at birth by her mother. She had recovered from severe AIDS after HAART was initiated five years earlier. This is the first case reported in the literature of retroviral rebound syndrome in a vertically transmitted HIV-infected patient. Primary acute retroviral syndrome develop in more than 50% of patients infected with HIV ,2 and moIn rare cases, symptoms similar to those of acute HIV infection can develop after antiretroviral treatment interruption -9. The cMycobacterium avium intracellulare sepsis. After treatment initiation with stavudine (30 mg QD), lamivudine (150 mg QD) and indinavir (600 mg TID) a remarkable recovery took place and her CD4-cell count increased from 10 to 410 in one year, and further to 920 × 106/L during the following three years.A 15 year old girl with HIV since birth had to stop her antiretroviral treatment due to side effects. She started zidovudine monotherapy at the age of six, but continued to deteriorate clinically and immunologically during four years until she started HAART when it became available 1996. At the time she was hospitalized and severely ill with a However, the TID dosage of indinavir was inconvenient and to render BID dosing possible, a ritonavir boosted regimen with indinavir (800 mg BID) and ritonavir (100 mg BID) was started about 1.5 months before treatment cessation. It was not known at that time (2001) that such high indinavir dosage very often resulted in nephrotoxic side effects, and the serum creatinine concentration increased from 59 to 132 μmol/L after the change. Consequently, her antiretroviral treatment was stopped and the creatinine concentration normalized again within two months.6/L, figure Twelve days after the treatment discontinuation she presented with fever (39–39.5°C), lymphadenopathy, splenomegaly and abundant sweating during the nights. Her physical examination was normal and a chest radiography showed clear lung fields. Besides confirmed enlargement of the spleen, nothing abnormal was found with ultrasound or CT-scan of the abdomen. Blood cultures for bacteria, including mycobacteria, were negative. Serological testing for Epstein-Barr Virus (EBV), CMV and toxoplasmosis did not give any evidence of an ongoing infection. Routine laboratory showed discrete leucopenia and thrombocytopenia and slightly increased hepatic aminotransferase levels. Serum lactate and C-reactive protein were normal. Two weeks after treatment interruption the plasma HIV RNA level had increased from <50 copies/mL to >750000 copies/mL and the CD4 cell count decreased from 770 to 210 × 10Treatment with stavudine (30 mg BID), lamivudine (150 mg BID) and efavirenz (600 mg QD) was re-started just over one months after cessation, resulting in decreased HIV RNA and increased CD4 cell count again. The fever disappeared a few days before treatment was re-initiated.Retroviral rebound syndrome has been described in several reports after discontinuation of successful antiretroviral treatment in patients with chronic HIV infection -9. To ouThe clinical presentation of retroviral rebound syndrome is mostly mild, although more severe manifestations have been described ,9. A draThis case shows that retroviral rebound syndrome can develop after cessation of successful antiretroviral treatment also in patients infected with HIV since birth.The author(s) declare that they have no competing interests.VF and MG contributed to the patient care, data interpretation, and writing of the paper.


Lamivudine treatment has been recently demonstrated to increase the serum albumin levels in cirrhotic patients with hepatitis B virus (HBV) infection, but the precise mechanism remains unclear. We hypothesized that the improvement of hypoalbuminemia by lamivudine may be attributable to the reduction of HBV replication itself, rather than to cessation of hepatitis. In order to confirm this hypothesis, in this study we evaluated factors which correlated with the increase in serum albumin levels. Fifty-four patients  with HBV-related liver cirrhosis who had been treated with lamivudine for more than 12 months were evaluated. We analyzed the correlation between the increase in serum albumin levels at month 12 after starting treatment  and various pretreatment variables. We also analyzed the correlation between Δ-albumin and the reduction in serum levels of HBV-DNA (Δ-HBV-DNA) or alanine aminotransferase (Δ-ALT) at month 12.The average Δ-albumin was 0.38 g/dL and only serum HBV-DNA levels before treatment correlated significantly with Δ-albumin. We also analyzed the correlation in patients whose alanine aminotransferase levels were normalized after 12 months so that the possible influence of breakthrough hepatitis could be excluded. Even among this subgroup of patients, there was no significant correlation between Δ-albumin and either pretreatment alanine aminotransferase levels or Δ-ALT. In contrast, in patients whose serum HBV-DNA was undetectable at month 12, we found a significant correlation between Δ-albumin and both pretreatment serum HBV-DNA levels and Δ-HBV-DNA.Our results demonstrated that albumin levels are associated with pretreatment HBV-DNA but not with alanine aminotransferase levels. Chronic hepatitis B is an important cause of morbidity and mortality resulting from cirrhosis-related liver failure and hepatocelluar carcinoma (HCC) -3. Lamivp < 0.01), and decreased further to 2.87 ± 0.14 log copies/mL and 2.94 ± 0.18 log copies/mL at 6 and 9 months, respectively. Similarly, ALT levels also decreased significantly from 102.1 ± 10.4 U/L to 42.0 ± 2.7 U/L at 3 months after treatment (p < 0.01), and to 38.8 ± 4.1 U/L and 33.1 ± 2.4 U/L at 6 and 9 months, respectively. However, at 12 months there was a slight increase in both HBV-DNA and ALT levels , although the differences between values at 9 and 12 months were not statistically significant. The serum levels of albumin increased from 3.56 ± 0.09 g/dL to 3.76 ± 0.08 g/dL at 3 months after treatment, and increased further to 3.89 ± 0.08 g/dL (p < 0.05) and 3.95 ± 0.08 (p < 0.01) g/dL at 6 and 9 months, respectively. At 12 months, albumin levels remained steady at 3.94 ± 0.08 g/dL.Fifty-four cirrhotic patients with HBV infection were analyzed Table . HBV-DNA2 = 0.120089, p = 0.0103), whereas age, sex, HBeAg, ALT, bilirubin, platelet count, and Child-Pugh classification did not  and basic variables before treatment were examined using the data for all patients. In this analysis, only HBV-DNA load correlated significantly with Δ-albumin . We also evaluated the correlation between Δ-albumin and reduction in ALT levels at month 12 after starting treatment (Δ-ALT) in this group, but there was still no significant correlation between Δ-albumin and Δ-ALT   at 12 months after treatment. We next evaluated the correlation between Δ-albumin and pretreatment serum ALT levels among the 32 patients in whom serum ALT levels were normalized (< 35 U/L) at 12 months after the start of therapy. As shown in Figure ) Figure .r = 0.42459, p < 0.0001)   Figure .This study demonstrated the followings: 1) HBV-DNA, but not ALT levels, before lamivudine treatment was associated with increased serum albumin levels at 12 months after treatment ; 2) Even among those patients who showed cessation of hepatitis following treatment, there was no correlation between either pretreatment ALT levels or Δ-ALT and Δ-albumin; 3) In contrast, in the analysis of subjects with undetectable HBV-DNA levels after treatment, there was significant correlation between both pretreatment HBV-DNA levels and Δ-HBV-DNA and Δ-albumin. Taken together, these results suggest that the improvement of hypoalbuminemia following lamivudine treatment is attributable to a reduction of HBV replication, but not to cessation of hepatitis.We do not deny the idea that cessation of hepatitis, which is represented by lowering of serum ALT levels, contributed to and increase of serum albumin levels. In true, we think that replicative HBV and inflammation are closely related; however, in our study, HBV reduction statistically showed more effect improving serum albumin levels than decreasing the inflammation marker ALT. This may happen perhaps because, in cirrhotic patients, fibrosis is the main pathological change (compared with inflammation), and the correlation between, on the one hand, serum albumin or HBV-DNA levels and, on the other hand, ALT levels was in some degree weakened as the cirrhotic change proceed. Therefore, in cirrhotic patients, Δ-ALT is within a narrower range and ALT levels cannot influence albumin levels significantly.How does lowering of HBV load induces the increase of albumin levels in an inflammation-independent manner? Hui et al.  recentlyOur results indicate that increased serum albumin levels should be expected in cirrhotic patients following lamivudine treatment, and that this occurs independently of serum ALT levels and Child-Pugh's score before treatment, as shown by the lack of a correlation between those variables and Δ-albumin. Previous studies of lamivudine treatment for liver cirrhosis showed that fatalities occur because of acute liver failure after discontinuation of lamivudine ,26 or em3.7–108.7 genome equivalents/mL; 3.7–8.7 log genome equivalents [LGE]/mL)  or by a Roche Monitor kit   before treatment. HBe-Ag was positive in 29 patients and negative in 25 patients. Patients with fatty liver, viral hepatitis C, a history of alcohol abuse, or autoimmune disorders such as autoimmune hepatitis and primary biliary cirrhosis were excluded. None of the patients had a prior history of treatment for hepatocellular carcinoma.A total of 54 cirrhotic patients with HBV infection were evaluated, including 38 males and 16 females, ranging in age from 28 to 71 years (mean 52.6 years)  without interruption for more than twelve months at Kyushu University Hospital and its affiliated hospitals. Basic laboratory data, such as platelet counts, serum ALT levels, bilirubin, albumin, serum HBV-DNA load (Roche Monitor kit: Roche Diagnostics) and HBe-Ag were determined at least every 3 months.Data are expressed as mean ± SD, and statistical comparisons were performed using chi-squared test for categorical data and one-way ANOVA for numeric data. In cases where the serum HBV-DNA load was less than 2.6 log copies/mL, it was entered as 2.6 log copies/mL. For the analysis of correlations between two continuous variables, a simple regression model was used. For the analysis of discontinuous variables, such as sex and HBe-Ag, statistical differences were confirmed using Mann-Whitney U test or Kruskal-Wallis test.The author(s) declare that they have no competing interests.MN and ME participated in the experimental design and writing of the manuscript. JH participated in the experimental design. KK performed most of the analysis. YT, EK, JS, AM, TM, NF, HN, HS, KT, KA, and SS collected and supplied the clinical data of patients.


Objective: To compare ertapenem therapy with piperacillin–tazobactam therapy for the management of acutepelvic infections.Methods: In a multicenter, double-blind study, 412 women with acute pelvic infection were assigned to one oftwo strata, namely obstetric/postpartum infection or gynecologic/postoperative infection, and were thenrandomized to ertapenem, 1 g once a day, or piperacillin–tazobactam, 3.375 g every 6 hours, both administeredintravenously.Results: In total, 163 patients in the ertapenem group and 153 patients in the piperacillin–tazobactam group wereclinically evaluable. The median duration of therapy was 4.0 days in both treatment groups. The most commonsingle pathogen was Escherichia coli . At the primary efficacy endpoint 2–4 weeks post therapy, 93.9% of patientswho received ertapenem and 91.5% of those who received piperacillin–tazobactam were cured , indicating that cure rates for bothtreatment groups were equivalent. Cure rates for both treatment groups were also similar when compared bystratum and severity of infection. The frequency and severity of drug-related adverse events were generallysimilar in both groups.Conclusions:  In this study, ertapenem was as effective as piperacillin–tazobactam for the treatment of acute pelvicinfection, was generally well tolerated, and had an overall safety profile similar to that of piperacillin–tazobactam.


To determine the efficacy of adding abacavir  to optimal stable background antiretroviral therapy (SBG) to AIDS dementia complex (ADC) patients and address trial design.Phase III randomized, double-blind placebo-controlled trial.Tertiary outpatient clinics.ADC patients on SBG for ≥8 wk.Participants were randomized to ABC or matched placebo for 12 wk.The primary outcome measure was the change in the summary neuropsychological Z score (NPZ). Secondary measures were HIV RNA and the immune activation markers β-2 microglobulin, soluble tumor necrosis factor (TNF) receptor 2, and quinolinic acid.p = 0.735). The lack of efficacy was unlikely related to possible limited antiviral efficacy of ABC: at week 12 more ABC than placebo participants had plasma HIV RNA ≤400 copies/mL (p = 0.002). There were, however, other factors. Two thirds of patients were subsequently found to have had baseline resistance to ABC. Second, there was an unanticipated beneficial effect of SBG that extended beyond 8 wk to 5 mo, thereby rendering some of the patients at baseline unstable. Third, there was an unexpectedly large variability in neuropsychological performance that underpowered the study. Fourth, there was a relative lack of activity of ADC: 56% of all patients had baseline cerebrospinal fluid (CSF) HIV-1 RNA <100 copies/mL and 83% had CSF β-2 microglobulin <3 nmol/L at baseline.105 participants were enrolled. The median change in NPZ at week 12 was +0.76 for the ABC + SBG and +0.63 for the SBG groups  was first identified early in the HIV epidemic and at that time affected a substantial proportion of patients with AIDS. Patients with ADC experience dementia as well as disordered behavior and problems with movement and balance. ADC is now much less common in locations where patients have access to HAART , consisting of combinations of several drugs that attack the virus at different stages of its life cycle. At present, however, there are no generally accepted guidelines for the best treatment of people with ADC. It has been thought for some time that the best treatment regimens for people with ADC would include drugs that cross the barrier between blood and brain well. Shortly following the introduction of HAART, a trial was carried out to find out whether adding one particular drug, abacavir, to existing combinations of drugs would be beneficial in people with ADC. This drug is known to cross the barrier between the blood and brain. The trial enrolled HIV-positive individuals with mild to moderate ADC and who were already receiving antiretroviral drug treatment. 105 participants were assigned at random to receive either high-dose abacavir or a placebo, in addition to their existing therapy. The primary outcome of the trial was a summary of performance on a set of different tests, designed to evaluate cognitive, behavior, and movement skills, at 12 weeks. Other outcomes included levels of HIV RNA  in fluid around the brain, as well as other neurological evaluations, and the level of HIV RNA and CD4+ T cells (the cells infected by HIV) in blood.What this trial shows: When comparing the change in performance scores for individuals randomized to either abacavir or placebo, the results showed an improvement in scores for both groups, but no significant difference in improvement between the two groups. Similarly, the levels of HIV RNA in the cerebrospinal fluid did not differ between the two groups being compared, and other neurological tests did not show any differences between the two groups. However, at 12 weeks, patients receiving abacavir were more likely to have low levels of HIV RNA in their blood, suggesting that abacavir was active against the virus, but this did not translate into an additional improvement of these patients' dementia. The overall rates of adverse events were roughly comparable between the two groups in the trial, although participants receiving abacavir were more likely to experience certain types of events, such as nausea.Strengths and limitations: The trial was appropriately randomized and controlled, using central telephone procedures for randomizing participants and subsequent blinding of patients and trial investigators. These procedures help minimize the chance of bias in assigning participants to the different arms as well as in the subsequent performance of individuals within the trial and the assessment of their outcomes. Limitations in the study design have been identified. One limitation is that individuals enrolled into the trial may not in fact have been receiving their existing HAART regimen for long enough to experience its optimal effect, and therefore the improvement seen in both groups could have resulted from an ongoing response to their existing regimen. It is also possible that patients improved in their test scores over the course of the trial simply because they became more familiar with the tests and not because their condition improved. This is a problem in all such trials that try to improve mental function. Finally, a limitation may have been the inclusion of patients who did not have active disease leading to worsening dementia.Contribution to the evidence: The findings from this trial suggest that adding high-dose abacavir to existing HAART is not beneficial for patients with ADC. However, the trial provides several insights into the way that future studies of this type can be done, and which typically pose a number of challenging design problems. In particular, sensitive markers are needed that will allow researchers to monitor progression of ADC and patients' response to therapy. AIDS dementia complex (ADC) is a relatively common complication of advanced HIV disease, occurring in approximately 20% of patients in the era before highly active antiretroviral therapy (HAART) . ADC is overall there does not appear to be any benefit from a brain-penetrating regimen in neurologically asymptomatic patients, there is neuropsychological benefit in a subset of patients with significant dysfunction [For an antiretroviral therapy (ART) to be effective in ADC, theoretically it should have potent antiviral activity, ability to penetrate the brain at efficacious concentrations, and activity in macrophages and microglia, the primary targets of HIV infection within the brain. While the need for adequate brain penetration is controversial, studies addressing this issue thus far have been incomplete. There has been variability in the number of drugs that have been assessed in the regimen (at times one drug and at other times three), in the comprehensiveness of neuropsychological assessments, in the level of impairment of the patients, and in the potential for drug interactions. Moreover, there has been no head-to-head comparison of a brain-penetrating three-drug regimen versus one that is not penetrating. In a recent study, we have found that while function .chronic infection in resting monocyte lineage cells, ABC is active against both [Abacavir  is metabolized to a novel 2′ deoxyguanosine analog nucleoside reverse transcriptase inhibitor (NRTI) that fulfils these criteria. The compound has potent antiviral efficacy, can cross the blood brain barrier to an extent similar to ZDV, and has good antiviral activity in macrophages in vitro  and micrnst both . Consequnst both . Results.Thirteen sites in Australia, Canada, the United Kingdom, and the United States participated. Each site was a tertiary referral outpatient clinic. Confirmed HIV-1 seropositive male or female participants, aged 18 to 65 y, diagnosed with Stage 1 or 2 (mild to moderate) ADC  and stabThis was a phase III randomized, placebo-controlled, double-blind study. Ethics approval was obtained from each site. Informed consent was obtained from each participant or from their legal guardian. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.Participants received 600 mg of ABC or matched placebo twice a day in addition to their current SBG for the 12 wk of the study; changes in drugs or drug dosages within the SBG were not permitted during this time. Participants who experienced progression or severe antiretroviral drug toxicity not related to ABC during the study could receive open label ABC, 600 mg twice a day, and change the SBG as appropriate if a minimum of 6 wk on study had been completed. Participants were defined as having clinically progressed if their ADC clinical status deteriorated by at least one stage  with thiThe objective of the trial was to determine the efficacy of adding ABC to SBG to patients with ADC.+ cell count, mutations in the reverse transcriptase (RT) gene, and pharmacokinetic analyses.The primary outcome measure was the change in the summary neuropsychological Z score (NPZ). Secondary measures were CSF HIV RNA and the immune activation markers β-2 microglobulin and soluble tumor necrosis factor (TNF) receptor 2 and quinolinic acid. Ancillary measures were semi-quantitative neurological evaluations, plasma HIV RNA, CD4Neuropsychological performance was measured by a test battery comprised of the Rey Auditory Verbal Learning Test (RAVLT) Trials I–V ; Delayed Recall, Grooved Pegboard (dominant and nondominant hand); Trail Making B, Symbol Digit, Cal Cap Reaction Time ; and Verbal Fluency (word generation on FAS test). These tests are widely used in the United States, the United Kingdom, and Australia and have been validated in these populations. Z scores were constructed using the Multicentre-AIDS Cohort Study (MACS) reference data corrected for age and education .Collection of CSF samples was compulsory at day 7, but voluntary at weeks 6 and 12. CSF HIV-1 RNA was stored with appropriate precautions at −70 °C and later batch-extracted, amplified, hybridized, and detected using NASBA HIV-1 QT technology (Organon Teknika) with a detection limit of 100 copies/mL.β-2 microglobulin and soluble TNF receptor 2 (sTNF-R2)  were meaNeurological evaluations were performed using the AIDS Clinical Trials Group (ACTG) assessments, pre-study (day 14), weeks 6 and 12. Cognitive function, motor function, behavior/mood, mental status, level of consciousness, adapted mini-mental status exam, response slowing, cranial nerves, ocular motility, facial expression, limb strength, coordination, reflexes, and neuropathy were examined. The total neurological subscore was calculated  and used as an objective tool to confirm the participants' ADC stage (see Text S1). The neurological subscores were as follows: ADC Stage 1 (4–6), Stage 2 (7–9), and Stage 3 (10–12). Neuropathy was defined as the presence of symptoms of numbness and/or pain in the feet with absent or depressed ankle reflexes and diminished perception of pain, temperature, and vibration in the feet.http://www.roche-diagnostics.com) .Plasma HIV-1 RNA was assessed pre-study (day 7), at weeks 2, 4, 6, 8, and 12. Quantitation of plasma HIV-1 RNA was carried out using the RNA PCR technique developed by Roche Molecular Systems  and resolved on an ABI 373 DNA sequencer. Data were aligned and analyzed using the Sequencher program. Where mixed viral populations were present, a ratio of mutant to wild-type electropherogram peak size greater than 70% was designated as mutant.The HIV-1 coding region was amplified using the rTth XL RT-PCR kit (Perkin-Elmer). Purified cDNA was sequenced using the PRISM FS dye terminator cycle sequencing kit  were collected from a subset of participants at weeks 6 and 12 at various times after dosing. ABC concentrations were determined by a validated analytical method. Results are reported in four pre-defined time intervals.Safety and tolerability were evaluated by assessing clinical adverse events and clinical laboratory values. Adverse events and toxicities were graded using the ACTG grading scale.We calculated a priori that a sample size of 45 participants per treatment group would be required to provide 90% power to detect a difference between treatment groups of 0.6 in the change from baseline of summary NPZ at week 12. This sample size assumes α = 0.05, SD = 0.75, and a dropout rate of 20%–25%.Randomization was stratified by ZDV use (use versus nonuse) as part of their SBG to determine if there was any synergy between ZDV and ABC: stratum A if their existing SBG contained ZDV or stratum B if it did not. There were no limits on sample size within each stratum. Participants were then centrally randomized by ClinPhone at GlaxoSmithKline. The randomization schedule was loaded into the IVRS at ClinPhone and subsequently administered by them. The randomization schedule remained blinded until the database authorization was complete and after the data had been collected and cleaned. The patient, the investigator, the assessor, and GlaxoSmithKline were all blind to the treatment status of each patient. The ABC and placebo tablets were identical in appearance and taste. No steps, however, were undertaken to check the success of the blinding.All efficacy analyses were performed on the Intent-to-Treat (ITT) population, defined as all participants with data who were enrolled in the 12-wk phase of the study as randomized, regardless of actual treatment and the eventual outcome of study participation. Missing data were dealt with by carrying the last observation forward.The NPZ was calculated as the actual test result minus the reference group mean divided by reference group SD. A summary NPZ was computed as the mean of the eight individual NPZ. Treatment groups were compared using the stratified Wilcoxon rank sum test on the change from baseline to week 12 in the summary NPZ. Study termination at week 12 was chosen on the basis of the previously mentioned randomized placebo controlled trial of ZDV in ADC .Several retrospective exploratory sub-analyses were targeted at treatment effect within each of the three neuropsychological domains, effect of impairment at baseline on neuropsychological outcome and impact of background therapy. In addition to NPZ analyses, neuropsychological performance data were also examined using NP deficit score analysis as described by Heaton et al. . The resA total of 105 participants were randomized: 52 to the ABC + SBG group and 53 to the SBG alone group. Three participants from each group withdrew from the study prior to baseline evaluation for personal reasons. There were three protocol violations: two participants with ADC Stage 3 and one with ADC Stage 0.5 were entered into the trial and allowed to complete the study. Of the 99 participants from whom data were collected, 42 (86%) in the ABC + SBG group and 41 (82%) in the SBG group completed the 12-wk randomized phase . Seven pp = 0.735).10 copies/mL  was slightly more favorable than that observed for the SBG alone group of −0.26 log10 copies/mL  but still not statistically significant. There was no statistically significant correlation between change in CSF HIV-1 RNA and changes in either NPZ or plasma HIV-1 RNA.The baseline HIV-1 RNA levels in CSF, measured in a subset of 79 participants, were similar between treatment groups; 25/45 (56%) of participants from the ABC + SBG group and 19/34 (56%) from the SBG alone group had HIV-1 RNA levels of ≤100 copies/mL. At week 12, the majority of available CSF samples had HIV-1 RNA levels below the limit of detection; 19/23 (83%) of participants from the ABC + SBG group and 12/16 (75%) of participants from the SBG alone group had CSF HIV-1 RNA ≤100 copies/mL. If the median reductions in CSF HIV-1 RNA from baseline are estimated using week 12 data , the median HIV-1 RNA reduction for the ABC + SBG group of −0.64 logn = 7) for the ABC + SBG group and 88 pg/mL (n = 6) for the SBG alone group, and a decrease from baseline in quinolinic acid of 80 μg/mL (n = 8) for the ABC + SBG group and 186 μg/mL (n = 6) for the SBG group, but no significant associations with CSF HIV-1 RNA changes were identified. At baseline, 12/16 (75%) of participants from the SBG alone group and 22/25 (88%) of participants from the ABC + SBG group had CSF β-2 microglobulin levels <3.0 nmoles/mL; by week 12 decreases of 0.10 nmoles/mL (n = 7) in the ABC + SBG group and 0.12 nmoles/mL (n = 5) in the SBG group were observed. None of these changes in CSF markers reached statistical significance, even when the analyses were repeated as a percent change from baseline.Changes in sTNF-R2, quinolinic acid, and β-2 microglobulin levels from baseline were compared with CSF HIV-1 RNA changes by treatment group. There were decreases in sTNF-R2 from baseline of 30 pg/mL  in favor of ABC (p = 0.029)  .Due primarily to low HIV-1 RNA copy number, only 67 baseline plasma samples and 26 baseline CSF samples were successfully genotyped. Approximately 90% (60/67) of participants for whom baseline genotyping of plasma viral isolates was successfully completed had evidence of mutations in the HIV-1 RT related to prior NRTI use, reflecting the extensive prior treatment of these participants. A baseline M184V plasma HIV-1 RT mutation was detected in 50/67 (75%) of participants. Three or more mutations associated with NRTI resistance at baseline were seen in 44/67 (66%) participants. Despite this, 46% of participants in the ABC + SBG group and 13% in the SBG alone group had plasma HIV-1 RNA ≤400 copies/mL at week 12.CSF and plasma HIV-1 RT genotypes were discordant in 14/21 (67%) of baseline pairs. The majority of the differences were minor changes in ZDV/d4T mutation profiles. At baseline, one participant in the ABC + SBG group and six participants from the SBG alone group had the M184V mutation in virus from plasma but not from CSF.Correlations between CSF HIV-1 RNA response at week 12 and baseline CSF viral genotype were available for five participants in the ABC + SBG group and six participants in the SBG alone group. In the ABC + SBG group, 3/5 baseline CSF isolates carried ≥3 NRTI-associated mutations and 2/3 had CSF HIV-1 RNA ≤100 copies/mL at week 12, and in the SBG alone group 5/6 baseline CSF isolates carried ≥3 NRTI-associated mutations and 3/5 had CSF HIV-1 RNA ≤100 copies/mL at week 12.3 (range 194 to +411 cells/mm3) in the ABC + SBG group and −1 cells/mm3 (range −162 to +278 cells/mm3) in the SBG alone group.There was no notable difference in response between treatment groups with a median change from baseline at week 12 of +9 cells/mm50 for ABC (0.08 μg/mL) [Thirty-five CSF pharmacokinetic samples were obtained from participants randomized to receive ABC. The mean CSF ABC concentration increased consistently between the first and last collection intervals . While peak CSF concentrations may not have been attained due to the limited collection period , the observed peak values are 9-fold greater than a representative IC8 μg/mL) .In order to further investigate why a difference between treatment groups was not detected, additional analyses were conducted on completion of the study. These focused on two hypotheses: (1) the presence of a PI in the therapy influenced the result and (2) the degree of neuropsychological impairment influenced the trial result. Analyses of these hypotheses did not reach statistical significance though positive trends were evident in favor of the ABC + SBG group in participants not receiving PIs and in those who were more severely neurologically impaired .p = 0.01).In the ABC + SBG and SBG alone groups, 96% (ABC + SBG group) and 92% (SBG group) of participants experienced an adverse event during the randomized study period. The most frequent drug-related adverse events were nausea , diarrhea , malaise and fatigue , nausea and vomiting , and headache . The incidences of these drug-related adverse events were not significantly different between treatment groups, with the exception of nausea in the ABC + SBG group  and 1.15 (SBG group). Because the variability of the neuropsychological data was much greater than expected, the likelihood of detecting any treatment differences was compromised. Indeed the power of the study was reduced to 52%. With the same sample size, but with the larger SD of 1.20, only differences between treatment group responses on the order of 0.96 would have been detected. Had the study been planned with an SD of 1.20  rather than 0.75, approximately 115 patients per treatment group  would have been required. It should be noted that two HAART era studies conducted after the completion of this study also showed unexpectedly large SDs of 1 and 1.5 ,34. It tLastly, and perhaps most importantly, the study was designed to include participants with a diagnosis of ADC not confounded by other illnesses, but there was no provision to restrict entry to those who had “active” disease . Some patients may have had virologically or immunologically inactive disease while others may have been in a “reparative” phase, perhaps analogous to head injury or stroke patients who may take months to slowly improve after the initial insult. Studies have shown a correlation between ADC severity and CSF HIV-1 RNA and β-2 microglobulin levels when used in pre-HAART era ADC patients without other confounding conditions . HoweverMoreover, this study highlights an important change in CSF ADC markers in HAART-treated patients. No longer does the CSF compartment as assessed by HIV RNA and immune activation markers such as β-2 microglobulin reflect what is occurring in the brain: there is no relationship to the severity of ADC or to the risk of its worsening. This has been confirmed independently in another publication using a different cohort of patients . There aThis study highlights four issues that are critical in the design of future ADC trials and in individual patient management. Firstly, if a new antiretroviral agent is to be trialed in ADC the details of resistance mutations to it should be known before commencement of the trial so that patients with resistant virus can be excluded from the trial. A potential means of circumventing this problem in the case of a novel agent where resistance patterns have not yet been described  would be to recruit only antiretroviral naïve patients. However, this would mean that a large number of study sites would have to be involved to enable the requisite number of patients to be reached. Secondly, HAART has a beneficial effect on ADC which continues for at least 5 mo after commencement of therapy. Thus, future ADC trials should enroll patients after at least 5 mo of HAART. Thirdly, the variability in neuropsychological performance over time is greater than previously reported. These data should be used to estimate the required sample size in future trials. Fourthly, ADC patients should only be recruited into future anti-retroviral trials if they have active virally mediated ADC. At an individual patient level, it is not possible to be certain of the degree of activity of ADC in a HAART-treated patient. Consequently, clinicians are forced to consider an empirical trial either of intensification or change of HAART. Thus, markers that allow “real time” evaluation of ADC activity, as opposed to its retrospective identification by history, are urgently needed. In this regard, emerging data on the CSF concentrations of the neuronal markers neurofilament and perhaps t-tau are promising –39.While this trial delivered a negative result, it highlights important factors that must be incorporated into a new design methodology for future ADC trials in HAART-treated patients.CONSORT ChecklistClick here for additional data file.(50 KB PDF)Trial ProtocolClick here for additional data file.(4.5 MB PDF)Text S1 Clinical Evaluation FormClick here for additional data file.(1.7 MB PDF)


HIV-infected patients on long-term highly active antiretroviral therapy often present peculiar patterns of fat redistribution, referred to as lipodystrophy. In spite of recent investigations, it is not known whether and to what extent the main features of lipodystrophy – that is lipoatrophy of peripheral fat at face, limbs and buttocks, as well as fat accumulation at breasts, abdomen and the dorso-cervical region – can be reversible once clinically manifest.A 35 year old Caucasian HIV infected female developed severe diffuse lipodystrophy while on highly active antiretroviral therapy. A remarkable increase of breast size, fat accumulation at waist, and a fat pad on her lumbar spine were paralleled by progressive and disfiguring lipoatrophy of face, limbs and buttocks. The patient decided to interrupt her therapy after 20 months, with a stably suppressed viremia and a CD4 lymphocyte count >500/μL. She could carry on a safe treatment interruption for longer than 4 years. Most sites of fat accumulation switched to nearly normal appearance, whereas lipoatrophy was substantially unchanged at all affected sites.our observation provides pictorial evidence that lipoatrophy may not be reversible even under ideal circumstances. Therefore, strategies to prevent lipoatrophy should be considered when defining therapeutic regimens for HIV infected patients, especially those at high risk. HIV-infected patients on long-term highly active antiretroviral therapy (HAART) often present peculiar patterns of fat redistribution, involving both visceral and peripheral adipose tissue, referred to as lipodystrophy ,2. This Complex methods for objective measurements of fat deposits on affected sites involve the use of Dual-energy X-ray absorptiometry, Magnetic Resonance Tomography or CT scans. These methods, however, are costly and not always accessible in routine clinical practice. Moreover, they still lack adequate standardization, so that the diagnosis of lipodystrophy more frequently relies on concordant patient's and physician's evaluation -5.Cross sectional cohort studies indicate that lipodystrophy affects some 50% of patients continually treated with first-generation antiretroviral drugs for at least 18–24 months. Combined or severe abnormalities, however, develop only in 5 to 20% of affected patients -6, more Several strategies have been evaluated in clinical trials, with the aim of controlling such a stigmatizing side-effect. Switching to regimens including Nucleoside Reverse Transcriptase Inhibitors other than stavudine and/or a Non-Nucleoside Reverse Transcriptase Inhibitor instead of a Protease Inhibitor yielded objectively measured, significant increases in subcutaneous fat -12; thesHere we report on the evolution of HAART-induced severe combined lipodystrophy in one patient who carried out a very long lasting spell of therapy interruption.th, 2004, with a CD4 lymphocyte count of 250/μL and a viral load of 1250 copies/mL.A 35 year old Caucasian female was found to be infected with HIV1 in 1989, when she tested after heterosexual exposure. She was put on zidovudine in 1995, when her CD4 lymphocyte count steadily declined. She took the drug intermittently until 1997, when she was still asymptomatic, with CD4 lymphocytes <100/μL and a high HIV1 viral load (>500 000 copies/mL). In July 1997, she started her first line HAART regimen including stavudine 30 mg twice a day (bid), lamivudine 150 mg bid and indinavir 800 mg 3 times a day. At that time her body weight was stable, her body shape was lean and preserved, with a body mass index (BMI) of 18.3. Adherence and response to treatment were optimal; she reached undetectable viremia (< 400 copies/mL) and a >200/μL CD4 lymphocyte gain by the 12th week of treatment. Since April 1998, the patient complained about remarkable breast size increase, fat accumulation at waist, and a fat pad grown over her lumbar spine. The pad was 7 × 10 × 3 cm in size by July, 1998. At that time indinavir was replaced with ritonavir/saquinavir 400/400 mg bid due to renal stones. Rapidly progressive, severe lipoatrophy at limbs, buttocks and face ensued in the following months, together with a further increase in size of her fat pads. HIV1 viremia remained constantly undetectable; metabolic parameters were normal throughout follow-up, with an isolated abnormal value of triglycerides (306 mg/dL) in August 1998. Adherence to treatment was full until April 2000, when the CD4 lymphocyte count was >500/μL. The patient was offered a simplified regimen, which she refused, preferring a sharp interruption of HAART. At that time, she did not allow us to take pictures. After interrupting HAART, HIV1 viremia rebounded to lower than baseline, remaining <100 000 copies/mL  thereafter. CD4 lymphocyte counts declined very slowly; the patient remained asymptomatic, regularly attending her follow-up visits. Her metabolic parameters, including triglycerides, remained within the normal range at all further checks. She decided to carry on without any treatment for over 4 years, until July 2004, when the CD4 lymphocyte count had dropped to 84/μL. Pads of fat accumulation at waist had reverted to nearly normal appearance; the lumbar pad was no longer appreciable; breasts were still enlarged, although to a lesser extent Fig. . At variOur observation provides pictorial evidence that severe combined lipodystrophy in our patient was only partially reversible, even under the ideal condition of a long lasting and safe interruption of HAART. Recent reports indicate that the loss of CD4 lymphocytes during treatment interruptions is frequently rapid in patients with a Nadir CD4 lymphocyte count <200/μL and a high rate of cell gain under treatment, irrespective of the level of CD4 lymphocyte count at the interruption of HAART ,14. In sSevere lipoatrophy at buttocks and legs, instead, was unchanged both on patient's and on our judgment Fig.  and 1d. Lipodystrophy represents a major drawback of antiretroviral therapy for HIV infection. Its clinical and psychological impact may ultimately jeopardize HAART efficacy in many cases ,5. At thAs a growing body of clinical evidence suggests that newer HAART regimens may be less toxic on the adipose tissue, causing a clear-cut lower rate of body shape changes in the long run , preventμL = microlitermL = milliliterbid = bis in diemg = milligramshighly active antiretroviral therapy = HAARTThe author(s) declare that they have no competing interests.GP was in charge of the patient since 1997 at the AIDS Unit in Pescara General Hospital and carried out most of her follow-up visits; report of this case was conceived during a conversation with GMT, who also favoured presentation of the case at the Glasgow meeting in 2004. In depth discussion of pertinent medical literature led to an agreed description of the case and to the draft of manuscript. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The objective of the trial was to evaluate in a pilot setting the safety and efficacy of interleukin-2 (IL-2) therapy when used without concomitant antiretroviral therapy as a treatment for HIV infection.This was a multicentre randomised three-arm trial conducted between September 1998 and March 2001 at three clinical centres in the United Kingdom.3.Participants were 36 antiretroviral treatment naïve HIV-1-infected patients with baseline CD4 T lymphocyte counts of at least 350 cells/mmParticipants were randomly assigned to receive IL-2 at 15 million international units (MIU) per day (12 participants) or 9 MIU/day (12 participants) or no treatment (12 participants). IL-2 was administered by twice-daily subcutaneous injections for five consecutive days every 8 wk.Primary outcome was the change from baseline CD4 T lymphocyte count at 24 wk. Safety and plasma HIV RNA levels were also monitored every 4 wk through 24 wk. The two IL-2 dose groups were combined for the primary analysis.3 for those assigned IL-2 (both dose groups combined) and 13 cells/mm3 for control participants . Compared to the control group, significant increases in CD4 cell count were observed for both IL-2 dose groups: 104.2/mm3 (p = 0.008) and 128.4 cells/mm3 (p = 0.002) for the 4.5 and 7.5 MIU dose groups, respectively. There were no significant differences between the IL-2 (0.13 log10 copies/ml) and control (0.09 log10 copies/ml) groups for AUC of change in plasma HIV RNA over the 24-wk period of follow-up . Grade 4 and dose-limiting side effects were in keeping with those previously reported for IL-2 therapy.Area under curve (AUC) for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm3, intermittent subcutaneous IL-2 without concomitant antiretroviral therapy was well tolerated and produced significant increases in CD4 T lymphocyte counts and did not adversely affect plasma HIV RNA levels.In participants with HIV infection and baseline CD4 T lymphocyte counts of at least 350 cells/mm Background: There is very good trial evidence that combinations of antiretroviral drugs improve the prognosis of people with HIV infection. However, these drugs can have major side effects, and HIV can become resistant to them. The development of alternative treatments might allow antiretroviral use to be delayed in some people, thereby reducing toxicity and the emergence of resistant strains of HIV.What this trial shows: The researchers studied 36 adult patients in the United Kingdom who were infected with HIV and who had not previously been prescribed antiretrovirals. Participants in the trial were given either one of two different dosage levels of IL-2  by injection under the skin or no treatment at all. Patients given IL-2 at either dosage experienced an increase in levels of CD4 T lymphocytes, the type of immune cell depleted by HIV infection, as compared to patients receiving no treatment. The viral load in patients receiving IL-2 did not differ from that of patients in the control arm.Strengths and limitations: The rationale for this trial—to delay administration of antiretroviral drugs—is sound, as is the experimental design. The results are limited, however, by the short follow-up of patients in the trial and by the lack of clinical endpoints (such as disease progression), so it is not possible to tell whether patients in the trial benefited directly from the IL-2 treatment.Contribution to the evidence: The clinical effectiveness and safety of IL-2 together with antiretrovirals as a treatment for HIV infection is currently being evaluated in other, large-scale trials. To date, no other study has assessed the outcomes arising from administration of IL-2 alone. Data from the current trial will be useful in planning further research to examine whether IL-2 might help delay antiretrovirals in HIV-positive people. The development of combination antiretroviral therapy for the treatment of HIV infection has produced a marked decline in AIDS and death, but enthusiasm for these treatments in patients with early stages of HIV infection has been tempered by long-term toxicity, such as lipodystrophy and lactic acidosis, difficulties with maintaining rigorous compliance, and the evolution of drug resistant HIV –5. The uIL-2 is a cytokine that in vivo is secreted by activated T lymphocytes. IL-2 regulates the proliferation, differentiation, and survival of lymphocytes, including CD4 T cells . IncreasThe purpose of this randomised controlled pilot trial was to determine whether intermittent IL-2 therapy administered without concomitant antiretroviral therapy safely increased CD4 T lymphocyte counts. Ultimately, if this strategy were to be successful, it might lead to a delay in the time at which chronic antiretroviral therapy would need to be initiated. Further trials would be required from which to draw any definitive conclusions.3 at screening were eligible for enrollment if they had never received IL-2 or antiretroviral therapy. Additional eligibility criteria required that participants had no history of AIDS-defining illness and had received no corticosteroids, cytotoxic chemotherapy, or experimental cytotoxic therapy in the preceding 4 wk. Participants were required to have blood cell profiles and serum chemistry values within acceptable ranges. The study was approved by the National Institute of Allergy and Infectious Diseases' institutional review board and also by each site's research ethics committee. All participants provided written informed consent. An independent data and safety monitoring board reviewed safety and efficacy data on one occasion during the conduct of the trial. Patients were recruited and followed, and one of three participants' sites provided primary healthcare.Patients 18 y or older who had HIV-1 infection and CD4 T lymphocyte counts of at least 350 cells/mmParticipants were randomly assigned in equal proportions to intermittent subcutaneous injections of IL-2 at two dosage levels  or no treatment. The study was not placebo controlled, as the constitutional side effects of IL-2 make blinding impractical. IL-2  was administered either in a hospital clinic or through an outpatient department. Dose modifications in decrements of 1.5 MIU were allowed for the management of clinical or laboratory toxicities.Our primary hypothesis was that intermittent cycles of IL-2 would result in significant increases in CD4 T lymphocyte counts relative to no therapy. Our secondary hypotheses were that there would be no significant increases in plasma HIV RNA between treatment groups and that IL-2 cycles would be safe and well tolerated, in keeping with the experience of earlier studies.Over the 24-wk study period, participants were evaluated monthly, with additional visits of the IL-2-treated participants at day 5 of each cycle. Clinical assessments involved physical examination, complete blood counts with differentials and platelet counts, serum chemistry profiles, T lymphocyte subset enumeration, and plasma HIV RNA quantitation.Absolute CD4 and CD8 T lymphocyte counts were determined from 100 μl of fresh EDTA blood, by direct immunofluorescence using the Ortho-Trio method ,24. PartA treatment failure was prospectively defined as any patient who experienced either at least a 1-log increase in plasma HIV RNA on two consecutive occasions more than 29 d apart in the absence of an intercurrent illness, a greater than 25% reduction from the baseline CD4 T lymphocyte count on two occasions more than 29 d apart in the absence of intercurrent illness, and/or initiation of antiretroviral therapy for any reason.3 at a two-sided significance level of 5%. With this sample size, power was also 80% to detect a difference of 0.7-log copies of HIV RNA per cubic millimeter between treatment groups. These estimates were considered conservative because they did not consider the averaging of multiple follow-up measurements of CD4 and HIV RNA that were to be used for the primary analysis.Sample size was specified as 36 participants in order to provide 80% power to detect a difference between both IL-2 dose groups combined and the control group of 150 CD4 T lymphocytes/mmRandomisation was performed through using a central randomisation office located at the University of Minnesota. Computer-generated randomisation lists were generated at this office using a blocking factor of 6. Allocation of patients was by facsimile request from participant sites to the University of Minnesota randomisation office.10 transformed prior to analyses.The primary end points of the study were area under the curve (AUC) for CD4 T lymphocyte count change from baseline and AUC for plasma HIV RNA change from baseline over the 24 wk of the study. The AUC estimates were standardised for the timing of the last measurement for each person . SecondaBaseline was the average of three measurements made within 30 d of randomisation. Levels at 24 wk were the average of three measurements within 2 wk of one another. Follow-up levels at other weeks were based on a single reading.p-value of <0.05, indicating statistical significance.Data for patients assigned IL-2 were analysed on an intention-to-treat basis; i.e., all follow-up measurements were included even if the patient was not taking IL-2. Data from one participant in the control group who initiated antiretroviral therapy are only included up to the time antiretroviral therapy commenced. As stated in the protocol, for the primary analyses, the combined data from the two IL-2 dose groups were compared with control participants. Pairwise comparisons between each of the randomly assigned treatment arms and the control group and with one another were also carried out. In addition to AUC analyses, longitudinal regression methods that take into account correlations within and between participants were used to estimate the average difference between treatment groups (IL-2 and control) over follow-up and to estimate the differences in CD4 T lymphocytes and plasma HIV RNA at each follow-up timepoint . These aA total of 45 patients were screened for participation. Disposition of the cohort over the entire period of follow-up is shown in The exposure of participants randomised to receive IL-2 is summarised in 3 (p = 0.02). AUC for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm3 for those assigned IL-2 (both dose groups combined) and 13 cells/mm3 for control participants . As shown in 3) compared to control (+13.1 cells/mm3) . Longitudinal regression analysis yielded a similar difference between treatment groups . Statistically significant differences were also observed for the pairwise comparisons of each IL-2 dose with control , but not for the comparison of IL-2 doses 4.5 MIU versus 7.5 MIU (p = 0.57). The numbers of CD8 T lymphocytes in each treatment group remained stable throughout the period of observation in each treatment group (unpublished data).CD4 T lymphocyte counts over follow-up for each treatment group, based on longitudinal regression, are illustrated in 10 copies/ml) and control (0.09 log10 copies/ml)  .The AUC for change in plasma HIV RNA from baseline was similar for those assigned IL-2 (0.13 log = 0.70) . Similar10 HIV RNA in 32% of patients in cycle 1, 40% of patients in cycle 2, and 37% of patients in cycle 3. These increases ranged from 0.5 to 1.6 log10 HIV RNA. There were no statistically significant differences between the 4.5 MIU and 7.5 MIU dose groups (unpublished data).Evaluation of plasma HIV RNA at the end of each 5-d cycle of IL-2 administration revealed a transient increase of at least 0.5 logFollowing randomisation, one participant in each IL-2 dose group declined IL-2 therapy before receiving their first cycle, but their data have been included in the 24-wk analyses. One additional participant in the 4.5 MIU dose group permanently discontinued IL-2 after completing one cycle, citing personal reasons. Two additional participants in the 7.5 MIU dose group discontinued therapy, citing toxicity (one participant after completing two cycles), and multiple reasons, including toxicity and CD4 T lymphocyte count decrease (one participant after completing three cycles), as the reasons for discontinuation. No new side effects were encountered. The most numerous dose-limiting events were constitutional signs and symptoms, including fever and nausea. Five grade 4 events were reported during the trial as follows: diarrhea (4.5 MIU), pancreatitis (7.5 MIU), abdominal pain with hyperamylasemia (7.5 MIU), elevated alanine aminotransferase (4.5 MIU), and abdominal cramps with diarrhea (control). There were no deaths during follow-up.On the basis of the protocol definition, three patients experienced treatment failure during the 24-wk follow-up period: two control participants ; and one participant assigned 7.5 MIU IL-2 .+ T cell count resulting from a preferential increase in CD4+ T cell survival and decreased cell turnover in the setting of decreased immune activation [Studies of intermittent administration of IL-2 in combination with antiretroviral therapy have demonstrated significant and sustained increases in CD4tivation ,30. In ttivation . Despite3 and HIV RNA levels of <10,000 copies/ml, and the latter in participants with ≥300 cells/mm3 and no restriction on viral load.The clinical significance of the increase in CD4 T lymphocytes that are produced under the influence of IL-2 therapy is uncertain and has led to the initiation of two large clinical endpoint studies (SILCAAT and ESPRIT ) to asse3, considerably less than that observed in the other three Vanguard studies  were about 198–225 MIU, while in this study the average total dose of IL-2 given over the first three cycles to the 7.5 MIU arm was only minimally lower (192 MIU).+ T lymphocytes that are believed to be of significance in the immunopathogenesis of HIV disease. In many other trials of subcutaneous IL-2, a consistent observation has been that the functionality and/or immunophenotype of T cells present prior to IL-2 administration remains following IL-2 treatment, although in some settings there appears to be a preferential expansion of naïve CD4+ T lymphocytes [In this protocol we did not assess T-cell function. Neither did we choose to examine distinct subsets of CD4phocytes –30,32. AAs observed in other trials, this study demonstrates that IL-2 is well tolerated at doses that produce significant increases in CD4 T lymphocyte counts. Toxicities occurred only during the intermittent cycles of IL-2, were mostly mild to moderate in severity, and were managed with a comprehensive approach that included dose modification and the use of medications to control signs and symptoms. Grade 4 events occurred once in four IL-2 recipients and once in a control patient. Across the 66 treatment cycles initiated in this trial, this number of grade 4 events indicates a prevalence of approximately 6% for events of this severity. No novel toxicities were observed.3) and the upper limit for plasma HIV RNA difference from control (0.32 copies/ml) indicate that at least modest CD4 T lymphocyte increases are possible without adversely affecting viral load. Thus, these findings are sufficiently encouraging to plan other studies of intermittent monotherapy with IL-2 to study its potential for increasing or maintaining CD4 T cell counts and prolonging the time to initiation of antiretroviral therapy.While the sample size for this study was only 36 and not all patients provided data at the final timepoint for the primary measure of interest, the lower limit of the 95% CI for CD4 T lymphocyte Trial ProtocolClick here for additional data file.(337 KB DOC)


Successful highly active antiretroviral therapy (HAART) regimens have resulted in substantial improvements in the systemic health of HIV infected persons and increased survival times. Despite increased systemic health, the prevalence of minor HIV-associated cognitive impairment appears to be rising with increased longevity, and it remains to be seen what functional outcomes will result from these improvements. Cognitive impairment can dramatically impact functional ability and day-to-day productivity. We assessed the relationship of quality of life (QOL) and neuropsychological functioning with successful HAART treatment.In a prospective longitudinal study, subjects were evaluated before instituting HAART (naïve) or before changing HAART regimens because current therapy failed to maintain suppression of plasma viral load (treatment failure). Subjects underwent detailed neuropsychological and neurological examinations, as well as psychological evaluation sensitive to possible confounds. Re-evaluation was performed six months after institution of the new HAART regimen and/or if plasma viral load indicated treatment failure. At each evaluation, subjects underwent ultrasensitive HIV RNA quantitative evaluation in both plasma and cerebrospinal fluid.HAART successes performed better than failures on measures exploring speed of mental processing (p < .02). HAART failure was significantly associated with increased self-reports of physical health complaints (p < .01) and substance abuse (p < .01). An interesting trend emerged, in which HAART failures endorsed greater levels of psychological and cognitive complaints (p = .06). Analysis between neuropsychological measures and QOL scores revealed significant correlation between QOL Total and processing speed (p < .05), as well as flexibility (p < .05).Our study investigated the relationship between HIV-associated neurocognitive impairment and quality of life. HAART failures experienced slower psychomotor processing, and had increased self-reports of physical health complaints and substance abuse. Contrariwise, HAART successes experienced improved mental processing, demonstrating the impact of successful treatment on functioning. With increasing life expectancy for those who are HIV seropositive, it is important to measure cognitive functioning in relation to the actual QOL these individuals report. The study results have implications for the optimal management of HIV-infected persons. Specific support or intervention may be beneficial for those who have failed HAART in order to decrease substance abuse and increase overall physical health. Cognitive impairments are known to be associated with human immunodeficiency virus (HIV) infection. In HIV-1-associated minor cognitive/motor disorders patient profiles are characterized by impaired motor speed and working memory -4. In HISuccessful HAART regimens have resulted in substantial improvements in the systemic health of patients with HIV infection and increased survival times. However, with the increased longevity of HIV patients, the prevalence of minor HIV-associated cognitive impairment appears to be rising among HAART successes. HAART has been shown to successfully restore immune function and reduce the effects of opportunistic infection. This restoration of immune function results in a marked improvement of HIV-associated diseases and in the reduction of AIDS-related mortality . HoweverIn addition to neurocognitive deficits, patients afflicted with HIV often exhibit affective disorders such as depression and anxiety. In fact, lower quality of life scores have been found to be associated with a diagnosis of HIV and with disease-related symptoms ,15-17. NQuality of life in HIV infection has been shown to be directly associated with disease stage, disease symptoms, and cognitive function . SpecifiWhile the effects of HAART have resulted in substantial improvements in the systemic health of patients with HIV infection, it remains to be seen what functional outcomes will result from these improvements. Impairment in cognition can have dramatic impacts on the ability to function on a day-to-day basis, and to be productive. Initial studies have demonstrated that neurocognitive improvement occurs in most patients on HAART therapy. In this study, we assess the relationship of quality of life and neuropsychological functioning with successful HAART treatment.The University of North Carolina Institutional Review Board approved the study, and all participants gave informed consent for participation. Participants were enrolled in the study under the following conditions: 1) if they were about to start HAART; or 2) if, in the opinion of their infectious disease clinician, their current HAART had failed and they required a different HAART regimen. There was no requirement for (or stratification by) presence of neurologic disease at study entry. Prior to starting or changing an antiretroviral regimen, a baseline evaluation was conducted. Participants were reevaluated after 6 months of stable HAART or when, in the opinion of the treating infectious disease physician, the new regimen failed. A neurologist conducted a quantified previously validated examination particularly sensitive to the changes found in HIV disease at each evaluation. At each evaluation, a neuropsychologist conducted detailed psychological and neuropsychological evaluations that have also been validated as sensitive to the neurocognitive changes found in HIV disease. At each evaluation, subjects also underwent ultrasensitive HIV RNA quantitative evaluation of both plasma and cerebrospinal fluid.Viral load assessment was performed through plasma and cerebrospinal fluid measurements. Within eight hours of the neurologic evaluation, specimens for viral load and immune functioning were obtained. Blood and cerebrospinal fluid samples were obtained within 3 hours of each other. Cerebrospinal fluid samples were centrifuged to remove cells. The Roche Ultrasensitive assay was used to measure Quantitative HIV-1 RNA load. Prior to viral load analysis, neurologic and neuropsychological evaluations were completed in a blinded fashion.The Price and Sidtis  AIDS CliThe neuropsychological evaluation included assessment of the following domains: attention/concentration , speed of processing , executive functioning , visuospatial (Rey complex figure copy), verbal memory (RAVLT), figural memory , gross motor (timed gait), fine motor , and language (WAIS-R Vocabulary).The Neurological Quality of Life questionnaire (NeuroQOL) is a self report instrument which assesses eleven domains: Security, Food, Housing, Financial, Productivity, Social support, Relationships, Psychological health, Physical health, Substance abuse, and Cognitive/Neurological problems. The NeuroQOL questionnaire contains 114 items answered in Likert format. The items are summed for a total score, with higher scores reflecting better quality of life ,26.Subsequent to each visit, the Memorial Sloan Kettering dementia scale was determined for each participant at a consensus conference, utilizing the neurologic and neuropsychological evaluations, the psychiatric interview, and the quality of life scale. The Memorial Sloan Kettering dementia scale is as follows: normal, 0; equivocal (deficits that do not reach the stage of clear dementia), 0.5; and dementia, 1-3 (depending on severity) .HAART treatment success and failureWe defined success and failure on HAART by both virological and immunological changes. We defined virological success as a decrease in plasma HIV RNA by 1.5 log copies/ml and to less than 2.5 log copies/ml. Virological failures were defined as a decrease of less then 1.5 log copies/ml or a failure to reduce HIV RNA below 2.5 log copies/ml. We defined immunological success as an increase in CD4+ cell count. Immunological failure was defined as stable or decreased absolute CD4+ cell count.First, HAART treatment and results on the neuropsychological battery were compared between groups (HAART success group and HAART failure group) by using t tests and an alpha level of 0.05. Next, HAART treatment and results on the NeuroQol were compared between groups (HAART success group and HAART failure group) by using t tests and an alpha level of 0.05. Pearson product-moment correlation was used to analyze the relationship between performance on the neurocognitive tasks and NeuroQol domains.Eighty-six subjects were evaluated at baseline before treatment with HAART or after failing one treatment regimen and before instituting a different HAART regimen. Fifty nine of those then underwent six-month follow-up on stable HAART. As an ongoing study with continuous enrollment, seven of these participants did not have opportunity to attend their 6-month followup, as the data base was cut prior to their 6-month follow up. The dropout characteristics of the remaining participants include: five participants refused lumbar puncture, five had illicit drug problems, 2 never started HAART, 2 went to prison, 2 had other health related problems, and 2 moved out of the area. Of those with follow-up (N = 59), the median age was 42.52 years (SD = 7.58) and a median educational level of 12 years (SD = 2.15 years). The median CD4+ cell count was 290 (SD = 242.89), and the median plasma HIV RNA was 3.04 (SD = 1.84). Demographic, virologic, and immunologic variables are listed on Table Forty (68%) subjects were male and 19 were female (32%). Forty-four (75%) were black, 13 (22%) white, 1 was Asian and 1 was Native American. Forty (68%) had AIDS by CDC criteria, 7 (12%) were symptomatic and 12 (20%) were asymptomatic.A quantitative scoring procedure was utilized for the neurological exam, and summary z-scores were calculated for the neuropsychological battery.Participants with successful HAART treatment performed better than failure patients on measures exploring speed of mental processing . For complete results comparing Success and Failure groups on neuropsychological measures, see Table Our study investigated the relationship between HIV-associated neurocognitive impairment and quality of life. Our findings revealed that subjects who failed HAART experienced slower psychomotor processing, and had increased self-reports of physical health complaints and substance abuse. On the other hand, those with successful HAART experienced improved mental processing, demonstrating the impact of successful treatment on functioning.Restoration of immune function results in a marked improvement of HIV-associated diseases and in the reduction of AIDS-related mortality . With inThe presence of HAART failure was significantly associated with increased self-reports of physical health complaints. These findings reflect current literature, in which lower quality of life scores have been found to be associated with a diagnosis of HIV and with disease-related symptoms ,15-17. FQuality of life in HIV infection has been shown to be directly associated with disease stage, disease symptoms, and cognitive function ,28. SpecThe study results have implications for the optimal management of HIV-infected patients' neurocognitive impairment. Our findings support continued investigation of the presence of neurocognitive impairment in the HAART era. The association we found with poor quality of life scores further emphasizes this need. Given these findings, specific support or intervention may be beneficial for those who have failed HAART in order to decrease substance abuse and increase overall physical health. As a subjective evaluation of persons with HIV related illness, quality of life provides information relevant to patient care, and health promoting activities. Specific support or intervention may be beneficial for those who have failed HAART in order to increase a person's ability to achieve and maintain a level of overall functioning necessary to decrease substance abuse and increase overall physical health. The identifying of factors that diminish quality of life in HIV cases is an important step towards improving quality of life in this population. Further, it allows for screening of these factors, and in situations where these factors are present, it aides the clinician in planning and implementing interventions.Future studies should look at the relations among quality of life, adherence, substance abuse, neurocognitive scores, and virological and immunological outcome. Adherence is a critical component for therapeutic success in HIV infection and has been shown to be a major determinant of biological outcome measures in HIV. Substance abuse has been associated with decreased adherence in several studies ,30. DiveIn summary, our assessment of quality of life and neuropsychological functioning with HAART treatment revealed that HAART success was significantly related to processing speed. HAART failure was significantly associated with increased physical health complaints, substance abuse, and a trend toward increased psychological and cognitive complaints. Significant correlations were found between quality of life and processing speed, as well as flexibility. Future studies should include risk and/or severity factors and look at the relationship between quality of life, adherence, and neurocognitive sequelae.TDP, KRR and CDH planned the study and collected the data. KRR identified the patient cohort and collected the data. TDP performed the statistical analysis and drafted the manuscript together with KRR, CDH, and AJB . All authors read and approved the final manuscript.


Human immunodeficiency virus (HIV) infection is very prevalent in Brazil. HIV therapy has been recently associated with coronary heart disease (CHD). Dyslipidemia is a major risk factor for CHD that is frequently described in HIV positive patients, but very few studies have been conducted in Brazilian patients evaluating their lipid profiles.In the present work, we evaluated the frequency and severity of dyslipidemia in 257 Brazilian HIV positive patients. Two hundred and thirty-eight (93%) were submitted to antiretroviral therapy .The average time on drug treatment with antiretroviral therapy was 20 months. None of the patients was under lipid lowering drugs. Cholesterol, triglyceride, phospholipid and free fatty acids were determined by enzymatic colorimetric methods. Lipoprotein profile was estimated by the Friedewald formula and Fredrickson's phenotyping was obtained by serum electrophoresis on agarose. Apolipoprotein B and AI and lipoprotein "a" were measured by nephelometry.The Fredrickson phenotypes were: type IIb (51%), IV (41%), IIa (7%). In addition one patient was type III and another type V. Thirty-three percent of all HIV+ patients presented serum cholesterol levels ≥ 200 mg/dL, 61% LDL-cholesterol ≥ 100 mg/dL, 65% HDL-cholesterol below 40 mg/dL, 46% triglycerides ≥ 150 mg/dL and 10% have all these parameters above the limits. Eighty-six percent of patients had cholesterol/HDL-cholesterol ratio ≥ 3.5, 22% increased lipoprotein "a", 79% increased free fatty acids and 9% increased phospholipids. The treatment with protease inhibitors plus nucleoside reverse transcriptase inhibitors increased the levels of cholesterol and triglycerides in these patients when compared with naïve patients. The HDL-cholesterol (p = 0.01) and apolipoprotein A1 (p = 0.02) levels were inversely correlated with the time of protease inhibitor therapy while total cholesterol levels had a trend to correlate with antiretroviral therapy (p = 0.09).The highly varied and prevalent types of dyslipidemia found in Brazilian HIV positive patients on antiretroviral therapies indicate the urgent need for their early diagnosis, the identification of the risk factors for CHD and, when needed, the prompt intervention on their lifestyle and/or with drug treatment. The prognosis of patients with acquired immune deficiency syndrome (AIDS) was so limited until recently, that the medical interest in other long term health problems was irrelevant. The potency and sustained efficacy of the highly active antiretroviral therapy (HAART) for treating these patients brought a profound positive impact on their life expectancy reducing their mortality rates from AIDS .Several reports -10 descrDyslipidemia is a major risk factor for the development of CHD. It has also been reported that the AIDS infection itself is capable of inducing dyslipidemia -14.Hypertriglyceridemia was the first finding to be reported in HIV-infected patients, but other lipid abnormalities have also been described such as hypocholesterolemia, hypobetalipoproteinemia, hypoalphalipoproteinemia and, more rarely, hypercholesterolemia ,13,15-17Brazil is the epicenter of the epidemic in South America and accounts for three-fifths of reported AIDS cases and 57% in Latin America and Caribbean. Among the population of high risk the prevalence is 42% .Up to now two local studies ,19 exploTherefore the aim of this study was to determine the prevalence and severity of different types of dyslipidemia in a large local HIV+ Brazilian population using antiretroviral therapy. Serum lipids, lipoproteins and apolipoproteins were measured and the effects on them of the viral load, CD4 counting and duration of therapy were evaluated.This study was approved by the Medical Ethics Committee of the Medical Sciences Faculty of the University of Campinas. Written consent was obtained from the patients or their relative for publication of study.2. Two hundred and thirty-eight (93%) were submitted to antiretroviral therapy . The average time on drug treatment with protease inhibitors was 20 months (range 2 to 47 months). None of the patients was under lipid lowering drugs and any other disease was described in their records.Two hundred and fifty seven HIV+ patients were enrolled in the protocol. They were attended in the Infectious Diseases Clinic at the University of Campinas. Sixty-two percent were men and 38% were women, with an average age of 35 ± 8 years, body weight average 67 ± 13 Kg and body mass indexes (BMI) 24 ± 4 Kg/mThe measurements of fasting serum cholesterol (Chol), HDL-cholesterol (HDL-chol) and triglycerides (TG) were obtained by enzymatic colorimetric methods (automated Mega-Bayer system). The LDL-cholesterol (LDL-chol) and VLDL-cholesterol (VLDL-chol) were estimated by Friedewald's equation. In patients with triglyceride levels above 400 mg/dL (n = 16), Friedwald's equation was not used. The apolipoproteins A1 (Apo A1), B100 (Apo B) and lipoprotein "a" [Lp (a)] were measured by nephelometric methods (semi-automated Beckman Array-360 system) . Free faIn a sub-group of patients presenting Chol and/or TG, respectively equal to or above 200 and 150 mg/dL (n = 141), the criterion for describing the dyslipidemia was in accord with WHO/ Fredrickson's classification .The lipid profiles were analyzed using the values recommended by the National Cholesterol Education Program  . The desThe reference intervals for apolipoproteins, Lp (a), PL and FFA were obtained from the manufacturers' recommendations. Apo A1: 94–178 mg/dL and 101–199 mg/dL; Apo B100: 52–109 mg/dL and 40–103 mg/dL for men and women, respectively; Lp(a) below 30 mg/dL; PL: 150–250 mg/dL and FFA: 0.1–0.6 mEq/L.Immunologic evaluation included measurements of lymphocyte sub-populations, CD4 and CD8, by flow citometry and the determination of the viral load by PCR.Kruskal-Wallis with post test Dunn was employed to compare the lipidic parameter averages between the 2 groups of antiretroviral therapy users and between the treated groups and naïve patients. Ancova and Pearson's tests were employed to correlate lipid profiles and CD4 cells, viral load and time of use of protease inhibitors. BMI, age and gender were chosen as covariates. Differences were considered significant when p ≤ 0.05.3) and CD8 counting (average 947 cells/mm3) that may be explained by the fact that approximately 44% of the patients belonged to the C3 category.The patients were classified according to the Center for Disease Control (CDC) -1993  as folloForty-four percent of the patients who had their viral load measured presented less than 400 copies/mL, 29% between 400–10,0000 copies/mL and 27% above 10,000 copies/mL.Fifty-five percent of total HIV+ population (141 patients) was selected by their high Chol and/or TG levels for further serum electrophoresis analysis. In eighteen patients the electrophoresis were not done and in 20 patients the results were inconclusive. The most frequent patterns according to Fredrickson's classification were type IV (41%) and IIb (51%) , no differences were found between the two drugs groups.The treatment with protease inhibitors plus nucleoside reverse transcriptase inhibitors increased significantly Chol and TG levels (p < 0.05) in these patients when compared to naïve HIV+ patients  in 22%, increased free fatty acids in 79% and increased phospholipids in 9%. All of these profiles are strongly related to CHD risk.In this study we showed that in patients using antiretroviral therapy there was an augment in the concentrations of plasma cholesterol and triglycerides when compared to naïve patients. We also found negative associations between the time on PI therapy and HDL-chol and Apo A1 levels and a trend to a positive correlation between the viral load and cholesterol levels.Although HIV infection itself has been associated with altered lipid metabolism, substantial evidence indicates a role for some protease inhibitors and reverse transcriptase inhibitors in causing metabolic complications -32. ManySeveral reports have associated hypertriglyceridemia with the use of antiretroviral therapy ,30,33-37We did not find significant correlations between triglycerides and viral load , CD4 levLow HDL-Chol was one of the major findings in this Brazilian HIV+ population (65%). These findings are in accordance with several authors ,35,42. SHypercholesterolemia was very prevalent in the dyslipidemic individuals described here: 58% are types IIa and IIb. Grunfeld et al. didn't f3). In this study, 29% of the patients presented hypocholesterolemia. We found an inverse correlation between plasma cholesterol levels and the viral load.Grunfeld et al  showed aThe observed high frequency of hypercholesterolemia and hyperbetalipoproteinemia in HIV+ Brazilian patients were never reported previously Table . Also anThe high frequency of phenotypes IIb and IV found in the Brazilian HIV positive patients and the severity of the disturbances such as: hypercholesterolemia up to 672 mg/dL, hyperbetalipoproteinemia up to 227 mg/dL, hypertriglyceridemia up to 1512 mg/dL and hypoalphalipoproteinemia below 13 mg/dL, indicate the urgent need for their early diagnosis, the identification of the presence of other risk factors for CHD and, when needed, the prompt intervention on their lifestyle and/or drug treatment ,50.The author(s) declare that they have no competing interests.EMVA performed the biochemical analyses, data calculations and interpretation of results and helped to write the manuscript. ECF helped in the clinical trials and to write the manuscript. HCFO helped to write the manuscript. DOM participated in the clinical trial of HIV patients. LNC planned and coordinated the whole study, and helped to write the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here: