Ubaldo Visco-Comandini

Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors.

Objective:Although highly active antiretroviral therapy (HAART) can reverse HIV-related neurocognitive impairment (NCI), neuropsychologic (NP) deficits may persist in a substantial proportion of patients despite antiretroviral treatment. We assessed the prevalence and predictors of persistent NP deficits despite long-term HAART in patients with HIV-related NCI. Methods:A group of 94 patients with HIV-related NCI underwent 2 to 7 serial NP batteries, neurologic examination, and brain imaging studies. Patients received HAART for a mean of 63 (range: 6-127) months. According to NP assessment results, patients were considered to have reversible or persistent NP deficits. Kaplan-Meier analyses and Cox proportional hazards models were used to analyze time to first evidence of NP deficit reversion. Results:Persistent NP deficits were observed in 59 (62.8%) patients. Age, gender, Centers for Disease Control and Prevention stage, risk category, CD4+ cell count, plasma viral load, and use of central nervous system-penetrating drugs were not associated with persistent NP deficits. By contrast, patients with persistent NP deficits were less educated and showed poorer baseline performances in NP measures exploring concentration and speed of mental processing, memory, and mental flexibility. In multivariable analyses, only the baseline severity of NCI, as measured by the composite NPZ8 global score (odds ratio = 3.07, 95% confidence interval: 1.54 to 6.08; P = 0.001) remained significantly associated with persistent NP deficits. Conclusions:The severity of NCI at HAART initiation seems to be the strongest predictor of persistent NP deficits despite long-term HAART. Our data indicate that HAART should be initiated as soon as NCI is diagnosed to avoid potentially irreversible neurologic damage.

Prevalence and risk factors for human immunodeficiency virus–associated neurocognitive impairment, 1996 to 2002: Results from an urban observational cohort

To assess prevalence and risk factors for human immunodeficiency virus (HIV)-related neurocognitive impairment (NCI), the authors performed a 7-year survey in the period 1996 to 2002. A total of 432 patients were examined. HIV-related NCI was diagnosed in 238 patients (55.1%), meeting the HIV dementia (HIV-D) criteria in 45 (10.4%). The prevalence of both NCI and HIV-D did not change significantly during the study period. Compared with patients without NCI, patients with NCI were older (40.4 versus 38.2 years; P = .003), had a higher prevalence of positive HCV serology (61.1% versus 38.9%; P = .003), and a lower nadir CD4 cell count (156 versus 222 cells/μl; P < .001). Compared with patients seen during 1996 to 1999, patients with NCI seen during 2000 to 2002 were older (40.7 versus 38.8 years; P = .004), had a less advanced disease stage (previous acquired immunodeficiency syndrome [AIDS] 28.8% versus 65.7%; P < .001) and a higher nadir CD4 count (174 versus 132 cells/μl; P = .026). This study showed an unchanged prevalence of both HIV-related NCI and HIV-D in the period 1996 to 2002. The authors found evidences for new additional potential risk factors for HIV-related NCI (older age, lower nadir CD4 count, positive hepatitis C virus [HCV] serology), and for a change of risk factors for NCI in the late highly active antiretroviral therapy (HAART) era (older age, less advanced disease, higher nadir CD4 count).

Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients

Objective:To evaluate the effect of drug class-wide resistance (CWR) on survival in HIV-infected individuals who underwent genotypic resistance test after antiretroviral failure. Design:Observational, longitudinal cohort study. Methods:HIV-infected individuals experiencing treatment failure were enrolled at first genotypic resistance test. End-points were death for any cause, AIDS-related death and AIDS-defining event/death. CWR was defined according to the International AIDS Society consensus. Survival analysis was performed with Coxs model. Results:Among 623 patients enrolled and followed for a median of 19 months (interquartile range, 12–29), Kaplan–Meier analyses for end-points at 48 months in patients with no CWR, one CWR, two CWR or three CWR were 8.9, 11.7, 13.4 and 27.1%, respectively, for death; 6.1, 9.9, 13.4 and 21.5%, respectively, for AIDS-related death; and 16.0, 17.7, 19.3 and 35.9%, respectively, for new AIDS event/death. In a multivariate Coxs model, higher HIV RNA level, previous AIDS and detection of three CWR (hazard ratio, 5.34; 95% confidence interval, 1.76–16.24) were all significantly associated with increased risk of death, while higher CD4 cell count and use of a new boosted protease inhibitor drug after identifying genotypic resistance were associated with reduced risk. Detection of three CWR was also significantly associated with higher risk of AIDS-related death and new AIDS event/death. Conclusions:Even in the late era of highly effective antiretroviral treatments, detection of CWR, particularly if extended to all three drug classes is related to poorer clinical outcome and represents a risk-marker of disease progression and death.

Drug resistance at low viraemia in HIV-1-infected patients with antiretroviral combination therapy

Objective To study the appearance of drug-induced mutations at low viraemia in treated HIV-1-infected patients. Design and methods Fourteen patients, who received their first (n = 5), second (n = 7) or third (n = 2) line antiretroviral combination therapy, developed a persistent low-grade viraemia after an initial decrease of the viral load (VL) to less than 500 copies/ml. The amount of HIV-1 RNA (n = 71) and reverse transcriptase (RT)/protease sequences (n = 56) were determined in longitudinally obtained plasma samples during a mean period of 16.6 months. Results In the vast majority (93%) of patients, new primary resistance mutations were found in the RT and/or protease genes at virological failure at a median VL of 500 and 200 copies/ml, respectively. Drug-experienced patients developed mutations at a lower VL than naive patients. In one previously protease inhibitor-naive patient, primary RT and protease mutations were detected, although the VL was less than 50 copies/ml. A serial accumulation of drug resistance mutations was seen despite the VL increase being mostly modest, reaching a median of 1450 copies/ml at the end of the study, and the CD4 T cell counts continued to increase. One patient still had a VL of 300 copies/ml after 28 months, despite the presence of the multidrug-resistance Q151M mutation. Conclusion Low viraemia after virological treatment failure can select for virus with several new drug resistance mutations, despite a concomitant increase in CD4 T cell counts. This serial accumulation of mutations is likely to exhaust future drug options

Tuberculoid leprosy in a patient with AIDS: a manifestation of immune restoration syndrome

An HIV positive male from Brazil, living in Italy since 1989, developed a single non-itching, papulo-erythematous infiltrative lesion on the face after 2 months from the beginning of HAART. A diagnosis of leprosy was made, suggesting that the immunodeficiency masked the disease, until the skin manifestation became evident with immune-recovery.

Specific Enfuvirtide-Associated Mutational Pathways in HIV-1 Gp41 Are Significantly Correlated With an Increase in CD4+ Cell Count, Despite Virological Failure

BACKGROUND Human immunodeficiency virus type 1 (HIV-1) gp41 is a crucial determinant for HIV-1 pathogenicity. We investigated the correlation of enfuvirtide (ENF)-associated gp41 mutational clusters with viroimmunological parameters, as well as the potential underlying mechanisms. METHODS A total of 172 gp41 sequences and clinical follow-up data from 73 ENF-treated patients were analyzed monthly, from baseline to week 48. RESULTS There were 7 novel gp41 mutations positively associated with ENF treatment and correlated with classic ENF mutations. The ENF-associated clusters [V38A + N140I ] and [V 38A +T18A ] significantly correlated with an increase in CD4 cell count at week 48 ( an increase from baseline of 112 and 209 cells/microL, respectively), whereas [Q40H + L45M + 268A] significantly correlated with a decrease in CD4 cell count (-53 cells/microL), without a change in the level of viremia. Residues 38 and 18 are located complementarily to each other in the Rev-responsive element, whereas analysis of molecular dynamics showed that the copresence of [V38A + N140 I] abolishes the interaction between residue 38 and 145 important for stabilization of the 6-helix bundle. In contrast, T268A localizes in the gp41 calmodulin-binding domain responsible for gp41-induced CD4(+) T lymphocyte apoptosis. CONCLUSION Specific gp41 mutational clusters associated with ENF treatment significantly correlate with increases in CD4(+) cell count. Structural analysis suggests that this immunological gain is associated with mechanisms that act at both the protein level and the RNA level (even under conditions of virological failure). This result may help in the selection of patients who can benefit most from ENF treatment and represents a driving force for the design of the next generation of entry inhibitors.

underevaluation of Hiv-1 Plasma Viral Load by a Commercially Available Assay in a Cluster of Patients Infected With Hiv-1 A/g Circulating Recombinant Form (crf02)

The authors studied the correlation and agreement of commercially available assays in detection and quantification of the HIV-1 intersubtype A/G circulating recombinant form CRF02. The assays under comparison were Bayer Versant HIV-1 RNA, version 3.0; Roche Amplicor HIV-1 Monitor, version 1.5 (standard procedure); and Organon Teknika NucliSens HIV-1 RNA QT. Plasma samples from 114 patients infected with CRF02 were tested by the three assays under standard conditions. Although correlation among the assays was high and statistically significant for subtype B and CRF02, in the latter instance, NucliSens measured average viral load values (3.29 +/- 0.71 log(10) copies/mL) about 4 and >8 times lower than those obtained by Versant (3.90 +/- 0.90 log(10) copies/mL) and Amplicor (4.22 +/- 1.05 log(10) copies/mL), respectively. Furthermore, in a statistically significant percentage of CRF02-harboring samples, NucliSens produced viral load values undetectable or 1 log(10) lower than those obtained in Versant and Amplicor assays. Altogether, these data underline a low performance of NucliSens in detecting and quantifying viremia in plasma samples harboring the CRF02. These results are potentially important as global distribution of new HIV-1 subtypes is expanding, and recombinant strains, particularly CRF02, are emerging and becoming highly prevalent.

Longitudinal quantification of human immunodeficiency virus type 1 DNA and RNA in long-term nonprogressors.

Twenty patients with human immunodeficiency virus type 1 (HIV-1) infection for >7 years, no HIV-1-related symptoms, no treatment, and CD4+ cell counts >500/microL were included in a prospective study in 1993. Four years later, 12 patients had progressed (SPs), while 8 had not (long-term nonprogressors [LTNPs]). At inclusion, HIV-1 RNA, but not DNA, levels were higher in SPs. During follow-up, a consistent increase in HIV-1 RNA was seen in only 1 LTNP. In 2 LTNPs, plasma viremia was persistently undetectable or <110 copies/mL. Infectious virus was isolated from only 1 LTNP and from 11 SPs. In 4 LTNPs, HIV-1 DNA levels decreased spontaneously with time. The restricted viral replication and the declining HIV-1 DNA levels suggest that the HIV-1 infection can be controlled efficiently in a few LTNPs, leading to a decrease in the total virus burden with time.

Long-term effects of antiretroviral combination therapy on HIV type 1 DNA levels

HIV-1 RNA and DNA levels were measured in 58 patients, of whom 37 and 11, respectively, received triple or double combination therapy. At baseline, strong correlations were found between the number of HIV-1 DNA copies per 106 CD4+ cells, the plasma HIV-1 RNA levels, and the isolation rate of HIV-1 from blood cells. In comparison with HIV-1 RNA, a much slower decline in HIV-1 DNA levels was seen, which probably represents a long lifetime of provirus-bearing CD4+ cells. In 10 untreated patients, the proviral load was stable. In patients receiving triple therapy, a significant decline in HIV-1 DNA was seen independent of whether the proviral load was expressed as copies per 106 CD4+ cells or as copies per milliliter of blood. In contrast, a decline was seen only when the proviral load was expressed as copies per 10(6) CD4+ cells in patients given two drugs. The difference between the two patient categories is likely to be due to a more frequent infection of CD4+ cells during therapy in the patients with double therapy. Interpretation of changes in HIV-1 DNA levels is thus dependent on how the proviral burden is expressed. Further studies should evaluate whether changes in HIV-1 DNA load can be used as markers of viral replication during efficient antiretroviral combination therapy.

Proviral HIV‐1 dynamics and evolution in patients receiving efficient long‐term antiretroviral combination therapy

Different experimental approaches have shown that, despite plasma viral loads under the threshold of detection, HIV‐1 frequently continues to replicate in patients receiving potent antiretroviral therapy. However, whether this low‐grade viral replication is sufficient for the generation of new major quasispecies has not been studied. Thus, in order to evaluate the extent of variation in the major proviral HIV‐1 population, we monitored proviral DNA sequences in such patients over a time period of up to 30 months.