Roger LeBlanc

High Rates of Forward Transmission Events after Acute/Early HIV-1 Infection

BACKGROUND A population-based phylogenetic approach was used to characterize human immunodeficiency virus (HIV)-transmission dynamics in Quebec. METHODS HIV-1 pol sequences included primary HIV infections (PHIs; <6 months after seroconversion) from the Quebec PHI cohort (1998-2005; n=215) and the provincial genotyping program (2001-2005; n=481). Phylogenetic analysis determined sequence interrelationships among unique PHIs (n=593) and infections from untreated (n=135) and treated (n=660) chronically infected (CI) potential transmitter populations (2001-2005). Clinical features, risk factors, and drug resistance for clustered and nonclustered transmission events were ascertained. RESULTS Viruses from 49.4% (293/593) of PHIs cosegregated into 75 transmission chains with 2-17 transmissions/cluster. Half of the clusters included 2.7+/-0.8 (mean+/-SD) transmissions, whereas the remainder had 8.8+/-3.5 transmissions. Maximum periods for onward transmission in clusters were 15.2+/-9.5 months. Coclustering of untreated and treated CIs with PHIs were infrequent (6.2% and 4.8%, respectively). The ages, viremia, and risk factors were similar for clustered and nonclustered transmission events. Low prevalence of drug resistance in PHI supported amplified transmissions at early stages. CONCLUSIONS Early infection accounts for approximately half of onward transmissions in this urban North American study. Therapy at early stages of disease may prevent onward HIV transmission.

HIV-associated Lipodystrophy Syndrome: A Review of Clinical Aspects

Approximately two years after the introduction of highly active antiretroviral therapy for the treatment of HIV infection, body shape changes and metabolic abnormalities were increasingly observed. Initially, these were ascribed to protease inhibitors, but it is now clear that nucleoside reverse transcriptase inhibitors also contribute to lipodystrophy syndrome. The syndrome groups together clinical conditions describing changes in body fat distribution that include lipoatrophy, lipoaccumulation or both. However, there does not appear to be a direct link between lipoatrophy and lipoaccumulation that would support a single mechanism for the redistribution of body fat. Currently, there is no clear definition of lipodystrophy, which explains the difficulty in determining its prevalence and etiology. There are no current guidelines for the treatment of fat distribution abnormalities that occur in the absence of other metabolic complications. The present article reviews the current state of knowledge of the definition, symptoms, risk factors, pathogenesis, diagnosis and treatment of the morphological changes associated with lipodystrophy syndrome.

Immunosuppressive tryptophan catabolism and gut mucosal dysfunction following early HIV infection

BACKGROUND Tryptophan (Trp) catabolism into kynurenine (Kyn) contributes to immune dysfunction in chronic human immunodeficiency virus (HIV) infection. To better define the relationship between Trp catabolism, inflammation, gut mucosal dysfunction, and the role of early antiretroviral therapy (ART), we prospectively assessed patients early after they acquired HIV. METHODS Forty patients in the early phase of infection were longitudinally followed for 12 months after receiving a diagnosis of HIV infection; 24 were untreated, and 16 were receiving ART. Kyn/Trp ratio, regulatory T-cells (Tregs) frequency, T-cell activation, dendritic cell counts, and plasma levels of gut mucosal dysfunction markers intestinal-type fatty acid-binding protein, soluble suppression of tumorigenicity 2, and lipopolysaccharide were assessed. RESULTS Compared with healthy subjects, patients in the early phase of infection presented with elevated Kyn/Trp ratios, which further increased in untreated patients but normalized in ART recipients. Accordingly, in untreated subjects, the elevated Treg frequency observed at baseline continued to increase over time. The highest CD8(+) T-cell activation was observed during the early phase of infection and decreased in untreated patients, whereas activation normalized in ART recipients. The Kyn/Trp ratio was positively associated with CD8(+) T-cell activation and levels of inflammatory cytokines (interleukin 6, interferon γ-inducible protein 10, interleukin 18, and tumor necrosis factor α) and negatively associated with dendritic cell frequencies at baseline and in untreated patients. However, ART did not normalize plasma levels of gut mucosal dysfunction markers. CONCLUSIONS Early initiation of ART normalized enhanced Trp catabolism and immune activation but did not improve plasma levels of gut mucosal dysfunction markers.

Human Immunodeficiency Virus (HIV)-Specific Effector CD8 T Cell Activity in Patients with Primary HIV Infection

The interferon-gamma ELISPOT assay was used to assess and compare the magnitude and breadth of human immunodeficiency virus (HIV)-specific CD8 T cell responses in treatment-naive subjects during the first year of HIV primary infection and during the chronic phase of infection. Twenty-five subjects tested within a year of exposure to HIV resulting in seroconversion and 20 subjects with chronic infection were screened for HIV peptide-specific activity by stimulating peripheral blood mononuclear cells with a panel of 5-21 HLA class I-restricted HIV peptides (mean, 11.2 +/- 3.5 HIV peptides). There was a significant correlation between the magnitude and breadth of HIV-specific effector responses and time elapsed from exposure (r=0.63 for magnitude vs. time and r=0.64 for breadth vs. time; P<.02, paired t test). Maximal breadth of the HIV gene product reactivity was achieved within 2 months of exposure for Nef-specific responses and by 4 months of exposure for responses directed to Env, Gag, and reverse transcriptase.

Comparison of Clinical Features of Acute HIV-1 Infection in Patients Infected Sexually or Through Injection Drug Use.

Acute HIV-1 infection (AHI) may present with a clinical picture that represents a diagnostic challenge. We tested the hypothesis that two different routes of infection, that is, sexual versus parenteral, might be associated with a difference in the clinical features of AHI. A prospective cohort of seroconvertors was established in Montréal in private medical clinics and hospitals from February 1996 to May 1999. The prevalence of the symptomatic presentation was almost overlapping within the two groups of newly infected individuals 69% (42 of 61) for men having sex with men (MSM) and 69% (18 of 26) for injection drug users (IDUs; p =.98). Comparison of all types of symptoms and signs as well as their duration was also similar in both groups. Of particular interest, the site of lymph node enlargement was not different despite the estimated sites of intravenous inoculation. Oral and anal ulcers were more frequently observed in MSM than in IDUs (6 versus 0 and 4 versus 1, respectively). Neither the mean CD4+ count (514.8 and 414.7 cells/mm3; p =.14) nor the mean viral load (4.45 and 4.70 log copies/ml; p =.40) were different between the two groups at the time of the first study visit. Our study results clearly indicate that health care workers can expect similar clinical presentation of AHI in MSM and in IDUs despite the different routes of infection.

Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts

BACKGROUND CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. METHODS Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. RESULTS At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. CONCLUSIONS ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.

Virologic and Immunologic Response to a Boosted Double-Protease Inhibitor-Based Therapy in Highly Pretreated HIV-1-Infected Patients

Abstract Purpose: To assess the virologic and immunologic response to a boosted doubleprotease inhibitor (PI) regimen of highly pretreated patients infected with HIV-1 and to examine the role of PI resistance and concentration of serum saquinavir. Method: In an open-label prospective study, lopinavir/ritonavir, saquinavir-sgc, lamivudine, and other nucleoside analogues were offered to highly pretreated patients who had advanced HIV-1 infection and who had failed at least 2 previous highly active antiretroviral therapy regimens including at least 1 nonnucleoside reverse transcriptase inhibitor. The relationship between baseline drug resistance and steadystate saquinavir serum levels and early (week 4) and sustained (week 48) virologic response was documented. Results: 35 advanced HIV-1 patients were enrolled. The boosted double-PI regimen was well tolerated. Twenty-two (63%) of the 35 patients had a > 0.8 log10 decrease in HIV viral load at week 4. After 48 weeks of follow-up, the 22 patients who remained on the study therapy had an average decrease in viral load of 1 log10 and had a median increase in CD4 cells of 60 cell/μL. Multiple logistic regression analysis indicated that genotypic resistance to both PIs and the week-3 trough concentrations of saquinavir were associated with virologic outcome at week 4. The presence of ≥ 6 lopinavir mutations [odds ratio (OR) 0.03; 95% CI 0.01 to 0.79] and the 48V mutation (OR 0.01; 95%CI <0.01 to 0.88) was independently associated with lower odds of achieving an early response, whereas a higher saquinavir concentration at week 3 (OR 8.36; 95% CI 1.28 to 54.70) was associated with greater odds of an early response. Conclusion: These findings suggest that baseline PI resistance and saquinavir concentration were associated with virologic response and should be considered when planning salvage therapy.

The plasma levels of soluble ST2 as a marker of gut mucosal damage in early HIV infection.

Objective: Following tissue barrier breaches, interleukin-33 (IL-33) is released as an ‘alarmin’ to induce inflammation. Soluble suppression of tumorigenicity 2 (sST2), as an IL-33 decoy receptor, contributes to limit inflammation. We assessed the relationship between the IL-33/ST2 axis and markers of gut mucosal damage in patients with early (EHI) and chronic HIV infection (CHI) and elite controllers. Design: Analyses on patients with EHI and CHI were conducted to determine IL-33/sST2 changes over time. Methods: IL-33 and sST2 levels were measured in plasma. Correlations between sST2 levels and plasma viral load, CD4+ and CD8+ T-cell counts, expression of T-cell activation/exhaustion markers, gut mucosal damage, microbial translocation and inflammation markers, as well as kynurenine/tryptophan ratio were assessed. Results: Plasma sST2 levels were elevated in EHI compared with untreated CHI and uninfected controls, whereas IL-33 levels were comparable in all groups. In EHI, sST2 levels were positively correlated with the CD8+ T-cell count and the percentage of T cells expressing activation and exhaustion markers, but not with viral load or CD4+ T-cell count. Plasma sST2 levels also correlated with plasma levels of gut mucosal damage, microbial translocation and kynurenine/tryptophan ratio and for some markers of inflammation. Prospective analyses showed that early antiretroviral therapy had no impact on sST2 levels, whereas longer treatment duration initiated during CHI normalized sST2. Conclusion: As sST2 levels were elevated in EHI and were correlated with CD8+ T-cell count, immune activation, and microbial translocation, sST2 may serve as a marker of disease progression, gut damage and may directly contribute to HIV pathogenesis.

Effectiveness of Step-Wise Intervention Plan for Managing Nelfinavir-Associated Diarrhea: A Pilot Study

Abstract Purpose: Pilot study to evaluate the effectiveness of a step-wise diarrhea management strategy for nelfinavir-associated diarrhea. Method: HIV-infected adults (CD4 count ≥100 cells/mm3, and no evidence of enteric pathogens) developing symptoms of diarrhea after initiation of nelfinavir for a duration of =1 month were enrolled into this 9-week prospective pilot study. Step-wise interventions, reviewed and adjusted additively at 2-week intervals, included nutritional counseling (± lactase and/or psyllium), calcium carbonate, and loperamide. Outcome measure included stool-form consistency, bowel movement frequency, and incidents of associated morbidity (urgency, incontinence) daily. Patient quality of life was also assessed. Results: Eighteen patients completed the study. Mean daily bowel movement frequency decreased by 32%, from 2.98 to 2.03 (p = .005). Mean daily stool form shifted from a rating of 4.24 to 2.37 (p = .0001), representing a shift to firmer stools. Period prevalence of incontinence (28%) and urgency (33%) decreased to 6% each, respectively. Quality of life ratings relating to gastrointestinal disturbance and overall physical/psychosocial function were improved. Conclusion: The results of this pilot study demonstrated that a step-wise intensified approach may be successful in managing nelfinavir-associated diarrhea and will need to be validated in a larger scale, randomized controlled trial.

A Model of Quality of Life of Women Living With HIV

Data collected from 224 women living with HIV were analyzed to study quality of life. Quality of life was operationalized as mental health and physical functioning. A structural equation model was tested. The final model demonstrates good fit to data (χ2 = 17.63, p = .48). Mental health was directly and positively associated with being born outside of Canada, social support, and physical functioning but negatively associated with the proportion of people aware of serostatus and experienced discrimination. Physical functioning was directly and positively associated with being born outside of Canada and social support; however, it was negatively associated with time since diagnosis. The proportion of people aware of serostatus was negatively associated with being born outside of Canada and being a mother. Social work interventions aimed at improving quality of life in women living with HIV should target contexts of serostatus disclosure to minimize HIV discrimination and to improve social support sources without compromising existing ones.