Psychopathology and psychosocial adjustment in patients with HIV-associated lipodystrophy

OBJECTIVE: To study whether patients with HIV-1 associated lipodystrophy (LD) on highly active antiretroviral treatment (HAART) have more psychopathology and worse psychosocial adjustment than a similar group without this syndrome. METHODS: In a cross-sectional, observational study we compared 47 HIV-1 infected patients with LD (LD group) with 39 HIV-1 infected patients without LD (non-LD group). All participants were on HAART. The Beck Depression Inventory (BDI), the State and Trait Anxiety Inventory (STAI) and the Goldberg Health Questionnaire (GHQ-60) were administered. Levels of familial, work and social adjustment and adjustment to stressful events were evaluated in a semi-structured interview. Clinical information was extracted from the clinical records. RESULTS: In the univariate analysis patients with LD showed higher state anxiety scores (p = 0.009) and worse work adjustment (p = 0.019) than those without LD. A total of 45.3% of LD patients scored above the cut-off point on the trait anxiety scale, and over 33.3% scored above the cut-off point on the BDI, GHQ and state anxiety scales. However, in multivariate analyses LD was not independently associated with psychopathology or with worse adjustment in the studied areas. CONCLUSIONS: The finding that LD was not a predictor of greater psychopathology or worse psychosocial adjustment in HIV-1 infected patients, despite the high scores found, suggests that factors not taken into account in this study, such as LD severity and self-perception should have been included in the analysis. Further studies including a greater number of variables and a larger sample size will advance our understanding of this complex condition.

Psychopathology and psychosocial adjustment in patients with HIV-associated lipodystrophy.

OBJECTIVE: To study whether patients with HIV-1 associated lipodystrophy (LD) on highly active antiretroviral treatment (HAART) have more psychopathology and worse psychosocial adjustment than a similar group without this syndrome. METHODS: In a cross-sectional, observational study we compared 47 HIV-1 infected patients with LD (LD group) with 39 HIV-1 infected patients without LD (non-LD group). All participants were on HAART. The Beck Depression Inventory (BDI), the State and Trait Anxiety Inventory (STAI) and the Goldberg Health Questionnaire (GHQ-60) were administered. Levels of familial, work and social adjustment and adjustment to stressful events were evaluated in a semi-structured interview. Clinical information was extracted from the clinical records. RESULTS: In the univariate analysis patients with LD showed higher state anxiety scores (p=0.009) and worse work adjustment (p=0.019) than those without LD. A total of 45.3% of LD patients scored above the cut-off point on the trait anxiety scale, and over 33.3% scored above the cut-off point on the BDI, GHQ and state anxiety scales. However, in multivariate analyses LD was not independently associated with psychopathology or with worse adjustment in the studied areas. CONCLUSIONS: The finding that LD was not a predictor of greater psychopathology or worse psychosocial adjustment in HIV-1 infected patients, despite the high scores found, suggests that factors not taken into account in this study, such as LD severity and self-perception should have been included in the analysis. Further studies including a greater number of variables and a larger sample size will advance our understanding of this complex condition.

Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis.

OBJECTIVES: To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (PIs). METHODS: Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions. RESULTS: Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. CONCLUSIONS: There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.

Effect of genetic variants of CCR2 and CCL2 on the natural history of HIV-1 infection: CCL2-2518GG is overrepresented in a cohort of Spanish HIV-1-infected subjects.

BACKGROUND AND OBJECTIVES: Polymorphisms in the genes that encode for the CCR2 chemokine receptor and its natural ligand CCL2 have been shown to influence the natural history of HIV-1 infection, although data are inconsistent. Our aim was to determine whether functionally active CCR2 and CCL2 genetic variants influence the risk of infection and disease progression in a cohort of white Spaniards. PATIENTS AND METHODS: This was a multicenter genetic association case-control study. Two single nucleotide polymorphisms (SNPs), V64I (G > A) of the CCR2 gene and -2518 (A > G) of the CCL2 gene, were assessed in 318 individuals: 73 HIV-1-infected long-term nonprogressors (LTNPs) of >16 years duration, 109 HIV-1-infected usual progressors (UPs), 36 heavily exposed to HIV-1 but uninfected individuals (EUs), and 100 control subjects. The distribution of the CCR5Delta32 allele was also assessed. Genotyping was performed using polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) or PCR and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared by the chi2 test and the Fisher exact test. RESULTS: CCR2 genotype distribution and allele frequencies showed nonsignificant differences between groups. The distribution of CCL2 alleles showed no significant differences between groups. HIV-1-infected individuals had, however, a significantly higher prevalence of the variant homozygous CCL2 GG genotype compared with EUs (P = 0.02). This result persisted when we studied only individuals with wild-type CCR5. Genotype and allele distribution of CCL2 was similar in HIV-1-infected UPs and LTNPs. CONCLUSIONS: In our cohort of white Spaniards, homozygosity for the variant CCL2-2518GG genotype is overrepresented in HIV-1-infected subjects.

Group A streptococcal infections in injection drug users in Barcelona, Spain: epidemiologic, clinical, and microbiologic analysis of 3 clusters of cases from 2000 to 2003.

An unexplained resurgence of Group A streptococci (GAS) infections has been observed since the mid-1980s in the United States and Europe, particularly among intravenous drug users (IDUs). Several risk factors have been identified. Mutations in the capsule synthesis regulator genes (csrRS) have been associated with an increase in virulence. From January 1998 to December 2003, we conducted a prospective and retrospective descriptive analysis of invasive GAS soft-tissue infections in IDUs in Barcelona, Spain. Clinical features were collected, and we conducted a surveillance study to identify risk factors associated with GAS soft-tissue infections. We analyzed chromosomal DNA by low cleavage restriction enzymes and used pulsed-field gel electrophoresis (PFGE) and variable gene sequence typing (VGST) of the emm gene to disclose the epidemiologic relationship between the strains. We analyzed the influence of clonality (M-type) and mutations in csrRS genes of these strains on clinical features. We identified 44 cases, all of which were grouped in 3 clusters: fall 2000, fall 2002, and fall 2003. Cellulitis with or without abscesses (75%) and fever (90.9%) were the most common clinical manifestations. Distant septic complications were infrequent (18.2%). Although all patients had severe infections (mainly bacteremic needle abscesses), their outcome with antibiotic therapy, usually beta-lactam, was successful in all cases. However, surgery was needed in 40.9% of patients. Through the surveillance study we found that infected patients had a higher number of drug injections per day (odds ratio [OR], 18.84; 95% confidence interval [CI], 4.83-79.4; p<0.00001), shared paraphernalia for drug use more frequently (OR, 11.11; 95% CI, 3.24-39.04; p<0.0001), were in a higher proportion both currently unemployed and homeless (OR, 4.22; 95% CI, 1.5-12.15; p<0.0001), were not in a methadone maintenance program (OR, 0.03; 95% CI, 0-0.19; p<0.00001), and more often bought drugs at a specific site (OR, 33.92; 95% CI, 7.44-174.93; p<0.00001) and from a specific dealer (OR, 72; 95% CI, 8-3090; p<0.00001), compared with patients not infected. The fall 2000 cluster was polyclonal, whereas the other 2 clusters were mainly due to the same strain of GAS (emm 25.2), and were defined as epidemic outbreaks. Clinically, the cases due to the clonal strain presented abscesses and needed surgery more frequently (p<0.001 and p=0.005, respectively). On the other hand, mutations in the csrRS genes were not associated with invasive GAS soft-tissue infection. There has been an increase in the number of cases of invasive GAS soft-tissue infections in IDUs in Barcelona, which seems to be related to drug users' habits and their socioeconomic status. Clonality (emm 25.2) but not mutations in the csrRS genes was associated with more severe GAS soft-tissue infections.

Polymorphism of RANTES chemokine gene promoter is not associated with long-term nonprogressive HIV-1 infection of more than 16 years.

To examine whether polymorphisms of the RANTES chemokine gene promoter are associated with long-term nonprogressive HIV-1 infection in white Spanish subjects, we performed a cross-sectional genetic association case-control study. Two-hundred sixty-seven white Spaniards were studied: 58 were HIV-1-infected long-term nonprogressors (LTNPs) of more than 16 years, 109 were HIV-1-infected usual progressors (UPs), and 100 were control subjects. Three RANTES single nucleotide polymorphisms (SNPs) at positions -28C>G, -109T>C, and -403G>A were assessed. The prevalence of the CCR5Delta 32 allele was also examined. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods. Genotype and allele frequencies between the 3 groups were compared by the chi2 test and the Fisher exact test. The distribution of allelic variants of RANTES in controls, UPs, and LTNPs, respectively, was 3%, 2%, and 5% for -28G; 4%, 2%, and 2% for -109C; and 18%, 18%, and 18% for -403A (P = not significant). The differences were still nonsignificant when we exclusively analyzed individuals not carrying the CCR5Delta32 allele. We conclude that LTNP of more than 16 years is not associated with SNPs in the RANTES gene promoter in white Spanish HIV-1-infected subjects.

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.

BACKGROUND: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. PATIENTS AND METHODS: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. RESULTS: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. CONCLUSION: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.

Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3.

OBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved. METHODS: Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years. RESULTS: VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88). CONCLUSIONS: STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.