Immune restoration and onset of new AIDS-defining events with combination antiretroviral therapy in HIV type-1-infected immigrants in the Netherlands.

BACKGROUND: We investigated differences in immune restoration and onset of new AIDS-defining events on combination antiretroviral therapy (cART) among HIV type-1 (HIV-1)-infected patients of different regional origin now living in the Netherlands. METHODS: Treatment-naive adults reaching plasma viral load (pVL)<400 copies/ml within 9 months of starting cART were selected from the Netherlands ATHENA cohort. CD4(+) T-cell response on cART was determined over 7 years using mixed models. CD4(+) T-cell counts were excluded from the analyses at the first of two consecutive measurements of pVL≥400 copies/ml following prior suppression to <400 copies/ml. Multivariate analyses included gender, age, CD4(+) T-cell count and pVL prior to cART, hepatitis coinfection, HIV-1 transmission and region of origin (Western Europe/North America [WN], sub-Saharan Africa [SSA], Southeast Asia [SEA], Latin America/Caribbean [LAC] or other). RESULTS: For 6,057 selected patients (WN 3,947, SSA 989, SEA 237, LAC 695 and other 189), median follow-up was 3.2 years (WN 3.3, SSA 2.9, SEA 3.2, LAC 2.7 and other 2.7). CD4(+) T-cell increase in the first 6 months of cART was lower in males than females (-26 cells/mm(3); P<0.0001) and in patients from SSA compared with WN (-36 cells/mm(3); P<0.0001). Because men from SSA started with lower CD4(+) T-cell counts than men from WN, they continued to lag behind and had lower absolute CD4(+) T-cell counts after 7 years of cART. Furthermore, cumulative tuberculosis incidence after 7 years of cART was higher in SSA compared with WN (4.5% versus 0.5%, hazard ratio 5.08, 95% confidence interval 2.22-11.60). CONCLUSIONS: HIV-1-infected immigrants from SSA have blunted immune restoration on fully suppressive cART and should be identified at an earlier disease stage. Our results call for more intensive screening for both latent and active tuberculosis in these patients.

InforMatrix nucleoside/nucleotide reverse transcriptase inhibitor 'backbones'.

InforMatrix is an interactive decision matrix technique. This paper describes the use of InforMatrix to determine an order of merit within the various nucleoside and nucleotide reverse transcriptase inhibitors. In the order of merit, six criteria (effectiveness, safety, tolerance, convenience, usability and costs) are weighted against each other. Data necessary for this weighting process are derived from literature as well as personal practical experience. This article gives an overview of the most relevant information from clinical trials, cohort studies and databases concerning backbones consisting of two nucleoside/nucleotide reverse transcriptase inhibitors in the treatment of HIV infections, as well as a description of the interactive decision matrix technique. By using this interactive matrix technique, a rational consideration of the treatment options for backbones consisting of two nucleoside/nucleotide reverse transcriptase inhibitors becomes possible.

Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals.

BACKGROUND: Both virological failure and the toxicity of HIV protease inhibitors have been related to interindividual variability of plasma drug concentrations. Therapeutic drug monitoring (TDM) offers the possibility to detect patients with drug concentrations outside therapeutic ranges, who can subsequently benefit from dose modifications. METHODS: ATHENA was a randomized controlled clinical trial. Subjects were randomly assigned to either a TDM group, in which the results of drug concentration measurements plus advice were reported to their treating physician, or to a control group for whom TDM results were not reported. This analysis refers to treatment-naive patients who started a regimen containing indinavir or nelfinavir before November 1999. FINDINGS: A total of 147 patients were randomly assigned: 92 to nelfinavir, 55 to indinavir. After one year of follow-up significantly fewer patients in the TDM group had discontinued nelfinavir or indinavir than in the control group: 17.4 versus 39.7%. This was mainly driven by a significantly lower rate of discontinuation because of virological failure in nelfinavir patients: 2.4% in the TDM group versus 17.6% in the control group, and by a non-significant difference in the rate of discontinuation because of toxicity in indinavir patients: 14.3% in the TDM group versus 29.6% in the control group. In a non-completer equals failure analysis of all randomized patients, the TDM group showed a significantly higher proportion of patients with a viral load below 500 copies after 12 months of treatment (78.2 versus 55.1%). INTERPRETATION: TDM of nelfinavir and indinavir in treatment-naive patients improves treatment response.

Treatment failure of nelfinavir-containing triple therapy can largely be explained by low nelfinavir plasma concentrations.

The relationship between plasma concentrations of nelfinavir and virologic treatment failure was investigated to determine the minimum effective concentration of nelfinavir. Plasma samples were prospectively collected from treatment-naive patients who began taking nelfinavir, 1,250 mg BID + two nucleoside reverse transcription inhibitors (NRTIs). Nelfinavir concentration ratios were calculated by dividing each individual nelfinavir level by the time-adjusted population value. Virologic failure was defined as either no response (a detectable viral load after 6 months) or a relapse (detectable viral load after being undetectable, or an increase in viral load >1 log above nadir). Forty-eight patients were included with a median follow-up period of 8 months. The median concentration ratio of nelfinavir was 0.98 (interquartile range, 0.76-1.47). Virologic failure was observed in 29% of the patients. In a univariate analysis, the nelfinavir concentration ratio appeared to be the single determinant that was related to virologic failure (P = 0.039). Patients with a median ratio <0.90 had a relative risk of 3.0 (95% CI, 1.2-7.6) for virologic failure. Using this threshold, virologic failures were detected with 64% sensitivity and 74% specificity (P = 0.014). Virologic failure of nelfinavir-containing triple therapy can be explained, to a large extent, by low plasma levels of nelfinavir.

A delay in CD4 cell response after initiation of highly active antiretroviral therapy is associated with the presence of anti-cytomegalovirus but not with anti-herpes simplex virus antibodies.

After the successful initiation of highly active antiretroviral therapy (HAART) in HIV-1-infected patients, the mean CD4 cell response was lower in cytomegalovirus (CMV)-seropositive patients than in CMV-seronegative patients (P < 0.05). The difference between the mean CD4 cell counts of CMV-seronegative and CMV-seropositive patients was maximal (163 x 10(6)/l) at 76 weeks after the start of HAART, and decreased gradually thereafter. No association was found between herpes simplex virus types 1 and 2 serostatus and CD4 cell response.

Post-exposure prophylaxis.

The mean risk of acquiring HIV after an occupational exposure, injecting drug use or sexual exposure varies from < 0.1 to 3%. A high plasma HIV-RNA of the source increases the risk of each of the exposures. Other factors, such as the volume of the inoculum involved to which the individual was exposed, other sexually transmitted diseases and ruptures of mucous membranes are associated with a higher risk of HIV transmission. Based on the calculated risk, post-exposure prophylaxis (PEP) should be recommended. In the Netherlands, prescription of PEP in the occupational setting is a standard procedure and has proved to be feasible. This was associated with a high percentage (62%) of mild and reversible toxicity and a small percentage (2%) of serious adverse events related to antiretroviral drugs, i.e. nephrolithiasis (due to indinavir) and toxic hepatitis (due to nevirapine). In The Netherlands so far no HIV-seroconversions have been recorded after an occupational accident.