Biomedical subjects

J M A Lange

Publications and source records attributed to J M A Lange.

15 recordsLinked to original sources

PubMed2006

Pharmacokinetic parameters of nevirapine and efavirenz in relation to antiretroviral efficacy.

Optimal adherence is essential for successful antiretroviral therapy. We analyzed the relation between minimum plasma drug concentration (Cmin) and total drug exposure over 24 hr (AUC24) with virologic failure for therapy-adherent patients in the nevirapine (NVP) and efavirenz (EFV) groups of the double nonnucleoside study (2NN), which compared the efficacy of NVP and/or EFV together with stavudine and lamivudine. The objective was to find cutoff values of the Cmin and AUC24 below which the risk of virologic failure increased. The relation between Cmin and AUC24 with virologic failure (never a plasma viral load [pVL] < 50 copies/ml or a rebound to two consecutive pVL > 50 copies/ml) was analyzed with proportional hazard analyses. Data were censored at end of study or change of allocated treatment. The risk of virologic failure with NVP (n = 511) started to increase at a Cmin < 3.1 mg/L (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.89-1.97), but there was no cutoff value below which a statistically significant increased risk occurred. Neither was such a cutoff point identified for the AUC24. The risk of virologic failure with EFV (n = 312) was significantly increased at a Cmin < 1.1 mg/L (HR, 1.95; 95% CI, 1.08-3.54) and an AUC24 < 40 mg x hr x L1 (HR, 1.95; 95% CI, 1.07-3.54). Both cutoff values represent the median values for adherent patients. These associations were driven by patients from Thailand. Adjusting for geographical region made the association between Cmin and AUC24 with virologic failure statistically nonsignificant. The sensitivity of the Cmin values was too low (29% for NVP, 64% for EFV) to be an adequate predictor for virologic failure. We conclude that identifying the Cmin value for the sole purpose of predicting virologic failure in patients who report to be adherent to NVP or EFV is questionable because of the absence of a concentration-response relation (NVP) or the low sensitivity for such a cutoff value (NVP and EFV).

Adult↗

PubMed2006

Plasma lipid concentrations after 1.5 years of exposure to nevirapine or efavirenz together with stavudine and lamivudine.

OBJECTIVES: To assess long-term changes in lipids and lipoproteins concentrations associated with exposure to non-nucleoside reverse transcriptase inhibitors. METHODS: Long-term analysis of plasma lipid concentrations was performed in patients starting first-line antiretroviral therapy with stavudine (d4T) and lamivudine, and either nevirapine or efavirenz. RESULTS: Concentrations of total cholesterol, low-density lipoprotein cholesterol and triglycerides continued to increase, while high-density lipoprotein cholesterol showed a slight decrease compared with earlier reported increases after 48 weeks. CONCLUSIONS: Changes in body fat distribution expected to occur with continued exposure to d4T could offer a potential explanation for these findings.

Alkynes↗

PubMed2005

Is there a difference in the efficacy of peripartum antiretroviral regimens in reducing mother-to-child transmission of HIV in Africa?

BACKGROUND: Peripartum antiretroviral regimens have been shown to prevent mother-to-child transmission of HIV (MTCT) in randomized clinical trials; however, direct comparison of published results is impossible given methodological and population differences. OBJECTIVE: To directly compare the efficacy of different antiretroviral regimens in reducing the risk of 6-week MTCT rate in African breastfeeding populations. METHODS: Pooled analysis including all mother-infant pairs from any relevant trial: West African ZDV-placebo trials, Petra ZDV+3TC [two regimens A (pre/intra/post-partum) and B (intra/post-partum), placebo from Uganda and Tanzania], SAINT (NVP and Petra arm B), HIVNET012 (NVP, ultra short ZDV pp) and the Vitamin A trial (as placebo arm in South Africa). Peripartum HIV infection was any positive RNA or DNA polymerase chain reaction test < day 60. The MTCT risk was estimated at 6 weeks for each treatment arm and compared with placebo or single-dose NVP using logistic regression adjusting for maternal CD4 cell count, breastfeeding and birthweight. RESULTS: Overall, 4125 singleton live-births were included; 3629 (88%) were assessed for HIV status at 6 weeks of age. In comparison with placebo, zidovudine + lamivudine (ZDV+3TC) arm A [adjusted odds ratio (AOR), 0.23; P < 0.0001], ZDV+3TC arm B (AOR, 0.49; P < 0.001), antenatal ZDV short (AOR, 0.55; P = 0.006) and nevirapine (NVP) (AOR, 0.60; P = 0.0007) significantly reduced MTCT. In comparison with NVP, only the longest regimen of ZDV+3TC (AOR, 0.39, P < 0.0005) was significantly more effective. CONCLUSION: These results are in line with current World Health Organisation guidelines suggesting equivalence of choice between single-dose NVP and short-course ZDV, and confirm the greater efficacy of ZDV+3TC than with any single antiretroviral drug.

Adult↗

PubMed2005

The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART.

BACKGROUND: A substantial number of patients start their first-line antiretroviral therapy at an advanced stage of an HIV-1 infection. Potential differences between specific drug regimens in antiviral efficacy and safety in these patients are of major importance. METHODS: A post-hoc analysis within the randomized controlled 2NN trial comparing efficacy between regimes containing nevirapine (NVP), efavirenz (EFV), or both, in addition to stavudine and lamivudine. PRIMARY OUTCOME: risk of virologic failure in different strata of baseline CD4 T-lymphocyte counts and plasma HIV-1 RNA concentrations (pVL). Virologic failure: never reaching a pVL < 400 copies/ml, or a rebound to two consecutive values > 400 copies/ml. RESULTS: The risk of virologic failure was increased at very low CD4 counts (< 25 x 10(6) cells/l) compared to CD4 counts > 200 x 10(6) cells/l [hazard ratio (HR), 1.28; 95% confidence interval (CI), 0.93-1.77]. The same was seen for a pVL > or = 100,000 copies/ml compared to a lower pVL (HR, 1.20; CI, 0.96-1.50). There were no statistically significant differences between NVP and EFV in risk of virologic failure within any of the CD4 or pVL strata, although EFV performed slightly better in the low CD4 stratum. The incidence of rash in the NVP group was significantly higher in female patients with higher CD4 cell counts, while adverse events in the EFV group were not associated with CD4 cell count. CONCLUSIONS: Initial antiretroviral therapy including NVP or EFV is effective in patients with an advanced HIV-1 infection. A high baseline CD4 cell count is associated with the occurrence of rash in female patients using NVP.

Adult↗

PubMed2005

Occult hepatitis B virus infection before and 1 year after start of HAART in HIV type 1-positive patients.

Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies and HBV-DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. The clinical relevance of this phenomenon in HIV-1 patients starting highly active antiretroviral therapy (HAART) is unknown. We followed 93 therapy naive HIV-1-infected adults who were anti-HBc positive, HBsAg and HBeAg negative, during first year of HAART. At baseline, HBV-DNA was quantified, and HBV genotype was determined in the HBV-DNA-positive patients by sequencing a part of the HBV genome. Four of 93 patients (4%) were HBV DNA positive at baseline. All four patients tested negative for HBV-DNA after 1 year. They all received lamivudine as part of their HAART. They had no clinically significant liver enzyme elevations (LEE) during the first year of HAART. Two of the patients had a genotype A, one genotype E, and in the fourth patient sequencing was not possible. In one patient we found significant mutations in the a determinant region of HBsAg, at positions 142 and 144. In our population of therapy-naive HIV-1-infected adults who were anti-HBc positive, we found occult HBV infection in 4% of the patients. We did not find an increased risk for LEE in our population of patients after the start of HAART. Our results illustrate that occult HBV infection is more a diagnostic than a clinical problem. It may be caused by very low levels of HBV replication, concurrent presence of HBsAg and anti-HBs, or mutations in the HBsAg a determinant.

Adult↗

PubMed2005

Indinavir/ritonavir 800/100 mg bid and efavirenz 600 mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009.

OBJECTIVE: Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity. METHODS: Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat. RESULTS: Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9-4.7) years; baseline median viral load was 4.09 log(10) HIV-1 RNA copies/mL (range 3.75-4.61 log(10) copies/mL); baseline median CD4 count was 169 cells/microL (range 60-277 cells/microL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was -2.1 (0.7) and -2.1 (0.8) log(10) copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA <50 copies/mL. Sixteen per cent of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved. CONCLUSIONS: IDV/r 800/100 mg bid+EFV 600 mg qd gave a potent, durable response in these NRTI failures and was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters. Lower doses of boosted IDV might improve toxicity while maintaining efficacy, and this possibility warrants further investigation.

Adult↗

PubMed2004

Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study.

BACKGROUND: The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS: In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS: Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION: Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.

Adult↗

PubMed2004

Greater and more rapid depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine+didanosine or zidovudine+zalcitabine) vs. single (zidovudine) nucleoside reverse transcriptase inhibitors.

BACKGROUND: Most toxicities associated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) are thought to result from mitochondrial toxicity. These toxicities include peripheral neuropathy, pancreatitis, lactic acidosis, and peripheral lipoatrophy. Unfortunately, there are no validated laboratory markers for clinically assessing, let alone predicting, the onset of mitochondrial toxicity associated with NRTI therapy. OBJECTIVES: To provide preliminary evidence of the potential clinical utility of an assay which has been developed for quantifying mitochondrial DNA (mtDNA) in clinical samples from HIV-infected patients. METHODS: A single-tube duplex real-time DNA-nucleic acid sequence-based amplification (NASBA) assay (Mitox, Primagen, Amsterdam, the Netherlands) was used to quantify mtDNA in cryopreserved peripheral blood mononuclear cells (PBMC) obtained from HIV-1-infected patients during their prior participation in a randomized placebo-controlled trial comparing zidovudine (ZDV) monotherapy with combinations of ZDV plus either dideoxycytidine (ddC) or didanosine (ddI) (the Delta trial). Patients were antiretroviral naïve prior to entering the trial. Samples obtained during the initial 48 weeks of treatment were tested. RESULTS: A significant decline of mtDNA, both in an intent-to-treat and in an as-treated analysis, was observed in patients treated with ZDV+ddC and ZDV+ddI, but not with ZDV alone, consistent with the results expected from the degree of mtDNA depletion described for each of these drugs in vitro. CONCLUSIONS: This single-tube duplex real-time DNA-NASBA assay was shown to measure mtDNA accurately in PBMC. Treatment with a combination of two NRTIs was associated with greater reductions in mtDNA than obtained for ZDV monotherapy. The relevance of these results in predicting treatment toxicity requires further evaluation.

Analysis of Variance↗

PubMed2004

Differential CD4 T-cell response in HIV-1-infected patients using protease inhibitor-based or nevirapine-based highly active antiretroviral therapy.

OBJECTIVES: To study the dynamics of CD4 T-lymphocyte counts (CD4 counts) after the initiation of either protease inhibitor (PI)-based or nevirapine (NVP)-based first-line highly active antiretroviral therapy (HAART). DESIGN AND METHODS: A retrospective cohort study of 1029 HIV-infected antiretroviral therapy-naive patients initiating either PI-based or NVP-based HAART was carried out. Patients were censored as soon as they experienced virological failure, or changed their original antiretroviral regimen for any reason. RESULTS: In total, 920 and 109 patients initiated PI- and NVP-based HAART, respectively. The patients in the PI group more often had AIDS (15 vs. 6% in the NVP group), had a lower median baseline CD4 count (234 vs. 250 cells/microL in the NVP group) and had higher median baseline plasma HIV-1 RNA levels (pVL) (5.0 vs. 4.7 log10 HIV-1 RNA copies/mL in the NVP group). After 96 weeks of follow-up, the mean increase from baseline in CD4 count, adjusted for baseline CD4 count, age, gender and baseline pVL, was 310 cells/microL in the PI group and 212 cells/microL in the NVP group (P=0.003). This difference was mainly attributable to the patients in the NVP group initiating HAART with a baseline CD4 count below 200 cells/microL. There were no differences between the PI and NVP groups with respect to the change in the number of CD4 cells as a proportion of the total number of lymphocytes. CONCLUSION: Patients successfully treated with NVP-based HAART have a smaller increase in absolute CD4 cells compared with those treated with PI-based HAART.

Adult↗

PubMed2004

Antiretroviral therapy in previously untreated adults infected with the human immunodeficiency virus type I: established and potential determinants of virological outcome.

The aim of highly active antiretroviral therapy (HAART) for patients chronically infected with the human immunodeficiency virus type I is to achieve maximal and durable viral suppression. Maintaining the blood plasma HIV-I-RNA concentration (pVL) <50 copies/ml is currently considered appropriate for this goal. With the current treatment options, the percentage of previously untreated patients who achieve a pVL <50 copies/ml after one year of initial HAART is about 70%. Characteristics of the host, virus, drugs and the treatment team have been associated with the virological response to initial HAART. Adjusting the initial HAART regimen and patient management to a risk profile based on these factors is possibly helpful in improving the virological response to HAART. Adherence to a potent and well-tolerated HAART regimen is likely to be the most relevant factor for virological success. The additive value of the other factors needs to be clarified.

Antiretroviral Therapy, Highly Active↗

PubMed2002

A Bayesian approach to parameter estimation in HIV dynamical models.

In the context of a mathematical model describing HIV infection, we discuss a Bayesian modelling approach to a non-linear random effects estimation problem. The model and the data exhibit a number of features that make the use of an ordinary non-linear mixed effects model intractable: (i) the data are from two compartments fitted simultaneously against the implicit numerical solution of a system of ordinary differential equations; (ii) data from one compartment are subject to censoring; (iii) random effects for one variable are assumed to be from a beta distribution. We show how the Bayesian framework can be exploited by incorporating prior knowledge on some of the parameters, and by combining the posterior distributions of the parameters to obtain estimates of quantities of interest that follow from the postulated model.

Bayes Theorem↗

PubMed2002

Detection of late pp67-mRNA by NASBA in peripheral blood for the diagnosis of human cytomegalovirus disease in AIDS patients.

OBJECTIVE: To evaluate the value of late-pp67-mRNA nucleic acid sequence-based amplification (NASBA) in comparison to DNA-PCR, blood culture and pp65-antigenemia assay for the detection of human cytomegalovirus (HCMV) disease in HIV-infected patients. METHODS: The results of pp67-mRNA NASBA, DNA-PCR, culture and pp65-antigenemia assay were compared in 402 whole blood specimens of 98 HIV-infected patients with a low CD4 lymphocyte count who had not yet received highly active antiretroviral therapy (HAART). Thirty-seven samples were obtained from 30 patients with a diagnosis of HCMV disease and 365 samples from 68 patients without HCMV disease. RESULTS: The highest agreement of test results was observed between pp67-mRNA NASBA and quantitative pp65-antigenemia, with a threshold of nine antigen-positive cells/10(5) leukocytes (kappa-value 0.70, 95% CI=0.58-0.82). The sensitivity of pp67-mRNA NASBA for the diagnosis of HCMV disease (59.3%) was identical to that of the quantitative pp65-antigenemia assay, higher than that of the blood culture (48.2%) but lower than that of the DNA-PCR (77.8%). Pp67-mRNA NASBA (92.3%), quantitative pp65-antigenemia assay (92.3%) and blood culture (93.9%) were highly specific for the diagnosis of HCMV disease and as a result, had a higher positive predictive value (76.2, 76.2 and 76.5%, respectively) than the qualitative DNA-PCR (58.3%) and the qualitative pp65-antigenemia assay (47.6%). CONCLUSION: pp67-mRNA NASBA, an easy and rapid to perform assay, well-standardised by virtue of co-amplified internal system control RNA, provides a high specificity and positive predictive value for the diagnosis of HCMV disease in HIV-infected patients, comparable to that of the quantitative pp65-antigenemia assay and blood culture.

AIDS-Related Opportunistic Infections↗

PubMed2002

The impact of the M184V substitution in HIV-1 reverse transcriptase on treatment response.

The M184V mutation in the HIV-1 reverse transcriptase gene is primarily associated with rapid, high-level lamivudine (3TC) resistance. It has also been observed to arise under selective pressure by abacavir, to which it confers low-level resistance. Although the development of viral drug resistance remains a major concern in antiretroviral therapy, it is known that some immunological and clinical benefit can still be derived from highly active antiretroviral therapy (HAART) regimens despite resistance-associated virological failure. This residual benefit on a failing regimen is commonly attributed to the preservation of fitness-reducing protease inhibitor (PI) resistance mutations under continued drug pressure. However, fitness-reducing nucleoside reverse transcriptase inhibitor (NRTI) mutations may also contribute to the effect. M184V is both common in the treated population and fitness-reducing. A number of studies, both of dual nucleoside therapy and HAART, have noted a residual treatment effect for 3TC despite the assumed or observed presence of M184V and high-level phenotypic resistance. The speed and consistency with which this mutation is selected by 3TC under suboptimal viral suppression therefore makes M184V a particularly interesting model for further clinical studies on the association of drug resistance with ongoing treatment benefit. While fitness considerations are likely to be a major contributor to the clinical observations noted, there are a number of other potential mechanisms that may contribute to a continuing response to 3TC in the presence of M184V. These include the delay and reversal of zidovudine (ZDV) resistance, hypersensitization to other NRTIs, reduced reverse transcriptase (RT) processivity and a possible reduction in RT pyrophosphorolysis. The full impact of M184V on therapeutic prospects will require further elucidation; ideally, the risk/benefit of preserving this substitution would be investigated in randomized trials. However, existing data suggest that the presence of this mutation may preserve some benefit in spite of the loss of 3TC susceptibility which, with further study, may prove valuable.

Antiretroviral Therapy, Highly Active↗

PubMedDate not supplied

Comparison of two once-daily regimens with a regimen consisting of nelfinavir, didanosine, and stavudine in antiretroviral therapy-naïve adults: 48-week results from the Antiretroviral Regimen Evaluation Study (ARES).

BACKGROUND: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. METHOD: HIV-1-infected, antiretroviral drug-naïve adults were randomized to either twice-daily nelfinavir and stavudine and once-daily didanosine (regimen A) or simplified once-daily dosed antiretroviral regimens consisting of nevirapine, didanosine, and lamivudine (regimen B) or saquinavir, ritonavir, didanosine, and lamivudine (regimen C). RESULTS: At 48 weeks of therapy, the proportion of patients with a blood plasma HIV-1 RNA concentration (pVL) <50 copies/mL by intention-to treat analysis was 42.3%, 50.0%, and 56.5% for regimens A (n = 26), B (n = 22), and C (n = 23), respectively. The time to a pVL <50 copies/mL for the first time was significantly shorter in regimen C, and there was significantly more progression to CDC events in regimen B. These differences are possibly due to differences in baseline characteristics. Adverse events were lowest for regimen C; more signs associated with mitochondrial toxicity occurred in regimen A. Increase in CD4 count was comparable between arms. CONCLUSION: No statistically significant difference in efficacy was found between the two investigated once-daily dosed treatment regimens (B and C) and the reference (A). Regimen C possibly had a better virological response and less toxicity than regimens A and B.

Adult↗

PubMedDate not supplied

Database-supported teleconferencing: an additional clinical mentoring tool to assist a multinational company HIV/AIDS treatment program in Africa.

BACKGROUND: The lack of human resources for health is presently recognized as a major factor limiting scale-up of antiretroviral treatment (ART) programs in resourcelimited settings. The mobilization of public and private partners, the decentralization of care, and the training of non-HIV specialist nurses and general practitioners could help increase the number of HIV-infected patients receiving ART. In addition to other forms of training, scheduled teleconferences (TCs) have been organized to support a comprehensive HIV treatment program delivered by a private company's health team. OBJECTIVE: To describe the role of the TC as an additional tool in mentoring a company's health care workers (HCWs). METHOD: For this study, all TC reports were retrospectively reviewed and the questions classified by topic. Participating Heineken physicians evaluated the technical quality and scientific relevance of the TCs through an anonymous survey. RESULTS: From October 2001 to December 2003, 10 HCWs working in 14 operating companies in 5 African countries raised 268 problems during 45 TCs. A total of 79 questions (29%) were asked about antiretroviral (ARV) therapy, 53 (20%) about the diagnosis and treatment of opportunistic infection, 43 (16%) about ARV toxicity, 40 (15%) about care organization and policy, 32 (12%) about laboratory or drug supply, and 21 (8%) about biological parameters. The mean TC attendance rate was 70%. The level of satisfaction among local company physicians was 65% for logistics, 89% for scientific relevance, 84% for applicability of advice, and 85% overall. The most common complaints concerned the poor quality of the telephone connection and language problems for francophone participants. CONCLUSION: Database-supported teleconferencing could be an additional tool to mentor company HCWs in their routine care of HIV-infected workers and family members. The role and costeffectiveness of telemedicine in improving health outcomes should be further studied.

Africa↗