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PubMed1996

Risks and synergies from drug interactions.

AIM: To review what is known from in vitro and in vivo studies about the interactions, both potentially beneficial and potentially harmful, of antiretroviral agents with each other and with other classes of drugs. INTERACTIONS WITH NUCLEOSIDE ANALOGUES: Some interactions between nucleoside HIV reverse transcriptase inhibitors and between nucleoside analogues and HIV protease inhibitors result in greater antiretroviral activity (e.g. zalcitabine with saquinavir). Others may increase the risks of toxicity and there are a number of combinations of nucleoside agents with other drugs that should be used with caution or avoided completely. INTERACTIONS WITH PROTEASE INHIBITORS: These drugs are metabolized by cytochrome P450 CYP3A4 in the liver; because they have the potential to inhibit this enzyme they may interact with many other drugs that are metabolized by this pathway. Ritonavir also inhibits other cytochrome P450 enzymes and so interacts with numerous drugs from a range of classes. Potentially beneficial interactions between protease inhibitors include the increase in saquinavir levels brought about by ritonavir. CONCLUSIONS: Knowledge of additive and synergistic interactions between antiretroviral agents should facilitate development of therapeutic regimens with prolonged antiretroviral activity. Thorough investigation of possibly harmful interactions with co-administered drugs and education of clinicians and patients about the risks of these interactions is required.

Anti-HIV Agents↗
PubMed2000

Biochemical mechanisms involved in overcoming HIV resistance to nucleoside inhibitors of reverse transcriptase.

The development of drug combinations that act effectively against both wild-type and mutated resistant forms of HIV-1 reverse transcriptase (RT) is a major goal in management of HIV disease. Recent studies have shown that resistance to different nucleoside analog RT inhibitors (NRTIs), an important class of anti-viral drugs, can result in different amino acid substitutions in close proximity to the dNTP binding pocket of the enzyme. Some of these mutations have been shown to cause cross- or multiple resistance among various members of this family of inhibitors. In contrast, certain combinations of amino acid substitutions can sometimes lead to increased drug susceptibility and may also result in resensitization of formerly resistant viruses. A biochemical understanding of these complex viral phenotypes may be of major importance in regard to development of novel chemotherapeutic strategies that can act at the level of drug-resistant mutated enzymes. In this review, we discuss several principles that help to explain the increased susceptibility and resensitization to some antiviral agents used in the context of combination treatment. The conclusions are largely based on our current understanding of mechanisms involved in drug-resistance to 3TC and AZT. Copyright 2000 Harcourt Publishers Ltd.

Journal Article↗
PubMed2006

API consensus guidelines for use of antiretroviral therapy in adults (API-ART guidelines). Endorsed by the AIDS Society of India.

With rational use of antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection has been transformed into a chronic manageable illness like diabetes and hypertension. These guidelines provide information on state of art, evidence based approach for use of ART in Indian context. When to initiate ART? Antiretroviral therapy is indicated for all symptomatic HIV infected persons regardless of CD4 counts and plasma viral load (PVL) levels. In asymptomatic patients, ART should be offered when the CD4 counts < 200/mm3 and should be considered in patients with CD4 counts between 200-250/mm3. Therapy is not recommended for patients with CD4 count more than 350/ mm3. Involvement of patient in all treatment decisions and assessing readiness is critical before initiating ART. What to start with? A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen is recommended for antiretroviral naïve patients. The choice between nevirapine and efavirenz is based on differences in adverse events profiles; cost and availability of convenient fixed dose combinations and need for concomitant use of rifampicin. A backbone of 2-nucleoside reverse transcriptase inhibitors (NRTIs) is combined with the NNRTI. Various combinations and ART strategies not to be used in clinical practice has been enlisted. How to follow up? Recommendations have been made for baseline evaluation and monitoring of patients on ART. These include guidelines on laboratory and clinical evaluation. A plasma viral load at 6 months after initiation of first-line ART is strongly recommended. Yearly estimation of lipid profile has been recommended. How to identify and manage ART failure? The guidelines recognize the issue of identifying ART failure late if only CD4 counts are used for monitoring. In the absence of resistance testing various second-line regimens have been enlisted. A boosted protease inhibitor based regimen is recommended in this situation to be combined with 2-NRTIs. Special situations Recommendations have been made for use of ART in HIV-TB, HIV-HBV, and HIV-HCV co-infected patients. In patients with active TB and a CD4 count < 200/mm3, initiation of ART is recommended as soon as the anti-TB treatment is tolerated. Efavirenz is the only ARV drug, which can be safely used with rifampicin. In pregnancy use of single dose nevirapine for reducing risk of mother to child transmission of HIV is not recommended, because of the risk of development of resistance. For post-exposure prophylaxis taking ART treatment history of the source patient is crucial in designing an effective regimen.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Activation of c-Jun N-terminal kinase mediates gp120IIIB- and nucleoside analogue-induced sensory neuron toxicity.

Peripheral neuropathy is the most common neurological symptom in patients with acquired immunodeficiency syndrome (AIDS). Here, we examine possible mechanisms of gp120 and nucleoside reverse transcriptase inhibitors (NRTIs) in the pathogenesis of AIDS peripheral neuropathy. Neonatal dorsal root ganglion (DRG) neurons were found to undergo apoptosis in response to chronic treatment with gp120IIIB, an effect enhanced by the co-application of hCD4, as well as upon exposure to the nucleoside reverse transcriptase inhibitor (NRTI), 2',3'-dideoxyinosine (ddI). DRG neurons were rescued from the neurotoxic effects of these agents by CEP-1347, an inhibitor of the mixed lineage kinases (MLKs), upstream activators of the c-Jun N-terminal kinase (JNK) signaling pathway. In addition, gp120- or ddI-mediated toxicity were also inhibited by neuronal expression of dominant negative versions of the MLKs. Our results suggest that both gp120 and the NRTIs cause sensory neuron apoptosis through the activation of the JNK pathway, and that CEP-1347-like compounds may serve as a therapeutic option in patients with AIDS-associated peripheral neuropathy.

Animals↗
PubMed2000

Efavirenz- and adefovir dipivoxil-based salvage therapy in highly treatment-experienced patients: clinical and genotypic predictors of virologic response.

OBJECTIVE: To determine the impact of prior nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy, genotypic resistance, and other variables on response to efavirenz (EFV)- and adefovir dipivoxil (ADV)-based salvage therapy. DESIGN: Retrospective clinical cohort study. SETTING: One university and one community-based HIV clinic. STUDY SUBJECTS: All 33 patients who were coenrolled in both the EFV and ADV expanded access programs. INTERVENTIONS: Patients received EFV 600 mg/day and ADV 120 mg/day in addition to other antiretroviral agents. OUTCOME MEASURE: HIV viral load (<500 copies/ml) at 12 and 24 weeks. RESULTS: 10 of 33 (30%) patients at 12 weeks and 8 of 33 (24%) patients at 24 weeks had viral loads <500 copies/ml. Prior NNRTI use and a history of any NNRTI-associated mutations predicted failure. Patients with Y181C or G190A single mutations had an initial greater magnitude of viral load suppression than those with K103N, but this advantage was short lived. No one with any NNRTI mutations responded with a viral load <500 copies/ml at 12 or 24 weeks. CONCLUSIONS: EFV/ADV-based salvage yielded viral load suppression at 24 weeks in 42% (8 of 19) of patients who were highly NRTI and protease inhibitor experienced but NNRTI naive. NNRTI-experienced study subjects had a poor response regardless of the specific NNRTI resistance mutation they harbored.

Adenine↗
PubMed2004

Immune restoration in HIV-positive, antiretroviral-naive patients after 1 year of zidovudine/lamivudine plus nelfinavir or nevirapine.

OBJECTIVES: To evaluate the immunological response in HIV-1-infected, antiretroviral-naive patients receiving highly active antiretroviral therapy regimen of two nucleosides plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. DESIGN AND METHODS: Of 142 patients included in a randomized, open, multicentre trial comparing zidovudine/lamivudine plus nelfinavir (NFV) or nevirapine (NVP), 36 patients (16 NFV, 20 NVP) were enrolled in an immunological substudy. Mean baseline CD4 T-cell counts was 360/mm3 (range: 11-679) and mean baseline plasma viral load >50000 copies/ml (range: 2240-1468210). Viral load (VL), T-cell subsets and T-cell functions were analysed at baseline and after 1 year of treatment. RESULTS: After 12 months of follow-up, plasma viral load was reduced similarly in both groups, with 78% (NFV) and 83% (NVP) of patients achieving a VL <200 copies/ml. A significant increase in CD4 T cells was observed in both groups (mean: +182 cells, P=0.001). Both regimens were similarly effective in reducing activated T cells (CD38 and DR). A significant increase of both CD4 and CD8 CD28 T cells occurred in both arms of treatment. Patients of both regimens showed a significant decrease of activated memory (CD45RA-CD45RO+) CD8 T cells and a clear increase of naive (CD45RA+CD45RO-) CD8 T cells. Peripheral blood mononuclear cell proliferative responses to polyclonal stimuli (CD3 and CD3 +CD28) as well as to ubiquitous cytomegalovirus antigen increased significantly in both groups after 12 months of follow-up. Nevertheless, neither at baseline nor after 1 year of treatment, these patients showed any significant T-cell responsiveness to HIV-1 recombinant proteins gp160 or p24. CONCLUSIONS: Our data indicate that immune restoration achieved after 1 year of therapy with either NFV or NVP was similar. This reinforces the role of NVP-containing regimens as a valid option for initiating antiretroviral therapy. Nevertheless, additional therapeutic approaches should be envisaged to restore HIV-1-specific T-cell responses.

Adult↗
PubMed2003

Subtherapeutic antiretroviral plasma concentrations in routine clinical outpatient HIV care.

The objective of this study was to evaluate plasma concentrations of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) within several dosing schemes in a cohort of HIV-infected patients in routine clinical practice and to find possible explanations for subtherapeutic plasma concentrations. Patients were included if a PI or NNRTI was part of their antiretroviral regimen, at least one plasma concentration was obtained, and a complete medication overview from community pharmacy records was available. The study period was from January 1998 to September 2001. Each plasma concentration was related to median plasma concentrations of a pharmacokinetic reference curve, yielding a concentration ratio (CR). A cutoff CR was defined for each antiretroviral drug per specific regimen, discriminating between >or=therapeutic and subtherapeutic concentrations. For the patients with subtherapeutic concentrations, it was sorted out whether drug interactions, adverse events and self-reported symptoms, or nonadherence could be the cause of the lower than expected plasma concentration. Ninety-seven HIV-infected patients fulfilled the criteria. During the defined period, 1145 plasma concentrations were available (median, 11; interquartile range, 8-14). Three hundred fourteen (27.4%) plasma concentrations were classified subtherapeutic. Drug interactions (2; 0.6%), adverse events and self-reported symptoms (67; 21.3%), and nonadherence (14; 4.5%) could only partly explain the subtherapeutic drug levels. Consequently, a large number of the subtherapeutic plasma concentrations (73.6%) remained inexplicable. A high number of subtherapeutic plasma concentrations were observed. No clear causes were found; thus, corrective measures will be difficult to employ. Therefore, therapeutic drug monitoring (TDM) must maintain its crucial place in routine clinical care to be able to identify patients who need extra attention so that therapeutic plasma concentrations are achieved.

Adult↗
PubMed2003

Frequency, risk factors, and outcome of hyperlactatemia in HIV-positive persons: implications for the management of treated patients.

BACKGROUND: The nucleoside reverse transcriptase inhibitors used for the treatment of HIV-positive persons are now clearly associated with metabolic disorders. We determined the prevalence of and risk factors for hyperlactatemia in HIV-positive persons to assess the relevance of lactate venous blood concentrations during antiretroviral therapy. METHODS: We conducted a prospective cross-sectional study of venous lactate determinations with 282 consecutive HIV-positive persons who, in addition to a physical examination, had blood samples taken every 3-4 months for routine biochemical, immunologic, and viral assessment. The frequencies of hyperlactatemia and lactic acidosis were determined, and the risk factors were analyzed by a multivariate logistic regression model. The effect of modification of antiretroviral therapy in patients with moderate hyperlactatemia was also assessed. RESULTS: From 782 blood lactate determinations, we identified 65 (23%) patients with moderate hyperlactatemia and 5 (1.8%) with lactate concentrations >5 mmol/L (2 with severe lactic acidosis; 0.7%). Older age, drug regimens containing stavudine [adjusted odds ratio (OR) = 2.5] or a combination of stavudine-didanosine (adjusted OR = 3.1), and the use of buprenorphine (adjusted OR = 14.7) were independent predictors of hyperlactatemia. Among 65 patients with moderate hyperlactatemia, 39 did not have their treatments changed, and 26 had a new combination therapy that was associated with a clinical improvement and a more pronounced decrease in lactate (-1.66 vs -0.99 mmol/L; P <0.05). CONCLUSIONS: Chronic compensated and moderate hyperlactatemia was common in our population study. Measurement of lactate, under standardized conditions, may be useful in optimizing management of HIV-positive persons on antiretroviral therapy.

Acidosis, Lactic↗
PubMed2001

[Antiretroviral therapy 2001. Basic principles and current status].

For antiretroviral therapy (ART) nucleosidereverse transcriptase inhibitors (NRTI), protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) are available, and are used in combination treatments. The use of PI is associated with new side effects, in particular affecting lipid metabolism. The objective of treatment continues to be a maximum reduction of the viral load. The question whether to treat the HIV early on or later is under controversial discussion. Simplified therapeutic regimens making possible single or twice-daily doses and the use of small numbers of tablets represent a major advance in ART.

Anti-HIV Agents↗
PubMed1999

Antiretroviral Drug Resistance in HIV-1.

Progress in understanding antiretroviral resistance has evolved rapidly in recent years. Specific resistance mutations have been associated with virologic failure of different nucleoside reverse transcriptase inhibitors (NRTIs). These mutations vary in the extent of cross resistance they confer to other drugs in the same class. In addition, two novel mutational patterns conferring resistance to multiple NRTIs have been recognized. Considerable class-specific cross resistance also exists among viruses with reduced susceptibility to nonnucleoside reverse transcriptase inhibitors (NNRTIs). Among protease inhibitors, low level resistance that arises early during virologic failure may be drug specific in some situations, but high level resistance seen later during suboptimal therapy is likely to confer cross resistance to the entire class. Prevalence of drug resistance in infected patients appears to be considerable, and transmission of multidrug-resistant virus has been documented. Current methods of testing for resistance are promising, but they have significant limitations and require further clinical validation. The best approach to prevent resistance is to start treatment early during infection with a regimen that engenders good compliance and is potent enough to decrease viral load to below detection limits of the most sensitive assay available. Once resistance arises, salvage regimens in general have compromised efficacy and should be planned with attention to the patient's prior drug treatment history and the viruses' suspected or demonstrated resistance patterns.

Journal Article↗
PubMed2003

Differences in the frequency of resistance to antiretroviral drug classes among human immunodeficiency virus type 1 clinical isolates.

Genotypic resistance to all antiretroviral classes was widespread among human immunodeficiency virus type 1 isolates failing therapy. Resistance to nonnucleoside reverse transcriptase inhibitors was found most frequently and resistance to protease inhibitors was found least frequently, most likely due to differences in the number of enzymatic amino acid substitutions leading to resistance to each particular drug class.

Anti-HIV Agents↗
PubMedDate not supplied

Protease inhibitors: a new weapon and a new strategy against HIV.

Until recently, reverse transcriptase inhibitors have been the mainstay for treating HIV infection. Now, three protease inhibitors have been approved. Early evidence suggests that triple therapy delays the progression of HIV infection. An understanding of these new drugs and treatment strategies is imperative for clinicians. This article (1) reviews HIV's structure and replication process, (2) discusses currently approved reverse transcriptase and protease inhibitors, (3) describes the antiretroviral drugs' modes of action, (4) discusses important nursing implications for monitoring clients on these drugs, and (5) presents current scientific evidence regarding the effectiveness of combination therapy strategies.

Disease Progression↗
PubMed1999

Changing cost of English HIV service provision 1996-1997. NPMS Steering Group. National Prospective Monitoring System.

The objectives of this study were to provide individual and population-based unit cost estimates of HIV treatment and care by stage of HIV infection for adults in England and estimate the financial impact of the use of combination antiretroviral therapy. Individual unit cost estimates were calculated, based on 1997 activity data, and linked to the number of diagnosed HIV-infected individuals using statutory medical services by clinical stage of HIV infection in England during 1997 to obtain population-based cost estimates; these were compared with 1996 estimates. Most clinical guidelines now recommend the use of 3 antiretroviral agents, but cost estimates for mono and dual therapy were included as baseline estimates. Baseline costs for treating AIDS patients with zidovudine (AZT) monotherapy were estimated at pound sterling 16,830 (95% CI 14,633-18,985) per patient-year which was substantially lower than the 1996 estimate; costs for asymptomatic individuals and people with symptomatic non-AIDS were pound sterling 4450 (95% CI 3521-5612) and pound sterling 7289 (95% CI 6169-8386) per respective patient-year which did not differ substantially from 1996. The total annual population cost estimate for HIV service provision amounted to pound sterling 128 million (95% CI pound sterling 109m to pound sterling 147m), if all patients with HIV disease were treated with AZT monotherapy only. For all eligible patients to be treated with 2 nucleoside reverse transcriptase inhibitors (NRTI) (AZT and didanosine (ddI) or zalcitabine (ddC)), cost estimates amounted to pound sterling 161m (95% CI pound sterling 141m to pound sterling 181m), while for triple therapy, annual estimated expenditure amounted to pound sterling 185m (95% CI pound sterling 165m to pound sterling 206m) when a non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine) was included or pound sterling 205m (95% CI pound sterling 186m to pound sterling 235m) when a protease inhibitor was included. Compared with 1996 population-based cost estimates, the estimates for monotherapy decreased by 14%, by 11% for dual therapy, by 10% for triple therapy which included a NNRTI and by 9% if a protease inhibitor was used as part of a triple therapy regimen. Similarly, compared with 1996 estimates, the proportion of total costs attributable to treating asymptomatic individuals increased by 5% and 2-3% for people with symptomatic non-AIDS, while the proportion attributable for treating people with AIDS decreased by 8-9%.

Adult↗
PubMedDate not supplied

Role of immune modulation in primary HIV infection.

Hydroxyurea inhibits HIV without attacking the virus directly. By inhibiting a cellular enzyme (ribonucleotide reductase) the drug decreases the intracellular concentration of deoxynucleotide triphosphates, thus favoring the incorporation of other drugs, such as the reverse transcriptase inhibitors, into the nascent viral DNA. A large body of data has shown that hydroxyurea can be successfully used during chronic infection. In this manuscript we review the use of hydroxyurea during primary HIV infection. In several independent studies hydroxyurea has been shown to: 1) inhibit HIV in combination with a reverse transcriptase inhibitor and a protease inhibitor as efficiently as with standard highly active antiretroviral therapies; 2) stimulate the immune system by increasing the percentage of naïve cells and the percentage of cells capable of responding to antigens; 3) "cool down" the immune system hyper-activation. The role of hydroxyurea in inducing control of HIV during structured treatment interruptions remains to be clarified.

CD4 Lymphocyte Count↗
PubMed2003

Hyperlactatemia in human immunodeficiency virus-infected children receiving antiretroviral treatment.

BACKGROUND: Hyperlactatemia and lactic acidosis occur in HIV-infected adults receiving antiretroviral treatment. Our objective was to determine the incidence, course and risk factors for hyperlactatemia in our HIV-infected pediatric patients. DESIGN: A prospective observational study of venous lactate concentrations during a 28-month period in 80 HIV-infected children, most of whom were receiving antiretrovirals. METHODS: Venous blood lactate concentrations were measured every 6 months under optimal sample-obtaining conditions. Alanine values from the same blood sample were performed when lactate concentrations were elevated. Hyperalaninemia is observed only when mitochondrial oxidative phosphorylation is chronically disturbed. RESULTS: Twenty-three patients (29%) were identified with hyperlactatemia, in 9 of the cases with normal alaninemia, probably caused by difficult venous punctures. The other 14 children (17%) had pathologic alanine concentrations with a mean lactate peak of 2.67 mmol/l (range, 2.05 to 4.9 mmol/l); none of them showed metabolic acidosis, and they were all symptom-free. Treatment was continued in all cases, and lactate has progressed spontaneously to normal values in 5 patients. CONCLUSIONS: Symptom-free hyperlactatemia was observed in HIV-infected children receiving nucleoside analog reverse transcriptase inhibitors. In our study, only a younger age at the beginning of antiretroviral treatment was a statistically significant risk factor for hyperlactatemia. Random measurements of blood lactate concentrations should be included in the clinical follow-up of those HIV-infected children <3 years of age who are treated with nucleoside analog reverse transcriptase inhibitors, symptomatic or not.

Acidosis, Lactic↗
PubMed1995

In vitro inhibition of human immunodeficiency virus type 1 by a combination of delavirdine (U-90152) with protease inhibitor U-75875 or interferon-alpha.

Delavirdine (bisheteroarylpiperazine, U-90152), a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1), was evaluated in a two-drug combination with recombinant human interferon-alpha (IFN-alpha) or the peptidomimetic protease inhibitor U-75875 against HIV-1 replication in vitro. Viral growth was assayed in a CD4+ T cell line (H9) infected with HIVIIIB and in human peripheral blood mononuclear cells infected with the clinical isolate HIVJRCSF. Drug synergy, estimated by the combination index method and the method of Pritchard and Shipman, was observed when delavirdine was combined with U-75875 or IFN-alpha over a range of drug concentrations (delavirdine: 0.001, 0.003, 0.01, 0.03 microM; U-75875: 0.01, 0.03, 0.1, 0.3, 1.0 microM; IFN-alpha: 2, 6, 17, and 50 or 10, 30, 100, and 300 IU/mL). The combinations showed no detectable drug antagonism or cytotoxicity. These in vitro synergy data support the potential use of delavirdine with either a protease inhibitor or IFN-alpha in patients with AIDS.

Antiviral Agents↗
PubMed2005

Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection.

BACKGROUND: Structured treatment interruption (STI) may allow viral replication in the presence of decreased plasma drug levels, with risk of selection of resistance mutations. METHODS: For patients recruited for an STI study, genotypic resistance testing was performed at baseline (before receipt of any treatment), immediately before the STI, and 2 weeks after each interuption of therapy. RESULTS: During 20 (18%) of 112 STI cycles (95% CI, 11%-26%), resistance mutations were selected; 6% of the mutations were de novo (i.e., not detected before the start of STI), and 12% were archived mutations (i.e., mutations already detected before the STI). Overall, resistance mutations during STI were selected in 9 (26%) of 35 patients; 5 (14%) of the mutations were de novo, and 4 (12%) were archived mutations. Mutations conferring resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were selected in 3 (23%) of 13 patients receiving NNRTI-based regimens (all mutations were de novo). Mutations conferring resistance to lamivudine were selected in 9 (50%) of 18 patients receiving lamivudine-containing regimens (4 [22%] were de novo, and 5 [28%] were archived mutations). Mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs), excluding the M184V mutation, were selected in 2 (6%) of 35 recipients of NRTIs (1 [3%] of these mutations was de novo, and 1 [3%] was an archived mutation. Finally, mutations conferring resistance to protease inhibitors were selected in none of the 22 patients receiving protease inhibitors. In most cases, de novo and archived mutations were selected during the first STI cycle, and their number did not increase during successive cycles. Plasma viral load decreased to undetectable levels in all the patients when the earlier drug regimen was reintroduced. CONCLUSIONS: Genotypic mutations are selected during STI in a high proportion of patients (especially in patients receiving NNRTIs or lamivudine). Approximately one-half of selected mutations were archived mutations. Patients who had archived mutations did not have a higher risk of accumulating new mutations than did patients who were infected with wild-type virus before the STI.

Adult↗
PubMed2006

Need for therapeutic drug monitoring in HIV-1 infected children receiving efavirenz doses according to international guidelines.

BACKGROUND: International guidelines for the treatment of HIV-1 infected children recommend efavirenz plus nucleoside reverse transcriptase inhibitor combination therapy for first line therapy. Until now little is known about the steady state pharmacokinetics of efavirenz in children. METHODS: 11 HIV-1 infected children at the age of 4 to 10 years received efavirenz according to body weight adjusted dose recommendations at 10 -15 mg/kg body weight. All children were non nucleoside reverse transcriptase inhibitor (NNRTI) naive, 5/11 received efavirenz as first line therapy. Efavirenz plasma concentrations were assessed before daily dose and 1, 2, 4, 8, 24 h post-dose after medication by established HPLC. RESULTS: 7 of 11 children exhibited efavirenz plasma concentrations below targeted ranges. Mean (95% CI) minimum concentrations (C subsetmin) was 1293 ng/mL (range: 889 -1697) and maximum concentration (C subsetmax) was 5552 ng/mL (3951 - 7153) and the mean area under the time-concentration curve at steady state (AUCss) was 63608 ng*h/mL (44222 - 82989). The linear regression analysis of bodyweight adjusted efavirenz AUCss showed a close correlation between dose/bodyweight and plasma concentrations (r superset2 = 0.79). Efavirenz doses below 12.5 mg/kg lead to an AUC < 60000 ng*h/mL in 7 of 8 cases. Higher efavirenz doses exhibited an AUC within the recommended therapeutic range of 60000 - 120000 ng*h/mL (n = 3). CONCLUSIONS: The data show insufficient plasma concentrations for some children despite efavirenz dosing according to recommendations. Antiretroviral therapy needs to be carefully adjusted in children. Therapeutic drug monitoring is strongly recommended to meet efavirenz plasma levels within the therapeutic range.

Alkynes↗