Nucleoside Reverse Transcriptase Inhibitors Combinations Research Articles

Assessment of complex genomic alterations induced by AZT, 3TC, and the combination AZT +3TC

Highly active antiretroviral therapy (HAART) regimens are based on the use of nucleoside reverse transcriptase inhibitors (NRTIs), which are the main drugs used by patients infected with the human immunodeficiency virus (HIV). The use of NRTIs combinations has afforded clear clinical benefits to patients undergoing HAART. However, the combination of two NRTIs may increase the risk of genomic instability in comparison with the drugs administered individually. We analyzed the ability of zidovudine (AZT) and lamivudine (3TC), and the combination AZT +3TC to induce complex genomic alterations using the cytokinesis-block micronucleus (CBMN) assay in Chinese hamster ovary (CHO)-K1 cells. The 24-h cell treatment with individual NRTIs showed that AZT increased micronucleus frequencies and nucleoplasmic bridges (NPBs). No significant differences were observed for any parameters investigated after exposure of CHO-K1 cells to 3TC. The combination AZT +3TC significantly increased micronucleus frequencies. Analysis of interaction between these drugs suggested that antagonism occurs in all AZT +3TC concentrations. These results highlight the importance to investigate the genotoxic profile of NRTIs to develop safer intervention strategies in antiretroviral treatment protocols.

Single-tablet antiretroviral treatment (once daily).

Current guidelines recommend combination antiretroviral treatment for all patients with HIV infection.[1][1],[2][2] The backbone of this treatment regimen is a dual nucleoside reverse transcriptase inhibitor combination, typically tenofovir/emtricitabine or abacavir/lamivudine, which is combined

Top-down and bottom-up modeling in system pharmacology to understand clinical efficacy: An example with NRTIs of HIV-1

A major aim of Systems Pharmacology is to understand clinically relevant mechanisms of action (MOA) of drugs and to use this knowledge in order to optimize therapy. To enable this mission it is necessary to obtain knowledge on how in vitro testable insights translate into clinical efficacy. Mathematical modeling and data integration are essential components to achieve this goal.Two modeling philosophies are prevalent, each of which in isolation is not sufficient to achieve the above described: In a ‘top-down’ approach, a minimal pharmacokinetic–pharmacodynamic (PK–PD) model is derived from- and fitted to available clinical data. This model may lack interpretability in terms of mechanisms and may only be predictive for scenarios already covered by the data used to derive it. A ‘bottom-up’ approach builds on mechanistic insights derived from in vitro/ex vivo experiments, which can be conducted under controlled conditions, but may not be fully representative for the in vivo/clinical situation.In this work, we employ both approaches side-by-side to predict the clinical potency (IC50 values) of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, emtricitabine and tenofovir. In the ‘top-down’ approach, this requires to establish the dynamic link between the intracellularly active NRTI-triphosphates (which exert the effect) and plasma prodrug PK and to subsequently link this composite PK model to viral kinetics. The ‘bottom-up’ approach assesses inhibition of reverse transcriptase-mediated viral DNA polymerization by the intracellular, active NRTI-triphosphates, which has to be brought into the context of target cell infection. By using entirely disparate sets of data to derive and parameterize the respective models, our approach serves as a means to assess the clinical relevance of the ‘bottom-up’ approach.We obtain very good qualitative and quantitative agreement between ‘top-down’ vs. ‘bottom-up’ predicted IC50 values, arguing for the validity of the ‘bottom-up’ approach. We noted, however, that the ‘top-down’ approach is strongly dependent on the sparse and noisy intracellular pharmacokinetic data. All in all, our work provides confidence that we can translate in vitro parameters into measures of clinical efficacy using the ‘bottom-up’ approach. This may allow to infer the potency of various NRTIs in inhibiting e.g. mutant viruses, to distinguish sources of interaction of NRTI combinations and to assess the efficacy of different NRTIs for repurposing, e.g. for pre-exposure prophylaxis.

Immunologic response in treatment-naïve HIV-2-infected patients: the IeDEA West Africa cohort.

IntroductionResponse to antiretroviral therapy (ART) among individuals infected with HIV-2 is poorly described. We compared the immunological response among patients treated with three nucleoside reverse-transcriptase inhibitors (NRTIs) to boosted protease inhibitor (PI) and unboosted PI-based regimens in West Africa.MethodsThis prospective cohort study enrolled treatment-naïve HIV-2-infected patients within the International Epidemiological Databases to Evaluate AIDS collaboration in West Africa. We used mixed models to compare the CD4 count response to treatment over 12 months between regimens.ResultsOf 422 HIV-2-infected patients, 285 (67.5%) were treated with a boosted PI-based regimen, 104 (24.6%) with an unboosted PI-based regimen and 33 (7.8%) with three NRTIs. Treatment groups were comparable with regard to gender (54.5% female) and median age at ART initiation (45.3 years; interquartile range 38.3 to 51.8). Treatment groups differed by clinical stage (21.2%, 16.8% and 17.3% at CDC Stage C or World Health Organization Stage IV for the triple NRTI, boosted PI and unboosted PI groups, respectively, p=0.02), median length of follow-up (12.9, 17.7 and 44.0 months for the triple NRTI, the boosted PI and the unboosted PI groups, respectively, p<0.001) and baseline median CD4 count (192, 173 and 129 cells/µl in the triple NRTI, the boosted PI and the unboosted PI-based regimen groups, respectively, p=0.003). CD4 count recovery at 12 months was higher for patients treated with boosted PI-based regimens than those treated with three NRTIs or with unboosted PI-based regimens (191 cells/µl, 95% CI 142 to 241; 110 cells/µl, 95% CI 29 to 192; 133 cells/µl, 95% CI 80 to 186, respectively, p=0.004).ConclusionsIn this observational study using African data, boosted PI-containing regimens had better immunological response compared to triple NRTI combinations and unboosted PI-based regimens at 12 months. A randomized clinical trial is still required to determine the best initial regimen for treating HIV-2 infected patients.

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds.

The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold. PENPACT-1 had a 2 × 2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and switch at a 1000 copies/mL versus 30,000 copies/mL threshold. Switch criteria were not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or Center for Disease Control and Prevention stage C event. Resistance tests were performed on samples ≥1000 copies/mL before switch, resuppression, and at 4-years/trial end. Sixty-seven children started PI-based ART and were randomized to switch at 1000 copies/mL (PI-1000), 64 PIs and 30,000 copies/mL (PI-30,000), 67 NNRTIs and 1000 copies/mL (NNRTI-1000), and 65 NNRTI and 30,000 copies/mL (NNRTI-30,000). Ninety-four (36%) children reached the 1000 copies/mL switch criteria during 5-year follow-up. In 30,000 copies/mL threshold arms, median time from 1000 to 30,000 copies/mL switch criteria was 58 (PI) versus 80 (NNRTI) weeks (P = 0.81). In NNRTI-30,000, more nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000 copies/mL (23% NNRTI-1000, 27% NNRTI-30,000). Sixty-two children started abacavir + lamivudine, 166 lamivudine + zidovudine or stavudine, and 35 other NRTIs. The abacavir + lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30,000, 64% NNRTI-1000, and 100% NNRTI-30,000 were <400 copies/mL 24 weeks later. Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet resuppressed on second-line. An abacavir + lamivudine NRTI combination seemed protective against development of NRTI resistance.

Comparative analysis of genetic toxicity of antiretroviral combinations in somatic cells of Drosophila melanogaster

Nucleoside reverse-transcriptase inhibitor (NRTI) drugs are a major component of highly-active antiretroviral therapy (HAART). NRTI combinations have been demonstrated as producing a sustained reduction in plasma viremia with an increased CD4 count, thereby showing clear clinical benefits. Therefore, the secondary effects caused by the combination of two NRTIs, mainly those related to amplification of genotoxic effects, due to increased risk of DNA damage caused by these drugs, should be carefully examined. We employed the standard version of the wing SMART in Drosophila melanogaster to obtain more detailed knowledge about the genotoxic profile of NRTI combinations of AZT+ddI, AZT+3TC and AZT+d4T. Our results showed that all combinations increased the frequencies of induction of mutant spots. The combinations AZT+ddI and AZT+3TC were shown to induce recombination rates ranging from 86.38% to 98.36% while AZT+d4T showed a large discrepancy between recombination and mutation percentages. The combination index demonstrated that 3TC and d4T produced antagonism while ddI showed synergistic effects in combination with AZT.

Effect of efavirenz versus nevirapine in antiretroviral-naive individuals in the HIV-CAUSAL Collaboration Cohort

Effect of efavirenz versus nevirapine in antiretroviral-naive individuals in the HIV-CAUSAL Collaboration Cohort

Spillover adherence effects of fixed-dose combination HIV therapy

The impact of fixed-dose combination (FDC) products on adherence to other, non-fixed regimen components has not been examined. We compared adherence to a third antiretroviral (ART) component among patients receiving a nucleoside reverse transcriptase inhibitor (NRTI) backbone consisting of the FDC Epzicom®, GlaxoSmithKline Inc, Research Triangle Park, NC (abacavir sulfate 600 mg + lamivudine 300 mg; FDC group) versus NRTI combinations taken as two separate pills (NRTI Combo group) using data from a national sample of 30 health plans covering approximately 38 million lives from 1997 to 2005. Adherence was measured as the medication possession ratio (MPR). Multivariate logistic regression compared treatment groups based on the likelihood of achieving ≥95% adherence, with sensitivity analyses using alternative thresholds. MPR was assessed as a continuous variable using multivariate linear regression. Covariates included age, gender, insurance payer type, year of study drug initiation, presence of mental health and substance abuse disorders, and third agent class. The study sample consisted of 650 FDC and 1947 NRTI Combo patients. Unadjusted mean adherence to the third agent was higher in the FDC group than the NRTI Combo group (0.92 vs 0.85; P < 0.0001). In regression analyses, FDC patients were 48% and 39% more likely to achieve 95% and 90% third agent adherence, respectively (P ≤ 0.03). None of the other MPR specifications achieved comparable results. Among managed care patients, use of an FDC appears to substantially improve adherence to a third regimen component and thus the likelihood of achieving the accepted standard for adherence to HIV therapy of 95%.

Impact of NRTIs on lipid levels among a large HIV-infected cohort initiating antiretroviral therapy in clinical care

to assess the associations between nucleoside reverse transcriptase inhibitors (NRTIs) and change in lipid levels among a large cohort of HIV-infected patients in routine clinical care initiating their first potent antiretroviral regimen. longitudinal observational cohort study from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. we used generalized estimating equations to examine the association between NRTIs and lipids accounting for within-patient correlations between repeated measures and key clinical and demographic characteristics including other antiretroviral medications. among 2267 individuals who started their first antiretroviral regimen, tenofovir with emtricitabine or lamivudine was associated with lower levels for total cholesterol, low-density lipoprotein (LDL), triglycerides, non-high-density lipoprotein (HDL), and HDL, compared with other NRTI pairs in adjusted analyses. LDL levels were highest among patients receiving didanosine/lamivudine. Triglyceride levels were highest in stavudine/lamivudine users. HDL levels were highest among patients receiving didanosine/stavudine. Hepatitis C infection and younger age were also associated with lower lipid levels. we found clinically important heterogeneity within the NRTI class of antiretroviral medications regarding their effect on lipid levels over time. Although the lipid profile of tenofovir with emtricitabine or lamivudine appeared to be less pro-atherogenic in this large longitudinal study of HIV-infected patients in routine clinical care, there was no association with beneficial HDL levels. In general, the change in lipid levels associated with most antiretroviral agents, particularly those NRTI combinations currently in common use, are relatively modest. Additional studies are needed to understand the long-term implications of these findings on cardiovascular disease risk.

Pharmacokinetic Characterization of Three Doses of Tipranavir Boosted with Ritonavir on Highly Active Antiretroviral Therapy in Treatment-Experienced HIV-1 Patients

Purpose: This study characterized the pharmacokinetic effects, safety, and antiretroviral activity of three different doses of the nonpeptidic protease inhibitor tipranavir, in combination with ritonavir administered twice daily for 28 days, on a number of triple-combination regimens containing a nonnucleoside reverse transcriptase inhibitor (efavirenz or nevirapine) plus two nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, and zidovudine) or a three nucleoside reverse transcriptase inhibitor combination (zidovudine, lamivudine, and abacavir).Methods: The study enrolled 208 HIV-1–positive patients who had been on stable antiretroviral treatment for at least 12 weeks prior to study entry and had an HIV-1 RNA load of δ 20,000 copies/mL. The patients were randomized to receive one of three dose combinations of tipranavir and ritonavir (1250/100 mg, 750/100 mg, and 250/200 mg) in addition to their antiretroviral (ARV) regimen for the next 22 days. The effects of twice-daily tipranavir and ritonavir combinations on the steady-state pharmacokinetics of the antiretrovirals were assessed by comparing pharmacokinetic parameters at baseline and after 3 weeks of coadministration.Results: No clinically relevant changes were observed in the Cmin, Cmax, or AUC parameters for nevirapine, efavirenz, lamivudine, stavudine, or didanosine, when coadministered with tipranavir and ritonavir at the dose combinations studied. All three dose combinations of tipranavir and ritonavir decreased the systemic exposure of abacavir (by 35% to 44%) and zidovudine (by 31% to 42%). Consistent with previous tipranavir studies, gastrointestinal adverse events were those most frequently observed. These reactions tended to be mild, with the majority being of Grade 1, and only 8 being of Grade 3 or 4 in intensity. Virologic response improved from 40.4% of participants at baseline with <50 copies/mL to 67.6% at Day 28 of study following addition of tipranavir and ritonavir.Conclusions: Tipranavir coadministered with ritonavir has been demonstrated to be safe, effective, and pose little potential for clinically meaningful drug interactions when added to the highly active antiretroviral therapy regimens containing nevirapine, efavirenz, lamivudine, stavudine, or didanosine.

Abacavir/Lamivudine Fixed Dose Combination in the Treatment of Patients with HIV Infection

HIV infection remains a common cause of morbidity and mortality worldwide. Fortunately, patients treated with combination antiretroviral therapy (ART) have significantly improved survival rates and quality of life. The standard of care for the treatment of ART-naive patients includes three drugs, two of which should be nucleoside reverse transcriptase inhibitors (NRTIs). Abacavir/lamivudine (ABC/3TC) is a fixed dose combination NRTI tablet that has been approved as an NRTI backbone. ABC/3TC is among the NRTI combinations that are recommended as first line in the most recent International AIDS Society–USA guidelines and WHO European Region protocol. However, owing to recently published data raising the possibility of an association between abacavir and heart disease, as well as data regarding efficacy in patients with higher HIV RNA levels, ABC/3TC has now been listed as an alternative NRTI backbone in the latest USA Department of Health and Human Services guidelines. While ABC has been associated with a hypersensitivity reaction that may be severe, a new test has been demonstrated to be effective in screening for the gene that is associated with this reaction.

Incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors

Long-term studies of tolerance to perinatal exposure to antiretroviral nucleoside reverse transcriptase inhibitors are required, in view of the potential genotoxicity of some of these molecules. To evaluate the incidence of cancers in uninfected children born to HIV-infected mothers. Cancers were detected in a nationwide prospective cohort of children born to HIV-infected mothers by standardized questionnaire during the prospective follow-up period of 2 years; thereafter, they were detected by spontaneous pharmacovigilance declaration and by crosschecking data with the national registries of childhood cancer. Standardized incidence ratio for incidence comparisons with general population. Ten cases of cancer were detected among the 9127 exposed HIV-uninfected children (median age: 5.4 years, 53 052 person-years of follow-up). The overall incidence did not differ significantly from that expected for the general population: 10 cases observed versus 8.9 and 9.6 expected depending on whether 1990-1999 or 2000-2004 national rates were used as reference [standardized incidence ratio of 1.1 (0.3-1.5) and 1.0 (0.5-1.9)]. Five cases of central nervous system cancer were observed (standardized incidence ratio of 3.1 [1.0-7.2] P = 0.05 and 2.4 [0.8-5.6], P = 0.12). The relative risk of cancer for children exposed to didanosine-lamivudine combination was higher than that for zidovudine monotherapy [hazard ratio: 13.6 (2.5-73.9)]. This study did not evidence an overall increase in cancer risk in nucleoside reverse transcriptase inhibitor exposed children until 5 years of age. Results suggesting associations with specific nucleoside reverse transcriptase inhibitor combinations need further investigations. A longer surveillance, including differential analysis of the different cancer sites and various nucleoside reverse transcriptase inhibitors administered is warranted.

Impact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondrial DNA and RNA in Human Skeletal Muscle Cells

We previously reported that 2',3'-dideoxyinosine (didanosine, or ddI) significantly altered mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells in human immunodeficiency virus type 1 (HIV-1)-infected children who had undetectable plasma HIV-1 RNA for more than 2 years while receiving highly active antiretroviral therapy. This research examines the in vitro effects of nucleoside reverse transcriptase inhibitors (NRTIs) on mitochondria of human skeletal muscle cells (HSMCs), including myoblasts and differentiated myotubes. mtDNA, mitochondrial RNA (mtRNA), and mRNA levels for nuclear mitochondrial regulatory factors were quantified in vitro using HSMCs, including myoblasts and differentiated myotubes, treated with NRTIs singly and in combination. After 5 days of treatment, mtDNA was significantly decreased in myoblasts and myotubes treated with ddI (P < 0.001 and P = 0.01, respectively) and ddI-containing regimens (P < 0.001 and P < 0.001, respectively) compared to levels in untreated cells. mtRNA (MTCYB) was also significantly decreased in the myoblasts and myotubes treated with ddI (P = 0.004) and ddI-containing regimens (P < 0.001). Regardless of the NRTI regimens examined, NRTI combinations significantly decreased mtRNA (MTCO3) in myoblasts and myotubes (P = 0.02 and P = 0.01, respectively). No significant differences were observed for nuclear mitochondrial regulatory factor mRNA in myoblasts or myotubes when treated with NRTIs (P > 0.07). ddI and ddI-containing regimens significantly decrease mtDNA and mtRNA in HSMCs, most notably in myoblasts. These findings may be of particular importance in developing countries, where ddI is widely used for first-line treatment of HIV-infected children.

HIV-related nephropathies associated with changes in blood and kidney tissue virus load

Department of Virology, Hoˆpital La Pitie´ Salpe´tiere, Universite´Paris VI, Paris, FranceCASE PRESENTATIONA 39-year-old African woman was admitted to ourNephrology Department in June 2004 for explorationof a nephrotic syndrome. Relevant past medical historyincluded HIV-1-positive infection since 1997. She had beentreated with a combination of nucleoside reversetranscriptase inhibitors (AZT, 3TC, and abacavir) sinceApril 2002. One week before admission, her CD4 þlymphocyte count was 350 mm

Changes in the Peripheral Blood mtDNA Levels in Naive Patients Treated by Different Nucleoside Reverse Transcriptase Inhibitor Combinations and Their Association with Subsequent Lipodystrophy

Nucleoside reverse transcriptase inhibitors (NRTIs) differ in the type and severity of adverse effects resulting from mitochondrial abnormalities. mtDNA in peripheral blood mononuclear cells (PBMCs) was measured during the first 12 months of different NRTIs combinations and its association with clinical lipodystrophy was estimated. Extended follow-up of a randomized trial, ALBI-ANRS 070, including antiretroviral naive patients was conducted. Total DNA was extracted from available cryopreserved PBMCs at baseline and months 6 and 12. Nuclear and mitochondrial genes were amplified using a real-time PCR assay. Clinical lipodystrophy was assessed 30 months after randomization using a standardized questionnaire. A logistic regression analysis assessed the value of mtDNA to predict lipodystrophy. Mean mtDNA level (copies/cell) significantly decreased from 5847 at baseline to 3176 at month 12 (p < 0.0001). In the zidovudine + lamivudine (ZDV + 3TC) arm (n = 37), the mean mtDNA was 6098, 6807, and 3725 copies/cell for baseline, month 6, and month 12, respectively. In the stavudine + didanosine (d4T + ddI) arm (n = 40), the mean values were 5616, 5731, and 2648 copies/cell, respectively. The proportion of patients in the lowest quartile of mtDNA (<1421 copies/cell) at month 12 was higher in 18 patients with lipodystrophy (44%) than in 28 without lipodystrophy (7%) (p = 0.008). At 12 months, a larger reduction of mtDNA from baseline was observed in those started on the d4T + ddI arm. Furthermore, a low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy. This marker may be of value for the early prevention of lipodystrophy in treated HIV-infected patients.

Fixed-Dose Combination of Abacavir, Lamivudine and Zidovudine for HIV Therapy

Triple-nucleoside therapy with abacavir (ABV)/lamivudine (3TC)/zidovudine (ZDV) combination tablets provides simple, nonfood-dependent, twice-daily, well-tolerated therapy with the potential to improve long-term adherence at a lower cost than other triple-drug regimens. Of all the triple nucleoside reverse transcriptase inhibitor combinations currently available, ABV/3TC/ZDV is most extensively studied. Although ABV/3TC/ZDV is possibly less potent than other treatment options when used alone, other attributes described in this review make it an attractive option for selected patients. This combination spares the use of protease inhibitors and their associated side effects, such as metabolic abnormalities, which may contribute to premature cardiovascular disease. Furthermore, by using only one drug class, it may maintain a greater number of future treatment options. Data from ongoing clinical trials may result in expanding the use of ABV/3TC/ZDV as a component of multidrug, highly active antiretroviral therapy regimens.

Tenofovir Plus Didanosine as Nrti Backbone in HIV-Infected Subjects

Nucleoside reverse transcriptase inhibitors (NRTI) are essential components of highly active antiretroviral treatment (HAART). Although several combinations can be used as NRTI backbones, not all are associated with good virological and/or immunological results. In particular, some NRTI combinations should be avoided due to antagonism (zidovudine plus stavudine) or to high rate of toxicity (didanosine plus stavudine). Tenofovir (TDF) and didanosine (ddI) are among the more often prescribed NRTI for their convenient posology (one pill each per day), relatively high genetic barrier for resistance, quite acceptable safety profile and remarkable antiviral potency when such drugs have been used as single drug or in combinations with other NRTIs. However, antiretroviral regimens containing TDF and ddI have been associated with a high rate of virological failure in HIV-infected naïve patients due to possible drug-interactions. The virological efficacy of this backbone in HIV-infected, HAART pre-treated subjects, is still controversial. Aim of this review is to assess the possible role that antiretroviral regimens containing TDF and ddI can have in the treatment of HIV-positive subjects, focusing on their plasmatic and/or intracellular interactions to optimize the antiretroviral efficacy and minimize the toxicities of this combination.

Antagonism between the HIV‐1 Reverse‐Transcriptase Mutation K65R and Thymidine‐Analogue Mutations at the Genomic Level

Prior virologic and biochemical studies have shown phenotypic antagonism between K65R and multiple thymidine-analogue mutations (TAMs) in site-directed mutants tested in vitro. We hypothesized, on the basis of this observed antagonism, that K65R and T215Y/F with multiple TAMs would not be selected on the same human immunodeficiency virus type 1 genome in vivo. We searched a large database of patient genotypes (n=59,262) for the frequency of K65R in combination with >or=3 TAMs as determined by standard population sequencing. K65R and multiple TAMs were rarely detected (<0.1%) in the same plasma sample. Samples with both K65R and >or=3 TAMs (n=21) were further analyzed by use of single-genome sequencing. K65R was never found on the same genome with T215F/Y and >or=2 other TAMs, except in the presence of the Q151M multiple nucleoside reverse-transcriptase inhibitor (NRTI)--resistance complex. These results indicate that antagonism between the K65R and T215Y/F pathways of NRTI resistance occurs at the genomic level. Therapy with NRTI combinations that select both pathways simultaneously may delay the emergence of NRTI resistance and prolong treatment response.

Acute Pancreatitis Associated with Different Combination Therapies in Patients Infected with Human Immunodeficiency Virus

To assess the risk of acute pancreatitis in patients receiving various combinations of protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for treatment of human immunodeficiency virus (HIV) infection. Retrospective cohort study. Ohio Medicaid claims database, January 1997-December 2002. Four thousand nine hundred seventy-two patients with HIV infection who had received at least one antiretroviral drug. Three combination regimens were evaluated: didanosine plus other antiretroviral agents, protease inhibitors plus NRTIs or NNRTIs, and NRTI combinations (no didanosine) or NRTIs plus NNRTIs. We used Cox proportional hazard regression and Kaplan-Meier plots to examine the risk for acute pancreatitis. We identified 159 (3.2%) cases of acute pancreatitis during the study period. For patients who were newly treated for HIV, the incidence of acute pancreatitis was 1.95/100 person-years. Half of these cases developed within 500 days of the start of drug therapy. Hazard ratios (HRs) for acute pancreatitis were 39-54% higher for nonwhite patients than Caucasians and 240-290% higher for symptomatic versus nonsymptomatic patients. Hazard ratios also were significantly associated with increased age, liver injuries (HR 2.94, 6.73), and cardiovascular diseases (HR 1.68, 2.36), respectively, for both newly treated and previously diagnosed patients with HIV. The risk for patients receiving either protease inhibitors plus an NRTI or an NNRTI, or NRTI plus NNRTI combinations was not significantly different from the risk associated with didanosine combination therapy (p>0.10). The risk of acute pancreatitis was significantly associated with age, race, symptomatic HIV infection, and liver and cardiovascular diseases. However, risk did not differ significantly among patients with different antiretroviral regimens. Our results can be used by the medical community to enhance patient safety and minimize costly adverse drug reactions among patients with HIV infection.

The role of nucleoside and nucleotide reverse transcriptase inhibitor backbones in antiretroviral therapy.

Several dual nucleoside reverse transcriptase inhibitor (NRTI) combinations provide efficacy when combined with a 3rd agent. However, there are a number of issues with current NRTI and nucleotide reverse transcriptase inhibitor (NtRTI) combinations that often lead to treatment failure and limited treatment options. These issues include suboptimal potency, drug interactions, toxicities, tolerability issues, and selection of resistance mutations that confer cross-resistance. Options for simplified NRTI backbones include fixed-dose combinations and agents that allow once-daily dosing; however, once-daily treatment choices are currently limited because of a lack of data on potential combinations. This article provides an historical perspective on the use of NRTI backbones in the treatment of HIV infection and outlines the advantages and disadvantages of currently available backbone combinations. In addition, it provides a brief introduction to backbone combinations under investigation as potential options for initial therapy. In an environment where several NRTI/NtRTI backbones offer comparable efficacy, treatment decisions will increasingly be made based on toxicity, resistance, and convenience considerations.