Treatment Experience and Repeat Pregnancy Impact the Effectiveness of Non-Nucleoside Reverse Transcription Inhibitor-Highly Active Antiretroviral Therapy for the Prevention of Mother to Child Transmission of Human Immunodeficiency Virus.

Non-nucleoside reverse transcription inhibitor (NNRTI)-containing antiretroviral therapy (ART) for the prevention of mother to child transmission (PMTCT) of human immunodeficiency virus (HIV) has led to dramatic reductions in perinatal HIV infection in resource-constrained settings. Nonetheless, PMTCT programs are complicated by repeat pregnancies, in which long-term or repeat exposures to PMTCT regimens over time may lead to the acquisition of HIV drug resistance mutations, and consequent treatment failure. In this study, we retrospectively assessed the effectiveness of the NNRTI-based PMTCT protocol from 2008 to 2010 in The Bahamas National HIV/AIDS Program. We show that women who had been in repeat pregnancies and those who were already prescribed ART at conception were at increased risk of virologic failure, relative to treatment-inexperienced women and primigravida, respectively (AOR 3.1, 95% CI: 1.3-7.1, p = .008 and AOR 5.0, 95% CI: 1.8-14.1, p = .002). In addition, women undergoing treatment at conception were more likely to possess HIVDR mutations relative to treatment-naive women (AOR 447.1, 95% CI: 17.9-11,173.5, p = .001). Therefore, individual treatment history is a key metric determining the effectiveness of current and future PMTCT interventions. The implications of this to PMTCT programmatic success in light of the most recent WHO guidelines are discussed.

Structure-based design of conformationally flexible reverse transcriptase inhibitors to combat resistant HIV.

Reverse transcriptase (RT) is one of the most important targets for HIV drug discovery. However, the emergence of resistant mutants has become one of the biggest challenges in HIV-1 RT drug discovery/development and attracted great research interests worldwide. It is particularly important to develop novel anti-HIV-1 RT agents that have improved potency and efficacy against the wild-type (WT) RT, but also target resistant RT forms. Previous crystal complex structures of HIV-1 RT revealed the interaction mechanism between the enzyme and inhibitors, which promoted the exploitation of inhibitor that had sufficient conformational flexibility to combat resistance. Hence, the potential flexibility of a drug should be part of the strategy considered in the early stages of designing drugs that are intended to be broadly effective against mutated targets associated with drug resistance. This review provides an overview of the state of the art in this field, including design strategies and challenges for medicinal chemists.

Antiretroviral rounds. Too many options?

We asked three experts which antiretroviral regimen they would recommend next for a patient with triple-class resistance and low viremia--and got three different answers.

The current status of the NNRTI family of antiretrovirals used in the HAART regime against HIV infection.

Acquired immunodeficiency syndrome (AIDS) remains, after 25 years of its discovery, as one of the major threats to human life. Reverse Transcriptase is an essential enzyme for virus replication, and therefore constitutes a major target in HIV-1 therapy. Among the different types of drugs targeting RT, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) act by binding in an induced-fit allosteric pocket. In this review, we explore the several NNRTIs' structures and binding interactions, as well as their mechanisms of action. The conformational changes that they cause in RT and their effects on the topology of the active site are discussed. The emergence of mutant, resistant viruses is analysed, focussing on the mutations responsible for the loss of antiviral efficacy of NNRTIs. Explanations for the role of those mutations are presented. Emergent drugs in the pipeline, together with the underlying strategies for drug development, are also analysed.

Plasma HIV load and proviral DNA decreases after two standard antiretroviral regimens in HIV-positive patients naïve to antiretrovirals.

(i) To compare early decrease of HIV plasma viral load (pVL) after two standard combinations of highly active antiretroviral therapy (HAART). (ii) To evaluate variations of proviral HIV-DNA load on conditions of sustained pVL undetectability. Two different sub-studies of a multicentre prospective randomized controlled trial which compared two first-line HAART (i.e., zidovudine+lamivudine+lopinavir/ritonavir versus tenofovir+lamivudine+ efavirenz). Only patients enrolled at the coordinating centre (University of Brescia) were included in the two sub-studies. In the first sub-study, we calculated pVL decrease with respect to baseline at any of the following time-points: days 1, 3, 7, 14 and 28. Decreases of the pVL were compared between the two treatment groups. In the second sub-study, we analyzed variation of proviral HIV-DNA load in CD4+ T-cells from baseline to week 52 only in patients who maintained the same treatment regimen and had sustained undetectable pVL. In either studies, linear regression analysis was used to investigate what factors could influence variations of pVL and of proviral HIV-DNA load. (i) 64 patients were studied. A significant decrease of pVL was found from day 3 on, without statistically significant differences between the two study groups. However, after adjusting for possible confounders, tenofovir+lamivudine+efavirenz resulted to be associated with greater pVL decreases. (ii) 45 patients were studied. Mean proviral HIV-DNA load decreased from 1,610 (95%CI: 879-2,341) to 896 (95% CI 499-1,293) copies/10(6) cells (P=0.05). Linear regression analysis showed that the decrease of proviral DNA load during follow-up was independently and inversely correlated with age. Further studies are needed to compare pVL decay between antiretroviral regimens and assess whether proviral HIV-DNA load is a surrogate marker of treatment effectiveness.

Haemostatic activation in HIV infected patients treated with different antiretroviral regimens.

HIV infected patients treated with highly active antiretroviral therapy (HAART) may be at increased risk of cardiovascular events, particularly if based upon the use of protease inhibitors (PI). We investigated the haemostatic markers of cardiovascular risk in 115 HIV infected subjects, divided into four groups : 1) patients naïve to antiretroviral therapy (Naïve; n=34 patients), or subjects that had been on a stable combination therapy for > or =12 months with either: 2) double reverse transcriptase nucleoside analogue inhibitors therapy (2NRTI; n=26), 3) 2NRTI backbone plus a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI; n=27), and 4) on a PI based regimen (PI; n=28). Forty-four healthy subjects were included as controls. Naïve as well as 2NRTI and NNRTI differed from controls for higher F1+2 (P<.0001) and FVII (P<.007) levels. When comparing PI patients with controls we observed significantly higher levels of Fbg (P=.035), FVII (P<.0001), TM (P<.0089), vWF (P=.009), and F1+2 (P<.0001). The only difference observed among the 4 groups of HIV infected patients was a significantly lower level of F1+2 in PI as compared with NNRTI patients (P=.05) At least one abnormal result was observed in > or = 90.6% of HIV infects groups, vs 43.2% of controls (P<.0001 in all cases). In conclusion, a) HIV infection per se may alter the haemostatic markers of cardiovascular risk, b) minor differences were observed among the different classes of HIV infected patients, namely between NNRTI and PI treated patients.

Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy.

BACKGROUND: Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. METHODS: We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. RESULTS: Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. CONCLUSIONS: Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.

Advances in pharmacogenomics of antiretrovirals: an update.

Recent developments in the pharmacogenomics of antiretroviral drugs provide new prospects for predicting the efficacy of treatment and potential adverse effects. HIV/AIDS is a serious but treatable infectious disease, yet current treatment is limited by high rates of adverse drug reactions and development of resistance due to suboptimal drug concentrations in a significant proportion of patients. Antiretroviral therapy is especially suitable for pharmacogenomic investigation as both drug exposure and treatment response can be quantified and certain adverse effects can be assessed with validated measures. Additionally, there is increasing knowledge of the pharmacokinetics and dynamics of antiretroviral drugs, and some candidate genes implicated in the metabolism, transport and adverse effects have been identified. However, recent studies of the association of particular genes and their genetic variants with HIV management and adverse drug reactions have not provided unifying conclusions. This article reviews the most recently published work and summarizes the state of research in this area. Future directions for research and the application of this technology to the clinical practice of individualizing treatment for HIV management are discussed.

Discontinuation of non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy due to nucleoside analogue reverse transcriptase inhibitor-related metabolic toxicity.

We aimed to evaluate the reasons for, and timing of, treatment changes in a cohort of treatment-naïve patients initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing highly active antiretroviral therapy (HAART). All 268 patients initiating these regimens between January 1998 and September 2003 were included. Median follow up was 103 weeks. The median baseline CD4 count was 150 cells/microL. Seven patients (3%) died and 155 patients (58%) experienced a change in their HAART regimen. The reasons drugs were discontinued included toxicity in 106 patients (40%), virological failure in 21 (8%), other reasons in 23 (9%) and unknown reasons in five (2%). Fifty-one patients (19%) stopped NRTIs due to peripheral neuropathy, hyperlactataemia, lipoatrophy, lipodystrophy or myelosuppression, and these events were more likely in patients with baseline CD4 count below the median (P = 0.039). The findings in this cohort show that discontinuation of HAART was commonly due to toxicity, especially metabolic or mitochondrial toxicity in those with lower baseline CD4 count.

[Hypersensitivity reactions to antiretroviral agents in HIV-infected patients]. / Reacciones de hipersensibilidad a antirretrovirales en pacientes con infección por el virus de la inmunodeficiencia humana.

Drug hypersensitivity reactions in the HIV-positive patient are a major problem in management of these patients and, nowadays the antiretroviral agents are the main cause of those reactions, exceeding cotrimoxazole. The present review focuses on immunologic reactions that have been reported associated with antiretroviral agents. We have reviewed case reports on Medline(R) to September 2005. Evidence that these reactions are immune mediated is largely based on the typical symptomatology and few studies have been done to determine the pathogenesis mechanisms. The clinical management of this type of reactions is complex because of differential diagnosis and of potential severity. It is essential that research is now carried out into the pathogenic mechanisms and so, we shall be able to offer an efficacious protocol to manage these situations.

Molecular mechanism by which the K70E mutation in human immunodeficiency virus type 1 reverse transcriptase confers resistance to nucleoside reverse transcriptase inhibitors.

The K70E mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has become more prevalent in clinical samples, particularly in isolates derived from patients for whom triple-nucleoside regimens that include tenofovir (TNV), abacavir, and lamivudine (3TC) failed. To elucidate the molecular mechanism by which this mutation confers resistance to these nucleoside RT inhibitors (NRTI), we conducted detailed biochemical analyses comparing wild-type (WT), K70E, and K65R HIV-1 RT. Pre-steady-state kinetic experiments demonstrate that the K70E mutation in HIV-1 RT allows the enzyme to discriminate between the natural deoxynucleoside triphosphate substrate and the NRTI triphosphate (NRTI-TP). Compared to the WT enzyme, K70E RT showed 2.1-, 2.3-, and 3.5-fold-higher levels of resistance toward TNV-diphosphate, carbovir-TP, and 3TC-TP, respectively. By comparison, K65R RT demonstrated 12.4-, 12.0-, and 13.1-fold-higher levels of resistance, respectively, toward the same analogs. NRTI-TP discrimination by the K70E (and K65R) mutation was primarily due to decreased rates of NRTI-TP incorporation and not to changes in analog binding affinity. The K65R and K70E mutations also profoundly impaired the ability of RT to excise 3'-azido-2',3'-dideoxythymidine monophosphate (AZT-MP) and other NRTI-MP from the 3' end of a chain-terminated primer. When introduced into an enzyme with the thymidine analog mutations (TAMs) M41L, L210W, and T215Y, the K70E mutation inhibited ATP-mediated excision of AZT-MP. Taken together, these findings indicate that the K70E mutation, like the K65R mutation, reduces susceptibility to NRTI by selectively decreasing NRTI-TP incorporation and is antagonistic to TAM-mediated nucleotide excision.

Evolving simplified treatment strategies for HIV infection: the role of a single-class quadruple-nucleoside/nucleotide regimen of trizivir and tenofovir.

Simplified antiretroviral regimens have been developed with the aim of improving treatment adherence and quality of life of HIV-infected patients. The single-class triple-nucleoside reverse transcriptase inhibitor combination has contributed to the improvement of the management of HIV infection, especially in patients with adherence problems and special groups of the patient population. Such a regimen remains an alternative option because of lower virological efficacy compared with the preferred multiclass antiretroviral regimens. However, recently, a nucleoside reverse transcriptase inhibitor abacavir/lamivudine/zidovudine plus tenofovir has been investigated in both antiretroviral-naive patients and in heavily pre-treated patients, as well in the setting of simplification/switching strategies. This experimental combination could be a safe and attractive option that offers the advantages of limited toxicity, few drug interactions and the use of future treatment options with new drugs, especially for patients in later stages of infection.

Efavirenz trough levels are not associated with virological failure throughout therapy with 800 mg daily and a rifampicin-containing antituberculosis regimen.

OBJECTIVES: To assess the safety and efficacy of efavirenz 800 mg daily in HIV-infected patients with tuberculosis receiving a rifampicin-containing regimen and to analyse whether a relationship exists between efavirenz Cmin and its virological efficacy. METHODS: Prospective, open-labelled study including HIV-infected patients on rifampicin and efavirenz 800 mg daily. Treatment adherence, adverse events (AEs), HIV-RNA levels, CD4 cell counts and efavirenz Cmin during and after finishing rifampicin treatment were evaluated. RESULTS: Eighty patients met the inclusion criteria. A permanent drug withdrawal due to AEs occurred in 10 patients, 5 attributable to efavirenz, and 10 patients were lost to follow-up before the third month. Efavirenz Cmin levels with 800 mg plus rifampicin were similar to those with 600 mg after withdrawing rifampicin. Sixty patients were included in the efficacy analysis, eight experiencing virological failure. No relation was observed between the rate of virological failure and efavirenz Cmin, previous antiretroviral treatment or not, baseline CD4 counts or RNA-HIV. The only variable related to virological failure was irregular adherence [odds ratio, 81 (95% CI: 5-1280); P=0.002]. CONCLUSIONS: Given the lack of a demonstrated relationship between efavirenz Cmin and its efficacy in our study, a firm recommendation cannot be made to always increase the dose to 800 mg/day when concomitantly given with rifampicin, but it seems a cautious approach to maintain the same efavirenz plasma levels as with 600 mg daily without rifampicin. Patients weighing<55 kg and also black, Asian and Hispanic subjects in whom genetic-based increased efavirenz plasma levels and rates of AEs have been observed may benefit from a dose of 600 mg.

5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family.

2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F(2)-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C(2)-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C(2)-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C(5)-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C(2)-NH side chain and the presence of two methyl groups (at C(5) and benzylic positions) being crucial for high antiviral action.

HIV reverse transcriptase structures: designing new inhibitors and understanding mechanisms of drug resistance.

HIV reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. The selection of drug-resistant HIV is a key problem in the continued treatment of the infection and thus new drugs are required. A significant body of information consisting of HIV-1 RT crystal structures with bound inhibitors has become available during the past several years, and, increasingly, such data will be of use in developing novel inhibitors. Two examples of crystal structures of HIV-1 RT with bound inhibitors have been published recently, one with the non-nucleoside CP94707 and the second with the nucleotide analogue drug tenofovir. Such structures will help the design of new drugs and improve our understanding of the mechanisms of resistance.

Classification and regression trees--studies of HIV reverse transcriptase inhibitors.

In this paper, the application of Classification And Regression Trees (CART) is presented for the analysis of biological activity of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). The data consist of the biological activities, expressed as pIC50, of 208 NNRTIs against wild-type HIV virus (HIV-1) and four mutant strains (181C, 103N, 100I, 188L) and the computed interaction energies with the Reverse Transcriptase (RT) binding pocket. CART explains the observed biological activity of NNRTIs in terms of interactions with individual amino acids in the RT binding pocket, i.e., the original data variables.

[Development of new reverse transcriptase inhibitors].

Highly active anti-retroviral therapy(HAART) using two or more reverse transcriptase inhibitors(RTIs) and protease inhibitors, has dramatically improves the quality of life and survival of patients infected with human immunodeficiency virus(HIV). RTIs are categorized by their mechanism of action, into two groups, nucleoside(N) and non-nucleoside(NN) RTIs. However, resistant HIV variants against NRTIs and/or NNRTIs including multi-drug resistant, emerge after the prolonged therapy. To suppress the replication of such resistant variants, numerous anti-HIV drugs have been developed. In this review, the mechanisms of action and characters of the major drugs in clinical or under preclinical are described.