Class Of Non-nucleoside Reverse Transcriptase Inhibitors Research Articles

Reverse Transcriptase Inhibitors as Microbicides

The CAPRISA 004 study in South Africa has accelerated the development of vaginal and rectal microbicides containing antiretrovirals that target specific enzymes in the reproduction cycle of HIV, especially reverse transcriptase inhibitors (RTI). In this review we discuss the potential relevance of HIV-1 RTIs as microbicides, focusing in the nucleotide RTI tenofovir and six classes of nonnucleoside RTIs (including dapivirine, UC781, urea and thiourea PETTs, DABOs and a pyrimidinedione). Although tenofovir and dapivirine appear to be most advanced in clinical trials as potential microbicides, several issues remain unresolved, e.g., the importance of nonhuman primates as a "gatekeeper" for clinical trials, the emergence and spread of drug-resistant mutants, the combination of microbicides that target different phases of viral reproduction and the accessibility to microbicides in low-income countries. Thus, here we discuss the latest research on RTI as microbicides in the light of the continuing spread of the HIV pandemic from the point of view of medicinal chemistry, virological, and pharmaceutical studies.

Drug Resistance Profiles Among HIV-1–Infected Children Experiencing Delayed Switch and 12-Month Efficacy After Using Second-Line Antiretroviral Therapy: An Observational Cohort Study in Rural China

To analyze the genotypic resistance profiles of HIV-infected children from rural China who were experiencing virologic failure to first-line antiretroviral therapy regimens and to evaluate 1-year regimen efficacy after switching to second-line therapy. A prospective cohort study was performed. Seventy-six children from the first rural pilot program with HIV viral load >1000 copies per milliliter on 2 consecutive occasions were studied. We analyzed genotype results and observed second-line therapy efficacy to 12 months. After 33.1 (23.3, 41.1) months on first-line treatment after enrollment into national program, 98.7% of genotyped patients developed high-level resistance to nevirapine and 81.6% of patients had high-level resistance to efavirenz. High-level resistance to lamivudine was observed in 82.9%, followed by 57.9% for stavudine and 52.6% for zidovudine. In the nonnucleoside reverse transcriptase inhibitor class, the most common mutations were K103N/S at 50% and Y181C/I at 48.7%. M184V/I was the most common nucleoside reverse transcriptase inhibitor resistance mutation at 77.6%, the mutation rate for ≥3 thymidine analogue mutations, Q151M, and K65R were 33%, 12%, and 9%, respectively. After 12 months of boosted protease inhibitor-based second-line therapy, CD4 counts had on average increased 256 cells per cubic millimeter compared with switch baseline and 83.1% of patients had undetectable viral loads (<50 copies/mL). HIV-1-infected children who continued their first-line regimen regardless of virologic failure harbored multiple resistance mutations. Although the extent of resistance to nucleoside reverse transcriptase inhibitor class drugs would be expected to limit subsequent treatment options, the current second-line regimen remained effective during a 1-year observational period.

Is lower serum 25-hydroxy vitamin D associated with efavirenz or the non-nucleoside reverse transcriptase inhibitor class?

Is lower serum 25-hydroxy vitamin D associated with efavirenz or the non-nucleoside reverse transcriptase inhibitor class?

Do nevirapine and efavirenz affect vitamin D homeostasis similarly?

Pasquet and colleagues observed, in keeping with previous studies [1–5], an association between exposure to non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing antiretroviral therapy and vitamin D deficiency in their cross-sectional cohort study [6]. Their study was insufficiently powered to look at individual NNRTI, and no significant association between vitamin D deficiency and either efavirenz or nevirapine was observed. However, comparable crude and adjusted coefficients for efavirenz and nevirapine led the authors to question whether the observed association between vitamin D deficiency and NNRTI reflects an NNRTI class effect rather than a phenomenon restricted to efavirenz as reported by ourselves [2]. An increasing body of evidence supports an association between efavirenz and 25-hydroxy-vitamin D [25(OH)D] deficiency [2,7,8]. Initiation of efavirenz appears to be consistently associated with reductions in 25(OH)D levels [5,6,9], and preliminary data suggest that etravirine and efavirenz may have similar effects on 25(OH)D homeostasis [10]. Although we found an association between efavirenz use and severe 25(OH)D deficiency [adjusted odds ratio (aOR) 2.0 (1.5, 2.7)] as well as raised alkaline phosphatase levels [aOR 1.6 (1.02, 2.4)], nevirapine use appeared to be protective against 25(OH)D deficiency [aOR 0.6 (0.3, 1.5)] and raised alkaline phosphatase [aOR 0.5 (0.3, 0.9)] in multivariate models adjusted for sex, ethnicity, season and CD4 cell count [2], and no association between nevirapine and 25(OH)D deficiency or insufficiency was observed in the SUN cohort [7]. Whilst comparable reductions in 25(OH)D have been observed in patients initiating efavirenz and nevirapine [5], the small sample size of this study precluded inclusion of individual NNRTI in multivariate analyses. Furthermore, no significant reductions in 25(OH)D from baseline were observed in 18 patients who initiated zidovudine, lamivudine and nevirapine [11] and in 27 patients who commenced nevirapine together with ritonavir-boosted lopinavir [12]. Whereas the effects of antiretroviral treatment-associated reductions in 25(OH)D on bone remain to be defined, a trend toward lower bone mineral density (BMD) with efavirenz and higher BMD with nevirapine has been reported in HIV infected children [13]. In clinical practice, efavirenz and nevirapine are preferentially used in some patients and avoided in others; associations with either NNRTI in observational cohort studies may thus be subject to channelling bias. For example, nevirapine may be the drug of choice for premenopausal African women with low CD4 cell counts and efavirenz for white men with preserved CD4 cell counts. As black ethnicity, female sex and low nadir CD4 cell count were all independently associated with severe vitamin D deficiency in our study [2], an inability to adjust for these factors may lead to a spurious association between nevirapine and vitamin D deficiency in cross-sectional studies. On the contrary, 61% of our patients were black, and it is possible that the effects of nevirapine on 25(OH)D homeostasis differ by ethnicity [14]. Of note, the two studies that reported a decline in 25(OH)D with nevirapine or an association between nevirapine and vitamin D deficiency predominantly included white men with preserved CD4 cell counts, did not adjust for sex, ethnicity and nadir CD4 cell count, and showed that 25(OH)D levels in black patients were minimally affected by antiretroviral treatment [5,6]. The consistent finding that vitamin D deficiency is very common in HIV-infected patients raises more important questions than which antiretroviral drug(s) may be implicated, namely what is the clinical significance of low 25(OH)D and is there any benefit from vitamin D supplementation? Vitamin D deficiency in the general population has been associated with numerous adverse health outcomes including cardiovascular disease, cancer, infection, osteopenia and fractures [15]. HIV infection is associated with an increased risk of (opportunistic) infections, cancer [16] and low BMD [17], and exposure to antiretroviral therapy with an increased risk of cardiovascular events [18] and further reductions in BMD [19]. As the greatest reductions in BMD are observed in patients who initiate antiretroviral therapy [12,20–21], the contribution of vitamin D deficiency and the potential of vitamin D supplementation to reduce this initial bone loss deserve further study. An effect of ethnicity and specific antiretrovirals, especially efavirenz and tenofovir, should be considered in the design of these studies. Acknowledgements None of the authors has any financial or personal relationships with people or organizations that could inappropriately influence this work, although all authors have, at some stage in the past, received funding from a variety of pharmaceutical companies for travel grants. In addition, F.A.P. has received research funding, speaking engagements or consultancy fees from GlaxoSmithKline, ViiV, Tibotec, Bristol-Meyers Squibb and Gilead Sciences.

Relative bioavailability of two formulations of nevirapine 200-mg tablets in healthy Chinese male volunteers: A single-dose, randomized-sequence, open-label, two-way crossover study

Background: Nevirapine was the first member of the nonnucleoside reverse transcriptase inhibitor class to be approved for the treatment of HIV infection. It binds directly to the allosteric site on the reverse transcriptase and inhibits the activity of both RNA- and DNA-dependent DNA polymerases. Objective: This study compared the pharmacokinetics and relative bioavailability of a test and reference formulation of nevirapine 200-mg tablets after single oral doses in healthy Chinese men to meet regulatory criteria for marketing of the new generic formulation. Methods: This single-dose, randomized-sequence, open-label, 2-way crossover study was conducted at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Healthy male Chinese volunteers were randomized in a 1∶1 ratio to receive a single 200-mg (3.2-mg/kg) tablet of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Concentrations of nevirapine were assayed using an HPLC-UV method. For analysis of nevirapine pharmacokinetic parameters, blood samples were obtained before dosing and at regularly scheduled intervals over 168 hours after administration. The 2 formulations would be assumed to be bioequivalent for regulatory purposes if the 90% CIs for the log-transformed ratios of nevirapine AUC and C max were within the range established by the US Food and Drug Administration (0.80–1.25). Tolerability was evaluated throughout the study based on vital signs, physical examinations, 12-lead ECGs, and subject interviews concerning adverse events (AEs). Results: Twenty Chinese male subjects were enrolled in and completed the study. Their mean age was 23 years (range, 21–25 years), mean weight was 63 kg (range, 56–70 kg), and mean height was 171 cm (range, 166–176 cm). No period or sequence effect was observed. The mean (SD) t ½ was 38.12 (2.23) hours for the test tablet and 36.79 (5.06) hours for the reference tablet; T max was 3.1 (0.7) and 3.0 (0.7) hours, respectively; C max was 2.52 (0.31) and 2.60 (0.48) mg · L −1; AUC 0–168 was 155.66 (22.41) and 150.66 (22.11) mg · h · L −1; and AUC 0–∞ was 163.30 (22.88) and 157.75 (22.87) mg · h · L −1. Mean relative bioavailability was 103.6% (8.6%). The 90% CIs for the log-transformed ratios of C max (93.51–102.13) and AUC 0–168 ( 99.84–106.74) were within the predetermined range for the assumption of bioequivalence. One subject reported mild headache after receiving the test formulation; the relationship of this AE to study drug was considered uncertain. No serious or clinically significant AEs were observed or reported during the study. Conclusions: In this single-dose study in healthy fasted Chinese males, the test tablet met the regulatory criterion for assumption of bioequivalence to the reference tablet. Both formulations were well tolerated in the population studied. SFDA registration no: 2009L04358.

Clinical Management of Treatment-Experienced, HIV/AIDS Patients in the Combination Antiretroviral Therapy Era

Despite the success of combination antiretroviral therapy (ART) in improving clinical outcomes, treatment failure remains a significant challenge, particularly for highly treatment-experienced patients. This review evaluates current issues in the management of HIV-infected, treatment-experienced patients. It may provide guidance in selecting active, tolerable drug combinations that promote a reasonable quality of life, full adherence and a durable treatment response. Current treatment guidelines and clinical trial data were reviewed to identify reasons for treatment failure and to summarize therapy options for treatment-experienced and highly treatment-experienced patients. Current treatment options include nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and inhibitors of viral fusion, entry and integration. The use of NRTIs may be limited by resistance and short- and long-term toxicities. Resistance has restricted the NNRTI class with cross-resistance preventing their sequential use. Etravirine, a next-generation NNRTI, however, demonstrates effective virological suppression in patients with baseline NNRTI resistance. Boosted PIs are key components of ART for treatment-experienced patients. The newer boosted PIs tipranavir and darunavir have demonstrated impressive activity in patients with resistance to NRTIs, NNRTIs and PIs, as well as in less treatment-experienced patients for darunavir. The fusion inhibitor enfuvirtide has demonstrated efficacy in heavily treatment-experienced patients, although injection-site reactions can be problematical. The recently approved integrase inhibitor raltegravir has also shown impressive potency and tolerability in highly treatment-experienced patients. Finally, the entry inhibitor maraviroc has also been approved recently, although its use is somewhat limited by the need for HIV tropism testing. The availability of potent next-generation PIs, NNRTIs, integrase and entry-inhibitors may offer improved therapy for treatment-experienced patients, including those with multiresistant virus. These new drugs may reduce HIV immunological and clinical progression and in doing so may also reduce treatment costs.

Design, Synthesis, and Evaluation of Diarylpyridines and Diarylanilines as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

On the basis of the structures and activities of our previously identified non-nucleoside reverse transcriptase inhibitors (NNRTIs), we designed and synthesized two sets of derivatives, diarylpyridines (A) and diarylanilines (B), and tested their anti-HIV-1 activity against infection by HIV-1 NL4-3 and IIIB in TZM-bl and MT-2 cells, respectively. The results showed that most compounds exhibited potent anti-HIV-1 activity with low nanomolar EC50 values, and some of them, such as 13m, 14c, and 14e, displayed high potency with subnanomolar EC50 values, which were more potent than etravirine (TMC125, 1) in the same assays. Notably, these compounds were also highly effective against infection by multi-RTI-resistant strains, suggesting a high potential to further develop these compounds as a novel class of NNRTIs with improved antiviral efficacy and resistance profile.

Evolving patterns of HIV‐1 transmitted drug resistance in Poland in the years 2000–2008

The aim of the study was to determine the rate of transmission of drug resistant human immunodeficiency virus-1 (HIV-1) variants among therapy-naïve HIV positive patients in Poland in the year 2008, to compare the data with the results from the years 2000 to 2007 and to monitor patterns of HIV-1 subtypes present in Polish population and their evolution. Complete protease and part of reverse transcriptase regions were sequenced from the sera of patients directed to the laboratory for drug resistance testing. The Stanford's HIVdb program was used for the interpretation of results and subtyping. The variants scoring at least "intermediate resistance" for at least one drug were considered as resistant. The results obtained were compared to those obtained in the years 2000-2007. A total of 95 patients were enrolled in the 2008 study. Homosexual transmission of infection was documented in more than 55% of all cases. The overall prevalence of transmitted drug resistance (TDR) was 5.3% (3.9% in 2007, 5.8% in 2006, and 14.1% in the years 2002-2005). The study from the years 2000 to 2001 revealed 28.7% prevalence. Preliminary analysis of the first half of 2009 shows the ratio of 7.8%. In four (4.2%) cases drug resistance was associated with protease inhibitors class, in one case (1.1%) with resistance to non-nucleoside reverse transcriptase inhibitors class. In four cases (4.2%) non-B subtype was identified (C, G, CRF01_AE, CRF02_AG). An increase of percentage of drug resistant mutants-from 3.9% (2007) to 5.3% (2008)-was recognized. In this study, TDR was limited to single classes of antiretroviral drugs. HIV-1 subtype B prevails in Poland.

Progress of Bis(heteroaryl)piperazines (BHAPs) as Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) against Human Immunodeficiency Virus Type 1 (HIV-1)

Since the first case of acquired immunodeficiency syndrome (AIDS) was reported in 1981, AIDS, as the global disease affecting 33.2 million people in 2007, has always been an unsolved problem worldwide. Reverse transcriptase (RT) is a crucial enzyme in the life cycle of human immunodeficiency virus type 1 (HIV-1), and thereby has been the prime drugs target for antiretroviral (ARV) therapy against AIDS. To date, two classes of RT inhibitors (RTIs), e.g., nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), and a lot of compounds tested as RTIs have been described. To our knowledge, bis(heteroaryl)piperazines (BHAPs) have been considered as one class of promising NNRTIs, such as structurally and chemically related NNRTI delavirdine, which was approved by the U. S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection in 1997. In this mini-review, we make attempts to report the progress of synthesis and structure-activity relationship (SAR) of BHAPs, in the meantime, the synergistic inhibition of HIV-1 replication by combining delavirdine with other HIV-1 inhibitors is also discussed. It will pave the way for the design and development of BHAPs as anti-HIV-1 agents in AIDS chemotherapy in the future.

Etravirine for HIV-I: Addressing the Limitations of the Nonnucleoside Reverse Transcriptase Inhibitor Class

Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) specifically designed for treatment-experienced patients infected with HIV-1. Its unique strength over other, older agents in the NNRTI class is its higher genetic barrier to resistance, allowing it to be used effectively in patients with limited treatment options. The arrival of ETR in the market has made sequential NNRTI therapy possible for the first time in the history of HIV treatment, as it can maintain virologic activity in the presence of certain (and sometimes multiple) NNRTI mutations. Although ETR has demonstrated efficacy in treatment-experienced and NNRTI-resistant patients in large trials, further analyses on its resistance profile are ongoing. As new data emerge on the weighting of ETR's resistance-associated mutations (RAMs), investigators and clinicians will no doubt be able to further characterize its specific place in the HIV treatment armamentarium.

Design, synthesis, and structure–activity relationships of 1,3-dihydrobenzimidazol-2-one analogues as anti-HIV agents

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become very important components in the antiretroviral combination therapies used to treat HIV. Recently, our group identified some 1,3-dihydrobenzimidazol-2-one derivatives and their sulfones as a potent and novel class of NNRTIs. We herein report the synthesis and biological evaluation of the new compounds in which different structural modifications have been introduced in order to investigate their effects on RT inhibition.

Sulfanyltriazole/tetrazoles: A Promising Class of HIV-1 NNRTIs

There is an urgent need for the design and development of new and safer drugs for the treatment of human immunodeficiency virus (HIV) infection, specifically active against drug-resistant viral strains. Recently, sulfanyltriazole/tetrazole derivatives were reported as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), with low nanomolar intrinsic activity against RT and submicromolar antiviral activity in HIV infected cells. In this review, the structural modifications, SAR analysis and docking studies of sulfanyltriazole/tetrazoles HIV-1 NNRTIs are discussed, and other interesting NNRTIs with the same or similar pharmacophore as the sulfanyltriazole/tetrazole derivatives are also presented and analyzed for their in SAR.

Etravirine: A Second-Generation Nnrti for Treatment-Experienced Adults with Resistant HIV-1 Infection

Etravirine, a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), was approved in the USA in January, 2008, with approval in Europe expected later this year. It is dosed at 200 mg (two 100 mg tablets) twice daily foll owing a meal. It is approved for treatment of HIV-1 infection in adults failing a stable antiretroviral regimen with resistance to other NNRTIs and other antiretroviral agents. Etravirine is active against HIV with single mutations in the reverse transcriptase (e.g., K103N) that confer class resistance to first-generation NNRTIs. Clinical efficacy in Phase III trials has been demonstrated for up to 48 weeks of follow-up. In these Phase III trials, rash was the only adverse event that was significantly more prevalent with etravirine than with placebo. Etravirine has a tolerability and safety profile comparable to placebo with the exception of rash. Rash was generally grade 1 or 2, was not associated with prior NNRTI-related rash, was more common in women than in men, appeared a median of 12 days after treatment initiation and resolved spontaneously with continued therapy. Etravirine is the first agent in the NNRTI class that can be used for HIV-1 virus with resistance to other NNRTIs owing to a higher genetic barrier to resistance.

The Structure-Activity Relationships of 2,4(1H,3H)-pyrimidinedione Derivatives as potent HIV type 1 and type 2 inhibitors

Since the discovery of the 2,4 (1H,3H)-pyrimidinediones as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase (RT) this class of compounds has yielded a number of N-1 acyclic substituted pyrimidinediones with substantial antiviral activity, which is highly dependent upon their molecular fit into the binding pocket common to this inhibitory class. We have specifically examined the structure activity relationships of compounds with chemical modification made by substituting homocyclic rather than acyclic moieties at N-1 of the pyrimidinedione. Seventy-four compounds were synthesized and evaluated for antiviral activity against HIV-1 and HIV-2. The homocyclic modifications resulted in compounds with significant activity against both HIV-1 and HIV-2, suggesting these compounds represent a new class of non-nucleoside RT inhibitors. The structure-activity relationship (SAR) evaluations indicated that cyclopropyl, phenyl and 1- or 3-cyclopenten-1-yl substitutions at the N-1 of the pyrimidinedione, the addition of a methyl linker between the cyclic moiety and the N-1 and the addition of a benzoyl group at the C-6 of the pyrimidinedione had the greatest contribution to antiviral activity. Five pyrimidinedione analogues with therapeutic indexes (TIs) > 450,000 and a specific analogue (1-cyclopropylmethyl-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4(1H,3H)-pyrimidinedione), which exhibited a TI of > 2,000,000, were identified. None of the analogues were cytotoxic to target cells at the highest in vitro test concentration, which is the upper limit of compound solubility of the analogues in aqueous solution. Thus, we have identified a series of pyrimidinediones with substantially improved antiviral efficacy and range of action and with significantly reduced cellular cytotoxicity.

Treatment resistance after sequential interruption of a non-nucleoside reverse transcriptase inhibitor-based regimen

Stopping HIV therapy may reduce costs and side effects, but carries the risk of increased immune suppression and the emergence of resistance. To investigate this issue, the Strategies for Management of Anti-Retroviral Therapy (SMART) randomized study was conducted to compare the long-term consequences of two antiretroviral management strategies: continuous therapy versus scheduled treatment interruption. The study was interrupted for harm [1]. Non-nucleoside reverse transcriptase inhibitors (NNRTI), namely efavirenz and nevirapine, are frequently part of recommended combinations for the treatment of HIV-1 infection. NNRTI, however, have a low genetic barrier to the selection of resistance, and a single key mutation in the NNRTI-specific pocket site or in the surrounding domain of reverse transcriptase poses a major therapeutic problem for this class [2]. If administered as monotherapy, NNRTI selects for resistant mutants within one week, most commonly those harbouring the K103N or Y181C mutation, which confer cross-resistance to other approved drugs in the NNRTI class. The K103N mutation appears to have little effect on the replicative capacity of HIV-1, allowing variants to persist long after nevirapine therapy has been stopped. Resistance mutations have been observed after exposure to a single dose of nevirapine [3]. For the reasons described above, the SMART protocol recommended that NNRTI should be discontinued 7 days before nucleoside reverse transcriptase inhibitor (NRTI) backbone. Here we report the case of a patient who was included in the SMART study and who developed resistance after sequentially stopping a nevirapine-containing regimen. Case report A 44-year-old Caucasian man, diagnosed HIV-1 positive in 1994, was enrolled in SMART in March 2005 in the scheduled interruption treatment group. At this time, the CD4 lymphocyte count was 896 cells/μl (36%, CD4/CD8 0.87) and RNA HIV was undetectable (< 50 copies/ml). The nadir CD4 cell count was 2 cells/μl in 1995. He had no history of opportunistic infections. Lamivudine (300 mg once a day) was initiated in 1995. In April 1996, the patient received indinavir (2400 mg/day), lamivudine (300 mg/day) and didanosine (400 mg/day). In March 1998, indinavir was stopped and switched to ritonavir (1000 mg/day). NNRTI with efavirenz (600 mg/day) substituted ritonavir in May 1999 for simplification. Efavirenz was switched to nevirapine (400 mg/day) in August 2003. Our case had had undetectable RNA HIV of less than 400 copies/ml since 1996 and less than 50 copies/ml since 1999 in all 3-month routine follow-ups until May 2005. According to the protocol, he stopped nevirapine on 12 April 2005 and stopped didanosine and lamivudine on 19 April 2005. His CD4 lymphocyte count decreased (Table 1).Table 1: Immunovirological history according to antiretroviral therapy.In October 2005, the CD4 lymphocyte count was 129 cells/μl and according to the SMART protocol, the treatment was reinitiated with cotrimoxazole for the prevention of opportunistic infections. We chose to restart the same treatment with didanosine (400 mg), lamivudine (300 mg) and nevirapine (200 mg once a day for 14 days and then 200 mg twice a day). An HIV-1 genotypic resistance test for each drug was performed in March 2006, and revealed Y181C and M184I reverse transcriptase mutations, which confer drug resistance to NNRTI and lamivudine, respectively. The NRTI backbone was changed and lopinavir–ritonavir replaced nevirapine with virological control. NNRTI is an attractive class of treatment for HIV-1 infection because of its good bioavailability, long half-life and convenient administration. It should be stressed that the necessity to stop NNRTI is not uncommon in clinical practice, because of adverse events, concomitant conditions or other patient non-medical related factors. Two factors have been associated with the emergence of NNRTI resistance: previous suboptimal treatment [4] and treatment interruptions [5,6]. Both were present in our case, and the emergence of resistance occurred despite sequential treatment interruption. Even with relatively long-term virological control, antiretroviral therapy cessation clearly triggered resistance in this case. Our report has potential important implications when stopping an NNRTI, in particular in patients with previous NRTI suboptimal therapy. The current protocol for NNRTI cessation requires that two NRTI alone are sufficient to control RNA-HIV replication during the 7 days of NNRTI clearance, and thus avoid HIV replication in the presence of subtherapeutic NNRTI levels [7]. This may not be possible in patients with previous suboptimal NRTI treatment, suggesting the presence of archived resistant viruses, even in the case of long-term virological control. We suggest that in this setting, protease inhibitors should replace NNRTI in addition to NRTI, during the delay of NNRTI clearance (which remains to be determined) in order to preserve this potent antiretroviral option. Acknowledgement We wish to dedicate our work to our SMART volunteer who consented to make a sacrifice of himself for the good of others. The authors also thank Pascale Goubin for data management.

Depressive Symptoms Predict Increased Incidence of Neuropsychiatric Side Effects in Patients Treated with Efavirenz

Depressive Symptoms Predict Increased Incidence of Neuropsychiatric Side Effects in Patients Treated with Efavirenz

Anti-Human Immunodeficiency Virus Type 1 Activity of the Nonnucleoside Reverse Transcriptase Inhibitor GW678248 in Combination with Other Antiretrovirals against Clinical Isolate Viruses and In Vitro Selection for Resistance

GW678248, a novel nonnucleoside reverse transcriptase inhibitor, has been evaluated for anti-human immunodeficiency virus activity in a variety of in vitro assays against laboratory strains and clinical isolates. When GW678248 was tested in combination with approved drugs in the nucleoside and nucleotide reverse transcriptase inhibitor classes or the protease inhibitor class, the antiviral activities were either synergistic or additive. When GW678248 was tested in combination with approved drugs in the nonnucleoside reverse transcriptase inhibitor class, the antiviral activities were either additive or slightly antagonistic. Clinical isolates from antiretroviral drug-experienced patients were selected for evaluation of sensitivity to GW678248 in a recombinant virus assay. Efavirenz (EFV) and nevirapine (NVP) had > or = 10-fold increases in their 50% inhibitory concentrations (IC50s) for 85% and 98% of the 55 selected isolates, respectively, whereas GW678248 had a > or = 10-fold increase in the IC50 for only 17% of these isolates. Thus, 81 to 83% of the EFV- and/or NVP-resistant viruses from this data set were susceptible to GW678248. Virus populations resistant to GW678248 were selected by in vitro dose-escalating serial passage. Resistant progeny viruses recovered after eight passages had amino acid substitutions V106I, E138K, and P236L in the reverse transcriptase-coding region in one passage series and amino acid substitutions K102E, V106A, and P236L in a second passage series.

Predictors of virologic failure and resistance in HIV-infected patients treated with nevirapine- or efavirenz-based antiretroviral therapy.

Resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) increases with the wider use of this class of antiretroviral therapy. The association between adherence and resistance to NNRTI-based regimens is poorly understood. Predictors of virologic failure and resistance according to a baseline evaluation of nonadherence risk factors were determined in a cohort of 71 human immunodeficiency virus (HIV)-infected patients with early virologic response who received an NNRTI-based regimen. During the median follow-up of 29 months, 20 (28%) of 71 patients experienced virologic failure with an NNRTI-based regimen. Virologic failure was associated with repeated drug holidays (> or =48 h of unplanned drug cessation), depression, younger age, and low adherence to therapy during baseline evaluation. Moreover, repeated drug holidays was the only risk factor for developing a major mutation conferring cross-resistance to the NNRTI class (hazard ratio, 22.5; 95% confidence interval, 2.8-180.3; P<.0001). Patients' previous adherence to therapy and drugs genetic barriers, not only the number of pills or doses involved, should be taken into consideration in the decision to simplify highly active antiretroviral therapy.

Efficacy and durability of nevirapine in antiretroviral-experienced patients.

The non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) has been used as a component of salvage therapy for patients who have experienced virologic failure while taking nucleosides and protease inhibitors (PIs). In spite of broad cross-resistance within the NNRTI class, NVP may also play a role in salvage therapy for patients who have experienced failure while taking NNRTIs Another role for NVP in treatment-experienced patients is in so-called "PI switch" strategies, in which NVP is substituted for a PI within a virologically successful combination regimen. This paper reviews the clinical data that support the use of NVP in salvage regimens and PI switch strategies.

Factors related to virologic failure among HIV-positive injecting drug users treated with combination antiretroviral therapy including two nucleoside reverse transcriptase inhibitors and nevirapine.

Treatment strategies in human immunodeficiency virus (HIV)-positive active injecting drug users (IDUs) must take into account their lifestyles, that often result in low adherence to therapy. The nonnucleoside reverse transcriptase inhibitors (NNRTI) offer simpler treatment regimens, but the appearance of drug resistance during treatment failure may cause high levels of cross-resistance to all NNRTIs. We adopted a combination therapy of two NRTIs and nevirapine (NVP) for treatment of IDU patients to evaluate its feasibility in such patients. From October 1998 to December 1999, demographic, clinical, and laboratory data from 80 IDUs on this regimen were collected. Fisher's exact test, Kaplan Meier method, and Cox model were used for statistical analysis. Overall, 20 IDUs discontinued the treatment because of side effects and 20 IDUs experienced treatment failure. Considering the treatment failure as an end point, 55.6% (95% confidence interval [CI]: 37.9%-72.6%) of patients was still undergoing treatment after 12 months compared to 44.6% (31.8%-58.6%) when discontinuation was also taken into account. An increasing trend over time was observed in the CD4+ lymphocyte count, among failing and nonfailing IDUs. By multivariate analysis, baseline HIV-RNA, treatment breaks and low adherence and active injecting drug use turned out to be significantly associated with treatment failure. Our results show that continuing injecting drug use and treatment breaks are the main factors that can lead to treatment failure in IDUs and easily to NNRTI class resistance.