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PubMed2004

Efficacy, safety and predictive factors of virological success of a boosted amprenavir-based salvage regimen in heavily antiretroviral-experienced HIV-1-infected patients.

BACKGROUND: Amprenavir (APV) has been shown to be effective in naive or treatment-experienced HIV-1 infected patients. However, the safety and efficacy of the APV 600 mg/ritonavir (RTV) 100 mg twice a day (bid) combination, the usually recommended dosage for boosted APV, have been less well studied. We assessed the predictive factors associated with virological success of APV/RTV-based regimens. METHODS: Patients in the PharmAdapt study receiving an APV/RTV-containing regimen were included in the study. The predictivity of covariates on virological response at 4 months was analysed according to the data analysis plan. We processed logistic regression using bootstrapping to allow several covariates in the models. RESULTS: Forty patients received an APV/RTV-containing regimen, 38 of whom were male (95%). Risk factors were heterosexual contacts (four patients; 10%), homosexual contacts (31 patients; 78%), and intravenous drug use (four patients; 10%). Twenty-seven per cent of patients were Centers for Disease Control and Prevention Classification System (CDC) stage A, 38% were stage B and 35% were stage C. The median baseline CD4 count was 313 cells/microL [interquartile range (IQR) 211, 414], and the median baseline viral load was 4.4 log(10) HIV-1 RNA copies/mL (IQR 3.7, 4.9). Patients were exposed to a median number of 7.5 (IQR 6, 9) drugs for a median number of 3.8 (IQR 3.3, 4.3) years. The baseline number of resistance mutations was 4 [IQR 3, 5 for nucleoside reverse transcriptase inhibitors (NRTIs), 1 (IQR 0, 2)] for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 6 [IQR 5, 8 for protease inhibitors (PIs)]. At month 4, median viral load decreased to 1.2 log(10) copies/mL (IQR 0.3, 1.6); 50% of patients had a viral load<200 copies/mL by intention-to-treat analysis. The number of APV resistance mutations was associated with viral load changes. Median APV concentration was 1750 ng/mL (IQR 1130, 2520). At month 4, using several cut-offs, neither APV concentration nor the genotypic inhibitory quotient was predictive of viral load changes. Baseline viral load and the number of protease mutations were associated with outcome. CONCLUSIONS: Efficacious APV concentrations need to be determined for antiretroviral-experienced patients. Baseline viral load and the number of mutations on the protease coding region (PRO) were associated with the virological outcome of APV/RTV-based regimens.

Adult↗
PubMedDate not supplied

[Side effects of antiretroviral therapy].

Highly active antiretroviral therapy (HAART) has changed the natural history of HIV infection, but the presence of adverse events may limit its efficacy. Nucleoside reverse transcriptase inhibitors can cause mitochondrial toxicity and anemia, non-nucleoside reverse transcriptase inhibitors are associated with rash and central nervous system disturbance; protease inhibitors elicit gastrointestinal adverse effects and metabolic abnormalities including lipodystrophy syndrome, hyperlipidemia and insulin resistance. These complications have the potential to increase morbidity and mortality significantly in those requiring long-term treatment of HIV-infection. The presence of such abnormalities also has an impact on adherence to treatment. Besides providing health benefits, HAART may have a negative impact on patients' quality of life. Identifying and treating these complications has important implications for patient survival.

Anemia↗
PubMed1996

(s4dU)35: a novel, highly potent oligonucleotide inhibitor of the human immunodeficiency virus type 1 reverse transcriptase.

Oligodeoxycytidylates were converted to s4dUMP-containing oligomers by treatment with liquid H2S. The inhibitory potency of the modified oligonucleotides on human immunodeficiency virus type 1 reverse transcriptase depended on the chain length and on the percentage of modification. The most potent reverse transcriptase inhibitor was (s4dU)35. The inhibitory pattern was competitive, when either poly(A) x (dT)16 or poly(C) x (dG)l6 was used as template-primer (variable substrate), suggesting that the free enzyme interacts with (s4dU)35. The Ki values were 3.0 and 2.2 nM in the presence of poly(A) x (dT)16 and poly(C) x (dG)16, respectively.

Chromatography, High Pressure Liquid↗
PubMed2006

Antiretroviral treatment of HIV infection: Swedish recommendations 2005.

On 2 earlier occasions, in 2002 and 2003, the Swedish Medical Products Agency (MPA) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly publicized recommendations for the treatment of HIV infection. A working group from the same expert team that produced the 2002 report has now revised the text again. Since the publication of the last treatment recommendations, 4 new medicines have become available: emtricitabine, atazanavir, fosamprenavir, and enfuvirtid. The last-mentioned belongs to a new class of HIV medications called fusion inhibitors (Box 1). It is likely that tipranavir will also be on the market soon. Simultaneously, the drug zalcitabin has been deregistered. The following updated recommendations parallel the earlier ones, but increased knowledge allows us to be more specific in our recommendations. Thus, it is now suggested that the initial treatment for HIV infection consist of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI); or 2 NRTIs and 1 protease inhibitor (PI). In the group of the NRTIs, stavudine is no longer recommended for this purpose. In the NNRTI group, efavirenz should be preferred to nevirapine, except under special circumstances. Finally, PIs ought to be boosted with ritonavir (PI/r). Also new are recommendations regarding treatment choices for patients co-infected with hepatitis B virus (HBV) or tuberculosis (TB). As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels), and have been supplemented with references to newly-added sections and data not referred to in earlier background documentation.

Anti-Retroviral Agents↗
PubMed1998

New perspectives for the treatment of HIV infections.

Eleven compounds have now been licensed for the treatment of HIV (human immunodeficiency virus) infections: the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV, AZT), didanosine (DDI), zalcitabine (DDC), stavudine (D4T) and lamivudine (3TC), the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and delavirdine, and the protease inhibitors saquinavir, ritonavir, indinavir and nelfinavir. Several other compounds that interact with the reverse transcriptase or protease or other targets of the viral replication cycle are in clinical or preclinical development. High expectations are vested in the acyclic nucleoside phosphonates PMEA and PMPA (which have proved clearly efficacious against HIV infections in phase II/III and phase I/II trials, respectively) and the bicyclam derivatives, which have recently been shown to block HIV infection through interference with the viral co-receptor CXCR4 (fusin). It has become increasingly clear that only the concomitant use of several anti-HIV agents combined can completely suppress HIV replication and offer the potential for a complete cure. To this end, the different compounds should be administered from the start at sufficiently high doses, and treatment should be started as soon as possible after the infection. Under these conditions, HIV-drug resistance development could be prevented, and progression to AIDS, arrested. Whether this procedure would also be able to eradicate the virus from the organism still needs to be proven.

Anti-HIV Agents↗
PubMed2006

Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth.

OBJECTIVE: To determine the relationship between maternal antiretroviral regimens during pregnancy and adverse infant outcomes [low birth weight (LBW) and preterm birth]. The a priori hypothesis was that protease inhibitor (PI)-containing regimens are associated with an increased risk of LBW and preterm birth. DESIGN: Prospective cohort study of HIV-1-infected women and their infants (NISDI Perinatal Study). METHODS: Data were analysed from 681 women receiving at least one antiretroviral drug [in order of increasing complexity: one or two nucleoside reverse transcriptase inhibitors (1-2 NRTI), two NRTI plus one non-nucleoside reverse transcriptase inhibitor (NNRTI) (HAART/NNRTI), or two NRTI plus one PI (HAART/PI)] for at least 28 days during pregnancy, and who delivered live born, singleton infants with known birth weight and gestational age by 1 March 2005. Multivariable logistic regression modeling was used to assess the relationship of maternal ART with LBW and with preterm birth, adjusting for covariates. RESULTS: The incidence of LBW and preterm birth, respectively, was 9.6% and 7.4% (1-2 NRTI), 7.4% and 5.8% (HAART/NNRTI), and 16.7% and 10.6% (HAART/PI). There was no statistically significant increased risk of LBW [adjusted odds ratio (AOR), 1.5; 95% confidence interval (95% CI), 0.7-3.2] or preterm birth (AOR, 1.1; 95% CI, 0.5-2.8) among women who received HAART/PI compared with women receiving 1-2 NRTI. CONCLUSIONS: Among a population of HIV-1-infected women in Latin America and the Caribbean, maternal receipt of PI-containing ART regimens during pregnancy was not associated with a statistically significant increase in risk of LBW or preterm birth.

Adult↗
PubMed2001

Conformational analysis of the HIV-1 virus reverse transcriptase nonnucleoside inhibitors: TIBO and nevirapine.

TIBO (Tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2-one) and nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one) are models for two classes of nonnucleoside inhibitors of the HIV-1 virus reverse transcriptase (NNRTI). This work presents the parameterization of compounds belonging to these two classes in the Cornell et al. force field through ab initio and semiempirical methods. The new parameters were used in the conformational analysis for TIBO R82913, TIBO R79882, and nevirapine. Various conformational search protocols were tested and the pseudosystematic method SUMM led to the best results. A better understanding of the distribution of conformers was obtained through clustering techniques in the data reduction stages. It was possible to reproduce various experimental data such as the crystallographic structures of the isolated or reverse transcriptase-complexed (RT) molecules. The proton-proton coupling constants (\documentclass{article}\pagestyle{empty}\begin{document}$\,J^{3}_{\mathrm{HH}}$\end{document}) obtained for TIBO through NMR were also reproduced. Cremer and Pople puckering parameters enabled a precise description of both the conformation of the seven-membered rings and the relative position of the substituents on them. These parameters also demonstrated the efficiency and precision of the two-stage clustering method. Copyright 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1817-1829, 2001

Journal Article↗
PubMed2003

Towards the design and development of agents with broad spectrum chemotherapeutic properties for the effective treatment of HIV / AIDS.

HIV is the most significant risk factor for many opportunistic infections like fungal, tuberculosis, etc. The intense media coverage of AIDS puts the public on an emotional roller caster, and inflated promises are engendered by each success. For the moment drugs acting as both HIV-reverse transcriptase inhibitors along with antimicrobial properties are one of the brightest hope. The Non-nucleoside reverse transcriptase inhibitors (NNRTIs) appear ideally suited for further development in the chemoprophylaxis and therapy of HIV infections. In recent years, isatinimino compounds have been reported to exhibit broad-spectrum chemotherapeutic properties that include anti-HIV, antituberculous, antifungal and antibacterial activities. Hence these leads should be regarded as structural hits in the search for more potent antimicrobial compounds with broad-spectrum chemotherapeutic properties for the effective treatment of HIV / AIDS. This review focuses on the design of isatinimino compounds, which resemble the NNRTIs for the development of an ideal anti-HIV drug.

Acquired Immunodeficiency Syndrome↗
PubMed2002

New developments in anti-HIV chemotherapy.

Virtually all the compounds that are currently used, or are subject of advanced clinical trials, for the treatment of human immunodeficiency virus (HIV) infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e. zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e. nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e. saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir. In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 [bicyclam (AMD3100) derivatives] and CCR5 (TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs (i.e. TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii) as in the case of PIs, a different, nonpeptidic scaffold [i.e. cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)]. Nonpeptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating the mode of action of these agents from cell-free enzymatic assays to intact cells. Two examples in point are L-chicoric acid and the nonapeptoid CGP64222, which were initially described as an integrase inhibitor or Tat antagonist, respectively, but later shown to primarily act as virus adsorption/entry inhibitors, the latter through blockade of CXCR4.

Anti-HIV Agents↗
PubMed2004

Essential benefits of nucleoside analogue regimens in failing therapy.

Since the introduction of highly active antiretroviral therapy, nucleoside and more recently nucleotide reverse transcriptase inhibitors (NRTIs) have provided a highly effective backbone to antiretroviral regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Nonetheless, treatment failure can result from poor adherence, unfavourable pharmacokinetics, advanced disease or infection with a drug-resistant virus. Recent data have also indicated a high risk of virological failure with triple NRTI regimens, reflecting overall lower potency compared to combinations of NRTIs with either NNRTIs or PIs. Resistance mutations emerging upon failure can cause extensive cross-resistance among available NRTIs, and potentially affect susceptibility to newly developed antiretroviral drugs. However, despite the emergence of resistance, NRTIs can retain significant antiviral activity in treatment-experienced patients. This may reflect residual direct viral load suppression, as well as indirect effects related to impaired viral fitness of NRTI-resistant mutants and antagonist interactions between resistance mutations.

Antiretroviral Therapy, Highly Active↗
PubMed2003

Impact of protease inhibitor substitution with efavirenz in HIV-infected children: results of the First Pediatric Switch Study.

OBJECTIVE: Simplification of antiretroviral regimen in human immunodeficiency virus (HIV)-infected children has not yet been investigated. In general, children have a more difficult time maintaining viral suppression because of many factors, including frequent nonadherence and less availability of antiretrovirals in palatable forms. In addition, many serious metabolic complications have emerged in HIV-infected adults and are believed to be attributable to antiretroviral therapy. Some of these complications--hypercholesterolemia, hypertriglyceridemia, and insulin resistance--are believed to be the result of the use of protease inhibitor (PI) therapy, whereas the cause of others, such as lipodystrophy, remains undetermined. Recent reports underline that children experience long-term metabolic abnormalities in the same manner that adults do, and perhaps these consequences are even more worrisome in children secondary to long-term expected survival. We report here the results of the first open-label PI-switch study in HIV-infected children. METHODS: Seventeen children, 24 to 160 months of age (median: 120), were enrolled into the study. All were receiving a stable PI-containing antiretroviral regimen that containing 2 to 3 nucleoside analogue reverse transcriptase inhibitors (NRTIs) in addition to 1 to 2 PIs for a median duration of 21 months (range: 5-50) before study entry. All children had HIV-1 RNA <400 copies/mL at screening; their baseline plasma HIV-1 RNA level had been <400 copies/mL for a median of 13 months (range: 4-55) before study entry. All patients were naïve to nonnucleoside reverse transcriptase inhibitor therapy. Their protease inhibitor(s) was switched to efavirenz while their NRTI therapy was maintained. RESULTS: All children were heavily pretreated; 88% of the patients had previous NRTIs, and 41% had previous PI use. The most common PI at study entry was nelfinavir (47%), followed by ritonavir (29%), then amprenavir (18%); only 1 was on saquinavir/ritonavir. At study entry, the duration of previous antiretroviral therapy was between 21 and 123 months (median: 88). All patients completed the 48-week study. No acquired immunodeficiency syndrome-defining events occurred. There were no rashes and no changes in liver transaminases. Mild, transient insomnia and dizziness each occurred in 1 child. Two other subjects (6 and 8 years old) experienced unusual vivid dreams, mostly pleasant, which decreased in intensity and frequency after the first 12 weeks of the study. One subject, a 10-year-old girl, had an episode of generalized seizure at week 6; study drugs were not interrupted, and seizure never recurred. The patient had a strong family history of epilepsy, although she had never experienced previous seizures. No anticonvulsants were given. Sixteen of 17 patients had HIV-1 RNA levels of <50 copies/mL (1 HIV-1 RNA was 61 copies/mL) at week 48. The mean CD4% remained stable initially from a mean of 35.1% (+/-2.8%) at baseline to 36.8% (+/-5%) at week 24, but increased to 38% (+/-6%) at week 48. Fasting triglycerides decreased from a mean of 126 mg/dL (+/-50) at baseline to 86 mg/dL (+/-45) at week 24 and to 94 mg/dL (+/-38) at week 48. At study entry, 12 (71%) of 17 children had triglyceride levels greater than the 95th percentile for age, race, and gender, compared with only 6 (35%) of 17 at week 48. Fasting cholesterol levels decreased from a mean of 203 mg/dL (+/-50) at baseline to 173 mg/dL (+/-31) at week 24 and to 174 mg/dL (+/-27) at week 48. At study entry, 5 (29%) of 17 children had cholesterol levels greater than the 95th percentile for age, race, and gender, compared with only 1 (6%) of 17 at week 48. The decrease in low-density lipoprotein cholesterol was also significant, from a mean baseline of 124 mg/dL (+/-42) to 100 mg/dL (+/-28) at week 24 and to 105 mg/dL (+/-20) at week 48. High-density lipoprotein (HDL) cholesterol did not change significantly, but the changes in cholesterol:HDL ratio, a better marker of atherogenic risk, significantly decreased from a mean baseline of 3.8 (+/-0.8) to 3.2 (+/-0.7) at week 24 and to 3 (+/-0.6) at week 48. Detailed dietary history revealed no significant changes during the study. In addition, none of the patients initiated therapy with lipid-lowering agents. There were no significant changes in insulin or C-peptide throughout the study period. In addition, anthropometric measurements that included mid-thigh and mid-arm circumferences, triceps and thigh skinfolds, and waist:hip ratio were stable throughout the study period. For bioelectrical impedance measurements, lean body mass increased from a mean baseline of 32.1 lb (+/-9.3) to 35.7 lb (+/-11.4) at week 24 and to 36.5 lb (+/-11.5) at week 48. Bioelectrical impedance measurements of fat content were unchanged throughout the study period. CONCLUSION: This is the first study in children to evaluate the substitution of PI in a virologically successful regimen with efavirenz, a potent once-daily nonnucleoside reverse transcriptase inhibitor therapy. We were able to show significant improvement in fasting total cholesterol, low-density lipoprotein cholesterol, triglycerides, and, more important, the cholesterol:HDL ratio. In addition, switching to an efavirenz-containing regimen was well tolerated and successfully maintained virologic suppression in all HIV-infected children in this study. This study should encourage large randomized trials to investigate simplification strategies in HIV-infected children.

Age Factors↗
PubMed2004

Primary drug-resistance in HIV-positive patients on initiation of first-line antiretroviral therapy in Germany.

BACKGROUND: Resistance against antiretroviral drugs in previously untreated HIV-infected persons is of growing relevance. The aim of the study is to determine the prevalence of resistance-associated mutations in this patient group. METHODS: In a prospective multicenter-study in Nordrhein-Westfalen, Germany, genotypic resistance testing was performed in untreated HIV-positive patients before administration of first-line highly active antiretroviral therapy (HAART). RESULTS: Between January 2001 and August 2002 resistance testing was performed in 184 therapy-naive individuals. HAART was initiated in 143 patients, who were included into the study. 70.6 % were males, mean age was 39 years, mean duration of diagnosis of HIV-infection was 1.5 years. The proportion of cases at CDC stage C was 45.4%, mean CD4-cell count was 199 /ml, mean viral load was 206,855 copies/ml. Resistance-associated mutations were detected in 20 patients (14.0%). 10.5% showed mutations indicating nucleoside reverse transcriptase inhibitor- (NRTI) resistance (M41L, E44D, D67N, T69D/N, L74V, V118I, M184V, L210W, K219Q), 2.8% showed non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (K103N, V108I, Y181C), and 2.1% showed protease-inhibitor- (PI) associated resistance (V82A, L90M), respectively. Multi-class-resistance was found in 2.1%, mutations indicating revertant variants of resistant strains were found in 4.2% (T215C/E/L/S). 86.7% of the isolates showed secondary mutations in the protease gene. No significant difference in the distribution of the parameters age, sex, duration of HIV diagnosis, CDC stage, CD4-cell count, and viral load, between groups with and without resistance was identified. CONCLUSION: The prevalence of primary resistant virus strains can be estimated at 14% in chronically infected HAART-naive HIV-patients in Germany. The majority of these cases show NRTI-associated resistance. Resistance against NNRTI or PI as well as multi-class-resistance is of low prevalence. No risk factor of predictive value can be identified for the diagnosis of resistance mutations in the individual. In conclusion, routine genotypic resistance testing in untreated HIV-positive patients should be performed before administration of first-line HAART in this region.

Adult↗