Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Reverse Transcriptase Inhibitors”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,747 records · Page 97Linked to original sources
PubMed2002

Clinically significant interactions with drugs used in the treatment of tuberculosis.

Clinically significant interactions occurring during antituberculous chemotherapy principally involve rifampicin (rifampin), isoniazid and the fluoroquinolones. Such interactions between the antituberculous drugs and coadministered agents are definitely much more important than among antituberculous drugs themselves. These can be associated with consequences even amounting to therapeutic failure or toxicity. Most of the interactions are pharmacokinetic rather than pharmacodynamic in nature. The cytochrome P450 isoform enzymes are responsible for many interactions (especially those involving rifampicin and isoniazid) during drug biotransformation (metabolism) in the liver and/or intestine. Generally, rifampicin is an enzyme inducer and isoniazid acts as an inhibitor. The agents interacting significantly with rifampicin include anticoagulants, anticonvulsants, anti-infectives, cardiovascular therapeutics, contraceptives, glucocorticoids, immunosuppressants, psychotropics, sulphonylureas and theophyllines. Isoniazid interacts principally with anticonvulsants, theophylline, benzodiapines, paracetamol (acetaminophen) and some food. Fluoroquinolones can have absorption disturbance due to a variety of agents, especially the metal cations. Other important interactions of fluoroquinolones result from their enzyme inhibiting potential or pharmacodynamic mechanisms. Geriatric and immunocompromised patients are particularly at risk of drug interactions during treatment of their tuberculosis. Among the latter, patients who are HIV infected constitute the most important group. This is largely because of the advent of new antiretroviral agents such as the HIV protease inhibitors and the non-nucleoside reverse transcriptase inhibitors in the armamenterium of therapy. Compounding the complexity of drug interactions, underlying medical diseases per se may also contribute to or aggravate the scenario. It is imperative for clinicians to be on the alert when treating tuberculosis in patients with difficult co-morbidity requiring polypharmacy. With advancement of knowledge and expertise, it is hoped that therapeutic drug monitoring as a new paradigm of care can enable better management of these drug interactions.

AIDS-Related Opportunistic Infections↗
PubMed2005

Interactions between antiretrovirals and antineoplastic drug therapy.

Despite the established impact of highly active antiretroviral therapy (HAART) in reducing HIV-related morbidity and mortality, malignancy remains an important cause of death. Patients who receive the combination of cancer chemotherapy and HAART may achieve better response rates and higher rates of survival than patients who receive antineoplastic therapy alone. However, the likelihood of drug interactions with combined therapy is high, since protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are substrates and potent inhibitors or inducers of the cytochrome P450 (CYP) system. Since many antineoplastic drugs are also metabolised by the CYP system, coadministration with HAART could result in either drug accumulation and possible toxicity, or decreased efficacy of one or both classes of drugs. Although formal, prospective pharmacokinetic interaction studies are not available in most instances, it is possible to infer the nature of drug interactions based on the metabolic fates of these agents. Paclitaxel and docetaxel are both metabolised by the CYP system, although differences exist in the nature of the isoenzymes involved. Case reports describing adverse consequences of concomitant taxane-antiretroviral therapy exist. Although other confounding factors may have been present, these cases serve as reminders of the vigilant monitoring necessary when taxanes and HAART are coadministered. Similarly, vinca alkaloids are substrates of CYP3A4 and are, thus, vulnerable to PI- or NNRTI-mediated changes in their pharmacokinetics. Interactions with the alkylating agents cyclophosphamide and ifosfamide are complicated as a result of the involvement of the CYP3A4 and CYP2B6 isoenzymes in both the metabolic activation of these drugs and the generation of potentially neurotoxic metabolites. Existing data regarding the metabolic fate of the anthracyclines doxorubicin and daunorubicin suggest that clinically detrimental interactions would not be expected with coadministered HAART. Commonly used endocrine therapies are largely substrates of the CYP system and may, therefore, be amenable to modulation by concomitant HAART. In addition, tamoxifen itself has been associated with reduced concentrations of both anastrozole and letrozole, raising the concern that similar inducing properties may adversely affect the outcome of PI- or NNRTI-based therapy. Similarly, dexamethasone is both a substrate and concentration-dependent inducer of CYP3A4; enhanced corticosteroid pharmacodynamics may result with CYP3A4 inhibitors, while the efficacy of concomitant HAART may be compromised with prolonged dexamethasone coadministration. Since PIs and NNRTIs may also induce or inhibit the expression of P-glycoprotein, the potential for additional interactions to arise via modulation of this transporter also exists. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary.

Animals↗
PubMed1999

[Immunologic reconstruction after antiretroviral treatment].

DATA FAVORING IMMUNE RECONSTITUTION: Multiple drug therapies for HIV infection have enabled a major reduction in the viral load, higher CD4 counts, and a lower incidence of opportunistic infections and tumor formations, and subsequently lower hospitalization rates and mortality. TWO STAGES OF CD4 RECONSTITUTION: In HIV-positive patients with advanced stage disease treated with a protease inhibitor associated with 2 nucleoside analog reverse transcriptase inhibitors and followed prospectively, it has been observed that CD4 counts rise considerably, with a rapid increase during the first 2 months followed by a slower but still positive slope over a period of 18 months. Discordant results have however also been observed suggesting an ineffective anti-viral effect or a retarded immune reconstitution. SEVERAL MECHANISMS: The lymphocyte amplification observed during the early phase corresponds to re-circulation of CD4 and CD8 lymphocytes which had been sequestered in lymphoid organs; most of these CD4 lymphocytes are memory cells. A second phase corresponds to a more moderate and progressive rise in naive CD4 cells which originate from an unknown source. This biphasic reconstitution of CD4 lymphocytes is associated with a correction of the chronic lymphocyte overactivation. PARTIAL IMMUNE RECONSTITUTION: With treatment, the capacity to respond to known antigens reappears. This restored capacity is secondary to the amplification of CD4 memory cells and appears prior to the expansion phase of naive cells. The response remains moderate and is only observed against antigens from microorganisms highly prevalent during advanced stage infection.

Antiviral Agents↗
PubMed1997

Protease Inhibitors Therapy for AIDS Patients.

Protease inhibitors have had a significant clinical impact on treatment of previously treated and untreated patients with HIV infection. In the treatment of previously treated patients, the addition of a protease inhibitor and at least one other antiretroviral agent likely to be sensitive to that particular isolate, has resulted in significant increases in CD(4)(+) cell counts, decreases in plasma viral burden and substantial decreases in the rate of development of new clinical events and mortality. Dramatic and sustained reductions in viral burden have been noted in a majority of patients treated with such regimens. In addition to combining a protease inhibitor with one or more nucleoside analogs, pilot studies of combinations of two protease inhibitors or a protease inhibitor plus a non-nucleoside reverse transcriptase inhibitor, have also demonstrated impressive drug efficacy and tolerance.

Journal Article↗
PubMed1997

Clinically relevant drug interactions with antiretroviral agents.

With the advent of the human immunodeficiency virus (HIV) protease inhibitors and the non-nucleoside reverse transcriptase inhibitors, the importance of drug-drug interactions with antiretroviral agents is becoming increasingly recognized. Every clinician involved in the care of HIV-infected persons should have a broad knowledge of these drug-drug interactions and their underlying mechanisms. This paper will review currently known clinically relevant interactions with antiretroviral agents reported thus far. Alternative strategies will be proposed where possible, in order to improve patient safety and the therapeutic efficacy of the antiretroviral agents. It must be emphasized, however, that in many cases these proposals are not backed up by authoritative clinical consensus panels and that clinical experience with many of these combinations is limited.

Anti-HIV Agents↗
PubMed2001

Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience.

The use of highly active antiretroviral therapy, the combination of at least three different antiretroviral drugs for the treatment of HIV-1 infection, has greatly improved the prognosis for HIV-1-infected patients. The efficacy of a combination of a protease inhibitor (PI) plus two nucleoside analogue reverse transcriptase inhibitors has been well established over a period of up to 3 years. However, virological treatment failure has been reported in 40-60% of unselected patients within 1 year after initiation of a PI-containing regimen. This observation may, at least in part, be attributed to the poor pharmacokinetic characteristics of the PIs. Given as a single agent the PIs have several pharmacokinetic limitations; relatively short plasma-elimination half-lives and a modest and variable oral bioavailability, which is, for some of the PIs, influenced by food. To overcome these suboptimal pharmacokinetics, high doses (requiring large numbers of pills) must be ingested, often with food restrictions, which complicates patient adherence to the prescribed regimen. Positive drug-drug interactions increase the exposure to the PIs, allowing administration of lower doses at reduced dosing frequencies with less dietary restrictions. In addition to increasing the potency of an antiretroviral regimen, combinations of PIs may enhance patient adherence, both of which will contribute to a more durable suppression of viral replication. The favourable pharmacokinetics of PIs in combination are a result of interactions through cytochrome P450 3A4 (CYP3A4) isoenzymes and, possibly, the multi-drug transporting P-glycoprotein (P-gp). Antiretroviral synergy between PIs and non-overlapping primary resistance patterns in the HIV-1 protease genome may further enhance the antiretroviral potency and durability of combinations of PIs. Many combinations contain ritonavir because this PI has the most pronounced inhibiting effects on CYP3A4. The combination of saquinavir and ritonavir, both in a dose of 400 mg twice-a-day, is the most studied double PI combination, with clinical experience extending over 3 years. Combination of a PI with a low dose of ritonavir (< or = 400 mg/day), only to boost its pharmacokinetic properties, seems an attractive option for patients who cannot tolerate higher doses of ritonavir. A recently introduced PI, lopinavir, has been co-formulated with low-dose ritonavir, which allows for a convenient three-capsules, twice-a-day dosing regimen. In an attempt to prolong suppression of viral replication combinations of PIs are becoming increasingly popular. However, further clinical studies are needed to identify the optimal combinations for treatment of antiretroviral naive and experienced HIV-1-infected patients. This review covers combinations of saquinavir, indinavir, nelfinavir, amprenavir and lopinavir with different doses of ritonavir, as well as the combinations of saquinavir and indinavir with nelfinavir.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Mitochondria and HIV infection: the first decade.

In the last few years, the interactions between mitochondria and infection with the human immunodeficiency virus (HIV) have received careful attention. Starting from the first studies regarding the presence of mitochondrial damage in cardiac tissue from patients who died of AIDS, researchers have investigated different aspects of the interactions between the virus and mitochondria, from acute primary infection to the final stages of the disease. Only recently a significant impulse to this type of research has come from the observation that the so called "highly active antiretroviral therapy" (HAART), a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, is capable of damaging these organelles and cause a clinical syndrome called lipodystrophy. There is still an open debate concerning the exact responsibility of HAART as well as on metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The hypothesis that drug-induced damage to mitochondrial (mt) DNA is able to alter mitochondria functionality to a similar extent as that occurring in genetic disease affecting mtDNA suggests that mitochondria plays a crucial role in the pathogenesis of this syndrome. In this paper, data concerning the interactions between mitochondria and HIV infection will be reviewed.

Animals↗
PubMed2002

Response to antiretroviral therapy among patients exposed to three classes of antiretrovirals: results from the EuroSIDA study.

There is an increasing proportion of HIV-positive patients exposed to all licensed classes of antiretrovirals, and the response to salvage regimens may be poor. Among over 8500 patients in EuroSIDA, the proportion of treated patients exposed to nucleosides, protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI) increased from 0% in 1996 to 47% in 2001. Four-hundred-and-thirteen patients, who had failed virologically two highly active antiretroviral therapy (HAART) regimens and experienced all three main drug classes, started a salvage regimen of at least three drugs, in which at least one new PI or NNRTI was included. Median viral load was 4.7 log copies/ml [Interquartile range (IQR) 4.2-5.2], CD4 lymphocyte count 150/mm3 (IQR 60-274/mm3) and follow-up 14 months. Of these patients, 283 (69%) subsequently experienced at least a 1 log decline in viral load and 202 (49%) achieved a viral load < 500 copies/ml. Conversely, the CD4 count halved from the baseline value in 88 (21%), and 45 (11%) experienced a new AIDS-defining disease. In multivariable analyses, a 1 log viral load reduction was related to baseline viral load [relative hazard (RH) 1.27 per 1 log higher; P = 0.008], a previous viral load of less than 500 copies/ml (RH 1.69; P = 0.002), more recent initiation of the regimen (RH 1.36 per year more recent; P = 0.02), number of new drugs in the regimen (RH 1.20 per drug; P = 0.02), time since start of antiretroviral therapy (RH 0.94 per extra year; P = 0.035) and time spent on HAART with viral load > 1000 copies/ml (RH 0.96 per extra month; P = 0.0001). Analysis of factors associated with CD4 count decline and new AIDS disease also indicated improved outcomes in more recent times and a tendency for a better response in those starting more new drugs, but no relationship with the total number of drugs. Outcomes in people starting salvage regimens appear to depend on the number of new drugs started but not on the total number of drugs being used.

Acquired Immunodeficiency Syndrome↗
PubMed2004

[Opportunistic diseases--current aspects in 2004].

Opportunistic diseases (OD) are still the most common cause of death in patients with HIV infection. The occurrence of OD is the most important single prognostic factor for survival. While in the pre-HAART era, many patients died of the wasting syndrome, today, ever more patients suffer from obesity and its consequences. Tuberculosis is widespread among those affected with HICV, and when treating it must be remembered that tuberculostatic agents and antiretroviral drugs interact with cytochrome P450. Until recently, the combination of rifampicin with protease inhibitors and non-nucleoside reverse-transcriptase inhibitors was contraindicated. Now, however, the Centers for Disease Control (CDC) has updated its recommendations for treatment.

AIDS-Related Opportunistic Infections↗
PubMed2006

API TB Consensus Guidelines 2006: Management of pulmonary tuberculosis, extra-pulmonary tuberculosis and tuberculosis in special situations.

INTRODUCTION: The World Health Organization (WHO) has declared Tuberculosis (TB) a global emergency in 1993. Prevalence of TB and Human Immunodeficiency Virus (HIV) co-infection worldwide is 0.18% and about 8% TB cases have HIV infection. Effective chemotherapy has been available for treatment of TB for over 50 years now. In World Health Organization (WHO)-International Union Against Tuberculosis and Lung Disease (IUATLD) Working Group Global Anti-Tuberculosis Drug Resistance Surveillance (1994-1997), the incidence of MDR TB in Delhi was found to be 14%, of which primary multi-drug resistance was only 1.4%, indicating that most of MDR TB is acquired as a result of poor chemotherapy. DIAGNOSIS OF TB: Since TB is an infectious disease caused by Mycobacterium (M) tuberculosis the diagnosis of TB should (as far as possible) be by demonstration of M. tuberculosis on culture or acid-fast bacilli (AFB) on smear examination. The World Health Organization (WHO) has strongly recommended sputum smear examination as the preferred screening test and suggests examination of 3 deeply coughed out sputum samples - spot sample on day 1, overnight sample and a spot sample in the morning on day 2. Recently it has been shown that sputum smear positivity is greater than 90% where greater than 5 ml of sputum is used for smear diagnosis of pulmonary TB. Culture of M. tuberculosis is the gold standard for diagnosis of TB. Culture of mycobacteria is a much more sensitive test than smear examination and has been estimated to detect 10-100 viable mycobacteria per ml of sample and in case of active disease they are found to be 81% sensitive and 98.5% specific. Culture methods are also required for further drug sensitivity testing in cases of suspected drug resistant cases. Isoniazid and rifampicin resistance can be reliably measured; resistance to pyrazinamide, ethambutol, and streptomycin is more difficult due to limitations of technique. The therapeutic index for a given drug is low for certain second-line drugs such as ethionamide, cycloserine, viomycin and para amino salicylic acid (PAS) and it leads to misinterpretation of results due to failure to distinguish between sensitive and resistant strains. Misdiagnosis of MDR-TB due to laboratory related errors has been reported recently. MANAGEMENT OF TB: Chemotherapy of TB consists of prevention of infection, also called primary chemoprophylaxis, when isoniazid 5 mg/kg is given to prevent infection in newborn infants of infectious mothers till mother is sputum smear positive (2-3months). Treatment of latent tuberculosis, also called secondary chemoprophylaxis, when isoniazid 5 mg/kg is given for 6 months to prevent disease in infected persons (asymptomatic MT positive individuals) and treatment of disease with Short Course Chemotherapy (SCC), as per WHO categories. Essential anti-tuberculosis (ATT) drugs Isoniazid (H), Rifampicin (R), Ethambutol (E), Pyrazinamide (Z) and Streptomycin (S) are the essential first line anti-tuberculosis drugs. Anti TB regimen consists of two phases: an initial intensive phase (IIP) and a continuation phase (CP). Best effective SCC for treatment of TB, for adults and children, for pregnant and lactating females, for cases associated with diabetes mellitus and HIV infection, for cases with pre-existing liver diseases (but normal liver functions) and mild renal failure is 2EHRZ, 4HR given daily or thrice weekly. Higher dose SCC intermittent therapy given in thrice weekly (2E3H3R3Z3, 4H3R3) has now been advocated by WHO and implemented by the Revised National TB Control Programme. DOTS, directly observed therapy short course, where the patient takes the drugs under the direct observation (DO) of a health worker to ensure regularity of consumption of drugs. Fixed dose combinations (FDCs) drugs consisting of two or three antituberculosis medications, provide a realistic and welcome alternative to DO that minimizes the opportunity for a patient to selectively take only a single medication. MANAGEMENT OF TB IN SPECIAL SITUATIONS: Pregnancy: All drugs, that is, rifampicin, isoniazid, ethambutol, and pyrazinamide can be used during pregnancy. Streptomycin is not given due to ototoxicity to the fetus. Prophylactic pyridoxine in the dose of 10mg/day is recommended along with ATT. Diabetes mellitus: The drug regimen is same as in nondiabetic. Strict control of blood glucose is mandatory. Also, doses of oral hypoglycemic agents may have to be increased due to interaction with Rifampicin. Prophylactic pyridoxine is indicated. Renal failure: Dosages may have to be adjusted according to the creatinine clearance especially for streptomycin, ethambutol and isoniazid. In acute renal failure, ethambutol should be given 8 hours before hemodialysis. In post renal transplant patients: Rifampicin-containing regimens are avoided as rifampicin causes increased clearance of cyclosporin. Pre-existing liver disease: In stable disease with normal liver enzymes, all anti-tuberculous drugs may be used but frequent monitoring of liver function tests is required. Treatment in unconscious patient (patients unable to swallow): If patients are fed by Ryle's tube or gastrostomy tube, usual doses and drugs may be powdered and administered avoiding feeds 2-3 hours before and after the dose. In cases where enterostomy has been performed or parenteral nutrition is being used, intramuscular streptomycin and isoniazid and intravenous quinolones may be used and switch to oral therapy once oral feed resume. Treatment of TB with HIV co-infection: In early stages the presentations of TB in TB-HIV co-infection is the same as HIV negative but in late stages extra-pulmonary and dissemination are common. The usual short course chemotherapy is indicated in HIV positive patients. The response is usually good but relapse is frequent. After initiating ATT or anti-retroviral therapy (ART) worsening of preexisting lesions or appearance of new lesions is seen, "paradoxical response" or "immune reconstitution phenomenon". Multidrug resistant TB can occur due to poor compliance to ATT due to behavioural pattern, increased incidence of side effects and malabsorption of drugs due to associated diarrhea. ART for HIV, containing protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) cannot be used along with R, as R induces metabolism of PI and reduces the efficacy. The various options are i) to postpone anti-retroviral therapy ii) to use no PI or NNRTI containing anti-retroviral combinations iii) to use certain PI/ and/or NNRTIs with modification in doses iv) Efavirenz (EFZ) or Saquinavir with Ritonavir, without the need to adjust the doses v) to use non R regimens e.g. 2SHEZ+10HE MANAGEMENT OF MDR TB: As far as possible treatment of MDR TB should be referred to specialized units with facilities for quality controlled DST and experienced in handling such cases. If such referrals are not possible, one must remember that while initiating or revising therapy for MDR-TB, drugs selection must rely on prior treatment history, results of susceptibility testing and an evaluation of the patient's adherence.

Algorithms↗
PubMed1996

Rational approaches to resistance: using saquinavir.

AIM: To review drug-resistance patterns of HIV protease inhibitors, with particular reference to saquinavir, and how resistance and cross-resistance patterns may influence disease management. RESISTANCE TO SAQUINAVIR: Resistance to saquinavir in vitro and in vivo is associated with mutations L90M and G48V in HIV protease. L90M is the predominant mutation in vivo. Clinically, G48V is uncommon and the double mutation rare. This pattern of mutation differs from those seen with other protease inhibitors. CROSS-RESISTANCE: Long-term treatment with saquinavir in most cases does not induce a significant decrease in sensitivity to saquinavir itself or other protease inhibitors. Where significant resistance to saquinavir does develop (i.e. fourfold increase in the median inhibitory concentration), there are observed instances of cross-resistance. Preliminary phenotypic studies of patients on combination therapy with saquinavir (plus zalcitabine and/or zidovudine) for 1 year indicate that > 80% should subsequently respond to indinavir, ritonavir or VX-478. CONCLUSIONS: Resistance to saquinavir develops slowly and in a minority of patients on long-term therapy. Reduced susceptibility to saquinavir is associated with mutations different from those associated with other HIV protease inhibitors. Saquinavir appears to be a good first-choice protease inhibitor for combination therapy with HIV reverse transcriptase inhibitors as it should provide prolonged antiretroviral activity without limiting subsequent therapeutic options.

Anti-HIV Agents↗
PubMed1993

Antiviral therapy in human immunodeficiency virus infections. Current status (Part I).

Antiviral therapy has in the past met with limited success and only a few antiviral drugs have been available. The human immunodeficiency virus (HIV) epidemic has created an urgent need for the development of antiviral therapy against this infection. HIV replication offers several targets for inhibitory compounds, the foremost presently being the HIV reverse transcriptase and protease enzymes. Despite the short time since the beginning of the epidemic, 3 nucleoside analogue drugs (zidovudine, didanosine and zalcitabine) which act at the reverse transcriptase site are already licensed for use against HIV, and others (stavudine, alovudine and 3-TC) are still under clinical evaluation. Part II of this article discusses non-nucleoside reverse transcriptase inhibitors undergoing investigation, protease inhibitors, and compounds active against various other targets in HIV. Treatment guidelines are also provided in Part II.

Animals↗
PubMed2000

Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine.

OBJECTIVE: To assess the HIV-1-RNA response and drug concentrations in cerebrospinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RTV) or SQV/RTV plus stavudine (d4T) in HIV-1 -infected patients. DESIGN: A multicentre, open-label, randomized controlled trial. METHODS: A total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. RESULTS: The median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P = 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P = 0.005). CSF RTV and SQV concentrations were < LLQ in most patients. CONCLUSION: RTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF.

Adult↗
PubMed2001

Multiple drug rescue therapy for HIV-infected individuals with prior virologic failure to multiple regimens.

OBJECTIVES: To characterize the antiviral response and tolerability of a multi-drug rescue therapy (MDRT) among heavily pretreated patients. METHODS: Observational study conducted in a single, university-based tertiary referral clinic. Patients (n = 106) who failed several prior regimens started MDRT including at least five antiretroviral (ARV) drugs between August 1997 and June 1998. The most common starting regimen included three nucleoside reverse transcriptase inhibitors and two protease inhibitors, which was prescribed to 45 (42.5%) patients. Virologic response was defined as plasma viral load < 400 copies/ml on at least two consecutive visits. RESULTS: Median prior ARV exposure was seven drugs over a median time of 43 months. Fifty-nine percent of the patients were phenotypically (VIRCO Antivirogram) resistant at baseline to seven or more ARV. Median plasma viral load change following initiation of MDRT was -1.04 log10 copies/ml over a median of 15 months. Using intention-to-treat analysis 40% of patients had plasma viral load values < 400 copies/ml between weeks 47 and 57 of follow-up. Twenty-six patients (25%) experienced severe laboratory abnormalities or subjective adverse drug effects and six of these participants discontinued therapy. CONCLUSION: MDRT induced a substantial antiviral response in this heavily pretreated group of patients despite extensive phenotypic resistance at baseline. Adverse effects were frequent but generally manageable. Our data suggest that relying exclusively on historical, clinical and laboratory evidence may not be sufficient to rule out a possible antiviral response when multiple drug regimens are used in this heavily pretreated patient population.

Adult↗
PubMed2002

Simplifying protease inhibitor therapy with once-daily dosing of saquinavir soft-gelatin capsules/ritonavir (1600/100 mg): HIVNAT 001.3 study.

OBJECTIVE: To determine the feasibility of switching therapy for HIV-1-infected patients with plasma viral loads of <50 HIV-1 RNA copies/mL who are receiving twice-daily saquinavir soft-gelatin capsules (SQV-SGC) plus dual nucleoside reverse transcriptase inhibitors (NRTIs) to a regimen containing once-daily SQV-SGC/ritonavir (RTV). DESIGN: Therapy for patients with plasma viral loads of <50 copies/mL after 2 years of treatment with twice-daily SQV-SGC (1400 mg) plus zidovudine/lamivudine or didanosine/stavudine was switched to once-daily SQV-SGC/RTV (1600/100 mg) with continuing NRTI treatment. METHODS: Safety and efficacy (determined by plasma viral load and CD4 cell count) were evaluated (week 24). For 12 patients, steady-state plasma pharmacokinetics of SQV was determined (week 4). RESULTS: Once-daily SQV-SGC/RTV was well tolerated. No patient changed regimens. After 24 weeks, 64 (93%) of 69 patients had plasma viral loads of <50 copies/mL (the remaining 5 patients had plasma viral loads of <300 copies/mL). The median CD4 cell count increased from 534/mL at the start of once-daily SQV-SGCs/RTV to 695/mL after 24 weeks (p <.001). Compared with the preceding 24 weeks of treatment with twice-daily SQV-SGC, the CD4 cell count improved significantly during once-daily SQV-SGC/RTV therapy (p <.001). All patients maintained SQV trough concentrations (C(24h)) of >0.05 mg/L. Median values for the area under the plasma concentration-versus-time curve from 0 to 24 hours (AUC(0-24h)), maximal concentration (C(max)), and C(24h) for SQV were 48.1 (h.mg)/L, 6.98 mg/L, and 0.17 mg/L, respectively. Body weight was inversely correlated with SQV AUC(24h) and C(24h) (p <.01). CONCLUSIONS: Clinical and pharmacokinetic data support once-daily SQV-SGC/RTV (1600/100 mg) with two NRTIs as a convenient and safe therapeutic regimen to maintain viral suppression and immune function in HIV-1-infected patients with plasma viral loads of <50 copies/mL.

Adult↗
PubMed2003

FDA notifications. NRTI Emtriva receives FDA approval.

The Food and Drug Administration has approved Emtriva (FTC, emtricitabine), a new nucleoside reverse transcriptase inhibitor to be used in combination with other antiretroviral agents for the treatment of patients with HIV infection.

Adult↗
PubMed2001

Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion.

Since antiretroviral drugs are known to inhibit many cytochrome P450 isoforms, the inhibition of CYP2B6 by non-nucleoside reverse transcriptase inhibitors and viral protease inhibitors was studied in vitro in human liver microsomes using bupropion hydroxylation as the CYP2B6 index reaction. Mean IC(50) values (microM) for inhibition of bupropion hydroxylation were: nelfinavir (2.5), ritonavir (2.2), and efavirenz (5.5). The reaction was only weakly inhibited by indinavir, saquinavir, amprenavir, delavirdine, and nevirapine. The inhibition of bupropion hydroxylation in vitro by nelfinavir, ritonavir, and efavirenz indicates inhibitory potency versus CYP2B6 and suggests the potential for clinical drug interactions.

Alkynes↗
PubMed2006

Changes in body composition and mitochondrial nucleic acid content in patients switched from failed nucleoside analogue therapy to ritonavir-boosted indinavir and efavirenz.

BACKGROUND: Body composition changes complicate antiretroviral therapy. Improvements in lipoatrophy after a switch in nucleoside reverse-transcriptase inhibitors (NRTIs) have been demonstrated. We investigated 60 patients switching from failed NRTIs to ritonavir-boosted indinavir and efavirenz. METHODS: Body composition (assessed by dual-energy x-ray absorptiometry scan and by single-slice computed tomography of the abdomen through the level of the fourth lumbar vertebra [L4] and the mid-right thigh) and fasted metabolics were measured at the baseline time-point at switch and at weeks 48 and 96 thereafter. Mitochondrial DNA and RNA were extracted from right-thigh subcutaneous fat and peripheral-blood mononuclear cells (PBMCs) at weeks 0 and 48. The primary end point was the change in mean limb fat over 48 weeks. RESULTS: At week 96, we observed increases in mean (standard deviation [SD]) limb fat (+620 [974] g; P=.003), L4 subcutaneous adipose tissue (+20 [35] cm(2); P<.001), mid-thigh subcutaneous adipose tissue (+5 [10] cm(2); P<.001), and L4 visceral adipose tissue (+11 [34] cm(2); P=.01), but we also observed reduced lean limb mass (-831 [1,100] g; P=.3). Mean (SD) mtDNA content in subcutaneous fat and in PBMCs increased (+109 [274] and +45 [100] copies/cell, respectively). Improved virological control or immune recovery did not explain the results. Triglyceride, total cholesterol, estimated low-density lipoprotein cholesterol, ratio of total cholesterol to high-density lipoprotein cholesterol, and blood glucose levels deteriorated (i.e., had increased by 206%, 67%, 58%, 19%, and 6%, respectively, at week 96). CONCLUSIONS: This regimen was associated with statistically significant but clinically modest increases in peripheral fat, visceral fat, and mitochondrial nucleic acid content. A predominantly adverse metabolic profile developed.

Absorptiometry, Photon↗