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PubMed2000

Using pharmacokinetics to optimize antiretroviral drug-drug interactions in the treatment of human immunodeficiency virus infection.

Better understanding of the pharmacokinetics of antiretroviral drugs has resulted in the design of combination therapies for the treatment of human immunodeficiency virus (HIV) infection. This has improved the bioavailability and prolonged the plasma half-life of some of the drugs, resulting in enhanced antiviral activity. However, antiviral combination therapy can also result in adverse drug-drug interactions and diminished antiretroviral activity. In this review, we examine drug interactions involving combinations of protease inhibitors, combinations of protease inhibitors with nonnucleoside reverse transcriptase inhibitors, and combinations of nucleoside analogues for the treatment of patients with HIV infection. We discuss examples and mechanisms of pharmacokinetic interactions that improve or decrease antiviral efficacy.

Anti-HIV Agents↗
PubMed2007

Adherence to generic reverse transcriptase inhibitor-based antiretroviral medication at a Tertiary Center in North India.

At least 95% adherence to medications is required for sustained response to antiretroviral therapy (ART). In resource constraint restrained settings it is not possible to use electronic methods to determine adherence. We determined adherence during the previous 4 weeks by the recall method in 200 patients (138 males) receiving generic triple drug reverse transcriptase inhibitor-based antiretroviral medications. They were administered a uniform questionnaire to determine the number of time they forgot or were unable to take their medications and the reasons thereof. One hundred and fifty received two and 50 took three pills daily. One hundred and forty-seven did not miss any dose. Fifty-three (26.5%) missed at least one dose during the preceding 4 weeks. Thirty-one took treatment on and off. Seven missed a dose in the preceding 3 days, nine more between the last 3 and 7 days, and six from 1 to 4 weeks. The major reasons for non-adherence were financial constraints, forgetting to take the medication, drug toxicity, lack of access to the drug, fear of getting immune to the benefit of the drug, and to avoid adverse effects. Non-adherence in 26.5% individuals could be an additional factor that can increase the risk of drug resistance.

Adult↗
PubMed1999

The use of antiretroviral agents in patients with renal insufficiency.

Current guidelines for the dosing of antiretroviral agents in HIV-positive patients with renal insufficiency including those requiring dialysis are limited, as revealed by a literature search performed using Health Knowledge Network MEDLINE and HealthSTAR. Pharmacokinetic and chemical aspects were taken into consideration to develop further recommendations. Results showed reverse transcriptase inhibitor dosage adjustment guidelines are available, but for patients receiving dialysis, guidelines are limited to zidovudine and didanosine. There are limited clinical data on dosage adjustments required for the use of protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Indinavir appears to require no dose modification. For nelfinavir, ritonavir and saquinavir, the chemical and pharmacokinetic characteristics along with the pathophysiology of renal dysfunction and dialysis suggest that these agents can likely be given at usual doses with close monitoring for toxicities. More data is required to make recommendations for use of NNRTIs in renal insufficiency. Combining the information from previous dosing guidelines and the pharmacokinetic data of antiretroviral agents allows for preliminary recommendations to be made until confirmed by definitive clinical data.

Anti-HIV Agents↗
PubMed2002

Paediatric antiretroviral therapy audit in South London.

OBJECTIVES: To audit clinical and surrogate marker outcome data following the introduction of combination antiretroviral therapy to HIV-infected children in South London. METHODS: We performed a retrospective cohort study of 110 HIV-infected children under the care of the Paediatric HIV in South London Network (PHILS-NET) from January 1996 to September 1999. The following were identified: type of antiretroviral therapy used; duration of therapy; toxicity; impact on viral load and CD4 count; reasons for changing therapy; and clinical progression. RESULTS: Ninety-one (83%) of the 110 children (55 females; median age 6.3 years) received 166 antiretroviral therapy regimens. Sixty per cent of the regimens were triple therapy: either two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (58; 34.9%) or two NRTIs and one non-nucleoside reverse transcriptase inhibitor (39; 23.5%). The mean duration of completed therapy was 46 weeks for first line therapy with a standard deviation (SD) of 38 weeks and 40 weeks in third line therapy with an SD of 22 weeks. Changes in antiretroviral regimens were owing to virological failure in 60% and toxicity in 10%. Overall, 46% of children on first line and 37% on second line antiretroviral therapy achieved an undetectable viral load of < 400 HIV-1 RNA copies/mL. Clinical progression for the whole cohort fell from 3.7% per year for children on dual therapy to 0.7% per year for children on highly active antiretroviral therapy. CONCLUSIONS: This audit shows the clinical benefit of antiretroviral therapy use in a cohort of children with moderately advanced HIV disease. The surrogate outcome data seen for the viral load and CD4 count are similar to those of reports from clinical trials. Antiretroviral therapy regimens were sequenced rapidly, mainly owing to virological failure.

Adolescent↗
PubMed1999

Interactions among combinations of two and three protease inhibitors against drug-susceptible and drug-resistant HIV-1 isolates.

Protease inhibitors used in combination with reverse transcriptase inhibitors have demonstrated potent anti-HIV-1 activity in vitro as well as in vivo. We evaluated interactions among five protease inhibitors: indinavir (IDV), ritonavir (RTV), saquinavir (SQV), amprenavir (APV), and nelfinavir (NFV), when used in combinations of two and three drugs in vitro against several HIV-1 isolates, including those susceptible and resistant to various nucleoside and nonnucleoside reverse transcriptase inhibitors. Interactions ranged from synergy to slight antagonism depending on the viral isolates and the experimental conditions employed. Further clinical evaluation of protease inhibitor combinations is warranted.

Anti-HIV Agents↗
PubMed2003

Stable prevalence of genotypic drug resistance mutations but increase in non-B virus among patients with primary HIV-1 infection in France.

OBJECTIVE: To evaluate the frequency of drug-resistant HIV-1 viral strains from patients presenting with primary infection in 1999-2000 and to survey the molecular epidemiology of these viruses circulating in France. METHODS: Resistance mutations were detected by sequencing the reverse transcriptase and the protease genes in plasma samples from 249 individuals. Phylogenetic analysis was performed on the reverse transcriptase genes. RESULTS: Ten per cent of patients [26/249; 95% confidence interval (CI) 7-15%] presented with virus mutations associated with resistance to at least one antiretroviral drug. The distribution of the resistance mutations was as follows: to nucleoside reverse transcriptase inhibitors in 19 (8%; 95% CI 5-12%) and to non-nucleoside reverse transcriptase inhibitors in 10 (4%; 95% CI 2-7%). Primary resistance mutations to protease inhibitors were detected in 14 (6%; 95% CI 3-9%). Twelve patients (5%; 95% CI 3-8%) presented with virus harbouring mutations associated with resistance to two or three classes of antiretroviral drugs. The median HIV RNA in plasma at enrollment was lower in patients with one or more drug resistance mutations than in patients with no mutations (5.05 log versus 5.47 log, P = 0.05). Phylogenetic analysis revealed that 19% (14-24%) of patients harboured HIV-1 non-B subtype strains; this proportion remained high when Caucasian patients only were considered (14%). CONCLUSION: This study, performed within the French network on HIV-1 primary infection survey, revealed no change in the frequency of resistant viral strains over time, but showed an increasing prevalence of non-B subtypes overall and among Caucasian individuals.

Drug Resistance, Viral↗
PubMed2004

[Primary HIV drug resistance in a prison population. REPRICOVA-2 Study].

INTRODUCTION: Currently, there are few reports on primary human immunodeficiency virus (HIV) drug resistance in the prison population. METHODS: This is a descriptive, one-day prevalence study to identify HIV drug-resistant mutations in chronically infected treatment-naïve prisoners. Systematic randomized sampling was performed and genotyping was done by automatic sequencing. RESULTS: A total of 90 patients were studied. Two samples were found to have nucleoside reverse transcriptase inhibitor (NRTI)-resistant mutations, four had non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutations and one had protease inhibitor (PI)-resistant mutations. CONCLUSIONS: There was a low rate of primary resistance in our series. Therefore, resistance testing is not required before prescribing initial antiretroviral therapy in these patients.

Adolescent↗
PubMed2001

Disorders of lipid metabolism in patients with HIV disease treated with antiretroviral agents: frequency, relationship with administered drugs, and role of hypolipidaemic therapy with bezafibrate.

OBJECTIVES: To assess the correlation between antiretroviral treatment and dyslipidaemia in HIV-infected patients, and the role of bezafibrate as a lipid-lowering agent. METHODS: We retrospectively compared serum lipid levels of five groups of 40 patients, each of them treated with either saquinavir hard gel, indinavir, or ritonavir (associated with two nucleoside analogues), or dual nucleoside reverse transcriptase inhibitors (NRTI) with or without a non-nucleoside reverse transcriptase inhibitor (NNRTI), or not treated with antiretrovirals, randomly selected from nearly 1000 HIV-infected patients followed-up for >or= 12 months, while on the relevant therapy. Hypertriglyceridaemia was defined by triglyceride levels >or= 172 mg/dl, and hypercholesterolaemia by cholesterol levels >or= 200 mg/dl. All patients with triglyceridaemia > 300 mg/dl and cholesterolaemia > 220 mg/dl for at least 6 months, and unresponsive to a >or= 3-month diet, started bezafibrate (400 mg/day), and were prospectively followed-up at a <or= 3-month interval, evaluating both efficacy and tolerability of the hypolipidaemic treatment, provided that they did not change their protease inhibitor treatment for reasons other than metabolic abnormalities. RESULTS: Hypertrygliceridaemia occurred in 75 patients out of 200 (37.5%), but was significantly more frequent and severe with ritonavir vs. indinavir (P<0.001), and in subjects given indinavir vs. all remaining patients (either treated or not) (P<0.001), while isolated saquinavir use was associated with higher tri glyceride levels than NRTI-NNRTI treatment alone, or no antiretroviral therapy (P<0.03). Hypercholesterolaemia was found in 27 subjects (13.5%), and a significantly higher frequency and severity was shown in patients treated with indinavir and ritonavir vs. saquinavir, NRTI-NNRTI, and no anti-HIV therapy (P<0.05 to P<0.001). No appreciable difference was found between patients undergoing NRTI-NNRTI and untreated controls, for all evaluated variables. Bezafibrate was administered once daily for 6-18 months to 49 patients with elevated and diet-resistant hyperlipidaemia due to ritonavir or indinavir (27 and 22 subjects, respectively), and reduced triglyceride and cholesterol levels by 35% and 25%, respectively over 6 months, without differences between the underlying protease inhibitor regimen. Thirty-three patients (67.3%) reached a normal triglyceridaemia after 6-9 months, and normal cholesterol levels were obtained in all subjects. Bezafibrate proved safe and well tolerated. CONCLUSIONS: Careful monitoring of the serum lipid profile is needed during antiretroviral therapy, including protease inhibitors, to identify the need for a diet and/or an hypolipidaemic treatment, and to prevent clinical sequelae related to long-term dyslipidaemia. Specific guidelines for the management of disorders of lipid metabolism in HIV-infected patients are needed.

Bezafibrate↗
PubMed2002

Antiretroviral pharmacokinetics in the paediatric population: a review.

Characteristics unique to paediatric pharmacotherapy should be considered when treating children infected with human immunodeficiency virus (HIV). Processes of growth and development in the paediatric patient can significantly affect drug absorption and disposition. Immature renal function, altered hepatic enzyme activity and differences in drug absorption lead to variations in systemic exposure of antiretrovirals among children. Paediatric patients are also subject to unique circumstances that may prevent adherence to antiretroviral regimens. The pharmacokinetics of nucleoside reverse transcriptase inhibitors differ significantly among preterm infants, full-term infants and older children. Decreased hepatic glucuronidation activity in neonates results in pharmacokinetic differences in zidovudine disposition when compared with older children. Didanosine, stavudine and lamivudine are renally eliminated, thus resulting in differences among young children with immature renal function. Pharmacokinetic data for non-nucleoside reverse transcriptase inhibitors in children are limited. Decreased elimination of nevirapine among neonates has been observed, primarily due to decreased enzymatic activity. Pharmacokinetic differences across age groups have been noted for efavirenz, but no formal assessments have been conducted in children weighing less than 10kg. Protease inhibitors are metabolised by the cytochrome P450 enzyme system, which is not fully developed in younger children. Decreased metabolism can result in elevated plasma concentrations, thereby increasing the chance of toxicity. Unfortunately, few studies exist evaluating the pharmacokinetics of antiretrovirals in children. As a result, dosage selection of antiretrovirals in children often occurs without adequate data. As the life expectancy of HIV-infected children increases, use of antiretrovirals to prevent disease progression also increases. If prevention of treatment failure continues to be the goal of antiretroviral therapy, the pharmacokinetics of antiretrovirals in children need to be assessed early in the drug development process.

Age Factors↗
PubMed2000

Update on highly active antiretroviral therapy: progress and strategies.

HIV patients who have detectable viral loads (1,000-5,000 copies/mL) and/or evidence of immunologic dysfunction (CD4+ T-lymphocyte count < 500/mm3) should be treated with a potent combination antiretroviral regimen. Currently, this is to consist of two nucleoside reverse transcriptase inhibitors (NRTIs) with at least one protease inhibitor (PI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI), or another combination with adequate potency. The specific regimen should be designed to achieve an undetectable viral load by an ultrasensitive method (< 50 copies/mL). It should be chosen with a view towards maximizing adherence and minimizing significant drug-drug interactions and side effects. Long-term adherence with the initial highly-active regimen will minimize development of resistant viral mutants and preclude the use of higher complexity regimens. If a regimen is failing in the setting of adequate patient adherence, a new regimen should be chosen using at least two new medications to which viral strains are likely to be sensitive (by genotyping determination). If this is not possible, one may consider treatment interruption or, depending on the clinical status of the patient, continue the current suboptimal regimen until new drugs become available. The predictive value of resistance testing is currently being examined in patients who have failed their first therapy. Further developments include vaccine, cytokine-, and gene therapy-based treatment strategies.

Anti-HIV Agents↗
PubMed2003

Simultaneous determination of the HIV drugs indinavir, amprenavir, saquinavir, ritonavir, lopinavir, nelfinavir, the nelfinavir hydroxymetabolite M8, and nevirapine in human plasma by reversed-phase high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatography method for the simultaneous quantitative determination of the currently available HIV protease inhibitors amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, the active nelfinavir metabolite M8, and the nonnucleoside reverse transcriptase inhibitor nevirapine in human plasma is described. The method involved liquid-liquid extraction from plasma, followed by high-performance liquid chromatography with an OmniSpher 5 C18 column and ultraviolet detection set at a wavelength of 215 nm for the protease inhibitors and 280 nm for nevirapine. The runtime was 25 minutes. The assay has been validated over the concentration range of 0.05 to 30 mg/L for indinavir, nelfinavir, ritonavir, and saquinavir, 0.07 to 30 mg/L for amprenavir and lopinavir, and 0.05 to 15 mg/L for M8 and nevirapine. This method proved to be simple, accurate, and precise and is useful for the therapeutic drug monitoring of protease inhibitors and the nonnucleoside reverse transcriptase inhibitor nevirapine on a routine basis.

Adult↗
PubMed2004

Genetic correlates of efavirenz hypersusceptibility.

BACKGROUND: Non-nucleoside reverse transcriptase inhibitor (NNRTI) hypersusceptibility is seen in approximately 30% of HIV isolates with nucleoside reverse transcriptase inhibitor (NRTI) resistance. NNRTI hypersusceptibility has been associated with improved outcomes to NNRTI-based therapy. OBJECTIVE: To determine the genetic correlates of efavirenz hypersusceptibility. METHODS: Paired baseline genotypes and phenotypes were obtained from 444 NRTI-experienced, NNRTI-naive patients. Fisher's exact tests, recursive partitioning (classification and regression trees; CART), and stepwise binary regression were used to identify specific reverse transcriptase (RT) mutations associated with efavirenz hypersusceptibility. RESULTS: In univariate analyses, 26 RT codons were associated with efavirenz hypersusceptibility (P < 0.05), the top five were 215 > 41 > 210 > 118 > 208 (all P < 0.000001). From stepwise model selection, the 215, 208 and 118 mutations remained independently predictive of efavirenz hypersusceptibility. A final binary regression model to predict efavirenz hypersusceptibility included one covariate for the 215 mutation (relative risk 2.6, P < 0.0001) and a second covariate representing either the 208 or 118 mutation (relative risk 1.8, P < 0.0001). Similarly, in a CART analysis, a mutation at codon 215 was the first split selected, followed by mutations at 208 and 118. An efavirenz hypersusceptibility genotypic score using the three mutations 208, 118 and 215 was as accurate at predicting efavirenz hypersusceptibility as a more complex scoring system using 26 mutations. CONCLUSION: Mutations at 215, 208 and 118 were independently associated with NNRTI hypersusceptibility. After confirmatory studies using other large datasets, incorporating a hypersusceptibility score into genotype interpretation algorithms will improve the prediction of NNRTI hypersusceptibility.

Alkynes↗
PubMed1999

[Evaluation of mutations that confer resistance to nucleoside analogs and protease inhibitors in HIV-1-infected patients. Study Group on Resistance to Antiretroviral Agents].

Genotypes that confer drug resistance to reverse transcriptase inhibitors and protease inhibitors were evaluated in HIV-1 proviral DNA obtained from peripheral blood mononuclear cell samples. Fifty-three HIV-1-infected patients were studied, 19 of whom had not received antiretroviral treatment. In the other 34 patients, 9 had been treated with combinations of two reverse transcriptase inhibitors (AZT, ddI, d4T, 3TC) and 25 had been treated with triple antiretroviral therapy including a protease inhibitor (nelfinavir, indinavir, saquinavir, ritonavir). To determine the presence of mutations involved in the development of resistance to reverse transcriptase inhibitors a hybridization Microtiter assay was carried out. Mutations were detected in treated patients as well as in those without previous antiretroviral treatment, with the most frequent mutations being those that confer resistance to AZT, followed by those that develop cross-resistance to ddI/ddC and 3TC, which are the most commonly used drugs to date. No mutations were detected to any nucleoside analog in only 13 cases. To analyze the presence of mutations in the protease gene a dot-blot hybridization was carried out which included the mutations in codons 36, 82 and 90. Mutation 82 was detected in one case. Therefore, with the aim of determining the pattern of genotypic mutations in patients infected with HIV-1 and in order to make the best therapeutic choice, it would be recommended to consider carrying out genotypic resistance assays in clinical practice.

Anti-HIV Agents↗
PubMed2003

Medium-term survival, morbidity and immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Côte d'Ivoire.

OBJECTIVES: To evaluate survival, morbidity, and CD4 and viral load (VL) evolution in HIV-infected adults receiving antiretroviral therapy (ART) in Côte d'Ivoire. METHODS: Since 1996, 723 HIV-infected adults have been followed up in the ANRS 1203 cohort study in Abidjan. For those patients who received ART, we describe data between ART initiation and August 2002. RESULTS: One-hundred-and-one adults (61% women) were followed up under ART for a median of 17 months. At ART initiation, median age, CD4 count and VL were 36 years, 135/mm3 and 5.3 log10 copies/ml, respectively. Initial ART regimens were two nucleoside reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor in 74 patients, two NRTIs plus one non-nucleoside reverse transcriptase inhibitor in 16, and two NRTIs in 11. No patient was lost to follow-up. The most frequent causes of severe morbidity were bacterial infections [11.6/100 person-years (PY), 95% CI: 7.2-18.7], drug-related events (6.5/100 PY, 3.5-12.0), tuberculosis (3.1/100 PY, 1.3-7.4) and malaria (3.1/100 PY, 1.3-7.4). The incidence of death was 3.0/100 PY (1.1-8.0) in patients with baseline CD4 > or = 50/mm3 and 16.1/100 PY (7.2-35.9) in patients with CD4 < 50/mm3. Fifty percent of causes of death were active infections pre-existing ART initiation, mainly atypical mycobacteriosis. After 1 year, 51% of patients had undetectable VL, 28% had detectable VL reduced by more than 0.5 log10 copies/ml since ART initiation, and the median gain in CD4 was +115/mm3. CONCLUSION: Medium-term survival under ART may be as good in Africa as in industrialized countries, provided that patients benefit from access to care for opportunistic infections, including bacterial diseases, tuberculosis and malaria.

AIDS-Related Opportunistic Infections↗
PubMed1987

Suramin in the treatment of AIDS: mechanism of action.

Suramin is a potent inhibitor of the reverse transcriptase (RNA-directed DNA polymerase) of retroviruses, including the HTLV-III/LAV (human T-cell lymphotropic virus type III/lymphadenopathy-associated virus) reverse transcriptase. Although suramin is far from specific as a reverse transcriptase inhibitor and known to interact with a multitude of proteins and enzymes, it is able to suppress the replication and cytopathic effect of HTLV-III/LAV at concentrations which are nontoxic for the host cells and readily attainable in humans. Consequently, suramin is also able to block HTLV-III/LAV replication in patients. The mechanism of action of suramin at the molecular biological level, its mode of transport and accumulation by the infected host cells, and the bases for its rather selective virustatic activity remain, to a large extent, to be elucidated.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Triple nucleoside analogue antiretroviral therapy: expanding the treatment approaches for management of HIV infection.

The expanding range of drug options for the management of persons with HIV infection and concerns about the long-term safety of some treatment approaches has precipitated the HIV treatment community to examine a wider range of treatment approaches. One new therapeutic approach is to consider using three nucleoside analogue reverse transcriptase inhibitors, particularly as initial therapy. Recent data comparing triple nucleoside analogue therapy with established 'standard of care' triple therapy regimens have demonstrated similar antiviral effects and tolerability for such regimens. Efficacy and tolerability of triple nucleoside therapy has been demonstrated up to 96 weeks of therapy. This approach has advantages over conventional two nucleoside plus either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor in terms of drug interactions and maintenance of multiple class options. It creates regimens which are, for the most part, compact, twice daily and non-food dependent. Specifically, this approach has already become widely established for individuals for whom drug interactions exclude the use of protease or non-nucleoside antiretrovirals. Triple nucleoside analogue therapy is likely to represent an attractive option for both physicians and patients; its use in clinical practice is likely to further expand.

Journal Article↗