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PubMed2001

Rapid and simple phenotypic assay for drug susceptibility of human immunodeficiency virus type 1 using CCR5-expressing HeLa/CD4(+) cell clone 1-10 (MAGIC-5).

We describe a rapid and simple novel phenotypic assay for drug susceptibility of human immunodeficiency virus type-1 (HIV-1) using a CCR5-expressing HeLa/CD4(+) cell clone 1-10 (MAGIC-5). MAGIC-5 cells produced large amounts of HIV-1 in culture supernatants, which enabled us to perform the phenotypic resistance assay. Determination of HIV-1 susceptibility to various protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors was completed within 15 days in T-cell-tropic (X4) and macrophage-tropic (R5) viruses using fresh plasma samples containing at least 10(4) copies/ml. The nucleotide sequence of the envelope V3 region of HIV-1 in plasma was almost identical to that of the virus isolated by MAGIC-5 cells, suggesting a lack of selection bias in our assay. The assay variability was confined to within five-fold in all drugs examined. Accordingly, we used a 10-fold increase in the 50% inhibitory concentration as the cutoff value for viral resistance in the present assay. HIV-1 resistant to lamivudine, which was not detected by conventional genotypic assays, was isolated. In HIV-1 with PI-associated primary amino acid substitutions, our assay showed that drug resistance profiles correlated well with previously reported genotypic-assay data. Furthermore, our assay provided comprehensive results regarding PI resistance in the presence of multiple mutations. The novel assay successfully quantified the level of resistance of clinical HIV-1 isolates to a battery of anti-HIV drugs, indicating its clinical usefulness, particularly in patients who failed to respond to antiretroviral chemotherapy.

Amino Acid Sequence↗
PubMed2003

Validation of a model for the complex of HIV-1 reverse transcriptase with nonnucleoside inhibitor TMC125.

The structure for the complex of nonnucleoside inhibitor TMC125 and HIV-1 reverse transcriptase has been determined and validated through computation of resistance profiles using Monte Carlo/free-energy perturbation calculations. The good quantitative agreement between the computed and experimental anti-HIV activities for TMC125, nevirapine, and efavirenz with wild-type RT and four common mutants (L100I, K103N, Y181C, and Y188L) confirms the correctness of the predicted structure and provides insights into the improved potency of this novel NNRTI. The blue shading in the figure indicates basic residues.

Anti-HIV Agents↗
PubMed2005

Oligonucleotide ligation assay for detection of mutations associated with reverse transcriptase and protease inhibitor resistance in non-B subtypes and recombinant forms of human immunodeficiency virus type 1.

The oligonucleotide ligation assay is a genotypic assay for the detection of resistance-associated mutations to reverse transcriptase and protease inhibitors in human immunodeficiency virus type 1 subtype B. This assay has been modified and developed for non-B subtypes and recombinant strains and has been evaluated with sequencing, resulting in a more sensitive assay than sequencing for non-B subtypes.

Anti-HIV Agents↗
PubMed2006

Declining prevalence of HIV-infected individuals at risk of transmitting drug-resistant HIV in Denmark during 1997-2004.

BACKGROUND: Transmission of drug-resistant HIV is a potential threat to the substantial clinical benefit of highly active antiretroviral therapy (HAART). To explore the background for the low rates of drug resistance transmission (2.5%) in our population, we estimated acquisition of HIV drug resistance and examined temporal trends in the prevalence of patients at risk of transmitting drug-resistant HIV. METHODS: The study population included all 4,025 patients from The Danish HIV Cohort Study seen during the period 1995-2004. Virological failure to a given drug class was defined as a viral load (VL) > 1,000 copies/ml for 120 days while on a HAART regimen including that drug class. In addition, receiving nucleoside reverse transcriptase inhibitors (NRTIs) for 180 days before HAART counted as NRTI failure irrespective of VL. Having experienced failure was considered a proxy for harbouring drug-resistant virus in subsequent observation time. Patients with a current VL > 1,000 copies/ml were considered at risk of transmitting HIV. RESULTS: We found a decrease from 1997 to 2004 in the prevalence of potential transmitters of drug-resistant HIV. The number of these patients with previous NRTI failure decreased from 429 (24% of all patients) in 1998 to 213 (8.0% of all patients) in 2004. Previous protease inhibitor (PI) failure peaked at 279 (14%) in 1999, declining to 142 (5.3%) in 2004. Previous NNRTI failure peaked at 121 patients (4.7%) in 2002, and occurred in 113 patients (4.2%) in 2004. Of all 686 potential transmitters in 2004, 31% had previously experienced NRTI failure, 21% PI failure, and 16% non-NRTI failure. CONCLUSION: In the population of HIV-infected individuals in Denmark with complete follow-up, the number at risk of transmitting drug-resistant virus declined over time.

Antiretroviral Therapy, Highly Active↗
PubMed2003

The effect of NNRTIs on HIV reverse transcriptase dimerization.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are chemically diverse compounds that allosterically inhibit HIV-1 reverse transcriptase (RT). NNRTIs are highly effective in the treatment of HIV-infected individuals when used in combination with other anti-HIV drugs. Recent studies have demonstrated that various NNRTIs can enhance, destabilize or have no effect on HIV-1 RT dimerization, suggesting that these drugs have different modes of binding to the HIV-1 RT. The strong enhancement of RT dimerization by many conventional NNRTIs such as efavirenz may contribute in part to the inhibitory activity of these drugs, while subunit destabilization by unconventional NNRTIs is thought to interfere with the RT heterodimerization-induced conformational changes that are essential for enzyme function. These studies suggest that modulation of subunit interaction by NNRTIs represents a previously unrecognized property of these RT inhibitors that could be exploited to produce more potent inhibitors of HIV-1 RT.

Anti-HIV Agents↗
PubMed2001

Primary genotypic and phenotypic HIV-1 drug resistance in recent seroconverters in Madrid.

OBJECTIVE: Transmission of drug-resistant HIV-1 strains is increasing with widespread use of antiretroviral drugs in developed countries. This study examined the prevalence of resistant viruses in recent seroconverters in Madrid, Spain. DESIGN: HIV isolates from 30 consecutive participants with positive or indeterminate HIV antibody test results and a negative test result at a mean of 6.6 months earlier were examined for HIV drug resistance. All study subjects admitted to having very recently engaged in high-risk practices. All were therapeutically naive and were recruited between 1997 and 1999 in a referring health care facility for sexually transmitted diseases. METHODS: Population-based sequencing of the viral reverse transcriptase (RT) and protease (PR) regions derived from plasma viral RNA was performed. Phenotypic resistance was assessed by a recombinant virus assay. RESULTS: Overall prevalence of genotypes associated with reduced susceptibility was 26.7% (8 of 30 participants). Resistance mutations were seen against nucleoside analogues in 7 (23.3%), nonnucleoside reverse transcriptase inhibitors in 1 (3.3%), and protease inhibitors in 2 (6.7%). Zidovudine-resistance mutations M41L and/or T215Y were the commonest, found in 20% (6 of 30 participants). Resistance mutations to at least two antiretroviral families (multidrug-resistance) were detected in 2 (6.7%) study subjects. A median infectious dose (IC50) increase of fourfold for any drug was found in 7 patients, and in 2 was > tenfold for zidovudine (genotype M41L + T215Y) and lamivudine (genotype M184V), respectively. CONCLUSIONS: Drug-resistant HIV variants were present in over one quarter of individuals recently diagnosed as infected in Madrid, Spain. Therefore, resistance testing at baseline should be considered for the optimal design of first-line antiretroviral combinations.

Drug Resistance, Microbial↗
PubMed2006

Novel tight binding PETT, HEPT and DABO-based non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are a key component of effective combination antiretroviral therapies for HIV/AIDS. NNRTIs despite their chemical diversity, bind to a common allosteric site of HIV-1 RT, the primary target for anti-AIDS chemotherapy, and noncompetitively inhibit DNA polymerization. NNRTIs currently in clinical use have a low genetic barrier to resistance and therefore, the need for novel NNRTIs active against drug-resistant mutants selected by current therapies is of paramount importance. We describe the chemistry and biological evaluation of highly potent novel phenethylthiazolylthiourea (PETT), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the hydrophobic binding pocket of HIV-1 RT. These NNRTIs were rationally designed by molecular modeling and docking studies using a novel composite binding pocket that predicted how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up and how these changes could affect NNRTI binding. Several ligand derivatization sites were identified for docked NNRTIs that fit the composite binding pocket. The best fit was determined by calculating an inhibition constant (Ludi Ki) of the docked compound for the composite binding pocket. Compounds with a Ludi Ki of <1 microM were identified as the most promising tight binding NNRTIs. These NNRTIs displayed high selective indices with robust anti-HIV-1 activity against the wild-type and drug-resistant isolates carrying multiple RT gene mutations. The high rate of treatment failure due to the emergence of drug resistance mutations makes the discovery of broad-spectrum PETT, HEPT and DABO-based NNRTIs useful as a component of effective combination regimens.

Acquired Immunodeficiency Syndrome↗
PubMed2006

An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults.

OBJECTIVE: To compare the effectiveness of three drug combination antiretroviral therapy (ART) in treatment-naive HIV-infected persons, and identify the predictors of responses. DESIGN AND METHODS: Overview of trials identified by searching public domain publications and conference presentations. The three-drug combination therapy was defined as two nucleoside reverse transcriptase inhibitors (NRTI) or nucleotide and NRTI, and either: (1) a protease inhibitor (PI); (2) a non-nucleoside RTI (NNRTI); (3) a third NRTI; or (4) a ritonavir-boosted PI (BPI). Week 24 and 48 results for the proportions of patients with plasma HIV RNA levels < 400 and < 50 copies/ml, and change in CD4(+) cell counts were recorded. RESULTS: Fifty-three trials met the entry criteria, and enrolled 14 264 patients into 90 treatment arms. Overall 55% of patients had plasma HIV RNA levels < 50 copies/ml at week 48 and this percentage increased with later publication dates. In unadjusted pairwise comparisons at week 48, significantly greater percentages of patients receiving NNRTI (64%) and BPI (64%) had RNA < 50 copies/ml than NRTI (54%) or PI (43%), and CD4(+) cell count increases were significantly greater in the BPI group (+200 cells/microl) than the PI (+179), NNRTI (+173), or NRTI (+161) groups. Pill count and percentage of patients with week 48 plasma HIV RNA levels < 50 copies/ml were correlated in the univariate analysis (P = 0.0053; r = -0.323), but pill count was not a significant predictor in the multivariate analyses. Drug class and baseline CD4(+) cell counts were significant predictors, but explained only a modest amount of the treatment effect, (R(2) = 0.355). CONCLUSIONS: NNRTI and BPI-containing regimens offer superior virologic suppression over 48 weeks, supporting existing guidelines for the choice of initial ART. Pill count was not a consistent predictor of virologic suppression.

Anti-HIV Agents↗
PubMed1998

Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers.

The potential pharmacokinetic drug-drug interaction between delavirdine, a nonnucleoside analogue reverse transcriptase inhibitor, and indinavir, an inhibitor of HIV protease, was evaluated in healthy volunteers. Subjects received a single 800-mg dose of indinavir sulfate on day 1 (baseline). Delavirdine mesylate 400 mg was administered three times daily on days 2 through 10. On day 9, a single 400-mg dose and on day 10 a single 600-mg dose of indinavir were given along with morning doses of delavirdine. Pharmacokinetic evaluations of indinavir were made on days 1, 9, and 10, and of delavirdine on days 8, 9, and 10. Fourteen healthy male volunteers completed the study. Single doses of indinavir had no clinically important effects on the pharmacokinetics of delavirdine. Mean indinavir Cmax values for the 400-mg and 600-mg doses administered concomitantly with delavirdine were dose proportionally lower than that observed following the 800-mg dose administered alone. Mean Tmax values were similar and ranged from 1.0 +/- 0.3/hour for indinavir 800 mg administered alone to 1.3 +/- 0.4/hour for indinavir 600 mg administered with delavirdine. These results indicate that delavirdine had no clinically important effect on the rate of indinavir absorption. In contrast, the mean indinavir AUC0-infinity, value following the 400-mg dose administered with delavirdine was only 14% lower than the baseline value determined for the 800-mg indinavir dose (25,400 +/- 6960 nM hour versus 29,600 +/- 7920 nM hour), and the mean indinavir AUC0-infinity value for the 600-mg indinavir dose administered with delavirdine (42,700 +/- 9800 nM hour) was 44% greater than the baseline value. All differences among mean AUC0-infinity values were statistically significant. Mean indinavir half-life values were slightly longer when indinavir was given in a dose with delavirdine than when indinavir was administered alone. These results suggest that delavirdine inhibits metabolism of indinavir and support the possibility of a reduction in the magnitude or frequency of indinavir dosage when given in combination with delavirdine.

Administration, Oral↗
PubMed2004

Antiretroviral drugs with adverse effects on adipocyte lipid metabolism and survival alter the expression and secretion of proinflammatory cytokines and adiponectin in vitro.

OBJECTIVE: The lipodystrophy syndrome is a major adverse effect of highly active antiretroviral therapy (HAART), associated with altered circulating levels and adipose tissue mRNA expression of proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor (TNF)alpha, and adiponectin. Proinflammatory cytokines and adiponectin, which are secreted by adipose tissue, regulate fat metabolism, insulin sensitivity and adipose cell apoptosis. We examined the direct effects of individual antiretrovirals on lipid metabolism and cytokine and adiponectin production by cultured adipocytes. METHODS: Differentiating 3T3-F442A cells and differentiated 3T3-L1 adipocytes were treated for 12 or 4 days, respectively, with protease inhibitors (PIs) indinavir, nelfinavir, amprenavir, lopinavir and ritonavir, or nucleoside reverse transcriptase inhibitors (NRTIs) stavudine and zidovudine, at near-Cmax concentrations. Lipid metabolism was estimated by Oil Red O staining of intracellular lipids, mRNA expression of fatty acid synthase and adipocyte lipid binding protein 2, and insulin activation of lipogenesis. Apoptosis was estimated by flow cytometry. The expression and secretion of proinflammatory cytokines (IL-6, TNFalpha and IL-1beta) and adiponectin were evaluated by real-time reverse transcription PCR and ELISA. RESULTS: Chronic treatment of 3T3-F442A differentiating adipocytes and differentiated 3T3-L1 adipocytes with PIs and NRTIs reduced lipid accumulation, mRNA expression of lipid markers and insulin-induced lipogenesis. IL-6, TNFalpha, IL-1beta and adiponectin expression and secretion were markedly altered in differentiating 3T3-F442A adipocytes. PIs had either no effect on differentiated 3T3-L1 adipocytes (TNFalpha expression and sucretion) or their effect was less marked than in 3T3-F442A cells. Indinavir and amprenavir did not alter cytokine secretion and expression by mature adipocytes. The effects of stavudine and zidovudine on differentiating and mature adipocytes were similar, despite the difference in treatment procedure. The drugs with the strongest effect on TNFalpha expression also increased adipocyte apoptosis, in contrast to the drugs that only moderately increased TNFalpha expression. CONCLUSIONS: These results suggest that increased cytokine and decreased adiponectin secretion and expression induced by some PIs and NRTIs may contribute to the adipose tissue loss (via apoptosis and lipid leakage) and insulin resistance associated with the lipodystrophy syndrome.

3T3-L1 Cells↗
PubMed2002

Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir.

Cells of macrophage lineage represent a key target of human immunodeficiency virus (HIV) in addition to CD4-lymphocytes. The absolute number of infected macrophages in the body is relatively low compared to CD4-lymphocytes. Nevertheless, the peculiar dynamics of HIV replication in macrophages, their long-term survival after HIV infection, and their ability to spread virus particles to bystander CD4-lymphocytes, make evident their substantial contribution to the pathogenesis of HIV infection. In addition, infected macrophages are able to recruit and activate CD4-lymphocytes through the production of both chemokines and virus proteins (such as nef). In addition, the activation of the oxidative pathway in HIV-infected macrophages may lead to apoptotic death of bystander, not-infected cells. Finally, macrophages are the most important target of HIV in the central nervous system. The alteration of neuronal metabolism induced by infected macrophages plays a crucial role in the pathogenesis of HIV-related encephalopathy. Taken together, these results strongly support the clinical relevance of therapeutic strategies able to interfere with HIV replication in macrophages. In vitro data show the potent efficacy of all nucleoside analogues inhibitors of HIV-reverse transcriptase in macrophages. Nevertheless, the limited penetration of some of these compounds in sequestered districts, coupled with the scarce phosphorylation ability of macrophages, suggests that nucleoside analogues carrying preformed phosphate groups may have a potential role against HIV replication in macrophages. This hypothesis is supported by the great anti-HIV activity of tenofovir and other acyclic nucleoside phosphonates in macrophages that may provide a rationale for the remarkable efficacy of tenofovir in HIV-infected patients. Non-nucleoside reverse transcriptase inhibitors (NNRTI) do not affect HIV-DNA chain termination, and for this reason their antiviral activity in macrophages is similar to that found in CD4-lymphocytes. Interestingly, protease inhibitors (PIs), acting at post-integrational stages of virus replication, are the only drugs able to interfere with virus production and release from macrophages with established and persistent HIV infection (chronically-infected cells). Since this effect is achieved at concentrations and doses higher than those effective in de-novo infected CD4-lymphocytes, it is possible that lack of adherence to therapy, and/or suboptimal dosage leading to insufficient concentrations of PIs may cause a resumption of virus replication from chronically-infected macrophages, ultimately resulting in therapeutic failure. For all these reasons, therapeutic strategies aimed to achieve the greatest and longest control of HIV replication should inhibit HIV not only in CD4-lymphocytes, but also in macrophages. Testing new and promising antiviral compounds in such cells may provide crucial hints about their efficacy in patients infected by HIV.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Clinical lipoatrophy in HIV-1 patients on HAART is not associated with increased abdominal girth, hyperlipidaemia or glucose intolerance.

OBJECTIVE: To compare information on body fat changes from questionnaire and clinical examination and to study lipoatrophy in HIV-1 patients on highly active antiretroviral therapy (HAART). METHODS: The study was cross-sectional within a randomized trial. One hundred and sixty-eight male HIV-1 patients were examined by questionnaire and clinical examination. Clinical lipoatrophy was studied and defined as fat wasting in the face, legs and/or arms. Fasting blood samples reflecting lipid and glucose metabolism were taken and the role of indinavir, ritonavir (RTV) and RTV/saquinavir (SQV) on lipoatrophy was investigated. RESULTS: After a median of 17 months on HAART, concordance rates between information on changes in body fat from questionnaire and clinical examination were significant and varied from 70 to 96%. With a positive criteria of lipoatrophy in both assessments, 14% of patients had lipoatrophy. These patients had lower weight (P = 0.0007), weight loss from baseline (P = 0.003), lower circumferences at all measurements (P < 0.01), lower plasma triglycerides and low-density lipoprotein (LDL) (P < 0.05) and longer treatment with stavudine (P = 0.0009). Homeostasis model assessment (HOMA) estimates for insulin resistance and beta-cell function were comparable. Plasma cholesterol, triglycerides and very low-density lipoprotein (VLDL) were higher in patients receiving RTV or RTV/SQV (P < 0.03). CONCLUSION: Questionnaire and clinical assessment provide concordant information on changes in body fat. Lipoatrophic patients on HAART with neither increase in abdominal circumference, nor hyperlipidaemia nor glucose intolerance may have side-effects to protease inhibitor treatment, to nucleoside reverse transcriptase inhibitor treatment (stavudine) or suffer from a drug-independent condition.

Adult↗
PubMed2003

Combination antiretroviral therapy and the risk of myocardial infarction.

BACKGROUND: It remains controversial whether exposure to combination antiretroviral treatment increases the risk of myocardial infarction. METHODS: In this prospective observational study, we enrolled 23,468 patients from 11 previously established cohorts from December 1999 to April 2001 and collected follow-up data until February 2002. Data were collected on infection with the human immunodeficiency virus and on risk factors for and the incidence of myocardial infarction. Relative rates were calculated with Poisson regression models. Combination antiretroviral therapy was defined as any combination regimen of antiretroviral drugs that included a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. RESULTS: Over a period of 36,199 person-years, 126 patients had a myocardial infarction. The incidence of myocardial infarction increased with longer exposure to combination antiretroviral therapy (adjusted relative rate per year of exposure, 1.26 [95 percent confidence interval, 1.12 to 1.41]; P<0.001). Other factors significantly associated with myocardial infarction were older age, current or former smoking, previous cardiovascular disease, and male sex, but not a family history of coronary heart disease. A higher total serum cholesterol level, a higher triglyceride level, and the presence of diabetes were also associated with an increased incidence of myocardial infarction. CONCLUSIONS: Combination antiretroviral therapy was independently associated with a 26 percent relative increase in the rate of myocardial infarction per year of exposure during the first four to six years of use. However, the absolute risk of myocardial infarction was low and must be balanced against the marked benefits from antiretroviral treatment.

Adult↗
PubMed2006

Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects.

Concurrent use of natural health products (NHPs) with antiretroviral drugs (ARVs) is widespread among human immunodeficiency virus-infected patients. This article reviews the clinical pharmacokinetic and pharmacodynamic interactions between NHPs and ARVs. Many NHPs are complex mixtures and are likely to contain organic compounds that may induce and/or inhibit drug metabolizing enzymes and drug transporters. Although the weight of evidence for the effects of certain NHPs varies and many studies of these products lack scientific rigor, it has been observed that St. John's wort clearly induces cytochrome P450 3A4 and P-glycoprotein and reduces protease inhibitor and nonnucleoside reverse-transcriptase inhibitor concentrations, thereby increasing the likelihood of therapeutic failure. Limited clinical research suggests that intake of garlic and vitamin C results in reductions in ARV concentrations. The intake of milk thistle, Echinacea species, and goldenseal inhibits cytochrome P450 enzymes in vitro and may increase ARV concentrations, but by clinically unimportant amounts. Intake of fish oil reduces ARV-induced hypertriglyceridemia without significantly affecting lopinavir concentrations. Before recommending the use of NHPs as adjuncts to ARV use, studies should first exclude significant pharmacokinetic interactions and ensure that ARV efficacy is maintained.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Serotonin syndrome in HIV-infected individuals receiving antiretroviral therapy and fluoxetine.

OBJECTIVE: To describe HIV-infected individuals taking antidepressants who developed the serotonin syndrome due to drug--drug or drug--food interactions. DESIGN AND SETTING: Case studies carried out at the HIV Outpatient Clinic, Atlanta Veterans Affairs Medical Center. PARTICIPANTS AND INTERVENTIONS: HIV-positive patients who were receiving antiretroviral and antidepressant therapies and presented with symptoms consistent with the serotonin syndrome. Their antidepressants were discontinued or the doses reduced in order to resolve the symptoms. RESULTS: Five cases of serotonin syndrome developed after patients who were taking antidepressants ingested P450 inhibitors. CONCLUSIONS: Serotonin syndrome should be suspected in patients on serotonergic medications who present with mental status change, autonomic dysfunction, and neuromuscular abnormalities. Suspicion should be heightened in those who are ingesting substances known to inhibit P450 enzymes, such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and grapefruit juice.

Adult↗
PubMed1997

Advances in antiviral therapy.

For many years, acyclovir has been used to treat herpes simplex and varicella zoster infections in adults and children, although new drugs with improved bioavailability and dosage regimens (ie, famciclovir, valaciclovir) are replacing it for the outpatient management of these conditions in adults. Acyclovir remains the treatment of choice for severe herpes infections in both immunocompetent and immunosuppressed patients. Data on the newer antiherpes drugs in children are not available. Treatment of severe cytomegalovirus infections with ganciclovir and foscarnet is difficult because of toxicity; whether improved formulations of these drugs or newer agents prove clinically useful remains to be seen. For the most part, treatment of other herpesviruses is not indicated. The major advance in pediatric HIV treatment is the reduction in vertical transmission with peripartum zidovudine, although the optimal use of antiretrovirals in this situation remains to be determined. The nucleoside analogues zidovudine, zalcitabine, didanosine, and stavudine have been assessed in HIV-infected children; pediatric data about appropriate combinations (eg, with the protease inhibitors and the nonnucleoside reverse transcriptase inhibitors) and dosage regimens lag well behind the adult literature. The effectiveness of ribavirin in respiratory syncytial virus disease is uncertain. Preliminary data suggest that interferons may have a role in the management of chronic hepatitis B and C.

Adult↗
PubMed1999

A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease.

The immunologic and virologic activity of nevirapine in combination with two nucleosides (zidovudine [ZDV] and didanosine [ddI]) was evaluated in antiretroviral-naive patients with a CD4 count <200/mm3 or clinical AIDS. In all, 68 patients were enrolled in a 48-week double-blind, placebo-controlled trial. A group of 32 patients received ZDV + ddI + nevirapine, and 36 patients received ZDV + ddI. Primary efficacy parameters were the activity on HIV-1 RNA and on peripheral blood CD4+ cells, with differences between groups analyzed by the Wilcoxon's nonparametric two-sample test. Baseline RNA was high in both treatment groups (median values, 5.8 and 5.7 log10). RNA and CD4 responses were significantly higher with the triple combination (median RNA reductions, 2.69 versus 1.05 log10 at 24 weeks and 1.97 versus 1.20 log10 at 48 weeks; median CD4 increases, 81 versus 64 cells/mm3 at 24 weeks and 101 versus 27 cells/mm3 at 48 weeks). This study demonstrates that a triple combination of ZDV + ddI + nevirapine used as first-line regimen in antiretroviral-naive patients can induce sustained virologic and immunologic response in patients with low CD4 count or a previous diagnosis of AIDS.

Acquired Immunodeficiency Syndrome↗