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Biomedical subjects

Robert L Murphy

Publications and source records attributed to Robert L Murphy.

At least 19 recordsLinked to original sources
PubMed2005

Transient viremia in HIV-infected patients and use of plasma preparation tubes.

Using plasma preparation tubes for the collection and storage of plasma resulted in factitious, low-level human immunodeficiency virus type 1 (HIV-1) viremia among patients receiving highly active antiretroviral therapy who incurred unnecessary additional clinic visits, laboratory testing, and medication changes. We caution clinicians against the routine use of plasma preparation tubes for collection of blood samples for HIV-1 level 1 quantification.

Adult↗
PubMed2005

Incidence of pancreatitis in HIV-1-infected individuals enrolled in 20 adult AIDS clinical trials group studies: lessons learned.

OBJECTIVE: To report on the incidence of clinical- and laboratory-defined pancreatitis in HIV-1-infected individuals treated with antiretrovirals (ARVs). METHODS: Pancreatitis incidence rates were calculated based on a Poisson distribution for subjects enrolled in 1 or more of 20 Adult AIDS Clinical Trials Group studies from October 1989 through July 1999. RESULTS: A total of 8451 subjects were enrolled. The overall pancreatitis rates were 0.61 per 100 person-years (PYs) clinical and 2.23 per 100 PYs clinical/laboratory. Pancreatitis rates for single, dual, and triple nucleoside reverse transcriptase inhibitors (NRTIs) were similar. Rates of pancreatitis in didanosine (ddI) arms seemed to be dose dependent. Pancreatitis rates in ddI/hydroxyurea (HU) arms were not significantly different from the rates for ddI alone. Overall pancreatitis rates for ddI/stavudine (d4T) trials were high at 4.16 per 100 PYs clinical and 6.25 per 100 PYs clinical/laboratory. The highest rates were seen with the combination of indinavir (IDV)/ddI/d4T with or without HU. CONCLUSIONS: The combination of NRTIs and definition has an impact on the incidence of pancreatitis. Standardization of definition and more comprehensive evaluations are needed to determine how much of this pancreatitis is directly caused by ARVs and how much is attributable to preexisting comorbidities and other known risk factors.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy.

OBJECTIVE: To evaluate risk factors for mortality among patients with AIDS in the era of highly active antiretroviral therapy (HAART), particularly the effect of cytomegalovirus (CMV). DESIGN: Prospective cohort study of patients with AIDS, conducted from 1998 through 2003. PARTICIPANTS: One thousand five hundred eighty-three patients with AIDS, of whom 374 had CMV retinitis. METHODS: Patients were contacted every 3 months, with examinations at least every 6 months, in which standardized data were collected on AIDS history and treatment, eye examinations, and hematologic, virologic, and immunologic laboratory data. MAIN OUTCOME MEASURE: Mortality. RESULTS: The overall mortality rate was 0.07 deaths/person-year. In a multivariate analysis, the following baseline risk factors were associated with an increased mortality: higher human immunodeficiency virus (HIV) viral load (relative risk [RR] = 4.6 for HIV viral load >100,000 copies/ml vs. <400 copies/ml; P<0.0001), lower CD4+ T-cell count at enrollment (RR = 3.8 for CD4+ T cell count 0-49 cells/microl vs. > or = 200 cells/microl; P<0.0001), CMV viral load > or = 400 copies/ml (RR = 1.9; P = 0.002), lower hemoglobin (RR = 1.7 for hemoglobin <10 g/dl; P = 0.009), a history of cryptococcal meningitis (RR = 1.7; P = 0.02), CMV retinitis (RR = 1.6; P = 0.0002), and Karnofsky score < or = 80 (RR = 1.4; P = 0.008). CONCLUSIONS: In the era of HAART, CMV disease as manifested by CMV retinitis and a detectable CMV viral load were associated with an increased risk for mortality, even after adjusting for demographic, treatment, immunologic, and HIV virologic factors.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Clinical, microbiological, and immunological characteristics in HIV-infected subjects at risk for disseminated Mycobacterium avium complex disease: an AACTG study.

The clinical, microbiologic, and immunologic parameters in HIV-infected subjects first presenting with disseminated Mycobacterium avium complex (DMAC) were determined. Four HIV-positive groups not yet on DMAC treatment were enrolled: 19 subjects with CD4 lymphocyte counts < or =50/microl thought to have DMAC on clinical grounds; 18 subjects newly found to have a positive blood culture for MAC; 25 asymptomatic controls (CD4 cell counts < or =50); and 25 asymptomatic controls (CD4 counts 100-250/microl). Outcome measures include comparisons between groups for clinical characteristics; results of cultures from blood, marrow, and gastrointestinal and respiratory tracts; immunological markers from staining of marrow and flow cytometry of circulating lymphocytes; and cytokine production of PBMCs. Only 21% of the 19 patients entered on suspicion of having DMAC grew MAC from blood or marrow. Neither clinical presentation nor laboratory tests differentiated those culture-positive from those culture-negative patients. However, prior PCP or multiple other opportunistic infections were more common in the DMAC group. MAC was isolated from 82% of marrow and 50% of blood specimens from the DMAC group. Respiratory or gastrointestinal colonization was present in 36% of DMAC subjects, but only 5% of non-DMAC subjects with CD4 counts <50 cells/microl. CD8+ cells were more frequent in bone marrow, and CD4 cells recognizing MAC antigen were more frequent in blood from DMAC subjects vs. controls. Results suggest an early stage of tissue dissemination preceding persistent bacteremia, and mucosal entry without persistence of colonization. MAC-specific T cell responses apparently develop and persist during DMAC, but are dysfunctional or too infrequent to prevent persistence.

Adult↗
PubMed2005

Challenges for the clinical development of new nucleoside reverse transcriptase inhibitors for HIV infection.

There is a need for new antiretroviral drugs with activity against HIV isolates resistant to currently available agents and improved short and long-term tolerability profiles. Clinical trial designs for nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs) are restricted by the characteristics of these agents (for example, their cross-resistance, resistance threshold and interaction profiles), the ethical need to ensure that patients are not maintained on suboptimal regimens, and regulatory requirements (for example, with regards to trial designs and patient populations). For example, consideration of cross-resistance profiles must influence the way in which an NRTI in development is sequenced to minimize any impact on future treatment options. The resistance threshold is determined by the number of mutations required to diminish sensitivity to a given drug. Pharmacokinetic or pharmacodynamic interactions restrict how NRTIs may be combined during clinical development. Doses may be selected on the basis of results from short-term monotherapy studies in treatment-naive patients, but such studies cannot establish the long-term efficacy or tolerability of new agents used in combination regimens. Confirmatory studies in treatment-naive populations do not meet the medical and regulatory needs for clinical data in treatment-experienced populations, while studies in treatment-experienced populations are subject to numerous clinical and logistical difficulties. Intensification, switch and hybrid study designs all offer suitable approaches to the evaluation of NRTIs with novel resistance profiles. Switch studies are particularly useful for agents with resistance profiles that suggest a specific sequencing approach in treatment and for those with the potential, based on pharmacokinetic data, for interactions with other agents. The successful development of new NRTIs will depend upon a thorough appreciation of these many and complex issues, not only among those involved in the design of clinical studies, but also those contributing to their review and conduct.

Anti-HIV Agents↗
PubMed2004

Long-term follow-up of HIV-infected individuals who have significant increases in CD4+ cell counts during antiretroviral therapy.

BACKGROUND: Descriptions of the durability and consequences of immune reconstitution in patients who start highly active antiretroviral therapy (HAART) while severely immunosuppressed are limited. METHODS: Patients with previous CD4+ cell counts <50 cells/mm3, all of whom had HAART-induced increases in CD4+ cell counts of >100 cells/mm3 on 2 separate occasions (measured sequentially at least 4 weeks apart), were enrolled in a prospective trial and observed every 16-32 weeks. Evaluations included assessments for new opportunistic complications, virologic (human immunodeficiency virus [HIV] RNA load) and immunologic (CD4+ cell count) responses, or death. RESULTS: The median follow-up duration for 612 subjects was 184 weeks (range, 8-216 weeks). The rate of increase in CD4+ cell counts was approximately 5.9 cells/mm3 every 8 weeks, with the degree of increase associated with the baseline HIV RNA load (<500 vs. > or =500 copies/mL). Subsequent measurements of virologic suppression based on HIV RNA levels were also associated with predicted CD4+ cell responses. Thirty-three AIDS-defining illnesses were reported (1.75 events per 100 person-years of follow-up); >40% (14 cases) occurred with higher than expected CD4+ cell counts. CONCLUSIONS: CD4+ cell count increases are related to virological control, with continuing increases seen in individuals who are immunosuppressed. Opportunistic illnesses and/or complications are infrequent but can occur at any time, even in patients who maintained an elevated CD4+ cell count.

Adult↗
PubMed2004

Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1.

BACKGROUND: Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV). METHODS AND FINDINGS: Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (-4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. CONCLUSION: NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease.

Adult↗
PubMed2004

Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection.

BACKGROUND: Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited. METHODS: This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz. RESULTS: We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10 (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use of prespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P< or =0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups. CONCLUSIONS: In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides.

Adult↗
PubMed2004

Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study.

OBJECTIVE: Combination antiretroviral therapy with lopinavir/ritonavir (LPV/r) has been highly effective in clinical trials. Results of long-term therapy with LPV/r-based regimens have not been previously reported. This study describes the 4-year (204-week) safety and antiretroviral activity of LPV/r-based treatment in antiretroviral-naive individuals. DESIGN: Long-term, open-label follow-up of a phase II, prospective, randomized, multicenter trial. METHODS: A group of 100 antiretroviral-naive HIV-infected patients were randomized to one of three blinded doses of LPV/r [200/100 mg (n = 16), 400/100 mg (n = 51), or 400/200 mg (n = 33)] with stavudine 40 mg and lamivudine 150 mg every 12 hours. After 48 weeks, LPV/r was dosed open-label at 400/100 mg every 12 hours with stavudine and lamivudine. RESULTS: : Mean baseline plasma HIV-1 RNA and CD4 cell count were 4.9 log10 copies/ml and 338 x 10 cells/l, respectively. At week 204, 72 patients remained on study, 70 of whom had HIV-1 RNA < 50 copies/ml (70% by intent-to-treat analysis). Twenty-eight patients discontinued therapy prior to week 204 because of adverse events (n = 10), lost to follow-up (n = 9), or other reasons (n = 9). Of 15 patients who met protocol-defined criteria for virologic failure, seven remained on the study regimen and their HIV-1 RNA was re-suppressed to < 50 copies/ml at week 204. Genotypic analysis of rebound viral isolates was available from 10 patients, including all eight patients who discontinued the study prematurely. No isolate demonstrated primary or active site mutations in protease. The most common adverse events were gastrointestinal symptoms and lipid elevations. CONCLUSIONS: LPV/r-based therapy provides durable antiretroviral response and is generally well tolerated through 204 weeks of therapy.

Adult↗
PubMed2004

Potent antiviral effect of reverset in HIV-1-infected adults following a single oral dose.

Reverset (2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, RVT) is a potent inhibitor of HIV-1 replication in cell culture, with a 90% effective concentration at or below 1 microM. In vitro, RVT retains its activity against isolates harbouring mutations in the reverse transcriptase (RT) gene that otherwise confer resistance to lamivudine and/or zidovudine. The pharmacokinetics and safety of single oral doses of RVT (10-200 mg) were evaluated in an initial Phase I clinical trial. The viral load changes were determined on 18 HIV-1-infected antiretroviral therapy-naive subjects that were randomized into three cohorts, each cohort consisting of three study periods. The subjects received up to two oral doses of active drug and one placebo dose with a 1-week washout period separating the three study periods. Quantification of viral RNA was performed on the pre-dose, 12, 24 and 48 h post-dose plasma samples. A single oral dose of RVT to antiretroviral-naive subjects significantly reduced plasma viral load by 0.45 +/- 0.10 log10 copies/ml (P=0.0003). A mean drop of 0.37 +/- 0.12 log10 copies/ml (P=0.001) was obtained at the lowest dose of 10 mg. Sequence analysis of the HIV-1 RT gene performed before and after RVT dosing detected no genotypic changes in this short-term study. The viral RT gene of one subject had at predose the following genotype: L41 + N103 + C181 + W210 + D215, indicating prior exposure to zidovudine and non-nucleoside analogues, and anticipating high-level resistance against these agents. A single 10 mg RVT dose resulted in a viral load drop of 0.61 +/- 0.05 log10 providing evidence that a viral strain with the indicated genotype is susceptible to RVT.

Administration, Oral↗
PubMed2003

Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection.

BACKGROUND: The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. METHODS: This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen. RESULTS: A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression. CONCLUSIONS: The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study.

Adult↗
PubMed2003

Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results.

OBJECTIVE: To compare the efficiency and safety of atazanavir and nelfinavir in antiretroviral-naive patients. DESIGN: Randomization to atazanavir 400 mg or 600 mg once daily; nelfinavir 1250 mg twice a day, plus lamivudine and stavudine. METHODS: A blinded (to the atazanavir dose), 48-week trial in patients with HIV-1 RNA > or = 2000 copies/ml, CD4 cell count > or = 100 x 10(6) cells/l. Primary end-point: change in HIV-1 RNA from baseline at 48 weeks. Secondary end-point: subjects with HIV-1 RNA < 400, and < 50 copies/ml, CD4 cell count changes, adverse events. RESULTS: The 467 randomized subjects had comparable baseline characteristics across treatments. With atazanavir 400 mg, 600 mg and nelfinavir, respectively, mean changes in HIV-1 RNA (log10 copies/ml) from baseline to 48 weeks were -2.51, -2.58, -2.31; HIV-1 RNA < 400 copies/ml [intent-to-treat population (ITT), non-completion = failure (NC = F)], 64%, 67%, 53%; HIV-1 RNA < 50 copies/ml (ITT NC = F), 35%, 36%, 34%; mean CD4 cell count increased comparably at 48 weeks (234 x 10(6), 243 x 10(6), 211 x 10(6) cells/l). Adverse events were similar across treatments with the exception of diarrhea (more frequent with nelfinavir) and jaundice (more frequent with atazanavir). Mean changes from baseline to 48 weeks were: fasting low density lipoprotein cholesterol, +5.2%, +7.1% and +23.2% (at 56 weeks) and fasting triglycerides (48 weeks), +7.2%, +7.6% and +49.5%, in the atazanavir 400 mg, 600 mg, and nelfinavir groups, respectively (P < 0.01, atazanavir versus nelfinavir). CONCLUSIONS: Atazanavir is a potent, safe, well tolerated, and effective once-daily protease inhibitor with low pill burden (two capsules/day). Lipid changes with atazanavir were significantly less than with nelfinavir, however, clinical significance of these finding in terms of decreased cardiovascular risk is unknown.

Acidosis, Lactic↗
PubMed2003

A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients.

OBJECTIVE: To compare one protease inhibitor (PI)-based and two PI-sparing antiretroviral therapy regimens. METHODS: International, open label, randomized study of antiretroviral drug-naive patients, with CD4 lymphocyte counts >/= 200 x 106 cells/l and plasma HIV-1 RNA levels > 500 copies/ml. Treatment assignment to stavudine and didanosine plus indinavir or nevirapine or lamivudine. Primary study endpoint was the percentage of patients with plasma HIV-1 RNA levels < 500 copies/ml after 48 weeks in the intention-to-treat analysis (ITT). RESULTS: In total, 298 patients were enrolled. After 48 weeks, the percentage of patients in the indinavir, nevirapine and lamivudine arms with HIV-1 RNA < 500 copies/ml was 57.0%, 58.4% and 58.7%, respectively, in an ITT analysis. After 96 weeks of follow-up, these percentages were 50.0%, 59.6% and 45.0%, respectively. The percentage of patients with HIV-1 RNA < 50 copies/ml was significantly less for those allocated to lamivudine in an on-treatment analysis after 48 and 96 weeks of follow-up. Patients in the nevirapine arm experienced a smaller increase in the absolute number of CD4 T lymphocytes. There were no significant differences in the incidence of serious adverse events. CONCLUSIONS: A comparable virological response can be achieved with first-line PI-base and PI-sparing regimens. The triple nucleoside regimen utilized may be less likely to result in viral suppression to < 50 copies/ml, while the nevirapine-based regimen is associated with a lower increase in CD4 T lymphocytes.

Adolescent↗
PubMed2003

A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy.

OBJECTIVES: The primary objective was to determine the long-term safety of the subcutaneous self-administration of enfuvirtide. Secondary objectives included the determination of enfuvirtide pharmacokinetics and antiviral activity and the immunological response to the enfuvirtide-containing regimen. METHODS: A multicenter 48-week uncontrolled open-label rollover study was conducted on 71 HIV-infected adults recruited from previous enfuvirtide clinical trials. Patients with extensive previous use of protease and reverse transcriptase inhibitors received a twice-daily dose of 50 mg enfuvirtide subcutaneously (45 mg deliverable) combined with two or more antiretroviral drugs selected for each individual, guided by resistance testing and previous treatment history. RESULTS: The mean baseline plasma HIV-RNA level was 4.81 log(10) copies/ml and the mean CD4 cell count was 134.8 cells/microl. The majority (86.9%) of treatment-emergent adverse events were grade 2 or less in severity. Injection site reactions were common, but no patients discontinued treatment. A mean HIV-RNA change of -1.33 log(10) was achieved within 14 days of treatment initiation. At week 48, approximately one-third of all patients in the intent-to-treat population maintained significant suppression of plasma HIV RNA, with either less than 400 copies/ml or more than a 1.0 log(10) decline from baseline. The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/microl. Trough plasma concentrations of enfuvirtide were consistently higher than target concentrations. CONCLUSION: Self-administration of enfuvirtide is not associated with unexpected toxicities for up to one year, and combined with oral antiretroviral drugs was associated with a significant decrease in HIV RNA and an increase in CD4 cell counts.

Adult↗
PubMed2003

Defining the toxicity profile of nevirapine and other antiretroviral drugs.

Since there is currently no cure for HIV-1 infection, long-term remission of the disease is achieved by administering combinations of antiretroviral (ARV) agents for an indefinite period. During this time, the likelihood of developing toxicities is high, since all ARV drugs are associated with both short- and long-term toxicities. The major toxicity observed with nevirapine (NVP) is rash, which is usually mild and occurs early in treatment. However, in some cases, it may be severe or potentially life threatening. Using the recommended lead-in dosing schedule in conjunction with good health care management, this adverse event can be controlled in the vast majority of patients. The development of guidelines for management of NVP-associated rash, which are easy to use, have proven to be very effective; approximately half of the patients with mild or moderate rash can continue NVP therapy under close supervision. In order to facilitate better monitoring of toxic events associated with ARV therapy, a Toxicity Evaluation Group has been set up, with the objective of standardizing reporting of drug-related toxicities in all Adult AIDS Clinical Trials Group (AACTG) studies. These measures may help to identify potential toxicities better and any risk factors that predispose patients to the development of treatment-related side-effects.

Exanthema↗
PubMed2003

Genetic and functional analysis of full-length human immunodeficiency virus type 1 env genes derived from brain and blood of patients with AIDS.

The genetic evolution of human immunodeficiency virus type 1 (HIV-1) in the brain is distinct from that in lymphoid tissues, indicating tissue-specific compartmentalization of the virus. Few primary HIV-1 envelope glycoproteins (Envs) from uncultured brain tissues have been biologically well characterized. In this study, we analyzed 37 full-length env genes from uncultured brain biopsy and blood samples from four patients with AIDS. Phylogenetic analysis of intrapatient sequence sets showed distinct clustering of brain relative to blood env sequences. However, no brain-specific signature sequence was identified. Furthermore, there was no significant difference in the number or positions of N-linked glycosylation sites between brain and blood env sequences. The patterns of coreceptor usage were heterogeneous, with no clear distinction between brain and blood env clones. Nine Envs used CCR5 as a coreceptor, one used CXCR4, and two used both CCR5 and CXCR4 in cell-to-cell fusion assays. Eight Envs could also use CCR3, CCR8, GPR15, STRL33, Apj, and/or GPR1, but these coreceptors did not play a major role in virus entry into microglia. Recognition of epitopes by the 2F5, T30, AG10H9, F105, 17b, and C11 monoclonal antibodies varied among env clones, reflecting genetic and conformational heterogeneity. Envs from two patients contained 28 to 32 N-glycosylation sites in gp120, compared to around 25 in lab strains and well-characterized primary isolates. These results suggest that HIV-1 Envs in brain cannot be distinguished from those in blood on the basis of coreceptor usage or the number or positions of N-glycosylation sites, indicating that other properties underlie neurotropism. The study also demonstrates characteristics of primary HIV-1 Envs from uncultured tissues and implies that Env variants that are glycosylated more extensively than lab strains and well-characterized primary isolates should be considered during development of vaccines and neutralizing antibodies.

Acquired Immunodeficiency Syndrome↗