Vitamin D deficiency in HIV-infected postmenopausal Hispanic and African-American women.

UNLABELLED: We evaluated vitamin D status in HIV+ and HIV- postmenopausal African-American (AA) and Hispanic women. Most women (74-78%) had insufficient 25-hydroxyvitamin D (25OHD) levels, regardless of HIV status. 25OHD was lower in AA women and women lacking supplement use, providing support for screening and supplementation. Among HIV+ women, 25OHD was associated with current CD4 but not type of antiretroviral therapy. INTRODUCTION: To evaluate vitamin D status and factors associated with vitamin D deficiency and insufficiency in HIV-infected (HIV+) postmenopausal minority women. METHODS: In this cross-sectional study, 89 HIV+ and 95 HIV- postmenopausal women (33% AA and 67% Hispanic) underwent assessment of 25OHD, 1,25-dihydroxyvitamin D, parathyroid hormone, markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry. RESULTS: The prevalence of low 25OHD did not differ by HIV status; the majority of both HIV+ and HIV- women (74-78%) had insufficient levels (<30 ng/ml). Regardless of HIV status, 25OHD was significantly lower in AA subjects, and higher in subjects who used both calcium and multivitamins. In HIV+ women on antiretroviral therapy (ART), 25OHD was directly associated with current CD4 count (r=0.32; p<0.01) independent of age, ethnicity, BMI, or history of AIDS-defining illness. No association was observed between 1,25(OH)(2)D and CD4 count or between serum 25OHD, 1,25(OH)(2)D or PTH and type of ART. CONCLUSIONS: In postmenopausal minority women, vitamin D deficiency was highly prevalent and associated with AA race and lack of supplement use, as well as lower current CD4 cell count. These results provide support for screening and repletion of vitamin D in HIV+ patients.

Associations of CCR5, CCR2, and stromal cell-derived factor 1 genotypes with human immunodeficiency virus disease progression in patients receiving nucleoside therapy.

Genotype data for CCR5, CCR2, and stromal cell-derived factor 1 (SDF-1) were obtained from 354 human immunodeficiency virus type 1 (HIV-1)-positive subjects who were being treated with nucleosides. Associations with HIV-1 load, HIV syncytium-inducing (SI) phenotype, CD4 cell count, and disease progression were analyzed. No differences in HIV-1 load or CD4 cell count were observed between wild type (+) and variant genotypes. Changes from non-SI to SI viral phenotype were more frequent in heterozygotes with a 32-bp deletion (Delta32) in the CCR5 gene than in + homozygotes (40% vs. 7%; P=.01). In a multivariate analysis, heterozygous CCR5 Delta32 was associated with reduced hazard of progression (hazard ratio, 0.32; P=.02). Subjects homozygous for the SDF-1 3'A variant had more-rapid disease progression (P=.008). The SDF-1 homozygous 3'A variant was related to more-rapid disease progression, and CCR5 Delta32 was associated with reduced rates of hazard for disease progression in nucleoside-treated subjects.

Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. AIDS Clinical Trials Group Protocol 320.

BACKGROUND: A substantial proportion of patients with HIV infection will not respond to antiretroviral therapy. Early predictors of response to treatment are needed to identify patients who are at risk for treatment failure. OBJECTIVE: To determine predictors of virologic and clinical response to indinavir, zidovudine, and lamivudine therapy. DESIGN: Observational analysis of one treatment group in a phase III trial. SETTING: 40 AIDS Clinical Trials units. PATIENTS: 489 patients receiving indinavir, zidovudine, and lamivudine who had 1) a CD4 count of 0.200 x 10(9) cells/L or less after 8 or more weeks of study therapy and 2) plasma HIV-1 RNA measurements obtained at baseline and week 8. MEASUREMENTS: HIV-1 RNA level and CD4 cell count at weeks 0, 4, 8, 24, and 40. Clinical progression was defined as a new AIDS-defining illness or death. RESULTS: Patients' levels of HIV-1 RNA at the 8th study week of therapy predicted whether patients would achieve virologic suppression to below 500 (or 50) copies/mL at study week 24. An HIV-1 RNA level less than 500 copies/mL at week 24 was achieved in 71% of patients whose level at week 8 had been less than 500 copies/mL, 53% of those with a level of 500 copies/mL or more and at least 2-log(10) copies/mL reduction since baseline, 29% of those with a level of 500 copies/mL or more with a 1- to 1.99-log(10) copies/mL reduction, and 9% of those with a level of 500 copies/mL or greater and less than 1-log(10) copies/mL reduction since baseline (P < 0.001). HIV-1 RNA level at week 8 also predicted clinical progression. HIV-1 disease progressed in 2.2% of the patients with a week-8 HIV-1 RNA level less than 500 copies/mL, 2.3% of patients with 500 copies/mL or greater and at least 2-log(10) copies/mL reduction since baseline, 4.9% of patients with 500 copies/mL or greater and 1- to 1.99-log(10) copies/mL reduction since baseline, and 10.6% of patients with 500 copies/mL or greater and less than 1-log(10) copies/mL decrease since baseline (P = 0.009). After adjustment for HIV-1 RNA level, patients with a higher week-8 CD4 cell count were more likely to have a week-24 HIV-1 RNA level less than 500 copies/mL (relative risk for patients with a week-8 CD4 count >/= 0.10 x 10(9) cells/L, 1.47 [95% CI, 1.00 to 2.16] compared with <0.050 x 10(9) cells/L; relative risk for patients with a week-8 CD4 count of 0.05 to 0.099 x 10(9) cells/L, 0.98 [CI, 0.61 to 1.57] compared with <0.050 x 10(9) cells/L). After adjustment for HIV-1 RNA level, patients with a week-8 CD4 count of 0.05 x 10(9) cells/L or greater (compared with <0.05 x 10(9) cells/L) had a decreased hazard for clinical progression (hazard ratio, 0.25 [CI, 0.09 to 0.67]). CONCLUSIONS: The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.

Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection.

BACKGROUND: The optimal antiretroviral treatment for patients who have human immunodeficiency virus (HIV) viremia despite treatment with nucleoside reverse-transcriptase inhibitors (nucleoside analogues) remains uncertain. We studied treatment with regimens that combined two nucleoside analogues, at least one of which was new, with the protease inhibitor nelfinavir, the nonnucleoside reverse-transcriptase inhibitor efavirenz, or both. METHODS: The study included 195 patients who had been treated with nucleoside analogues only, and had a plasma HIV type 1 (HIV-1) RNA level of at least 500 copies per milliliter. Patients were randomly assigned to receive, in addition to two nucleoside analogues, nelfinavir, efavirenz, or nelfinavir plus efavirenz. The primary end point was a plasma HIV-1 RNA level of less than 500 copies per milliliter at week 16. A secondary end point was the composite of the HIV-1 RNA levels measured at weeks 40 and 48. RESULTS: At week 16 and at weeks 40 and 48, the proportions of patients in whom a plasma HIV-1 RNA level of less than 500 copies per milliliter was achieved were, respectively, 81 percent and 74 percent in the nelfinavir-plus-efavirenz group, 69 percent and 60 percent in the efavirenz group, and 64 percent and 35 percent in the nelfinavir group. Quadruple therapy resulted in a higher rate of viral suppression in both the short term (P=0.03) and the long term (P=0.001) than did triple therapy with nelfinavir. Triple therapy with efavirenz conferred a higher rate of long-term suppression than triple therapy with nelfinavir (P=0.004). Quadruple therapy also achieved a higher rate of virologic suppression than triple therapy with efavirenz (P=0.008). CONCLUSIONS: In HIV-infected patients previously treated with nucleoside analogues, treatment with nelfinavir plus efavirenz and at least one new nucleoside analogue achieves a higher rate of viral suppression than do regimens with nucleoside analogues and nelfinavir or efavirenz alone.

Vancomycin-resistant Enterococcus faecium meningitis successfully managed with linezolid: case report and review of the literature.

Enterococci cause serious illness in immunocompromised patients and severely ill, hospitalized patients. Resistance to vancomycin has increased in frequency during the past few years. Limited therapeutic options are available for vancomycin-resistant enterococcal infections and the optimum therapy has not been established. We report a case of nosocomial vancomycin-resistant Enterococcus faecium meningitis in the setting of hyperinfection with Strongyloides stercoralis that was successfully treated with linezolid. We also review the previously reported cases of vancomycin-resistant E. faecium meningitis.

Host determinants in HIV infection and disease. Part 1: cellular and humoral immune responses.

The course of HIV infection varies widely among individuals. Long-term nonprogressors or slow progressors may remain asymptomatic and have normal CD4 counts despite more than a decade of untreated HIV infection. In contrast, rapid progressors develop AIDS within 5 years. In addition, some persons remain uninfected despite repeated exposure to HIV. Immunologic and genetic studies of long-term nonprogressors and exposed yet uninfected persons, as well as data from studies of primary HIV infection, have helped to elucidate the mechanisms by which some persons are protected from HIV acquisition or have slow rates of disease progression. This review (the first of two parts) describes what is currently known about host factors in HIV-1 infection. Studies for inclusion were identified by a systematic search of PubMed for English-language literature published from 1988 through June 2000. Abstracts of presentations at major meetings convened in 2000 were also included if appropriate. Growing evidence suggests a crucial role of cytotoxic T cells and T-helper cells in controlling viremia, slowing disease progression, and perhaps preventing establishment of infection. Humoral and mucosal immunity, soluble inhibitory factors, the cytokine milieu, and concomitant infections also affect outcome. Genetic host factors, such as inheritance of mutant chemokine receptors or certain HLA types, affect susceptibility to infection and subsequent clinical course. The role of cellular and humoral immunity, mucosal immunity, and other local factors in determining the course of HIV infection is discussed.

Host determinants in HIV infection and disease. Part 2: genetic factors and implications for antiretroviral therapeutics.

The course of HIV infection varies widely among individuals. Immunologic and genetic studies of long-term nonprogressors and exposed yet uninfected persons have helped to elucidate the mechanisms by which some persons are protected from HIV acquisition or have slow rates of disease progression. This two-part review describes what is currently known about host factors in HIV-1 infection. Studies for inclusion were identified by a systematic search of PubMed for English-language literature published from 1988 through June 2000. Abstracts of presentations at major meetings convened in 2000 were also included if appropriate. The first part of the review discussed cellular and humoral immunity to HIV infection. This second part describes genetic host factors-namely, inheritance of mutant chemokine receptors or ligands, such as CCR5-Delta32, CCR2-V64I, stromal cell-derived factor-1 3'alpha, and CCR5 promoter polymorphisms, as well as HLA type-that affect susceptibility to infection and subsequent clinical course. Soluble inhibitory factors, the cytokine milieu, and concomitant infections also affect outcome. Knowledge of host responses is increasingly being applied to new therapeutic strategies, including early treatment, immune modulation, structured treatment interruptions, therapeutic vaccination, and new chemotherapeutic agents, as well as to vaccine development.

Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults: A randomized equivalence trial.

CONTEXT: Abacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor-containing regimen for initial antiretroviral treatment. OBJECTIVE: To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen. DESIGN AND SETTING: A multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe. PATIENTS: Five hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L. INTERVENTIONS: Patients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy. MAIN OUTCOME MEASURE: Virologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48. RESULTS: The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment difference of -0.6% (95% confidence interval [CI], -9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of -14% (95% CI, -27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment. CONCLUSIONS: In this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.

Virologic and regimen termination surrogate end points in AIDS clinical trials.

Suppression of plasma human immunodeficiency virus (HIV) RNA levels has been widely accepted as an appropriate surrogate end point for HIV disease progression, and it is currently used as the primary end point to determine efficacy in many antiretroviral trials. However, this end point does not always measure other important effects of treatment, such as inducement of multidrug resistance, which depletes future therapy options, and toxic effects. An alternative that directly factors in these treatment costs is a composite regimen termination end point, defined as a protocol-determined change in regimen due to either virologic failure or treatment-related toxic effects. Pros and cons for using purely virologic vs various composite primary end points are discussed. Conclusions include (1) a trial's clinical objective guides the choice of primary end point, (2) a purely virologic end point is often preferable, (3) it may be important to analyze both end point types in interpreting study results, and (4) long-term clinical outcome studies are needed for identifying the most predictive surrogate end points.

Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The Aids Clinical Trials Group 175 Team.

OBJECTIVE: To prospectively examine differences in baseline characteristics and study outcomes between HIV-infected women and men during a clinical trial of nucleoside analogue therapy. METHODS: ACTG 175 randomized HIV-infected patients with CD4+ counts between 200 and 500 cells/mm3 to one of four nucleoside analogue regimens: zidovudine (ZDV), didanosine (ddI), ZDV + ddI, or ZDV + zalcitabine (ddC). Differences in time to first dose modification, voluntary withdrawal, development of toxicity and symptomatology, and AIDS progression were compared by gender. RESULTS: The study included 438 women and 2029 men. Baseline values of HIV RNA plasma concentrations were significantly lower for women (0.3 log10) than men in a subset of patients in whom assays were taken and this difference persisted after adjustment for CD4+ count. Women reported reducing dosage and discontinue ddI-containing regimens more frequently than men did; adjustment for weight did not completely explain this difference. Women were at lower risk than men for progression to a study endpoint (19% of women versus 24% of men; p <.0001). Among those antiretroviral-naive study subjects receiving ZDV, men were four times more likely to progress to a study endpoint than women. CONCLUSIONS: Differences in pretreatment characteristics and on study experiences were demonstrated between women and men enrolled in this clinical trial. The suggestion of a gender difference in response to ZDV monotherapy by antiretroviral-naive study subjects and the lower baseline values for HIV RNA in women compared with those in men provides evidence for gender differences in the relationship between virus replication, CD4+ decline, and responses to nucleoside analogue therapy.

Effect of lamivudine in HIV-infected persons with prior exposure to zidovudine/didanosine or zidovudine/zalcitabine.

Nucleoside analog-based regimens remain an integral component of combination therapy for use in both antiretroviral treatment-naive and experienced HIV-infected patients. To further define treatment responses to new antiretroviral therapy in patients with long-term experience to dual nucleoside analog therapy (zidovudine [ZDV] plus didanosine [ddI] or ZDV plus zalcitabine [ddC]), 325 subjects derived from the AIDS Clinical Trials Group (ACTG) 175 trial were randomized to three different combination regimens: (1) continuation of ZDV + ddI or ZDV + ddC (continuation arm), (2) addition of 3TC to ZDV + ddI or ZDV + ddC (addition arm), or (3) a switch to ZDV + 3TC therapy (switch arm). Both the addition and switch arms sustained significantly greater short-term (baseline to week 4) mean CD4+ cell count increases compared with the continuation arm (+36, +28 versus -4 cells/mm3; p = 0.012) and long-term CD4+ cell count responses (baseline to weeks 40/48: +32, +19 versus -9 cells/mm3; p = 0.003). Superior short-term (baseline to week 8) mean decreases in plasma HIV RNA (p < 0.001) were achieved by both the addition and switch arms (0.53 log10 and 0.54 log10 copies/ml, respectively) compared with the continuation arm (0.13 copies/ml) whereas no differences in long-term virologic suppression were observed (p = 0.30). At week 48, no differences were observed in the proportions of subjects who had HIV RNA levels below 500 copies/mL: 18% of subjects in each treatment arm (3-way p = 1.0). Overall, the treatments were well tolerated and only nine subjects (3%) died or developed one or more AIDS-defining events. While this study confirms the intrinsic antiretroviral activity of 3TC, only modest marker changes and limited short-term viral suppression are seen with incremental addition of the drug. The current approach of using 3TC in maximally suppressive regimens is preferred.

The values of quantitative serum HIV-1 RNA levels and CD4 cell counts for predicting survival time among HIV-positive individuals with CD4 counts of < or = 50 x 10(6) cells/l.

OBJECTIVE: To evaluate the HIV-1 RNA level as a predictor of survival time among individuals with advanced AIDS. METHODS: The serum HIV-1 RNA level, the CD4 cell count, and other clinical variables were evaluated at baseline, as predictors of survival time, among 56 retrospectively identified HIV-1 positive individuals with < or = 50 x 10(6) CD4 cells/l who attended the Beth Israel Deaconess Medical Center, Division of Infectious Diseases, between 1 July 1989 and 30 September 1993. RESULTS: During follow-up, 55 of these 56 patients died. The median survival time was 20.5 months. In univariate Cox proportional hazard modeling neither the baseline HIV-1 RNA level nor the CD4 cell count were predictive of survival time. However, in multivariate models longer survival time was associated with the use of trimethoprim-sulphamethoxazole at entry [hazard ratio (HR), 0.42; P = 0.007], whereas shorter survival time was associated with a history of an AIDS-defining illness other than Pneumocystis carinii pneumonia (HR, 2.87; P = 0.007). Correlative analysis revealed a modest correlation of the baseline CD4 cell count with survival time (Spearman p = 0.41; P = 0.002). However, no correlation was found between HIV RNA levels and survival time (P = 0.5). CONCLUSIONS: In this population with very advanced disease, the HIV-1 RNA level was a poor discriminator of survival time, being inferior to the CD4 cell count and to specific clinical variables such as the nature of the prior AIDS-defining illness and the type of Pneumocystis carinii pneumonia prophylaxis employed. Among individuals with advanced AIDS, these data emphasize the relative importance of the CD4 cell count and of specific clinical factors, over the HIV-1 RNA level in predicting survival time.

A comparison of two dosing regimens of zidovudine in Thai adults with early symptomatic HIV infection. Conducting clinical HIV trials in South-East Asia.

AIM: To compare the clinical and immunological efficacy, and tolerance of two dosage regimens of zidovudine (ZDV) in an adult Thai population with early symptomatic human immunodeficiency virus (HIV) disease and to identify important clinical issues associated with conducting HIV trials in South-East Asia. METHODS: HIV-infected Thai adults, with early symptomatic HIV disease and CD4 lymphocyte counts less than 400/mm3, who were managed in the infectious diseases clinics at two university teaching hospitals in Bangkok, Thailand, were enrolled in a randomised, open-label, dose-regimen comparison trial of ZDV. Two oral ZDV dosing regimens: regimen A, 100 mg tid+200 mg nocte (ZDV-A) vs regimen B, 250 mg bid (ZDV-B) were compared. The main outcome measures were: 1. Clinical efficacy: rate of progression to acquired immunodeficiency syndrome (AIDS) or death. 2. Immunologic efficacy: changes in CD4 lymphocyte numbers compared to baseline; rate of decline of CD4 lymphocyte numbers to less than 100/mm3. 3. Toxicity, as defined by clinical symptomatology and laboratory parameters. RESULTS: Two hundred and four patients were enrolled (103 ZDV-A; 101 ZDV-B) of whom 195 were followed beyond baseline. Patients were typical of those encountered with HIV in Thailand: mean age 33 years; 89% male; 88% heterosexual HIV acquisition; mean baseline CD4 lymphocyte count 241/mm3. Follow-up while on therapy was comparable for the two groups (mean+/-SD): 533+/-236 days (ZDV-A) vs 592+/-210 days (ZDV-B). One hundred and eleven patients (57%; 51 ZDV-A; 60 ZDV-B) were treated for at least 22 months (669+/-30 days). Clinical and immunological outcomes for ZDV-A and ZDV-B, including rate of progression to AIDS or death, development of non-AIDS-defining opportunistic infections, mean changes in CD4 lymphocyte numbers/mm3, difference in area under the CD4:time distribution curve and difference in the rate of decline of CD4 lymphocyte numbers to less than 100/mm3, were not significantly different. The presence of oral hairy leukoplakia or unintentional weight loss of 10-20% at enrollment were significantly associated with the later development of AIDS (p=0.03 and 0.04, respectively). ZDV-associated toxicity was similar for both regimens. Maintaining protocol adherence and appropriate clinical follow-up emerged as important practical issues. CONCLUSION: In Thai adults, ZDV 100 mg tid+200 mg nocte and ZDV 250 mg bid have similar clinical and immunological efficacy. Rates of ZDV toxicity are comparable to those reported in non-Asian populations. Despite limitations in medical care access and maintaining long-term follow-up, successful trials of antiretroviral agents are feasible in South-East Asia and multi-drug treatment trials should be pursued in appropriate institutions.

Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel.

OBJECTIVE: Assays for drug resistance testing in human immunodeficiency virus type 1 (HIV-1) infection are now available and clinical studies suggest that viral drug resistance is correlated with poor virologic response to new therapy. The International AIDS Society-USA sought to update prior recommendations to provide guidance for clinicians regarding indications for HIV-1 resistance testing. PARTICIPANTS: An International AIDS Society-USA 13-member physician panel with expertise in basic science, clinical research, and patient care involving HIV resistance to antiretroviral drugs was reconvened to provide recommendations for the clinical use of drug resistance testing. EVIDENCE AND CONSENSUS PROCESS: The full panel met regularly between January and October 1999. Resistance and resistance testing data appearing in the last decade through April 2000 and presentations at national and international research conferences were reviewed. Recommendations and considerations were developed by 100% group consensus, acknowledging that definitive data to support final recommendations are not yet available. CONCLUSIONS: Emerging data indicate that despite limitations, resistance testing should be incorporated into patient management in some settings. Resistance testing is recommended to help guide the choice of new regimens after treatment failure and for guiding therapy for pregnant women. It should be considered in treatment-naive patients with established infection, but cannot be firmly recommended in this setting. Testing also should be considered prior to initiating therapy in patients with acute HIV infection, although therapy should not be delayed pending the results. Expert interpretation is recommended given the complexity of results and assay limitations.

Both serum HIV type 1 RNA levels and CD4+ lymphocyte counts predict clinical outcome in HIV type 1-infected subjects with 200 to 500 CD4+ cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team.

To evaluate HIV-1 RNA and CD4+ cell responses to therapy as predictors of clinical progression and to evaluate levels and trends of these markers prior to clinical failure, HIV-1 RNA measurements were retrospectively obtained on subjects who progressed to AIDS or death and a random sample of subjects who did not. Samples were taken from AIDS Clinical Trials Group Study 175, a randomized trial comparing nucleoside analog therapies in subjects with CD4+ cell counts of between 200 and 500 cells/mm3. HIV-1 RNA and CD4+ cell count independently predicted clinical progression. Risk of subsequent progression is best captured by the change to the last measured value for CD4+ cell count and the area under the curve minus baseline, a measure of viral replication over time, for HIV-1 RNA. Subjects who failed had lower CD4+ cell counts, greater rates of CD4+ cell decline, and higher HIV-1 RNA levels, but not greater rates of HIV-1 RNA increase than subjects who did not. Subjects who maintained more than 200 CD4+ cells/mm3 and fewer than 10,000 copies of HIV-1 RNA per milliliter had low risk of progression. During the first few months of therapy, treatments are best monitored by regular HIV-1 RNA and less frequent CD4+ cell measurements. Thereafter, both markers should be monitored on a similar schedule to identify rapidly declining CD4+ cell counts, or adverse levels of either. These results further delineate the prognostic significance of HIV-1 RNA and CD4+ cell count and should help to better define their utility in the practice setting.

Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine.

OBJECTIVE: To evaluate the phenotypic susceptibilities and genotypic resistance patterns to both didanosine and stavudine of baseline and follow-up HIV-1 isolate pairs, derived from antiretroviral naive subjects treated with this dual nucleoside combination. DESIGN AND METHODS: Phenotypic drug susceptibility testing was performed in peripheral blood mononuclear cells on 34 viral isolate pairs derived from patients participating in the BMS AI-460 trial. Sequencing of the complete reverse transcriptase of 36 study isolate pairs, baseline and follow-up, was performed using standard dideoxy techniques. RESULTS: The mean fold change in susceptibilities to didanosine was 1.6 (P= 0.278) and to stavudine 1.9 (P= 0.002, Wilcoxon's signed rank test). Mutations classically associated with zidovudine resistance were observed to emerge in 7 out of 36 isolates, T215Y/F (four), M41L +T215Y/F (two) and D67N (one). Other mutations observed included the A62V, V751, F77L, F116Y, Q151 M multinucleoside resistance complex (one), the Q151M mutation (two) and the rare V75T mutation (two). No mutations classically associated with didanosine exposure and resistance were observed. No relationship was evident between the emergence of zidovudine associated mutations and the level of phenotypic resistance to either stavudine or didanosine or between the emergence of zidovudine associated mutations and changes in plasma HIV RNA levels. CONCLUSION: These comprehensive data demonstrate modest (< twofold) mean reductions in didanosine and stavudine susceptibilities at follow-up. The emergence of zidovudine associated mutations in this retroviral-naive population treated with combination didanosine and stavudine therapy is notable. Furthermore, the emergence of these mutations and of the Q151 M multinucleoside resistance complex raise concerns for potential nucleoside analog cross-resistance. The potential mechanisms driving the selection of the zidovudine associated mutations in the setting of didanosine and stavudine therapy and the relevance of these findings to current three and four drug regimens merit further evaluation.

Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.