Sub-optimal CD4 recovery on long-term suppressive highly active antiretroviral therapy is associated with favourable outcome.

OBJECTIVES: To examine risk factors for sub-optimal CD4 recovery on suppressive highly active antiretroviral therapy (HAART) and assess long-term clinical and immunological outcomes. METHODS: Retrospective analysis of 286 HIV-positive patients from a university clinic who initiated HAART with CD4 count <350 cells/microL between January 1996 and July 2006 and achieved > or =52 weeks of viral suppression (VS). Sub-optimal and optimal CD4 count recovery were defined by gains of <150 and > or =150 cells/microL during the first year of VS, respectively. Risk factors were analysed by multivariate logistic regression and markers of immune maturation and activation were evaluated prospectively for a sub-group of patients with prolonged (>5 years) VS. RESULTS: One hundred and two (36%) patients had sub-optimal CD4 recovery. Male gender, lower pre-HAART viral load, HAART toxicity and use of opportunistic infection (OI) prophylaxis were independent risk factors on multivariate analysis (P<0.05). Outcomes of duration of VS on HAART (4 years), new OI events (1%) and mortality (5%) were similar between groups. Markers of immune maturation and activation were higher among patients with sub-optimal CD4 recovery (P<0.05). CONCLUSIONS: Among HIV-positive patients with long-term VS, sub-optimal CD4 recovery was common but morbidity and mortality remained low. In addition, persistent CD4 T-cell activation appeared to blunt long-term CD4 gains.

T lymphocyte-mediated protection against Pseudomonas aeruginosa infection in granulocytopenic mice.

BALB/c mice immunized with Pseudomonas aeruginosa immunotype 1 polysaccharide develop protective T cell immunity to bacterial challenge. In vitro, T cells from immunized mice kill P. aeruginosa by production of a bactericidal lymphokine. The present study demonstrates that adoptive transfer of T cells from immunized BALB/c mice to granulocytopenic mice resulted in 97% survival on challenge with P. aeruginosa, compared with 17% survival with adoptive transfer of T cells from nonimmune BALB/c mice. This protection is specifically elicited by reexposure to the original immunizing antigen; adoptive recipients cannot withstand challenge with immunotype 3 P. aeruginosa. However, the adoptive recipients do survive simultaneous infection with both P. aeruginosa immunotypes 1 and 3. Adoptive transfer of T cells from the congenic CB.20 mice, which are unable to kill P. aeruginosa in vitro, provides only 20% protection to granulocytopenic mice. These studies indicate that transfer of specific immune T lymphocytes can significantly enhance the resistance to P. aeruginosa infection in granulocytopenic mice.

Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA.

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.

Nelfinavir, a new protease inhibitor: early clinical results.

Nelfinavir is a potent inhibitor of the HIV-1 protease, which shows good inhibitory activity against HIV-1 in vitro. Initial clinical trials have shown that it has excellent activity in vivo in HIV-infected patients. The combination of 750 mg nelfinavir three times daily with zidovudine and lamivudine has been shown to cause a median reduction in HIV plasma RNA of approximately 2 log10 copies/ml, and to reduce plasma levels of RNA below the limit of detection (< 400 copies/ml) in 50-75% of patients after 12 months of treatment. This combination was associated with a mean increase of almost 200 CD4+ lymphocytes per mm3 at 12 months of therapy. The drug is well-tolerated, with mild diarrhea, which occurs in 12-20% of patients, being the most common side-effect. The pattern of initial protease mutations associated with nelfinavir resistance appears to be different from that seen with resistance to the other protease inhibitors, with the predominant initial mutation occurring at codon 30 of the HIV protease gene. Thus, initial trials indicate that nelfinavir is equivalent to other potent protease inhibitors and can be considered as a component in first-line combination therapy for HIV-infected patients.

Molecular typing of candida albicans isolated from oral lesions of HIV-infected individuals.

OBJECTIVE: To evaluate the epidemiology of Candida albicans infection in HIV-infected patients with oral lesions using molecular techniques. METHODS: Thirty-nine isolates from HIV-positive patients with oral candidiasis were examined using two DNA probes (a Histoplasma capsulatum ribosomal DNA probe that cross-hybridizes with C. albicans and a C. albicans strain-specific probe derived from repetitive sequence DNA). C. albicans obtained from the oral cavity of patients receiving cytotoxic chemotherapy was used as controls. RESULTS: Using the H. capsulatum ribosomal DNA probe, isolates were shown to members of many distinct classes of C. albicans. Forty-nine per cent (19 out of 39) of isolates were members of the same class; however, 46% (6 out of 13) of control C. albicans isolates were also members of this class. Further analysis of the class-restricted isolates from the HIV-infected patients using the C. albicans strain-specific probe showed that these could be further separated into distinct strains. CONCLUSIONS: These data indicate that strains of C. albicans that cause oral candidiasis in HIV-positive individuals are not clonally restricted and are similar to those colonizing the oral cavity of other severely immunocompromised hosts. Most patients appear to be infected with unique strains of C. albicans.

Timing of antiretroviral therapy. Use of Markov modeling and decision analysis to evaluate the long-term implications of therapy.

BACKGROUND: The timing of initiation of antiretroviral therapy is controversial. Current guidelines are heavily based on the principle of 'hit early, hit hard', although the long-term implications of this approach are unknown. METHODS: Using Markov modeling and decision analysis we modeled the virologic outcomes over 10 years in a hypothetical population of 10 000 HIV-infected patients in which therapy (with the possibility of three sequential regimens before the development of multidrug-resistant virus) is started immediately versus starting progressively at rates of 5, 10, 15, 20 or 30% of the original population each year. The model used inputs from available clinical trial data: virologic success rate and durability of the response of the first and subsequent regimens. We performed one-way and two-way sensitivity analysis to evaluate changes in the input variables. RESULTS: If therapy is started immediately in all patients, by 10 years 57% would be undetectable, but 38% would have detectable multidrug-resistant virus. In contrast, the population as a whole would have had better virologic outcomes if one waited before starting treatment at any progression rate; for example, initiating therapy in 10% of the subjects per year results in 64% of patients being undetectable and 24% with multidrug-resistant virus. Two-way sensitivity analysis demonstrates that immediate initiation should be at least 15 to 20% better than delayed antiretroviral therapy to justify immediate initiation of therapy over a wide range of success rates of the delayed start. CONCLUSION: Our analysis, utilizing optimistic outcomes based on short-term clinical trials, provides a theoretical basis for questioning the current aggressive early use of therapy and should help prompt studies that look at when and how to start antiretroviral therapy.

Amphotericin B oral suspension for fluconazole-refractory oral candidiasis in persons with HIV infection. Adult AIDS Clinical Trials Group Study Team 295.

OBJECTIVE: To determine the efficacy and safety of amphotericin B oral suspension (ABOS) for the treatment of fluconazole refractory oral candidiasis in persons with HIV infection. DESIGN AND SETTING: A prospective, multicenter, open label trial at 25 study centers within the AIDS Clinical Trials Group. PATIENTS AND METHODS: Individuals with diffuse oral candidiasis after 14 days of treatment with 200 mg of fluconazole daily (more than five plaques or a single plaque > 3 cm largest length) were treated with ABOS, 100 mg/ml, 5 ml swish and swallow, four times daily for 14 days. Thereafter incomplete or non-responders received an additional 14 days of therapy and responders received maintenance ABOS twice daily for up to 6 months. Relapses during maintenance ABOS were treated by increasing the dose to four times daily. MAIN OUTCOME MEASURES: To demonstrate an ABOS clinical response rate > 33% and a treatment-limiting toxicity rate < 50%. Clinical response was defined as the absence of mouth pain and the presence of less than five oral plaques, the largest being < 3 cm largest dimension. RESULTS: Fifty-eight subjects with a median age of 39 years and a median CD4 count of 10 x 10(6) cells/l were enrolled. Four subjects were excluded from the analysis because of inadequate follow-up after randomization (n = 3) or the presence of active esophageal disease (n = 1). Of the remaining 54 subjects, 23 (42.6%; 95% lower confidence interval, 31.1%) were classified as responders after 28 days. Five subjects (9%) stopped treatment due to toxicity. Relapse occurred in 16 responders (70%). CONCLUSIONS: Amphotericin B oral suspension is well tolerated but has limited efficacy for the treatment of fluconazole refractory oral candidiasis.

Predictors of optimal virological response to potent antiretroviral therapy.

BACKGROUND: Current potent antiretroviral therapy (using a protease inhibitor and two nucleoside reverse transcriptase inhibitors) produces a durable suppression of HIV replication in less than 75% of treated patients. Identification of predictors of successful therapy might allow the development of improved strategies to increase response rates. METHODS: We analyzed retrospectively the results from a multicenter, randomized, double-blind Phase III study of combination anti-HIV therapy with nelfinavir, zidovudine, and lamivudine to evaluate the relationship between virological response over 48 weeks of treatment to variables which could potentially serve as early predictors of long-term response. The goal was to produce long-term suppression of viral load to sensitive (<400 copies HIV RNA/ml) and ultrasensitive (<50 copies HIV RNA/ml) limits of quantification with the Amplicor PCR assay. FINDINGS: Baseline viral load, the change in viral load over the first 4 weeks of treatment, the 2 h post-dose nelfinavir levels and the time to respond to HIV RNA levels of <400 copies/ml and <50 copies/ml have the best predictive value in determining response and response duration. Patients who achieved very low viral nadirs (<50 copies HIV RNA/ml) had significantly longer responses than those who achieved nadirs of 50-400 copies HIV RNA/ml. INTERPRETATION: Parameters that can be measured easily at baseline or early after therapy is started can identify patients at high risk of failure with standard treatment. Such patients may be candidates for more aggressive therapy or for alternative strategies designed to improve outcome. In addition, these results support the use of ultra-sensitive HIV RNA assays to predict long-term outcome of anti-HIV therapy.

Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy.

BACKGROUND: The use of highly active antiretroviral therapy (HAART) has been associated with multiple metabolic complications whose pathogenesis is poorly understood at the present time. METHODS: We performed a cross-sectional analysis of whole-body, lumbar spine (L1-L4) and proximal femur bone mineral density in 112 male subjects (HIV-infected patients on HAART that included a protease inhibitor, HIV-infected patients not receiving a protease inhibitor and healthy seronegative adults) using dual energy x-ray absorptiometry. RESULTS: Men receiving protease inhibitors had a higher incidence of osteopenia and osteoporosis according to World Health Organization definitions: relative risk = 2.19 (95% confidence interval 1.13-4.23) (P = 0.02). Subjects receiving protease inhibitors had greater central: appendicular adipose tissue ratios than the other two groups (P < 0.0001). There was no relationship between the central: appendicular fat ratio and the lumbar spine or proximal femur bone mineral density t- or z- scores, suggesting that osteoporosis and body fat redistribution are independent side effects of HAART. CONCLUSIONS: Osteopenia and osteoporosis are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution.

Impact of protease inhibitor therapy on HIV-related oropharyngeal candidiasis.

OBJECTIVE: To determine the relationship between antiretroviral therapy and changes in prevalence and amount of oropharyngeal candidiasis (OPC) and skin test reactivity for delayed type hypersensitivity. DESIGN: Observational cohort. SETTING: University-based public hospital AIDS clinic. PATIENTS: Adults with advanced HIV infection who had been taking nucleoside transcriptase inhibitor drugs but had not taken a protease inhibitor and who started antiretroviral treatment with ritonavir. MAIN OUTCOME MEASURES: OPC lesions score, oral candidal colonization, oral candidal quantification, skin test reactivity for delayed type hypersensitivity (purified protein derivative, candidal and streptokinase antigens), plasma HIV RNA and CD4 cell count at weeks 8, 16 and 48 weeks. RESULTS: In the 99 patients who entered the study, there was a significant reduction in the HIV plasma RNA (mean log decrease from baseline at 48 weeks 0.88) and a significant increase in CD4 cell counts (mean CD4 cell increase from baseline at 48 weeks 128 x 10(6) cells/l). Only 17% of patients had < 200 copies/ml HIV RNA at 48 weeks. There were significant decreases in the prevalence of OPC lesions (31% at baseline to 1% at 48 weeks; P < 0.001), and in oral candidal loads [2226 to 811 colony-forming units (CFU)/ml; P = 0.0171]. The percentage of patients with at least one positive skin test increased significantly (6 to 28%; P < 0.05). Patients whose CD4 lymphocyte count was > 200 x 10(6) cells/l at 48 weeks had significantly lower oral candidal loads and were more likely to have a positive skin test than patients whose CD4 cell count was < 200 x 10(6) cells/l. CONCLUSION: In patients with advanced HIV infection, antiretroviral treatment including a protease inhibitor has a positive impact in the natural history of OPC. This positive impact appears to be correlated with a better immunological function and occurs despite continuous HIV replication.

Virologic responses to a ritonavir--saquinavir-containing regimen in patients who had previously failed nelfinavir.

OBJECTIVES: The effectiveness of a second protease inhibitor in patients who failed an initial protease inhibitor is unclear but believed to be low. It has been postulated, however, that patients who fail nelfinavir may respond differently. We therefore assessed the virologic response to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir. METHODS: A total of 26 patients enrolled in the nelfinavir clinical trials AG506 and AG511 at our two sites who failed (two consecutive HIV viral loads > 5000 copies/ml; branched DNA assay) were switched to a combination of stavudine 40 mg twice daily, lamivudine 150 mg twice daily, ritonavir 400 mg twice daily and saquinavir 400 mg twice daily. RESULTS: The mean viral load at enrollment in this study was 46 674 copies/ml (range, 1075-146400 copies/ml). The median CD4 cell count was 222 x 10(6)/l (range, 82-448 x 10(6)/l). The median duration of nelfinavir use with a detectable viral load before the switch occurred was 48 weeks. Two patients discontinued the study at 3 weeks. All of the remaining patients (n = 24) reached undetectable viral loads (< 500 copies/ml) that were sustained at week 24 in 17 (71%) out of 24 subjects. The most frequent baseline mutations in the protease gene prior to switching were D30N (13 out of 18), N88D (eight out of 18) and M36I (eight out of 18). The presence or absence of these mutations was not predictive of a short-term virologic response. CONCLUSIONS: Most patients who failed a nelfinavir-containing regimen responded to a switch to a combination regimen with saquinavir-ritonavir.

A prospective study of discontinuing primary and secondary Pneumocystis carinii pneumonia prophylaxis after CD4 cell count increase to > 200 x 106 /l.

OBJECTIVE: To assess the incidence of Pneumocystis carinii pneumonia (PCP) after discontinuation of either primary or secondary prophylaxis. DESIGN: This was a prospective, non-randomized, non-blinded study. SETTING: Twenty-five University-based AIDS Clinical Trials Group units. PARTICIPANTS: Participants either had a CD4 cell count < or = 100 x 106/l at any time in the past and no history of confirmed PCP (group I; n = 144), or had a confirmed episode of PCP > or = 6 months prior to study entry (group II; n = 129). All subjects had sustained CD4 cell counts > 200 x 106/l in response to antiretroviral therapy. INTERVENTIONS: Subjects discontinued PCP prophylaxis within 3 months or at the time of study entry. Evaluations for symptoms of PCP and CD4 cell counts were performed every 8 weeks. Prophylaxis was resumed if two consecutive CD4 cell counts were < 200 x 106/l. MAIN OUTCOME MEASURE(S): The main outcome was development of PCP. RESULTS: No cases of PCP occurred in 144 subjects (median follow-up, 82 weeks) in group I or in the 129 subjects (median follow-up, 63 weeks) in group II (95% upper confidence limits on the rates of 1.3 per 100 person-years and 1.96 per 100 person-years for groups I and II, respectively). Eight subjects (five in group I and three in group II) resumed PCP prophylaxis after two consecutive CD4 cell counts < 200 x 106/l. CONCLUSIONS: The risk of developing initial or recurrent PCP after discontinuing prophylaxis is low in HIV-infected individuals who have sustained CD4 cell count increases in response to antiretroviral therapy. Neither lifelong primary nor secondary PCP prophylaxis is necessary.

A phase II/III trial of antimicrobial therapy with or without amikacin in the treatment of disseminated Mycobacterium avium infection in HIV-infected individuals. AIDS Clinical Trials Group Protocol 135 Study Team.

OBJECTIVE: To determine the clinical and microbiologic benefit of adding amikacin to a four-drug oral regimen for treatment of disseminated Mycobacterium avium infection in HIV-infected patients. DESIGN: A randomized, open-labeled, comparative trial. SETTING: Outpatient clinics. PATIENTS: Seventy-four patients with HIV and symptomatic bacteremic M. avium infection. INTERVENTIONS: Rifampin 10 mg/kg daily, ciprofloxacin 500 mg twice daily, clofazimine 100 mg every day, and ethambutol 15 mg/kg orally daily for 24 weeks, with or without amikacin 10 mg/kg intravenously or intramuscularly 5 days weekly for the first 4 weeks. MAIN OUTCOME MEASURE: Clinical and microbiologic response at 4 weeks; quantitative level of bacteremia with M. avium. RESULTS: No difference in clinical response was noted with the addition of amikacin to the four-drug oral regimen, and only 25% in either group had a complete or partial response at 4 weeks. A comparable quantitative decrease in bacteremia was noted in both treatment groups, with 16% of patients being culture-negative at 4 weeks and 38% at 12 weeks. Toxicities were mainly gastrointestinal. Amikacin was well tolerated. Median survival was 30 weeks in both groups. CONCLUSIONS: The addition of amikacin to a four-drug oral regimen of rifampin, ciprofloxacin, clofazimine, and ethambutol did not provide clinical or microbiologic benefit.

The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3.

We conducted a double-blind, randomized phase II study to evaluate the safety and activity of combination therapy with N-butyl-deoxynojirimycin (SC-48334) (an alpha-glucosidase I inhibitor) and zidovudine versus zidovudine alone. Patients with 200 to 500 CD4 cells/mm3 who tolerated < or = 12 weeks of prior zidovudine therapy received SC-48334 (1000 mg every 8 h) and zidovudine (100 mg every 8 h) or zidovudine and placebo. Sixty patients received combination therapy and 58, zidovudine and placebo. Twenty-three patients (38%) and 15 (26%), in the combination and zidovudine groups, respectively, discontinued therapy (p = 0.15). The mean SC-48334 steady-state trough level (4.04 +/- 0.99 micrograms/ml) was below the in vitro inhibitory concentration for human immunodeficiency virus (HIV). The mean increase in CD4 cells at week 4 was 73.8 cells/mm3 and 52.4 cells/mm3 for the combination and zidovudine groups, respectively (p > 0.36). For patients with prior zidovudine therapy, the mean change in CD4 cells in the combination and zidovudine groups was 63.7 cells/mm3 and 4.9 cells/mm3 at week 8 and 6.8 cells/mm3 and -45.1 cells/mm3 at week 16, respectively. The number of patients with suppression of HIV p24 antigenemia in the combination and zidovudine groups was six (40%) and two (11%) at week 4 (p = 0.10) and five (45%) and two (14%) at week 24 (p = 0.08), respectively. Diarrhea, flatulence, abdominal pain, and weight loss were common for combination recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B-resistant yeast infection in severely immunocompromised patients.

Systemic yeast infections are a major cause of morbidity and mortality in severely immunocompromised patients. The in vitro susceptibility to amphotericin B of 29 yeasts causing fungemia was examined in 26 patients undergoing allogeneic or autologous bone marrow transplantation and/or myelosuppressive chemotherapy. The minimal inhibitory concentrations (MICs) of amphotericin B observed with blood isolates from these patients were significantly higher than those observed with blood, sputum, or skin isolates from non-immunocompromised patients (p less than 0.01). All episodes (10 of 10) of bloodstream infection in immunocompromised patients caused by isolates with MICs greater than 0.8 micrograms/ml were fatal, versus eight of 17 episodes of bloodstream infection caused by yeasts with MICs of 0.8 micrograms/ml or less (p = 0.04). Although 15 of 26 patients received empiric treatment with amphotericin B before laboratory evidence of fungemia developed, the amphotericin B susceptibilities of their isolates were not significantly different from those of patients who had not received empiric amphotericin B treatment. It is concluded that yeast fungemia in severely immunocompromised patients is often caused by organisms resistant to the usual concentrations of amphotericin B obtainable in vivo, and that this finding is clinically significant.

Failure of high-dose oral acyclovir with or without immune globulin to prevent primary cytomegalovirus disease in recipients of solid organ transplants.

PURPOSE: To assess the efficacy of acyclovir and intravenous immune globulin (IVIG) for cytomegalovirus (CMV) prophylaxis in high-risk recipients of solid organ transplants. PATIENTS AND METHODS: We randomized 21 CMV-seronegative organ transplant recipients with seropositive donors (D+R-) to receive oral acyclovir, 800 mg four times daily, or, in addition to acyclovir, IVIG, 300 mg/kg, every 2 weeks for six doses. Patients were followed closely for the development of CMV infection and disease. RESULTS: All but one prophylactically treated patient (95%) developed CMV infection. Fifteen of 21 patients (71%) who received prophylaxis fulfilled criteria for CMV disease. Disease onset was delayed in those who received IVIG, but this did not reach statistical significance. Ganciclovir was used for treatment in 15 of the 21 patients (71%). CONCLUSIONS: Acyclovir, with or without IVIG, did not prevent primary CMV infection or disease in D+R- solid organ transplant recipients at our institution. Moreover, most patients were treated with ganciclovir despite the use of prophylaxis. Given the ready availability of ganciclovir to treat CMV disease, we recommend a reappraisal of the role of CMV prophylaxis by these means in the solid organ transplant population.

Resistant candidiasis.

Mucosal (oropharyngeal, esophageal, and, in women, vaginal) candidiasis is a common infectious complication in HIV-infected patients. There is a wide range of drugs to treat or suppress Candida infections. However, with the increasingly common use of fluconazole as treatment or prophylaxis in patients with relatively advanced HIV disease, mucosal candidiasis that is clinically resistant to fluconazole is increasingly recognized. Susceptibility testing for fluconazole has not been well standardized, and laboratory and clinical correlations often have been difficult to demonstrate. However, the frequency with which Candida strains resistant to fluconazole can be isolated appears to be increasing, particularly in patients with advanced HIV disease. Anecdotal results suggest that patients who fail fluconazole therapy usually do not respond to higher doses of fluconazole, but may occasionally respond to itraconazole or ketoconazole. In vitro susceptibility to these agents does not necessarily ensure clinical efficacy. Amphotericin B is usually effective initially but requires parenteral administration. However, with any therapy, relapses tend to occur and progressively recalcitrant disease often occurs, with increasing morbidity for patients. There is a clear need for studies addressing the incidence of resistance, the risk factors for its development, and more effective therapy.

Diagnosis and treatment of oropharyngeal candidiasis in patients infected with HIV: a critical reassessment.

Oropharyngeal candidiasis is the most common opportunistic infection seen in patients infected with the human immunodeficiency virus (HIV). As HIV disease progresses and immunosuppression worsens, the incidence and severity of oropharyngeal candidiasis increase. The predominant pathogen in initial and recurrent episodes is Candida albicans, which responds to a variety of topical (nystatin and clotrimazole) and systemic azole antifungal agents (ketoconazole, itraconazole, and fluconazole). Since the introduction of the oral azoles, increasing evidence indicates that C. albicans strains are developing resistance to azoles, particularly fluconazole, and other Candida strains are emerging that are intrinsically less susceptible to azole therapy. The advent of effective antiretroviral therapies for the treatment of HIV disease has led to a scenario in which antifungal strategies are likely to be highly effective. To minimize the risk of resistance, topical therapies should be considered first-line candidates for treatment of initial or recurrent cases of uncomplicated oropharyngeal candidiasis. Systemic azole therapy should be reserved for cases unresponsive to topical therapies or for more severe oropharyngeal candidiasis with esophageal involvement.

Alterations in spliced and unspliced HIV-1-specific RNA detection in peripheral blood mononuclear cells of individuals with varying CD4-positive lymphocyte counts.

Reverse transcriptase-polymerase chain amplification reactions (RT-PCR) were used to identify transcripts for HIV-1 structural and regulatory proteins in peripheral blood mononuclear cells of a cohort of 48 patients. At least one set of PCR primers was capable of detecting HIV-1 transcripts in 94% of patients. Unspliced gag-pol transcripts were detected with gag or pol primer sets in 60 and 63% of samples, respectively. A significant inverse correlation was noted between transcript identification with the gag primer set and the number of CD4-positive lymphocytes in the blood sample and the clinical stage of infection. Single-spliced env transcripts were identified in 44% of individuals. Multiple-spliced tat or nef transcripts were detected in 6.2 and 53% of individuals, respectively. These findings indicate that viral transcripts are expressed throughout the course of HIV-1 infection.

Elevated lactate levels in hospitalized persons with HIV infection.

Lactic acidosis has been described in persons with HIV infection particularly in association with the use of nucleoside reverse transcriptase inhibitors (NRTIs). Little is known about the epidemiology of this problem. We reviewed the records of all HIV-infected adults with elevated lactate levels admitted to Barnes-Jewish hospital from 1996 to 1998. There were 37 patients identified with elevated lactate levels. The annual rate of elevated lactate levels was 22.6, 33.9, and 30.8 per 1,000 admissions in 1996, 1997, and 1998, respectively. The median age of the patients was 40.4 years; median CD4(+) count was 148 cells/mm(3); and the median HIV-1 RNA level was 4,401 copies/ml. The median lactate level was 4.5 mmol/liter (range, 2.2-19 mmol/liter). Twenty-nine patients (78%) had elevated lactate levels at admission. Elevated lactate levels were associated with sepsis (48.7%), pancreatitis (13.5%), liver failure (8.1%), multiorgan failure (8.1%), and other conditions. Five patients had lactic acidosis associated with the use of antiretroviral medications; one patient with unexplained lactic acidosis and four patients with pancreatitis. The mortality rate was 45.9% (17/37). Higher lactate levels were associated with increased mortality. In conclusion, elevated lactate levels were uncommon but not rare in hospitalized patients with HIV infection. Sepsis was the most commonly associated condition and antiretroviral medications were the second most frequently associated factor. There was no significant increase in the annual rate of lactic acidosis during this 3-year period.