The long-term efficacy of making resistance testing routinely available to clinicians has not been established. We conducted a clinical trial at 6 US military hospitals in which volunteers infected with human immunodeficiency virus type-1 were randomized to have routine access to phenotype resistance testing (PT arm), access to genotype resistance testing (GT arm), or no access to either test (VB arm). The primary outcome measure was time to persistent treatment failure despite change(s) in antiretroviral therapy (ART) regimen. Overall, routine access to resistance testing did not significantly increase the time to end point. Time to end point was significantly prolonged in the PT arm for subjects with a history of treatment with > or =4 different ART regimens or a history of treatment with nonnucleoside reverse-transcriptase inhibitors before the study, compared with that in the VB arm. These results suggest that routine access to resistance testing can improve long-term virologic outcomes in HIV-infected patients who are treatment experienced but may not impact outcome in patients who are naive to or have had limited experience with ART.

We identified 10 individuals who had undiagnosed human immunodeficiency virus type 1 (HIV-1) infection at the time of smallpox vaccination. Mean CD4 cell count was 483 cells/mm3 (range, 286-751 cells/mm3), and mean log10 plasma HIV-1 RNA load was 4.13 copies/cm3 (range, 2.54-5.16 copies/cm3). All vaccinees (3 primary and 7 repeat) had a normal, robust reaction without complications. Smallpox vaccine was well-tolerated in this small series of HIV-1-infected military personnel.

BACKGROUND Hepatitis A is a major health risk for many human immunodeficiency virus (HIV)-infected individuals. Vaccination is a potentially attractive measure to reduce the incidence of hepatitis A among this population, but data on its safety and immunogenicity are incomplete. METHODS Ninety HIV-uninfected adults received an inactivated hepatitis A vaccine (VAQTA; Merck), and 90 HIV-infected subjects were randomized, in double-blind fashion, to receive either the vaccine or placebo. The HIV-infected subjects were stratified by CD4 cell count, with 45 subjects having CD4 cell counts of > or =300 cells/mm3 and 45 subjects having CD4 cell counts of <300 cells/mm3. Vaccine was given at weeks 0 and 24 of the study.Results. Seroconversion rates at week 28 of the study were 94% among the HIV-infected subjects and 100% among the HIV-uninfected control subjects. HIV-infected subjects with CD4 cell counts of <300 cells/mm3 had a seroconversion rate of 87%, and HIV-infected subjects with CD4 cell counts of > or =300 cells/mm3 had a seroconversion rate of 100%. The vaccine was generally well tolerated, and no adverse effect on either HIV load or CD4 cell count was found. CONCLUSION Hepatitis A vaccine was both immunogenic and safe among HIV-infected subjects.

Objective: To describe the demographics, risk behaviors, and HIV-1 subtypes in a large cohort of recently HIV-infected military personnel. Design: Descriptive, cross-sectional study. Methods: US military personnel with recent HIV seroconversion from six medical referral centers were enrolled with a self-administered questionnaire, CD4 cell counts, syphilis and hepatitis B serologies, plasma viral RNA levels, and HIV-1 subtype nucleic acid sequencing. Results: Between February 1997 and May 2000, 520 patients were enrolled. Most [488 (94.3%)] were infected with HIV-1 subtype B. The most prevalent non-B subtype was a circulating recombinant form (CRF01_AE) [17 (61%)]; however, two pure subtypes (C and D), as well as CRF02_AG, CRF09_cpx and a BE recombinant were identified. The likely area of HIV-1 acquisition was the United States for 70% of the volunteers. At least three non-B subtype infections (two subtype C, one subtype CRF01_AE) were apparently acquired domestically. Risk behaviors and comorbid sexually transmitted diseases were reported during the seroconversion period. Volunteers with non-B subtype HIV infection were more likely to report heterosexual contacts [92% vs. 39%; odds ratio (OR), 10.0], including contacts with commercial sex workers (41% vs. 13%; OR, 4.9). The Roche Amplicor version 1.0 assay was less sensitive for non-B subtype infections than the Roche Amplicor version 1.5 assay. Conclusion: There is a high prevalence and diversity of non-B HIV subtypes in this large cohort. Efficient diagnosis of acute primary HIV-1 infection was identified as a goal for prevention programs. Modifiable risk behaviors and target populations for intervention were identified.

Background: Human herpesvirus 8 (HHV-8), the cause of Kaposi's sarcoma, is common among HIV-infected persons. The exact route of transmission of HHV-8 in various populations is still debated.Goal: The goal was to define the correlates of HHV-8 infection among men recently infected with human immunodeficiency virus.Study Design: Three hundred forty-two HIV-infected U.S. military men were evaluated using a questionnaire. regarding potential risk factors and laboratory data, including HHV-8, herpes simplex virus 2 (HSV-2), syphilis, hepatitis B, and hepatitis C serologies.Results: The seroprevalence of HHV-8 was 32%. HHV-8 was significantly associated with hepatitis B seropositivity (odds ratio [OR], 2.44; 95% confidence interval [CI], 1.5-4.1), and black ethnicity was negatively associated with HHV-8 (OR, 0.6; 95% Cl, 0.3-0.9) in the multivariate analysis. HHV-8 was not associated with drug use or hepatitis C seropositivity. Among men who have sex with men (MSM), HHV-8 infection correlated with hepatitis B seropositivity (OR, 2.2; 95% CI, 1.1-4.3) and HSV-2 (OR, 2.6; 95% CI, 1.4-4.9). Among heterosexuals, the correlates of HHV-8 were different; blacks as compared with whites (OR, 0.3; 95% Cl, 0.1-0.8) and married versus single status (OR, 0.4; 95% Cl, 0.2-0.9) were associated with a lower rate of HHV-8 infection. Among heterosexuals, hepatitis B, HSV-2, and sexual behaviors were not associated with HHV-8.Conclusion: This study suggests that the seroprevalence of HHV-8 is increased in both MSM and heterosexual men with HIV infection, and that the route(s) of HHV-8 acquisition might be different between MSM and heterosexuals.

We determined the immunogenicity and safety of reimmunization with the 23-valent polysaccharide pneumococcal vaccine in patients infected with human immunodeficiency virus type 1 (HIV-1). Patients immunized >5 years earlier (initially within 1 year of HIV-1 seroconversion) were randomized to receive vaccine (n=57) or placebo (n=30). Persons with recent HIV-1 seroconversion (n=14) were immunized for the first time. Preimmunization levels of capsule-specific immunoglobulin G were similar in all groups. Reimmunized patients showed a significantly lower frequency and magnitude of antibody responses compared with persons with recent HIV-1 seroconversion. Reimmunized patients did not show adverse virologic or immunologic changes, but some reported local discomfort (15%) or fever (8%). Thus, the limited responses after reimmunization of HIV-1-infected patients with the current 23-valent vaccine mandates the need for a more effective reimmunization schedule, more immunogenic vaccines, or other behavioral and therapeutic interventions.

Bartonella henselae has been implicated as a significant cause of HIV-associated dementia. We attempted to confirm this association by utilizing the database of the San Diego HIV Neurobehavioral Research Center, which collects longitudinal neurocognitive and laboratory data on over 500 HIV-infected participants. Utilizing an immunofluorescent assay we found that 11% of 177 subjects, half of whom had documented neurocognitive decline, were seropositive for B. hensalae. There was no correlation between B. hensalae seropositivity and neurocognitive decline. The role of B. hensalae in HIV-associated dementia remains ambiguous.

New advances in human immunodeficiency virus (HIV) monitoring and therapeutics have led to dramatic changes in the course of HIV disease. We evaluated our closed clinic of 425 HIV patients over the period 1995-1998 to determine the cost effectiveness of these changes in care. We found that the costs of antiretroviral therapy tripled over the period of observation, but that these increases were largely offset by major declines in inpatient and home health expenditures. In addition, we found that annual mortality among our HIV patients had declined by 90%. We calculated that the cost per life-year gained is about $17,500, which compares favorably with medical expenditures for renal dialysis or advanced cardiac disease.

Objective While transmission of drug-resistant HIV-1 has been reported, estimates of prevalence of resistance in drug-naïve populations are incomplete. We investigated the prevalence of genotypic mutations and phenotypic antiretroviral resistance in a cohort of HIV-1 infected U.S. military personnel prior to the institution of antiretroviral therapy. Design Cross-sectional cohort study. Methods Plasma was obtained from 114 recently HIV-1 infected subjects enrolled in an epidemiological study. Genotypic resistance was determined by consensus sequencing of a PCR product from the HIV-1 pol gene. Sequences were interpreted by a phenotypic–genotypic correlative database. Resistance phenotypes were determined by a recombinant virus cell culture assay. Results Genotypic mutations and phenotypic resistance were found at a higher than expected frequency. Resistance to non-nucleoside reverse transcriptase inhibitors was most common, with a prevalence of 15% of 95 subjects by genotype and 26% of 91 subjects by phenotype. Genotypic and phenotypic resistance respectively were found in 4% and 8% of subjects for nucleoside reverse transcriptase inhibitors and in 10% and 1% for protease inhibitors. One subject harbored virus with resistance to all three drug classes. Conclusions A substantial frequency of resistance to antiretroviral drugs was identified in a therapy-naïve U.S. cohort. In most cases, the genotypic and phenotypic assays yielded similar results, although the genotypic assay could detect some protease inhibitor resistance-associated mutations in the absence of phenotypic resistance. These data suggest the need for optimization of treatment guidelines based on current estimates of the prevalence of drug resistance in HIV-1 seroconverters.

Antigenic stimulation from invasive bacterial infections, and the vaccines designed to prevent them, may promote T cell activation and enhancement of HIV-1 replication. Changes in viral load have been correlated with antigen-specific responses. We prospectively determined the impact of immunization with 23-valent pneumococcal vaccine (PVAX) and Haemophilus influenzae type b (Hib)-modified diphtheria toxoid CRM197 (DT) vaccine on HIV-1 replication in recent HIV-1 seroconverters (n = 14; median, 5.5 months from infection; median CD4+ T cells, 535 microl), and correlated results with vaccine-related immune activation. Specific antibody responses, markers of CD4+ T cell activation (transferrin and interleukin 2 receptors), and viral burden were measured at weeks -2 (pre), 0, 1, 2, 6, and 12 after immunization. By week 2, levels of IgG had increased significantly over baseline in both HIV-1-infected patients and HIV-1-seronegative control subjects (n = 9) for each antigen (geometric mean fold rise: PVAX, 10.1 versus 5.3; Hib, 16.0 versus 11.7; and DT, 26.2 versus 24.5, respectively). Despite these vigorous responses to both polysaccharide and protein antigens, HIV-1-infected patients showed limited evidence of CD4+ T cell activation at 1 week, no consistent rise in HIV-1 burden at any point, and no decline in CD4+ T cell number over time. We conclude that recent HIV-1 seroconverters show vigorous humoral responses to vaccine antigens and limited early evidence of T cell activation, but no substantial or sustained increase in viral replication or decline in CD4+ T cell number. Thus, respiratory bacterial vaccines appear immunogenic and safe early in HIV-1 infection.

Background: Regular testing of military personnel identifies early HIV infection; this identification provides a sentinel cohort in which to describe the evolving molecular epidemiology of HIV-1 transmission.Objective: To describe the prevalence and epidemiologic correlates associated with the acquisition of non-subtype B and drug-resistant HIV infections.Design: Cross-sectional study.Setting: Military referral hospital.Patients: 95 military personnel with HIV-1 seroconversion.Measurements: Self-reported questionnaire, CD4 cell counts, plasma HIV-1 RNA levels, and nucleic acid sequence analysis for drug-resistant mutations and HIV-1 genetic subtype.Results: 95 patients were enrolled between February 1997 and February 1998. The likely geographic location of HIV-1 acquisition was overseas in 8% of patients, the United States in 68%, and either overseas or the United States in 24%. Seven patients (7.4%) had subtype E infection; the remainder had subtype B infection. Eight of 31 (26%) treatment-naive patients had mutations in the reverse transcriptase or protease gene associated with drug resistance.Conclusions: The percentage of HIV-1 non-subtype B infection and antiretroviral drug-resistant mutations was relatively high in U.S. military personnel with recently acquired HIV-1 infection.

BACKGROUNDAlthough influenza vaccination is recommended in persons infected with HIV-1, its efficacy is unknown.OBJECTIVETo assess the immunogenicity, efficacy, and risks associated with influenza vaccination in persons infected with HIV-1.DESIGNRandomized, double-blind, placebo-controlled trial.SETTINGOutpatient military clinic.PATIENTS102 patients with HIV-1 infection.INTERVENTIONInfluenza vaccine (n = 55) or saline placebo (n = 47).MEASUREMENTSInfluenza antibody titers, CD4+ cell counts, and plasma HIV-1 RNA levels at baseline, 1 month after immunization, and 3 months after immunization; viral cultures from persons presenting with respiratory illness; and respiratory symptom interview.RESULTSTwenty-three placebo recipients (49%) and 16 vaccine recipients (29%) reported respiratory symptoms (P = 0.04). Ten placebo recipients but no vaccine recipients had laboratory-confirmed symptomatic influenza (P < 0.001) (protective efficacy, 100% [95% CI, 73% to 100%]). No effect on plasma HIV-1 RNA levels or CD4+ cell counts was noted.CONCLUSIONInfluenza vaccination is highly effective in HIV-1-infected persons and does not seem to be associated with substantial changes in viral load or CD4 cell count.

Annual influenza vaccine is recommended for persons with HIV infection. Recent reports indicate that immunizations may increase HIV replication in infected individuals. Forty-seven HIV-infected patients were randomized to influenza vaccine or saline placebo using a double blind study design. One month after vaccination, plasma HIV-1 RNA increased in the vaccinated but not placebo group (p = 0.029). At 3 months, CD4% dropped an average of 1.6 points in the vaccinated group compared to an increase of 0.1 points in the placebo group (p = 0.039). Patients on stable antiretroviral regimens had CD4% drop an average of 2.3 points in the vaccinated group at 3 months versus 0.1 points in the placebo group (p = 0.015). It is concluded that HIV-infected patients are at risk for increased HIV replication and decreases in CD4% following influenza vaccination. Since influenza has not been associated with significant morbidity in this population, further study of routine influenza vaccination for HIV-infected patients is warranted.

To the Editor: With the advent of azole resistance and a lack of convenient topical or oral therapy, Candida vaginitis can be a difficult problem for women with AIDS. We describe what we believe is the first such case in the literature of an AIDS patient who has achieved complete relief using boric acid vaginal suppositories. A 32-year-old woman with a long antecedent history of recurrentCandida vaginitis was found to test positive for HIV and had a CD4 count of 10/mm3. After 9 months using fluconazole, 100 mg daily, she redeveloped thrush and vulvovaginal candidiasis. A culture grew Candida krusei and Tornlopsis glabrata, both with fluconazole minimum inhibitory concentrations(MICs) of >64 µg/ml. Itraconazole did not control her symptoms. Topical nystatin controlled the thrush but only minimally improved the vulvar symptoms. Topical gentian violet provided relief but was unacceptable to the patient because it permanently stained her clothing and bathtub. We then initiated boric acid, 600-mg vaginal suppositories and 5% lanolin ointment, which provided rapid relief of symptoms within 24 hours. The therapy was well tolerated by the patient. After 10 days of continuous, twice-daily use, there was no boric acid detected in the serum. Three relapses in the subsequent 5 months have all been easily controlled with 2- to 3-day courses of boric acid. A more recent vaginal culture grew only Candida albicans, which was azole-sensitive. Available gynecologic literature has described boric acid suppositories as a beneficial therapy for non-HIV-related Candida vaginitis(1-3). In the single-blind study by Swate and Weed, they report achieving rapid symptomatic relief in 40(100%) patients using 600-mg vaginal suppositories in conjunction with 5% boric acid in lanolin ointment topically. Two of the patients (5%) relapsed within 30 days after treatment. In the double-blind randomized study by Keller-Van-Slyke et al.(3), 108 patients were treated with either nystatin or boric acid suppository therapy. The study showed boric acid to be superior, with a 92% (48/52) cure rate compared with a 64% (36/56) cure rate with nystatin. Both groups had frequent episodes of relapse, with relapse-free rates of only 72% (boric acid) and 50% (nystatin) at 30 days. Another study by Jovanovic et al.(2) showed that boric acid was superior in patients with vaginal candidiasis refractory to miconazole and clotrimazole topical therapy. Boric acid has fungistatic properties, but the exact mechanism of action is unknown. It is postulated that the fungistatic effects of boric acid may be the result of its inherent properties as a weak acid. The acid penetrates the cell wall and disrupts the cell membrane, whereas current antifungal agents bind and inhibit ergosterol synthesis. Toxicity was not a problem. We were unable to detect any vaginal absorption of boric acid; however, the possibility that denuded or ulcerated vaginal mucosa might absorb a measurable amount is a concern. Serum concentrations <200 µg/ml are considered safe(4). Our HIV-positive patient displayed a pattern of vulvovaginal candidiasis resolution that was comparable with those reported in patients who were not HIV-positive. The patient was free of vaginitis symptoms within 24 hours of treatment, boric acid was not detected in the blood, and occasional relapses were easily controlled with short courses of boric acid. We conclude that vaginal and topical boric acid is a useful alternative for azole-refractory Candida vaginitis in a woman with AIDS. It has limited side effects and is well tolerated. Further evaluation of safety and efficacy is warranted. Acknowledgments: The Chief, Bureau of Medicine and Surgery, Navy Department, Washington, DC, Clinical Investigation Program sponsored this report #84-16-1968-607, as required by HSETCINST 6000.41A. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. Y. Todd Shinohara Sybil A. Tasker Departments of Pharmacy and Internal Medicine (Infectious Disease Division) and Clinical Investigation; Naval Medical Center; San Diego, California