Acute HIV infection: the impact of anti-retroviral treatment on cellular immune responses.

The overall value of initiating anti-retroviral therapy during the acute phase of human immunodeficiency virus type 1 (HIV-1) infection remains unclear. From a clinical perspective, the lack of data from controlled randomized clinical trials limits understanding of long-term effects of treatment on the clinical course of HIV infection. Based on available data, the impact of anti-retroviral therapy during acute infection on the immune response against HIV-1 is not particularly encouraging. Recent observations on the very early depletion of lymphocyte reservoirs in the gastrointestinal tract may partially explain the limited benefit of anti-retroviral therapy initiated during the acute phase of HIV-1 infection. This may also help to explain the dichotomy between early observations demonstrating apparent immunological benefit with early anti-retroviral treatment that were associated none the less with inability to control viral replication following treatment interruption.

HIV in body fluids during primary HIV infection: implications for pathogenesis, treatment and public health.

OBJECTIVE: To describe initial viral dissemination to peripheral tissues and infectious body fluids during human primary HIV infection. DESIGN: Observational cohort study. METHODS: Blood plasma, cerebrospinal fluid (CSF), seminal plasma, cervicovaginal lavage fluid and/or saliva were sampled from 17 individuals with primary HIV infection (range of time from symptoms onset to sampling, 8--70 days) and one individual with early infection (168 days). Subjects' HIV-1 RNA levels in each fluid were compared with levels from antiretroviral-naive controls with established HIV infection. For study subjects, correlations were assessed between HIV-1 RNA levels and time from symptoms onset. Responses to antiretroviral therapy with didanosine + stavudine + nevirapine +/- hydroxyurea were assessed in each compartment. RESULTS: HIV-1 RNA levels were highest closest to symptoms onset in blood plasma (18 patients) and saliva (11 patients). CSF HIV-1 RNA levels (five patients) appeared lower closer to symptoms onset, although they were higher overall in primary versus established infection. Shedding into seminal plasma (eight patients) and cervicovaginal fluid (two patients) was established at levels observed in chronic infection within 3--5 weeks of symptoms onset. High-level seminal plasma shedding was associated with coinfection with other sexually transmitted pathogens. Virus replication was suppressed in all compartments by antiretroviral therapy. CONCLUSIONS: Peak level HIV replication is established in blood, oropharyngeal tissues and genital tract, but potentially not in CSF, by the time patients are commonly diagnosed with primary HIV infection. Antiretroviral therapy is unlikely to limit initial virus spread to most tissue compartments, but may control genital tract shedding and central nervous system expansion in primary infection.

Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection.

The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.

Behavioral auditory assessment of young infants: methodological limitations or natural lack of auditory responsiveness?

The determination of auditory thresholds by means of behavioral techniques in young infants can be difficult. This could be the result of limitations in methodology, a lack of observable auditory responsiveness, or both. In the current study, 2- and 4-month old infants were tested under enhanced conditions for obtaining behavioral responses (i.e., salient auditory stimuli, reduced visual distractions, reinforced correct responses). A two-interval, forced-choice task with four intensity levels was used. Although a behavioral threshold was obtained for the 4-month-olds, threshold determination for the 2-month-olds remained elusive. In light of the current findings and previous studies of visual acuity of infants, these results suggest a lack of behavioral responsiveness to auditory stimuli for the younger infants rather than methodological limitations. With infants in the 2-month-old age range, clinical audiologists should expect few behavioral responses to auditory stimuli at intensity levels below those that elicit startle responses.

Opportunistic thoracic infections. Bacteria, viruses, and protozoa.

The range of potential bacterial, viral, and protozoan pathogens that can cause pulmonary infections in immunocompromised patients is extensive. An aggressive diagnostic approach is essential to maximizing chances for a successful outcome. This article discusses the general diagnostic approach and provides a discussion of the most important bacterial, viral, and protozoan chest infections occurring in this setting.

Safety and immunogenicity of an HLA-based HIV envelope polyvalent synthetic peptide immunogen. DATRI 010 Study Group. Division of AIDS Treatment Research Initiative.

OBJECTIVE: To evaluate the safety and immunogenicity of a polyvalent (PV) HIV envelope synthetic peptide immunogen, C4-V3. The immunogen comprised four peptides containing T-helper epitopes from the fourth constant region (C4) of gp120 of HIV-1MN, and T-helper, cytotoxic T-lymphocyte HLA-B7-restricted, and B-cell neutralizing epitopes from the gp120 third variable region (V3) of four clade B HIV-1 isolates, HIV-1MN, HIV-1RF, HIV-1EV91, and HIV-1Can0A. DESIGN: A pilot, Phase I controlled trial [Division of AIDS Treatment Research Initiative (DATRI) 010] conducted at a single center. METHODS: Ten HIV-infected, HLA-B7-positive patients with CD4 cells > 500 x 10(6)/l were enrolled. Eight patients received the C4-V3 PV immunogen emulsified in incomplete Freund's adjuvant in five intramuscular injections over 24 weeks, and two controls received incomplete Freund's adjuvant alone. All subjects were followed for 52 weeks. RESULTS: Four out of eight C4-V3 PV recipients generated at least fourfold rise in serum antibody titers to at least three immunogen peptides in contrast to none of the control subjects. Four out of eight C4-V3 PV recipients and none of the controls had an at least fourfold rise in neutralizing antibodies to either HIV-1MN, HIV-1RF, or HIV-1(4489-5) laboratory-adapted HIV isolates. 3H-Thymidine incorporation assays of peripheral blood mononuclear cells increased at least fivefold over the baseline stimulation index to at least one of the immunogen peptides in two consecutive post-immunization timepoints in five out of eight C4-V3 PV recipients versus none of the controls. CD4 cell counts and plasma HIV RNA levels did not change in patients who received either C4-V3 PV or adjuvant alone. Adverse events consisted primarily of grade 1 injection site reactions in six subjects (four C4-V3 recipients, two controls). CONCLUSIONS: C4-V3 PV synthetic peptides demonstrated both immunogenicity and safety in HIV-infected patients.

Update on antiretroviral therapy.

The availability of 11 antiretroviral agents has greatly expanded options in the treatment of HIV-infected patients. Newer treatment strategies using combination therapy have significantly improved outcomes for patients with all stages of infection. Antiretroviral drugs have also proved to be valuable in special clinical situations, such as occupational exposure, pregnancy, and acute HIV infection. This article discusses current treatment options and recommendations and reviews clinical trials to establish the rationale for treatment of persons with HIV infection.

Clinical complications of HIV infection.

HIV infection results in a profound weakening of the immune system that leaves the patient vulnerable to a bewildering array of clinical complications. Understanding of the pathogenesis of these clinical complications, knowledge of the current stage and treatment of HIV infection, and recognition of certain clinical syndromes can help the clinician sort through these potential complications, prioritize them, and formulate a plan for diagnosis and treatment. This article provides a summary of the clinical presentation, diagnosis, treatment, and prevention of the most common complications of HIV infection.

Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. A randomized double-blind study.

OBJECTIVE: To evaluate the use of single-dose azithromycin for empirical treatment of nongonococcal urethritis. DESIGN: Randomized, double-blind, multicenter trial comparing azithromycin vs doxycycline therapy, with a 2:1 randomization ratio. Patients were evaluated clinically and microbiologically for Chlamydia trachomatis and Ureaplasma urealyticum infection before therapy and at 2 and 5 weeks after study entry. SETTING: Eleven sexually transmitted disease clinics throughout the United States. PATIENTS: A total of 452 men aged 18 years or older with symptomatic nongonococcal urethritis of less than 14 days' duration. INTERVENTION: Patients were treated with either 1.0 g of azithromycin as a single oral dose or 100 mg of doxycycline taken orally twice daily for 7 days. MAIN OUTCOME MEASURES: Clinical resolution of symptoms and signs of nongonococcal urethritis, microbiological cure of C trachomatis and U urealyticum, and occurrence of adverse experiences. RESULTS: Of the 452 patients enrolled, 248 in the azithromycin-treated group and 123 in the doxycycline-treated group were evaluable for clinical response. The two treatment groups were comparable in terms of age, weight, ethnic distribution, sexual preference, sexual activity, and history of prior nongonococcal urethritis or gonorrhea. Sixteen percent of the azithromycin group and 24% of the doxycycline group were culture positive for C trachomatis before therapy, while 38% and 28%, respectively, were culture positive for U urealyticum. The cumulative clinical cure rate was 81% (95% confidence interval [CI], 75% to 85%) in the azithromycin-treated group and 77% (95% CI, 69% to 84%) in the doxycycline-treated group. Clinical cure rates in the two groups were also comparable when patients were stratified by presence or absence of infection with C trachomatis or U urealyticum prior to therapy. Among those infected with C trachomatis, overall microbiological cure rates were 83% (95% CI, 65% to 94%) for azithromycin-treated patients (n = 30) and 90% (95% CI, 68% to 98%) for doxycycline-treated patients (n = 21). Among those infected with U urealyticum, overall microbiological cure rates were 45% (95% CI, 34% to 57%) for azithromycin-treated patients (n = 75) and 47% (95% CI, 30% to 65%) for doxycycline-treated patients (n = 32). Adverse reactions were generally mild to moderate and occurred in 23% of the azithromycin-treated group and 29% of the doxycycline-treated group. CONCLUSIONS: For empirical treatment of the acute nongonococcal urethritis syndrome in men, a single oral dose of azithromycin was as effective as a standard 7-day course of doxycycline in achieving clinical cure. Further, clinical cure rates were comparable with either regimen, regardless of the presence or absence of Chlamydia or Ureaplasma infection.

Syphilis and HIV infection.

The management of an HIV-infected patient with syphilis is an evolving and difficult area of clinical medicine. Many such patients initially present with dermatologic problems, and the practicing dermatologist must be alert to the variety of presentations syphilis may take in these patients. The role of biopsy with immunofluorescent or Warthin-Starry silver staining is often crucial in correctly diagnosing confusing cases. The treatment of early syphilis in HIV-infected patients may need to be more intensive than has previously been recommended, because the immunosuppression induced by HIV can accelerate the pace of the infection and increase the risk of progression to neurosyphilis. After treatment, careful and frequent follow-up is essential so that the often irreversible consequences of late syphilis can be avoided.

Human infection with B virus following a needlestick injury.

A 26-year-old veterinary technician who became infected with B virus at the site of a needlestick injury is described. After the patient was treated with intravenous acyclovir, all cultures became negative for B virus and have remained so during treatment with oral acyclovir. The literature on infections due to B virus in humans is reviewed, and a detailed discussion of the various aspects of this simian herpesvirus is presented.

Tuberculous psoas muscle abscess following chemoprophylaxis with isoniazid in a patient with human immunodeficiency virus infection.

A 34-year-old man with human immunodeficiency virus infection and disseminated Mycobacterium avium and Mycobacterium intracellulare infection developed a right psoas muscle abscess due to Mycobacterium tuberculosis. The abscess occurred 18 months after completion of a 12-month course of chemoprophylaxis with isoniazid that was given because of a positive reaction with purified protein derivative of tuberculin. The adjacent vertebrae did not appear to be involved. The abscess was drained with a percutaneously inserted catheter, and he received standard antituberculous chemotherapy. Three weeks into therapy, a second drainage with a catheter was required. The isolation of two mycobacteria in this patient and the apparent failure of chemoprophylaxis with isoniazid are noted.

B virus (Herpesvirus simiae) and human infection.

B virus (Herpesvirus simiae) infections in macaque colonies are common. Herpetiform lesions as well as asymptomatic shedding of virus in bodily secretions from macaques pose a risk to animal handlers and laboratory workers. Fatal encephalitis in humans infected with B virus has occurred. Dermatologists may become involved in the initial evaluation of animal handlers exposed to this virus through bites or infectious secretions.

A prospective randomized trial of ofloxacin vs. doxycycline in the treatment of uncomplicated male urethritis.

One hundred fourteen men with uncomplicated urethritis were randomized to receive 1 week of therapy with either doxycycline (100 mg twice daily) or ofloxacin (300 mg twice daily). Of the 109 men completing the post-treatment visit, 56 received ofloxacin and 52 (93%) were clinically cured. Forty four (83%) of the 53 men treated with doxycycline were cured. All 30 patients with gonorrhea (including three with penicillinase-producing Neisseria gonorrhoeae [PPNG] isolates) who were treated with ofloxacin became culture-negative, as compared with 32 of 34 patients receiving doxycycline. In contrast, three of 18 patients with Chlamydia trachomatis were microbiologic failures after ofloxacin therapy, while all ten treated with doxycycline were cured. Adverse effects of both treatment regimens were generally mild, and compliance was excellent except for one patient receiving doxycycline. These results show that ofloxacin, in a dosage of 300 mg taken orally twice daily for seven days, is an effective treatment for uncomplicated urethritis in men but may not reliably cure chlamydial infections.

Seronegative secondary syphilis in a patient infected with the human immunodeficiency virus (HIV) with Kaposi sarcoma. A diagnostic dilemma.

Reagin and treponemal antibody tests are highly reliable in diagnosing secondary syphilis. However, patients infected with the human immunodeficiency virus (HIV) respond abnormally to antigenic stimulation and may fail to develop typical serologic responses to infections. We report the case of an HIV-infected man with Kaposi sarcoma and secondary syphilis whose VDRL test and fluorescent treponemal antibody-absorbed test were repeatedly nonreactive. Correct diagnosis required biopsy of a skin lesion with silver staining to show spirochetes. Clinicians treating HIV-infected patients should be aware of the problems of serologic diagnosis of syphilis in these patients. Biopsy samples of appropriate tissues and staining for spirochetes may be needed to arrive at the correct diagnosis.

Evidence of serum antibodies to Neisseria gonorrhoeae before gonococcal infection.

To characterize the serum antibody response to urethral infection with Neisseria gonorrhoeae, we examined pre- and postinfection sera from 13 men experiencing their first gonococcal infection. Using western blot analysis, we found that nine of 13 patients developed new serum IgG antibodies against one or more antigens, most commonly against lipooligosaccharide, followed in order by the H.8-antigen, pili, proteins I and II, and protein III. Twelve of 13 patients had preexisting IgG to gonococcal antigens, most commonly against the H.8 antigen, followed by pili, lipooligosaccharide, protein I, and protein III. Using serum obtained from other patients before and after nasopharyngeal carriage of Neisseria meningitidis, we demonstrated that carriage resulted in serum IgG cross-reactive to N. gonorrhoeae antigens. This is likely explanation for the presence of antigen-specific antibody in preinfection sera.