Treatment of high-grade anal dysplasia in high-risk patients: outcome at an urban community health centre.

Human immunodeficiency (HIV)-infected patients and men who have sex with men (MSM) have a higher rate of high-grade anal intraepithelial neoplasia (HGAIN), a likely precursor to anal cancer. This retrospective study describes the outcome of treating MSM with incident biopsy-proven HGAIN in an urban community health setting with access to outpatient ablation or operative treatment. The main outcome was freedom from HGAIN at follow-up. One hundred and fifty-three met inclusion criteria; 86 (56%) were HIV-infected. Eighty (52%) received outpatient ablation, 49 (61%) had a follow-up within nine months. Among those, 26 (53%) were free of high-grade disease, 19 (39%) had high-grade disease; and 4 (8%) had unknown grading. In a logistic regression model, a lower extent of anal disease (1 quadrant versus 2, 3 or 4 quadrants) at the time of treatment was significantly associated with a lower probability of high-grade disease (P value 0.04). HGAIN could be managed in a community health setting; however, systems are needed to ensure follow-up care.

Mycobacterium avium complex peritonitis in an AIDS patient.

Mycobacterium avium complex (MAC) frequently disseminates in AIDS patients, where the gastrointestinal tract is a major target organ. While ascites in AIDS patients is common, peritonitis secondary to MAC is rare. We describe the first case of MAC peritonitis in an AIDS patient without underlying cirrhosis, portal hypertension, chylous ascites or peritoneal dialysis. This case highlights the need to be aware of atypical presentations of MAC disease in AIDS patients with a history of disseminated MAC, even those who compliantly take highly active antiretroviral therapy.

Genital tract human immunodeficiency virus type 1 (HIV-1) shedding and inflammation and HIV-1 env diversity in perinatal HIV-1 transmission.

This study sought to identify genital tract characteristics associated with vertical transmission of human immunodeficiency virus type 1 (HIV-1). HIV-1 DNA and RNA, HIV-1 env diversity, and inflammatory cells were quantified in cervicovaginal lavages (CVLs) of 24 women enrolled in the Women and Infants Transmission Study; 7 women transmitted HIV-1 perinatally. Vaginal candidiasis, HIV-1 culture positivity, levels of HIV-1 DNA and cell-free RNA, and HIV-1 env diversity were significantly higher in the CVLs of transmitters. CVL HIV-1 DNA levels correlated with higher levels of inflammatory cells and cell-free HIV-1 RNA. Of subjects with paired blood and CVL specimens, there was more HIV-1 env heterogeneity between blood and CVLs in transmitters than in nontransmitters. In summary, increased HIV-1 shedding is correlated with a more complex population of HIV-1 quasispecies in the genital tracts of parturient women, which may increase the probability that a fetotropic strain is transmitted.

Unintegrated HIV-1 circular 2-LTR proviral DNA as a marker of recently infected cells: relative effect of recombinant CD4, zidovudine, and saquinavir in vitro.

Unintegrated HIV-1 proviral DNA is one of the earliest detectable forms of HIV-1, and the influence of an antiretroviral drug on its appearance may reflect the efficacy of that agent in preventing infection of new cells. We characterized the dynamics of HIV-1 p24 (p24) antigen production, HIV-1 gag DNA, tandem long-terminal-repeat circular unintegrated proviral (2-LTR) HIV-1 DNA, HIV-1 tat mRNA, and cell viability in the presence of three antiretroviral agents: recombinant soluble CD4 (rsCD4), zidovudine, and saquinavir. Interference with HIV-1 entry by rsCD4 decreased p24 antigen levels modestly, decreased HIV-1 gag by twofold, and 2-LTR was detectable at the end of the culture period. Inhibition of reverse transcription by zidovudine decreased p24 antigen levels modestly, decreased HIV-1 gag by 19-fold, and inhibited detection of 2-LTR HIV-1 DNA. The protease inhibitor, saquinavir, had the greatest overall effect, with the lowest levels of p24 antigen and HIV-1 gag, and inhibition of 2-LTR. There was no detection of tat mRNA in the saquinavir-treated cultures. In addition, cell viability was significantly higher in cultures treated with saquinavir. In these experiments, 2-LTR HIV-1 DNA was indicative of the relative inhibitory effects of three antiretroviral agents acting at different steps of the HIV-1 replication cycle. We demonstrated in vitro that 2-LTR HIV-1 DNA was a useful indicator of an antiretroviral drug in preventing new cell infection and could be utilized as a dynamic marker of drug efficacy in HIV-1-infected patients.

Unintegrated circular HIV-1 DNA in the peripheral mononuclear cells of HIV-1-infected subjects: association with high levels of plasma HIV-1 RNA, rapid decline in CD4 count, and clinical progression to AIDS.

We observed 36 HIV-infected patients to evaluate whether the presence of tandem 2-long terminal repeat circular unintegrated HIV-1 DNA (2-LTR) in peripheral blood mononuclear cells (PBMC) at baseline was associated with acceleration of HIV disease. Detection of 2-LTR at baseline correlated with high plasma HIV-1 RNA levels (p < .01), recovery of culturable HIV-1 from plasma (p = .02), and progression to AIDS during follow-up (p = .01). More patients with 2-LTR (68%) than without 2-LTR (31%) had a decline in CD4 levels of >50 cells/mm3 over the first 18 months of follow-up (p = .04), and the average annual CD4 decline was 35% in patients with 2-LTR compared with 16% in those without 2-LTR (p = 0.06). Detection of 2-LTR in PBMC at baseline was an independent predictor of high plasma HIV-1 RNA levels and subsequent CD4 cell decline in this cohort of patients with predominantly nonsyncytium-inducing (NSI) isolates at baseline. The presence of 2-LTR in PBMC appears to be reflective of ongoing HIV-1 replication, as measured by plasma HIV-1 RNA levels, and identifies persons at risk for immunologic and clinical decline.

Acute infection of Macaca nemestrina by human immunodeficiency virus type 1.

The pigtail macaque (Macaca nemestrina) has a marked sensitivity to infection by simian immunodeficiency virus and human immunodeficiency virus type 2 (HIV-2). On this basis, we previously studied this species' susceptibility to HIV-1 and demonstrated infection in six macaques inoculated with either cell-associated HIV-1 or cell-free virus alone. This report expands upon our initial in vitro and in vivo findings. Five laboratory-adapted and one primary clinical strain of HIV-1 replicated in vitro in human and M. nemestrina peripheral blood mononuclear cells (PBMCs). Replication was enhanced when CD4+ purified PBMCs were infected and inhibited when PBMC cultures were treated with zidovudine. All six macaques demonstrated HIV-1 infection of PBMCs from 2 to 8 weeks after inoculation but nearly all PBMC cultures were negative from weeks 10 to 40. Polymerase chain reaction showed HIV-1 gag DNA in the PBMCs of all infected macaques, including times when the macaques were culture negative. All macaques developed and maintained antibodies to gag and envelope HIV-1 proteins from week 4 after inoculation through the period of observation. Five macaques showed neutralizing antibody. These findings suggest that M. nemestrina can be infected by cell-free and cell-associated HIV-1. This model of acute HIV-1 infection may help in evaluating the pathogenesis of HIV-1 replication and candidate vaccines and therapies.

Cryptococcal meningitis in the acquired immunodeficiency syndrome.

Cryptococcosis is the most common, deep-seated fungal infection in AIDS patients, and cryptococcal meningitis is the most frequently observed syndrome. AIDS patients with cryptococcal meningitis usually have an indolent presentation and nonspecific findings on physical examination. Routine laboratory tests are of little assistance in diagnosing cryptococcal meningitis. Cerebrospinal fluid (CSF) white blood cell counts tend to be low, and glucose and protein levels are nonspecific. Serum cryptococcal antigen (CRAG) is a sensitive test for cryptococcal meningitis, and CSF CRAG is usually also positive. Definitive diagnosis is made by culture of the CSF. Therapy of cryptococcal meningitis is changing to antifungal agents that are easy to administer as outpatient therapy. Amphotericin B continues to be the primary antifungal used in initial treatment of cryptococcal meningitis; addition of flucytosine is of no benefit. Recent data suggest oral fluconazole is effective as primary therapy, and may be superior to amphotericin B as maintenance therapy. Maintenance therapy decreases the incidence of relapse and increases survival.

Vasoactive drugs produce selective changes in flow to experimental brain tumors.

Most vasoactive drugs do not readily penetrate the blood-brain barrier and do not affect cerebral blood flow. We tested the hypothesis that vasoactive drugs may alter blood flow to brain tumors in which the blood-brain barrier is abnormal. Blood flow was measured with microspheres in dogs with brain tumors induced by avian sarcoma virus. Intravenously administered adenosine increased blood flow to tumor more than twofold but did not alter flow to normal brain. Intravenously administered norepinephrine decreased blood flow to tumor but not to normal brain. Thus, vasoactive drugs, which have little effect on blood flow to normal cerebrum, produce large changes in blood flow to brain tumors. We also examined responses to systemic hypercapnia. Hypercapnia increased blood flow to normal cerebrum more than twofold but failed to increase flow to tumors. Impaired vasodilator responses to hypercapnia in brain tumors, which cannot be explained primarily by an abnormality of the blood-brain barrier, probably reflect another fundamental difference between vessels in normal brain and brain tumors. The finding that vasoactive drugs have selective effects on blood flow to brain tumors has important implications for delivery of lipid-soluble chemotherapeutic drugs to the tumors.