Brett Tindall

A controlled trial of zidovudine in primary human immunodeficiency virus infection.

BACKGROUND It is possible that antiretroviral treatment given early during primary infection with the human immunodeficiency virus (HIV) may reduce acute symptoms, help preserve immune function, and improve the long-term prognosis. METHODS To assess the effect of early antiviral treatment, we conducted a multicenter, double-blind, placebo-controlled trial in which 77 patients with primary HIV infection were randomly assigned to receive either zidovudine (250 mg twice daily; n = 39) or placebo (n = 38) for six months. RESULTS The mean time from the onset of symptoms until enrollment in the study was 25.1 days. Among the 43 patients who were still symptomatic at the time of enrollment, there was no appreciable difference in the mean (+/- SE) duration of the retroviral syndrome between the zidovudine group (15.0 +/- 4.1 days) and the placebo group (15.8 +/- 3.6 days). During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, and oral hairy leukoplakia in two. Disease progression was significantly less frequent in the zidovudine group (one opportunistic infection) than in the placebo group (seven opportunistic infections; P = 0.009 by the log-rank test). After adjustment for the base-line CD4 cell count, the patients treated with zidovudine had an average gain of 8.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, -1.4 to 19.1) during the first six months of the study, whereas those receiving placebo had an average loss of 12.0 CD4 cells per cubic millimeter per month (95 percent confidence interval, 5.2 to 18.7), for a between-group difference of 20.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, 8.5 to 33.2; P = 0.001). CONCLUSIONS Antiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

Primary HIV infection: host responses and intervention strategies.

In this review we summarize the concepts that have emerged regarding primary HIV infection and discuss the possibility of chemotherapeutic intervention

Long-term symptomless HIV-1 infection in recipients of blood products from a single donor

There have been reported cases of long-term symptomless human immunodeficiency virus type 1 (HIV-1) infection, but it is not clear whether the benign course of infection was due to host, viral, or other unknown factors. During follow-up of subjects with transfusion-acquired HIV-1 infection in New South Wales, Australia, we identified a group of 6 subjects who had been infected through a single common donor. We were therefore able to study the contributions of various factors to the course of infection. Throughout follow-up (range 6.8-10.1 years after infection), 5 of the recipients and the donor (last follow-up 10.2 years after infection of the first recipient) remained clinically free of symptoms, with normal CD4 cell counts and no p24 antigenaemia. HIV-1 was isolated from only 1 recipient; the isolate did not induce syncytia in a SUPT1 co-culture assay and had a limited in-vitro host range. 1 infected recipient (who had received extensive immunosuppressive treatment for systemic lupus erythematosus) developed Pneumocystis carinii pneumonia and died 4.3 years after infection. The frequency of progression to AIDS or a CD4 cell count below 0.50 x 10(9)/l was significantly lower among the 6 subjects with a common donor (1/6) than among 101 other HIV-infected transfusion recipients for whom data from 7 years of follow-up were available (94/101; p less than 0.0001). These findings suggest that the subjects were infected by a less virulent strain of HIV-1. The identification of this group of subjects should stimulate a search for other similar groups, which will provide important information on the immunopathogenesis of HIV-1 disease.

Low-Dose Trimethoprim-Sulfamethoxazole Prophylaxis for Toxoplasmic Encephalitis in Patients with AIDS

OBJECTIVE To determine the efficacy of low-dose trimethoprim-sulfamethoxazole (trimethoprim, 160 mg plus sulfamethoxazole, 800 mg; one tablet twice daily, 2 days per week) as primary prophylaxis against toxoplasmic encephalitis in patients with human immunodeficiency virus (HIV) infection and previous Pneumocystis carinii pneumonia. DESIGN A retrospective study. SETTING Tertiary referral teaching hospital. PATIENTS During a 3-year period after primary episodes of P. carinii pneumonia, 60 patients received trimethoprim-sulfamethoxazole, and 95 patients received pentamidine (aerosolized in 78 patients and intravenous in 17 patients) as secondary prophylaxis. RESULTS No patient in the trimethoprim-sulfamethoxazole group and no patient seronegative for Toxoplasma gondii developed toxoplasmic encephalitis, compared with 12 of 36 (33%; 95% Cl, 19% to 51%) seropositive patients in the pentamidine group (trimethoprim-sulfamethoxazole compared with pentamidine, P = 0.008). A significant difference was seen in the time to development of toxoplasmic encephalitis between the trimethoprim-sulfamethoxazole group (no case at 1153 days) and the pentamidine group (median time, 460 days) (P = 0.004). Neither the CD4+ lymphocyte count at the start of prophylaxis nor zidovudine therapy during the period of prophylaxis influenced the rate of toxoplasmic encephalitis in any group. CONCLUSIONS Low-dose trimethoprim-sulfamethoxazole (four tablets per week) appears to be effective prophylaxis against toxoplasmic encephalitis in HIV-infected patients with previous P. carinii pneumonia. A prospective, randomized, controlled study is needed to further evaluate these findings.

Gastrointestinal Viral Infections in Homosexual Men Who were Symptomatic and Seropositive for Human Immunodeficiency Virus

Abstract Gastrointestinal viruses, predominantly rotaviruses and adenoviruses, were detected by enzyme-linked immunosorbent assay, electron microscopy, or cell culture in >50% of two groups of homosexual men with symptomatic human immunodeficiency virus (HIV) infection, who did (54%) or did not (50%) have diarrhea. Lower detection rates were observed in HIV-seronegative (15%) and asymptomatic HIV-seropositive (16%) men. In the patients with diarrhea, 95% of the isolates of virus were found in the most immuno suppressed patients, those patients with AIDS-related complex or opportunistic infections associated with AIDS. High excretion rates of these viruses are probably associated with both anal-oral transmission and immunosuppression. These viruses apparently cause acute episodes or relapses of diarrhea in some patients but may be co-pathogens or noncontributory to chronic diarrhea in others.

In vitro cytotoxicity as a marker of hypersensitivity to sulphamethoxazole in patients with HIV.

Hypersensitivity to trimethoprim‐sulphamethoxazole (TMP‐SMX) in patients with HIV infection may be a result of either immune dysregulation, a direct cytotoxicity of the SMX‐hydroxylamine metabolite (SMX‐HA) (rather than SMX per se), or glutathione deficiency. We evaluated the in vitro cytotoxicity of SMX and SMX‐HA to peripheral blood mononuclear cells (PBMC) of HIV‐infected subjects to determine if the degree of in vitro cytotoxicity is associated with hypersensitivity, whether glutalhione inhibits cytotoxicity, and whether in vitro cytotoxicity is predictive for the development of hypersensitivity. Given that fever is often a prominent feature of hypersensitivity, we also assessed whether SMX or SMX‐HA could induce the in vitro production of IL‐lβ, IL‐6 or tumour necrosis factor‐alpha (TNF‐α) by PBMC. Thecytotoxicitics of SMX and SMX‐HA to PBMC were assessed in 45 HFV‐infected patients with prior TMP‐SMX therapy, and in eight HIV controls. Twelve HIV‐infected subjects were studied prospectively before primary Pnvumocystis carinii pneumonia (PCP) therapy or reehallenge with TMP‐SMX in previously hypersensitive subjects. Cylokine production was measured in four hypersensitive and two non‐hypersensitive HlV‐infccted subjects, and three HIV‐uninfected controls. The cytotoxicity of SMX‐HA to PBMC was significantly greater in the 22 HIV‐infectcd patients with prior hypersensitiviiy than both the 23 HIV‐infeeled paiients without hypersensitivity and the control group. Cytotoxicity was significantly reduced by glutalhione only in the hypersensitive group. SMX did not induce eylotoxicity in any group. In 12 subjects studied prospectively. SMX‐HA cytotoxicity was also significantly greater in those with subsequent hypersensitivity. Exposure of PBMC to SMX‐HA resulted in a modest increase in the production of IL‐6, IL‐1β and TNF‐α. although no major difference was detected between subjects with or without hypersensitivity. These data suggest that SMX‐HA and glutathione deficiency are involved in the pathogenesis of hypersensilivity to TMP‐SMX in HI V‐infected patients, and that in vit ro cytotoxicity could be useful in the diagnosis of hypersensilivity and predicting its likelihood.

Sexual dysfunction in advanced HIV disease

Abstract Although there is an emerging body of literature on quality of life in persons with human immunodeficiency virus (HIV) disease (Barker et al., 1990; Wu et al., 1990; Wachtel et al., 1992), there is a paucity of published data on the prevalence of sexual dysfunction in HIV-infected persons or on the impact of such dysfunction on quality of life. One previous study has reported that 67% of homosexual men with acquired immunodeficiency syndrome (AIDS) reported a decreased libido and 33% reported impotency (Dobbs et al., 1993). We here describe the findings from an investigation of sexual dysfunction in a large group of homosexual men with severe HIV disease.

Identification of HIV-1 in semen following primary HIV-1 infection

ObjectiveTo determine whether HIV could be identified in semen samples during the first few weeks after infection. DesignA series of three homosexual men with symptomatic primary HIV-1 infection. MethodsEach subject provided a series of semen samples that was examined for HIV-1 by virus culture, polymerase chain reaction (PCR) and transmission electron micrography. ResultsThe first samples obtained for each subject (17, 22 and 24 days following onset of primary HIV-1 infection) were all positive by PCR and negative by viral culture. Of 13 samples obtained during the first 80 days after onset of primary HIV-1 infection and analysed by PCR, 10 were positive. Only one of these samples was virus culture-positive. Four semen samples obtained from two subjects during treatment with zidovudine were PCR-positive. Eight samples were examined for presence of HIV-1 by electron microscopy and one was found to be positive. ConclusionsThese results indicate that men with HIV-1 infection are potentially infectious through sexual transmission during the first few weeks after infection. The findings emphasize that individuals in all stages of HIV-1 infection should practise safer sex to reduce transmission of HIV-1.

Zidovudine in the management of primary Hiv-1 infection

Eleven subjects who presented with a clinical illness characteristic of primary HIV-1 infection were treated with 1 g zidovudine daily for a median period of 56 days (range, 28–111 days). Primary HIV-1 infection was confirmed in each subject by seroconversion and virus isolation. The acute phase of the illness resolved a median of 4 days (range, 3–14 days) from commencement of zidovudine. Six subjects reported symptoms that may have been side-effects of zidovudine, the most common being nausea in four subjects and headache in two. Treatment was discontinued in one subject who had persistent headache and nausea. Haemoglobin, haematocrit and erythrocyte counts decreased and mean corpuscular volume increased significantly during the treatment. None of the subjects developed anaemia and none required dose modification or blood transfusion as a result of haematological side-effects. There were no significant differences in the granulocyte count or the lymphocyte count during any week of treatment when compared with baseline levels. There were no significant differences in T-cell subset numbers of the subjects during treatment compared with a group of historical controls. HIV-1 was isolated from several subjects during and after termination of zidovudine treatment. The results of this investigation indicate that zidovudine is a safe drug to administer to people with primary HIV-1 infection. There was no clear evidence, however, of any clinical benefit in terms of resolution of the acute illness and no indication that the treatment would prevent development of persistent infection. Nevertheless, the results urge the establishment of a placebo-controlled trial to further evaluate this treatment and its effect on long-term outcome in people with primary HIV-1 infection.

Severe clinical manifestations of primary HIV infection

Three cases of oesophageal candidiasis in association with primary HIV infection are described. In each case the candidiasis was associated with a decreased number of circulating CD4+ cells and responded well to treatment with ketoconazole. Clinicians should be aware that severe opportunistic infections may develop during this stage of infection, presumably as a result of transient immunodeficiency. We argue that the definition of primary HIV infection should be extended to include severe opportunistic infections and neurologic presentations.