Incubation time of acute human immunodeficiency virus (HIV) infection and duration of acute HIV infection are independent prognostic factors of progression to AIDS.

The severity and the duration of acute human immunodeficiency virus (HIV) infection (AHI) are associated with a faster rate of progression to AIDS, but the prognostic value of the length of incubation time of AHI (IncAHI), defined as the time between HIV infection and AHI, on progression to AIDS has not been assessed. We explored this issue prospectively in 70 individuals with documented AHI and a known date of HIV infection. The median IncAHI was 21.5 days (range, 5-70 days), and the median duration of AHI was 15.5 days (range, 3-67 days). The adjusted relative hazard of progression to AIDS or to a CD4(+) count <200x103/mL was 4.23 (95% confidence interval [CI], 1.40-12.73; P=.01) for the patients with an IncAHI <21.5 days, compared with those with longer IncAHI, and was 3.53 (95% CI, 1.09-11.36; P=.03) for the patients with a duration of AHI >15.5 days, compared with those with shorter duration. Both IncAHI and duration of AHI were independent predictors of progression. This suggests that early pathogenic events before the onset of AHI influence the rate of HIV disease progression.

Comparison of clinical features, CD4 and CD8 responses among patients with acute HIV-1 infection from Geneva, Seattle and Sydney.

OBJECTIVE: To compare the clinical features and T-cell subsets among 160 patients with acute HIV-1 infection not treated with antiretroviral agents from three different locations (Geneva, Seattle and Sydney). DESIGN: Patients with documented acute HIV-1 infection were enrolled in four prospective studies: one randomized placebo controlled trial (RCT) and three observational cohort studies. SETTING: All patients were diagnosed and followed in three university affiliated tertiary clinical care centers. METHODS: The chi-square test was used for comparing proportions and one way analysis of variance (ANOVA) for comparing continuous variables among these groups. Multiple regression analysis was used to identify the variables independently associated with the duration of acute HIV-1 infection. The differences in mean CD4 and CD8 load between centers were assessed using the random-effect models for the longitudinal data. RESULTS: Minor differences were noted in the frequency of symptoms among subjects enrolled at different locations. RCT patients reported a longer duration of symptoms (31 days) compared with that for observational patients (15 days; P < 0.0001). For the most common symptoms such as fever, skin rash, arthralgia, myalgia, and headaches, a longer duration was observed in the RCT group compared with that for observational patients (P range, 0.001 to < 0.0001). T-cells subsets within 100 days of seroconversion did not statistically differ by centre or by mode of recruitment. CONCLUSIONS: These results suggest a selection bias toward patients with longer symptomatic acute HIV-1 infection enrolled in the RCT. Data collected from RCT are not comparable to that collected in observational studies. However, data from collaborative international studies can be combined.

Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia.

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.

Comprehensive classification of symptoms and signs reported among 218 patients with acute HIV-1 infection.

Acute HIV-1 illness presents a wide range of clinical manifestations. We assessed a classification and data reduction of clinical features among 218 patients with acute HIV-1 infection enrolled in four prospective seroincidence studies. Factor analysis allows the definition of eight factors based on groups of symptoms and signs: gastrointestinal transit disturbances, weight loss/abdominal pain, lymphadenopathy, myalgia/arthralgia, neurologic features, constitutional and mucocutaneous features, oral candidiasis, and anorexia/pharyngitis. These groups reflected the main target systems involved at the time of acute HIV-1 disease. Grouping of symptoms and signs based on groups of patients is potentially more informative than observations made on individual patients. It might facilitate diagnosis, suggest pathogenic mechanisms and reduce the number of variables for characterizing acute HIV-1 illness.

Long-term prognosis following zidovudine monotherapy in primary human immunodeficiency virus type 1 infection.

Eighty-five subjects with symptomatic primary (P) human immunodeficiency virus (HIV) type 1 infection were analyzed in a retrospective cohort study to investigate the long-term clinical benefit of antiretroviral treatment during PHIV infection. Zidovudine treatment was initiated (PHIV treatment group) in 21 persons a median of 9 days after onset of PHIV symptoms and continued for a median of 55 days (range, 21-99). Sixty-four subjects did not receive early antiretroviral treatment (PHIV nontreatment group). After follow-up for 3-10 years, 33 subjects had developed AIDS and 22 subjects had died of AIDS. The median times for progression to AIDS and death were 6.4 and 9.1 years, respectively. Progression rates did not differ between the PHIV treatment and nontreatment groups. Zidovudine treatment initiated during PHIV infection did not improve long-term outcome after symptomatic PHIV infection.

Impact of early HIV-1 RNA and T-lymphocyte dynamics during primary HIV-1 infection on the subsequent course of HIV-1 RNA levels and CD4+ T-lymphocyte counts in the first year of HIV-1 infection. Sydney Primary HIV Infection Study Group.

Plasma HIV-1 RNA and CD4+ T-cell counts after HIV-1 seroconversion are important independent markers that predict the clinical course of HIV-1 infection. The prognostic significance of these parameters during primary HIV-1 infection, however, remains largely unknown. In a cohort of 53 male study subjects (age, 33 +/- 7 years), who consecutively presented with primary HIV-1 infection, we analyzed the relationship between early plasma HIV-1 RNA, CD4+ and CD8+ T-cell counts, beta2-microglobulin, and p24-antigen levels determined in the first 3 months and subsequent plasma HIV-1 RNA levels and CD4+ T-cell counts 6 to 12 months after onset of primary symptoms. Peak, nadir, and median HIV-1 RNA levels in the first 30 days were already significantly associated with HIV-1 RNA levels at 6 to 12 months (p = .02, p < .0001, and p = .01, respectively). Similarly, early nadir and median CD4+ T-lymphocyte counts in the first 30 days showed a significant relationship with CD4+ T-cell counts at 6 to 12 months (p = .009 and p = .0008, respectively). Study subjects with an early decline of CD4+ counts to <500 cells/microl had an eightfold higher risk that CD4+ counts were <500 cells/microl at 1 year. Of all evaluated virologic parameters, only nadir HIV-1 RNA at 76 days predicted CD4+ counts at 6 to 12 months (p = .006). Early HIV-1 RNA levels and CD4+ counts are already associated with the time course of those parameters 6 to 12 months after onset of symptoms. Nadir viral load was the strongest predictor of HIV-1 RNA levels as well as of CD4+ counts at 6 to 12 months. An early decline of CD4+ T lymphocytes may be a useful clinical prognostic marker for rapid disease progression.

Patterns of viral dynamics during primary human immunodeficiency virus type 1 infection. The Sydney Primary HIV Infection Study Group.

This study used curve-fitting techniques to detail the dynamics of human immunodeficiency virus (HIV)-1 and its relationship to circulating T lymphocyte changes in a cohort of 41 male patients (mean age 36+/-7 years) infected with HIV-1. The following characteristics of viral kinetics were obtained: virus load peak, 6. 35+/-0.71 log10 RNA copies/mL at 12.2+/-7.1 days; virus load drop from peak, 2.02+/-0.93 log10 copies/mL; viral decay rate from peak, 0.071+/-0.042 log10 RNA copies/mL/day; and steady state virus load, 4.57+/-0.68 log10 copies/mL at 135+/-81 days. Analysis of individual virus load curves revealed highly variable viral kinetics. Although these could be grouped into three distinct patterns, virus load and CD4 lymphocyte counts were similar in all patterns at 12 months, but the interval from infection to achievement of steady state virus load varied significantly.

Severity and prognosis of acute human immunodeficiency virus type 1 illness: a dose-response relationship.

This study examined the relationship between the severity of acute human immunodeficiency virus type 1 (HIV-1) illness and disease progression and death. The population included 218 patients with acute HIV-1 illness and 41 asymptomatic patients who underwent HIV-1 seroconversion; the patients were followed up prospectively. We analyzed progression to Centers for Disease Control and Prevention clinical categories B and C (AIDS-defining conditions) and death according to an additive clinical score (CS) based on six predictive clinical features at the time of acute HIV-1 infection. Compared with patients with a CS of 0 (asymptomatic patients), those with a CS of 3-4 and 5-6 had faster progression to category B disease (adjusted hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.01-1.92; and HR, 1.80; 95% CI, 1.34-2.40; respectively); those with a CS of 5-6 had faster progression to category C disease (HR, 1.37; 95% CI, 1.01-1.89) and death (HR, 2.05; 95% CI, 1.27-3.32). Thus, the number of symptoms and signs at the time of acute HIV-1 illness affects disease progression and survival, even in symptomatic patients who have undergone seroconversion.

Transmission of human immunodeficiency virus type 1 resistant to nevirapine and zidovudine. Sydney Primary HIV Infection Study Group.

Human immunodeficiency virus type 1 (HIV-1) resistant to the nonnucleoside reverse transcriptase inhibitor nevirapine and to the nucleoside analogue zidovudine was transmitted from a homosexual man to his sex partner. The virus source patient had commenced combination zidovudine and nevirapine therapy 2.5 years prior to his partner's primary HIV infection. He received both therapies for 7 months, then discontinued nevirapine treatment, continuing to receive zidovudine monotherapy for a further 16 months. He had ceased zidovudine therapy 6 months before the time of his partner's seroconversion. Analysis of major and minor isolates obtained from both patients soon after onset of the recipient's primary HIV infection illness confirmed that an HIV-1 variant mutant at codons 70, 98, and 181 of the viral reverse transcriptase was transmitted. This is the first documented case of transmission of HIV-1 resistant to two antiretroviral compounds.

Acute human immunodeficiency virus type 1 disease as a mononucleosis-like illness: is the diagnosis too restrictive?

The purpose of this study was to describe the frequency and duration of clinical features at the time of acute human immunodeficiency virus type 1 (HIV-1) disease in 218 patients with documented symptomatic primary HIV-1 infection. The mean duration of acute HIV-1 disease was 25.1 days (median, 20.0 days) and did not differ by gender, age, and risk factor. The frequency and mean duration of clinical features occurring in >50% of patients were as follows: fever, 77.1% and 16.9 days; lethargy, 65.6% and 23.7 days; cutaneous rash, 56.4% and 15 days; myalgia, 54.6% and 17.7 days; and headache, 50.9% and 25.8 days. Only 15.6% of patients presented with a typical mononucleosis-like illness (MLI) defined as fever, pharyngitis or sore throat, and cervical adenopathy, and 10% had no features of an MLI. A meningitis-like syndrome occurred in 20 patients (9.2%). Acute HIV-1 disease is more diverse than previously reported, and the absence of fever or other MLI features does not rule out acute HIV-1 disease.

Primary infection with zidovudine-resistant human immunodeficiency virus type 1 does not adversely affect outcome at 1 year. Sydney Primary HIV Infection Study Group.

Human immunodeficiency virus type 1 (HIV-1) variants with reduced in vitro sensitivity to zidovudine, conferred by specific mutations in the viral reverse transcriptase, emerge during prolonged therapy. Late-stage disease and declining CD4 cell count are associated with more rapid emergence of these resistant variants. Isolates of HIV-1 from seroconverters were screened for the zidovudine-resistance marker mutation at codon 215. HIV-1 with the altered genotype was detected in 5 (8.2%) of 61 patients soon after onset of symptomatic primary illness and from the sex partner of 1 patient. These transmitted resistant viruses were either replaced by strains susceptible to zidovudine within a few months of infection or persisted for up to 1 year in the absence of prolonged zidovudine therapy. The resistant genotype persisted in 3 of 5 seroconverters but in 2 patients had reverted to wild type at 48 and 52 weeks. Primary infection with zidovudine-resistant variants of HIV-1 was not associated with a more severe symptomatic primary illness or more rapid CD4 cell decline at 1 year after infection.

The inter-relationship of premenstrual symptoms.

The prospective symptom reports of women seeking treatment for premenstrual symptoms and control subjects was investigated. In order to compare symptom reports from premenstrual symptom sufferers and control subjects a method of combining and analysing prospectively collected menstrual cycle symptom data is required. A technique that uses the time of onset of menses and the time of ovulation (as measured by urinary luteinizing hormone excretion) to standardize each cycle into 14 time points was developed. Summary factors were then empirically derived from data collected prospectively from 30 premenstrual symptom sufferers and 19 control subjects. Twenty-two mood symptoms were summarized into a single factor and the 29 most frequently occurring physical symptoms were summarized into two factors. Factor scores were calculated on the basis of these factors and the effect of time during the menstrual cycle on these scores examined. Both physical symptom factor scores increased significantly in the luteal phase for both the premenstrual symptom sufferer group and the control group. The single mood factor score increased significantly in the luteal phase for the premenstrual sufferer group but not for the control group, suggesting that the only qualitative difference between the groups was the presence of cyclic mood symptoms in the premenstrual symptom sufferer group. The premenstrual symptom sufferer group recorded significantly higher scores on each of the three factors than the control group. The correlation between the scores on each of the factors over three cycles was high both in the follicular and luteal phase suggesting that these factor scores provide a reproducible measure of menstrual cycle symptomatology.

Body composition in anorexia nervosa - changes with treatment, determinants and techniques.

Body fat, total body water and totally body nitrogen were estimated twice before and after refeeding in 32 patients with anorexia nervosa. Body composition was estimated once in 29 normal controls using the techniques of anthropometry, impedance and IVNCA. The influence of weight gain and other variables, ie psychological status, biochemical parameters, exercise and dietary composition, on protein repletion was examined. Methods of assessment of body composition were compared. The results demonstrated that in anorexia nervosa patients, protein was more completely replenished than fat when patients had reached 85% of average body weight for height and age. Weight gain was the only determinant of protein gain. There was no correlation with psychological, biochemical or exercise status nor with dietary composition. Direct methods, ie deuterium dilution and IVNCA, were shown to be preferable in determination of body composition in anorexia nervosa.

Total body nitrogen as a predictor of clinical status in anorexia nervosa.

It has been demonstrated that clinical outcome is positively correlated with depletion of total body nitrogen (TBN) and therefore of body protein in certain serious medical conditions such as cystic fibrosis or patients receiving dialysis for chronic renal failure. Patients with anorexia nervosa are not suffering from medical illness per se yet the illness can be chronic and severely debilitating requiring numerous hospitalizations for refeeding and/or management of medical complications. The prediction of chronicity remains an important and difficult issue that this study seeks to address by examining the correlation between several clinical indices in 18 patients suffering from anorexia nervosa with parameters of body composition, namely TBN and percentage body fat. TBN was measured using the technique of in vivo neutron-activation analysis (IVNAA) and expressed as nitrogen index. Percentage body fat was estimated using skinfold measurements. The highest correlation was between nitrogen index and number of hospitalizations (r = -.80). The data support a relationship between depletion of body nitrogen/protein and chronicity in anorexia nervosa.

Protein repletion and treatment in anorexia nervosa.

Body fat and total body nitrogen (TBN) were quantified before and after refeeding in 32 female anorexia nervosa patients and in 29 matched control subjects by using the techniques of anthropometry and in vivo neutron-capture analysis (IVNCA). Mean body weight of patients (mean body mass index; BMI, in kg/m2), 15.4 +/- 1.3, was 72.7% of that of control subjects, increasing to 89.8% of mean weight of control subjects after refeeding (mean BMI 19.0 +/- 1.2). Mean BMI of control subjects was 21.6 +/- 2.7. Compared with the control group, patients' nitrogen was initially depleted by 24.5%, increased by 18.4%, but remained 10.6% below control values (P < 0.001). Body fat was depleted by 58.4%, increased by 89.7%, but remained 21.8% below control values (P < 0.001). Thus, despite a greater initial depletion and subsequently a greater net gain, body fat remained relatively more depleted after treatment than did nitrogen and protein. Anorexia nervosa patients were shown to readily replenish protein during nutritional rehabilitation.

Recovery after childbirth: a preliminary prospective study.

This prospective study examined the time for 93 women to cease to feel discomfort in their perineal areas after the births of their first babies. Sixty-two of the women had experienced a spontaneous delivery that did not require forceps assistance. In 58 patients, an episiotomy was performed. Of the 35 women in whom an episiotomy was not performed, 24 women required sutures and only four women did not suffer any perineal damage. The median time for perineal comfort in general (including walking and sitting) was one month (range, zero to six months); 20% of women took more than two months to achieve general perineal comfort. For comfort during sexual intercourse, the median time was three months (range, one to more than 12 months); 20% of women took longer than six months to achieve comfort during sexual intercourse. Factors that were associated with discomfort for longer than the median time were delivery by forceps; spontaneous vaginal (not perineal) tears; and, in the three to four days after the birth, oedema and the breakdown of muscle or skin sutures. There was no significant difference in these times between patients who did not undergo an episiotomy and those who underwent an episiotomy without a forceps delivery.

Reduction of food intake in the ovulatory phase of the menstrual cycle.

Food intake was weighed and recorded daily during one complete menstrual cycle in 18 healthy normally menstruating women. Urinary luteinizing hormone indicated the time of ovulation. Mean daily intakes of energy, macronutrients, and alcohol were calculated for five phases during the menstrual cycle: menses, postmenses, ovulatory, postovulatory, and premenses. Weekly variations were also measured. Energy intake was lowest during the ovulatory phase compared with postovulatory, premenses, and menses phases (p less than 0.05). The maximum difference, 1.36 MJ (324 kcal)/d, occurred between ovulatory and postovulatory phases and was twofold higher than the increase of 0.64 MJ (152 kcal)/d observed at weekends. This reduction of food intake at ovulation has not been previously described in humans. It coincides with the expected peak in circulating estrogen levels and is consistent with the hypothesis in animal models that estrogen is an appetite suppressant.

Women's attitudes to withdrawal bleeding and their knowledge and beliefs about the oral contraceptive pill.

One hundred and fifty-eight attenders at general practices and family-planning clinics, and 20 young female doctors volunteered to complete a questionnaire about how women take the oral contraceptive pill, their knowledge of the Pill and their attitudes to withdrawal bleeding. Forty-three per cent of female patients has used the Pill to alter the time of withdrawal bleeding. Twenty-two per cent of female patients had taken the Pill daily for more than six weeks on at least one occasion and all reported positive experiences. However, 83% of female patients believed that it was necessary to bleed monthly when taking the Pill and 69% of the female patients believed that continuous use of active medication is undesirable. The over-all knowledge of the Pill was poor and 43% of female patients did not know what to do if they missed two consecutive Pills. Female doctors were better informed but had similar attitudes about the Pill to those of other women. Forty-six per cent of the female patients and 55% of young female doctors would chose to bleed at intervals of three months or greater if they could determine their own Pill regimen.

PIP: Australian women's oral contraceptive (OC)-related behavioral practices and attitudes toward withdrawal bleeding were assessed in a questionnaire administered to 158 pill users (recruited either from general practice or family planning clinics) and 20 female physicians. The patients, the majority of whom were 20-29 years of age, had been taking the pill for an average of 5.3 years. 83% of the patients and 60% of the physicians believed a monthly bleed was essential for normal body functions. When given the hypothetical option of choosing how often they would bleed, 54% of patients and 45% of physicians still opted for monthly withdrawal bleedings. However, 43% of all female patients and 45% of physicians indicated they had used OCs to alter the time of withdrawal bleeding on at least 1 occasion, generally to prevent bleeding for special occasions or on holidays. These OC "manipulators" were more likely to be taking a monophasic than triphasic OC, to state that they did not always take the pill as directed, to believe that it was not physiologically essential to bleed every month, and to prefer a pill regimen that resulted in less frequent bleeding. Overall, knowledge of the mechanisms of OC use was poor among the female acceptors. 43% of female patients did not know what to do if they missed 2 consecutive pills. Few patients were aware that the pill functions by suppressing the release of endogenous estrogen and progesterone and that withdrawal bleeding is not menstruation. In general, the findings of this study suggest that there are many misconceptions that must be overcome before women would be willing to accept an OC regimen associated with a withdrawal bleed at intervals of 2-3 months.