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Objective To explain differences in survival in the first three years of combination anti-retroviral therapy (cART) between HIV treatment centres in the Netherlands. Methodology/Principal Findings We developed a mathematical simulation model, parameterised using data from the ATHENA cohort that describes patients entering care, being monitored and starting cART. Three scenarios were used to represent three treatment centres with widely varying mortality rates on cART that were differentiated by: (i) the distribution of CD4 counts of patients entering care; (ii) the age distribution of patients entering care; (iii) the average rate of monitoring the patients not on cART. At the level of the treatment centre, the fraction of Dutch MSM dying in the first three years of treatment ranged from 0% to 8%. The mathematical model captured the large variation in observed mortality between the three treatment centres. Manipulating the age-distribution of patients or the frequency of monitoring did not affect the model predictions. In contrast, when the same national average distribution of CD4 count at entry was used in all the scenarios, the variation in predicted mortality between all centres was diminished. Conclusions/Significance Patients entering care with low CD4 counts appears to be the main source of variation in the mortality rates between Dutch treatment centres. Recruiting HIV-infected individuals to care earlier could lead to substantial improvements in cART outcomes. For example, if patients were to present with at least 400 CD4 cells/mm3, as they do already in some centres, then our model predicts that the mortality in the first three years of cART could be reduced by approximately 20%.

For identification of risk factors for progression of human immunodeficiency virus (HIV) infection, 746 homosexual men participating in a cohort study in Amsterdam, The Netherlands, were studied since October 1984. A total of 234 of these men were HIV antibody-positive at baseline, and 52 seroconverted during follow-up. These 286 individuals were categorized as high- and low-risk for progression to the acquired immunodeficiency syndrome (AIDS) on the basis of the presence or absence of HIV antigenemia, antibody to HIV core antigen, or a number of T helper lymphocytes less than 0.5 x 10(9)/liter during three or more subsequential blood samples. Ninety-six (41%) of the seropositives and 32 (62%) of those who seroconverted remained low-risk throughout the study period. Bivariate analyses revealed that educational level and a history of herpes zoster were associated with a low- and high-risk status, respectively. In multivariate analyses, a history of herpes zoster and a history of sexual intercourse with a person who had AIDS were associated with a more rapid disease progression. While herpes zoster is considered to be a marker of progressive immunodeficiency, a history of having sexual intercourse with a person who had AIDS points to the more virulent properties of HIV in these persons. Because both seropositives and seroconverters who had sexual intercourse with a person with AIDS had a more rapid disease progression, it seems plausible that being infected by a person with AIDS is a risk factor for a relative short incubation period.

OBJECTIVES: In the industrialized world, lymphogranuloma venereum proctitis (LGVP) has been reported only in men who have sex with men. Factors responsible for the outbreak remain to be elucidated. GOAL: The goal of the present work was to elucidate risk factors associated with LGVP. STUDY DESIGN: The study design comprised a cross-sectional study including 32 men with LGVP and 93 men without LGVP (22 with gonorrheal proctitis, 30 with a non-LGV chlamydial proctitis, and 41 with proctitis of unknown etiology). Factors associated with LGVP were analyzed by (multinomial) logistic regression. RESULTS: Comparing men with LGVP with men without LGVP, factors significantly associated with higher risk of LGVP in multivariate analyses were as follows: anal enema use [odds ratio (OR): 7.8, 95% confidence interval (CI): 2.6-23.2], having sex on sex parties (OR: 5.7, 95% CI: 1.5-21.8), and having sex with human immunodeficiency virus-positive partners (OR: 3.2, 95% CI: 1.1-9.3). Evaluating the 4 proctitis groups separately in a multinomial logistic regression model, similar associations between anal enema use and LGVP were found. Men with non-LGV chlamydial proctitis showed less risk behavior than men with LGVP. No substantial difference in risk behavior was found, except for attending sex parties, between men with LGVP, and gonorrheal proctitis or proctitis of unknown etiology. CONCLUSIONS: Apart from men with LGVP, men with gonorrheal proctitis or proctitis of unknown etiology exhibit high risk behavior. Enema use seems to play a key role in transmission of LGVP, and needs further investigation

Data collected in a routine clinical setting are frequently used to compare antiretroviral treatments for human immunodeficiency virus (HIV). Differences in the frequency of measurement of HIV RNA levels and CD4-positive T-lymphocyte cell counts introduce a possible source of bias into estimates of the difference in effectiveness between treatments. The authors investigated the size of this bias when survival analysis methods are used to compare the initial efficacy of antiretroviral regimens. Data sets of clinical markers were simulated by use of differential equations that model the interaction between HIV and human T-cells. Cox proportional hazards and parametric models were fitted to the simulated data sets to evaluate the bias and coverage of 95% confidence intervals for the difference between regimens. The authors' results demonstrate that differences in the frequency of follow-up can substantially bias estimated treatment differences if methods do not correctly account for the intervals between measurements and if the statistical model chosen does not fit the data well. Analyses using methods applicable to interval-censored data reduce the bias. In the Athena cohort of HIV-infected individuals in the Netherlands from 1999 to 2003, there are differences in measurement frequency between current regimens that are of sufficient magnitude to conclude incorrectly that some regimens are more effective than others.

Mortality in HIV-infected patients has decreased dramatically since the introduction of highly active antiretroviral therapy (HAART). We analyzed progression to death in a population of 3678 antiretroviral treatment-naive patients from the ATHENA national observational cohort from 24 weeks after the start of HAART. Mortality was compared with that in the general population in the Netherlands matched by age and gender. Only log-transformed CD4 cell count (hazard ratio [HR] = 0.50, 95% confidence interval [CI]: 0.40 to 0.61 per unit increase) and plasma viral load (HR = 0.30, 95% CI: 0.15 to 0.60, HIV RNA level 6 CD4 cells/L and an HIV RNA level

We studied the dynamics of CD4 cell counts after the interruption of virologically successful highly active antiretroviral therapy (HAART) in 139 patients. Changes in CD4 cell counts during HAART interruption followed a biphasic pattern: an initial rapid decline during the first month followed by a slow decrease. During 48 weeks of follow-up mean CD4 cell counts remained just above the mean pre-HAART level. This limits the feasibility of structured treatment interruptions for patients with low nadir CD4 cell counts.

Objective: To compare the results of antiretroviral treatment (highly active antiretroviral therapy [HAART]) in indigenous Dutch (ID) and nonindigenous HIV-1-infected patients in Amsterdam, the Netherlands. We focused on the largest groups of nonindigenous people visiting our outpatient clinic: patients from other industrialized countries (western), from Surinam/Netherlands Antilles (SNA), and from sub-Saharan Africa (SSA). Design: Retrospective cohort analysis of 692 therapy-naive HIV-1 positive individuals who visited our outpatient clinic for the first time between July 1, 1996 and December 31, 2001. Methods: We compared the groups at the time of their first visit to our clinic; at the start of HAART; and according to the virological, immunologic, and clinical treatment response during the 96 weeks after the start of HAART. Results: Of the patients starting antiretroviral therapy, 362 were ID, 84 were western, 72 were from SNA, and I 10 were from S SA. SNA and SSA patients had a lower CD4 cell count at first visit (ID = 330 cells/mm(3), western = 330 cells/mm(3), SNA = 250 cells/mm(3), and SSA = 170 Cells/mm(3); P = 0.0002). Treatment in SNA and SSA patients was also started at a lower CD4 cell count, but the plasma HIV-1 RNA level was comparable. After the start of HAART, a similar rise in CD4 cell count was seen in the 4 groups (P = 0.33), but the baseline difference in CD4 cell count remained present during the follow-up period of 96 weeks. After adjusting for variables potentially influencing treatment outcome, the proportion of patients not reaching a plasma HIV-1 RNA level

A mathematical model is developed to characterize the distribution of cell turnover rates within a population of T lymphocytes. Previous models of T-cell dynamics have assumed a constant uniform turnover rate; here we consider turnover in a cell pool subject to clonal proliferation in response to diverse and repeated antigenic stimulation. A basic framework is defined for T-cell proliferation in response to antigen, which explicitly describes the cell cycle during antigenic stimulation and subsequent cell division. The distribution of T-cell turnover rates is then calculated based on the history of random exposures to antigens. This distribution is found to be bimodal, with peaks in cell frequencies in the slow turnover (quiescent) and rapid turnover (activated) states. This distribution can be used to calculate the overall turnover for the cell pool, as well as individual contributions to turnover from quiescent and activated cells. The impact of heterogeneous turnover on the dynamics of CD4(+) T-cell infection by HIV is explored. We show that our model can resolve the paradox of high levels of viral replication occurring while only a small fraction of cells are infected.

Background: The treatment of HIV-1-infected patients with triple-drug combination therapy results in profound suppression of viral replication. In most therapy-naive patients plasma HIV-1-RNA levels (pVL) drop below the lower limit of quantification (LLQ) of currently used assays. In a large percentage of such patients, more sensitive assays provide evidence of residual viral replication. The question is whether more potent therapy can further suppress this residual replication. Methods: Thirty control patients who, using very strict criteria, had not experienced virological failure during 3 years of standard therapy, were compared with 10 patients treated with a five-drug regimen, consisting of three different classes of antiretroviral drugs (alternative multidrug regimen). A modified ultrasensitive assay with an LLQ of 5 copies/ml was used to re-test plasma obtained at week 48 and at three timepoints at and around week 144. Results: At weeks 48 and 144 pVL could be quantified significantly more frequently in control patients than in patients using the alternative multidrug regimen (week 48: 42 versus 0% with quantifiable pVL, P = 0.017; week 144: 60 versus 14% with at least one quantifiable pVL, P = 0.036, respectively). A low baseline CD4T cell count was predictive of quantifiable pVL in control patients, but not in alternative multidrug patients. Conclusion: This proof-of-principle study demonstrates that the use of an alternative multidrug regimen results in stronger long-term suppression of pVL compared with clinically successful treatment with standard therapy. (C) 2002 Lippincott Williams Wilkins

Contains fulltext : 185695.pdf (Publisher’s version ) (Closed access) BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study. METHODS: Patients receiving HAART had their plasma concentrations of protease inhibitors or nevirapine measured and completed a questionnaire on adherence. We determined the percentage of patients who reported taking all antiretroviral medication on time and according to dietary instructions in the past week. Drug exposure was compared between patients reporting deviation from their regimen and fully adherent patients. Among patients who received HAART for at least 24 weeks, we assessed the association between adherence and virologic outcome. RESULTS: A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven percent reported taking all antiretroviral medication on time and according to dietary instructions. Patients who reported deviation from their regimen showed lower drug exposure compared with fully adherent patients (median concentration ratio, 0.81 vs 1.07; P =.001). Among those receiving HAART for at least 24 weeks, patients reporting deviation from their regimen were less likely to have plasma HIV-1 RNA levels below 500 copies/mL (adjusted odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent patients. CONCLUSIONS: Only half of the patients took all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Deviation from the antiretroviral regimen was associated with decreased drug exposure and a decreased likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection.

Accurate assessment of plasma HIV RNA levels at low concentrations is clinically important. We evaluated a second-generation quantitative HIV RNA assay (NucliSens HIV-1 QT), and three simple adaptations of the NucliSens standard protocol to lower the lower cutoff level. The assays were evaluated in constructed panels with known HIV RNA concentrations and in clinical samples. Results were compared with those obtained with the first generation (NASBA HIV-1 QT) and with two other commercially available assays: the Amplicor HIV Monitor test and the Quantiplex assay. In a constructed panel, results obtained by NASBA QT were on average 0.13 log10 copies/ml (SD 0.15) higher than those of NucliSens. The NucliSens assay could quantify HIV RNA in at least 50% of the samples down to 518 (2.71 log10) copies/ml and NASBA QT to 5.80 x 103 (3.76 log10) copies/ml). Both assays correlated well with the known input (R NucliSens = 0.99; R NASBA QT = 0.996), but results were more variable at lower input levels. With the three different ultrasensitive NucliSens adaptations, HIV RNA could be quantified in at least 50% of the samples down to 100 (2.00 log10), 46 (1.66 log10), and 10 (1.00 log10) copies/ml, respectively. In patient samples, Amplicor results were on average 0.11 (SD 0.20) log10 copies/ml above, NucliSens 0.02 (SD 0.29) copies/ml above, and Quantiplex 0.13 (SD 0.19) copies/ml below the mean of the three assay results per sample. The variation remained the same over the range of RNA levels with all three assays. The NucliSens assay can quantify HIV RNA at lower levels than theo NASBA QT and is comparable to other commercially available assays. The lower cutoff of the NucliSens can be lowered down to 10 copies/ml.

Objective: To assess the HIV-1-RNA response and drug concentrations in cerebro-spinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RIV) or SQV/RIV plus stavudine (d4T) in HIV-1-infected patients. Design: A multicentre, open-label, randomized controlled trial. Methods: A total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. Results: The median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P= 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P= 0.005). CSF RIV and SQV concentrations were < LLQ in most patients. Conclusion: RTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF. (C) 2000 Lippincott Williams and Wilkins.

Identification and weighting of factors that correlate with and possibly contribute to the outcome of infection with human immunodeficiency virus (HIV) is important for our understanding of the pathogenesis and natural history of HIV infection and in designing strategies for the treatment of infection. HIV infection runs a variable course in the population of infected individuals. Some develop AIDS within a few years post-infection; others do not develop AIDS in a decade.

We studied sequence differences in regulatory elements of the long terminal repeat (LTR) and primer-binding site (PBS) among various human immunodeficiency virus type 1 (HIV-1) subtypes. Phylogenetic sequence analysis of a fragment of 729 base pairs (bp) covering the Gag-coding region for half of p24 and all of p17 revealed the gag subtype of all 60 viruses included in the study: A (n = 20), B (n = 12), C (n = 7), D (n = 10), E (n = 3), F (n = 4), G (n = 3), and H (n = 1). The subtype was also determined by analysis of a 689-bp fragment comprising the LTR and the PBS motif. Comparison of the LTR versus gag sequences showed a mosaic genome for seven isolates. After analysis of all sequences, we could describe subtype-specific differences in sequences encompassing the regulatory elements of the LTR and the PBS motif.

Summary Background Treatment and prevention of HIV-1-related central-nervous-system disease may be dependent on penetration of antiretroviral drugs into the central nervous system. Few data are available about cerebrospinal-fluid penetration and concomitant changes of HIV-1-RNA concentrations during treatment with antiretroviral agents. We investigated these effects in HIV-1-infected people. Methods 28 antiretroviral-naive individuals with CD4 cell counts of 200μL or more and plasma HIV-1-RNA concentrations of 10 000 or more copies/mL who were free of neurological symptoms were randomly assigned lamivudine plus either stavudine (n=17) or zidovudine (n=11). We did lumbar punctures on 28 individuals before and 22 individuals after 12 weeks of treatment to assess HIV-1-RNA and drug concentrations in cerebrospinal fluid. Findings All 28 individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid (median 4·64 log 10 copies/mL and 4·20 log 10 copies/mL in the lamivudine plus zidovudine and lamivudine plus stavudine groups, respectively). There was no correlation between plasma and cerebrospinal-fluid HIV-1-RNA concentrations (r=0·18, p=0·35). After 12 weeks of treatment none of the individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid. The highest drug concentration in the cerebrospinal fluid was for lamivudine followed by stavudine and zidovudine. Concentrations were consistent over time, unlike plasma concentrations. Therefore, we found time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine. Interpretation The two drug combinations were equally effective in the decrease of cerebrospinal fluid HIV-1-RNA concentrations. All drugs penetrated the cerebrospinal fluid. Antiretroviral drugs other than zidovudine might be useful in the prevention of AIDS dementia complex.

Multiphasic HIV decrease in individuals treated with anti-retroviral drugs has been modeled as the independent decay, with different half-lives, of distinct pools of cells infected before the initiation of treatment. We analyzed the kinetics of plasma HIV RNA in individuals receiving combinations of up to five drugs. The initial rates of decline increased substantially with the efficacy of treatment. Decline rates decreased with time, approaching zero in some cases. These observations are better explained if most of the virus is produced by cells infected after the initiation of therapy. Accordingly, treatment results in ongoing HIV infection cycles of decreasing amplitude, but the decrease progressively attenuates and may cease altogether at some viral load. We propose that HIV replication occurs in multiple local bursts, associated with immune activation in response to antigens. Current anti-retroviral drugs substantially reduce the size of these bursts and diminish their frequency but fail to abolish them.

Objectives and design: The dynamics of viral decline following the initiation of antiretroviral treatment were studied in 29 HIV-1-infected patients participating in a two-arm trial comparing immediate (group A: ritonavir, zidovudine and lamivudine) and delayed (group B: ritonavir supplemented by zidovudine and lamivudine on day 21) triple therapy. Parameters underlying viral dynamics were estimated using mathematical models tailored to these treatment protocols. Results: The decline in plasma HIV-1 density between day 0 and 21 was steeper in group A (-2.27 ± 0.46 log10) than group B (-1.87 ± 0.56 log10). In a subset of patients amenable to full mathematical analysis, a short-lived productively infected cell compartment (producing ~ 97% of total virions) decayed with a half-life of 1.0-2.5 days, whereas a long-lived infected cell compartment decayed with a halflife of 18.8-32.8 days. Estimates for the time for the elimination of virus from these two cell populations ranged from 474 to 802 days. The rate of loss of productively infected CD4+ T cells was positively correlated with baseline viral load in group A and in the combined dataset. Conclusions: These results suggest that HIV-infected cell populations may have a faster turnover in patients with higher viral loads due to higher infection rate parameters, higher rates of virus production, or lower virus clearance rates.

Objective: To compare the viral suppression of two antiretroviral regimens using three drugs or five drugs. Design: Two open-label studies using a three-drug (zidovudine, lamivudine and ritonavir) and a five-drug regimen (zidovudine, lamivudine, abacavir, indinavir and nevirapine) in study-drug-naive patients, except for one in the five-drug study. Methods: Participants with ≤ 10,000 HIV-1 RNA copies/ml in plasma at baseline were compared by means of Kaplan-Meier curves for time to < 50 copies/ml, as well as linear regression analysis for the first phase of decline using log-transformed copy numbers. Results: The elimination rate constants For HIV-1 RNA in 15 participants of the three-drug study were compared with nine participants of the five-drug study. The level of < 50 copies/ml was reached earlier when using the five-drug than when using the three-drug regimen (P log rank = 0.0005): median time to reach this level was 4 weeks and 12 weeks, respectively. No differences were found in HIV-1 RNA elimination rate constants in the first 2 weeks after the initiation of therapy. When the viral load declines were calculated from day 2 onwards, adjusting for differences in pharmacological delay of the drugs used, again no differences in early viral load decline were found between the two regimens. Conclusion: With the five drugs used in this study, the median time to reach < 50 HIV-1 RNA copies/ml was 8 weeks shorter than with the three-drug regimen. This finding shows that suppression of viral load in HIV-infection by standard triple-drug therapy can be improved upon.

BACKGROUND: Highly active antiretroviral therapy (HAART) has led to health benefits for patients infected with HIV-1. However, long-term use of multidrug regimens is difficult to sustain. Simplifying antiretroviral treatment regimens would increase patients' adherence and minimise toxicity. We investigated the feasibility of a strategy of induction therapy followed by maintenance therapy with HAART in a randomised open-label study. METHODS: From March, 1997, we enrolled patients infected with HIV-1 with at least 200 CD4 cells/microL, at least 1000 HIV-1 RNA copies/mL in plasma, and no previous exposure to antiretroviral drugs. After 26 weeks of induction therapy (stavudine, lamivudine, saquinavir, and nelfinavir) patients were randomly allocated maintenance therapy (either stavudine and nelfinavir or saquinivir and nelfinavir) or prolonged induction therapy (if the plasma HIV-1 RNA concentration at weeks 24 and 25 was

Anti-human immunodeficiency virus type 1 (HIV-1) activity was assessed in HIV-1-infected homosexual and bisexual men receiving 18-36 MIU/day of recombinant interferon (IFN)-alpha2a for Kaposi's sarcoma (KS). The median baseline HIV-1 RNA level was 4.99 log10 copies/mL. Seventeen subjects (68%) showed an RNA decline > or = .5 log10/mL, with a maximum at week 4 (median decline = 1.91, range = 3.64-1.15; P = .0007), after which RNA levels stabilized. Eight subjects (32%) with lower median initial CD4+ T cell counts (60 vs. 350 x 10(6)/L; P = .01) did not show RNA responses. Neither RNA nor KS responses were negatively affected by IFN-alpha2a dose modifications. Anti-HIV responses of KS responders (n = 15) and nonresponders (n = 10) did not differ. High-dose IFN-alpha can exert potent anti-HIV activity that is not associated with anti-KS activity.

Introduction: Kinetics of human immunodeficiency virus type 1 (HIV-1) cytotoxic T lymphocyte (CTL) responses and viral load were evaluated in HIV-1 infected homosexual men who progressed to AIDS within 3–6 years after seroconversion and in long-term survivors who remained AIDS-free for >9 years with normal CD4 + T cell counts. Methods: CTL against four major HIV-1 gene products (i.e. Gag, reverse transcriptase (RT), Nef and Env) were expanded in vitro under limiting dilution conditions using antigen specific stimulation. CTL activity was measured in standard split-well 51 Cr-release assay. Viral load was measured both as serum HIV-1 RNA levels and frequency of circulating CD4 + T cells productively infected with HIV-1. Polyclonal T cell function in vitro was determined in whole blood lymphocyte cultures, measuring lymphoproliferative responses to CD3 monoclonal antibody. Results: Long-term survival was associated with either persistently high or stable low HIV-1 specific CTL responses, accompanied by preserved in vitro polyclonal T cell reactivity and low viral load. In progressors, HIV-1 specific CTL responses were initially generated with similar kinetics as compared to long-term survivors. However, with progression to AIDS antiviral CTL activity and T cell function deteriorated simultaneously, while viral load increased. Conclusions: Our results are consistent with the hypothesis that HIV-1 specific CTL are beneficial through control of viremia to the virologic set-point and contribute to maintenance of the asymptomatic phase. However, loss of HIV-1 specific immune control as part of a more general loss of T cell function is the precipitating event in AIDS pathogenesis.

The emergence of CXCR4-using HIV variants (X4-HIV) is associated with accelerated disease progression in the absence of antiretroviral therapy. However, the effect of X4-HIV variants on the treatment response remains unclear. Here we determined whether the presence of X4-HIV variants influenced the time to undetectable viral load and CD4+ T cell reconstitution after initiation of cART in 732 patients. The presence of X4-HIV variants was determined by MT-2 assay prior to cART initiation and viral load and CD4+ T cell counts were analyzed every 3 to 6 months during a three year follow-up period. Kaplan-Meier and Cox proportional hazard analyses were performed to compare time to viral suppression and the absolute CD4+ T cell counts and increases in CD4+ T cell counts during follow-up were compared for patients with and without X4-HIV at start of cART. Patients harboring X4-HIV variants at baseline showed a delay in time to achieve viral suppression below the viral load detection limit. This delay in viral suppression was independently associated with high viral load and the presence of X4-HIV variants. Furthermore, the absolute CD4+ T cell counts were significantly lower in patients harboring X4-HIV variants at all time points during follow-up. However, no differences were observed in the increase in absolute CD4+ T cell numbers after treatment initiation, indicating that the reconstitution of CD4+ T cells is independent of the presence of X4-HIV variants. The emergence of X4-HIV has been associated with an accelerated CD4+ T cell decline during the natural course of infection and therefore, patients who develop X4-HIV variants may benefit from earlier treatment initiation in order to obtain faster reconstitution of the CD4+ T cell population to normal levels.

An inverted chromosome 6, at bands p21 and q22, has been found as the sole chromosome abnormality in an endometrial polyp from a 50-year-old woman. Since two out of three previously reported endometrial polyps showed a rearrangement of the same band 6p21, the nonrandom involvement of the terminal region of the short arm of chromosome 6 in this benign tumor can be supported.

As part of the prospective AIDS study in Amsterdam, blood samples were collected from 741 healthy homosexual men with multiple sexual partners, between October 1984 and May 1985. Samples were analyzed for the presence of antibodies to the human immunodeficiency virus (anti-HIV). Anti-HIV was demonstrated in 233 (31%) of the respondents. Seropositive respondents engaged in anal receptive sexual techniques with more sexual partners than did seronegative respondents, whereas seronegatives engaged in manual sexual techniques with more sexual partners than did seropositives. As far as it was possible to control for the interrelations between the measured variables, a direct relation with anti-HIV was established. This leads to the conclusion that when the number of sexual partners is considered a risk factor for HIV, a clear distinction should be made between the sexual techniques practiced with these partners. Two other risk factors for the presence of anti-HIV were the use of cannabis and of nitrite.

Human immunodeficiency virus (HIV) is lymphotropic and neurotropic. In vivo clinical and immunological abnormalities develop in a large proportion of long-term HIV antibody seropositive persons. Different stages of HIV infection are marked by expression of HIV genes, production of HIV antibodies, formation of antigen/antibody complexes and clearance of such complexes. Transient HIV antigenemia appearing generally 6-8 wk prior to HIV antibody (HIV-Ab) seroconversion and lasting 3-4 mth is generally seen in acute infection. IgM antibodies predominantly to core proteins may occasionally be detectable when, or just before, IgG antibodies appear. If IgG antibodies to both envelope and core proteins persist in the absence of HIV-Ag the short-term prognosis is relatively good. However, HIV-Ag seroconversion may appear at any time after HIV-Ab seroconversion. Progression to AIDS is strongly associated with declining or absent levels of IgG antibodies to p24. IgG2 and IgG4 antibodies to HIV, which are mainly directed to p24, disappear most dramatically. Titers of antibodies to HIV p24 below 64 are strongly associated with the presence of HIV antigen and a poor clinical outcome. HIV antigen was detected frequently in sera from children in all stages of infection in contrast to adults whose sera were generally HIV-Ag negative when asymptomatic and positive when AIDS was apparent. HIV antigen may be less efficiently detected with the present assays in sera from regions where the prototype strains of HIV (HTLV-III and LAV) are less prevalent, like Central Africa. Persistence of HIV-Ag in cerebrospinal fluid (CSF) appears to be pathognomonic for progressive encephalopathy, particularly in children. Levels of HIV-Ag in serum, and possibly in CSF, can be decreased by nucleoside analogues, such as AZT. This indicates HIV-Ag and possibly antibody to HIV core protein p24 as suitable markers for selecting individuals for antiviral therapy as well as monitoring the efficacy of such therapy.

An enzyme immunoassay based on an E. coli-produced HIV-1 rev gene product was used to detect rev-specific antibodies in longitudinally collected serum samples from 196 initially symptom-free men who were seropositive for antibodies to HIV-1 structural proteins and 72 men who seroconverted for such antibodies. In 61% of men no rev-specific antibodies were detected at all, 30% had persistently detectable rev-specific antibodies, and in 9% rev-specific antibodies were only transiently or intermittently detected. When a persistent rev-specific antibody response occurred in subjects who seroconverted to structural proteins, it was always, with one exception, found within 12 months of seroconversion. The rev-specific antibodies were also studied in a transectional sample of sera from the men who remained symptom-free and from those who developed AIDS-related conditions or AIDS, as well as in sera from 31 other men with AIDS-related conditions and in sera from 6 of these men at the time they developed AIDS. The rev-specific antibodies were found in 34% of symptom-free men, in 28% of patients with AIDS-related conditions, and in 16% of patients with AIDS. The low incidence of rev-specific antibodies early after infection may be due to low antigenicity of rev. The lower prevalence of rev-specific antibodies in sera from patients with AIDS, compared with patients with AIDS-related conditions and symptom-free HIV-1-infected individuals, may be explained by a progressive HIV-1-induced immunodeficiency. Studying rev-specific antibodies in HIV-1-infected individuals will be of limited value in understanding the role of rev in the pathogenesis of HIV-1-related disease.

For the study of the impact of human immunodeficiency virus (HIV) antibody testing on high-risk sexual behavior with nonsteady and steady sexual partners, 307 homosexual men (118 seronegative, 75 seropositive, and 114 untested) were interviewed at three consecutive six-month intervals between July 1985 and December 1986. From the results, it appears that among seropositives the percentage who performed anogenital insertive intercourse with nonsteady partners remained constant (73, 64, and 61% during the first, second, and third intervals, respectively (nonsignificant]. Among seronegatives and those who were untested, the percentages who practiced anogenital receptive intercourse with nonsteady partners decreased from 44 to 29% and from 54 to 20%, respectively (p less than 0.05). The percentage who performed anogenital insertive intercourse and anogenital receptive intercourse with their steady partner remained constant in all groups: seropositives, +/- 70%; seronegatives, +/- 60%; and untested, +/- 55%. Seropositives were more likely to use condoms during anogenital insertive intercourse with their nonsteady and steady sexual partners than were seronegatives and untested persons during anogenital receptive intercourse with these partners (p less than 0.05). In the majority of cases, condoms were not used antibody testing in the three groups studied. The generalizability of these results, however, is limited.

Evidence exists of an association between the presence of a "lupus" anticoagulant in plasma, recurrent fetal loss, and repeated thromboembolic accidents, also in the absence of systemic lupus erythematosus. Presented is an example of this association, with morphologic and biologic studies to elucidate its pathogenesis. In the case reported, the placenta showed massive infarction. In the spiral arteries of the basal plate of the placenta, lesions of intimal thickening, fibrinoid necrosis, acute atherosis, and intraluminal thrombosis were observed. The plasma of the patient contained a lupus anticoagulant and inhibited the formation of prostacyclin by rat aortic rings. Vascular production of prostacyclin is a major natural defense mechanism against thrombosis. Lack of generation of prostacyclin may account for the decidual vasculopathy and consequent placental infarction and for the generalized thrombotic tendency of some patients with lupus anticoagulant.

Human immunodeficiency virus antigen (HIV-Ag) was detected in the serum of most adult (13/16) and paediatric (6/6) AIDS patients and rarely in the serum of symptomless seropositive controls (1/13). It was present in the cerebrospinal fluid (CSF) of all 5 children and most (5/9) adults with AIDS-related encephalopathy, but not in the CSF of 13 symptomless seropositive controls, of whom 8 had antibody in the CSF. A longitudinal study of 1 of the controls with antibody in the CSF showed that HIV-Ag in CSF was present transiently before the occurrence of antibody in the CSF. In serial samples of serum from 35 men who seroconverted HIV-Ag was detected in 11 persons—in 5 before seroconversion and in 6 after. 3 of the 6 who became antigenaemic after seroconversion remained so for the rest of the follow-up. AIDS was diagnosed in 1 patient, 3 months after HIV-Ag was first detected in serum and 6 months after seroconversion. The findings suggest that HIV-Ag appears early and transiently in primary HIV infection. Antibody production follows, after which HIV-Ag may disappear. Its persistence or reappearance seems to correlate with clinical, immunological, and neurological deterioration.

The relation between serological and immunologic profiles and the risk of developing AIDS was assessed in 306 initially asymptomatic, human immunodeficiency virus-infected homosexual men studied for 30 mo. Twenty-nine men developed AIDS (attack rate, 16.8%). The attack rate in core antibody-negative men was 35.7%; this rate was 43.9% in antigen-positive men, 51.9% in men with low (less than 0.5 x 10(9)/L) CD4+ cell counts, 6.8% in core antibody-positive men, 6.9% in antigen-negative men, and 6.1% in men with normal CD4+ cell counts. The disappearance of core antibody, the expression of antigen, and the occurrence of low CD4+ cell counts preceded AIDS by a median of 624, 544, and 466 d, respectively. Seronegativity for core antibody preceded AIDS in 21 of 26 patients, 20 of whom were also antigen positive. Four more cases of AIDS developed among the antigen-negative, core antibody-positive men with low CD4+ cell counts. Only one patient with AIDS escaped detection by using these three markers.

The genetic polymorphism of group-specific component (GC) was investigated with isoelectric focusing in 351 homosexual men at risk for HIV infection, 96 male patients with AIDS, and 86 heterosexual controls. No significant differences in GC phenotype distribution were seen between controls and any of the at risk groups or patients, neither between HIV-Ab-positive/Ag-negative and HIV-Ab-positive/Ag-positive homosexual men nor between HIV-Ab-positive/Ag-positive homosexual men and AIDS patients, suggesting that the GC system is not involved in the infective susceptibility or progression of HIV infection to AIDS-related complex and AIDS.