Search

Background Exposure to combination antiretroviral therapy (cART) can lead to important metabolic changes and increased risk of coronary heart disease (CHD). Computerized clinical decision support systems have been advocated to improve the management of patients at risk for CHD but it is unclear whether such systems reduce patients’ risk for CHD. Methods We conducted a cluster trial within the Swiss HIV Cohort Study (SHCS) of HIV-infected patients, aged 18 years or older, not pregnant and receiving cART for >3 months. We randomized 165 physicians to either guidelines for CHD risk factor management alone or guidelines plus CHD risk profiles. Risk profiles included the Framingham risk score, CHD drug prescriptions and CHD events based on biannual assessments, and were continuously updated by the SHCS data centre and integrated into patient charts by study nurses. Outcome measures were total cholesterol, systolic and diastolic blood pressure and Framingham risk score. Results A total of 3,266 patients (80% of those eligible) had a final assessment of the primary outcome at least 12 months after the start of the trial. Mean (95% confidence interval) patient differences where physicians received CHD risk profiles and guidelines, rather than guidelines alone, were total cholesterol -0.02 mmol/l (-0.09–0.06), systolic blood pressure -0.4 mmHg (-1.6– 0.8), diastolic blood pressure -0.4 mmHg (-1.5–0.7) and Framingham 10-year risk score -0.2% (-0.5–0.1). Conclusions Systemic computerized routine provision of CHD risk profiles in addition to guidelines does not significantly improve risk factors for CHD in patients on cART.

BackgroundTenofovir (TDF) use has been associated with proximal renal tubulopathy, reduced calculated glomerular filtration rates (cGFR) and losses in bone mineral density. Bone resorption could result in a compensatory osteoblast activation indicated by an increase in serum alkaline phosphatase (sAP). A few small studies have reported a positive correlation between renal phosphate losses, increased bone turnover and sAP.MethodsWe analysed sAP dynamics in patients initiating ( n=657), reinitiating ( n=361) and discontinuing ( n=73) combined antiretroviral therapy with and without TDF and assessed correlations with clinical and epidemiological parameters.ResultsTDF use was associated with a significant increase of sAP from a median of 74 U/l (interquartile range 60–98) to a plateau of 99 U/l (82–123) after 6 months ( PConclusionsWe document a highly significant association between TDF use and increased sAP in a large observational cohort. The lack of correlation between TDF use and sALT suggests that the increase in sAP is because of the bone isoenzyme and indicates stimulated bone turnover. This finding, together with published data on TDF-related renal phosphate losses, this finding raises concerns that TDF use could result in osteomalacia with a loss in bone mineral density at least in a subset of patients. This potentially severe long-term toxicity should be addressed in future studies.

BACKGROUND Drug resistance is a major barrier to successful antiretroviral treatment (ART). Therefore, it is important to monitor time trends at a population level. METHODS We included 11 084 ART-experienced patients from the Swiss HIV Cohort Study (SHCS) between 1999 and 2013. The SHCS is highly representative and includes 72% of patients receiving ART in Switzerland. Drug resistance was defined as the presence of ≥1 major mutation in a genotypic resistance test. To estimate the prevalence of drug resistance, data for patients with no resistance test was imputed based on the patient's risk of harboring drug-resistant viruses. RESULTS The emergence of new drug resistance mutations declined dramatically from 401 to 23 patients between 1999 and 2013. The upper estimated prevalence limit of drug resistance among ART-experienced patients decreased from 57.0% in 1999 to 37.1% in 2013. The prevalence of 3-class resistance decreased from 9.0% to 4.4% and was always

Background CD4+ T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+ T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART). Methods Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements 3 months apart during the 1st year of cART were included ( n=1,816 patients). We studied CD4+ T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2–3 and years 4–5 of suppression. Multiple median regression adjusted for repeated CD4+T-cell measurements was used to study the dependence of CD4+ T-cell slopes on clinical covariates and drug classes. Results Median CD4+ T-cell increases following VL suppression were 87, 52 and 19 cells/μl per year in the three periods. In the multiple regression model, median CD4+ T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+ T-cell + T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+T-cell increases compared with stavudine. Conclusions In our observational study, long-term CD4+ T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+ T-cell levels.

BACKGROUND: Hepatitis B virus (HBV) genotypes can influence treatment outcome in HBV-monoinfected and human immunodeficiency virus (HIV)/HBV-coinfected patients. Tenofovir disoproxil fumarate (TDF) plays a pivotal role in antiretroviral therapy (ART) of HIV/HBV-coinfected patients. The influence of HBV genotypes on the response to antiviral drugs, particularly TDF, is poorly understood. METHODS: HIV/HBV-co-infected participants with detectable HBV DNA prior to TDF therapy were selected from the Swiss HIV Cohort Study. HBV genotypes were identified and resistance testing was performed prior to antiviral therapy, and in patients with delayed treatment response (>6 months). The efficacy of TDF to suppress HBV (HBV DNA

Seit 2002 nahm die Zahl der gemeldeten Syphilisdiagnosen in der Schweiz kontinuierlich zu. 2013 sind beim Bundesamt fur Gesundheit 1069 Meldungen eingegangen, von denen jedoch wegen fehlender Angaben nur die Halfte als Syphilisfalle klassifiziert wurden. 2011 wurde durch das BAG eine wichtige Neuerung eingefuhrt: Auf der arztlichen Erganzungsmeldung kann seither eine Re-Infektion ausdrucklich als solche ge­kennzeichnet werden.

BACKGROUND: Stopping antiretroviral therapy in patients with HIV-1 infection can reduce costs and side-effects, but carries the risk of increased immune suppression and emergence of resistance. METHODS: 430 patients with CD4-positive T-lymphocyte (CD4) counts greater than 350 cells per muL, and viral load less than 50 copies per mL were randomised to continued therapy (n=146) or scheduled treatment interruptions (n=284). Median time on randomised treatment was 21.9 months (range 16.4-25.3). Primary endpoints were proportion of patients with viral load less than 50 copies per mL at the end of the trial, and amount of drugs used. Analysis was intention-to-treat. This study is registered at ClinicalTrials.gov with the identifier NCT00113126. FINDINGS: Drug savings in the scheduled treatment interruption group, compared with continuous treatment, amounted to 61.5%. 257 of 284 (90.5%) patients in the scheduled treatment interruption group reached a viral load less than 50 copies per mL, compared with 134 of 146 (91.8%) in the continued treatment group (difference 1.3%, 95% CI-4.3 to 6.9, p=0.90). No AIDS-defining events occurred. Diarrhoea and neuropathy were more frequent with continuous treatment; candidiasis was more frequent with scheduled treatment interruption. Ten patients (2.3%) had resistance mutations, with no significant differences between groups. INTERPRETATION: Drug savings with scheduled treatment interruption were substantial, and no evidence of increased treatment resistance emerged. Treatment-related adverse events were more frequent with continuous treatment, but low CD4 counts and minor manifestations of HIV infection were more frequent with scheduled treatment interruption.

Background: : Many intravenous opiate users are infected with hepatitis C virus (HCV) but few are treated. Although this complies with various guidelines, virtually no published evidence supports such a recommendation. Patients and Methods: : In a multicenter study, HCV-infected patients in opiate maintenance treatment programs received interferon plus high- or low-dose ribavirin (1,000/1,200 mg or 600 mg). HIV-coinfected patients were not included. Endpoints were feasibility, efficacy, side effects, and reasons for dropout. Results: : Of the 420 patients who tested positive for HCV, 27 (6%) were enrolled; 393 (94%) either failed to meet the inclusion criteria or refused treatment. Virologic end-of-treatment response was achieved in 12/27 patients, and sustained response in 13/27 (48%). Response depended on viral genotype, not ribavirin dose. The two doses of ribavirin did not differ in their side effects. Conclusion: : In a small fraction of HCV-infected intravenous drug users in an opiate maintenance treatment program, antiviral therapy was feasible, safe, and effective. The success rate was comparable to that achieved in controlled studies that excluded drug users

The results from the HPTN 052 trial have increased the focus on use of antiretroviral therapy (ART) for prevention of HIV transmission; however, condom use also effectively prevents HIV transmission. Studies in heterosexual serodiscordant couples with viral suppression have so far only reported follow-up data for 330 couple-years when condoms were not being used. Data are even more limited for anal sex in men who have sex with men. Additional data on the effectiveness of ART as prevention when practicing condom-less sex is urgently needed.

Background. We examined whether viral dynamics in the genital tract during the natural history of acute human immunodeficiency virus type 1 (HIV-1) infection could explain efficient heterosexual transmission of HIV. Methods. We measured HIV-1 concentration in blood and semen samples from patients with acute and long-term HIV-1 infection. We explored the effect of changes in viral dynamics in semen on the probability of transmission per coital act, using a probabilistic model published elsewhere. Results. Considered over time from infection, semen HIV-1 concentrations, in men with acute infection, increase and decrease in approximate parallel with changes occurring in blood. Modeling suggests that these acute dynamics alone are sufficient to increase probability of heterosexual transmission by 8-10-fold between peak (day 20 after infection, based on the model) and virologic set points (day 54 and later after infection). Depending on the frequency of coitus, men with average semen HIV-1 loads and without sexually transmitted diseases (STDs) would be expected to infect 7%-24% of susceptible female sex partners during the first 2 months of infection. The predicted infection rate would be much higher when either partner has an STD. Conclusions. Empirical biological data strongly support the hypothesis that sexual transmission by acutely infected individuals has a disproportionate effect on the spread of HIV-1 infection. Acute hyperinfectiousness may, in part, explain the current pandemic in heterosexual individuals

Objective Information about the virological response to sequential highly active antiretroviral therapy (HAART) for HIV infection is limited. The virological response to four consecutive therapies was evaluated in the Swiss HIV Cohort. Design Retrospective analysis in an observational cohort. Methods 1140 individuals receiving uninterrupted HAART for 4.8 ±0.6 years were included. The virological response was classified as success (5000 copies/ml). Potential determinants of the virological response, including patient demographics, treatment history and virological response to previous HAART regimens were analysed using survival and logistic regression analyses. Results 40.1% failed virologically on the first (22.0% LF; 18.1% HF), 35.1% on the second (14.2% LF; 20.9% HF), 34.2% on the third (9.9% LF; 24.3% HF) and 32.7% on the fourth HAART regimen (9% LF; 23.7% HF). Nucleoside pre-treatment (OR: 2.34; 95% CI: 1.67–3.29) and low baseline CD4 T-cell count (OR: 0.79/100 cells rise; 95% CI: 0.72–0.88) increased the risk of HF on the first HAART. Virological failure on HAART with HIV-1 RNA levels exceeding 1000 copies/ml predicted a poor virological response to subsequent HAART regimens. A switch from a protease inhibitor- to a non-nucleoside reverse transcriptase inhibitor-containing regimen significantly reduced the risk of HF. Multiple switches of HAART did not affect the recovery of CD4 T lymphocytes. Conclusion Multiple sequential HAART regimens do not per se reduce the likelihood of long-term virological suppression and immunological recovery. However, early virological failure increases significantly the risk of subsequent unfavourable virological responses. The choice of a potent initial antiretroviral drug regimen is therefore critical. This study has been presented in part at the 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, 2003. Abstract #571.

OBJECTIVES: To explore the effect of granulocyte macrophage colony stimulating factor (GM-CSF) on viral load and CD4 cell count during interruption of highly active antiretroviral therapy (HAART). METHODS: Patients on effective HAART (CD4 cell count > 400 x 10(6)/l; viral load < 50 HIV RNA copies/ml) were randomized to one of two groups: 12 weeks' treatment interruption plus, during the first 4 weeks, 300 microg GM-CSF (Leucomax-Novartis) by subcutaneous injection three times weekly (GM-CSF group); 12 weeks' scheduled treatment interruption (STI-only group). Viral load, CD4 cell count, clinical events and side effects of treatment were monitored. RESULTS: Thirty-three patients, 15 in the GM-CSF group and 18 in the STI-only group, were evaluated according to the intention-to-treat principle. The two groups were well matched with regard to pre-HAART viral loads and CD4 cell counts. During STI, viraemia was approximately two to three times lower in the group receiving GM-CSF (max 4.97 versus 5.45 in STI-only group; P = 0.03). Fifteen out of 17 patients in the STI-only group showed a decrease in their CD4 cell count between weeks 0 and 4 (median decrease 231 x 10(6) cells/l; P < 0.001); there was no such tendency in the GM-CSF group (P = non-significant when comparing CD4 cell counts at weeks 0 and 4). The median CD4 cell AUC (area under the curve) from week 0 to week 12 was higher in the GM-CSF group (9166 cells.week) than in patients without GM-CSF (7257), P = 0.02. GM-CSF produced local reactions in 88% of patients, and generalized symptoms such as fever, back pain or headache in 82% of patients. Seventy-six percent of patients completed the planned course of 12 injections. CONCLUSIONS: The administration of GM-CSF blunted the viral rebound following interruption of HAART, and largely prevented a decrease of CD4 cell counts during a 12-weeks-treatment interruption. A better understanding of the underlying mechanism(s) may help to identify synergistic treatment targets and improved administration protocols to enhance control of chronic HIV infection.

The probability of sexual transmission of HIV depends on the infectiousness of the index case and the susceptibility of the sexual contact. The risk of HIV transmission is heterogeneous and may be greatest during the initial sexual contacts in a steady partnership. Several factors, including systemic and mucosal acquired protective immune-response might be responsible for the apparent decrease of per-sex-act risk of transmission in a given partnership over time. Biological studies can be used to better understand the complex information obtained by epidemiological surveys. The infectiousness of HIV depends on the inoculum, and virologic factors. The genital tract viral load of the index case is likely the most important determinant of transmission. At the population level, interventions that reduce the genital shedding of HIV by reducing systemic blood viral load and/or local inflammatory processes are likely to have a beneficial impact on HIV incidence. Antiretroviral drugs are likely to reduce sexual transmission of HIV. However, these drugs may not all prove equally. Compartmentalized HIV replication in the male and female genital tract have been observed. Treatment with antiretroviral drugs that poorly penetrate the genital tract harbour the risk of local production and spread of resistant viruses. In addition, increased risk taking behaviour could offset the benefits of reduced probability of transmission at the population level. Biological data about HIV transmission must be used to inform public health policies and optimize HIV prevention strategies.

CD4+ T-helper cells appear to be essential in sustaining immune responses in chronic viral infections, as the maintenance of CD8+ cytotoxic T-lymphocyte responses and the control of viremia were demonstrated to depend on CD4+ T cell help. In order to investigate the function of HIV-specific CD4+ T cells in chronic HIV-1-infection, 49 chronically HIV-infected patients were analyzed before and 3 and 6 months after initiation of antiviral treatment. Ten patients showed a substantial, although weak, proliferative response to HIV-1-p55gag protein for which no improvement was observed upon initiation of HAART. From one individual, HIV-1-p55gag-specific CD4-positive T-cell clones were generated that were heterogeneous in their TCR Vbeta gene usage and HLA-DRB1*13 and DRB1*03 restricted, respectively. In addition, some CD4+ TCC produced substantial amounts of IFN-gamma and MIP-1alpha/beta were perforin-positive, and showed cytotoxic activity. These diverse functional features of HIV-specific CD4+ T cells suggest that they may exert direct antiviral activity.

BACKGROUND: Transmitted human immunodeficiency virus type 1 (HIV) drug resistance (TDR) mutations are transmitted from nonresponding patients (defined as patients with no initial response to treatment and those with an initial response for whom treatment later failed) or from patients who are naive to treatment. Although the prevalence of drug resistance in patients who are not responding to treatment has declined in developed countries, the prevalence of TDR mutations has not. Mechanisms causing this paradox are poorly explored. METHODS: We included recently infected, treatment-naive patients with genotypic resistance tests performed ≤1 year after infection and before 2013. Potential risk factors for TDR mutations were analyzed using logistic regression. The association between the prevalence of TDR mutations and population viral load (PVL) among treated patients during 1997-2011 was estimated with Poisson regression for all TDR mutations and individually for the most frequent resistance mutations against each drug class (ie, M184V/L90M/K103N). RESULTS: We included 2421 recently infected, treatment-naive patients and 5399 patients with no response to treatment. The prevalence of TDR mutations fluctuated considerably over time. Two opposing developments could explain these fluctuations: generally continuous increases in the prevalence of TDR mutations (odds ratio, 1.13; P = .010), punctuated by sharp decreases in the prevalence when new drug classes were introduced. Overall, the prevalence of TDR mutations increased with decreasing PVL (rate ratio [RR], 0.91 per 1000 decrease in PVL; P = .033). Additionally, we observed that the transmitted high-fitness-cost mutation M184V was positively associated with the PVL of nonresponding patients carrying M184V (RR, 1.50 per 100 increase in PVL; P < .001). Such association was absent for K103N (RR, 1.00 per 100 increase in PVL; P = .99) and negative for L90M (RR, 0.75 per 100 increase in PVL; P = .022). CONCLUSIONS: Transmission of antiretroviral drug resistance is temporarily reduced by the introduction of new drug classes and driven by nonresponding and treatment-naive patients. These findings suggest a continuous need for new drugs, early detection/treatment of HIV-1 infection.

Antiretroviral therapy to treat HIV, as we know it today, is nothing less than a huge success story in modern medical history. What used to be an almost certain death-sentence was transformed into a very manageable chronic disease by means of highly efficient und mostly well tolerated drugs. Today, HIV-infected patients treated according to international recommendations have a very good chance to outgo the negative effects of HIV-1 and are therefore able to reach an almost normal life expectancy. Furthermore, patients successfully treated with antiretroviral drugs are no longer infectious, which is an essential aspect of global strategies to overcome the pandemic. Nevertheless, due to the complexity of HIV, physicians treating patients with antiretroviral therapy require profound knowledge of aspects such as viral resistance mechanisms and immune reconstitution, as well as drug-toxicity und drug-drug-interactions. Many other aspects such as long-term side-effects of antiretroviral drugs are still unknown. Strict adherence to treatment is of utmost importance.Der Erfolg der antiretroviralen Therapie gegen HIV-1 ist einzigartig in der modernen Medizingeschichte. Eine zuvor fast 100 % letale Erkrankung konnte in eine chronisch behandelbare Krankheit umgewandelt werden. Wird heute gemäß internationaler Empfehlungen früh mit einer antiretroviralen Therapie begonnen, können die negativen Effekte des HIV-1 Virus auf den menschlichen Organismus minimiert werden. Dies führt bei sonst gesunden HIV-infizierten Menschen zu einer nahezu normalen Lebenserwartung. Zusätzlich sind Patienten unter erfolgreicher Therapie nicht mehr infektiös, was für die Eindämmung der Pandemie von entscheidender Bedeutung ist. Die antiretrovirale Therapie ist jedoch nach wie vor komplex. Viele Aspekte, insbesondere die langfristigen Nebenwirkungen und Medikamenteninteraktionen betreffend, sind noch offen. Behandelnde Ärzte benötigen sehr gute Kenntnisse im Bereich der HIV-Resistenz, der Immunrekonstitution sowie der Medikamententoxizität und Interaktionen. Von absoluter Wichtigkeit ist die Therapieadhärenz.

The number of new HIV-1 infections remains stable in Switzerland over the last years thanks to the effective prevention programs. However, the aim to halve the new HIV infection rate has not been reached. Early identification of patients at risk of acquiring HIV infection and counselling "safer sex" rules as well as treating HIV-infected patients plays a decisive role in this program. Studies are -ongoing to investigate additional preventive measures such as pre-exposure prophylaxis, microbicides and vaccines, but none of those approaches permit omitting "safer sex". Incidences of other sexual transmitted infections are increasing rapidly, in particular the incidence of Syphilis. Transmission occurs more often orally or rectally than vaginally and patients are often asymptomatic. Condoms provide only limited protection. In addition antibiotic resistance emerges complicating the therapy, as for example for gonorrhea. Testing and treatment of infected patients is primordial as well as contact tracing. In this work, we discuss the different elements for preventing STIs with major emphasis on HIV.In der Schweiz ist die Zahl der HIV-Neuinfektionen ist in den letzten Jahren dank der guten Präventionsarbeit stabil geblieben. Das Ziel die HIV-Neuinfektionsrate zu senken wurde jedoch nicht erreicht. Entscheidende Präventionselemente sind die Sexualanamnese, die Diskussion über „Safer Sex“, das frühzeitige Erkennen und Testen gefährdeter Patienten und deren Sexualpartner sowie die Beratung und Behandlung infizierter Patienten. Darüber hinaus gibt es verschiedene Ansätze, die HIV-Übertragungsraten zu senken, z. B. Präexpositionsprophylaxe, Mikrobizide und Impfung. Keine dieser Maßnahmen erlaubt es jedoch zum jetzigen Zeitpunkt auf die „Safer Sex“ Regeln zu verzichten. Andere sexuell übertragbare Erkrankungen fallen durch eine rasch ansteigende Inzidenz auf. In Bezug auf Syphilis nimmt die Schweiz dabei einen unrühmlichen Spitzenplatz in Europa ein. Die Übertragung erfolgt häufiger oral oder rektal als vaginal, die Patienten sind oft asymptomatisch. Kondome schützen nur eingeschränkt vor einer Ansteckung. Hinzu kommen Probleme durch zunehmende Antibiotikaresistenzen, beispielsweise bei Gonokokken gegen orale Cephalosporine. Im Vordergrund steht daher die frühzeitige Testung und Behandlung infizierter Patienten und ihrer Sexualpartner. In dieser Arbeit gehen wir auf die verschiedenen Elemente der Präventionsarbeit durch die Ärzte ein, mit Schwerpunkt der Prävention von HIV.

Antiretroviral therapy to treat HIV, as we know it today, is nothing less than a huge success story in modern medical history. What used to be an almost certain death-sentence was transformed into a very manageable chronic disease by means of highly efficient und mostly well tolerated drugs. Today, HIV-infected patients treated according to international recommendations have a very good chance to outgo the negative effects of HIV-1 and are therefore able to reach an almost normal life expectancy. Furthermore, patients successfully treated with antiretroviral drugs are no longer infectious, which is an essential aspect of global strategies to overcome the pandemic. Nevertheless, due to the complexity of HIV, physicians treating patients with antiretroviral therapy require profound knowledge of aspects such as viral resistance mechanisms and immune reconstitution, as well as drug-toxicity und drug-drug-interactions. Many other aspects such as long-term side-effects of antiretroviral drugs are still unknown. Strict adherence to treatment is of utmost importance., Der Erfolg der antiretroviralen Therapie gegen HIV-1 ist einzigartig in der modernen Medizingeschichte. Eine zuvor fast 100 % letale Erkrankung konnte in eine chronisch behandelbare Krankheit umgewandelt werden. Wird heute gemäß internationaler Empfehlungen früh mit einer antiretroviralen Therapie begonnen, können die negativen Effekte des HIV-1 Virus auf den menschlichen Organismus minimiert werden. Dies führt bei sonst gesunden HIV-infizierten Menschen zu einer nahezu normalen Lebenserwartung. Zusätzlich sind Patienten unter erfolgreicher Therapie nicht mehr infektiös, was für die Eindämmung der Pandemie von entscheidender Bedeutung ist. Die antiretrovirale Therapie ist jedoch nach wie vor komplex. Viele Aspekte, insbesondere die langfristigen Nebenwirkungen und Medikamenteninteraktionen betreffend, sind noch offen. Behandelnde Ärzte benötigen sehr gute Kenntnisse im Bereich der HIV-Resistenz, der Immunrekonstitution sowie der Medikamententoxizität und Interaktionen. Von absoluter Wichtigkeit ist die Therapieadhärenz.

Background: Atazanavir boosted with ritonavir (ATV/r) and efavirenz (EFV) are both recommended as fi therapies for HIV-infected patients. We compared the 2 therapies for virologic effi cacy and immune recovery. Methods: We included all treatment-naive patients in the Swiss HIV Cohort Study starting therapy after May 2003 with either ATV/r or EFV and a backbone of tenofovir and either emtricitabine or lamivudine. We used Cox models to assess time to virologic failure and repeated measures models to assess the change in CD4 cell counts over time. All models were fi t as marginal structural models using both point of treatment and censoring weights. Intent-to-treat and various as-treated analyses were carried out: In the latter, patients were censored at their last recorded measurement if they changed therapy or if they were no longer adherent to therapy. Results: Patients starting EFV (n = 1,097) and ATV/r (n = 384) were followed for a median of 35 and 37 months, respectively. During follow-up, 51% patients on EFV and 33% patients on ATV/r remained adherent and made no change to their fi rst-line therapy. Although intentto-treat analyses suggest virologic failure was more likely with ATV/r, there was no evidence for this disadvantage in patients who adhered to fitherapy. Patients starting ATV/r had a greater increase in CD4 cell count during the fi rst year of therapy, but this advantage disappeared after one year. Conclusions: In this observational study, there was no good evidence of any intrinsic advantage for one therapy over the other, consistent with earlier clinical trials. Differences between therapies may arise in a clinical setting because of differences in adherence to therapy. Key words: antiretroviral therapy, CD4, epidemiology, protease inhibitors, reverse transcriptase inhibitors, viral load

Die unkomplizierte Gonorrho wird mit einer Kombination einer Einzeldosis Ceftriaxon 500 mg intramuskular und Azithromycin 1 g per os behandelt.

HIV infection, even when well controlled, may be associated with important mental health problems. We sought to investigate anxiety, depression, and health-related quality of life using screening measurements in patients with HIV infection and to examine their dependency on biosocial parameters relating to HIV. Prospective clinical, virologic, and immunologic data were obtained in a cross-sectional study within the Swiss HIV Cohort Study. Four self-reported questionnaires were used in 397 HIV-infected individuals. The scores for anxiety and depression were high as measured by the Hospital Anxiety and Depression Scale (HADS) and the State Trait Anxiety Inventory (STAI). Half the population scored

Demonstration of long-lived HIV-reservoirs resistant to the effects of combination antiretroviral therapy raises concern over the ability of treatment to maintain long-term beneficial alterations in T-cell subset composition. To address this issue, we have examined the effect of antiretroviral therapy on T-cell subset change during early HIV-infection in a 2-year prospective open-label trial composed of treatment-naive asymptomatic HIV-infected patients with CD4 + T-cell counts ≥400 cells/μl. Therapy consisted of double (zidovudine and lamivudine) or triple (zidovudine, lamivudine, and ritonavir) combination antiretroviral therapy. Retrospective analysis based on magnitude of viral suppression was used to characterize responder and nonresponder groups. Among responders, long-term antiretroviral therapy maintained a significant increase in numbers of total CD4 + , naive CD4 + /CD45RA + , and memory CD4 + /CD45RO + T cells. A concomitant significant decrease in numbers of memory CD8 + /CD45RO + and both activated CD8 + /HLA-DR + and CD8 + /CD38 + T cells was also maintained. In contrast, long-term antiretroviral therapy among nonresponders led only to a significant increase in the numbers of CD4 + T cells and a significant reduction in numbers of activated CD8 + /HLA-DR + T cells. The long-term ability of antiretroviral therapy during early asymptomatic HIV-infection to maintain reversal of disease-induced T-cell activation and maturation abnormalities continues to support the concept that immunologic advantage is gained by commencing early aggressive antiretroviral therapy. Nevertheless, continued management of T-cell subset recovery is significantly more effective in the presence of completely suppressed viral replication.

Objective: To develop a model to predict transmission of HIV-1 from men to women. Design: HIV-1 in seminal plasma, and endocervical CCR5 receptors were correlated with epidemiological studies of HIV-1 transmission to develop a probabilistic model. Settings: Semen samples were collected from patient subjects in Seattle Washington, Chapel Hill, North Carolina, and St. Gallen, Switzerland. Endocervical biopsy specimens were obtained from women in Chicago, Illinois. Participants: Eighty-six men (not receiving antireroviral therapy) in whom CD4 cell count and semen volume were available, and 24 women in whom the number of endocervical CCR5 receptors were determined. Main outcome measures: Prediction of transmission of HIV-1 from men to women per episode of vaginal intercourse based on the absolute burden of HIV (volume 3 HIV RNA copies/ml seminal plasma). Results: The model suggests efficient heterosexual transmission of HIV-1 when semen viral burden is high. When semen contains 100 000 copies of non-syncytium-inducing (NSI) HIV RNA the probability of HIV-1 transmission is 1 per 100 episodes of intercourse; conversely, with 1000 copies NSI HIV RNA in semen, transmission probability is 3 per 10 000 episodes of intercourse. Conclusions: This model links biological and epidemiological data related to heterosexual HIV-1 transmission. The model can be used to estimate transmission of HIV from men with high semen viral burden from inflammation, or reduced burden after antiretroviral therapy. The results offer a biological explanation for the magnitude of the HIV epidemic in places where earlier studies have shown men have high semen viral burden, such as in sub-Saharan Africa. The model can be used to develop and test HIV-1 prevention strategies.

The relationship between viral infection with Kaposi sarcoma-associated herpesvirus (KSHV) and the onset of Kaposi sarcoma (KS) in AIDS patients is incompletely understood. This study investigates the use of three serological assays to predict the development of KS in HIV-positive patients. Serially collected serum samples from 36 patients with KS and matched controls in the Swiss HIV Cohort Study (SHCS) were analyzed in a case control study. Three serologic assays to detect antibodies against KSHV (nuclear and membrane antigen immunofluorescence assay, N-IFA, M-IFA and ORF 65.2 ELISA) were used to determine the predictive value of KSHV-seropositivity. Serial samples from the cases were also analyzed to determine longitudinal patterns of seroreactivity and identify cases of seroconversion. Assay sensitivity for detection of KSHV antibodies was highest for M-IFA (83%), followed by N-IFA (74%) and 65.2 ELISA (52%). At the time of initial serum sampling (median 4.7 years before KS), only the N-IFA distinguished case and control sera (61% vs. 32%) and no assay was clearly predictive of subsequent onset of clinical KS. Moreover, an unexpectedly high rate of reversions to seronegativity were observed by N-IFA (27/33) as well as by 65.2 ELISA (11/26) in the longitudinal analysis. Analysis of the ORF65.2 ELISA index indicated that these reversions before the clinical onset of KS were associated with antibody levels that frequently hovered around the level of detectability. A marked increase in ORF 65.2 antibody titer occurred in a third of the patients at the time of KS diagnosis. Only two seroconversions were documented. KSHV infection within the SHCS is likely to have preceded HIV infection. KSHV infection alone is not highly predictive of KS development in this cohort of HIV-infected homosexual men as compared with matched controls. Three KSHV serologic assays, though sensitive at the time of clinical KS are inconsistently positive before the development of AIDS-related KS.

We have examined cell-free viral populations in the blood plasma and seminal plasma compartments of men infected with subtype C human immunodeficiency virus type 1 (HIV-1) using the V3-specific heteroduplex tracking assay (V3-HTA). We studied two cohorts of subjects who had visited either a sexually transmitted disease (STD) clinic for genital tract inflammation in the form of urethritis ( n = 43) or a dermatology clinic (controls, n = 14) in Malawi. We have previously shown that the presence of urethritis is associated with an eightfold increase in virus load in the seminal plasma compartment (M. S. Cohen et al., Lancet 349:1868–1873, 1997). The purpose of this study was to determine whether genital tract inflammation and its treatment caused genetic instability in cell-free HIV-1 populations. In a cross-sectional analysis at study entry, three-fourths of the STD and control subjects had multiple V3 populations in their blood while 60% of the STD subjects and 79% of the control subjects had multiple V3 populations in their semen. Overall, one-fourth of all of the subjects showed discordance between results with blood and semen specimens when samples were compared for the presence and absence of subpopulations. When differences in the relative levels of abundance of bands were also taken into account, two-fifths of all of the subjects showed discordance between the compartments. Among the subset of subjects in whom multiple virus populations could be detected, half showed discordance between the compartments. There were no differences between STD and control cohorts for these comparisons of the compartments in this cross-sectional analysis at study entry. Longitudinal analysis of the viral populations from two separate clinic visits over 1 to 4 weeks showed that the complexity of each V3 population as measured by Shannon entropy was different in blood and semen at the two time points, indicating that the blood and semen constitute different compartments for HIV-1. The seminal plasma compartment was more dynamic than the blood plasma compartment for the STD subjects who were treated for urethritis, with changes being noted in the presence or absence of V3-HTA bands in the semen of 29% of these subjects but in the blood of only 9% of these subjects. However, the changes were generally small. Overall, our results suggest that 40% of male subjects show discordance between seminal and blood viral populations and that the complexity of each V3 population was different between the two compartments. Both of these results point to the partial independence of the seminal compartment as a viral niche within the body.

Objective and methods: In 1998 we reported on a randomized comparison between stavudine plus didanosine plus placebo versus stavudine plus didanosine plus hydroxyurea (HU), in patients with a CD4 count of 200‐500 3 10 6 cells/l. After 3 months, the HU group had a higher proportion of patients with viral load , 200 3 10 6 cells/l. At the end of the 3 months blinded period, patients in the placebo group had the option to add HU if their viral load remained . 200 3 10 6 cells/l. We report results after 24 months. Results: Seventy-two patients were randomized to the HU arm, and a further 30 elected to add HU after 12 weeks. Twenty-four months after the start of the trial, only 25% of the 72 patients originally randomized to HU, and 20% of the 30 who added HU after week 12, were still taking it. The reasons for stopping HU were: lack of efficacy (45%), adverse events (37%) and patient or physician preference (18%). Side effects were more frequent in the didanosine/stavudine/HU group than in the didanosine/stavudine group: neuropathy (35 versus 15%, P , 0.02), fatigue (22 versus 7%, P , 0.01), and nausea or vomiting (26 versus 9%, P ,0.01). Of those who had discontinued HU, 73% were taking three drugs including a protease inhibitor. Patients who had started HU were compared with similar patients who had started protease inhibitors in the Swiss cohort. The probability of stopping HU was higher than the probability of stopping nelfinavir or indinavir, and similar to the probability of stopping ritonavir. Conclusion: HU increased the antiviral effect of stavudine plus didanosine. However, side effects were more frequent, and after 24 months the majority of patients had switched to protease inhibitor regimens.

Objectives: To assess the impact of HIV-related immunodeficiency and antiretroviral treatment on the occurrence and evolution of abnormal Papanicolaou tests. Study design: Cohort of 485 HIV-infected women with a known date of infection, enrolled during May 1993-April 1998 in 23 centres (gynaecology, infectious disease or STD clinics, or drug treatment centres) in 12 European countries; in 21 centres, follow-up was performed every 6 months (median follow-up: 2 years). Methods: Human papillomavirus (HPV) was detected at inclusion by Southern blot and PCR. The prevalence of squamous intraepithelial lesions (SIL), the incidence of SIL and regression from low-grade SIL were studied according to CD4 count after controlling for HPV detection results. Results: Compared with women with CD4 cell counts > 500 × 10 6 /l, women with CD4 cell counts 500 × 10 6 /l, reference), whereas it was less marked and not statistically significant in treated women. Conclusions: Severe HIV-related immunodeficiency strongly increases the risk of occurrence of SIL; antiretroviral treatment may reduce this risk, probably by restoring or at least preserving immune function.

Five methods for the assessment of plasma viral load (VL) were evaluated in 103 seropositive patients infected with various subtypes of HIV-1. The methods included three RNA-based assays (Amplicor Monitor 1.5, Quantiplex version 2.0, NucliSens), one ultrasensitive reverse transcriptase (PERT) assay and one "boosted" p24 antigen (Ag) enzyme immunoassay (EIA). Subtyping was based on sequencing in env. The sensitivities were, in decreasing order, Amplicor > PERT > p24 Ag > NucliSens > Quantiplex. The low sensitivity of NucliSens was related to the missing of several non-B (A, E, F, G) or recombinant strains, whereas that of Quantiplex did not depend on subtype. In the 1 group O sample and 4 group M samples, only PERT assay or p24Ag EIA produced a positive result. In the quantitative range, correlation was best between Amplicor and Quantiplex (r = 0.8848), fair between Amplicor and NucliSens (r = 0.7064) or PERT assay (r = 0.7266), lowest between Amplicor and p24Ag EIA (r = 0.3989). Amplicor underestimated VL in 1 subtype E sample. Thus, Amplicor performed best in terms of sensitivity (compared with all other assays) and accuracy (compared with NucliSens, PERT assay, and p24Ag) for non-B subtypes in group M samples. PERT assay appears useful for VL assessment in infections by group O or other highly divergent viruses.

To assess the effects of early initiation of antiretroviral therapy on cell-free and cell-associated viral load in blood and lymphoid tissue, we performed a randomized, open-label, multicenter trial comparing a double (zidovudine + lamivudine) and triple (zidovudine + lamivudine + ritonavir) drug combination in treatment-naive, asymptomatic patients with CD4 counts >400 cells/microl. HIV-1 RNA was measured in plasma, peripheral blood mononuclear cells, and sequential tonsil or lymph node biopsies (27 patients); the study follow-up was 2 years. Among 42 randomized patients, the proportion with plasma HIV-1 RNA

Objective: The amount of HIV in semen likely influences infectiousness. Antiretroviral therapy decreases HIV-RNA in semen, but data on HIV concentrations in semen in a large cohort of men with suppressed HIV-RNA in blood is unavailable. Methods: Male patients with a treatment-induced reduction of HIV-RNA load in plasma below 400 copies/ml were asked to donate a semen and blood sample. Blood and seminal plasma were tested for the presence of HIV-RNA by the NucliSens method (detection limit 400 copies/ml). Seminal cell samples from 67 patients were further analysed for the presence of HIV-DNA using a nested DNA-polymerase chain reaction. Results of RNA and DNA testing in semen were compared with 55 HIV-positive antiretroviral therapy-naive men. Results: A total of 114 patients participated in the study. Seminal plasma HIV-RNA was detectable in only two patients [1.8%, 95% confidence ratio (CI), 0-4.2%] compared with a detection frequency of 67% in untreated controls [Odds ratio (OR), 0.01; 95% CI, 0-0.03]. Detection of cell-associated HIV-DNA in semen was significantly less frequent (16 versus 38%) in patients receiving suppressive therapy compared with untreated controls (OR, 0.32; 95% Cl, 0.12-0.80). Conclusion: In patients with treatment-induced suppression of blood viral load the likelihood of having detectable HIV in semen is very low (< 4%). In addition, seminal shedding of cell-free and cell-associated HIV is significantly lower than in an untreated population of HlV-infected asymptomatic men. On a population basis, this effect of therapy may help to reduce sexual transmission of HIV. However, individual patients may still be infected as evidenced by continued shedding of cells harbouring the HIV provirus.

Objective To compare the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients according to sex, route of HIV acquisition and education, and to assess the impact of differences in utilization on the probability of progression to AIDS. Design and setting Swiss HIV Cohort Study, a national prospective multi-centre study. Participants A total of 3342 patients, including 1007 (30%) women. HIV was acquired through injection drug use in 1155 (35%) cases and through sex between men in 1172 (35%). Twenty-eight per cent (957) of participants had attained only the minimum level of schooling. At baseline, the median CD4 cell count was 269x10(6)/l cells, median HIV-1 RNA was 4.3 log10 copies/ml and 2917 (87%) were free of AIDS. Methods Kaplan-Meier life tables and Cox proportional hazards regression. Results During 7007 person-years of follow-up 2285 (69%) patients started HAART and 318 (10%) developed a new AIDS event. In multivariable analysis controlling for CD4 cell count, viral load and disease stage at baseline, the probability of starting HAART was lower in injection drug users compared with men who have sex with men, hazard ratio 0.63 (95% confidence intervals 0.56-0.70) and in patients with minimum schooling compared with those with vocational training, hazard ratio 0.82 (0.75-0.91). The risk of progression to AIDS was similar among men and women, patients with a history of injecting drug use, and patients with lower educational attainment in both univariable and multivariable analysis. Conclusion HIV-infected injecting drug users and those with lower levels of educational attainment start HAART later than other patient groups. The deferred initiation of therapy in these patients does not, however, appear to translate into an increased risk of clinical disease progression. This observation has important implications for treatment policy and the design of future clinical trials.

Objective: To analyse prospectively the effect of highly active antiretroviral treatment (HAART) on CD4 T-cell responses in vitro and in vivo in HIV-infected patients. Design: Prospective study with 49 protease inhibitor-naive adult patients. Data were collected at baseline and after 3 and 6 months of HAART. Methods: In vitro CD4 T-cell reactivity was analysed by stimulation of peripheral blood mononuclear cells with several antigens. In vivo CD4 T-cell reactivity (delayed type hypersensitivity) was assessed by Multitest Merieux. Both measurements were correlated to CD4 (memory) T-cell count and HIV-1 viraemia. Results: Restoration of specific CD4 T-cell proliferation was observed in most patients. The in vitro T-cell response was restored more frequently against antigens to which the immune system is constantly exposed (Candida albicans, Mycobacterium tuberculosis, M. avium) as compared with a low-exposure antigen (tetanus toxoid). Overall, delayed type hypersensitivity detection rate increased under HAART. Multivariate analysis showed improvement of antigen-specific T-cell proliferation to be significantly associated with an increase in memory CD4 T-cells, whereas improvement of the delayed type hypersensitivity response was associated with a decrease in plasma HIV-1 RNA. Conclusions: HAART for 6 months restored antigen-specific CD4 T-cell response to several antigens. In vitro immune reconstitution was closely correlated with an increase in memory CD4 cells. Restoration of delayed type hypersensitivity was associated with suppression of viraemia. It appears that in addition to expansion of memory CD4 cells, suppression of viraemia following HAART may allow an improved inflammatory reaction, thus providing even stronger immune reconstitution.

Background It is unclear whether primary prophylaxis against Pneumocystis carinii pneumonia can be discontinued in patients infected with the human immunodeficiency virus (HIV) who are successfully treated with combination antiretroviral therapy. We prospectively studied the safety of stopping prophylaxis among patients in the Swiss HIV Cohort Study. Methods Patients were eligible for our study if their CD4 counts had increased to at least 200 cells per cubic millimeter and 14 percent of total lymphocytes while they were receiving combination antiretroviral therapy, with these levels sustained for at least 12 weeks. Prophylaxis was stopped at study entry, and patients were examined every three months thereafter. The development of P. carinii pneumonia was the primary end point, and the development of toxoplasmic encephalitis the secondary end point. Results Of the 262 patients included in our analysis, 121 (46.2 percent) were positive for IgG antibodies to Toxoplasma gondii at base line. The median CD4 co...

Summary Background The efficacy of highly active antiretroviral therapy (HAART) in suppression of HIV-1 is well documented. We investigated virological and clinical outcomes of HAART in routine practice. Methods We analysed prospective data from the Swiss HIV Cohort Study on suppression of viral load and progression to AIDS or death in 2674 outpatients (median age 36 years, 27·3% women) who started HAART in 1995–98. Viral rebound was defined as two consecutive HIV-1-RNA measurements of more than 400 copies/mL. We analysed separately outcomes in patients with a history of antiretroviral treatment and in treatment-naive patients. Findings An estimated 90·7% of treatment-naive patients reached undetectable viral load ( Interpretation The rate of virological failure of HAART was high among these patients, but the probability of clinical progression was low even in patients with viral rebound.

HIV can be transmitted through contaminated blood and blood products; from a mother to her offspring during pregnancy childbirth or breast feeding; or through sexual contact. Sexual transmission remains by far the predominant mode of transmission. Vertical and blood borne transmission of HIV are highly predictable and very efficient modes. The recipient of a unit of contaminated blood nearly always becomes infected whereas only about 0.3% of people pierced with large bore needles seroconvert. This difference in efficiency most probably reflects the dissimilar concentrations of viruses inoculated. Vertical transmission leads to infection in about 25% of newborns. Sexual transmission of HIV however appears to be considerably less efficient and highly variable. To develop effective prevention strategies a better understanding of the factors affecting transmission of HIV is required. (excerpt)

The objectives were to evaluate the impact of early initiation of highly active antiretroviral therapy (HAART) on disease-induced T-cell activation and maturation abnormalities during asymptomatic HIV infection. A prospective open-label trial of zidovudine lamivudine and ritonavir in treatment-naive asymptomatic HIV-infected individuals with CD4 cells = 400 x 10/6/l. Peripheral blood CD4+ and CD8+ T cells derived from 15 asymptomatic HIV-infected individuals (median baseline CD4+ cells 608 x 10/6/l; CD8+ cells 894 x 10/6/l; plasma HIV RNA 3.93 log10 copies/ml) undergoing therapy with zidovudine (300 mg twice daily) lamivudine (150 mg twice daily) and ritonavir (600 mg twice daily) were assessed for changes in expression of phenotypic markers of T-cell activation (HLA-DR and CD38) and maturation (CD45RA and CD45RO). At weeks 0 2 4 8 12 16 20 and 24 T-cell subsets were quantified by flow cytometry and plasma HIV viral loads determined using reverse transcription PCR. HAART-induced decrease in plasma HIV RNA levels coincided with a significant reduction in numbers of activated CD4+/HLA-DR+ (maximum change -36%; P £ 0.05) CD8+/HLA-DR+ (maximum change -66%; P = 0.005) and CD8+/CD38+ (maximum change -51%; P = 0.01) T cells. A concomitant significant increase in numbers of naive CD4+/CD45RA+ (maximum change +12%; P = 0.005) and memory CD4+/CD45RO+ (maximum change +6%; P = 0.05) T cells was also evident which contrasted with a significant decrease in memory CD8+/CD45RO+ cells (maximum change -42%; P = 0.005). The observed ability of HAART during early asymptomatic HIV infection to initiate rapid reversal of disease-induced T-cell activation and maturation abnormalities while preserving pretherapy levels of immune function supports the concept that therapeutic advantage is to be gained by commencing early aggressive antiretroviral therapy. (authors)

Objectives: To evaluate blood and genital secretions from HIV-infected men for HIV-1 resistant to antiretroviral agents. Design: A longitudinal study of 11 men with HIV infection and persistent detectable HIV RNA levels in blood and semen on antiretroviral therapy. Methods: HIV-1 from the blood and seminal plasma, obtained before the initiation of a new therapeutic regimen and on therapy, were evaluated by population-based sequencing of reverse transcriptase (RT) and protease RNA for the development of resistance to antiretroviral therapy. The genetic relatedness of sequences over time was compared. Results: RT genotypic resistance markers were present in seminal plasma at baseline in three out of six individuals with previous RT inhibitor experience. Eight out of 10 men, from whom the viral sequence was available on new therapy, demonstrated the evolution of new resistance mutations in the blood or seminal plasma, or both. The evolution of resistance mutations in blood and semen were frequently discordant, although over time similar patterns were seen. In two individuals, protease inhibitor resistance mutations evolved in the blood but not in the major variant in seminal plasma. Comparisons of the viral sequences between blood and seminal plasma from six men revealed two patterns. Three men showed a clustering of sequences from blood and semen. Three had sequences that appeared to evolve separately in the two compartments. Conclusions: HIV-1 variants with genotypic resistance markers are present in the male genital tract and evolve over time on incompletely suppressive antiretroviral therapy. The absence of genotypic changes consistent with protease inhibitor resistance in the semen, despite their presence in blood plasma, suggests the possibility of limited penetration of these agents into the male genital tract. Sexual transmission of resistant variants may have a negative impact on treatment outcome in newly infected individuals and on the spread of the diseases within a population. Therapeutic strategies that fully suppress HIV-1 in the genital tract should be a public health priority.

High levels of human immunodeficiency virus type 1 (HIV-1) replication, as reflected in HIV-1 RNA concentrations in blood and semen, probably contribute to both rapid disease progression and enhanced sexual transmission. Semen and blood were collected from 49 Malawian and 61 US and Swiss (US/Swiss) HIV-1-seropositive men with similar CD4 cell counts and no urethritis or exposure to antiretroviral drugs. Median seminal plasma and blood plasma HIV-1 RNA concentrations were >3-fold (P = .034) and 5-fold (P = .0003) higher, respectively, in the Malawian men. Similar differences were observed in subsets of the Malawian and US/Swiss study groups matched individually for CD4 cell count (P = .035 and P < .002, respectively). These observations may help explain the high rates of HIV-1 sexual transmission and accelerated HIV-1 disease progression in sub-Saharan Africa.

OBJECTIVE: To explore the short-term effects on surrogate markers for HIV progression of didanosine (ddl) plus stavudine (d4T), with or without hydroxyurea. DESIGN: Randomized, double-blinded, prospective study. SETTING: Swiss HIV Cohort Study. PATIENTS: A total of 144 patients (75% antiretroviral-naive) were studied (mean baseline HIV-1 RNA, 4.53 log10 copies/ml; mean CD4 cell count, 370 x 10(6)/l). INTERVENTION: Patients received ddl (200 mg twice daily) plus d4T (40 mg twice daily), with additional hydroxyurea (500 mg twice daily) or placebo. MAIN OUTCOME MEASURES: The primary endpoint was a reduction of viraemia below 200 copies/ml after 12 weeks. At that time, patients who did not reach the primary endpoint were withdrawn in the hydroxyurea arm, whereas patients in the placebo group had the option of adding hydroxyurea to ddl and d4T. All patients were followed until week 24. RESULTS: After 12 weeks, 54% of the patients randomized to hydroxyurea had viraemia below 200 copies/ml, compared with 28% on placebo (P < 0.001). Using an ultrasensitive assay with a limit of detection of 20 copies/ml, 19% of patients receiving hydroxyurea had viraemia levels below 20 copies/ml, compared with 8% on placebo (P = 0.05). Mean decrease in HIV-1 RNA was 2.3 and 1.7 log10 copies/ml for hydroxyurea and placebo groups, respectively (P = 0.001). Hydroxyurea was found to induce lymphopenia (-124 x 10(6)/l). Increase in CD4 cell counts was +28 x 10(6)/l during hydroxyurea treatment compared with +107 x 10(6)/l on placebo (P = 0.001). CONCLUSIONS: Hydroxyurea improved the antiviral activity of d4T and ddl over a 12-week period, but was associated with a smaller increase in CD4 cell counts due to hydroxyurea-induced lymphopenia.

Objective: The potential role of antiretroviral treatment on the infectiousness of HIV1-infected men was examined by studying the effect of antiviral treatment on the shedding of HIV-1 in semen. Methods: Forty-four patients enrolled in various treatment protocols were asked to donate a semen sample before they began a new antiviral treatment and at a followup visit after 6 to 15 weeks of treatment. Since most patients were on blinded protocols, patients were stratified by response of blood viral load. The effect of each patient’s treatment was classified as good (n = 24), fair (n = 8) and marginal (n = 13) by measurement of the HIV RNA reduction in blood plasma (> 1.0 log10; 0.5‐1.0 log 10 and

Objective: This study examined the concentration of HIV in semen and the effects of biological factors on HIV excretion. Methods: Semen samples from 101 men at different stages of the disease were evaluated by quantitative HIV culture and HIV RNA detection. Blood plasma samples were available from 56 patients. The effects of CD4 and CD8 count, blood plasma RNA levels, treatment status and clinical staging on the shedding of HIV were evaluated. Results: HIV RNA levels in semen correlated with quantitative HIV culture of seminal cells and a strong association of positive seminal cell culture with high RNA levels was observed. CD4 count and antiviral treatment were inversely correlated with the concentration of HIV in semen. Blood plasma HIV RNA values were correlated with HIV RNA levels in semen, although some patients had highly discrepant results. Conclusions: The strong correlation between seminal cell culture and concentration of HIV RNA in seminal plasma suggested that HIV detected in seminal plasma was released by productively infected cells in the male genital tract. The study showed that the concentration of HIV in semen, which was likely to be correlated with HIV infectivity, was a function of the immune status of the HIV-infected individual. The results suggested that antiviral therapy may have reduced the concentration of HIV in semen.

Summary Background Transmission of HIV-1 is predominantly by heterosexual contact in sub-Saharan Africa, where sexually transmitted diseases (STDs) are also common. Epidemiological studies suggest that STDs facilitate transmission of HIV-1, but the biological mechanism remains unclear. We investigated the hypothesis that STDs increase the likelihood of transmission of HIV-1 through increased concentration of the virus in semen. Methods HIV-1 RNA concentrations were measured in seminal and blood plasma from 135 HIV-1-seropositive men in Malawi; 86 had urethritis and 49 controls did not have urethritis. Men with urethritis received antibiotic treatment according to the guidelines of the Malawian STD Advisory Committee. Samples were analysed at baseline and at week 1 and week 2 after antibiotic therapy in urethritis patients, and at baseline and week 2 in the control group. Findings HIV-1-seropositive men with urethritis had HIV-1 RNA concentrations in seminal plasma eight times higher than those in seropositive men without urethritis (12·4 vs 1·51×10 4 copies/mL, p=0·035), despite similar CD4 counts and concentrations of blood plasma viral RNA. Gonorrhoea was associated with the greatest concentration of HIV-1 in semen (15·8×10 4 copies/mL). After the urethritis patients received antimicrobial therapy directed against STDs, the concentration of HIV-1 RNA in semen decreased significantly (from 12·4×10 4 copies/mL to 8·91×10 4 copies/mL at 1 week [p=0·03] and 4·12×10 4 copies/mL at 2 weeks [p=0·0001]). Blood plasma viral RNA concentrations did not change. There was no significant change in seminal plasma HIV-1 RNA concentrations during the 2-week period in the control group (p=0·421). Interpretation These results suggest that urethritis increases the infectiousness of men with HIV-1 infection. HIV-1-control programmes, which include detection and treatment of STDs in patients already infected with HIV-1, may help to curb the epidemic. Targeting of gonococcal urethritis may be a particularly effective strategy.

Eine 23-jahrige Frau war zwei Wochen in Thailand in den Ferien (Strand und Dschungelausflug). Ab dem letzten Tag des Ferienaufenthalts litt sie an starkem Juckreiz zwischen der 2. und 3. Zehe des rechten Fusses, und nach der Ruckkehr in die Schweiz trat eine wandernde, streifenformigen Hauteffloreszenz am rechten Fussrucken auf.