Prevalence of risk factors for cardiovascular disease in HIV-infected patients over time: the Swiss HIV Cohort Study.

OBJECTIVE: Metabolic changes caused by antiretroviral therapy (ART) may increase the risk of coronary heart disease (CHD). We evaluated changes in the prevalence of cardiovascular risk factors (CVRFs) and 10-year risk of CHD in a large cohort of HIV-infected individuals. METHODS: All individuals from the Swiss HIV Cohort Study (SHCS) who completed at least one CVRF questionnaire and for whom laboratory data were available for the period February 2000 to February 2006 were included in the analysis. The presence of a risk factor was determined using cut-offs based on the guidelines of the National Cholesterol Education Program (NCEP ATP III), the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), the American Diabetes Association, and the Swiss Society for Cardiology. RESULTS: Overall, 8,033 individuals completed at least one CVRF questionnaire. The most common CVRFs in the first completed questionnaire were smoking (57.0%), low high-density lipoprotein (HDL) cholesterol (37.2%), high triglycerides (35.7%), and high blood pressure (26.1%). In total, 2.7 and 13.8% of patients were categorized as being at high (>20%) and moderate (10-20%) 10-year risk for CHD, respectively. Over 6 years the percentage of smokers decreased from 61.4 to 47.6% and the percentage of individuals with total cholesterol >6.2 mmol/L decreased from 21.1 to 12.3%. The prevalence of CVRFs and CHD risk was higher in patients currently on ART than in either pretreated or ART-naive patients. CONCLUSION: During the 6-year observation period, the prevalence of CVRFs remains high in the SHCS. Time trends indicate a decrease in the percentage of smokers and individuals with high cholesterol.

Predictive value of adherence in patients starting highly active antiretroviral treatment for HIV infection.

Strict adherence to the prescribed drug regimen is one of the most important predictors of success in the antiretroviral therapy of HIV infection. Ideally, patients should learn to optimise their drug adherence before they start antiviral therapy. This study evaluated the predictive role of adherence during the first four weeks of treatment for mid-term treatment outcome. Adherence was evaluated using electronic dosing systems during the first 25 days of therapy in 66 drug-naïve patients starting a new antiretroviral therapy. Treatment outcome (HIV-RNA suppression) was evaluated at week 24 of treatment. Good adherence (>95%doses taken) was associated with better rates of viral suppression (77% vs. 44% Patients with HIV-RNA below 50 copies/ml). Specific education programmes targeted at the achievement of optimal adherence during the first few weeks of therapy might result in better treatment results.

Biological Correlates of Sexual Transmission of HIV Practical Consequences and Potential Targets for Public Health : Practical Consequences and Potential Targets for Public Health.

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.

Combined therapy with saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed HIV-infected protease inhibitor-naive patients.

OBJECTIVE: To assess the short-term and long-term effect of a combination of saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed protease inhibitor-naive patients. DESIGN: Prospective open-label multicentre study. PATIENTS AND METHODS: A total of 64 protease inhibitor-naive and stavudine-naive HIV-infected patients with a CD4 count of < 250 cells/microL and > 10 000 HIV-1 RNA copies/mL received saquinavir hard-gelatin capsules, ritonavir and stavudine. Full (drop in viraemia of > 2 log10 and/or < 500 copies/mL) and partial responders (drop to between 500 and 5000 viraemia copies/mL) at week 9 (end of phase I) entered the second phase (additional 12-month period). RESULTS: Fifty-six patients completed phase I, 45 (70%) full responders and nine (14%) partial responders by intent-to-treat analysis. Thirty-nine patients completed phase II, 33 (52%) full responders and two (3%) partial responders. Six patients had < 50 HIV-1 RNA copies/mL at week 9, and 20 (31%) patients at month 12 of phase II. Mean CD4 cell counts increased significantly in the 56 patients from 89 to 184 cells/microL after 9 weeks and from 100 to 292 cells/microL in the 39 patients treated for another 12 months. Higher baseline viraemia and lower baseline CD4 cell counts were not associated with an unfavourable virological response at week 9 and month 12 of phase II. HIV DNA in peripheral blood monocytes decreased substantially (- 1.5 log10) but was detectable in all except one patient at the end of phase II. CONCLUSION: In protease- and stavudine-naive HIV-infected patients with moderate to severe immunosuppression, saquinavir in combination with ritonavir and stavudine caused a substantial long-term decrease in plasma viral load in approximately half the participants and a substantial increase in CD4 cell counts.

Acute HIV infection: impact on the spread of HIV and transmission of drug resistance.

OBJECTIVE: To assess the impact of primary HIV infection (PHI) on the spread of HIV and the temporal trends in transmission of HIV drug resistance between 1996 and 1999 in Switzerland. METHODS: Sequencing of the genes for reverse transcriptase (RT) and protease was performed for 197 individuals with documented PHI. Phylogenetic analyses were confronted with epidemiological data. RESULTS: Significant clustering was demonstrated for 29% of the RT sequences. All these cases occurred closely together in place and time; contact tracing demonstrated transmission at the time of PHI in 30% of them. Genotypic drug resistance was detected in 8.6% of PHI individuals in 1996, 14.6% in 1997, 8.8% in 1998 and 5.0% in 1999. Drug-resistant variants were identified in 11.3% of individuals infected by homosexual contacts, 6.1% by heterosexual contacts, 13% of intravenous drug users and more frequently in men (10.4%) than women (2.6%). Potential factors involved in the recent decrease of transmission of drug-resistant variants include increase of HIV non-B subtypes from 23% in 1996 to 35% in 1999 (only one non-B subtype had resistance mutations) and a steady increase of patients with undetectable viraemia as documented in Swiss HIV Cohort Study (10% in 1996 vs 53% in 1999). CONCLUSIONS: Phylogenetic and epidemiological analyses underline the impact of PHI in the spread of HIV. Moreover, this study indicates that drug resistance transmission may have decreased recently in Switzerland through the increased frequency of infection with HIV non-B subtypes and the steady increase of patients with undetectable viraemia.

A single-nucleotide polymorphism in the sterol-regulatory element-binding protein 1c gene is predictive of HIV-related hyperlipoproteinaemia.

A single-nucleotide polymorphism (3'322C/G) was identified in the gene encoding a key cholesterol/triglyceride regulator, sterol-regulatory element-binding protein 1c (SREBP-1c). Although it did not alter the amino acid sequence, SREBP-1c-3'322C/G was predictive of highly active antiretroviral therapy-related hyperlipoproteinaemia. Increases in cholesterol were less frequently associated with homozygous SREBP-1c-3'322G (genotype 22) than with heterozygous/homozygous SREBP-1c-3'322C (genotypes 11/12) and correlated with leptin and insulin increases, particularly in genotype 11/12 carriers. A functional mutation linked to SREBP-1c-3'322C/G or messenger RNA conformation differences may explain our findings.

Long-term evaluation of T-cell subset changes after effective combination antiretroviral therapy during asymptomatic HIV-infection.

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 > or =400 cells/microl. 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.

Longitudinal sero-reactivity to human herpesvirus 8 (KSHV) in the Swiss HIV Cohort 4.7 years before KS.

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.

Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model.

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 antiretroviral 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 x 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.

A randomised prospective study to evaluate a rapid HIV-antibody assay in the management of cases of percutaneous exposure amongst health care workers.

A rapid start of post-exposure prophylaxis with an antiretroviral regime is recommended after percutaneous exposure to blood from an HIV-positive source. Since the HIV-antibody status of the source is usually not known at the time of injury, antiretroviral treatment is started pending the results of HIV testing of the source. A randomised prospective study was designed to compare the use of a rapid-screening assay in the management of cases of percutaneous exposure with the conventional procedure. Prior to the comparative study, the accuracy of a rapid-screening assay performed by non-laboratory trained personnel was evaluated. 123 blinded HIV-positive and HIV-negative samples were correctly identified. In a randomised comparison with the conventional procedure, the application of the rapid-screening assay resulted in a significant reduction of psychological stress, drug use and cost. The estimated net benefit per case was CHF 93.-(62 US$). This study strongly supports the use of the rapid-screening assay in the management of post-exposure prophylaxis for HIV after percutaneous exposure in health care workers.

[Cause of death and autopsy findings in patients of the Swiss HIV Cohort Study (SHCS)]. / Todesursachen und Autopsiebefunde bei Patienten der Schweizerischen HIV-Kohortenstudie (SHCS).

The Swiss HIV Cohort Study (SHCS) is a prospective cohort study of HIV-infected adolescents and adults seen at 7 outpatient clinics (Swiss University Hospitals in Basle, Berne, Geneva, Lausanne, Zurich, the St. Gall Cantonal Hospital and the Civico Hospital in Lugano). The SHCS serves as an infrastructure for different research projects and includes about 70% of all patients with advanced disease in Switzerland. From April 1984 to November 1995 3120 HIV-infected patients of the SHCS died. Autopsies were performed in 314 of these patients. The aim of our study is to analyse autopsy findings as well as causes of death in those 314 HIV-infected patients. An HIV-related cause of death was found in 271 (86%) of the patients, 12 patients (4%) died of a drug overdose, and 3 (1%) of the patients committed suicide. 28 (9%) died either from an HIV unrelated or unidentified cause. The five most frequent causes of death were: bacterial pneumonia (52 patients, 17%), Pneumocystis carinii pneumonia (40 patients, 13%), lymphoma (34 patients, 11%), cytomegalovirus infection (33 patients, 11%), and toxoplasmosis (30 patients, 10%). During our study marked progress occurred in treating HIV-infected patients and preventing opportunistic infections. These improvements have further changed the natural course of acquired immunodeficiency syndrome. They are reflected in the falling rate of Pneumocystis carinii pneumonia and toxoplasmosis, as well as an increase in lymphoma as a cause of death over the period of our study.

Long-term hydroxyurea in combination with didanosine and stavudine for the treatment of HIV-1 infection. Swiss HIV Cohort Study.

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 x 10(6) cells/l. After 3 months, the HU group had a higher proportion of patients with viral load < 200 x 10 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 x 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.

[HIV superinfection: myth or reality?]. / Zweitinfektion mit HIV: Mythos oder Realität?

Most viral infections result in lifelong immunity against the virus, which prevents subsequent superinfection. In the light of recent findings on recombination of different viral clades, infection with two different HIV strains is unlikely to occur during primary infection. However, it is unclear whether true superinfection occurs during chronic HIV infection. If it does occur, superinfection could constitute a risk for HIV-concordant couples, since transmission of drug-resistant or more virulent viruses may result in worsening of the disease or treatment failure. We review the available data on superinfection and conclude that HIV-discordant couples should be informed of the theoretical risk of superinfection, especially where only one partner is receiving effective antiretroviral treatment.

Effects of early antiretroviral treatment on HIV-1 RNA in blood and lymphoid tissue: a randomized trial of double versus triple therapy. Swiss HIV Cohort Study.

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 <50 copies/ml was 16% and 74% at week 24 (p<.001) in those randomized to double and triple therapy, respectively, necessitating frequent treatment intensification in the double arm. After a rapid decline within 4 weeks in both arms, cell-associated HIV-1 RNA decreased further only in those patients with sustained suppression of plasma viral load, but remained almost always detectable at low levels, indicating persisting transcription of viral RNA. CD4 counts increased by 200 to 250 cells/microl at week 96 in both arms without significant differences (intent-to-treat analyses). Thus, even if treatment is initiated early in asymptomatic patients with preserved CD4 counts, three drugs are necessary to achieve sustained decreases of HIV load in blood and lymphoid tissue.

Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. The Swiss HIV Cohort Study.

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% CI, 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 HIV-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.

Prevalence of hepatitis C infection in Malawi and lack of association with sexually transmitted diseases.

To investigate the role of sexual transmission for Hepatitis C virus (HCV) we studied its prevalence in sub-Saharan Africa where sexually transmitted diseases (STDs) are prevalent. Overall, HCV prevalence was 3.9% and similar in 206 STD patients, 127 dermatology patients, and 100 blood donors. No association with HIV or syphilis was observed. Despite high prevalence of STDs, sexual transmission does not appear to significantly contribute to HCV transmission in Malawi.

HAART in HIV-infected patients: restoration of antigen-specific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia.

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.