Martin Rickenbach

Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Swiss HIV Cohort Study.

Abstract Objectives: To examine trends in disease progression and survival among patients enrolled in the Swiss HIV cohort study during 1988–96 and to assess the influence of new antiretroviral combination therapies. Design: Prospective multicentre study, with follow up visits planned at six monthly intervals. Setting: Seven HIV units at university centres and cantonal hospitals in Switzerland. Patients: 3785 men (mean age 35.0 years) and 1391 women (30.3 years) infected with HIV. 2023 participants had a history of intravenous drug misuse; 1764 were men who had sex with men; 1261 were infected heterosexually; and 164 had other or unknown modes of transmission. 601 participants had had an AIDS defining illness. Results: During more than 15 000 years of follow up, there were 1456 first AIDS defining diagnoses and 1903 deaths. Compared with those enrolled during 1988-90, the risk of progression to a first AIDS diagnosis was reduced by 18% (relative risk 0.82 (95% confidence interval 0.73 to 0.93)) among participants enrolled in 1991-2, by 23% (0.77 (0.65 to 0.91)) among those enrolled in 1993-4, and by 73% (0.27 (0.18 to 0.39)) among those enrolled in 1995-6. Mortality was reduced by 19% (0.81 (0.73 to 0.90)), 26% (0.74 (0.63 to 0.87)), and 62% (0.38 (0.25 to 0.97)) respectively. Compared with no antiretroviral treatment, the risk of an initial AIDS diagnosis after CD4 lymphocyte counts fell to <200 cellsx106/l was reduced by 16% (0.84 (0.73 to 0.97)) with monotherapy, 24% (0.76 (0.63 to 0.91)) with dual therapy, and 42% (0.58 (0.37 to 0.92)) with triple therapy. Mortality was reduced by 23% (0.77 (0.68 to 0.88)), 31% (0.69 (0.60 to 0.80)), and 65% (0.35 (0.20 to 0.60)) respectively. Conclusions: The introduction of antiretroviral combination therapies outside the selected patient groups included in clinical trials has led to comparable reductions in disease progression and mortality. Key messages The Swiss HIV cohort study is an ongoing prospective study that includes a large proportion of the patients infected with HIV in Switzerland Antiretroviral combination therapy with two nucleoside analogues was introduced in 1995, and triple therapy with protease inhibitors was introduced in 1996 The risk of AIDS and death was substantially lower among patients enrolling in 1995 and 1996 than among those enrolled in earlier years Reductions in disease progression were similar among men and women and among patients from different transmission groups In Switzerland the introduction of antiretroviral combination therapies outside selected patient groups included in clinical trials has led to similar reductions in disease progression

Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study

BACKGROUND Evidence on the effectiveness of highly active antiretroviral therapy (HAART) for HIV-infected individuals is limited. Most clinical trials examined surrogate endpoints over short periods of follow-up and there has been no placebo-controlled randomised trial of HAART. Estimation of treatment effects in observational studies is problematic, because of confounding by indication. We aimed to use novel methodology to overcome this problem in the Swiss HIV Cohort Study. METHODS Patients were included if they had been examined after January 1996, when HAART became available in Switzerland, were not on HAART, and were free of AIDS at baseline. Cox regression models were weighted to create a statistical population in which the probability of being treated at each time point was unrelated to prognostic factors. RESULTS Low CD4 counts and increasing HIV-1 viral load were associated with increased probability of starting HAART. Overall hazard ratios were 0.14 (95% CI 0.07-0.29) for HAART compared with no treatment, and 0.49 (0.31-0.79) compared with dual therapy. Compared with no treatment, HAART became more beneficial with increasing time since initiation but was less beneficial for patients whose presumed mode of transmission was via intravenous drug use (hazard ratio 0.27, 0.12-0.61) than for other patients (0.08, 0.03-0.19). INTERPRETATION Our results, which are appropriately controlled for confounding by indication, are consistent with reported declines in rates of AIDS and death in developed countries, and provide a context in which to consider adverse effects of HAART.

Lipid Profiles in HIV-Infected Patients Receiving Combination Antiretroviral Therapy: Are Different Antiretroviral Drugs Associated with Different Lipid Profiles?

Levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c), as well as the TC:HDL-c ratio, were compared in patients receiving different antiretroviral therapy regimens. Patients receiving first-line regimens including protease inhibitors (PIs) had higher TC and TG levels and TC : HDL-c ratios than did antiretroviral-naive patients; patients receiving 2 PIs had higher levels of each lipid. Ritonavir-containing regimens were associated with higher TC and TG levels and TC : HDL-c ratios than were indinavir-containing regimens; however, receipt of nelfinavir was associated with reduced risk of lower HDL-c levels, and receipt of saquinavir was associated with lower TC : HDL-c ratios. Patients receiving nonnucleoside reverse-transcriptase inhibitors had higher levels of TC and LDL-c than did antiretroviral-naive patients, although the risk of having lower HDL-c levels was lower than that in patients receiving a single PI. Efavirenz was associated with higher levels of TC and TG than was nevirapine.

Discontinuation of Primary Prophylaxis against Pneumocystis carinii Pneumonia in HIV-1–Infected Adults Treated with Combination Antiretroviral Therapy

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 count at study entry was 325 per cubic millimeter (range, 210 to 806); the median nadir CD4 count was 110 per cubic millimeter (range, 0 to 240). During a median follow-up of 11.3 months (range, 3.0 to 18.8), prophylaxis was resumed in nine patients, and two patients died. There were no cases of P. carinii pneumonia or toxoplasmic encephalitis. The one-sided upper 99 percent confidence limit for the incidence of P. carinii pneumonia was 1.9 cases per 100 patient-years (based on 238 patient-years of follow-up). The corresponding figure for toxoplasmic encephalitis was 4.2 per 100 patient-years (based on 110 patient-years of follow-up). CONCLUSIONS Stopping primary prophylaxis against P. carinii pneumonia appears to be safe in HIV-infected patients who are receiving combination antiretroviral treatment and who have had a sustained increase in their CD4 counts to at least 200 cells per cubic millimeter and to at least 14 percent of total lymphocytes.

Characteristics, Determinants, and Clinical Relevance of CD4 T Cell Recovery to <500 Cells/µL in HIV Type 1—Infected Individuals Receiving Potent Antiretroviral Therapy

BACKGROUND The CD4 T cell count recovery in human immunodeficiency virus type 1 (HIV-1)-infected individuals receiving potent antiretroviral therapy (ART) shows high variability. We studied the determinants and the clinical relevance of incomplete CD4 T cell restoration. METHODS Longitudinal CD4 T cell count was analyzed in 293 participants of the Swiss HIV Cohort Study who had had a plasma HIV-1 RNA load <1000 copies/mL for > or =5 years. CD4 T cell recovery was stratified by CD4 T cell count 5 years after initiation of ART (> or =500 cells/microL was defined as a complete response, and <500 cells/microL was defined as an incomplete response). Determinants of incomplete responses and clinical events were evaluated using logistic regression and survival analyses. RESULTS The median CD4 T cell count increased from 180 cells/microL at baseline to 576 cells/microL 5 years after ART initiation. A total of 35.8% of patients were incomplete responders, of whom 47.6% reached a CD4 T cell plateau <500 cells/microL. Centers for Disease Control and Prevention HIV-1 disease category B and/or C events occurred in 21% of incomplete responders and in 14.4% of complete responders (P>.05). Older age (adjusted odds ratio [aOR], 1.71 per 10-year increase; 95% confidence interval [CI], 1.21-2.43), lower baseline CD4 T cell count (aOR, 0.37 per 100-cell increase; 95% CI, 0.28-0.49), and longer duration of HIV infection (aOR, 2.39 per 10-year increase; 95% CI, 1.19-4.81) were significantly associated with a CD4 T cell count <500 cells/microL at 5 years. The median increases in CD4 T cell count after 3-6 months of ART were smaller in incomplete responders (P<.001) and predicted, in conjunction with baseline CD4 T cell count and age, incomplete response with 80% sensitivity and 72% specificity. CONCLUSION Individuals with incomplete CD4 T cell recovery to <500 cells/microL had more advanced HIV-1 infection at baseline. CD4 T cell changes during the first 3-6 months of ART already reflect the capacity of the immune system to replenish depleted CD4 T lymphocytes.

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

ObjectiveTo 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. MethodsSequencing of the genes for reverse transcriptase (RT) and protease was performed for 197 individuals with documented PHI. Phylogenetic analyses were confronted with epidemiological data. ResultsSignificant 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). ConclusionsPhylogenetic 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.

Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study

Mortality among HIV‐infected persons is decreasing, and causes of death are changing. Classification of deaths is hampered because of low autopsy rates, frequent deaths outside of hospitals, and shortcomings of International Statistical Classification of Diseases and Related Health Problems (ICD‐10) coding.

Hyperlactatemia and Antiretroviral Therapy: The Swiss HIV Cohort Study

The prevalence, clinical presentation, and risk factors for hyperlactatemia among patients receiving antiretroviral therapy was determined during a 1-month period for patients in the Swiss HIV Cohort Study. Overall, 73 (8.3%) of 880 patients presented an increase in serum lactate of >1.1 times the upper normal limit (UNL). For 9 patients (1%), lactate elevation was moderate or severe (>2.2 times the UNL). Patients who presented with hyperlactatemia were more likely to be receiving stavudine with or without didanosine (odds ratio, 2.7; 95% confidence interval, 1.5-4.8), as compared with patients who received zidovudine-based regimens. The risk increased with increasing time receiving stavudine with or without didanosine. The association between hyperlactatemia and stavudine with or without didanosine was not biased by these medications being more recently available and, therefore, being given preferentially to patients who had prolonged use of nucleoside analog reverse-transcriptase inhibitors. Hyperlactatemia was associated with lipoatrophy, hyperlipidemia, and hyperglycemia. Age, sex, or stage of infection with human immunodeficiency virus were not predictive of hyperlactatemia. Determination of lactate levels may prove useful in the screening for mitochondrial toxicity.

Cardio- and cerebrovascular events in HIV-infected persons

Objective: Recent results from the D:A:D Study indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). The present study was performed to investigate whether this risk was similar when including other cardio- and cerebro-vascular disease events (CCVE). Design: D:A:D is an international collaboration of 11 cohorts, following 23 468 HIV-infected patients prospectively at 188 clinics in 21 countries situated in Europe, USA and Australia. Methods: The end-point was the occurrence of a first CCVE during prospective follow-up, defined as the first of: acute MI, invasive cardiovascular procedures, stroke, or death from other cardiovascular disease. Relative rates (RR) for CCVE from Poisson regression models and 95% confidence intervals (CI) are reported. All models are adjusted for other risk factors for CCVE, including age, gender, ethnicity, family history, body mass index, and smoking status as well as cohort and HIV transmission group. Results: Over 36 145 person-years of follow-up, 207 patients experienced at least one CCVE (23.7% fatal). The first event was MI in 126 patients, invasive cardiovascular procedure in 39 patients, stroke in 38 patients, and death from other cardiovascular disease in four patients. The incidence of first CCVE was 5.7 per 1000 person-years [95% confidence interval (CI) 5.0–6.5] and increased with longer exposure to CART (RR per year of exposure, 1.26; 95% CI, 1.14–1.38; P < 0.0001). Conclusion: CART increases the risk of CCVD, and this increase is comparable with how CART affects the risk of MI. This finding is consistent with the hypothesis that atherosclerosis is a side-effect of CART.

Unsafe Sex and Increased Incidence of Hepatitis C Virus Infection among HIV-Infected Men Who Have Sex with Men: The Swiss HIV Cohort Study

BACKGROUND Data on the incidence of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected persons are sparse. It is controversial whether and how frequently HCV is transmitted by unprotected sexual intercourse. METHODS We assessed the HCV seroprevalence and incidence of HCV infection in the Swiss HIV Cohort Study between 1988 and 2004. We investigated the association of HCV seroconversion with mode of HIV acquisition, sex, injection drug use (IDU), and constancy of condom use. Data on condom use or unsafe sexual behavior were prospectively collected between 2000 and 2004. RESULTS The overall seroprevalence of HCV infection was 33% among a total of 7899 eligible participants and 90% among persons reporting IDU. We observed 104 HCV seroconversions among 3327 participants during a total follow-up time of 16,305 person-years, corresponding to an incidence of 0.64 cases per 100 person-years. The incidence among participants with a history of IDU was 7.4 cases per 100 person-years, compared with 0.23 cases per 100 person-years in patients without such a history (P<.001). In men who had sex with men (MSM) without a history of IDU who reported unsafe sex, the incidence was 0.7 cases per 100 person-years, compared with 0.2 cases per 100 person-years in those not reporting unsafe sex (P=.02), corresponding to an incidence rate ratio of 3.5 (95% confidence interval, 1.2-10.0). The hazard of acquiring HCV infection was elevated among younger participants who were MSM. CONCLUSIONS HCV infection incidence in the Swiss HIV Cohort Study was mainly associated with IDU. In HIV-infected MSM, HCV infection was associated with unsafe sex.