Johan N. Bruun

Changing patterns of mortality across Europe in patients infected with HIV-1

BACKGROUND The introduction of combination antiretroviral therapy and protease inhibitors has led to reports of falling mortality rates among people infected with HIV-1. We examined the change in these mortality rates of HIV-1-infected patients across Europe during 1994-98, and assessed the extent to which changes can be explained by the use of new therapeutic regimens. METHODS We analysed data from EuroSIDA, which is a prospective, observational, European, multicentre cohort of 4270 HIV-1-infected patients. We compared death rates in each 6 month period from September, 1994, to March, 1998. FINDINGS By March, 1998, 1215 patients had died. The mortality rate from March to September, 1995, was 23.3 deaths per 100 person-years of follow-up (95% CI 20.6-26.0), and fell to 4.1 per 100 person-years of follow-up (2.3-5.9) between September, 1997, and March, 1998. From March to September, 1997, the death rate was 65.4 per 100 person-years of follow-up for those on no treatment, 7.5 per 100 person-years of follow-up for patients on dual therapy, and 3.4 per 100 person-years of follow-up for patients on triple-combination therapy. Compared with patients who were followed up from September, 1994, to March, 1995, patients seen between September, 1997, and March, 1998, had a relative hazard of death of 0.16 (0.08-0.32), which rose to 0.90 (0.50-1.64) after adjustment for treatment. INTERPRETATION Death rates across Europe among patients infected with HIV-1 have been falling since September, 1995, and at the beginning of 1998 were less than a fifth of their previous level. A large proportion of the reduction in mortality could be explained by new treatments or combinations of treatments.

Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter

BACKGROUND Zidovudine therapy is of benefit in the treatment of symptomatic and asymptomatic human immunodeficiency virus (HIV) infection in persons with CD4+ cell counts of less than 500 per cubic millimeter. The efficacy, safety, and duration of benefit of zidovudine in those with 500 or more CD4+ cells per cubic millimeter are uncertain. METHODS In a double-blind, placebo-controlled trial, 993 patients with asymptomatic HIV infection and CD4+ cell counts above 400 per cubic millimeter were randomly assigned to receive zidovudine (500 mg twice daily) or placebo for three years. The primary end point was progression of disease, as defined by the development of Centers for Disease Control and Prevention (CDC) group IV disease (including recurrent oral candidiasis, hairy leukoplakia, or progressive diarrhea) or two CD4+ cell counts below 350 per cubic millimeter. This outcome measure was changed from the original end point of the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex to reflect changes in recommendations for management. The study was terminated after the first interim analysis. RESULTS Disease progression was significantly less frequent in the zidovudine group (relative risk, 0.56; 95 percent confidence interval, 0.43 to 0.75; P < 0.001 by the log-rank test). The probability of disease progression at two years was 0.19 with zidovudine, as compared with 0.34 with placebo (95 percent confidence interval for the difference, -0.21 to -0.08). Progression to CDC group IV disease was reduced by half in the zidovudine recipients (relative risk, 0.49; P = 0.049) and decline in CD4+ cell counts to below 350 per cubic millimeter was reduced by 40 percent (relative risk, 0.60; P < 0.001). The inclusion of early HIV disease events (oral candidiasis, oral hairy leukoplakia, and herpes zoster) as end points confirmed the effects of zidovudine on the progression of clinical disease (relative risk, 0.55; 95 percent confidence interval, 0.37 to 0.84; P = 0.004). The median duration of treatment was 94 weeks. Severe hematologic or clinical side effects were rare. CONCLUSIONS Treatment with zidovudine benefits HIV-infected persons with CD4+ cell counts above 400 per cubic millimeter. Despite the use of doses larger than those now generally prescribed, zidovudine was well tolerated for up to three years by most of our patients.

Influence of Age on CD4 Cell Recovery in Human Immunodeficiency Virus–Infected Patients Receiving Highly Active Antiretroviral Therapy: Evidence from the EuroSIDA Study

Influence of age on the CD4 cell response to highly active antiretroviral therapy (HAART) was examined in 1956 patients (median age, 37.2 years) in the EuroSIDA study. Median initial CD4 cell count was 192x106 cells/L, follow-up was 31 months, and time to maximum CD4 cell response was 20 months. Age groups were not different for baseline CD4 cell count, baseline human immunodeficiency virus RNA load, or treatment history. CD4 cell increase, stratified by age quartiles, differed during months 3-36 of HAART (P=.023). Maximum CD4 cell increase from start of HAART differed by age group (P=.0003), as did maximum CD4 cell count (P<10-4). Multivariate analysis confirmed the inverse relationship between age and maximum CD4 cell response (P=.023). Time to a CD4 increase of >200x106 cells/L was shorter for patients in the younger age groups (P=.0026), as confirmed by multivariate analysis (P<10-4). Younger age may favor CD4 cell restoration because of preserved thymic function.

Predictors of mortality in HIV-infected patients starting antiretroviral therapy in a rural hospital in Tanzania

BackgroundStudies of antiretroviral therapy (ART) programs in Africa have shown high initial mortality. Factors contributing to this high mortality are poorly described. The aim of the present study was to assess mortality and to identify predictors of mortality in HIV-infected patients starting ART in a rural hospital in Tanzania.MethodsThis was a cohort study of 320 treatment-naïve adults who started ART between October 2003 and November 2006. Reliable CD4 cell counts were not available, thus ART initiation was based on clinical criteria in accordance with WHO and Tanzanian guidelines. Kaplan-Meier models were used to estimate mortality and Cox proportional hazards models to identify predictors of mortality.ResultsPatients were followed for a median of 10.9 months (IQR 2.9–19.5). Overall, 95 patients died, among whom 59 died within 3 months of starting ART. Estimated mortality was 19.2, 29.0 and 40.7% at 3, 12 and 36 months, respectively. Independent predictors of mortality were severe anemia (hemoglobin <8 g/dL; adjusted hazard ratio [AHR] 9.20; 95% CI 2.05–41.3), moderate anemia (hemoglobin 8–9.9 g/dL; AHR 7.50; 95% CI 1.77–31.9), thrombocytopenia (platelet count <150 × 109/L; AHR 2.30; 95% CI 1.33–3.99) and severe malnutrition (body mass index <16 kg/m2; AHR 2.12; 95% CI 1.06–4.24). Estimated one year mortality was 55.2% in patients with severe anemia, compared to 3.7% in patients without anemia (P < 0.001).ConclusionMortality was found to be high, with the majority of deaths occurring within 3 months of starting ART. Anemia, thrombocytopenia and severe malnutrition were strong independent predictors of mortality. A prognostic model based on hemoglobin level appears to be a useful tool for initial risk assessment in resource-limited settings.

Prevalence of Hypertension in HIV-Positive Patients on Highly Active Retroviral Therapy (HAART) Compared with HAART-Naïve and HIV-Negative Controls: Results from a Norwegian Study of 721 Patients

Abstract Highly active antiretroviral therapy (HAART) may induce dyslipidemia, insulin resistance and body fat distribution similar to that seen in the metabolic syndrome. Hypertension is often a part of the classic metabolic syndrome, but few studies are published about hypertension in HIV-positive patients on HAART. The aim of this study was to compare the prevalence of hypertension in HIV-positive patients on HAART with that in HIV-positive/HAART-naïve patients and HIV-negative controls. The cross-sectional study included 283 unselected HIV-positive ambulatory patients, 219 who were on HAART and 64 who were HAART-naïve. Age- and gender-matched controls (n=438) were randomly selected from a simultaneous health survey of the general population. The prevalence of hypertension was 21% in patients on HAART, 13% in HAART-naïve patients (P=0.20), and 24% in HIV-negative controls (P=0.28). Among several possible risk factors for hypertension, only body mass index (BMI) was found to be a confounder. BMI was similar in HAART-treated and HAART-naïve patients but elevated in controls compared to HAART-treated patients. After adjustment for BMI, the prevalence of hypertension in HIV-negative controls was slightly lower than that in patients on HAART (P=0.29). The results demonstrated a prevalence of hypertension in patients on HAART similar to that in HIV-negative controls. The prevalence of hypertension was somewhat higher in patients on HAART compared to HAART-naïve patients, but the difference was not statistically significant. Considering the marked drop in mortality following antiretroviral therapy, we conclude that the possible influence of HAART on the prevalence of hypertension appears to be a minor problem.

Randomized Trial to Evaluate Indinavir/Ritonavir versus Saquinavir/Ritonavir in Human Immunodeficiency Virus Type 1–Infected Patients: The MaxCmin1 Trial

This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1-infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively. The time to virological failure did not differ between study arms (P=.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/Rtv arm (P=.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P=.013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied.

Dried Blood Spots Perform Well in Viral Load Monitoring of Patients Who Receive Antiretroviral Treatment in Rural Tanzania

BACKGROUND Monitoring of antiretroviral treatment (ART) with human immunodeficiency virus (HIV) viral loads, as recommended in industrialized countries, is rarely available in resource-limited settings because of the high costs and stringent requirements for storage and transport of plasma. Dried blood spots (DBS) can be an alternative to plasma, but the use of DBS has not been assessed under field conditions in rural Africa. The present study investigates the performance of DBS in HIV viral load monitoring of patients who received ART in rural Tanzania. PATIENTS AND METHODS From November 2007 through June 2008, parallel plasma and DBS specimens were obtained from patients who received ART at Haydom Lutheran Hospital in rural Tanzania. DBS specimens were stored at tropical room temperature for 3 weeks before testing with the NucliSENS EasyQ HIV-1 v1.2 assay. Results obtained with DBS were compared with results obtained with use of a gold-standard plasma assay. RESULTS Ninety-eight plasma-DBS pairs were compared, and plasma viral loads ranged from <40 to >1,000,000 copies/mL. The correlation between plasma and DBS viral load was strong (R(2) = 0.75). The mean difference (+/- standard deviation) was 0.04 +/ 0.57 log(10) copies/mL, and only 8 samples showed >1 log(10) copies/mL difference. HIV type 1 RNA was detected in 7%, 60%, and 100% of DBS specimens with corresponding plasma viral loads of 40-999, 1000-2999, and 3000 copies/mL, respectively. CONCLUSIONS DBS, in combination with the NucliSENS EasyQ HIV-1 v1.2 asay, performed well in monitoring HIV viral loads in patients who received ART in rural Tanzania, although the sensitivity was reduced when viral burden was low. The use of DBS can simplify virological monitoring in resource-limited settings.

Virological efficacy and emergence of drug resistance in adults on antiretroviral treatment in rural Tanzania

BackgroundVirological response to antiretroviral treatment (ART) in rural Africa is poorly described. We examined virological efficacy and emergence of drug resistance in adults receiving first-line ART for up to 4 years in rural Tanzania.MethodsHaydom Lutheran Hospital has provided ART to HIV-infected patients since October 2003. A combination of stavudine or zidovudine with lamivudine and either nevirapine or efavirenz is the standard first-line regimen. Nested in a longitudinal cohort study of patients consecutively starting ART, we carried out a cross-sectional virological efficacy survey between November 2007 and June 2008. HIV viral load was measured in all adults who had completed at least 6 months first-line ART, and genotypic resistance was determined in patients with viral load >1000 copies/mL.ResultsVirological response was measured in 212 patients, of whom 158 (74.5%) were women, and median age was 35 years (interquartile range [IQR] 29–43). Median follow-up time was 22.3 months (IQR 14.0–29.9). Virological suppression, defined as <400 copies/mL, was observed in 187 patients (88.2%). Overall, prevalence of ≥1 clinically significant resistance mutation was 3.9, 8.4, 16.7 and 12.5% in patients receiving ART for 1, 2, 3 and 4 years, respectively. Among those successfully genotyped, the most frequent mutations were M184I/V (64%), conferring resistance to lamivudine, and K103N (27%), Y181C (27%) and G190A (27%), conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), whereas 23% had thymidine analogue mutations (TAMs), associated with cross-resistance to all nucleoside reverse transcriptase inhibitors (NRTIs). Dual-class resistance, i.e. resistance to both NRTIs and NNRTIs, was found in 64%.ConclusionVirological suppression rates were good up to 4 years after initiating ART in a rural Tanzanian hospital. However, drug resistance increased with time, and dual-class resistance was common, raising concerns about exhaustion of future antiretroviral drug options. This study might provide a useful forecast of drug resistance and demand for second-line antiretroviral drugs in rural Africa in the coming years.

HLA- and dose-dependent immunogenicity of a peptide-based HIV-1 immunotherapy candidate (Vacc-4x).

Objective: The Vacc-4x immunotherapy candidate is composed of four modified peptides corresponding to conserved domains of the HIV-1 protein p24 that preferentially include HLA-A2 restricted elements. Dose-dependent safety and immunogenicity of Vacc-4x and the significance of a HLA-A2 haplotype were examined. Design: Non-AIDS, HIV-1 infected healthy patients (n = 40) stable on HAART with CD4 counts > 300 × 106 cells/l were randomized to receive either low-dose or high-dose Vacc-4x over 26 weeks in an open, prospective phase II clinical trial. Methods: Patients received a total of 10 intradermal injections, using recombinant granulocyte-macrophage colony stimulating factor as a local adjuvant. Vacc-4x-specific cellular responses were monitored in vivo by delayed-type hypersensitivity (DTH) skin test infiltrates and in vitro by both T-cell proliferation, and induction /secretion of cytokines. Results: Most patients developed Vacc-4x-specific DTHs (90%) and proliferative T-cell responses (80%) that were inter-related in magnitude. High-dose Vacc-4x generally induced stronger specific immune responses than low dose in terms of DTH areas and CD4 and CD8 T-cell proliferation. Only HLA-A2 negative patients had a definite dose advantage, and this subgroup had in fact the best overall DTH and proliferative responses. In contrast, no significant dose difference was observed for HLA-A2 positive patients. No serious adverse events were reported. Conclusions: HIV-associated specific responses were safely induced in most patients by Vacc-4x in a dose-dependent manner and were also influenced by the HLA haplotype.

Important differences in components of the metabolic syndrome between HIV-patients with and without highly active antiretroviral therapy and healthy controls

The aim of this study was to compare the prevalence of metabolic syndrome and insulin resistance in HIV-positive patients with and without HAART and healthy HIV-negative controls. In total 357 subjects were examined: 56 HIV-positive HAART-naïve, 207 HIV-positive on HAART treatment and 94 HIV-negative controls. We measured blood pressure, abdominal circumference, weight and height, and fasting serum levels of glucose, insulin and lipids in all the subjects. The presence of lipodystrophy was assessed in the HAART-treated patients. In non-overweight subjects the prevalence of the metabolic syndrome was 15% (25 of 162) in HAART-treated patients, 2% (1 of 44) in HAART-naïve (p=0.019) and 2% (1 of 45) in controls (p=0.020). The prevalence of insulin resistance in non-overweight subjects was also higher in HAART-treated than in controls, 39% vs 18% (p=0.012) but similar to HAART-naive, 32% (p = 0.48 vs HAART, p = 0.22 vs controls). In non-overweight patients with lipodystrophy the metabolic syndrome was diagnosed in 21% and insulin resistance in 49%. In the entire HAART group 25% had the metabolic syndrome and/or insulin resistance without having lipodystrophy. We conclude that fasting glucose, HDL-cholesterol, triglycerides and blood pressure should be closely monitored in all HAART-treated patients, not only in overweighed or lipodystrophic individuals.