Alan E. Greenberg

Protease inhibitors and cardiovascular outcomes in patients with HIV-1

Protease inhibitors for treatment of HIV-1 have been linked with increased risk of hyperlipidaemia and hyperglycaemia. In a cohort of 5672 outpatients with HIV-1 seen at nine US HIV clinics between January, 1993, and January, 2002, the frequency of myocardial infarctions increased after the introduction of protease inhibitors in 1996 (test for trend, p=0.0125). We noted that 19 of 3247 patients taking, but only two of 2425 who did not take, protease inhibitors had a myocardial infarction (odds ratio 7.1, 95% CI 1.6-44.3; Cox proportional hazards model-adjusted for smoking, sex, age, diabetes, hyperlipidaemia, and hypertension-hazard ratio 6.5, 0.9-47.8). Our findings suggest that, although infrequent, use of protease inhibitors is associated with increased risk of myocardial infarction in patients with HIV-1.

Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Côte d'Ivoire: a randomised controlled trial

BACKGROUND There is a high incidence of opportunistic infection among HIV-1-infected patients with tuberculosis in Africa and, consequently, high mortality. We assessed the safety and efficacy of trimethoprim-sulphamethoxazole 800 mg/160 mg (co-trimoxazole) prophylaxis in prevention of such infections and in decrease of morbidity and mortality. METHODS Between October, 1995, and April, 1998, we enrolled 771 HIV-1 seropositive and HIV-1 and HIV-2 dually seroreactive patients who had sputum-smear-positive pulmonary tuberculosis (median age 32 years [range 18-64], median CD4-cell count 317 cells/microL) attending Abidjans four largest outpatient tuberculosis treatment centres. Patients were randomly assigned one daily tablet of co-trimoxazole (n=386) or placebo (n=385) 1 month after the start of a standard 6-month tuberculosis regimen. We assessed adherence to study drug and tolerance monthly for 5 months and every 3 months thereafter, as well as rates of admission to hospital. FINDINGS Rates of laboratory and clinical adverse events were similar in the two groups. 51 patients in the co-trimoxazole group (13.8/100 person-years) and 86 in the placebo group (25.4/100 person-years) died (decrease In risk 46% [95% CI 23-62], p<0.001). 29 patients on co-trimoxazole (8.2/100 person-years) and 47 on placebo (15.0/100 person-years) were admitted to hospital at least once after randomisation (decrease 43% [10-64]), p=0.02). There were significantly fewer admissions for septicaemia and enteritis in the co-trimoxazole group than in the placebo group. INTERPRETATION In HIV-1-infected patients with tuberculosis, daily co-trimoxazole prophylaxis was well tolerated and significantly decreased mortality and hospital admission rates. Our findings may have important implications for improvement of clinical care for such patients in Africa.

Survival Benefit of Initiating Antiretroviral Therapy in HIV-Infected Persons in Different CD4+ Cell Strata

Context When to start antiretroviral therapy (ART) for HIV infection is controversial. Starting too early exposes patients to side effects and uncertain benefits. Starting too late deprives patients of benefits. Contribution In this cohort study, HIV-infected patients with baseline CD4+ cell counts between 0.201 and 0.350 109 cells/L who began ART immediately had lower mortality rates than those who started therapy after their CD4+ cell count decreased to less than 0.201 109 cells/L. Optimal timing of therapy is unclear when the CD4+ cell count is greater than 0.350 109 cells/L. Cautions A randomized, controlled trial is the best way to identify the optimal timing of ART. The Editors Optimal timing of antiretroviral therapy (ART) initiation for persons with HIV infection is of great clinical and public health importance. Therapy reduces HIV-related mortality and morbidity for patients with substantial CD4+ cell depletion (<0.100 109 cells/L) who initiate treatment (1). Although data demonstrate the viral suppressive and immunologic (CD4+ cell count) benefits of therapy in persons with higher CD4+ cell counts (2-8), long-term improvements in disease-associated morbidity and mortality with earlier therapy are less clear (9, 10). In such patients, the potential benefits of ART and highly active ART (HAART) will probably be weighed against possible untoward sequelae of earlier treatment, including the development of metabolic abnormalities; emergence of drug-resistant virus, with resultant exhaustion of effective remaining therapies; cost; and access (9, 11-13). Current treatment guidelines allowing for the delay of ART until a lower CD4+ thresholdusually 0.350 109 cells/L or, for some patients, 0.200 109 cells/Lreflect a lack of consensus on the benefits of earlier initiation of therapy (13, 14). Sparse data exist on which to base specific recommendations for the initiation of ART relative to CD4+ cell count. Longitudinal data comparing ART recipients to appropriate comparison groups not receiving ART (especially patients with CD4+ cell counts > 0.200 109 cells/L) are limited (10, 15). Analyses that include extended follow-up data on such patients are critical because these patients are unlikely to develop or die of an HIV-related condition over the short term, in contrast to those who start therapy with lower CD4+ cell counts. Another challenge is related to the relatively brief time that HAART has been available (since early 1996), making comparative longitudinal studies of sufficient duration difficult. We compare mortality rates among ambulatory HIV-infected patients who initiated ART and those who delayed ART in various CD4+ strata. Patients were enrolled in the HIV Outpatient Study (HOPS), a dynamic cohort of ambulatory HIV-infected patients demographically representative of treated HIV-infected patients in the United States. Methods HOPS HOPS is an ongoing prospective observational cohort study into which patients have been continuously recruited and followed since 1993 (1, 16). Study sites are 10 clinics (8 private, 2 public) in 8 U.S. cities that provide care for more than 2400 HIV-infected patients per year. Participating physicians have extensive experience treating HIV-infected patients. Information is abstracted from outpatient charts at each visit and entered electronically by trained staff; it is then compiled centrally and reviewed and edited before being analyzed. Information abstracted includes demographic characteristics and risk factors for HIV infection; symptoms; diagnosed diseases (both definitive and presumptive); medications prescribed, including dose and duration; and laboratory values, including CD4+ cell counts and measurements of plasma HIV-1 RNA (viral load). Selection of Patients for Analysis We identified HOPS participants who had at least two CD4+ measurements and reliable data on ART initiation and use for at least 30 consecutive days from January 1994 through March 2001. We defined HAART as the use of at least three drugs simultaneously, including one protease inhibitor or non-nucleoside reverse-transcriptase inhibitor, or any regimen with at least two full-dose protease inhibitors. Three patient subgroups were analyzed: those observed to have a pre-ART CD4+ cell count of 0.501 to 0.750 109 cells/L, those with a pre-ART CD4+ cell count of 0.351 to 0.500 109 cells/L, and those with a pre-ART CD4+ cell count of 0.201 to 0.350 109 cells/L. Patients could be in more than one subgroup if they had a pre-ART CD4+ cell count in more than one of the defined ranges. Thus, analyses within a subgroup are distinct from analyses in other subgroups. We then stratified patients in each subgroup into one of three treatment groups: those who began ART while still in the same CD4+ subgroup range (subsequently called patients who initiated ART), those who began ART after their CD4+ cell count decreased to less than the CD4+ subgroup range (subsequently called patients who delayed ART), and those who never received ART (untreated patients). The closest (in time) CD4+ cell count available within 6 months before or 2 weeks after ART initiation was used to define the CD4+ cell count at the start of therapy. By definition, because patients who delayed ART had to have at least 1 additional CD4+ measurement during follow-up, patients who initiated ART and those who were untreated were also required to have at least 1 additional CD4+ measurement during follow-up to reduce potential bias in the analysis as a result of differential time under observation. For all treatment groups, time under observation began with the date of the earliest CD4+ cell count within the CD4+ stratum in which the patient was analyzed. Patients included in the analyses of the CD4+ subgroups of 0.201 to 0.350 109 cells/L and 0.351 to 0.500 109 cells/L were those whose earliest CD4+ cell count within the subgroup-defined range was observed after 1 January 1994. The analysis of the CD4+ subgroup of 0.501 to 0.750 109 cells/L was limited to those whose earliest CD4+ cell count within this range was observed between January 1994 and December 1995. This allowed longer elapsed time to observe clinical events. For analysis, the observation period for each patient ended at 6 months after the last contact with a HOPS clinic or at death. We analyzed all deaths, including those not directly due to AIDS or indirectly from conditions exacerbated by HIV infection (such as hepatic, renal, or cardiac disease). Causes of death were ascertained through review of clinic and hospital charts, death certificates, and national AIDS surveillance data. Deaths from suicide (one patient in the CD4+ subgroup of 0.201 to 0.350 109 cells/L who delayed ART and one patient in the CD4+ subgroup of 0.501 to 0.750 109 cells/L who initiated treatment) were treated as censored. Statistical Analysis We used SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina), for all analyses. Patient characteristics were compared by chi-square test or the Fisher exact test for categorical variables and the Wilcoxon rank-sum test or t-test for continuous variables. We analyzed mortality rates per 1000 person-years and calculated the relative risk for death, 95% CIs, and approximate two-sided P values for each subgroup (17). Cox proportional-hazards regression was used to estimate hazard ratios, adjusted for age, sex, race, insurance status, viral load (log scale) at time of first ART (a dummy variable was used to include patients missing viral load data), receipt of HAART, and CD4+ cell count at the time of first observation within each stratum. Role of the Funding Source The funding source participated in the design, conduct, analysis, and reporting of the study and in the decision to submit the manuscript for publication. Results We evaluated data from 1464 HIV-infected HOPS participants. Of these patients, 596 who initiated ART had at least one additional CD4+ measurement after ART initiation, and 175 who delayed ART had at least one additional recorded CD4+ cell count in a higher stratum before ART initiation. We compared the demographic and baseline characteristics of patients described in this report to those of the larger overall group of HOPS participants and found no meaningful differences (data not shown). We analyzed data from 399 patients (340 who initiated and 59 who delayed ART) with pre-ART CD4+ cell counts between 0.201 and 0.350 109 cells/L, 327 patients (240 who initiated and 87 who delayed ART) with pre-ART CD4+ cell counts between 0.351 and 0.500 109 cells/L, and 122 patients (55 who initiated and 67 who delayed ART) with pre-ART CD4+ cell counts between 0.501 and 0.750 109 cells/L. Median years of follow-up for patients who initiated and those who delayed ART, by CD4+ subgroup, were as follows: 3.8 and 3.9 years for the subgroup of 0.201 to 0.350 109 cells/L, 4.1 and 4.2 years for the subgroup of 0.351 to 0.500 109 cells/L, and 5.4 and 5.3 years for the subgroup of 0.501 to 0.750 109 cells/L, respectively. Table 1 shows the demographic, immunologic, virologic, and care characteristics of patients who initiated ART and those who delayed ART, by CD4+ subgroup. Across subgroups, at least 69% of patients were men, 64% were younger than 40 years of age, 62% were white, and 35% had private health care insurance. Patients who initiated ART and those who delayed ART did not differ significantly except for the following: Patients in the CD4+ subgroup of 0.351 to 0.500 109 cells/L with private insurance tended to initiate rather than delay ART, and men in the CD4+ subgroup of 0.501 to 0.750 109 cells/L tended to delay therapy. Table 1. Characteristics of the HIV Outpatient Study Patients Who Initiated or Delayed Antiretroviral Therapy, by Preantiretroviral CD4+ Cell Count Stratum In general, most patients in a CD4+ subgroup who delayed ART initiated therapy in the next lowest CD4+ subgroup, that is, those who did not start in one subgroup started approximat

Perinatal Transmission of the Human Immunodeficiency Virus Type 1 to Infants of Seropositive Women in Zaire

To examine perinatal transmission of the human immunodeficiency virus type 1 (HIV-1) in Zaire, we screened 8108 women who gave birth at one of two Kinshasa hospitals that serve populations of markedly different socioeconomic status. For up to one year, we followed the 475 infants of the 466 seropositive women (5.8 percent of those screened) and the 616 infants of 606 seronegative women matched for age, parity, and hospital. On the basis of clinical criteria, 85 of the seropositive women (18 percent) had the acquired immunodeficiency syndrome (AIDS). The infants of seropositive mothers, as compared with those of seronegative mothers, were more frequently premature, had lower birth weights, and had a higher death rate in the first 28 days (6.2 vs. 1.2 percent; P less than 0.0001). The patterns were similar at the two hospitals. Twenty-one percent of the cultures for HIV-1 of 92 randomly selected cord-blood samples from infants of seropositive women were positive. T4-cell counts were performed in 37 seropositive women, and cord blood from their infants was cultured. The cultures were positive in the infants of 6 of the 18 women with antepartum T4 counts of 400 or fewer cells per cubic millimeter, as compared with none of the infants of the 19 women with more than 400 T4 cells per cubic millimeter (P = 0.02). One year later, 21 percent of the infants of the seropositive mothers had died as compared with 3.8 percent of the control infants (P less than 0.001), and 7.9 percent of their surviving infants had AIDS. We conclude that the mortality rates among children of seropositive mothers are high regardless of socioeconomic status, and that perinatal transmission of HIV-1 has a major adverse effect on infant survival in Kinshasa.

Efficacy of a brief case management intervention to link recently diagnosed HIV-infected persons to care.

Objective:The Antiretroviral Treatment Access Study (ARTAS) assessed a case management intervention to improve linkage to care for persons recently receiving an HIV diagnosis. Methods:Participants were recently diagnosed HIV-infected persons in Atlanta, Baltimore, Los Angeles and Miami. They were randomized to either standard of care (SOC) passive referral or case management (CM) for linkage to nearby HIV clinics. The SOC arm received information about HIV and local care resources; the CM intervention arm included up to five contacts with a case manager over a 90-day period. The outcome measure was self-reported attendance at an HIV care clinic at least twice over a 12-month period. Results:A higher proportion of the 136 case-managed participants than the 137 SOC participants visited an HIV clinician at least once within 6 months [78 versus 60%; adjusted relative risk (RRadj), 1.36; P = 0.0005) and at least twice within 12 months (64 versus 49%; RRadj, 1.41; P = 0.006). Individuals older than 40 years, Hispanic participants, individuals enrolled within 6 months of an HIV-seropositive test result and participants without recent crack cocaine use were all significantly more likely to have made two visits to an HIV care provider. We estimate the cost of such case management to be US

Chemoprophylaxis with Tenofovir Disoproxil Fumarate Provided Partial Protection against Infection with Simian Human Immunodeficiency Virus in Macaques Given Multiple Virus Challenges

600–1200 per client. Conclusion:A brief intervention by a case manager was associated with a significantly higher rate of successful linkage to HIV care. Brief case management is an affordable and effective resource that can be offered to HIV-infected clients soon after their HIV diagnosis.

Triple-Antiretroviral Prophylaxis to Prevent Mother-To- Child HIV Transmission through Breastfeeding—The Kisumu Breastfeeding Study, Kenya: A Clinical Trial

We examined the efficacy of tenofovir disoproxil fumarate (TDF) in blocking simian human immunodeficiency virus (SHIV) infection in Chinese rhesus macaques. Once weekly for 14 weeks or until a macaque became infected, 12 male macaques were inoculated intrarectally with amounts of SHIV(SF162P3) (10 median tissue culture infective doses; 3.8 x 10(5) virus particles) that were approximately 5-fold higher than the human immunodeficiency virus type 1 RNA levels noted in human semen during an acute infection. Of the 12 macaques, 4 received oral TDF daily, 4 received oral TDF once weekly, and 4 (control animals) received no TDF. The control animals became infected after receiving a median of 1.5 virus inoculations; macaques receiving TDF daily (1 macaque remained uninfected after 14 inoculations) and those receiving TDF weekly became infected after a median duration of 6.0 and 7.0 weeks, respectively. Although infection was delayed in treated macaques, compared with control macaques, the differences were not statistically significant (P=.315); however, the study was limited by the small numbers of animals evaluated and the variability in blood levels of TDF that resulted from oral dosing. These data demonstrate that treatment with oral TDF provided partial protection against SHIV infection but ultimately did not protect all TDF treated animals against multiple virus challenges.

Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusion

Timothy Thomas and colleagues report the results of the Kisumu breastfeeding study (Kenya), a single-arm trial that assessed the feasibility and safety of a triple-antiretroviral regimen to suppress maternal HIV load in late pregnancy.

A peer-education intervention to reduce injection risk behaviors for Hiv and hepatitis C virus infection in young injection drug users

During the past decade the incidence of Plasmodium falciparum malaria in the United States has increased 10-fold. Treatment may be delayed because the therapy recommended for severe or complicated disease, intravenous quinine dihydrochloride, is available only from the Centers for Disease Control. We studied 17 patients who were treated for severe or complicated P. falciparum malaria in the United States between 1985 and 1987. Five patients were treated with a continuous infusion of quinidine gluconate, 10 with an exchange transfusion in addition to the continuous infusion of quinidine gluconate, and 2 with intermittently administered intravenous quinine dihydrochloride and an exchange transfusion. All 16 patients with P. falciparum malaria (1 patient had P. vivax malaria) had hyperparasitemia at the time of diagnosis (6 to 54 percent of the erythrocytes infected; median, 13 percent). Three patients with marked hyperparasitemia (54, 38, and 30 percent) and multiple other indicators of a poor prognosis, including advanced age, died. The 13 patients who completed their courses of quinidine with or without exchange transfusion had a parasitemia level of 1.1 percent or less 28 to 72 hours (mean, 44.4 hours) after the start of therapy. Side effects of quinidine treatment were observed in only two patients, one of whom had a serum quinidine concentration above the toxic level. We conclude that the continuous infusion of quinidine gluconate is well tolerated alone and with exchange transfusion and is effective in the treatment of severe and complicated malaria.

Plasmodium Falciparum malaria and perinatally acquired human immunodeficiency virus type 1 infection in Kinshasa, Zaire. A prospective, longitudinal cohort study of 587 children.

Objectives:To evaluate whether a behavioral intervention, which taught peer education skills, could reduce injection and sexual risk behaviors associated with primary HIV and hepatitis C virus infection (HCV) among young injection drug users (IDU). Design:We conducted a randomized controlled trial involving HIV and HCV antibody-negative IDU, aged 15–30 years, recruited in five United States cities. A six-session, small-group, cognitive behavioral, skills-building intervention in which participants were taught peer education skills (n = 431) was compared with a time-equivalent attention control (n = 423). Baseline visits included interviews for sociodemographic, psychosocial, and behavioral factors during the previous 3 months; HIV and HCV antibody testing; and pre/posttest counselling. Procedures were repeated 3 and 6 months postintervention. Results:The intervention produced a 29% greater decline in overall injection risk 6 months postintervention relative to the control [proportional odds ratio 0.71; 95% confidence limit (CL) 0.52, 0.97], and a 76% decrease compared with baseline. Decreases were also observed for sexual risk behaviors, but they did not differ by trial arm. Overall HCV infection incidence (18.4/100 person-years) did not differ significantly across trial arms (relative risk 1.15; 95% CL 0.72, 1.82). No HIV seroconversions were observed. Conclusion:Interventions providing information, enhancing risk-reduction skills, and motivating behavior change through peer education training can reduce injection risk behaviors, although risk elimination might be necessary to prevent HCV transmission.