Ruedi Lüthy

A controlled trial of zidovudine in primary human immunodeficiency virus infection.

BACKGROUND It is possible that antiretroviral treatment given early during primary infection with the human immunodeficiency virus (HIV) may reduce acute symptoms, help preserve immune function, and improve the long-term prognosis. METHODS To assess the effect of early antiviral treatment, we conducted a multicenter, double-blind, placebo-controlled trial in which 77 patients with primary HIV infection were randomly assigned to receive either zidovudine (250 mg twice daily; n = 39) or placebo (n = 38) for six months. RESULTS The mean time from the onset of symptoms until enrollment in the study was 25.1 days. Among the 43 patients who were still symptomatic at the time of enrollment, there was no appreciable difference in the mean (+/- SE) duration of the retroviral syndrome between the zidovudine group (15.0 +/- 4.1 days) and the placebo group (15.8 +/- 3.6 days). During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, and oral hairy leukoplakia in two. Disease progression was significantly less frequent in the zidovudine group (one opportunistic infection) than in the placebo group (seven opportunistic infections; P = 0.009 by the log-rank test). After adjustment for the base-line CD4 cell count, the patients treated with zidovudine had an average gain of 8.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, -1.4 to 19.1) during the first six months of the study, whereas those receiving placebo had an average loss of 12.0 CD4 cells per cubic millimeter per month (95 percent confidence interval, 5.2 to 18.7), for a between-group difference of 20.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, 8.5 to 33.2; P = 0.001). CONCLUSIONS Antiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only

Persons with immune deficiency may present with atypical results in serological tests for hepatitis B virus (HBV). Frozen serum specimens that were sequentially obtained over time from a cohort of 57 HIV-infected patients, all of whom tested positive only for antibody to hepatitis B core antigen (anti-HBcAg), were therefore restested for HBV markers, including HBV DNA. The results were assessed for their time course and correlated with clinical data and alanine aminotransferase (ALT) values. Forty-eight patients were male; intravenous drug users constituted the principal risk group (n=30), followed by homosexual men (n=22). Thirty-three persons tested positive for antibody to hepatitis C virus (anti-HCV). During a median of 31 months from the first to the last serum, anti-HBcAg remained the sole marker of HBV infection in 98.2% of the patients. Polymerase chain reaction (PCR) to detect DNA for HBV core and HBV surface gene was positive in 126 (62.4%) and 121 (59.9%) of all 202 serum samples, respectively. Over time, HBV DNA was detected at least once in 51 (89.5%) patients. In contrast, decomplexed hepatitis B surface antigen (HBsAg) was detected at least once in 14 (24.6%) patients. Among patients positive for HBV DNA and negative for anti-HCV, eight (36.4%) of 22 had chronic hepatitis (ALT elevation ≥6 months) that was attributable only to persisting HBV infection. Similarly, 12 (41.4%) of 29 patients positive for both HBV DNA andanti-HCV had chronic viral hepatitis, but their ALT values were significantly higher. In HIV-infected patients, anti-HBcAg as the sole serological HBV marker detected must be considered indicative of chronic HBV infection and is in part associated with chronic hepatitis and ALT elevation.

Gender and the use of antiretroviral treatment in resource-constrained settings: findings from a multicenter collaboration.

AIMS To compare the gender distribution of HIV-infected adults receiving highly active antiretroviral treatment (HAART) in resource-constrained settings with estimates of the gender distribution of HIV infection; to describe the clinical characteristics of women and men receiving HAART. METHODS The Antiretroviral Therapy in Lower-Income Countries, ART-LINC Collaboration is a network of clinics providing HAART in Africa, Latin America, and Asia. We compared UNAIDS data on the gender distribution of HIV infection with the proportions of women and men receiving HAART in the ART-LINC Collaboration. RESULTS Twenty-nine centers in 13 countries participated. Among 33,164 individuals, 19,989 (60.3%) were women. Proportions of women receiving HAART in ART-LINC centers were similar to, or higher than, UNAIDS estimates of the proportions of HIV-infected women in all but two centers. There were fewer women receiving HAART than expected from UNAIDS data in one center in Uganda and one center in India. Taking into account heterogeneity across cohorts, women were younger than men, less likely to have advanced HIV infection, and more likely to be anemic at HAART initiation. CONCLUSIONS Women in resource-constrained settings are not necessarily disadvantaged in their access to HAART. More attention needs to be paid to ensuring that HIV-infected men are seeking care and starting HAART.

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

Background:In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia. Design and methods:Multicohort study of 17 ART programmes. All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored viral load. We compared times to switching, CD4 cell counts at switching and obtained adjusted hazard ratios for switching (aHRs) with 95% confidence intervals (CIs) from random-effects Weibull models. Results:A total of 20 113 patients, including 6369 (31.7%) patients from 10 programmes with access to viral load monitoring, were analysed; 576 patients (2.9%) switched. Low CD4 cell counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months [interquartile range (IQR) 10.1–26.6] in programmes with viral load monitoring and 21.8 months (IQR 14.0–21.8) in programmes without viral load monitoring (P < 0.001). Median CD4 cell counts at switching were 161 cells/μl (IQR 77–265) in programmes with viral load monitoring and 102 cells/μl (44–181) in programmes without viral load monitoring (P < 0.001). Switching was more common in programmes with viral load monitoring during months 7–18 after starting ART (aHR 1.38; 95% CI 0.97–1.98), similar during months 19–30 (aHR 0.97; 95% CI 0.58–1.60) and less common during months 31–42 (aHR 0.29; 95% CI 0.11–0.79). Conclusion:In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with viral load monitoring compared with programmes without viral load monitoring.

Poor antibody response after tetanus and pneumococcal vaccination in immunocompromised, HIV-infected patients.

Ten patients with symptomatic HIV infection (six with ARC, four with AIDS) received tetanus and 23‐valent pneutnoeoccal vaccination. Anti‐tetanus IgG and IgM, and anti‐pneumococcal IgG against all 23 capsular types of the vaccine were measured on days 0, 11, 17, 30, and 90. Anti‐pneumococcal IgG were simultaneously determined in two plasma pools of 100 healthy unimmunized blood donors and of 112 healthy adults who had previously received a 14‐valent pneumococcal vaccination. Peak IgG responses to both vaccines were observed on day 17; thereafer, the antibody levels gradually fell again. Anti‐tetanus IgG rose from 0.6 U/ml (geometic mean) to 2.0 U/ml on day 17. Anti‐tetanus IgM remained unchanged, Anti‐paeumococcal IgG increased only by 1.14‐fold compared with pre‐vaccination levels (geometric mean of IgG rises against all 23 polysaccharides in 10 patients), and exceeded the upper 95% limit of unvaccinated blood donors in only 30 out of 230 specimens. Pre‐vaceination levels for pneumococcal type‐specific IgG were significantly higher in HIV‐infected patients compared with the pool of unimmunized healthy controls, possibly indicating a higher rate of previous pneumococcal infections in HIV‐seropositive subjects. However, post‐pneumococcai vaccination levels were significantly tower in HIV‐infected patients than in the pool of healthy controls. The increase in anti‐tetanus IgG significantly correlated with the level of CD4 lymphocytes and with in vitro lymphocyte proliferation by pokeweed mitogen (5 μg/ml) and phytohaemagglutinin (2.5 μg/ml), confirming a particularly low vaccination response in patients who were severely immunocompromied.

Comparison of high-pressure liquid chromatography and bioassay for determination of ciprofloxacin in serum and urine.

Ciprofloxacin was given orally to 10 healthy volunteers for seven consecutive doses of 250 mg every 12 h. Serum and urine samples were collected at distinct times between 0 and 96 h and analyzed both by high-pressure liquid chromatography and by a microbiological assay. The detection limits were 0.006 and 0.03 microgram/ml, respectively. For each method, imprecision coefficients of variation were less than 6.1% at various concentrations in serum and urine. The means +/- standard deviations of the absolute values of the relative differences between the two methods were 9.3 +/- 6.8% (n = 225) for serum samples and 58.5 +/- 50.4% (n = 70) for urine samples. Comparison of the concentrations in serum measured with high-pressure liquid chromatography and bioassay by regression analysis yielded a slope which was not significantly different from 1.0 (99.9% confidence limits: 0.984 less than slope less than 1.035). In urine, however, the bioassay results were markedly higher than the high-pressure liquid chromatography values (1.327 less than slope less than 1.698), which indicates the presence of antimicrobially active metabolites. The cumulative 12-h urinary recovery after the first and seventh doses averaged 30.2 +/- 8.5 and 26.4 +/- 4.6%, respectively, by high-pressure liquid chromatography, whereas with bioassay 38.2 +/- 5.9 and 45.5 +/- 5.9% activity was recovered. Protein binding appeared to be neither concentration nor pH dependent and averaged 21.9 +/- 4.1%.

Effect of standard breakfast on drug absorption and multiple-dose pharmacokinetics of ciprofloxacin

Ciprofloxacin was administered to 10 volunteers, who received seven oral doses of 250 mg each at 12-h intervals. Volunteers alternately fasted (F) or received a standard breakfast (B) before the morning dose. Pharmacokinetic parameters were derived from high-pressure liquid chromatography data from samples taken after the first and seventh doses and were analyzed in addition for differences caused by food intake. A significant (P less than 0.05) influence of the standard breakfast on the time to the peak was observed. Peak levels (+/- standard deviation) after the first and seventh doses averaged F (fasting): 1.35 +/- 0.17, B (breakfast): 1.02 +/- 0.28 micrograms/ml, and F: 1.41 +/- 0.32, B: 1.17 +/- 0.5 micrograms/ml, respectively. Mean trough concentrations after the first and seventh doses were F: 0.10 +/- 0.03, B: 0.14 +/- 0.03 micrograms/ml, and F: 0.16 +/- 0.05, B: 0.14 +/- 0.04 microgram/ml, respectively. As with the peak, trough concentrations were not affected significantly by food intake or by accumulation over the study period. Breakfast equally did not affect the terminal half-lives, which averaged F: 3.97 +/- 0.67, B: 4.35 +/- 0.88 h after the first dose and F: 4.64 +/- 0.91, B: 3.72 +/- 0.84 h after the seventh dose. Twelve-hour urinary recovery measured by high-pressure liquid chromatography averaged F: 31, B: 30% for the first dose and, in spite of a possible carry-over from the sixth dose, decreased to F: 25, B: 28% after the seventh dosing interval. When measured by bioassay, an increase of urinary recovery between the first dose (F: 38, B: 38%) and the seventh dose (F: 45, B: 45%) was observed. These differences suggest induction of drug metabolism with repeated doses. Ciprofloxacin was well tolerated by the volunteers.

Human Immunodeficiency Virus Type 1 p24 Concentration Measured by Boosted ELISA of Heat-Denatured Plasma Correlates with Decline in CD4 Cells, Progression to AIDS, and Survival: Comparison with Viral RNA Measurement

Human immunodeficiency virus type 1 (HIV-1) RNA and p24 antigen concentrations were determined in plasma samples from 169 chronically infected patients (median CD4 cell count, 140 cells/microL; range, 0-1500 cells/microL). p24 quantification involved heat-mediated immune complex dissociation and tyramide signal amplification-boosted ELISA, which has a diagnostic sensitivity similar to that of RNA quantification by a commercial polymerase chain reaction kit. In Coxs proportional hazard models adjusted for CD4 cell count, both RNA (P<.005) and p24 (P=.043) levels were significant predictors of progression to AIDS. Measurement of p24 was superior to measurement of RNA in the model for survival (P=.032 vs. P=.19). p24 level was a significant predictor of CD4 cell decline in models adjusted for CD4 cell counts and was superior or equivalent to RNA level, depending on the group analyzed. Stratification by CD4 cell counts at baseline showed that the superiority of p24 measurement was more pronounced at lower levels of CD4 cells (<200/microL). p24 level may be of interest as a simple and inexpensive predictive marker of disease progression.

Simple monitoring of antiretroviral therapy with a signal-amplification-boosted HIV-1 p24 antigen assay with heat-denatured plasma.

Objective:Virus load determination has become indispensable for the management of HIV patients, but depends on expensive assays of a low throughput. We evaluated whether a highly improved HIV-1 p24 antigen detection procedure which involves heat-mediated immune complex dissociation and signal-amplification-boosted enzyme-linked immunosorbent assay (ELISA) was suitable for antiretroviral treatment monitoring. Design and methods:Virus load in plasma was determined for 127 plasma samples taken at 0, 2, 6, 12, 18, 24, 30 and 36 weeks from 23 patients with CD4+ T cells <50 × 106/l who received indinavir 800 mg three times daily in addition to prior antiretroviral treatment. Tests included polymerase chain reaction (PCR) for viral RNA, measured prospectively with the Roche Amplicor kit, and retrospective batch testing of heat-denatured samples for p24 antigen by the DuPont HIV-1 p24 Core Profile ELISA linked with a tyramide signal amplification step. Particle-associated reverse transcriptase (RT) by the product-enhanced RT (PERT) assay was determined as an independent third-opinion viral load marker. Results:p24 antigen was detected as sensitively as viral RNA. Overall detection during a median observation time of 25 weeks (range, 0–39) amounted to 75.6% for antigen and 73.6% for RNA. The antigen detection limit was 0.2 pg/ml. Antigen was detectable in all 23 baseline samples, whereas RNA was undetectable in one. Antigen and RNA levels in 79 samples positive for both markers correlated with r = 0.714 (P < 0.0001). Average changes in levels of p24 antigen and RNA at eight timepoints correlated with r = 0.982 (P < 0.0001). In individual patients, the two parameters behaved similarly, and in certain cases virtually identically. RT activity was measurable in all samples. Conclusions:The performance of this antigen detection procedure is comparable to RNA PCR, thus providing a simple, high throughput alternative in monitoring the efficacy of antiretroviral treatment.

Comparative Multiple-Dose Pharmacokinetics of Cefotaxime, Moxalactam, and Ceftazidime

The pharmacokinetics of cefotaxime, moxalactam, and ceftazidime were investigated in six human volunteers who received in a crossover fashion doses of 0.5, 1.0, and 2.0 g of each drug by a 5-min infusion. Doses of 1.0 g were repeated after the administration of probenecid. Serum and urine concentrations were assayed with an agar diffusion method. Serum concentrations of moxalactam exceeded those of ceftazidime at all times and were distinctly higher than those of cefotaxime. The normalized area under the concentration time curve (defined as the ratio of the area under the curve per dose) reflects this relationship: compared with cefotaxime the normalized area under the curve of moxalactam was 3 to 4 times higher, and that of ceftazidime was 2 to 3 times higher. By intra-individual comparisons, the area under the curve of moxalactam was 44% larger than that of ceftazidime. With increasing doses, cefotaxime exhibited a nonlinear increase of the area under the curve. The half-lives of moxalactam, ceftazidime, and cefotaxime were 2.34, 1.95, and 1.16 h, respectively. The volume of distribution averaged 0.20 ± 0.03, 0.23 ± 0.02, and 0.25 ± 0.04 liters per kg, and the mean total body clearance was 84, 131, and 328 ml/min for moxalactam, ceftazidime, and cefotaxime, respectively. The 24-h urinary recovery was highest for moxalactam (75 ± 4%) followed by ceftazidime (68 ± 11%) and cefotaxime (53 ± 6%). The influence of probenecid on serum concentrations, half-life, area under the curve, and clearance was most apparent with cefotaxime, whereas the pharmacokinetics of moxalactam and ceftazidime were only slightly affected. After the 0.5− and 2.0− g doses of cefotaxime, desacetyl-cefotaxime activity (determined by high-pressure liquid chromatography) reached a peak of 2.7 and 9.9 μg/ml and declined with a half-life of 1.9 and 1.4 h. The ratio of the R(−) and S(−) epimers of moxalactam, which could be differentiated by high-pressure liquid chromatography, fell rapidly from 0.81 at 0.17 h to 0.5 at 5 h, indicating the presence of twice as much of the microbiologically less active S(−) epimer. From a pharmacokinetic standpoint it appears reasonable to conclude that moxalactam and possibly ceftazidime could be administered twice daily and that cefotaxime could be administered three or even four times daily.