Efficacy, tolerability and risk factors for virological failure of darunavir-based therapy for treatment-experienced HIV-infected patients: the Swiss HIV Cohort Study.

OBJECTIVES: Darunavir was designed for activity against HIV resistant to other protease inhibitors (PIs). We assessed the efficacy, tolerability and risk factors for virological failure of darunavir for treatment-experienced patients seen in clinical practice. METHODS: We included all patients in the Swiss HIV Cohort Study starting darunavir after recording a viral load above 1000 HIV-1 RNA copies/mL given prior exposure to both PIs and nonnucleoside reverse transcriptase inhibitors. We followed these patients for up to 72 weeks, assessed virological failure using different loss of virological response algorithms and evaluated risk factors for virological failure using a Bayesian method to fit discrete Cox proportional hazard models. RESULTS: Among 130 treatment-experienced patients starting darunavir, the median age was 47 years, the median duration of HIV infection was 16 years, and 82% received mono or dual antiretroviral therapy before starting highly active antiretroviral therapy. During a median patient follow-up period of 45 weeks, 17% of patients stopped taking darunavir after a median exposure of 20 weeks. In patients followed beyond 48 weeks, the rate of virological failure at 48 weeks was at most 20%. Virological failure was more likely where patients had previously failed on both amprenavir and saquinavir and as the number of previously failed PI regimens increased. CONCLUSIONS: As a component of therapy for treatment-experienced patients, darunavir can achieve a similar efficacy and tolerability in clinical practice to that seen in clinical trials. Clinicians should consider whether a patient has failed on both amprenavir and saquinavir and the number of failed PI regimens before prescribing darunavir.

Cost-effectiveness of raltegravir in antiretroviral treatment-experienced HIV-1-infected patients in Switzerland.

OBJECTIVES: Raltegravir, a novel integrase inhibitor, has shown great efficacy in reducing HIV viral load among treatment-experienced patients. A cohort state-transition model was used to assess the long-term effect of raltegravir treatment on costs and quality-adjusted life expectancy from a Swiss perspective. METHODS: Patients were stratified into health states according to opportunistic infection status, HIV RNA level, and CD4 count, with each group assigned a treatment cost and utility (quality of life) score. Model inputs came from published studies, clinical trials, and database analyses. Results were used to calculate incremental cost-effectiveness ratio (ICER) of raltegravir use, expressed in Swiss francs (CHF) as incremental cost/quality-adjusted life-year (QALY) gained. Future costs and QALYs were discounted at 3% per year. RESULTS: Five years of raltegravir treatment increased discounted quality-adjusted life expectancy by 3.73 years over placebo, with additional discounted cost of CHF 170,347, resulting in an ICER of CHF 45,687/QALY. ICERs ranged from CHF 42,751 to 53,478/QALY for treatment duration of 3 and 10 years, respectively. Results were most sensitive to changes in raltegravir treatment duration, source of estimated quality of life weights, and raltegravir price. CONCLUSIONS: Adding raltegravir to optimized background therapy was a cost-effective strategy for treatment-experienced patients in Switzerland.

Discontinuation of maintenance therapy against toxoplasma encephalitis in AIDS patients with sustained response to anti-retroviral therapy.

Discontinuation of maintenance therapy against toxoplasma encephalitis (TE) for individuals infected with human immunodeficiency virus (HIV) who are receiving successful anti-retroviral therapy is considered safe. Nevertheless, there are few published studies concerning this issue. Within the setting of the Swiss HIV Cohort Study, this report describes a prospective study of discontinuation of maintenance therapy against TE in patients with a sustained increase of CD4 counts to > 200 cells/microL and 14% of total lymphocytes, and no active lesions on cerebral magnetic resonance imaging (MRI). In addition to clinical evaluation, cerebral MRI was performed at baseline, and 1 and 6 months following discontinuation. Twenty-six AIDS patients with a history of TE agreed to participate, but three patients (11%) could not be enrolled because they still showed enhancing cerebral lesions without a clinical correlate. One patient refused MRI after 6 months while clinically asymptomatic. Among the remaining 22 patients who discontinued maintenance therapy, one relapsed after 3 months. During a total follow-up of 58 patient-years, there was no TE relapse among the patients who had remained clinically and radiologically free of relapse during the study. Thus, discontinuation of maintenance therapy against TE was generally safe, but may fail in a minority of patients. Patients who remain clinically and radiologically free of relapse at 6 months after discontinuation are unlikely to experience a relapse of TE.

Enteric infections and diarrhea in human immunodeficiency virus-infected persons: prospective community-based cohort study. Swiss HIV Cohort Study.

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) are at increased risk for diarrhea and enteric infections. We studied (1) the epidemiology of enteric pathogens associated with diarrhea, (2) the diagnostic yield of stool examination and endoscopic evaluation, (3) risks to develop diarrhea, and (4) the impact of diarrhea on patients' survival. METHODS: A total of 1933 participants in the Swiss HIV Cohort Study were prospectively followed up for a median of 25.5 months. A total of 560 diarrheal episodes were evaluated by standardized stool examination. Endoscopic evaluation was performed in 25% of patients with chronic diarrhea. RESULTS: The incidence of diarrhea was 14.2 per 100 person-years (95% confidence interval, 13.0-15.4). Among patients with CD4 cell counts below 0.05 x 10(9)/L, the probability to develop diarrhea within 1, 2, and 3 years was 48.5%, 74.3%, and 95.6%, respectively. The risk to develop diarrhea was increased among patients with severe immunodeficiency, homosexual men, and patients taking antiretroviral therapy. Pneumocystis carinii chemoprophylaxis did not reduce the risk of diarrhea. Diarrhea was an independent negative predictor of survival. Enteric pathogens were detected in 16.5% of 212 acute diarrheal episodes and in 46% of 348 chronic diarrheal episodes. The sensitivity of histological and stool examination was similar except for the diagnosis of intestinal cytomegalovirus infection and leishmaniasis, which required invasive evaluation. CONCLUSIONS: Intestinal infections were diagnosed in less than 50% of chronic diarrheal episodes. The prevalence of enteric pathogens tended to decrease during the observation period, possibly because of improved antiretroviral therapy. Endoscopic evaluation did not improve the diagnostic yield compared with stool examination except for the diagnosis of cytomegalovirus enteritis and leishmaniasis.

Clinical and epidemiologic features of infection with Mycobacterium genavense. Swiss HIV Cohort Study.

OBJECTIVES: To characterize clinical and epidemiologic features of infections with Mycobacterium genavense. DESIGN: Case series and case-control studies. Patients with M genavense were compared with two control groups: CD4 controls were matched on the basis of CD4 counts, and Mycobacterium avium-intracellulare complex controls had disseminated infection with M avium-intracellulare complex. RESULTS: Fifty-four patients with disseminated infections caused by M genavense were found, from Europe (37), North America (15), and Australia (two). All were infected with human immunodeficiency virus. The median CD4 count was 0.016 x 10(9)/L (16/mm3) (range, 0.001 to 0.082 x 10(9)/L). Eighty-seven percent had fever and weight loss, 44% had diarrhea, 43% had splenomegaly, 39% had hepatomegaly, and 72% had anemia. In Swiss university hospitals, M genavense was responsible for 12.8% of nontuberculous disseminated mycobacterial infections in patients with human immunodeficiency virus from 1990 to 1992. The median survival was 190 days after the first isolation of M genavense. Among the patients who had been treated with at least two antimycobacterial drugs for 1 month or more, median survival was 263 days (95% confidence interval, 144 to 382 days), compared with 81 days (95% confidence interval, 73 to 89 days) for those not treated (P = .0009). Survival in patients with M genavense was similar to the survival of M avium-intracellulare complex controls. However, patients with similar CD4 counts (CD4 controls) survived longer (median, 342 days; 95% confidence interval, 269 to 415 days; P < .0003). CONCLUSIONS: Infection with M genavense may be responsible for more than 10% of disseminated nontuberculous mycobacterial infections in patients with human immunodeficiency virus infection. Its clinical presentation and response to treatment are similar to those of infection with M avium-intracellulare complex.

Levels of HIV-infected peripheral blood cells remain stable throughout the natural history of HIV-1 infection. Swiss HIV Cohort Study.

OBJECTIVE: To clarify the relationship between the number of provirus-bearing peripheral blood mononuclear cells (PBMC) and HIV-1 disease progression during the natural history of infection. DESIGN: Twenty-four HIV-1-infected subjects with known seroconversion dates and long-term follow-up were retrospectively identified using the Swiss HIV Cohort Database. PBMC specimens from this cohort were retrieved from storage for analysis. METHODS: Infected PBMC equivalents were determined by HIV-1 DNA quantitative competitive (QC)-PCR. The results were analysed with respect to HIV-1 disease stage and compared with a mathematical model of long-term HIV-1 disease progression. RESULTS: PBMC HIV-1 DNA did not correlate with major indices of disease progression, including time following primary infection, time before reaching a CD4 cell count less than 200 x 10(6)/l, and time before death. The number of PBMC harbouring HIV-1 provirus was relatively constant throughout the clinical stages of HIV-1 infection, consistent with simulated data from a mathematical model of long-term HIV-1 infection. We also showed that a biased interpretation of the QC-PCR data may arise when the values are expressed as HIV-1 DNA copies per PBMC or per CD4 cell. CONCLUSIONS: This analysis suggests that levels of provirus-bearing PBMC remain constant during the natural course of HIV-1 infection, whereas plasma virus load typically increases logarithmically during the same period. The hypothesis that plasma virus levels are directly related to the number of infected cells may deserve reconsideration.

Time of initiation of antiretroviral therapy: impact on HIV-1 viraemia. The Swiss HIV Cohort Study.

OBJECTIVE: The current recommendation that patients infected with HIV-1 be treated early is based on little evidence. We examined whether the early initiation of antiretroviral treatment affects residual HIV-1 viraemia. METHODS: Viraemia was measured using an assay with a detection limit of 3 HIV-1 RNA copies/ml in drug-naive patients who started antiretroviral therapy at the time of primary HIV-1 infection (PHI) (n = 10), during chronic infection without immune suppression (CD4 cell counts > or = 500/mm3; median 577) (n = 10), or after immune suppression developed (CD4 cell counts < 500/mm3; median 113) (n = 21). RESULTS: In 249 samples collected 24 to 120 weeks after treatment initiation, the mean proportion of samples with HIV-1 RNA levels of less than 3 copies/ml was 75% for PHI patients compared with 32 and 8% for immunocompetent and immunosuppressed chronically infected patients, respectively. Fifty per cent of PHI patients, but none of the chronically infected patients, had persistently fewer than 3 HIV-1 RNA copies/mL. PHI patients had lower residual HIV-1 RNA levels than chronically infected patients, and immunocompetent patients had lower residual HIV-1 RNA levels than immunosuppressed patients (all pairwise, P< 0.001). The mean residual HIV-1 RNA level was independently associated with the initiation of therapy during PHI and baseline CD4 cell counts (P < 0.001 for both associations). CONCLUSION: Viraemia levels are associated with clinical progression and predict virological treatment failure. The initiation of antiretroviral therapy at the time of PHI and while CD4 cell counts are high results in lower residual viraemia. These results support early antiretroviral therapy in HIV-1-infected patients.

Impact of drug resistance mutations on virologic response to salvage therapy. Swiss HIV Cohort Study.

OBJECTIVE: To assess the prognostic significance of drug-associated mutations in the protease and reverse transcriptase (RT) genes on virological response to salvage therapy. PATIENTS: All patients from four centres of the Swiss HIV Cohort Study who were switched, between February and October 1997, to nelfinavir plus other antiretroviral drugs following failure of highly active antiretroviral therapy (HIV-1 RNA >1000 copies/ml after > 3 months). METHODS: Direct sequencing of RT and protease genes derived from plasma RNA was performed in 62 patients before salvage therapy. Baseline predictors (drug-resistance mutations, drug exposure, clinical and biological parameters) of virological response after 4-12 weeks of therapy were assessed by linear regression analyses. RESULTS: Patients had been treated with RT inhibitors and protease inhibitors for a median duration of 35.6 and 12.2 months, respectively. Baseline median CD4 cell count was 113 x 10(6)/l and HIV-1 RNA 5.16 log10 copies/ml. The median decrease of HIV-1 RNA was 0.38 log10; 32% of the patients showed > 1 log10 decrease. At baseline, 90% of the patients had RT inhibitor-resistance mutations with a median number per patient of four (range, 0-7). Primary and secondary protease inhibitor-resistance mutations were detected in 69% and 89% of the patients, respectively. The median number of total protease inhibitor-resistance mutations per patient was four (range, 0-9). In univariate analysis, virological response to salvage therapy was associated with number of RT inhibitors, primary and secondary protease inhibitor-resistance mutations, history of protease inhibitor use (duration and number), but not with clinical stage, HIV-1 RNA level or CD4 cell count. After adjustment for all variables, the number of RT inhibitor plus protease inhibitor-resistance mutations was the only independent predictor. CONCLUSIONS: In patients with advanced HIV infection, the virological response to salvage therapy containing nelfinavir is best predicted by the number of baseline RT inhibitor plus protease inhibitor-resistance mutations.

Discontinuation of primary prophylaxis in HIV-infected patients at high risk of Pneumocystis carinii pneumonia: prospective multicentre study.

OBJECTIVES: To assess the safety of discontinuation of primary prophylaxis in HIV-infected patients on antiretroviral combination therapy at high risk of developing Pneumocystis carinii pneumonia. DESIGN: Prospective multicentre study. PATIENTS AND METHODS: The incidence of P. carinii pneumonia after discontinuation of primary prophylaxis was studied in 396 HIV-infected patients on antiretroviral combination therapy who experienced an increase in their CD4 cell count to at least 200 x 10(6)/l and 14% of total lymphocytes; the study population included 191 patients with a history of CD4 cell counts below 100 x 10(6)/l (245 person-years) and 144 patients with plasma HIV RNA above 200 copies/ml (215 person-years). RESULTS: There was one case of Pneumocystis pneumonia, an incidence of 0.18 per 100 person-years [95% confidence interval (CI), 0.005--1.0 per 100 person-years]. No case was diagnosed in groups with low nadir CD4 cell counts (95% CI, 0--1.2 per 100 person-years) or detectable plasma HIV RNA (95% CI, 0--1.4 per 100 person-years). CONCLUSIONS: Discontinuation of primary prophylaxis against Pneumocystis pneumonia is safe in patients who have responded with a sustained increase in their CD4 cell count to antiretroviral combination therapy, irrespective of the CD4 cell count nadir and the viral load at the time of stopping prophylaxis.

Impact of TNFalpha, LTalpha, Fc gammaRII and complement receptor on HIV-1 trapping in lymphoid tissue from HIV-infected patients.

OBJECTIVES: To investigate HIV trapping mechanisms in patients with acute infection and in asymptomatic individuals prior to and during antiretroviral therapy. To determine the role of complement receptor (CR), Fc gamma receptor II (Fc gammaRII), tumour necrosis factor alpha (TNFalpha), and lymphotoxin alpha (LTalpha) expression in HIV trapping efficiency. METHODS: Lymphoid tissues from three acutely HIV-infected patients and six asymptomatic, chronically HIV-infected patients collected prior to and during antiretroviral therapy were compared with lymphoid tissues from six HIV-seronegative subjects. HIV, TNFalpha and LTalpha RNA expression was detected and quantified by fluorescence in situ hybridization. CR, Fc gammaRII and HIV p24 antigen were detected and quantified by fluorescence immunohistochemistry. RESULTS: The amount of trapped HIV did not differ significantly between patients with acute HIV infection and asymptomatic individuals, and was independent of the presence of CR or Fc gammaRII expression. However, in patients with acute infection, the amount of trapped virus was correlated inversely with the number of HIV-infected cells (P = 0.0092) and with the size of the light zone (P = 0.037). In these patients, the number of TNFalpha-expressing cells was correlated inversely with the amount of trapped virus (P = 0.014) and positively correlated with the size of the light zone in germinal centers (P = 0.041). No correlations were observed between TNFalpha or LTalpha expression and Fc gammaRII or CR expression. CONCLUSION: This report provides the first evidence that in humans TNFalpha is involved in the development of lymphoid follicles, HIV trapping, and, consequently, in early host immune responses. A model is proposed for early events in patients during acute HIV infection.

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 x 10(6)/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.

Change in circulating levels of the chemokines macrophage inflammatory proteins 1 alpha and 11 beta, RANTES, monocyte chemotactic protein-1 and interleukin-16 following treatment of severely immunodeficient HIV-infected individuals with indinavir.

OBJECTIVE: To evaluate the in vivo relationship between HIV replication and circulating levels of the chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, RANTES (acronym for Regulated upon Activation, Normal T-cell Expressed and presumably Secreted), interleukin (IL)-16 and monocyte chemotactic protein (MCP)-1, which have recently been characterized as factors capable of regulating in vitro HIV replication. DESIGN AND METHODS: We have compared changes in plasma HIV-RNA levels and circulating levels of MIP-1 alpha, MIP-1 beta, RANTES, IL-16 and MCP-1 in 20 severely immunodeficient HIV-infected individuals (CD4+ T cells = 14 +/- 3 cells x 10(6)/l; plasma HIV RNA = 4.45 +/- 0.27 log 10 copies/ml) undergoing treatment with the HIV protease inhibitor indinavir that added to pre-existing nucleoside-based therapy. At weeks 0, 2, 6 and 12, viral load was quantified using a commercial reverse-transcription polymerase chain reaction assay, peripheral blood T-cell subpopulations assessed by flow cytometry, and chemokine levels quantified using commercial sandwich enzyme-linked immunosorbent assay kits. RESULTS: Following initiation of indinavir-based therapy, significant decreases in plasma HIV-RNA levels (change = 2.0 +/- 0.75 log 10 copies/ml) were observed in conjunction with significant increases in absolute CD4+ (change = 83 +/- 19 cells x 10(6)/l) and CD8+ (change = 293 +/- 96 cells x 10(6)/l) T-cell numbers. Concomitantly, significant increases in MIP-1 alpha (19% increase), MIP-1 beta (14% increase), RANTES (15% increase) and IL-16 (1213% increase) levels occurred. In contrast, MCP-1 levels decreased significantly (47% decrease). CONCLUSION: The in vivo demonstration of an association between diminishing plasma HIV-RNA levels and the emergence of a circulating chemokine profile capable of inhibiting HIV replication corroborates recent in vitro observations and provides evidence for the restoration of chemokine capacity by HIV protease inhibitor-based therapy.

Highly active antiretroviral therapy during early HIV infection reverses T-cell activation and maturation abnormalities. Swiss HIV Cohort Study.

OBJECTIVES: To evaluate the impact of early initiation of highly active antiretroviral therapy (HAART) on disease-induced T-cell activation and maturation abnormalities during asymptomatic HIV infection. DESIGN: A prospective open-label trial of zidovudine, lamivudine and ritonavir in treatment-naive asymptomatic HIV-infected individuals with CD4 cells > or = 400 x 10(6)/l. METHODS: Peripheral blood CD4+ and CD8+ T cells derived from 15 asymptomatic HIV-infected individuals (median baseline CD4+ cells, 608 x 10(6)/l; CD8+ cells, 894 x 10(6)/l; plasma HIV RNA, 3.93 log10 copies/ml) undergoing therapy with zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and ritonavir (600 mg twice daily) were assessed for changes in expression of phenotypic markers of T-cell activation (HLA-DR and CD38) and maturation (CD45RA and CD45RO). At weeks 0, 2, 4, 8, 12, 16, 20 and 24, T-cell subsets were quantified by flow cytometry and plasma HIV viral loads determined using reverse transcription PCR. RESULTS: HAART-induced decrease in plasma HIV RNA levels coincided with a significant reduction in numbers of activated CD4+/HLA-DR+ (maximum change, -36%; P < or = 0.05), CD8+/HLA-DR+ (maximum change, -66%; P < or = 0.005) and CD8+/CD38+ (maximum change, -51%; P < or = 0.01) T cells. A concomitant significant increase in numbers of naive CD4+/CD45RA+ (maximum change, +12%; P < or = 0.005) and memory CD4+/CD45RO+ (maximum change, +6%; P < or = 0.05) T cells was also evident, which contrasted with a significant decrease in memory CD8+/CD45RO+ cells (maximum change, -42%; P < or = 0.005). CONCLUSION: The observed ability of HAART during early asymptomatic HIV infection to initiate rapid reversal of disease-induced T-cell activation and maturation abnormalities, while preserving pretherapy levels of immune function, supports the concept that therapeutic advantage is to be gained by commencing early aggressive antiretroviral therapy.

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.

A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection. The Swiss HIV Cohort Study.

OBJECTIVE: To explore the short-term effects on surrogate markers for HIV progression of didanosine (ddl) plus stavudine (d4T), with or without hydroxyurea. DESIGN: Randomized, double-blinded, prospective study. SETTING: Swiss HIV Cohort Study. PATIENTS: A total of 144 patients (75% antiretroviral-naive) were studied (mean baseline HIV-1 RNA, 4.53 log10 copies/ml; mean CD4 cell count, 370 x 10(6)/l). INTERVENTION: Patients received ddl (200 mg twice daily) plus d4T (40 mg twice daily), with additional hydroxyurea (500 mg twice daily) or placebo. MAIN OUTCOME MEASURES: The primary endpoint was a reduction of viraemia below 200 copies/ml after 12 weeks. At that time, patients who did not reach the primary endpoint were withdrawn in the hydroxyurea arm, whereas patients in the placebo group had the option of adding hydroxyurea to ddl and d4T. All patients were followed until week 24. RESULTS: After 12 weeks, 54% of the patients randomized to hydroxyurea had viraemia below 200 copies/ml, compared with 28% on placebo (P < 0.001). Using an ultrasensitive assay with a limit of detection of 20 copies/ml, 19% of patients receiving hydroxyurea had viraemia levels below 20 copies/ml, compared with 8% on placebo (P = 0.05). Mean decrease in HIV-1 RNA was 2.3 and 1.7 log10 copies/ml for hydroxyurea and placebo groups, respectively (P = 0.001). Hydroxyurea was found to induce lymphopenia (-124 x 10(6)/l). Increase in CD4 cell counts was +28 x 10(6)/l during hydroxyurea treatment compared with +107 x 10(6)/l on placebo (P = 0.001). CONCLUSIONS: Hydroxyurea improved the antiviral activity of d4T and ddl over a 12-week period, but was associated with a smaller increase in CD4 cell counts due to hydroxyurea-induced lymphopenia.

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.

Shortcomings of chest radiography in detecting Pneumocystis carinii pneumonia.

The radiographic presentation of Pneumocystis carinii pneumonia (PCP) was studied in 93 consecutive patients to determine the frequency of normal findings on chest roentgenograms and possible correlations with clinical or laboratory findings. The roentgenograms were reviewed by two radiologists in an independent, blinded way and judged with a score distinguishing between none, interstitial, and acinar infiltrates. Discordance mainly between absent versus interstitial and interstitial versus acinar infiltrates occurred in 23% of roentgenograms and was settled by consensus. The majority of patients presented with moderate-to-mild symptoms; the combination of dyspnea, cough, and fever was present in 53%. Lactate dehydrogenase (LDH) was elevated in 63%, hypoxemia (PaO2 < 75 mm Hg) was present in 57%. Findings on chest roentgenograms were normal in 39%, whereas 36% showed interstitial and 25% acinar infiltrates. These three radiographic groups represented an increasingly severe PCP, indicated by higher LDH levels and hypoxemia (both p < 0.05). In a multivariate logistic regression, normal roentgenograms were predicted by low LDH and low peripheral blood granulocytes (p < 0.005). Mortality within 3 weeks was only 4% and correlated with the severity of infiltrates (p < 0.05). Normal roentgenograms thus corresponded to an oligosymptomatic, less severe PCP. In immunodeficient HIV-infected patients, a normal chest roentgenogram does not exclude PCP and should not distract from attaining a definite diagnosis by examination of induced sputum or bronchoalveolar lavage.

Prediction of HIV-1 RNA suppression and its durability during treatment with zidovudine/lamivudine.

To predict the probability of long-term viral suppression during treatment with zidovudine and lamivudine, human immunodeficiency virus type 1 (HIV-1) RNA values were retrospectively pooled for 1083 patients from six randomized, double-blind clinical trials. All analyses of HIV-1 RNA were obtained using the Roche Amplicor assay or its earlier prototype. Time to loss of response was evaluated by Kaplan-Meier analysis; Cox proportional hazards models were used to assess the influence of baseline variables. Among 523 patients with < or = 6 months of prior zidovudine treatment, the probability of HIV-1 RNA suppression below 400 copies/ml at 48 weeks was 71% in those with baseline HIV-1 RNA < 5000 copies/ml, but only 14% in those with HIV-1 RNA between 50,000 and 200,000 copies/ml. Among 560 patients with > 6 months of prior zidovudine treatment, the rates of sustained viral suppression were lower, but also significantly associated with the baseline HIV-1 RNA. Multivariate analyses showed no independent effect of CD4 cell count, age, sex, race, or CDC disease stage on the probability of sustained HIV-1 RNA suppression. When patients with < or = 6 months of prior therapy were stratified based on the magnitude of HIV-1 RNA nadir achieved during treatment, those who reached a nadir of < 400 copies/ml retained this response for significantly longer time periods than the ones who only achieved partial viral suppression. In conclusion, baseline HIV-1 RNA levels and the duration of prior zidovudine therapy strongly predict the antiretroviral efficacy of zidovudine/lamivudine. The baseline parameters should influence the choice of the antiretroviral regimen.

Improvement in immune function due to treatment with indinavir despite severe immune deficiency.

To study the virological, immunological and clinical effects of the protease inhibitor indinavir in human immunodeficiency virus (HIV)-infected patients with CD4 counts < 50 cells/mm3, indinavir was added to prior treatment with nucleoside analogues in a prospective open-label study in 23 HIV-infected patients with median CD4 count of 10 cells/mm3 and median serum HIV-1 RNA load of 27,508 copies/ml. Addition of indinavir induced a decrease in HIV-1 RNA levels to < 400 copies/ml in 15 patients that was maintained until week 36 of the study in 8 (35%) patients. The median increase in CD4 cell counts was 92 cells/mm3 (range 55-258 cells/mm3) and in CD8 counts was 245 cells/mm3 (range 51-1552 cells/mm3) at week 30. The treatment induced a significant CD8 T cell expansion, consisting in the first 6 weeks of predominantly memory CD45RO+ cells and followed by expansion of naive cells from week 12 on, and a significant decrease in the proportion of activated CD8/CD38 cells. In addition, significant increases in T cell proliferation following stimulation with phytohaemagglutinin and significant decreases in the rates of spontaneous apoptosis of CD4+ and CD8+ T cells were observed. In conclusion, the addition of indinavir induced restoration of both memory and naive CD8 T cells. Corresponding evidence of improving T cell function, as assessed by enhanced lymphoproliferative capacity and diminished propensity to undergo apoptosis, provides evidence for treatment-induced regeneration of immune function even in patients with severe immunodeficiency.

Didanosine plus stavudine with or without hydroxyurea in HIV-1-infected patients: 1 year follow-up. Swiss HIV Cohort Study.

A total of 144 human immunodeficiency virus (HIV)-infected patients (mean CD4 cell count, 367 cells/mm3) were included in a double-blind placebo-controlled trial testing the efficacy on surrogate markers of HIV progression of the combination didanosine (2',3'-dideoxyinosine or DDI) plus stavudine (2',3'-didehydro-2',3'-dideoxythymidine or D4T) with or without hydroxyurea. The primary end point was a reduction of HIV RNA levels to below 200 copies/ml after 12 weeks of treatment. The results showed that the triple combination was associated with a more profound decrease in HIV RNA with an increased proportion of patients with viraemia < 200 copies/ml. This effect persisted for the majority of the patients after a 48 week follow-up. In contrast, the increase in CD4 cell counts was less in patients treated with hydroxyurea because of lymphopenia, and adverse events were more frequent in hydroxyurea-treated patients. In conclusion, the addition of hydroxyurea consistently improved the antiviral activity of the didanosine/stavudine combination over a 48 week follow-up. Increased toxicity and decreased effect on CD4 cell counts might inspire caution.