Cyclosporiasis: a point source outbreak acquired in Guatemala.

BACKGROUND: Cyclosporiasis is a disease due to Cyclospora cayetanensis, an emerging coccidian parasite first described in 1979. It is an orally transmitted disease that is more frequent in tropical and subtropical areas. Cyclospora cayetanensis has been mainly described as a cause of travelers' diarrhea. This pathogen has given rise to a number of epidemic outbreaks attributable to ingestion of imported foods, particularly from tropical areas. METHODS: Descriptive study of clinical and epidemiological data of a small epidemic outbreak of C cayetanensis-induced gastroenteritis. RESULTS: Seven confirmed cases of C cayetanensis among Spanish nationals who had traveled to Antigua Guatemala are described. The incubation period was 6 days. Diarrhea, asthenia, anorexia, borborygmi, flatulence, and abdominal distension were present in all cases. Fever and heart burn in 85.7%. Weight loss in 71.4%. Abdominal pain, rectal tenesmus, and nausea in 42.8%. Vomiting and eructation in 14.2%. Heart burn was a frequent symptom, a finding not often previously described. The infection was probably acquired from raspberry juice. All cases improved with trimethoprim/sulphametoxazol. CONCLUSIONS: Cyclosporiasis is a cause of travelers' diarrhea. Parasitology laboratories must be advised of clinical suspicion of cyclosporiasis so that they can conduct a suitable targeted study; otherwise, false negative results may arise.

Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir.

The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned. Since anecdotal cases of transient insulin-dependent diabetes mellitus were seen in our clinic in patients on ddI + TDF-containing regimens, we explored the rate of this complication in more detail. Retrospective analysis of plasma glucose levels in patients who completed 12 months of treatment with three different triple antiretroviral regimens including ddI + TDF, TDF, or ddI was done. Patients taking antidiabetic drugs and/or those with baseline glucose levels >125 mg/dl were excluded. Weight, age, concomitant antiretrovirals, and ddI dose were assessed. At 12 months without treatment changes, fasting glucose levels were compared to baseline. A multivariate analysis was performed to evaluate which variables were associated with glucose elevations. A total of 177 HIV-infected patients were assessed (78 on ddI + TDF, 42 on TDF, and 57 on ddI). Mean baseline features were well balanced between groups for age (mean, 39 years), gender (78% male), CD4+ count (mean, 507 cells/mm3), weight (mean, 67 kg), and glucose level (mean, 95 mg/dl). There were only significant differences between groups for baseline viral load and protease inhibitor (PI) use (13% in the ddI + TDF arm vs. 7% and 9% in the TDF and ddI arms, respectively). At 12 months, 60% of the patients in the ddI + TDF arm were taking ddI 250 mg/day and the rest were on ddI 400 mg/day. At 12 months, hyperglycemia was significantly more frequent in the ddI + TDF arm (33%) when compared to patients on TDF or ddI separately (5% and 10%, respectively). In the multiple linear regression analysis, a lower weight (beta -0.35; 95% CI -0.67 to -0.03; p = 0.033) and use of ddI + TDF (beta: 13.05; 95% CI: 0.2 to 26; p = 0.047) were independently associated with a higher risk of developing hyperglycemia. The risk of hyperglycemia is increased in patients treated with ddI + TDF, particularly in those with lower weight. As high ddI exposure has been associated with endocrine pancreatic dysfunction and diabetes, ddI "overdosing" as result of concomitant TDF use and low weight might explain our findings. These results add a further note of caution to the use of TDF and ddI in combination.

Rate of virologic failure and selection of drug resistance mutations using different triple nucleos(t)ide analogue combinations in HIV-infected patients.

Virologic failure seems to occur more frequently in HIV-infected patients treated with triple nucleoside analogue (NA) combinations than with regimens including nonnucleoside reverse transcriptase inhibitors or protease inhibitors. However, the rate of failure and resistance profiles may differ with distinct triple NA combinations. A retrospective review of all HIV-infected individuals who received triple NA combinations at our institution was conducted. Virologic failure was defined as lack of achievement of plasma HIV-RNA<50 copies/ml at week 16 following initiation of antiretroviral therapy or as viral rebound in subjects with prior undetectable viremia. Genotypic analyses were performed at the time of first virological failure. Of the 261 patients identified, 13 were drug naive, 126 had underwent simplification, and 122 were antiretroviral-experienced patients with detectable viral load. Virologic failure was recorded in 95 (36.4%) after an average follow-up of 19 months. Rates were 0.67 in drug-naive, 0.55 in simplification, and 2.38 in rescue interventions for 100 persons-month follow-up. Factors associated with virologic failure in the multivariate Cox regression analysis were rescue vs naive or simplification strategies (OR 2.6; 95% CI 1.6-4.2) and using tenofovir as part of the combination (OR 2.04; 95% CI 1.3-3.2). In contrast, the use of AZT prevented virologic failure (OR 0.52; 95% CI 0.3-0.8). M184V was the most frequent resistance mutation (75.4%), followed by T215Y (52.5%) and K65R (14.8%). Of note, K65R did not develop in patients taking AZT nor in those with prior thymidine-associated mutations (TAMs). Conversely, subjects who developed K65R did not accumulate TAMs. Virologic failure is relatively frequent in patients treated only with triple NA regimens, particularly in the setting of rescue therapy. The use of TDF might be associated with a higher risk of virologic failure and, conversely, AZT might be protective. The presence of TAMs precluded the selection of K65R in patients treated with TDF. Resistance pathways for TDF and thymidine analogues seem to be divergent and could be the basis to explore a synergism between these drugs.

Nucleoside/nucleotide backbones for the treatment of HIV infection.

Nucleoside/nucleotide analogs (NAs) are essential components of most current antiretroviral regimens. Although many dual NA combinations may be used as backbones, not all display optimal results. For instance, some associations should be avoided due to antagonism (eg, zidovudine plus stavudine), high rates of toxicity (eg, didanosine plus stavudine) and/or increased risk of virological failure (eg, didanosine plus tenofovir). Moreover, the knowledge of plasma and intracellular interactions between different NAs is important for choosing appropriate combinations and optimal doses in order to optimize antiviral efficacy and minimize toxicities.

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.

BACKGROUND: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. PATIENTS AND METHODS: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. RESULTS: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. CONCLUSION: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.

Predictors of virological response to atazanavir in protease inhibitor-experienced patients.

BACKGROUND: Atazanavir (ATV) is the latest approved HIV protease inhibitor (PI). Even though it is very convenient (only two capsules once a day), concerns have risen about its potency. METHOD: The clinical performance of ATV 400 mg once a day was examined in all PI-experienced patients who were included in the ATV expanded access program conducted in a single institution. The predictive value of baseline drug resistance HIV genotypes, ATV plasma trough levels, and the genotypic inhibitory quotient (GIQ) on the virological response at week 24 was assessed. RESULTS: Data from 92 patients were analyzed. ATV was prescribed as part of a rescue intervention (45%), a simplification strategy (11%), or an attempt to ameliorate hyperlipidemias (23%) or other toxicities (16%). Tenofovir (TDF) was concomitantly used with ATV in 78% of patients. None received ritonavir boosting. In patients with detectable viremia at baseline (65%), the median HIV RNA drop was 0.7 logs. The median ATV Cmin was 0.12 microg/mL (IQR, 0.05-0.22 microg/mL), which is clearly above the IC90 (90% inhibitory concentration) for ATV in wild-type viruses. The virological response did not correlate significantly with ATV Cmin. The median number of protease resistance mutations was lower in patients showing virological response than in nonresponders (1 vs. 5; p=.07). A higher HIV RNA drop was associated with a higher GIQ (p=.02; beta=-5.4; 95% CI, -10 to -1). Only 4 patients (4%) discontinued treatment due to ATV-related toxicities (hyperbilirubinemia in 1). Bilirubin levels were associated with ATV plasma concentrations (p=.05; beta=3.2; 95% CI, -0.1 to 6.5). The rate of hypertriglyceridemia and hypercholesterolemia declined significantly with respect to baseline. CONCLUSION: ATV is relatively safe and provides significant virological response in PI-experienced patients, mainly among those with a low number of protease resistance mutations. The GIQ predicts accurately the virological response in patients receiving ATV. Hyperbilirubinemia is associated with higher ATV plasma levels.

Changes in mitochondrial DNA copy number in blood cells from HIV-infected patients undergoing antiretroviral therapy.

Mitochondrial DNA (mtDNA) copy number was measured in peripheral blood mononuclear cells (PBMCs) from 69 individuals using a real-time NASBA quantitative assay. Patients with HIV infection harbored significantly lower mtDNA copy number in PBMC than HIV-negative controls. Besides, subjects on stavudine-containing regimens showed significantly lower median mtDNA amounts than HIV-positive patients receiving other antiretroviral drugs, and this was associated with higher lactate levels. Thus, either HIV infection itself or treatment with stavudine-containing regimens might induce mtDNA depletion and related metabolic disturbances as hyperlactatemia.

Combinations of nucleoside/nucleotide analogues for HIV therapy.

Nucleoside and nucleotide analogues are essential for the design of effective antiretroviral regimens. There are currently many options for the selection of such drug backbones, although not all combinations will display optimal results. The concomitant administration of certain drugs should be avoided due to high rates of toxicity (ddl/d4T, ddl/TDF), antagonism (AZT/d4T, 3TC/FTC) and/or a greater risk of virological failure (ddl/TDF, ABC/TDF). The understanding of the plasmatic and intracellular metabolism of nucleoside/nucleotide analogues is crucial for deciding the optimal posology of each drug and the better dual combinations to be selected. Interferences between the pathways involved into the intracellular activation of some nucleoside/nucleotide analogues may help to understand why certain drug combinations should be avoided.

Short communication: benefits in the lipid profile after substitution of abacavir for Stavudine: a 48-week prospective study.

Stavudine (d4T) has been associated with lipoatrophy and hyperlactatemia. In recent studies, d4T has also been related to both hypercholesterolemia and hypertriglyceridemia. Replacing d4T with another nucleoside analogue such as abacavir (ABC) may reduce lactate levels and improve lipoatrophy in the long term. However, the impact of this strategy on the lipid profile is still unclear. In a prospective and randomized study, fasting lipids were examined over 48 weeks in 112 subjects on d4T regimens, 49 of whom replaced d4T with ABC. The substitution of ABC for d4T was found to be safe and provided a reduction in both LDL cholesterol and the total cholesterol (TC)/HDLc ratio, which might impact favorably on cardiovascular risk.

Correlation between lopinavir plasma levels and lipid abnormalities in patients taking lopinavir/ritonavir.

Lopinavir (LPV)/ritonavir (RTV) used in combination, is a potent antiretroviral drug. However, its benefit is limited by its inherent effect on lipid metabolism, causing dislypemia in a large proportion of treated patients. Fasting triglyceride (TG) and cholesterol levels were assessed in 126 HIV-infected patients who initiated salvage therapy based on LPV/RTV. Both TG and cholesterol significantly increased from baseline to month 3. A positive correlation was found between the percentage increase in TG and LPV trough levels (r = 0.32; p = 0.003). Moreover, patients with TG elevations above the median (27%) showed higher LPV Ctrough levels than those with lower TG elevations (7.1 vs. 4.7 microg/ml, p = 0.004). In contrast, no correlation was found between LPV Ctrough and increases in cholesterol levels. Cholesterol elevations were positively correlated with RTV Ctrough concentrations (r = 0.32; p = 0.003).

Hydroxyurea plus didanosine as maintenance therapy for HIV-infected patients on long-term successful highly active antiretroviral therapy.

BACKGROUND: Toxicity and quality of life issues have moved to delay the initiation of highly active antiretroviral therapy (HAART) and to explore novel treatment strategies for HIV infection. The switch to simpler regimens or treatment discontinuation has been attempted with limited success. The combination of hydroxyurea (HU) plus didanosine (ddI) is a simple regimen that might be able to restrain virus replication for long periods of time and could be an acceptable option as maintenance therapy in patients on prolonged successful HAART. METHOD: The combination of HU (500 mg bid) plus ddI (400 mg qd) was offered to participants with viral load (VL) <50 HIV RNA copies/mL and CD4 counts >350 cells/microL for more than 6 months under HAART. The prior HAART regimen was resumed if VL rose to >5,000 copies/mL and/or the CD4 count fell to <200 cells/microL after being on HU + ddI maintenance therapy. RESULTS: A total of 187 participants replaced HAART with HU + ddI. In an intent-to-treat analysis at 48 weeks, 109 (58%) and 77 (41%) patients had VL below 5,000 and 500 HIV RNA copies/mL, respectively. The mean CD4 count dropped from 809 +/- 283 to 573 +/- 270 cells/microL, while 77% of patients remained above 350 cells/microL. The proportion of participants with hypercholesterolemia declined from 70% to 46% (p <.001), while those with hypertriglyceridemia fell from 36% to 21% (p <.05). Significant improvements in lipohypertrophy and lipoatrophy were observed in 52% and 64% of participants, respectively. Grade 3-4 toxicities appeared in 20 patients (11%), including 3 cases of pancreatitis and 1 of peripheral neuropathy. Prior history of VL >5 log, CD4 counts <200 cells/microL, and ddI experience were independently associated with lower response to HU + ddI maintenance therapy. CONCLUSION: The combination of HU + ddI may be a satisfactory maintenance therapy for more than half of patients on successful HAART who want to alleviate drug-related toxicities and/or pill burden. Patients with metabolic and/or body-shape abnormalities might particularly benefit from switching to this simple regimen.

Gynecomastia in HIV-infected patients receiving antiretroviral therapy.

Thirty-four HIV-positive men with gynecomastia were seen in an HIV outclinic during a 20-month period (incidence of 2.4 cases/100 patients receiving HAART per year). It developed mainly in subjects having good immunologic and virologic status, after an average of 3 years of HAART. No hormone abnormalities were found, or association with specific drugs. Although initially unilateral, more than half of cases progressed to bilateral gynecomastia. Spontaneous resolution occurred in most subjects with 12 months without modifying therapy.

First-line therapy and mitochondrial damage: different nucleosides, different findings.

BACKGROUND: Antiretroviral therapy has been associated with the development of morphologic body-shape changes and metabolic abnormalities, including dislipemia, insulin resistance, and hyperlactatemia. Mitochondrial damage secondary to the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) has been related to some of these complications, although the role of different NRTIs in their development is not well established. OBJECTIVES: To assess the incidence of hyperlactatemia and lipodystrophy body-shape changes in drug-naïve HIV-infected patients who began highly active antiretroviral therapy (HAART) based on a backbone of two different NRTI combinations. METHOD: Prospective, longitudinal, observational study of all consecutive drug-naïve HIV-infected individuals who started HAART with zidovudine (AZT) plus lamivudine (3TC) or didanosine (ddI) plus stavudine (d4T) between June 2000 and June 2001 at one single institution. Serum lactate levels and lipodystrophy body-shape changes were monitored periodically during 12 months. RESULTS: At 1 year, mean lactate values remained <2 mmol/L in all 26 patients who received AZT+3TC, but they significantly increased (mean, 2.6 mmol/L) in 50 patients treated with ddI+d4T. The percentage of patients with hyperlactatemia (lactate >or=2 mmol/L) steadily increased in those on ddI+d4T (from 30% at 3 months to 71% at 12 months), whereas it remained below 10% in patients treated with AZT+3TC. Two patients on ddI+d4T developed lactic acidosis. Mean serum lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), and amylase significantly increased in patients treated with ddI+d4T, whereas they remained unaltered in patients under AZT+3TC. Significant correlations were found between lactate and LDH, alkaline phosphatase (AP), and GGT. In the multivariate analysis, treatment with ddI+d4T, LDH, and AP was significantly associated with lactate levels. At 12 months, subcutaneous lipoatrophy was significantly more frequent in patients treated with ddI+d4T than in those on AZT+3TC (35% vs. 8%; p =.01). CONCLUSION: In drug-naïve HIV-infected patients who start antiretroviral therapy, ddI+d4T-based combinations produce a greater increase in serum lactate and lipoatrophy than therapies based on AZT+3TC within the first year of therapy. An increase in LDH, amylase, GGT, and AP levels may signal an increase in lactate, which may be harmful.

Effect of dietary intervention on highly active antiretroviral therapy-related dyslipemia.

Changes in cholesterol and triglyceride levels after prescribing a lipid-lowering diet were assessed in 230 HIV-infected patients with dyslipemia associated with antiretroviral therapy. Lipid levels decreased significantly in subjects having good diet compliance. The reduction in triglyceride levels was greater than in cholesterol levels. Patients on protease inhibitor-containing regimens experienced a slightly greater decline in lipid levels compared with the rest.

SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals.

PURPOSE: A randomized, open-label, pilot study was undertaken to explore the antiviral activity and tolerability of two nonnucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine (NVP) and efavirenz (EFV). METHOD: HIV-infected antiretroviral-naive adults with CD4 counts >100 cells/mm(3) and detectable plasma HIV RNA below 100,000 copies/mL were randomized to receive didanosine (ddI) and stavudine (d4T) plus either NVP or EFV. Assessments were made every 12 weeks. Primary endpoints were the proportion of patients reaching plasma HIV RNA <50 copies/mL and/or developing NNRTI-related toxicities leading to drug discontinuation. Baseline characteristics were comparable for participants in the EFV (n = 31) and NVP arms (n = 36). RESULTS: At 48 weeks, 23/31 (74%) patients in the EFV group and 23/36 (64%) in the NVP group had <50 HIV RNA copies/mL (intention-to-treat analysis). Adverse events led to NNRTI discontinuation in 4 and 3 patients in the EFV and NVP arms, respectively. There were no statistically significant differences between groups regarding any primary endpoint. NVP and EFV along with two NRTIs may be equally well tolerated and effective at achieving <50 HIV RNA copies/mL in naive patients with CD4 counts >100 cells/mm(3) and HIV RNA <10(5) copies/mL. CONCLUSION: A much larger study is needed to demonstrate any significant differences between NVP and EFV, if they exist at all.

Simplification of antiretroviral treatment--how to sustain success, reduce toxicity and ensure adherence avoiding PI use.

Shortly after protease inhibitors (PI) began to be widely prescribed for the treatment of HIV infection in 1996, we learned that the virological efficacy of highly active antiretroviral therapy (HAART) was frequently associated with severe quality of life impairment. In fact, failure of PI-based regimens is often due to poor adherence resulting from high pill burden, complex dosing schedules, adverse events, or long-term toxicity. The metabolic and morphologic abnormalities associated with prolonged PI use are of particular concern: fat accumulation and abnormalities of lipid and glucose metabolism may increase the risk of cardiovascular disease, and body-shape changes (lipodystrophy) may also have a psychological impact or decrease patients' willingness to adhere to therapy. The efficacy of PI-sparing regimens in drug-naïve subjects, which typically consist of nucleoside reverse transcriptase inhibitors (NRTIs) with or without non-nucleoside reverse transcriptase inhibitors (NNRTIs), gives support to simplification strategies. In patients who have maintained durable virologic suppression on a PI-based regimen, the replacement of a PI by an NRTI, usually abacavir (ABC), or an NNRTI, has been shown to be associated with maintenance of virologic suppression, while leading to improvements in adherence and in some PI-related toxicities. The replacement of a PI by an NNRTI or ABC is usually followed by reductions in total cholesterol and triglycerides, though this is less true with efavirenz (EFV) than with nevirapine (NVP) or ABC. While there may be some improvement in fat accumulation after switching from a PI-based regimen, no improvement in lipoatrophy has been demonstrated after PI switches, possibly because this toxicity is due to NRTIs rather than PIs. However, NVP should be used with caution in patients co-infected patients with hepatitis B or C, and EFV may be poorly tolerated in individuals with psychiatric morbidity. Patients taking methadone may require dosage increases with switches to either NVP or EFV.