Change to abacavir-lamivudine-tenofovir combination treatment in patients with HIV-1 who had complete virological suppression.

Patients who have not received previous antiretroviral treatment (ART) have a high failure rate on the combination treatment of abacavir, lamivudine, and tenovir. We assessed the virological failure rate in eight patients with HIV-1 who switched to this combination after having complete virological suppression from their previous long-term ART (median 8.0 months, range 7.5-18.0). Five of the eight patients showed virological failure. Four of these five patients had either the K65R mutation, the M184V/I mutation, or both. This combination of drugs cannot therefore be recommended as alternative treatment in patients with HIV-1 who are fully virologically suppressed.

Complications of varicella zoster virus reactivation in HIV-infected homosexual men.

OBJECT: To study the complication rate of varicella zoster virus (VZV) reactivation and the relationship between complications, presentation and localization of zoster and immune function in HIV disease. DESIGN AND METHODS: A total of 142 episodes of VZV reactivation in 113 out of 544 HIV-1-infected participants in the Amsterdam Cohort Study of homosexual men were studied. Persistent hyperkeratotic or necrotic skin lesions, post-herpetic neuralgia, other neurological events, ocular events and pneumonitis occurring within 6 months of the onset of the last episode of VZV reactivation were defined as complications, provided that other possible diagnoses were excluded and the event had been previously described in the literature as related to VZV reactivation. RESULTS: Twenty-four complications occurred in 15 (11%) of these 142 episodes. Complications occurred exclusively in the 40 episodes with either multidermatomal or disseminated presentation, or a trigeminal localization, or both. In the group of episodes of unidermatomal zoster at a non-trigeminal localization no complications occurred. Twenty-one episodes of herpes zoster were localized in the trigeminal area. Localization was not significantly associated with the level of immune function. Compared to unidermatomal presentation (n = 120), multidermatomal (n = 15) and disseminated presentation (n = 7) occurred at lower median CD4+ cell counts (330, 240 and 50 x 10(6)/l, respectively; P = 0.003) and significantly lower levels of CD3 monoclonal antibodies or phytohaemagglutinin-induced T-cell reactivity in vitro. Complications were related to CD4+ cell counts, but in the cases of disseminated, multidermatomal or trigeminal zoster a CD4+ cell measurement provided no additional information on the risk of complications. CONCLUSION: In HIV-infected individuals the extent of the clinical presentation and the occurrence of complications of VZV reactivation are related to the degree of immunodeficiency. In episodes of VZV reactivation with either multidermatomal or disseminated presentation or a trigeminal localization, or both the complication rate was high. CD4+ cell counts provided no additional information on the complication risk. Oral acyclovir appears to be sufficient as therapy for unidermatomal zoster at a non-trigeminal localization.

Toxicity and drug exposure in a quadruple drug regimen in HIV-1 infected patients participating in the ADAM study.

OBJECTIVE: To study the relationship between toxicity and the exposure to nelfinavir and saquinavir as part of a quadruple drug regimen. DESIGN: The ADAM study is a randomized study to investigate the feasibility of induction-maintenance therapy in HIV-1 infection. METHODS: HIV-1-infected patients with no prior use of antiretroviral treatment started induction therapy consisting of stavudine + lamivudine + nelfinavir + saquinavir for a period of 26 weeks. Data regarding toxicity of the quadruple regimen and exposure to the protease inhibitors were collected. RESULTS: Seven of the 65 patients enrolled had to switch therapy for reasons of toxicity within the first 26 weeks. Diarrhoea was frequently reported (49 of 65, one discontinuation), but could be relieved by using antidiarrhoeal agents. Laboratory monitoring revealed elevated liver enzymes (leading to four discontinuations) and mild to moderate elevations of triglycerides and cholesterol (nine and 23 of 65, respectively). The exposure to saquinavir and nelfinavir was lower than expected. Abdominal pain was associated with a higher exposure to nelfinavir or saquinavir. The association of nausea and abdominal distension with drug exposure appeared to vary over time. CONCLUSIONS: The quadruple drug regimen was quite well tolerated. Diarrhoea was frequently reported but could be relieved by the use of antidiarrhoeal agents. In comparison with other protease inhibitor combinations, lipid abnormalities in plasma were infrequent and mild. With the exception of diarrhoea, all gastrointestinal complaints observed were found to be associated with the level of exposure to nelfinavir or saquinavir. The exposure to the protease inhibitors was relatively low, although the virologic efficacy of the regimen used was satisfactory.

The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy.

OBJECTIVE: To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA. DESIGN: Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine]. METHODS: The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k. RESULTS: A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k. CONCLUSIONS: The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.

BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.

Prospective longitudinal analysis of viral load and surrogate markers in relation to clinical progression in HIV type 1-infected persons.

The temporal relationship between viral and surrogate markers and clinical status was analyzed prospectively every 8 weeks in 34 asymptomatic HIV-1-infected persons. After 3 years, 25 persons remained clinically healthy whereas 9 persons showed clinical progression. In accordance with other reports we found that at study entry HIV-RNA load was predictive of clinical progression. All markers tested evolved significantly in time in both progressors and nonprogressors. The HIV RNA load in plasma and HIV DNA load in T cells were linearly related only in nonprogressors. In addition, the RNA/DNA ratio during follow-up was significantly higher in progressors, indicating a higher replication rate in progressors. The HIV DNA load correlated inversely with CD4+ T cell counts and positively with p24 antigenemia in both nonprogressors and progressors. A significant correlation of HIV DNA load with SI phenotype occurred in progressors only. HIV RNA levels correlated with beta 2-microglobulin level and with p24 antigenemia but not with SI phenotype. These three markers can all routinely be measured in plasma; however, only the HIV RNA levels appear to be informative for clinical progression. Six to 8 months before clinical progression, an SI phenotype switch, increased HIV RNA in plasma, and decreased CD4+ T cell counts were all indicative of an impending clinical event.

Disseminated Penicillium marneffei infection as an imported disease in HIV-1 infected patients. Description of two cases and a review of the literature.

Two cases of disseminated Penicillium marneffei infection, as an imported disease, in HIV-1-infected patients with a severe immunodeficiency are reported. These patients had a history of travel in Southeast Asia where P. marneffei is endemic. Fever, cough, malaise, hepatosplenomegaly, anaemia, skin lesions and mucosal ulcers are the main clinical characteristics. Differentiation from histoplasmosis and leishmaniasis might be difficult. Treatment with amphotericin B was successful. Anti-fungal maintenance therapy is most likely indicated.

PIP: A 33-year-old, HIV-1 positive, white, homosexual man was hospitalized in May, 1991, because of fever, cough, skin eruptions, anorexia, and weight loss during the previous 2 months. In October, 1990, he had traveled in Sumatra. On examination he was ill, tachypneic, normotensive with a temperature of 39.1 degrees Celsius. The spleen was substantially enlarged. Laboratory investigations showed: ALAT 72 U/I (normal 23 U/1), LDH 508 U/1 (normal 275 U/1). A bronchoscopy with bronchoalveolar lavage revealed yeast cells. Gastroscopy showed an ulcer in the hypopharynx and an erosion in the stomach. Biopsies of this ulcer demonstrated the presence of Penicillium marneffei. Biopsies of the liver showed the same organism. The patient was treated with amphotericin B induction therapy (1 dd 0.5 mg/kg for 21 days, total dose of 730 mg) in combination with flucytosine (3 dd 2500 mg, total dose 142 g in 19 days). In the following 2 weeks the temperature became normal, and the dyspnea and the skin eruptions disappeared, except for the mollusca contagiosa. The spleen diminished by 50%. LDH and ALAT became normal. Oral maintenance therapy followed with fluconazole (the first 3 months 400 mg daily, followed by 200 mg a day). 24 months later, no recurrence had been observed. Case 2 was a 28-year-old, HIV-infected, homosexual man, born in Suriname, who was hospitalized in October, 1991, with prolonged fever, dyspnea, and a painful throat. In March, 1991, he had traveled in rural Thailand. AIDS was diagnosed on the basis of cerebral toxoplasmosis in August, 1991. A biopsy of the ulcer in the oropharynx showed an active aspecific inflammation and also P. marneffei. Treatment with amphotericin B intravenously (0.5 mg/kg, total dose 1052 mg in 32 days) was commenced. The lesions in the oral cavity and throat, the lymph nodes, and the shortness of breath disappeared within a few days. Ten months later he died from emaciation caused by cryptosporidiosis.

Langerhans cell histiocytosis of the vulva.

A case of an 82-year-old woman with an ulcerated vulvar nodule suspected to be malignant is presented. The lesion turned out to be the primary localization of a generalized Langerhans cell histiocytosis. Six cases with a similar presentation have been reported previously and are reviewed.

Takayasu's or pulseless disease in pregnancy.

A case of Takayasu's disease in pregnancy in a 27-yr-old Dutch Gravida I, para 0 is presented, in which the diagnosis was confirmed by angiography before pregnancy. Diagnostic and therapeutic problems occurred during pregnancy; however, a successful delivery of a healthy infant was accomplished. The obstetrical course of this patient is compared with 12 others so far described in the literature. The symptoms of this rare condition may improve or worsen during pregnancy. The best therapy is rest. Vaginal delivery is recommended and cesarean section should be reserved for specific obstetric indications.

Clinical symptoms associated with seroconversion for HIV-1 among misusers of intravenous drugs: comparison with homosexual seroconverters and infected and non-infected intravenous drug misusers.

OBJECTIVE: To study the clinical symptoms associated with seroconversion for HIV-1 among misusers of intravenous drugs. DESIGN: Case-control study in cohorts of drug misusers and homosexual men. SETTING: Outpatient clinic, Municipal Health Service, Amsterdam. SUBJECTS: Misusers of intravenous drugs from our prospective cohort who seroconverted for HIV. Controls were drug users positive for HIV, drug users negative for HIV, and homosexual men who had seroconverted. RESULTS: Five out of 18 (28%) drug users were admitted to hospital with bacterial pneumonia in the four to six months between their last visit at which they were HIV negative and their first visit when they were HIV positive. For comparison none of the 27 homosexual men who seroconverted for HIV, three out of 177 (2%) drug users negative for HIV, and 10 out of 112 (9%) drug users positive for HIV reported bacterial pneumonia. One out of the 18 drug users who seroconverted suffered from oesophageal candidiasis at the time of seroconversion. Other clinical symptoms did not differ between drug users who seroconverted and those who remained negative for HIV, probably due to the high background morbidity among the drug users. CONCLUSIONS: Seroconversion to HIV-1 among intravenous drug misusers is associated with bacterial pneumonia. Those drug users with previously negative test results for HIV who are admitted to hospital for bacterial pneumonia should be tested to detect primary infection with HIV-1.

[Reducing the risk of blood-transmitted infections of HIV, hepatitis B or C virus in a teaching hospital in Amsterdam--evaluation of a protocol for needlestick accidents among hospital staff during the period 1997-2001]. / Risicoreductie van bloedoverdraagbare besmetting met HIV, hepatitis-B- of -C-virus in een opleidingsziekenhuis in Amsterdam--evaluatie van een protocol voor 'prikaccidenten' bij ziekenhuismedewerkers, 1997-2001.

OBJECTIVE: To evaluate a protocol for hospital staff aimed at reducing their risk of exposure to blood-transmitted infections. DESIGN: Prospective. METHOD: In August 1997 a protocol was introduced to the Onze Lieve Vrouwe Gasthuis Hospital in Amsterdam, with procedures to be followed after percutaneous or mucocutaneous blood contact in which there was a chance of transmission of hepatitis B (HBV) or C (HCV), as well as guidelines for the prescription of post-exposure prophylaxis (PEP) after accidents with an HIV risk. In the period 1 August 1997-30 June 2001 data were collected from registration forms that reported accidents and the ensuing events. RESULTS: A total of 403 accidents were reported by 138 (34.2%) physicians, 135 (33.5%) ward nurses, 46 (11.4%) operation assistants, 30 (7.4%) co-assistants, 21 (5.2%) analysts and 33 (8.2%) persons with another position. There was a constant increase in the number of reports over the period. The seroprevalence of the source patients was: 6.9% (25/360) HIV, 8.1% (6/74) HBV and 6.3% (23/363) HCV. PEP was prescribed on 46 occasions: 15 times for an HIV positive source and 31 times for what was initially an unknown HIV source. Following the introduction of a rapid HIV test in September 1999, there was a reduction in the number of unnecessary PEP prescriptions from 4 in 1997, 7 in 1998 and 16 in 1999 to 3 in 2000 and 1 in 2001. All 15 persons who were correctly started on a PEP treatment took the medication for a period of 28 days despite many side effects. No seroconversions were established during the follow-up period of 6 months.

The serology and immunochemistry of HIV-induced platelet-bound immunoglobulin.

A study was carried out on the presence of platelet-bound immunoglobulins, platelet-bound complement and serum immunoglobulin reactive with platelets in the blood of persons infected with HIV and those at risk of HIV infection. Platelet-bound immunoglobulins, predominantly IgG and IgM, but not complement, were demonstrated by immunofluorescence in 16 out of 16 patients with AIDS, in 5 out of 7 with AIDS-related complex/persistent generalized lymphadenopathy and in 7 out of 10 apparently healthy sexually active homosexual men, of whom 2 were anti-HIV1 seropositive. There was no correlation between the presence of platelet-bound immunoglobulins and either the platelet count or the level of circulating immune complexes. The specificity of the platelet-bound immunoglobulins and platelet-reactive immunoglobulins in the corresponding sera was studied. Platelet-bound immunoglobulins were eluted and then investigated for cross-reactivity with HIV. Both sera and eluates were tested for reactivity with cardiolipin and reactivity with the major target antigen in classical autoimmune thrombocytopenia, the GP IIb/IIIa complex. Of 17 eluates containing platelet-reactive immunoglobulins, 5 reacted with HIV-determinants but 2 out of 5 eluates that did not contain platelet-reactive immunoglobulins also reacted. Although anti-cardiolipin antibodies were detected in all sera, none of the 17 eluates reacted with cardiolipin. Moreover, sera and eluates, reactive with normal platelets, did not react with type-1-Glanzmann disease platelets. This indicates that the antibodies are directed against the glycoprotein IIb/IIIa complex of platelets. This could not be confirmed by immunoprecipitation or by immunoblotting, however. We conclude that the presence of platelet-bound immunoglobulins is common in HIV-infection but may also occur in persons at risk and that the nature of the auto-antibodies is not different from that of the auto-antibodies observed in classical ITP.

Trimethoprim-sulphamethoxazole as primary Pneumocystis carinii prophylaxis does not increase serum homocysteine levels in HIV-positive subjects.

Background: We recently observed that a short course of trimethoprim 300 mg b.i.d. in healthy volunteers can cause a substantial increase in fasting plasma homocysteine levels, up to concentrations reportedly associated with atherothrombotic complications. The purpose of this study was to determine whether primary Pneumocystis carinii prophylaxis (PCP) with trimethoprim-sulphamethoxazole (TMP-SMX) adversely affects serum homocysteine levels in HIV-positive patients. Methods: We studied 34 subjects [29 male, 5 female, mean age 36.8+/-7.9 (S.D.) years] with no prior AIDS-defining disease who required primary PCP prophylaxis (CD4+ T-cell count <200/mm(3)). The common dose of TMP-SMX was 80/400 mg (80 mg trimethoprim and 400 mg sulphamethoxazole) once daily. Serum total homocysteine levels were determined in four samples: two collected prior to the start of TMP-SMX and two collected on average 2.6+/-2.2 and 5.3+/-3.5 months into the first year of prophylactic therapy. Results: Mean serum homocysteine was 13.9+/-3.7 &mgr;mol/l pre-treatment and 14.4+/-5.0 &mgr;mol/l during treatment with TMP-SMX, a non-significant increase of 0.5 &mgr;mol/l (95% CI: -0.5 to +1.4, P=0.34). Folate levels were equally unaffected by TMP-SMX (13.1+/-6.5 nmol/l versus 13.3+/-5.3 nmol/l, before and during therapy, respectively). Baseline folate levels did not predict the response of homocysteine to TMP-SMX, and neither did age, gender, or serum creatinine. Conclusion: Long-term therapy with 80/400 mg TMP-SMX does not adversely affect homocysteine levels.