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Biomedical subjects

F Mulcahy

Publications and source records attributed to F Mulcahy.

At least 37 records · Page 2Linked to original sources
PubMed2000

Late onset hepatitis and prolonged deterioration in hepatic function associated with nevirapine therapy.

The aetiology of hepatic dysfunction in patients with HIV infection is multifactorial. Re-activation of hepatitis C infection, drug toxicity, and opportunistic infections are all potential causes. Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used as part of combination antiretroviral therapy for the treatment of HIV infection. It is associated with a significant incidence of hepatotoxicity, usually occurring in the initial month of therapy. We report the case of a 49-year-old man who developed NVP-induced prolonged hepatotoxicity 5 months after commencing antiretroviral therapy.

Anti-HIV Agents↗
PubMed2000

The efficacy and tolerability of combination antiretroviral therapy in pregnancy: infant and maternal outcome.

Antiretroviral therapy (ART) and Caesarean section (CS) delivery significantly reduce the risk of vertically transmitted HIV infection. Attention must focus on determining the optimal management strategy for HIV-positive pregnancies. Guidelines must reflect not only the activity and tolerability of combination ART in pregnancy for mother and infant and the potential short and long-term infant toxicity, but also whether surgical delivery can confer an added benefit if combination ART had reduced plasma viraemia to undetectable levels. To aid the development of management strategies for the Republic of Ireland, a retrospective detailed review of all HIV-positive pregnancies since the introduction of combination ART was undertaken. Since 1997 there have been 25 deliveries to 24 women. Combination ART reduced plasma viraemia to undetectable levels in 76% mothers at delivery. The CS rate was 28% and no unanticipated infant toxicity was encountered. To date no infant has proven infected. Three infants have seroreverted and 24 of 26 infants have had at least 2 negative HIV ribonucleic acid (RNA) and polymerase chain reaction (PCR) tests. Two infants are less than one month old. In this study, the CS rate of 28% is below that reported from many centres yet no vertical transmission was found. Given the efficacy of ART in reducing plasma viraemia, the additional benefit of CS for these women is questionable.

Adolescent↗
PubMed1999

Interaction of sildenafil and indinavir when co-administered to HIV-positive patients.

OBJECTIVES: The prevalence of erectile dysfunction in HIV-infected men is estimated to be 33%. Sildenafil citrate (Viagra; Pfizer Ltd, Sandwich, Kent, UK) is the first oral drug for this condition. Since sildenafil and the protease inhibitors are both metabolized by, and act as inhibitors of cytochrome P450 3A4, we evaluated the pharmacokinetics of the combination sildenafil plus indinavir in HIV-infected patients. DESIGN AND METHODS: Six patients at steady state in treatment with indinavir participated in the study. On the first day blood samples for indinavir assay were drawn at times 0, 1, 2, 3, 4, 6 and 8 h after dosing. On the second study day patients received a single dose of 25 mg of sildenafil in addition to their routine morning medication. Blood samples were taken as described. Separated plasma was stored at -80 degrees C until analysis by high performance liquid chromatography. In a parallel study, the effect of indinavir, ritonavir, saquinavir and nelfinavir on the in vitro hepatic metabolism of sildenafil was assessed. RESULTS: The geometric mean area under the concentration curve for 0-8 h (AUC0-8h) and maximum plasma concentration (Cmax) for indinavir were 19.69 microg/ml h (range, 9.19-31.99 microg/ml h) and 7.02 microg/ml (range, 2.33-16.17 microg/ml), respectively, on the first study day. In the presence of sildenafil, the mean AUC0-8h and Cmax of indinavir were 22.37 microg/ml h [range, 10.08-37.25 microg/ml h; 95% confidence interval (CI) for difference between means, -15 to 13.25) and 9.11 microg/ml (range, 3.41-22.78 microg/ml; 95% CI, -13 to 6.37), respectively. The geometric mean AUC0-8h and Cmax for sildenafil were 1631 ng/ml h (range, 643-2970 ng/ml h) and 384 ng/ml (range, 209-766 ng/ml) respectively. The AUC for sildenafil was 4.4 times higher than data from historical controls given either 50 mg or 100 mg of sildenafil and dose normalized to 25 mg. Indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro [concentration producing 50% inhibition of control enzyme activity (IC50) = 0.39 +/- 0.17 microM, mean +/- SD]. CONCLUSIONS: Co-administration of sildenafil 25 mg did not significantly alter the plasma indinavir levels. However, plasma sildenafil AUC was markedly increased in the presence of indinavir compared with historical controls. From the in vitro data, the mechanism of increase is indinavir inhibition of the hepatic metabolism of sildenafil. The magnitude of this interaction suggests a lower starting dose of sildenafil may be more appropriate in this clinical setting.

Adult↗
PubMed1999

High rate of human T lymphotropic virus type IIa infection in HIV type 1-infected intravenous drug abusers in Ireland.

Serological and molecular analyses of a cohort of HIV-1-infected intravenous drug abusers (IVDAs) (n = 103) in Dublin, Ireland have demonstrated that 15 of 103 (14.6%) were infected with HTLV-II, which is the highest infection rate yet recorded for any European country. Restriction fragment length polymorphism (RFLP) analysis of the env region of the provirus demonstrated that the infection involved only the HTLV-IIa subtype; the HTLV-IIb subtype was not detected. Phylogenetic analysis of the nucleotide sequences of the long terminal repeat (LTR) confirmed infection with the HTLV-IIa subtype, and demonstrated that the viruses clustered closely with HTLV-IIa isolates from North American IVDAs. Previous observations that IVDAs in southern Europe, specifically Spain and Italy, appear to be infected predominantly with the HTLV-IIb subtype, along with the present report and evidence that IVDAs in Sweden are infected with the HTLV-IIa subtype, suggest different origins of HTLV-II infection in Europe.

Adult↗
PubMed1999

Does European or non-European origin influence health care and prognosis for HIV patients in Europe? The EuroSIDA Study Group.

BACKGROUND: Previous studies, especially in North America, have shown that socio-economic factors may influence the prognosis for patients with HIV. This study was performed in order to determine if European or non-European origin influence provision of health-care and survival among HIV patients in Europe. METHODS: Fifty HIV clinics in 17 European countries are involved in a European prospective, observational multicentre study. In total, 7230 consecutive patients with HIV attending a routine clinic visit were included in the study. Data on demographics, treatment and laboratory results were collected at time of recruitment into the study and thereafter every 6 months. RESULTS: The median CD4+ lymphocyte count at AIDS diagnosis was 60/mm3, and was similar for all ethnic groups (P = 0.87, Kruskall-Wallis test). The median terminal CD4+ lymphocyte count was 17/mm3 and, again, there was no significant difference between continents of origin (P = 0.35, Kruskall-Wallis test). Antiretroviral drugs were initiated at similar median CD4+ lymphocyte counts and there was no statistically significant difference in survival after a diagnosis of AIDS. CONCLUSIONS: AIDS was diagnosed at the same level of immunodeficiency independent of European or non-European origin and antiretroviral drugs were provided at similar levels of immunodeficiency. No differences in survival depending on continent of origin was found. In spite of these encouraging findings concerns remain that belonging to an ethnic minority can be an obstacle in getting into contact with treatment facilities and thus benefiting from developments in the management of HIV.

Adult↗
PubMed1999

Monitoring cytomegalovirus retinitis prevalence in an HIV-seropositive cohort: the assessment of improvements observed following the introduction of highly active antiretroviral triple therapy.

This paper concerns the ophthalmic assessment of patients with acquired immunodeficiency syndrome (AIDS) for a number of eye conditions and in particular cytomegalovirus (CMV) retinitis. CMV has been the most common opportunistic infection associated with AIDS and the leading cause of blindness among AIDS patients. There have been early indications of a widespread fall in CMV prevalence internationally following the introduction of a new highly active antiretroviral triple (HAART) therapy. Our study sought to assess the position for Ireland. Our cohort was the entire population of stage IV AIDS patients attending the country's leading referral centre. The total number of patients examined was 167 and the period of examination was 1 May 1995 to 30 April 1997. HAART was introduced in March 1996, so the data permitted a 'before and after' comparison of various clinical findings. The incidence of new CMV cases was found to be 4 among the 102 patients examined in the first 12-month period and one among 107 patients examined in the second 12-month period. There were accompanying declines in HIV-related noninfectious retinal vasculopathy (HIVR), keratitis and other conditions. The findings are promising, but we argue that caution is needed in assessing long-term trends. In the paper we discuss a number of methodological issues in the collection and analysis of the clinical data and in the interpretation of results.

AIDS-Related Opportunistic Infections↗
PubMed1999

Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection.

There are 3 groups of drugs available for the treatment of patients with HIV disease. These are the nucleoside reverse transcriptase inhibitors ('nucleoside analogues') [zidovudine, didanosine, zalcitabine, lamivudine and abacavir]; the non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz); and the protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir and amprenavir). The preferred initial regimen should reduce and maintain plasma HIV RNA below the level of detection. Presently, the regimen of choice consists of 2 nucleoside analogues plus a protease inhibitor with high in vivo efficacy. An alternative combination consists of 2 nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor. Drug interactions are one of the major problems associated with these multidrug regimens. Changes in plasma concentrations of the nucleoside analogues are unlikely to be of clinical relevance as drug effect is mainly dependent on the rate and extent of intracellular phosphorylation. Combinations of zidovudine plus stavudine, and probably zalcitabine plus lamivudine, should be avoided as competition for phosphorylating enzymes may occur. The antiviral efficacy of some nucleoside analogues, e.g. stavudine, may be compromised by prior treatment with other nucleosides (e.g. zidovudine). However, these data need to be clarified in further studies. It is unlikely that administration of other antiretrovirals will influence the activity of nucleoside analogues. Protease inhibitors are metabolised by hepatic cytochrome P450 (CYP) 3A4. Combination protease inhibitor therapy can result in drug interactions mediated by enzyme inhibition. Ritonavir is the most potent inhibitor, saquinavir the least. The protease inhibitors also interact with the non-nucleoside reverse transcriptase inhibitors. Nevirapine and efavirenz induce drug metabolising enzymes and may reduce plasma concentrations of protease inhibitors. A study in healthy volunteers showed that nelfinavir concentrations are increased by combination with efavirenz. Delavirdine inhibits drug metabolising enzymes and increases the plasma concentration of coadministered protease inhibitors. The nucleoside analogues would not be expected to interact with the protease inhibitors. Apart from the ability of didanosine to reduce the area under the concentration-time curve of delavirdine, there are no reports of clinically significant interactions of other antiretrovirals with the non-nucleoside reverse transcriptase inhibitors. Triple therapy is the current standard of care for patients with HIV disease. However, studies of quadruple therapy are already under way. Drug interactions are likely to remain one of the major considerations when selecting a therapeutic regimen for patients with HIV.

Antiviral Agents↗
PubMed1998

The pharmacokinetics of combination therapy with nelfinavir plus nevirapine.

OBJECTIVE: To investigate the pharmacokinetics of nelfinavir (NFV) administered alone and in combination with nevirapine (NVP) to HIV-positive patients. DESIGN: Seven patients with advanced HIV disease received dual nucleoside analogues in addition to NFV (750 mg three times daily) and subsequently NVP (200 mg daily for 2 weeks followed by 200 mg twice daily) as salvage therapy. On the first study day (day 3), blood samples were taken for assay of NFV. The second study day followed the introduction of NVP for 3 weeks. METHODS: Blood samples were obtained at 0, 1, 2, 3, 4, 6 and 8 h after dosing on both study days. Separated plasma was heated to 58 degrees C for 30 min to inactivate HIV and stored at -80 degrees C until analysis by high performance liquid chromatography for both NFV and NVP. RESULTS: The geometric mean NFV area under the concentration-time curve to 8 h (AUC0-8h) was 23.4 microg x h/ml (range, 13.5-49.2) and 11.6 microg x h/ml (range, 6.6-23.2) on the first and second study days, respectively. The geometric mean ratio was 0.49 (95% confidence interval, 0.33-0.72; P = 0.016). This represented a 50% reduction in plasma NFV concentrations. Maximum and minimum concentrations were also reduced during NVP therapy (from 4.4 to 2.5 microg/ml and from 1.7 to 0.8 microg/ml, respectively). Time to maximum concentration was reduced from 4 to 2 h. NVP concentrations were determined with a maximum concentration of 5.4 microg/ml at 4 h. CONCLUSIONS: NVP is currently being used in combination therapy with protease inhibitors for antiretroviral-experienced patients in the setting of treatment failure. This study demonstrates that when patients are coadministered NVP there is a 50% reduction in the plasma AUC of NFV. Although the mean trough concentrations of NFV remained above the stated minimum effective concentration of 0.4 microg/ml, there is nevertheless concern that some patients will fall below this value when NVP is added to treatment regimens. In the absence of therapeutic drug monitoring we suggest that an increase in the standard NFV dosage of 750 mg three times daily will be required to ensure satisfactory NFV plasma concentrations, thereby maintaining antiviral efficacy.

Adult↗
PubMed1998

Sexually transmitted diseases in HIV-positive patients.

The complex interaction between sexually transmitted diseases (STDs) and HIV has been demonstrated in many epidemiological studies and clinical trials over the last number of years. Herpes simplex virus, human papilloma virus, and syphilis are all accepted to have different manifestations, effects, and therapeutic responses in HIV positive patients. These and other issues are discussed in this article.

Drug Resistance, Microbial↗
PubMed1998

Successful use of protease inhibitors in HIV-infected haemophilia patients.

The haemophilias are a group of inherited haemostatic disorders that require regular clotting factor replacement therapy in the severe and moderately severe subgroups. Prior to the introduction of adequate viral inactivation methods in 1985, haemophilia patients were at exceptionally high risk of contracting blood-borne viruses from factor concentrates as each batch was derived from the plasma of thousands of donors. As a result, approximately 60% of these patients were infected with HIV between 1979 and 1985, and HIV infection now contributes significantly to the morbidity and mortality seen in this group. Protease inhibitors (PIs) have been shown to significantly log reduce viral loads and increase CD4 cell counts in HIV-infected individuals. Recently, there has been concern about their use in HIV-infected haemophilia patients following increased bleeding episodes in some patients during PI therapy. We prospectively studied the effect of PI therapy in 20 HIV-infected haemophilia patients at our centre over a 6-month period. The mean increase in CD4 cell count was 70 x 10(6)/l and the mean log decrease in viral load was 1.59 over the study period. Gastrointestinal side-effects (nausea and vomiting in five, diarrhoea in two) were the most frequent and resulted in discontinuation of the medication in two patients. Factor concentrate usage for the group on and off study was similar. One severe FVIII patient reported a single episode of an unusual bleed which responded promptly to FVIII concentrate infusion. The significant clinical and laboratory benefits in terms of HIV disease and the paucity of added bleeding complications suggest that PI therapy should not be withheld from HIV-infected haemophilics. Further prospective studies evaluating the efficacy and possible haemostatic complications related to these promising inhibitors of the HIV protease are needed.

AIDS-Related Opportunistic Infections↗
PubMed1998

Health risk profile of prostitutes in Dublin.

This study examined the health risk profile of prostitutes in Dublin. Clinical records of all 150 new prostitutes who attended a drop-in clinic for prostitutes in Dublin city during the period 1991-1997 were reviewed. Variables examined included: age, use of injectable drugs, human immunodeficiency virus (HIV) status, hepatitis B and C status, presence of sexually transmitted disease (STD), cervical cytology. Results showed the mean age of the women was 32 years. Among those tested, 2.5% were HIV positive, 5% were hepatitis B positive, 8% were hepatitis C positive and 25% had an STD. Almost 8% were injecting drug users (IDU) with higher prevalences of HIV, hepatitis B and C compared with non-IDU (P < 0.001). The clinic has been successful in providing a health-care facility for the specific health needs of this patient cohort.

Adult↗