Hypersensitivity to antiretroviral drugs.

Summary: Background. Antiretroviral therapy (ART) may be responsible for hypersensitivity reactions varying in severity, clinical manifestations and frequency. Case report. We report the case of a 47-year-old woman with HIV infection who developed a delayed mucocutaneous reaction after treatment with ART. Hypersensitivty reaction (HR) to emtricitabine and tenofovir was considered probable based on positive patch tests (PT) and hypersensitivity reaction to nevirapine was confirmed by drug provocation test. Discussion. The diagnosis of HR to ART remains a diagnostic challenge, partly due to unknown mechanism and the absence of validated diagnostic tools. Patch testing may represent a useful method for confirming hypersensitivity. Further investigation in this area is required, so that successful management strategies can be offered, preventing loss of potent and viable antiretroviral agents.

Seroconversión frente a primovacunación reforzada contra hepatitis B en niños con cáncer / Seroconversion in response to a reinforced primary hepatitis B vaccination in children with cancer

Introducción: La respuesta inmune a los antígenos de las vacunas está disminuida en los niños con cáncer. El objetivo de este estudio fue evaluar la seroconversión frente a vacuna ADN recombinante contra hepatitis B al momento del inicio de la quimioterapia y/o remisión en niños con cáncer. Pacientes y método: Estudio prospectivo, bicéntrico, controlado, no aleatorizado de niños con diagnóstico reciente de cáncer pareados con niños sanos. Los casos fueron vacunados a tiempo 0, 1 y 6 meses, a dosis de 20 y 40 μg si eran < ó > 10 años, respectivamente, con vacuna ADN recombinante contra hepatitis B, en el momento del diagnóstico en el caso de los tumores sólidos y luego de la remisión en el caso de los tumores hematológicos. El grupo control recibió el mismo esquema, con dosis de 10 o 20 μg respectivamente. Se midieron anticuerpos séricos anti-HBs a los 2, 8 y 12 meses posvacunación. Seroconversión se definió como títulos anti-HBs > 10 mUI/ml al octavo mes. Resultados: Un total de 78 niños con cáncer y 25 controles fueron evaluados con títulos anti-HBs al octavo mes. La tasa de seroconversión fue de 26,9%, en niños con cáncer, sin diferencia por edad, género ni tipo de tumor (p = 0,13; 0,29; y 0,44, respectivamente), y de 100% en el grupo control (p < 0,0001, comparado con los niños con cáncer). En el seguimiento a los 12 meses solo el 31,9% de los niños con cáncer presentaba títulos anti-HBs > 10 mUI/ml. Conclusiones: La vacunación contra hepatitis B con vacuna ADN recombinante, con esquema reforzado de 3 dosis, en el momento del inicio de la quimioterapia y/o remisión provee una respuesta inmune insuficiente en la mayoría de los niños con cáncer. En esta población debieran evaluarse vacunas de tercera generación, con adyuvantes más inmunogénicos, esquemas reforzados a los 0, 1, 2 y 6 meses, medición de títulos de anticuerpos al octavo y duodécimo mes, eventual uso de refuerzos y reevaluación de inmunogenicidad si correspondiese.

Introduction: Immune response against vaccine antigens may be impaired in children with cancer. The aim of this study was to evaluate the seroconversion response against hepatitis B vaccination (HBV) at the time of chemotherapy onset and/or remission in children with cancer. Patients and method: Prospective, two-centre, controlled, non-randomised study conducted on children recently diagnosed with cancer, paired with healthy subjects. Cases received HBV at time 0, 1 and 6 months with DNA recombinant HBV at a dose of 20 and 40 μg if < or > than 10 years of age, respectively, at the time of diagnosis for solids tumours and after the remission in case of haematological tumours. Controls received the same schedule, but at of 10 and 20 μg doses, respectively. HBs antibodies were measured in serum samples obtained at 2, 8 and 12 months post-vaccination. Protective titres were defined as > 10 mIU/ml at 8th month of follow up. Results: A total of 78 children with cancer and 25 healthy controls were analysed at month 8th of follow up. Seroconversion rates in the cancer group reached 26.9%, with no differences by age, gender or type of tumour (P = .13, .29, and .44, respectively). Control group seroconversion was 100% at the 8th month, with P < .0001 compared with the cancer group. At month 12 of follow up, just 31.9% of children with cancer achieved anti-HBs antibodies > 10 mIU/ml. Conclusions: Vaccination against hepatitis B with three doses of DNA recombinant vaccine at an increased concentration, administrated at the time of onset of chemotherapy and/or remission provided an insufficient immune response in a majority of children with cancer. More immunogenic vaccines should be evaluated in this special population, such as a third generation, with more immunogenic adjuvants, enhanced schedules at 0, 1, 2, 6 month, evaluation of antibody titres at month 8 and 12 h to evaluate the need for further booster doses.

CD41 T cell recovery during suppression of HIV replication: an international comparison of the immunological efficacy of antiretroviral therapy in North America, Asia and Africa.

BACKGROUND: Even among HIV-infected patients who fully suppress plasma HIV RNA replication on antiretroviral therapy, genetic (e.g. CCL3L1 copy number), viral (e.g. tropism) and environmental (e.g. chronic exposure to microbial antigens) factors influence CD4 recovery. These factors differ markedly around the world and therefore the expected CD4 recovery during HIV RNA suppression may differ globally. METHODS: We evaluated HIV-infected adults from North America, West Africa, East Africa, Southern Africa and Asia starting non-nucleoside reverse transcriptase inhibitorbased regimens containing efavirenz or nevirapine, who achieved at least one HIV RNA level <500/ml in the first year of therapy and observed CD4 changes during HIV RNA suppression. We used a piecewise linear regression to estimate the influence of region of residence on CD4 recovery, adjusting for socio-demographic and clinical characteristics. We observed 28 217 patients from 105 cohorts over 37 825 person-years. RESULTS: After adjustment, patients from East Africa showed diminished CD4 recovery as compared with other regions. Three years after antiretroviral therapy initiation, the mean CD4 count for a prototypical patient with a pre-therapy CD4 count of 150/ml was 529/ml [95% confidence interval (CI): 517­541] in North America, 494/ml (95% CI: 429­559) in West Africa, 515/ml (95% CI: 508­522) in Southern Africa, 503/ml (95% CI: 478­528) in Asia and 437/ml (95% CI: 425­449) in East Africa. CONCLUSIONS: CD4 recovery during HIV RNA suppression is diminished in East Africa as compared with other regions of the world, and observed differences are large enough to potentially influence clinical outcomes. Epidemiological analyses on a global scale can identify macroscopic effects unobservable at the clinical, national or individual regional level.

Stealth anti-CD4 conjugated immunoliposomes with dual antiretroviral drugs--modern Trojan horses to combat HIV.

Highly active antiretroviral therapy (HAART) is the currently employed therapeutic intervention against AIDS where a drug combination is used to reduce the viral load. The present work envisages the development of a stealth anti-CD4 conjugated immunoliposomes containing two anti-retroviral drugs (nevirapine and saquinavir) that can selectively home into HIV infected cells through the CD4 receptor. The nanocarrier was characterized using transmission electron microscopy, FTIR, differential scanning calorimetry, particle size and zeta potential. The cell uptake was also evaluated qualitatively using confocal microscopy and quantitatively by flow cytometry. The drug to lipid composition was optimized for maximum encapsulation of the two drugs. Both drugs were found to localize in different regions of the liposome. The release of the reverse transcriptase inhibitor was dominant during the early phases of the release while in the later phases, the protease inhibitor is the major constituent released. The drugs delivered via anti-CD4 conjugated immunoliposomes inhibited viral proliferation at a significantly lower concentration as compared to free drugs. In vitro studies of nevirapine to saquinavir combination at a ratio of 6.2:5 and a concentration as low as 5 ng/mL efficiently blocked viral proliferation suggesting that co-delivery of anti-retroviral drugs holds a greater promise for efficient management of HIV-1 infection.

HLA-dependent hypersensitivity reaction to nevirapine in Chinese Han HIV-infected patients.

In this study, one hundred and three HIV-positive Chinese Han patients treated with a nevirapine (NVP)-based regimens were investigated for the association between nevirapine hypersensitivity reaction (NVP HSR) and human leukocyte antigen (HLA) allele. HLA-Cw, -DRB1 alleles were determined in 32 NVP HSR cases and 71 NVP-tolerant patients. We found that considerable overlap was observed for the clinical and demographic characteristics of the 32 hypersensitive patients and 71 tolerant patients. Twelve out of 32 NVP HSR cases developed allergic hepatotoxicity. More HLA-Cw*04 alleles were observed in NVP HSR cases than in NVP-tolerant cases (p=0.029). The frequency of HLA-DRB1*15 in NVP-tolerant cases was significant higher than that in NVP HSR cases ( p=0.018). Multivariate logistic regression identified that HLA-Cw*04 presence was a risk factor related to NVP HSR (p=0.030, OR=3.611, 95% CI of OR: 1.135-11.489). To clearly understanding its value in clinical practice, further studies involving larger cohorts of patients from different races with different levels of immune suppression are needed.

HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine.

OBJECTIVE: To describe the prevalence of HIV-1 drug resistance mutations at the time of treatment initiation in a large cohort of HIV-infected children previously exposed to single-dose nevirapine (sdNVP) for prevention of transmission. DESIGN: Drug resistance mutations were measured pretreatment in 255 infants and young children under 2 years of age in South Africa exposed to sdNVP and initiating ritonavir-boosted lopinavir-based therapy. Those who achieved viral suppression were randomized to either continue the primary regimen or to switch to a nevirapine-based regimen. Pretreatment samples were tested using population sequencing and real time allele-specific PCR (AS-PCR) to detect Y181C and K103N minority variants. Those with confirmed viremia more than 1000 copies/ml by 52 weeks postrandomization in the switch group were defined as having viral failure. RESULTS: Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, predominantly Y181C, were detected by either method in 62% of infants less than 6 months of age, in 39% of children 6-12 months of age, 22% 12-18 months, and 16% 18-24 months (P = <0.0001). NNRTI mutations detected by genotyping, but not K103N or Y181C mutations detected only by AS-PCR, were associated with viral failure in the switch group. CONCLUSION: The prevalence of mutations known to compromise primary NNRTI-based therapy is high in sdNVP-exposed children, supporting current guidelines recommending use of protease inhibitor-based regimens for young children. Standard genotyping is adequate to identify children who could benefit from switching to NNRTI-based therapy.

Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent.

OBJECTIVE: Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. DESIGN: We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. METHODS: Cases and controls were matched 1: 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/µl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. RESULTS: We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. CONCLUSION: Among patients with at least 150 CD4 T cells/µl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening.

Women exposed to single-dose nevirapine in successive pregnancies: effectiveness and nonnucleoside reverse transcriptase inhibitor resistance.

OBJECTIVE: To assess the impact of prior exposure to single-dose nevirapine (sdNVP) on mother-to-child transmission and genotypic resistance in HIV-infected women. DESIGN: Prospective study of 120 women exposed to the HIVNET 012 sdNVP regimen in two successive pregnancies and 240 antiretroviral (ARV)-naïve, multiparous women who received sdNVP for the first time. RESULTS: One hundred and eight of 120 and 193 of 240 women returned for a postpartum visit by 6 weeks. HIV-1 was detected in 11.1% (95% confidence interval = 5.9-18.6) of the infants of women previously exposed to sdNVP and 4.2% (95% confidence interval = 1.3-7.0) of those exposed for the first time (P = 0.028). Rates of maternal HIV-1 genotypic resistance at 6 weeks postdelivery were 37.5% and 46.4%, respectively (P = 0.119). Sensitive mutation-specific real-time PCR testing found three of 12 previously exposed women who transmitted HIV-1 to their infants had either K103N or Y181C at baseline compared with one of eight ARV-naïve, transmitting women who had Y181C. None of 40 randomly selected nontransmitting women from either group had detectable NVP resistance mutations prior to sdNVP exposure. CONCLUSION: This study shows that effectiveness of sdNVP may be compromised by prior exposure to sdNVP, although the increase in transmission rate after prior exposure could not be explained by the detection of NVP resistance mutations prior to re-exposure as measured both by standard genotyping and highly sensitive allele-specific PCR assays. Furthermore, transmission rates of women with prior exposure were not higher than those reported elsewhere.

Impact of baseline CD4(+) T cell counts on the efficacy of nevirapine-based highly active antiretroviral therapy in Chinese HIV/AIDS patients: a prospective, multicentric study.

BACKGROUND: CD4(+) T cell counts have been used as the indicator of human immunodeficiency virus type 1 (HIV-1) disease progression and thereby to determine when to start highly active antiretroviral therapy (HAART). Whether and how the baseline CD4(+) T cell count affects the immunological and viral responses or adverse reactions to nevirapine (NVP)-containing HAART in Chinese HIV-1 infected adults remain to be characterized. METHODS: One hundred and ninety-eight HIV-seropositive antiretroviral therapy (ART)-naive subjects were enrolled into a prospective study from 2005 to 2007. Data were analyzed by groups based on baseline CD4(+) T cell counts either between 100 - 200 cells/microl or 201 - 350 cells/microl. Viral responses, immunologic responses and adverse events were monitored at baseline and at weeks 4, 12, 24, 36, 52, 68, 84, 100. RESULTS: Eighty-six and 112 subjects ranged their CD4(+) T cell counts 100 - 200 cells/microl and 201 - 350 cells/microl, respectively. The pre-HAART viral load in CD4 201 - 350 cells/microl group was significantly lower than that in CD4 100 - 200 cells/microl group (P = 0.000). After treatment, no significant differences were observed between these two groups either in the plasma viral load (pVL) or in the viral response rate calculated as the percentage of pVL less than 50 copies/ml or less than 400 copies/ml. The CD4(+) T cell counts were statistically higher in the 201 - 350 group during the entire follow-ups (P < 0.01) though CD4(+) T cell count increases were similar in these two groups. After 100-week treatment, the median of CD4(+) T cell counts were increased to 331 cells/microl for CD4 100 - 200 cells/microl group and to 462 cells/microl for CD4 201 - 350 cells/microl group. Only a slightly higher incidence of nausea was observed in CD4 201 - 350 cells/microl group (P = 0.05) among all adverse reactions, including rash and liver function abnormality. CONCLUSIONS: The pVLs and viral response rates are unlikely to be associated with the baseline CD4(+) T cell counts. Initiating HAART in Chinese HIV-1 infected patients with higher baseline CD4(+) T cell counts could result in higher total CD4(+) T cell counts thereby achieve a better immune recovery. These results support current guidelines to start HAART at a threshold of 350 cells/microl.

Is it safe to switch between efavirenz and nevirapine in the event of toxicity?

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are chemically distinct, but both may cause cutaneous hypersensitivity and hepatotoxicity. We reviewed the literature to assess the evidence for cross-reactivity between nevirapine and efavirenz. All papers, abstracts, or presentations, regardless of study design, that made reference to the response of patients who were switched from one NNRTI to another as a result of an adverse drug reaction were included. Most of the studies were retrospective. Recurrent reactions occurred in 30 (12.6%) of 239 reported patients with rash who were switched from nevirapine to efavirenz, compared with eight (50%) of 16 patients switched from efavirenz to nevirapine. Hepatitis did not recur in either the 11 reported patients switched from nevirapine to efavirenz, or in the single reported patient who was switched from efavirenz to nevirapine. Substituting efavirenz for nevirapine following hepatotoxicity or cutaneous hypersensitivity appears to be reasonable, providing that the adverse reaction to nevirapine was not life-threatening. There is insufficient evidence to recommend substituting nevirapine for efavirenz following either hepatotoxicity or cutaneous hypersensitivity.

HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients.

BACKGROUND: Hypersensitivity reaction to nevirapine, which in some cases can be fatal, shows a higher prevalence in Sardinia in comparison with other Italian regions. OBJECTIVE: This study demonstrates that hypersensitive reaction to nevirapine in Sardinian HIV-infected patients is associated with the HLA Cw8-B14 haplotype. These two HLA class I antigens are in strong linkage disequilibrium in the Sardinian population. METHODS: Forty-nine Sardinian HIV-positive patients treated with nevirapine were studied. Thirteen (26%), developed a hypersensitive reaction thus requiring the drug to be discontinued. HLA class I and II molecular typing was performed in both nevirapine-hypersensitive and nevirapine-tolerant patients. To avoid biased representation of the allele frequencies in the two groups of treated patients, molecular typing was also performed in 82 HIV-positive patients who had not been treated with nevirapine. RESULTS: Considerable overlap was observed for the clinical, immunological and demographic characteristics of the 13 hypersensitive patients and 36 tolerant patients. Clinical parameters included viral load, status of HIV infection, CD4 and CD8 cell counts, hepatitis C virus/hepatitis B virus co-infections. Forty-six percent (6/13) of the nevirapine-hypersensitive subjects had the HLA-Cw8 and HLA-B14(65) antigens compared with 5% (2/36) of the nevirapine-tolerant group (P = 0.004; Pc = 0.05). CONCLUSION: In agreement with other recent reports, the utility of HLA typing in HIV patients to identify genetic factors that may confer susceptibility to drug-induced hypersensitive reaction was confirmed. A careful choice of antiretroviral therapy in susceptible individuals should significantly reduce the risk of severe hypersensitive reaction.

Drug-specific T cells in an HIV-positive patient with nevirapine-induced hepatitis.

BACKGROUND: Nevirapine is associated with idiosyncratic reactions such as skin rash, hepatitis and hypersensitivity syndrome, which have the hallmarks of being immune mediated. However, there is little laboratory evidence to support an immune pathogenesis. METHODS: A HIV-positive individual who developed hepatitis within 6 weeks of starting nevirapine, in the absence of any cutaneous manifestations, is described. Other causes of hepatitis were excluded, and the patients liver function normalized on withdrawal of nevirapine. Lymphocytes from the patient, and six individuals with HIV who were on nevirapine without adverse effects, were exposed to nevirapine and its metabolites, and lymphocyte proliferation assessed by 3H-thymidine incorporation on day 5. RESULTS: The T cells taken from the nevirapine-hypersensitive patient proliferated in the presence of nevirapine with a stimulation index of greater than 2. There was no proliferation with nevirapine metabolites. T cells taken from HIV-positive control individuals showed no proliferation with either nevirapine or its metabolites. CONCLUSION: The results from our patient suggest that T cells may be involved in the pathogenesis of nevirapine-induced hepatitis. Larger numbers of patients need to be studied to fully evaluate the role of T cells in nevirapine-induced hepatitis and nevirapine hypersensitivity syndrome.

Differential CD4 T-cell response in HIV-1-infected patients using protease inhibitor-based or nevirapine-based highly active antiretroviral therapy.

OBJECTIVES: To study the dynamics of CD4 T-lymphocyte counts (CD4 counts) after the initiation of either protease inhibitor (PI)-based or nevirapine (NVP)-based first-line highly active antiretroviral therapy (HAART). DESIGN AND METHODS: A retrospective cohort study of 1029 HIV-infected antiretroviral therapy-naive patients initiating either PI-based or NVP-based HAART was carried out. Patients were censored as soon as they experienced virological failure, or changed their original antiretroviral regimen for any reason. RESULTS: In total, 920 and 109 patients initiated PI- and NVP-based HAART, respectively. The patients in the PI group more often had AIDS (15 vs. 6% in the NVP group), had a lower median baseline CD4 count (234 vs. 250 cells/microL in the NVP group) and had higher median baseline plasma HIV-1 RNA levels (pVL) (5.0 vs. 4.7 log10 HIV-1 RNA copies/mL in the NVP group). After 96 weeks of follow-up, the mean increase from baseline in CD4 count, adjusted for baseline CD4 count, age, gender and baseline pVL, was 310 cells/microL in the PI group and 212 cells/microL in the NVP group (P=0.003). This difference was mainly attributable to the patients in the NVP group initiating HAART with a baseline CD4 count below 200 cells/microL. There were no differences between the PI and NVP groups with respect to the change in the number of CD4 cells as a proportion of the total number of lymphocytes. CONCLUSION: Patients successfully treated with NVP-based HAART have a smaller increase in absolute CD4 cells compared with those treated with PI-based HAART.