Transmitted drug resistant HIV-1 and association with virologic and CD4 cell count response to combination antiretroviral therapy in the EuroSIDA Study.

OBJECTIVES: To investigate prevalence of transmitted drug-resistant human immunodeficiency virus (TDR) and factors associated with TDR and to compare virological and CD4 count response to combination antiretroviral therapy. METHODS: In this study, 525 mostly chronically infected EuroSIDA patients were included who had genotypic resistance tests performed on plasma samples collected while antiretroviral therapy naive. TDR was defined as at least one resistance mutation from a list proposed for genotypic TDR surveillance. Multivariable logistic regression was used to analyze factors associated with detection of TDR, with virological (viral load<500 copies/mL) and CD4 count response (>or=50% increase) to combination antiretroviral therapy at months 6-12. RESULTS: The overall prevalence of TDR was 11.4%, which was stable over 1996-2004. There were no significant differences in virological suppression (those resistant to at least one drug prescribed versus susceptible), adjusted odds ratio: 0.68 (95% confidence interval: 0.27 to 1.71; P=0.408) or CD4 count response, adjusted odds ratio: 1.65 (95% confidence interval: 0.73 to 3.73; P=0.231). CONCLUSIONS: Prevalence of TDR in antiretroviral-naive patients was found to be in line with other European studies. No significant differences were found in virological and CD4 count response after initiation of first-line combination antiretroviral therapy between resistant and susceptible patients, possibly due to the small number of patients with resistance and consequently low power.

Siglec-1 is a novel dendritic cell receptor that mediates HIV-1 trans-infection through recognition of viral membrane gangliosides.

Dendritic cells (DCs) are essential antigen-presenting cells for the induction of immunity against pathogens. However, HIV-1 spread is strongly enhanced in clusters of DCs and CD4(+) T cells. Uninfected DCs capture HIV-1 and mediate viral transfer to bystander CD4(+) T cells through a process termed trans-infection. Initial studies identified the C-type lectin DC-SIGN as the HIV-1 binding factor on DCs, which interacts with the viral envelope glycoproteins. Upon DC maturation, however, DC-SIGN is down-regulated, while HIV-1 capture and trans-infection is strongly enhanced via a glycoprotein-independent capture pathway that recognizes sialyllactose-containing membrane gangliosides. Here we show that the sialic acid-binding Ig-like lectin 1 (Siglec-1, CD169), which is highly expressed on mature DCs, specifically binds HIV-1 and vesicles carrying sialyllactose. Furthermore, Siglec-1 is essential for trans-infection by mature DCs. These findings identify Siglec-1 as a key factor for HIV-1 spread via infectious DC/T-cell synapses, highlighting a novel mechanism that mediates HIV-1 dissemination in activated tissues.

Molecular epidemiology and evolution of HIV-1 in Portugal and portuguese speaking african countries

The aims of this thesis were to better characterize HIV-1 diversity in Portugal, Angola, Mozambique and Cape Verde and to investigate the origin and epidemiological history of HIV-1 in these countries. The impact of these issues in diagnosis, disease progression and susceptibility to ARV therapy was also investigated. Finally, the nature, dynamics and prevalence of transmitted drug resistance (TDR) was determined in untreated HIV-1 infected patients. In Angola, practically all HIV-1 genetic forms were found, including almost all subtypes, untypable (U) strains, CRFs and URFs. Recombinants (first and second generation) were present in 47.1% of the patients. HIV/AIDS epidemic in Angola probably started in 1961, the major cause being the independence war, subsequently spreading to Portugal. In Maputo, 81% of the patients were infected with subtype C viruses. Subtype G, U and recombinants such as CRF37_cpx, were also present. The results suggest that HIV-1 epidemic in Mozambique is evolving rapidly in genetic complexity. In Cape Verde, where HIV-1 and HIV-2 co-circulate, subtype G is the prevailed subtype. Subtypes B, C, F1, U, CRF02_AG and other recombinant strains were also found. HIV-2 isolates belonged to group A, some being closely related to the original ROD isolate. In all three countries numerous new polymorphisms were identified in the RT and PR of HIV-1 viruses. Mutations conferring resistance to the NRTIs or NNRTIs were found in isolates from 2 (2%) patients from Angola, 4 (6%) from Mozambique and 3 (12%) from Cape Verde. None of the isolates containing TDR mutations would be fully sensitive to the standard first-line therapeutic regimens used in these countries. Close surveillance in treated and untreated populations will be crucial to prevent further transmission of drug resistant strains and maximize the efficacy of ARV therapy. In Portugal, investigation of a seronegative case infection with rapid progression to AIDS and death revealed that the patient was infected with a CRF14_BG-like R5-tropic strain selectively transmitted by his seropositive sexual partner. The results suggest a massive infection with a highly aggressive CRF14_BG like strain and/or the presence of an unidentified immunological problem that prevented the formation of HIV-1-specific antibodies. Near full-length genomic sequences obtained from three unrelated patients enabled the first molecular and phylogenomic characterization of CRF14_BG from Portugal; all sequences were strongly related with CRF14_BG Spanish isolates. The mean date of origin of CRF14_BG was estimated to be 1992. We propose that CRF14_BG emerged in Portugal in the early 1990s, spread to Spain in late 1990s as a consequence of IDUs migration and then to the rest of Europe. Most CRF14_BG strains were predicted to use CXCR4 and were associated with rapid CD4 depletion and disease progression. Finally, we provide evidence suggesting that the X4 tropism of CRF14_BG may have resulted from convergent evolution of the V3 loop possibly driven by an effective escape from neutralizing antibody response.

Estudos Sectoriais - Vulnerabilidade e Adaptação às Mudanças Climáticas em Cabo Verde

A temperatura média global do planeta à superfície elevou-se de 0,6 a 0,7 ºC nos últimos 100 anos, com acentuada elevação desde a década de 60. A última década apresentou os três anos mais quentes dos últimos 1000 anos da história recente da Terra. Hoje, através das análises sistemáticas do Painel Intergovernamental de Mudança do Clima (IPCC), sintetizando o conhecimento científico existente sobre o sistema climático e como este responde ao aumento das emissões antropogénicas de gases do efeito estufa (GEE) e de aerossóis, há um razoável consenso de que o aquecimento global observado nos últimos 100 anos é causado pelas emissões acumuladas de GEE, principalmente o dióxido de carbono (CO2), oriundo da queima de combustíveis fósseis - carvão mineral, petróleo e gás natural - desde a Revolução Industrial e, em menor escala, do desmatamento da cobertura vegetal do planeta, e o metano (CH4), e não por eventual variabilidade natural do clima. A mudança global do clima já vem se manifestando de diversas formas, destacando-se o aquecimento global, a maior frequência e intensidade de eventos climáticos extremos, alterações nos regimes de chuvas, perturbações nas correntes marinhas, retracção de geleiras e elevação do nível dos oceanos. A menos que acções globais de mitigação do aumento de emissões de gases de efeito estufa sejam efectivamente implementadas nas próximas décadas (seria necessária uma redução de cerca de 60% das emissões globais de GEE para estabilizar suas concentrações em níveis considerados seguros para o sistema climático global), a demanda futura de energia, principalmente nos países em desenvolvimento, à medida que suas economias se expandem, terá como consequência alterações climáticas significativamente mais graves, como por exemplo, um aumento das temperaturas médias globais entre 1,4 e 5,8 graus Celsius (ºC) até o final do século, acompanhadas por substantivas e perturbadoras modificações no ciclo hidrológico em todo o planeta. A Convenção do Clima surgiu em resposta às ameaças das mudanças climáticas para o desenvolvimento sustentável, a segurança alimentar e os ecossistemas do planeta, como um tratado internacional de carácter essencialmente universal – foi firmada e ratificada por praticamente todos os países. O objectivo da Convenção é o de estabilizar a concentração dos gases de efeito estufa na atmosfera, em níveis tais que evitem a interferência perigosa com o sistema climático. Ora, tal estabilização somente pode ser obtida pela estabilização das emissões líquidas (emissões menos remoções) dos gases de efeito estufa. Por outro lado, já é impossível evitar completamente a mudança global do clima. Desta forma, os esforços dos países acordados na Convenção visam diminuir a magnitude da mudança do clima. O Protocolo de Quioto representa o principal avanço obtido na Convenção, estabelecendo limites para a emissão de GEE dos países do Anexo I (Membros da OCDE e economias em transição), que em seu conjunto deverão no período 2008-2012 reduzi-las em 5,2% do total emitido por eles em 1990. Negociado em 1997, assinado por praticamente todos os países, e ratificado por uma grande maioria, o Tratado de Quioto entrou em vigor em 16 de Fevereiro de 2005. No entanto, os Estados Unidos (EUA) decidiram não buscar a sua ratificação, no que foram seguidos pela Austrália, embora esta última tenha declarado que limitará as suas emissões como se houvesse ratificado. Para os países em desenvolvimento e, sobretudo, para as maiores economias em desenvolvimento como China, Índia e Brasil, que devem, ao mesmo tempo, inserir-se na moderna economia globalizada e superar seus passivos social e económico, o Protocolo de Quioto é um dos itens prioritários na agenda ambiental. A importância do instrumento se dá, principalmente, por dois motivos: do ponto de vista político, o facto de os países do Anexo I terem metas, e os países em desenvolvimento não as terem, representou o claro fortalecimento do princípio das responsabilidades comuns, porém diferenciadas, um dos pilares da posição dos países em desenvolvimento nas negociações internacionais sobre mudança do clima. Do ponto de vista económico, o facto de os países fora do Anexo I não terem metas assegura flexibilidade para seus projectos de desenvolvimento. Nesse contexto, o Mecanismo de Desenvolvimento Limpo (MDL) do Protocolo de Quioto cria grande expectativa no país pelos benefícios que poderá trazer para Cabo Verde. Por um lado, os projectos a serem realizados no âmbito do MDL representam uma fonte de recursos financeiros para projectos de desenvolvimento sustentável e, por outro, esses projectos deverão incentivar o maior conhecimento científico e a adopção de inovações tecnológicas. Os países em desenvolvimento são de facto os mais vulneráveis à mudança do clima, em função de terem historicamente menor capacidade de responder à variabilidade natural do clima. A vulnerabilidade de Cabo Verde em relação à mudança do clima se manifesta em diversas áreas: por exemplo, aumento da frequência e intensidade de enchentes e secas, com perdas na agricultura e ameaça à biodiversidade; mudança do regime hidrológico, expansão de vectores de doenças endémicas. Além disso, a elevação do nível do mar pode vir a afectar todas as ilhas do arquipélago, em especial as ilhas mais planas. Cabo Verde é, indubitavelmente, um dos países que podem ser duramente atingidos pelos efeitos adversos das mudanças climáticas futuras, já que tem uma economia fortemente dependente de recursos naturais directamente ligados ao clima, a agricultura e no turismo. Para um país com tamanha vulnerabilidade, o esforço de mapear tal vulnerabilidade e risco, conhecer profundamente suas causas, sector por sector, e subsidiar políticas públicas de mitigação e de adaptação ainda é incipiente, situando-se aquém de suas necessidades.

Investigating barriers in HIV-testing oncology patients. The IBITOP study: phase I.

BACKGROUND: Since the advent of combined antiretroviral therapy (ART), the incidence of non-AIDS-defining cancers (non-ADCs) among HIV-positive patients is rising. We previously described HIV testing rates of <5% in our oncology centre, against a local HIV prevalence of 0.4% (1). We have since worked with the Service of Oncology to identify, how HIV testing can be optimized, we have conducted a study on investigating barriers in HIV-testing oncology patients (IBITOP) among treating oncologists and their patients. METHODS: After an initial two-month pilot study to examine feasibility (2), we conducted the first phase of the IBITOP study between 1st July and 31st October 2013. Patients of unknown HIV status, newly diagnosed with solid-organ non-AIDS-defining cancer, and treated at Lausanne University Hospital were invited to participate. Patients were offered HIV testing as a part of their initial oncology work-up. Oncologist testing proposals and patient acceptance were the primary endpoints. RESULTS: Of 235 patients with a new oncology diagnosis, 10 were excluded (7 with ADCs and 3 of known HIV-positive status). Mean age was 62 years; 48% were men and 71% were Swiss. Of 225 patients, 75 (33%) were offered HIV testing. Of these, 56 (75%) accepted, of whom 52 (93%) were tested. A further ten patients were tested (without documentation of being offered a test), which gave a total testing rate of 28% (62/225). Among the 19 patients who declined testing, reasons cited included self-perceived absence of HIV risk, previous testing and palliative care. Of the 140 patients not offered HIV testing and not tested, reasons were documented for 35 (25%), the most common being previous testing and follow-up elsewhere. None of the 62 patients HIV tested had a reactive test. CONCLUSIONS: In this study, one third of patients seen were offered testing and the HIV testing rate was fivefold higher than that of previously observed in this service. Most patients accepted testing when offered. As HIV-positive status impacts on the medical management of cancer patients, we recommend that HIV screening should be performed in settings, where HIV prevalence is >0.1%. Phase II of the IBITOP study is now underway to explore barriers to HIV screening among oncologists and patients following the updated national HIV testing guidelines which recommend testing in non-ADC patients undergoing chemotherapy.

Estudos Sectoriais - Vulnerabilidade e Adaptação às Mudanças Climáticas em Cabo Verde

A temperatura média global do planeta à superfície elevou-se de 0,6 a 0,7 ºC nos últimos 100 anos, com acentuada elevação desde a década de 60. A última década apresentou os três anos mais quentes dos últimos 1000 anos da história recente da Terra. Hoje, através das análises sistemáticas do Painel Intergovernamental de Mudança do Clima (IPCC), sintetizando o conhecimento científico existente sobre o sistema climático e como este responde ao aumento das emissões antropogénicas de gases do efeito estufa (GEE) e de aerossóis, há um razoável consenso de que o aquecimento global observado nos últimos 100 anos é causado pelas emissões acumuladas de GEE, principalmente o dióxido de carbono (CO2), oriundo da queima de combustíveis fósseis - carvão mineral, petróleo e gás natural - desde a Revolução Industrial e, em menor escala, do desmatamento da cobertura vegetal do planeta, e o metano (CH4), e não por eventual variabilidade natural do clima. A mudança global do clima já vem se manifestando de diversas formas, destacando-se o aquecimento global, a maior frequência e intensidade de eventos climáticos extremos, alterações nos regimes de chuvas, perturbações nas correntes marinhas, retracção de geleiras e elevação do nível dos oceanos. A menos que acções globais de mitigação do aumento de emissões de gases de efeito estufa sejam efectivamente implementadas nas próximas décadas (seria necessária uma redução de cerca de 60% das emissões globais de GEE para estabilizar suas concentrações em níveis considerados seguros para o sistema climático global), a demanda futura de energia, principalmente nos países em desenvolvimento, à medida que suas economias se expandem, terá como consequência alterações climáticas significativamente mais graves, como por exemplo, um aumento das temperaturas médias globais entre 1,4 e 5,8 graus Celsius (ºC) até o final do século, acompanhadas por substantivas e perturbadoras modificações no ciclo hidrológico em todo o planeta. A Convenção do Clima surgiu em resposta às ameaças das mudanças climáticas para o desenvolvimento sustentável, a segurança alimentar e os ecossistemas do planeta, como um tratado internacional de carácter essencialmente universal – foi firmada e ratificada por praticamente todos os países. O objectivo da Convenção é o de estabilizar a concentração dos gases de efeito estufa na atmosfera, em níveis tais que evitem a interferência perigosa com o sistema climático. Ora, tal estabilização somente pode ser obtida pela estabilização das emissões líquidas (emissões menos remoções) dos gases de efeito estufa. Por outro lado, já é impossível evitar completamente a mudança global do clima. O Protocolo de Quioto representa o principal avanço obtido na Convenção, estabelecendo limites para a emissão de GEE dos países do Anexo I (Membros da OCDE e economias em transição), que em seu conjunto deverão no período 2008-2012 reduzi-las em 5,2% do total emitido por eles em 1990. Negociado em 1997, assinado por praticamente todos os países, e ratificado por uma grande maioria, o Tratado de Quioto entrou em vigor em 16 de Fevereiro de 2005. No entanto, os Estados Unidos (EUA) decidiram não buscar a sua ratificação, no que foram seguidos pela Austrália, embora esta última tenha declarado que limitará as suas emissões como se houvesse ratificado. Para os países em desenvolvimento e, sobretudo, para as maiores economias em desenvolvimento como China, Índia e Brasil, que devem, ao mesmo tempo, inserir-se na moderna economia globalizada e superar seus passivos social e económico, o Protocolo de Quioto é um dos itens prioritários na agenda ambiental. A importância do instrumento se dá, principalmente, por dois motivos: do ponto de vista político, o facto de os países do Anexo I terem metas, e os países em desenvolvimento não as terem, representou o claro fortalecimento do princípio das responsabilidades comuns, porém diferenciadas, um dos pilares da posição dos países em desenvolvimento nas negociações internacionais sobre mudança do clima. Do ponto de vista económico, o facto de os países fora do Anexo I não terem metas assegura flexibilidade para seus projectos de desenvolvimento. Nesse contexto, o Mecanismo de Desenvolvimento Limpo (MDL) do Protocolo de Quioto cria grande expectativa no país pelos benefícios que poderá trazer para Cabo Verde. Por um lado, os projectos a serem realizados no âmbito do MDL representam uma fonte de recursos financeiros para projectos de desenvolvimento sustentável e, por outro, esses projectos deverão incentivar o maior conhecimento científico e a adopção de inovações tecnológicas. Os países em desenvolvimento são de facto os mais vulneráveis à mudança do clima, em função de terem historicamente menor capacidade de responder à variabilidade natural do clima. A vulnerabilidade de Cabo Verde em relação à mudança do clima se manifesta em diversas áreas: por exemplo, aumento da frequência e intensidade de enchentes e secas, com perdas na agricultura e ameaça à biodiversidade; mudança do regime hidrológico, expansão de vectores de doenças endémicas. Além disso, a elevação do nível do mar pode vir a afectar todas as ilhas do arquipélago, em especial as ilhas mais planas. Cabo Verde é, indubitavelmente, um dos países que podem ser duramente atingidos pelos efeitos adversos das mudanças climáticas futuras, já que tem uma economia fortemente dependente de recursos naturais directamente ligados ao clima, a agricultura e no turismo. Para um país com tamanha vulnerabilidade, o esforço de mapear tal vulnerabilidade e risco, conhecer profundamente suas causas, sector por sector, e subsidiar políticas públicas de mitigação e de adaptação ainda é incipiente, situando-se aquém de suas necessidades.

Disentangling human tolerance and resistance against HIV.

In ecology, "disease tolerance" is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis.

Improved HIV-1 RNA quantitation by COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, v2.0 using a novel dual-target approach.

BACKGROUND: HIV-1 RNA viral load is a key parameter for reliable treatment monitoring of HIV-1 infection. Accurate HIV-1 RNA quantitation can be impaired by primer and probe sequence polymorphisms as a result of tremendous genetic diversity and ongoing evolution of HIV-1. A novel dual HIV-1 target amplification approach was realized in the quantitative COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, v2.0 (HIV-1 TaqMan test v2.0) to cope with the high genetic diversity of the virus. OBJECTIVES AND STUDY DESIGN: The performance of the new assay was evaluated for sensitivity, dynamic range, precision, subtype inclusivity, diagnostic and analytical specificity, interfering substances, and correlation with the COBAS AmpliPrep/COBAS TaqMan HIV-1 (HIV-1 TaqMan test v1.0) predecessor test in patients specimens. RESULTS: The new assay demonstrated a sensitivity of 20 copies/mL, a linear measuring range of 20-10,000,000 copies/mL, with a lower limit of quantitation of 20 copies/mL. HIV-1 Group M subtypes and HIV-1 Group O were quantified within +/-0.3 log(10) of the assigned titers. Specificity was 100% in 660 tested specimens, no cross reactivity was found for 15 pathogens nor any interference for endogenous substances or 29 drugs. Good comparability with the predecessor assay was demonstrated in 82 positive patient samples. In selected clinical samples 35/66 specimens were found underquantitated in the predecessor assay; all were quantitated correctly in the new assay. CONCLUSIONS: The dual-target approach for the HIV-1 TaqMan test v2.0 enables superior HIV-1 Group M subtype coverage including HIV-1 Group O detection. Correct quantitation of specimens underquantitated in the HIV-1 TaqMan test v1.0 test was demonstrated.

Voyages et VIH: les points-clés [Key aspects regarding HIV and travel].

The risk of contracting a sexually transmitted infection while traveling abroad is increased in certain populations. Pre-travel consultation should include the education of travelers on the prevalence of HIV in the countries visited and on appropriate prevention measures. In patients infected with HIV (PHIV), combined antiretroviral therapy (cART) improves immunity, enabling them to travel with less risk for their health. Pre-travel consultation of PVIH has the following objectives: to determine immune status, to update immunization and to decide on anti-malaria drug prophylaxis, taking into account potential drug interactions with antiretroviral therapy. Vaccine response and duration of protection is shorter-lived in PVIH, especially if the CD4 count is below 200 cells/mm3 and the HIV viral load is detectable. Therefore cART is a cornerstone for disease prevention among patients infected with HIV who travel.

Phenotype and function of protective T cell immune responses in HIV.

PURPOSE OF REVIEW: Definition of T cell immune correlates in HIV infection remains a lofty goal towards our understanding of the HIV-specific immune response. This review will focus upon recent developments and controversies in our understanding of protective T cell responses against HIV. RECENT FINDINGS: It has become clear that multiple functions and phenotypic markers of T cells must be assessed to accurately characterize the complexity of CD4 and CD8 T cell responses. While evidence indicates that a hallmark of protective immune responses in HIV infection is the presence of 'polyfunctional' T cell responses, a disconnect remains between the function and phenotype of effective HIV-specific T cells. Moreover, there may be inherent differences in the ability of specific human leukocyte antigen class I families to promote CD8 T cell effector versus polyfunctional responses. It remains to be determined how polyfunctional responses arise in HIV infection, which functions are important for control, and whether surface phenotype markers provide an indication of protective capacity. SUMMARY: Polyfunctional and phenotypic assessment of T cell responses have clearly advanced our understanding of HIV specific immune responses. Critical questions remain, however, especially whether polyfunctional T cell responses control, or are controlled by, HIV replication.

Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification.

BACKGROUND: Antiretroviral therapy (ART) decreases morbidity and mortality in HIV-infected patients but is associated with considerable adverse events (AEs). METHODS: We examined the effect of AEs to ART on mortality, treatment modifications and drop-out in the Swiss HIV Cohort Study. A cross-sectional evaluation of prevalence of 13 clinical and 11 laboratory parameters was performed in 1999 in 1,078 patients on ART. AEs were defined as abnormalities probably or certainly related to ART. A score including the number and severity of AEs was defined. The subsequent progression to death, drop-out and treatment modification due to intolerance were evaluated according to the baseline AE score and characteristics of individual AEs. RESULTS: Of the 1,078 patients, laboratory AEs were reported in 23% and clinical AEs in 45%. During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality with an adjusted hazard ratio (HR) of 1.3 (95% confidence interval [CI] 1.2-1.5; P < 0.001) per score point. For clinical AEs no significant association with increased mortality was found. In contrast, an increasing score for clinical AEs (HR 1.11,95% CI 1.04-1.18; P = 0.002), but not for laboratory AEs (HR 1.07, 95% CI 0.97-1.17; P = 0.17), was associated with antiretroviral treatment modification. AEs were not associated with a higher drop-out rate. CONCLUSIONS: The burden of laboratory AEs to antiretroviral drugs is associated with a higher mortality. Physicians seem to change treatments to relieve clinical symptoms, while accepting laboratory AEs. Minimizing laboratory drug toxicity seems warranted and its influence on survival should be further evaluated.

Immune response to hepatitis B vaccination in HIV-positive adults with isolated antibodies to HBV core antigen.

OBJECTIVE: To investigate the merits of vaccination against hepatitis B virus (HBV) in HIV-positive individuals with isolated antibodies to hepatitis B core antigen (anti-HBc). METHODS: HIV-positive patients with isolated anti-HBc and CD4 counts >200 cells/mm(3) received HBV vaccination. An antibody titre to hepatitis B surface antigen (anti-HBs titres) ≥10 IU/L one month post-vaccination was termed an anamnestic response; a titre <10 IU/L was termed a primary response. Patients with primary responses received a 3-dose vaccine course. Anti-HBs titres in all responders were measured 12 and 24 months post-vaccination. RESULTS: 37 patients were studied: 19 (51%) were co-infected with hepatitis C; median CD4 count was 443 cells/mm(3). 8/37 patients (22%) elicited an anamnestic response. 29/37 patients (78%) elicited a primary response. After a 3-dose vaccine course, 15/25 primary responders (60%) achieved anti-HBs titres ≥10 IU/L. HIV acquisition through injecting drug use was the only independent predictor of an anamnestic response (OR 22.9, CI 1.71-306.74, P=0.018). Median anti-HBs titres for anamnestic and primary responders were 51 IU/L (13-127) and 157 IU/L (25-650) respectively. Of all responders, 12/23 (52%) retained anti-HBs titres ≥10 IU/L at 24 months. Anti-HBs duration was not significantly different between anamnestic and primary responders. CONCLUSIONS: 23/37 HIV-positive patients (62%) with isolated anti-HBc achieved anti-HBs titres ≥10 IU/L after 1-3 vaccine doses. However, duration of this immune response was short-lived (

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients.

OBJECTIVE: To measure the in vivo variations of CYP3A activity induced by anti-HIV drugs in human immunodeficiency virus (HIV)1-positive patients. METHODS: A low oral dose of midazolam (MID) (0.075 mg) was given to the patients and the 30-min total 1-OH midazolam (1-OHMID)/MID ratio was determined. Patients were phenotyped either before the introduction of antiretroviral treatments (control group, 90 patients) or after a variable period of antiretroviral treatment (56 patients). Twenty-one subjects underwent multiple phenotyping tests (before and during the course of the treatment). RESULTS: The median MID ratio was 3.51 in the control group (range 0.20-14.6). It was 5-fold higher in the group with efavirenz (28 patients; median, range: 16.0, 3.81-367; P < 0.0001), 13-fold lower with nelfinavir (18 patients; 0.27, 0.06-36.3; P < 0.0001), 17-fold lower with efavirenz + ritonavir (three patients; 0.21, 0.05-0.47; P = 0.006), 50-fold lower with ritonavir (four patients; 0.07, 0.06-0.17; P = 0.0007), and 7-fold lower with nevirapine + (ritonavir or nelfinavir or grapefruit juice) (three patients; 0.48, 0.03-1.83; P = 0.03). CYP3A activity was lower in the efavirenz + ritonavir group (P = 0.01) and in the ritonavir group (P = 0.04) than in the nelfinavir group, although already strongly inhibited in the latter. CONCLUSION: The low-dose MID phenotyping test was successfully used to measure the in vivo variations of CYP3A activity induced by antiretroviral drugs. Efavirenz strongly induces CYP3A activity, while ritonavir almost completely inhibits it. Nelfinavir strongly decreases CYP3A activity, but to a lesser extent than ritonavir. The inhibition of CYP3A by ritonavir or nelfinavir offsets the inductive effects of efavirenz or nevirapine administered concomitantly. Finally, no induction of CYP3A activity was noticeable after long-term administration of ritonavir at low dosages (200 mg/day b.i.d.) or of nelfinavir at standard dosages (2,500 mg/day b.i.d.).