HIV-1 co/super-infection in intravenous drug users.

BACKGROUND: The frequency of HIV-1 co/super-infection is unknown despite their implications for public health and vaccine development. This issue was addressed during an epidemic of both CRF11 and B subtype among intravenous drug users (IVDUs). METHODS: Bulk sequencing of reverse transcriptase, protease and C2V3 regions and subtype-specific nested polymerase chain reaction (PCR) in plasma and proviral DNA were performed using baseline and follow-up samples collected in recently infected IVDUs between 1998-2002 and in IVDUs with chronic infection living in the same area and presenting an unexpected rise of viremia (> 1 log10). RESULTS: In 58 recently infected patients, three B/CRF-11 co-infections, 25 B, 28 CRF-11 and two other subtypes were detected at baseline. In the three co-infected patients, both CRF-11 and B were detected in plasma and proviral DNA and persisted during follow-up. B- and CFR-11-specific PCR performed on follow-up samples of 40 of 58 recently infected patients (median follow-up, 14.5 months) revealed a transient B super-infection in a patient initially infected by CRF-11. Five of 156 chronic IVDUs (total follow-up: 346 years) had an unexpected rise of viremia. In two of them, aviremic without treatment for years after an initial B infection, a symptomatic CRF-11 super-infection occurred and was associated with high viral load and a fall of CD4 cell count. CONCLUSIONS: In recently infected IVDUs, co-infection B/CRF-11 is relatively frequent (5%). In chronically infected IVDUs super-infection may be transient and may occur in patients controlling efficiently HIV infection by the initial strain.

Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid.

OBJECTIVES: To determine HIV-1 RNA in cerebrospinal fluid (CSF) of successfully treated patients and to evaluate if combination antiretroviral treatments with higher central nervous system penetration-effectiveness (CPE) achieve better CSF viral suppression. METHODS: Viral loads (VLs) and drug concentrations of lopinavir, atazanavir, and efavirenz were measured in plasma and CSF. The CPE was calculated using 2 different methods. RESULTS: The authors analyzed 87 CSF samples of 60 patients. In 4 CSF samples, HIV-1 RNA was detectable with 43-82 copies per milliliter. Median CPE in patients with detectable CSF VL was significantly lower compared with individuals with undetectable VL: CPE of 1.0 (range, 1.0-1.5) versus 2.3 (range, 1.0-3.5) using the method of 2008 (P = 0.011) and CPE of 6 (range, 6-8) versus 8 (range, 5-12) using the method of 2010 (P = 0.022). The extrapolated CSF trough levels for atazanavir (n = 12) were clearly above the 50% inhibitory concentration (IC50) in only 25% of samples; both patients on atazanavir/ritonavir with detectable CSF HIV-1 RNA had trough levels in the range of the presumed IC50. The extrapolated CSF trough level for lopinavir (n = 42) and efavirenz (n = 18) were above the IC50 in 98% and 78%, respectively, of samples, including the patients with detectable CSF HIV-1 RNA. CONCLUSIONS: This study suggests that treatment regimens with high intracerebral efficacy reflected by a high CPE score are essential to achieve CSF HIV-1 RNA suppression. The CPE score including all drug components was a better predictor for treatment failure in the CSF than the sole concentrations of protease inhibitor or nonnucleoside reverse transcriptase inhibitor in plasma or CSF.

Transmission of HIV-1 drug resistance in Switzerland: a 10-year molecular epidemiology survey.

OBJECTIVES: Representative prevalence data of transmitted drug-resistant HIV-1 are essential to establish accurate guidelines addressing resistance testing and first-line treatments. METHODS: Systematic resistance testing was carried out in individuals in Switzerland with documented HIV-1 seroconversion during 1996-2005 and available samples with RNA > 1000 copies/ml obtained within 1 year of estimated seroconversion. Resistance interpretation used the Stanford list of mutations for surveillance of transmitted drug resistance and the French National Agency for AIDS Research algorithm. RESULTS: Viral sequences from 822 individuals were available. Risk groups were men having sex with men (42%), heterosexual contacts (32%) and intravenous drug users (20%); 30% were infected with non-B subtype viruses. Overall, prevalence of transmitted resistance was 7.7% [95% confidence interval (CI), 5.9-9.5] for any drug, 5.5% (95% CI, 3.9-7.1) for nucleoside reverse transcriptase inhibitors, 1.9% (95% CI, 1.0-2.8) for non-nucleoside reverse transcriptase inhibitors and 2.7% (95% CI, 1.6-3.8) for protease inhibitors. Dual- or triple-class resistance was observed in 2% (95% CI, 0.8-2.5). No significant trend in prevalence of transmitted resistance was observed over years. There were no differences according to ethnicity, risk groups or gender, but prevalence of transmitted resistance was highest among individuals infected with subtype B virus. CONCLUSIONS: The transmission rate of drug-resistant HIV-1 has been stable since 1996, with very rare transmission of dual- or triple-class resistance. These data suggest that transmission of drug resistance in the setting of easy access to antiretroviral treatment can remain stable and be kept at a low level.

The impact of transmission clusters on primary drug resistance in newly diagnosed HIV-1 infection.

OBJECTIVES: To monitor HIV-1 transmitted drug resistance (TDR) in a well defined urban area with large access to antiretroviral therapy and to assess the potential source of infection of newly diagnosed HIV individuals. METHODS: All individuals resident in Geneva, Switzerland, with a newly diagnosed HIV infection between 2000 and 2008 were screened for HIV resistance. An infection was considered as recent when the positive test followed a negative screening test within less than 1 year. Phylogenetic analyses were performed by using the maximum likelihood method on pol sequences including 1058 individuals with chronic infection living in Geneva. RESULTS: Of 637 individuals with newly diagnosed HIV infection, 20% had a recent infection. Mutations associated with resistance to at least one drug class were detected in 8.5% [nucleoside reverse transcriptase inhibitors (NRTIs), 6.3%; non-nucleoside reverse transcriptase inhibitors (NNRTIs), 3.5%; protease inhibitors, 1.9%]. TDR (P-trend = 0.015) and, in particular, NNRTI resistance (P = 0.002) increased from 2000 to 2008. Phylogenetic analyses revealed that 34.9% of newly diagnosed individuals, and 52.7% of those with recent infection were linked to transmission clusters. Clusters were more frequent in individuals with TDR than in those with sensitive strains (59.3 vs. 32.6%, respectively; P < 0.0001). Moreover, 84% of newly diagnosed individuals with TDR were part of clusters composed of only newly diagnosed individuals. CONCLUSION: Reconstruction of the HIV transmission networks using phylogenetic analysis shows that newly diagnosed HIV infections are a significant source of onward transmission, particularly of resistant strains, thus suggesting an important self-fueling mechanism for TDR.

Viral suppression rates in salvage treatment with raltegravir improved with the administration of genotypic partially active or inactive nucleoside/tide reverse transcriptase inhibitors.

BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs. METHODS: The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response. RESULTS: One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1-2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5-2.5) compared with 2.5 (2-3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively. CONCLUSIONS: Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.

Minor protease inhibitor mutations at baseline do not increase the risk for a virological failure in HIV-1 subtype B infected patients.

BACKGROUND: Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naïve patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential. METHODS: To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and ≥ 1 minor PI mutation. Models were adjusted for baseline HIV-1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs. RESULTS: We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or ≥ 4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and ≥ 1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0-1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5-1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome. CONCLUSIONS: The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals.

Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.

BACKGROUND: The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. METHODS: FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was -12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. FINDINGS: Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7-20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). INTERPRETATION: Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients. FUNDING: ViiV Healthcare and Shionogi & Co.

The Role of Second Generation Antiretroviral Drugs in HIV-1 Subtype B and non-B Variants Harboring Natural Polymorphisms and Drug Resistance Mutations.

Cette thèse traite de la résistance du VIH-1 aux antirétroviraux, en particulier de l'activité antivirale de plusieurs inhibiteurs non nucléosidiques de la transcriptase inverse (INNTI) ainsi que des inhibiteurs de protéase (IP). Nous avons exploré l’émergence et la spécificité des voies de mutations qui confèrent la résistance contre plusieurs nouveaux INNTI (étravirine (ETR) et rilpivirine (RPV)) (chapitres 2 et 3). En outre, le profil de résistance et le potentiel antirétroviral d'un nouvel IP, PL-100, est présenté dans les chapitres 4 et 5. Pour le premier projet, nous avons utilisé des sous-types B et non-B du VIH-1 pour sélectionner des virus résistants à ETR, et ainsi montré que ETR favorise l’émergence des mutations V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y et M230L, et ce, en 18 semaines. Fait intéressant, E138K a été la première mutation à émerger dans la plupart des cas. Les clones viraux contenant E138K ont montré un faible niveau de résistance phénotypique à ETR (3,8 fois) et une diminution modeste de la capacité de réplication (2 fois) par rapport au virus de type sauvage. Nous avons également examiné les profils de résistance à ETR et RPV dans les virus contenant des mutations de résistance aux INNTI au début de la sélection. Dans le cas du virus de type sauvage et du virus contenant la mutation unique K103N, les premières mutations à apparaître en présence d’ETR ou de RPV ont été E138K ou E138G suivies d’autres mutations de résistance aux INNTI. À l’inverse, dans les mêmes conditions, le virus avec la mutation Y181C a évolué pour produire les mutations V179I/F ou A62V/A, mais pas E138K/G. L'ajout de mutations à la position 138 en présence de Y181C n'augmente pas les niveaux de résistance à ETR ou RPV. Nous avons également observé que la combinaison de Y181C et E138K peut conduire à un virus moins adapté par rapport au virus contenant uniquement Y181C. Sur la base de ces résultats, nous suggérons que les mutations Y181C et E138K peuvent être antagonistes. L’analyse de la résistance au PL-100 des virus de sous-type C et CRF01_AE dans les cellules en culture est décrite dans le chapitre 4. Le PL-100 sélectionne pour des mutations de résistance utilisant deux voies distinctes, l'une avec les mutations V82A et L90M et l'autre avec T80I, suivi de l’addition des mutations M46I/L, I54M, K55R, L76F, P81S et I85V. Une accumulation d'au moins trois mutations dans le rabat protéique et dans le site actif est requise dans chaque cas pour qu’un haut niveau de résistance soit atteint, ce qui démontre que le PL-100 dispose d'une barrière génétique élevée contre le développement de la résistance. Dans le chapitre 5, nous avons évalué le potentiel du PL-100 en tant qu’inhibiteur de protéase de deuxième génération. Les virus résistants au PL-100 émergent en 8-48 semaines alors qu’aucune mutation n’apparaît avec le darunavir (DRV) sur une période de 40 semaines. La modélisation moléculaire montre que la haute barrière génétique du DRV est due à de multiples interactions avec la protéase dont des liaison hydrogènes entre les groupes di-tétrahydrofuranne (THF) et les atomes d'oxygène des acides aminés A28, D29 et D30, tandis que la liaison de PL-100 est principalement basée sur des interactions polaires et hydrophobes délocalisées à travers ses groupes diphényle. Nos données suggèrent que les contacts de liaison hydrogène et le groupe di-THF dans le DRV, ainsi que le caractère hydrophobe du PL-100, contribuent à la liaison à la protéase ainsi qu’à la haute barrière génétique contre la résistance et que la refonte de la structure de PL-100 pour inclure un groupe di-THF pourrait améliorer l’activité antivirale et le profil de résistance.

Immune reconstitution in HIV-1 infected patients treated for two years with highly active antiretroviral therapy

The aim of this paper was to evaluate the immune reconstitution of HIV-1 patients subjected to highly active antiretroviral therapy (HAART) for two years or more according to CD 45RA and CD 45RO cell count; determination of IL-2, IFN-γ, IL-4, IL-10 and TNF-α serum levels; CD 4 + T and CD 8 + T lymphocyte count; and plasma viral load (VL) determination. For this purpose, a cross sectional study was carried out in the Tropical Diseases Area, Botucatu School of Medicine, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil. Between June 2001 and April 2002, 37 HIV-1 infected patients were evaluated, 13 with treatment indication but untreated (G1), 9 subjected to HAART for 5-7 months (G2), and 15 treated for two years or more (G3); both treated groups used medication regularly and without failure. Forty-nine normal individuals were studied as controls (GC-1 and GC-2). There was a tendency (p<0.10) for the predominance of two nucleoside reverse transcriptase inhibitors (NRTI) associated with one non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen in G2; and two NRTI associated with a protease inhibitor (PI) in G3. Statistical differences between groups were seen for CD 45RA (G1<[G3=GC-2]; p<0.05) and CD 45RO (G1[G2=G3]; p<0.001), TNF-α serum determination ([G1>G3; G2=intermediate]>GC-1; p<0.001), IL-2 (G1<[G2=G3=GC-1]; p<0.01), IFN-γ ([G1=GC-1]>[GC-2=G3]; p<0.001), IL-4 and IL-10 ([G1=G2=G3]>GC-1; p<0.001), serum cytokine profiles, with a higher proportion of subtype 2 in G1 and mature subtype 0 in G2 and G3 (p<0.005). There was no statistical difference for CD 8 + T lymphocyte counts (G1=G2=G3; p<0.50). Consistency was seen between positive correlations of profile 1 definer cytokines (IL-2 and IFN-γ), CD 45RA and CD 45RO cells, and CD 4 + T lymphocyte counts and between positive correlations of profile 2 definer cytokines (IL-4 and IL-10) with TNF-α, and VL. The negative correlations were also consistent as they expressed the inverse of the positives. The variables with the highest number of correlations were IL-2, IFN-γ, and VL, followed by CD 45RA and CD 45RO cells, and IL-10. The variables with the lowest number of correlations were CD 4 + T and CD 8 + T lymphocytes. The results express the partial but important immune reconstitution in HIV-1 infected individuals with the interference of HAART and the importance of cytokines especially IL-2 and IFN-γ, and CD 45RA and CD 45RO cells as surrogate markers of this reconstitution.

Perfil de resistência genótica do HIV-1 em pacientes com falha na terapia antirretroviral atendidos pela Rede Nacional de Genotipagem (RENAGENO) na região de Botucatu, SP-Brasil

Pós-graduação em Pesquisa e Desenvolvimento (Biotecnologia Médica) - FMB

Genotipagem do HIV-1 no Pará em pacientes experimentando falha terapêutica antirretroviral

Terapia supressiva antirretroviral reduz significativamente morbidades e mortalidade relacionadas ao HIV, mas a emergência de vírus resistentes pode limitar o sucesso do tratamento. Objetivou-se neste estudo descrever, em portadores de HIV/sida experimentando falha à terapia antirretroviral (TARV), no estado do Pará, a prevalência de mutações nas enzimas transcriptase reversa e protease do HIV-1 e correlacioná-las à resistência aos antirretrovirais (ARV). Foi um estudo descritivo, retrospectivo, do tipo transversal, com dados obtidos na Unidade de Referência Especializada em Doenças Infecciosas e Parasitárias Especiais de Belém do Pará, de pacientes com perfil laboratorial de falha terapêutica. A presente amostra incluiu genotipagem de cinquenta pacientes no período de janeiro de 2004 a dezembro de 2005. Os critérios de inclusão foram: adesão à terapia imediata a genotipagem, falha terapêutica, perfil de resistência viral à TARV e ser paciente da rede pública de saúde. Foram descritos aspectos demográficos da população estudada, perfil de uso de TARV previamente a genotipagem, tempo conhecido de infecção pelo HIV, perfil quantitativo de células CD4+ e de carga viral, além do teste de genotipagem realizado. A resistência encontrada predominou em pacientes residentes em Belém (72%), no sexo masculino (90%) e na faixa etária de 30 a 49 anos de idade. As maiores prevalências de mutações na transcriptase reversa do HIV-1 foram: 214F (86%), 184V (76%), 215FY (56%), 211K (48%), 219QEN, 67N e 103N (42%) cada, 41L (32%), 70R (28%) e 210W (20%). Na protease 46IL (38%), 90M (32%) e 82AFT (20%) foram as mais prevalentes dentre as mutações principais e, dentre as secundárias, 63P (74%), 93LM (52%), 10FIV (48%) e 35D (46%). Atribuiu-se estas mutações a pressão seletiva dos ARV mais utilizados: 3TC, AZT, D4T, DDI, EFZ, IDV, NFV, RTV e SQV. O uso de múltiplos esquemas ARV, favoreceu a prevalência das mutações encontradas. Houve impacto dentro das classes com 32% de resistência completa a uma classe, 22% a duas classes e 4% a três classes. Conclui-se que pacientes expostos a única TARV previamente à genotipagem comparados aos expostos a mais de uma TARV, apresentaram menor prevalência de resistência aos ARV, com possibilidade de resgate terapêutico com ARV ativos disponíveis na época que, entretanto foi a minoria.

Caracterização molecular da resistência genotípica secundária aos antirretrovirais em pacientes com Aids e prevalência de subtipos do HIV-1 nos Estados do Pará e Amazonas, Brasil: 2002 a 2006

A resistência às drogas antirretrovirais é o inevitável resultado da incompleta supressão da replicação do HIV-1. No presente estudo foi caracterizado o perfil de resistência genética aos antirretrovirais em amostras sorológicas provenientes dos estados do Amazonas e Pará, Região Norte do Brasil, no período de 2002 a 2006. Um total de 127 amostras de plasmas obtidas de pacientes HIV positivos e/ou Aids foram submetidas ao teste de resistência pelo ViroSeq^TM Genotyping System (Celera Diagnostic-Abbott, USA). Considerando a informação genética derivada das regiões da protease e/ou transcriptase reversa do HIV-1, o subtipo B foi observado em 85% dos casos; seguido por ambos subtipo F1 e forma recombinante BF1 (4,6%) e CF1 (0,8%). A mutação M184V (81,1%) foi a mais comumente observada associada aos NRTI, em indivíduos positivos com TARV no estado do Pará, e a mutação T215F/Y (56,3%) em indivíduos do estado do Amazonas. A mutação K103N foi a mais prevalente (em torno de 33,5%) para os NNRTI em ambos os estados. O perfil de mutação de resistência associado ao gene da protease mostrou a mutação minor L63P como a mais frequente em ambos os estados. O estudo revelou a importância da identificação de mutações associadas com resistência às drogas antirretrovirais para o uso em futuros esquemas terapêuticos. Os resultados deste estudo foram similares aos outros realizados em várias regiões do Brasil.

Epidemiologia molecular do Vírus da imunodeficiência humana 1 (HIV-1) em mulheres (mães e grávidas) dos Estados do Acre e Tocantins, Brasil

A transmissão vertical é a principal fonte de infecção pelo HIV em crianças, e pode ocorrer antes, durante e depois do nascimento, dessa forma sendo um grande problema de saúde pública mundial. O presente trabalho teve como objetivo descrever a epidemiologia molecular e o perfil de susceptibilidade/resistência das cepas de HIV-1 identificadas em mulheres nos estados do Acre e do Tocantins. Coletou-se amostra de sangue de 36 mulheres, sendo 9 grávidas e 16 mães de Palmas (Tocantins) e 1 grávida e 10 mães do Rio Branco (Acre) entre abril de 2007 a outubro de 2008. Realizou-se a técnica molecular Reação em Cadeia mediada pela Polimerase (PCR) Nested, para a amplificação de duas regiões genômicas (pro e tr) do DNA proviral, seguido de sequenciamento nucleotídico e análise filogenética. No Acre, tanto em relação ao segmento da protease quanto da transcriptase reversa, todas as amostras foram do subtipo B. Em Tocantins, quanto ao segmento da protease, todas as amostras pertenceram ao subtipo B, já em relação ao segmento da transcriptase reversa 87,5% foram do subtipo B e 12,5% pertencente ao subtipo F. No estado do Acre, todas as cepas analisadas foram suscetíveis aos inibidores de protease (IP) e apenas uma grávida de Tocantins (4,7%) apresentou cepa com resistência aos IP utilizados atualmente. Além disso, verificou-se uma baixa prevalência de cepas com mutações de resistência aos inibidores de transcriptase reversa nucleosídicos (ITRN) e não nucleosídicos (ITRNN), sendo que a resistência as três classes desses ARV foi observada em apenas uma amostra proveniente do estado do Tocantins. Dessa forma, a maioria das cepas de HIV isoladas mostrou susceptibilidade aos ARV utilizados, indicando que há baixa circulação de cepas do HIV resistentes a estes medicamentos nesses estados.

Análise da expressão de genes selecionados do herpevírus associado ao sarcoma de Kaposi (KSHV) em células TIVE-LTC expostas à proteína tat do vírus da imunodeficiência humana (HIV-1)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Evaluation of HIV-1 resistance to antiretroviral drugs among 150 patients after six months of therapeutic interruption

Most of the antiretroviral (ARV) studies in Brazil have been reported in treatment-experienced and naive patients rather than in the setting of treatment interruption (TI). In this study, we analysed reasons given for TI and resistance mutations occurring in 150 HIV-1-infected patients who underwent TI. Of the patients analysed, 110 (73.3%) experienced TI following medical advice, while the remaining patients stopped antiretroviral therapy (ART) of their own accord. The main justifications for TI were: ARV-related toxicities (38.7%), good laboratory parameters (30%) and poor adherence (20%). DNA sequencing of the partial pol gene was successful in 137 (91.3%) patients, of whom 38 (27.7%) presented mutations conferring ARV resistance. A higher viral load prior to TI correlated with drug resistance (P < 0.05). Our results demonstrate that there are diverse rationales for TI and that detection of resistant strains during TI most likely indicates a fitter virus than the wild type. High viral loads coupled with unprotected sex in this group could increase the likelihood of transmission of drug-resistant virus. Thus, treating physicians should be alerted to this problem when the use of ARVs is interrupted.