Genotypic and Phenotypic Characterization of Replication-Competent HIV-2 Isolated from Controllers and Progressors.

Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2.

Immune reconstitution inflammatory syndrome in HIV infected late presenters starting integrase inhibitor containing antiretroviral therapy.

BACKGROUND: Integrase inhibitors (INI) induce a rapid decline of HIV-RNA in plasma and CD4+ T-cell recovery in blood. Both characteristics are also associated with immune reconstitution inflammatory syndrome (IRIS). Whether the use of INI-containing combination antiretroviral therapy (cART) increases the risk of IRIS is being questioned. METHODS: Study within the Dutch ATHENA HIV observational cohort. HIV-1 infected late presenters initiating cART after March 2009 were included if they had <200 CD4+ T-cells per µL and were diagnosed with an opportunistic infection. IRIS was defined either according to the criteria by French et al. (IRISFRENCH) or by a clinical IRIS diagnosis of the physician (IRISCLINICAL). The primary outcomes were the association between INI and the occurrence of IRISFRENCH and IRISFRENCH+CLINICAL in multivariable logistic regression. FINDINGS: 672 patients with a median CD4+ T-cell count of 35 cells per µL were included. Treatment with INI was independently associated with IRISFRENCH as well as IRISFRENCH+CLINICAL (OR 2·43, 95%CI:1·45-4·07, and OR 2·17, 95%CI:1·45-3·25). When investigating INI separately, raltegravir (RAL) remained significantly associated with IRISFRENCH (OR 4·04 (95%CI:1·99-8·19) as well as IRISFRENCH+CLINICAL (OR 3·07, 95%CI:1·66-5·69), while dolutegravir (DTG) became associated with IRISFRENCH+CLINICAL after it replaced RAL as preferred INI in the cohort after 2015 (OR 4·08, 95%CI:0·99-16·82, p=0·052). Too few patients used elvitegravir to draw meaningful conclusions. Steroid initiation for IRIS was more likely in those who initiated INI versus in those who did not, but no increased hospital (re)admission or mortality rates were observed. INTERPRETATION: In HIV late presenters from a resource rich setting, INI based treatment initiation increased the risk of IRIS. This was observed for RAL and DTG when being initiated as preferential INI in the presence of specific AIDS-conditions, indicative of channeling bias. Although we controlled for all relevant measured confounders, we cannot exclude that the observed association is partially explained by residual confounding. INI use was not associated with mortality nor hospitalization. Therefore, our observation is no reason to avoid INI in late presenters. FUNDING: The ATHENA database is maintained by Stichting HIV Monitoring and supported by a grant from the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment.

HIV-1 Resistance Dynamics in Patients With Virologic Failure to Dolutegravir Maintenance Monotherapy.

Background: A high genetic barrier to resistance to the integrase strand transfer inhibitor (INSTI) dolutegravir has been reported in vitro and in vivo. We describe the dynamics of INSTI resistance-associated mutations (INSTI-RAMs) and mutations in the 3'-polypurine tract (3'-PPT) in relation to virologic failure (VF) observed in the randomized Dolutegravir as Maintenance Monotherapy for HIV-1 study (DOMONO, NCT02401828). Methods: From 10 patients with VF, plasma samples were collected before the start of cART and during VF, and were used to generate Sanger sequences of integrase, the 5' terminal bases of the 3' long terminal repeat (LTR), and the 3'-PPT. Results: Median human immunodeficiency virus RNA load at VF was 3490 copies/mL (interquartile range 1440-4990 copies/mL). INSTI-RAMs (S230R, R263K, N155H, and E92Q+N155H) were detected in 4 patients, no INSTI-RAMs were detected in 4 patients, and sequencing of the integrase gene was unsuccessful in 2 patients. The time to VF ranged from 4 weeks to 72 weeks. In 1 patient, mutations developed in the highly conserved 3'-PPT. No changes in the terminal bases of the 3'-LTR were observed. Conclusions: The genetic barrier to resistance is too low to justify dolutegravir maintenance monotherapy because single INSTI-RAMs are sufficient to cause VF. The large variation in time to VF suggests that stochastic reactivation of a preexisting provirus containing a single INSTI-RAM is the mechanism for failure. Changes in the 3'-PPT point to a new dolutegravir resistance mechanism in vivo. Clinical Trials Registration: NCT02401828.

The S230R Integrase Substitution Associated With Virus Load Rebound During Dolutegravir Monotherapy Confers Low-Level Resistance to Integrase Strand-Transfer Inhibitors.

Background: Dolutegravir (DTG) is an integrase strand-transfer inhibitor (INSTI) used for treatment of human immunodeficiency virus (HIV)-infected individuals. Owing to its high genetic barrier to resistance, DTG has been clinically investigated as maintenance monotherapy to maintain viral suppression and to reduce complication and healthcare costs. Our study aims to explain the underlying mechanism related to the emergence of a S230R substitution in patients who experienced virologic failure while using DTG monotherapy. Methods: We evaluated the effect of the S230R substitution in regard to integrase enzyme activity, viral infectivity, replicative capacity, and susceptibility to different INSTIs by biochemical and cell-based assays. Results: The S230R substitution conferred a 63% reduction in enzyme efficiency. S230R virus was 1.29-fold less infectious than wild-type virus but could replicate in PM1 cells without significant delay. Resistance levels against DTG, cabotegravir, raltegravir, and elvitegravir in tissue culture were 3.85-, 3.72-, 1.52-, and 1.21-fold, respectively, in virus with the S230R substitution. Conclusions: Our data indicate that the S230R substitution is comparable to the previously reported R263K substitution in some respects. Virologic failure during DTG monotherapy can occur through the development of the S230R or R263K mutation, without the need for high-level DTG resistance.

Preconception use of cART by HIV-positive pregnant women increases the risk of infants being born small for gestational age.

BACKGROUND: The benefits of combination anti-retroviral therapy (cART) in HIV-positive pregnant women (improved maternal health and prevention of mother to child transmission [pMTCT]) currently outweigh the adverse effects due to cART. As the variety of cART increases, however, the question arises as to which type of cART is safest for pregnant women and women of childbearing age. We studied the effect of timing and exposure to different classes of cART on adverse birth outcomes in a large HIV cohort in the Netherlands. MATERIALS AND METHODS: We included singleton HEU infants registered in the ATHENA cohort from 1997 to 2015. Multivariate logistic regression analysis for single and multiple pregnancies was used to evaluate predictors of small for gestational age (SGA, birth weight <10th percentile for gestational age), low birth weight and preterm delivery. RESULTS: A total of 1392 children born to 1022 mothers were included. Of these, 331 (23.8%) children were SGA. Women starting cART before conception had an increased risk of having a SGA infant compared to women starting cART after conception (OR 1.35, 95% CI 1.03-1.77, p = 0.03). The risk for SGA was highest in women who started a protease inhibitor-(PI) based regimen prior to pregnancy, compared with women who initiated PI-based cART during pregnancy. While the association of preterm delivery and preconception cART was significant in univariate analysis, on multivariate analysis only a non-significant trend was observed (OR 1.39, 95% CI 0.94-1.92, p = 0.06) in women who had started cART before compared to after conception. In multivariate analysis, the risk of low birth weight (OR 1.34, 95% CI 0.94-1.92, p = 0.11) was not significantly increased in women who had started cART prior to conception compared to after conception. CONCLUSION: In our cohort of pregnant HIV-positive women, the use of cART prior to conception, most notably a PI-based regimen, was associated with intrauterine growth restriction resulting in SGA. Data showed a non-significant trend in the risk of PTD associated with preconception use of cART compared to its use after conception. More studies are needed with regard to the mechanisms taking place in the placenta during fetal growth in pregnant HIV-positive women using cART. It will only be with this knowledge that we can begin to understand the potential impact of HIV and cART on the fetus, in order to be able to determine the optimal individualised drug regimen for HIV-infected women of childbearing age.

A mutation in the progesterone receptor predisposes to HEV infection in HIV-positive patients.

BACKGROUND AND AIMS: Infection with Hepatitis E virus (HEV) can cause chronic liver disease in immunocompromised hosts. In transplant recipients, the use of certain immunosuppressants and food habits has been proposed as risk factors for HEV. In individuals infected with the human immunodeficiency virus (HIV), risk factors for HEV infection are less clear. We aimed to study the association between a mutation in the progesterone receptor (PR) named PROGINS and HEV-infected in HIV-positive individuals. METHODS: We evaluated the presence of the SNP PROGINS via KASP in serum samples of 64 HIV-positive individuals and 187 healthy controls. We performed ELISA tests to address the serum levels of IL-10 and IL-12, as well as T-cell stimulation assays in peripheral blood to address immune response in individuals with PROGINS. RESULTS: We found a significant association between the presence of PROGINS mutation and HEV seroprevalence in individuals infected with HIV (30% in HIV+/HEV+ versus 2% in HIV+/HEV, respectively, P = .009). Moreover, we found that HIV+/HEV+ individuals expressing the PROGINS mutation had lower serum levels of IL-10 and higher levels of IL-12. The presence of the mutation led to a reduced response upon stimulation of CD4+ and CD8+ T cells compared to those without the mutation, suggesting an immune modulation associated with PROGINS. CONCLUSIONS: Our study identified a mutation in the PR that provides significant insights into mechanisms of HEV infection in immunosuppressed individuals.

Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment.

We report the case of a patient with hereditary ceruloplasmin deficiency due to a novel gene mutation in ceruloplasmin gene (CP), treated with fresh frozen plasma (FFP) and iron chelation therapy. A 59-year-old man with a past history of diabetes was admitted to our department due to progressive gait difficulties and cognitive impairment. Neurological examination revealed a moderate cognitive decline, with mild extrapyramidal symptoms, ataxia, and myoclonus. Brain T2-weighted MR imaging showed bilateral basal ganglia hypointensity with diffuse iron deposition. Increased serum ferritin, low serum copper concentration, undetectable ceruloplasmin, and normal urinary copper excretion were found. The genetic analysis of the CP (OMIM #604290) reported compound heterozygosity for two mutations, namely c.848G > A and c.2689_2690delCT. Treatment with FFP (500 mL i.v./once a week) and administration of iron chelator (Deferoxamine 1000 mg i.v/die for 5 days, followed by Deferiprone 500 mg/die per os) were undertaken. At the 6-month follow-up, clinical improvement of gait instability, trunk ataxia, and myoclonus was observed; brain MRI scan showed no further progression of basal ganglia T2 hypointensity. This case report suggests that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and to improve the neurological symptoms.

Factors associated with presenting late or with advanced HIV disease in the Netherlands, 1996-2014: results from a national observational cohort.

OBJECTIVES: Early testing for HIV and entry into care are crucial to optimise treatment outcomes of HIV-infected patients and to prevent spread of HIV. We examined risk factors for presentation with late or advanced disease in HIV-infected patients in the Netherlands. METHODS: HIV-infected patients registered in care between January 1996 and June 2014 were selected from the ATHENA national observational HIV cohort. Risk factors for late presentation and advanced disease were analysed by multivariable logistic regression. Furthermore, geographical differences and time trends were examined. RESULTS: Of 20,965 patients, 53% presented with late-stage HIV infection, and 35% had advanced disease. Late presentation decreased from 62% (1996) to 42% (2013), while advanced disease decreased from 46% to 26%. Late presentation only declined significantly among men having sex with men (MSM; p <0.001), but not among heterosexual males (p=0.08) and females (p=0.73). Factors associated with late presentation were: heterosexual male (adjusted OR (aOR), 1.59; 95% CI 1.44 to 1.75 vs MSM), injecting drug use (2.00; CI 1.69 to 2.38), age ≥ 50 years (1.46; CI 1.33 to 1.60 vs 30-49 years), region of origin (South-East Asia 2.14; 1.80 to 2.54, sub-Saharan Africa 2.11; 1.88 to 2.36, Surinam 1.59; 1.37 to 1.84, Caribbean 1.31; 1.13 to 1.53, Latin America 1.23; 1.04 to 1.46 vs the Netherlands), and location of HIV diagnosis (hospital 3.27; 2.94 to 3.63, general practitioner 1.66; 1.50 to 1.83, antenatal screening 1.76; 1.38 to 2.34 vs sexually transmitted infection clinic). No association was found for socioeconomic status or level of urbanisation. Compared with Amsterdam, 2 regions had higher adjusted odds and 2 regions had lower odds of late presentation. Results were highly similar for advanced disease. CONCLUSIONS: Although the overall rate of late presentation is declining in the Netherlands, targeted programmes to reduce late HIV diagnoses remain needed for all risk groups, but should be prioritised for heterosexual males, migrant populations, people aged ≥ 50 years and certain regions in the Netherlands.

Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy.

BACKGROUND: The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. METHODS: An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. RESULTS: Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). CONCLUSIONS: Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. CLINICAL TRIALS REGISTRATION: NCT00825929.

von Willebrand Factor is elevated in HIV patients with a history of thrombosis.

BACKGROUND: Arterial and venous thrombotic events are more prevalent in HIV infected individuals compared to the general population, even in the era of combination antiretroviral therapy. Although the mechanism is not fully understood, recent evidence suggests a role for chronic immune activation. METHODS: We reviewed the Dutch National HIV registry database for HIV infected patients in Rotterdam with a history of arterial or venous thrombosis and calculated the incidence. We collected samples from patients with and without thrombosis and compared plasma levels of lipopolysaccharide (LPS), LPS binding protein (LBP), soluble CD14 (sCD14), and von Willebrand Factor antigen level (vWF). RESULTS: During a 10-year period, a total of 60 documented events in 14,026 person years of observation (PYO) occurred, resulting in an incidence rate of 2.50, 2.21, and 4.28 for arterial, venous and combined thrombotic events per 1000 PYO, respectively. The vWF was elevated in the majority of study subjects (mean 2.36 SD ± 0.88 IU/ml); we found a significant difference when comparing venous cases to controls (mean 2.68 SD ± 0.82 IU/ml vs. 2.20 SD ± 0.77 IU/ml; p = 0.024). This difference remained significant for recurrent events (mean 2.78 SD ± 0.75; p = 0.043). sCD14 was positively correlated with LPS (r = 0.255; p = 0.003). CONCLUSION: The incidence of venous thrombosis was two-fold higher in HIV infected patients compared to age-adjusted data from general population cohort studies. We couldn't find a clear association between immune activation markers to either arterial or venous thrombotic events. We observed a marked increase in vWF levels as well as a correlation of vWF to first and recurrent venous thrombo-embolic events. These findings suggest that HIV infection is an independent risk factor for coagulation abnormalities and could contribute to the observed high incidence in venous thrombosis. This could be a reason to prolong anti-thrombotic treatment in HIV patients with a history of thrombosis.

Peginterferon alfa-2a for AIDS-associated Kaposi sarcoma: experience with 10 patients.

In this observational cohort study, 10 patients with extensive or treatment-refractory AIDS-associated Kaposi sarcoma were treated with peginterferon alfa-2a. Tumor responses were observed in 9 patients with a median progression-free survival of 645 days. Peginterferon alfa-2a could be an effective therapy for extensive or treatment-resistant Kaposi sarcoma.

[Late diagnosis of HIV positive patients in Rotterdam, the Netherlands: risk factors and missed opportunities]. / Late diagnose van hiv-patiënten in Rotterdam: risicofactoren en gemiste kansen.

OBJECTIVE: To determine the percentage of patients in whom the diagnosis 'HIV infection' was made late, which factors are associated with an increased risk of a late HIV diagnosis, and if there are opportunities for an earlier diagnosis. DESIGN: Retrospective analysis. METHOD: We included all HIV positive patients who were treated at the Erasmus Medical Center Rotterdam in the period January 1996-March 2012. We divided these patients into two groups: patients with a timely diagnosis and patients with a late diagnosis (CD4+ T cell count < 350/mm3). We performed a structured interview in patients who were diagnosed in the period January 2009-March 2012. To determine possible risk factors for a late diagnosis we used univariate and multivariate analyses. RESULTS: A late diagnosis 'HIV infection' was made in 59% of the 2256 patients. Independent patient characteristics associated with a late diagnosis were heterosexual transmission (odds ratio (OR): 1.87; 95% CI: 1.44-2.43; p < 0.001), age > 50 years (OR: 1.73; 95% CI: 1.28-2.34; p < 0.001), and a Sub-Saharan African (OR: 1.66; 95% CI: 1.02-2.71; p = 0.043) or Asian origin (OR: 2.31; 95% CI: 1.20-4.43; p = 0.012). The interviews showed that more than 75% of patients with a late HIV diagnosis were already known with a risk factor for HIV, according to the STD practice guideline from the Dutch College of General Practitioners. CONCLUSION: In the past 15 years, 59% of HIV positive patients in Rotterdam presented late. This mainly concerned patients older than 50 years and immigrants originating from HIV endemic areas. It is important to prevent a late diagnosis, as this can lead to poorer response to combination antiretroviral therapy and higher mortality.

The efficiency of Vpx-mediated SAMHD1 antagonism does not correlate with the potency of viral control in HIV-2-infected individuals.

BACKGROUND: The presence of a vpx gene distinguishes HIV-2 from HIV-1, the main causative agent of AIDS. Vpx degrades the restriction factor SAMHD1 to boost HIV-2 infection of macrophages and dendritic cells and it has been suggested that the activation of antiviral innate immune responses after Vpx-dependent infection of myeloid cells may explain why most HIV-2-infected individuals efficiently control viral replication and become long-term survivors. However, the role of Vpx-mediated SAMHD1 antagonism in the virological and clinical outcome of HIV-2 infection remained to be investigated. RESULTS: Here, we analyzed the anti-SAMHD1 activity of vpx alleles derived from seven viremic and four long-term aviremic HIV-2-infected individuals. We found that effective Vpx-mediated SAMHD1 degradation and enhancement of myeloid cell infection was preserved in most HIV-2-infected individuals including all seven that failed to control the virus and developed AIDS. The only exception were vpx alleles from an aviremic individual that predicted a M68K change in a highly conserved nuclear localization signal which disrupted the ability of Vpx to counteract SAMHD1. We also found that HIV-2 is less effective than HIV-1 in inducing innate immune activation in dendritic cells. CONCLUSIONS: Effective immune control of viral replication in HIV-2-infected individuals is not associated with increased Vpx-mediated degradation of SAMHD1.

Long-term response rates of successful hepatitis B vaccination in HIV-infected patients.

BACKGROUND: Data on long-term response rates after successful primary hepatitis B (HBV) vaccination in HIV-infected patients are scarce. OBJECTIVE: To evaluate the durability of an effective anti-HBs titer up to 5 years after primary vaccination in a cohort of 155 HIV-infected adults. METHODS: From a previous multicenter HBV vaccination trial we selected patients with an anti-HBs titer of ≥10 IU/l 28 weeks after the first vaccination. The anti-HBs titer was measured in annually stored plasma samples up to 5 years after vaccination. Patients with decreasing anti-HBs titers <10 IU/I were defined as transient responders (TR) and with persistent anti-HBs titers ≥10 IU/I as long-term responders (LTR^). RESULTS: We included 155 patients, 87 were TR and 68 LTR. Mean age, percentage of female participants and duration of HAART use at primary vaccination were similar in LTR and TR. Anti-HBs level after primary vaccination was the strongest predictor for the durability of anti-HBs. Anti-HBs >100-1000 IU/I and >1000 resulted in an OR 8.3, 95% CI 3.38-20.16; p<0.0001 and OR 75.6, 95% CI 13.41-426.45; p<0.0001 versus anti-HBs titer of 10-100 IU/I after primary vaccination respectively. The mean time to loss of an effective anti-HBs titer was 2.0, 3.7 and 4.4 years respectively, for patients with an anti-HBs titer of 10-100 IU/I, >100-1000 IU/I and >1000 IU/I at primary vaccination. An undetectable HIV-RNA load and use of HAART during vaccination and at follow-up were, though not significantly, associated a higher long-term persistence of an effective antibody titer. CONCLUSION: The durability of an effective anti-HBs level appears to be significantly related to the height of the antibody titers after the primary immunization procedure. Schedules to improve the vaccination response in HIV-infected patients therefore seem to be justified. Whether a HBV booster is indicated remains to be elucidated.

Rehabilitation of brachial plexus injuries in adults and children.

Management of brachial plexus injury sequelae is a challenging issue in neurorehabilitation. In the last decades great strides have been made in the areas of early diagnosis and surgical techniques. Conversely, rehabilitation of brachial plexus injury is a relatively unexplored field. Some critical aspects regarding brachial plexus injury rehabilitation have to be acknowledged. First, brachial plexus injury may result in severe and chronic impairments in both adults and children, thus requiring an early and long-lasting treatment. Second, nerve damage causes a multifaceted clinical picture consisting of sensorimotor disturbances (pain, muscle atrophy, muscle weakness, secondary deformities) as well as reorganization of the Central Nervous System that may be associated with upper limb underuse, even in case of peripheral injured nerves repair. Finally, psychological problems and a lack of cooperation by the patient may limit rehabilitation effects and increase disability. In the present paper the literature concerning brachial plexus injury deficits and rehabilitation in both adults and children was reviewed and discussed. Although further research in this field is recommended, current evidence supports the potential role of rehabilitation in reducing both early and long-lasting disability. Furthermore, the complexity of the functional impairment necessitates an interdisciplinary approach incorporating various health professionals in order to optimizing outcomes.

Therapy failure resulting from superinfection by a drug-resistant HIV variant.

BACKGROUND: HIV-1-infected patients can be superinfected with additional HIV-1 variants. Therapy failure can be the consequence of an infection with a resistant strain. METHODS: A patient was diagnosed with a recent HIV-1 infection in April 2005 and subsequently clinically monitored. HIV-1 evolution was studied by population sequencing of the first 984 bases of the pol gene as well as 454 ultra-deep pyrosequencing (UDPS) of parts of the pol and env genes. RESULTS: The patient was diagnosed with a wild-type HIV-1 strain, but experienced rapid virological failure after initiating a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimen 3 years later. Population sequencing and UDPS revealed the presence of a second HIV-1 strain with a Y188L NNRTI resistance mutation in a sample obtained shortly prior to initiation of therapy. Phylogenetic analyses showed that the two HIV-1 strains were genetically distinct, providing evidence for superinfection. CONCLUSIONS: The virological treatment failure in this patient was probably due to the superinfection with an NNRTI-resistant HIV-1 variant. Superinfection with drug-resistant strains can undermine HIV-1 treatment regimens selected on the basis of resistance testing at diagnosis. Patients, especially in high-risk groups, as well as their clinicians, should be aware of the risks and dangers of superinfections.

Photodynamic therapy with systemic meta-tetrahydroxyphenylchlorin in the treatment of anal intraepithelial neoplasia, grade 3.

BACKGROUND AND OBJECTIVE: Anal cancer and preneoplastic anal lesions (anal intraepithelial neoplasia, AIN) rising especially in men having sex with men (MSM). There are no widely accepted treatment standards for AIN. Photodynamic therapy (PDT) using the systemic sensitizer meta-tetrahydroxyphenylchlorin (mTHPC) has the potential to treat the anal area even when the exact borders of the preneoplastic anal lesion cannot easily be visualized. STUDY DESIGN/MATERIALS AND METHODS: In this prospective intervention study, 15 HIV-positive MSM with AIN 3 were treated in 25 PDT-sessions using mTHPC intravenously administered at drug doses of 0.075-0.15 mg ml(-1) and illumination at 48 hours. The illumination was performed using a custom made applicator using either red light (652 nm) to a measured intended fluence of 10 and 20 J cm(-2) and green light (532 nm) to a measured intended fluence of 105, 210, and 340 J cm(-2) . Red and green illuminations were performed at a (green) equivalent fluence rate of 105 mW cm(-2) . RESULTS: Initial complete response was seen in 7/25 (28%) of treatments and another 4/25 (16%) initial partial responses. After an average 8 months, recurrences were detected in 7/11 (64%) of sessions that initially showed response. A total 4/25 (16%) showed persistent complete response 6-15 months after green light illumination. Red light illuminations caused more significant side effects combined with no persistent complete response. Reported side effects were intense pain, bloody and purulent rectal discharge, and anal stricture formation, in one patient. CONCLUSION: The results show that the use of systemic mTHPC is partially effective for the treatment of AIN 3.