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1. The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy.

Author

Prins, H.A., Crespo, R., Lungu, C., Rao, S., Li, L, Overmars, R.J., Papageorgiou, G., Mueller, Y.M., Stoszko, M., Hossain, T., Kan, T.W., Rijnders, B.J.A., Bax, H.I., Gorp, E.C. van, Nouwen, J.L., Vries-Sluijs, T.E.M.S. De, Schurink, C.A.M., Mendonça Melo, M. de, Nood, E. van, Colbers, A., Burger, D.M., Palstra, R.J., Kampen, J. J. A. van, Vijver, D.A. van de, Mesplède, T., Katsikis, P.D., Gruters, R.A., Koch, B.C.P., Verbon, A., Mahmoudi, T., Rokx, C., Prins, H.A., Crespo, R., Lungu, C., Rao, S., Li, L, Overmars, R.J., Papageorgiou, G., Mueller, Y.M., Stoszko, M., Hossain, T., Kan, T.W., Rijnders, B.J.A., Bax, H.I., Gorp, E.C. van, Nouwen, J.L., Vries-Sluijs, T.E.M.S. De, Schurink, C.A.M., Mendonça Melo, M. de, Nood, E. van, Colbers, A., Burger, D.M., Palstra, R.J., Kampen, J. J. A. van, Vijver, D.A. van de, Mesplède, T., Katsikis, P.D., Gruters, R.A., Koch, B.C.P., Verbon, A., Mahmoudi, T., and Rokx, C.

Abstract

Contains fulltext : 291084.pdf (Publisher’s version ) (Open Access), Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

Published
2023

3. Increased Virological Failure in Naive HIV-1-Infected Patients Taking Lamivudine Compared With Emtricitabine in Combination with Tenofovir and Efavirenz or Nevirapine in the Dutch Nationwide ATHENA cohort

Author

Rokx, C., Fibriani, A., Vijver, D.A. van de, Verbon, A., Schutten, M., Gras, L., Rijnders, B.J., Koopmans †, P.P., Keuter, M., Ven, A.J.A.M. van der, Hofstede, H.J.M. ter, Dofferhoff, A.S.M., Warris, A., Crevel, R. van, Internal Medicine, Virology, Med Microbiol, Infect Dis & Infect Prev, RS: CAPHRI School for Public Health and Primary Care, Graduate School, Amsterdam institute for Infection and Immunity, Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Global Health, General Internal Medicine, Amsterdam Public Health, Center of Experimental and Molecular Medicine, and Other departments

Subjects
Microbiology (medical), Adult, Male, medicine.medical_specialty, Nevirapine, Efavirenz, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], HIV Infections, Emtricitabine, Cohort Studies, chemistry.chemical_compound, SDG 3 - Good Health and Well-being, immune system diseases, Internal medicine, Antiretroviral Therapy, Highly Active, medicine, Humans, Treatment Failure, Netherlands, business.industry, Incidence, Hazard ratio, Lamivudine, virus diseases, Odds ratio, Middle Aged, Viral Load, Virology, Infectious Diseases, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, Anti-Retroviral Agents, Cohort, HIV-1, Female, business, Viral load, medicine.drug
Abstract

Contains fulltext : 153151.pdf (Publisher’s version ) (Closed access) BACKGROUND: Guidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivudine and emtricitabine to be interchangeable components in first-line combination antiretroviral therapy (cART). The evidence for their clinical equivalence in cART is inconsistent. The primary aim of this study was to evaluate the virological responses to lamivudine and emtricitabine in recommended cART. METHODS: This was an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide HIV cohort. The virological responses to lamivudine and emtricitabine were compared by multivariable adjusted logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models. RESULTS: Therapy-naive HIV-1-infected patients without baseline resistance (N = 4740) initiated lamivudine or emtricitabine with efavirenz/tenofovir or nevirapine/tenofovir. The use of lamivudine was associated with more virological failure at week 48 compared to emtricitabine with efavirenz/tenofovir (10.8% vs 3.6%; adjusted odds ratio [AOR], 1.78; 95% confidence interval [CI], 1.11-2.84) and nevirapine/tenofovir (27% vs 11%; AOR, 2.09; 95% CI, 1.25-3.52) in on-treatment analysis. Propensity score-adjusted models and intent-to-treat sensitivity analyses gave comparable results. The adjusted hazard ratio of virological failure at week 240 using lamivudine instead of emtricitabine was 2.35 (95% CI, 1.61-3.42) with efavirenz and 2.01 (95% CI, 1.36-2.98) with nevirapine. The inclusion of lamivudine or emtricitabine in cART did not influence the time to virological suppression within 48 weeks or the probability of virological rebound after successful virological suppression. CONCLUSIONS: The use of emtricitabine instead of lamivudine as part of cART was associated with better virological responses. These findings are relevant for settings with extensive use of lamivudine and for settings where generic lamivudine will be available.

Published
2015

4. Pre-exposure prophylaxis for the prevention of sexual HIV transmission; new preventative strategy using tenofovir/emtricitabine

Author

Boot, J., Rump, B.O., Boucher, C.A.B., Coul, E.L. Op de, Agtmael, M.A. van, Vijver, D.A. van de, Burger, D.M., Fanoy, E.B., Virology, and Medical Microbiology & Infectious Diseases

Subjects
SDG 3 - Good Health and Well-being, Poverty-related infectious diseases Infectious diseases and international health [N4i 3]
Abstract

Item does not contain fulltext The Netherlands has approximately 20,000 registered HIV-infected patients. The current HIV prevention policy consisting of condom use and active HIV testing does not effectively mitigate the HIV epidemic in all risk groups. In July of 2012, tenofovir/emtricitabine (TDF/FTC) was approved by the American Food and Drug Administration (FDA) for pre-exposure prophylaxis (PrEP) for long-term use in persons who exhibit frequent risky and unsafe sexual behaviour. With once-daily use and good therapy compliance, TDF/FTC has proved to be effective as PrEP, and few side effects are reported. Drawbacks in the use of TDF/FTC as PrEP are the potential risk of viral resistance and reduced condom use, the relatively high cost and the intensive counselling required. In special cases, long-term PrEP could enhance the current Dutch preventive policy. Further research is needed into the practical feasibility and protective efficacy of the ad hoc use of TDF/FTC as PrEP before a high-risk contact occurs.

Published
2013

5. The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes

Author

Vijver, D.A. van de, Wensing, A.M.J., Angarano, G., Asjo, B., Balotta, C., Camacho, R., Chaix, M., Costagliola, D., De Luca, A., Derdelinckx, I., Grossman, Z., Hamouda, O., Hatzakis, A., Hemmer, R., Hoepelman, A.I.M., Horban, A., Korn, K., Kücherer, C., Leitner, T., Loveday, C., MacRae, E., Maljkovic, I., Mendoza, C. de, Meyer, L., Nielsen, C., Op de Coul, E.L.M., Omaasen, V., Paraskevis, D., Perrin, L., Puchhammer-Stöckl, E., Salminen, M., Schmit, J., Scheider, F., Schuurman, R., Soriano, V., Stanczak, G., Stanojevic, M., Vandamme, A., Laethem, K. van, Violin, M., Wilde, K., Yerly, S., Zazzi, M., and Boucher, C.A.B.

Subjects
Geneeskunde, drug resistance, HIV, non-B subtypes, genetic barrier
Abstract

The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (9600 of non-B subtype) isolated from antiretroviral- naive patients in Europe. Methods: The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. Results: Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P G 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P G 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. Conclusions: Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected. Key Words: HIV, non-B subtypes, drug resistance, genetic barrier

Published
2006

6. Increasing the use of second-line therapy is a cost-effective approach to prevent the spread of drug-resistant HIV: a mathematical modelling study

Author

Nichols, B.E., Sigaloff, K.C., Kityo, C., Hamers, R.L., Baltussen, R.M., Bertagnolio, S., Jordan, M.R., Hallett, T.B., Boucher, C.A., Wit, T.F. de, Vijver, D.A. van de, Nichols, B.E., Sigaloff, K.C., Kityo, C., Hamers, R.L., Baltussen, R.M., Bertagnolio, S., Jordan, M.R., Hallett, T.B., Boucher, C.A., Wit, T.F. de, and Vijver, D.A. van de

Abstract

Contains fulltext : 138293.pdf (publisher's version ) (Open Access), INTRODUCTION: Earlier antiretroviral therapy (ART) initiation reduces HIV-1 incidence. This benefit may be offset by increased transmitted drug resistance (TDR), which could limit future HIV treatment options. We analyze the epidemiological impact and cost-effectiveness of strategies to reduce TDR. METHODS: We develop a deterministic mathematical model representing Kampala, Uganda, to predict the prevalence of TDR over a 10-year period. We then compare the impact on TDR and cost-effectiveness of: (1) introduction of pre-therapy genotyping; (2) doubling use of second-line treatment to 80% (50-90%) of patients with confirmed virological failure on first-line ART; and (3) increasing viral load monitoring from yearly to twice yearly. An intervention can be considered cost-effective if it costs less than three times the gross domestic product per capita per quality adjusted life year (QALY) gained, or less than $3420 in Uganda. RESULTS: The prevalence of TDR is predicted to rise from 6.7% (interquartile range [IQR] 6.2-7.2%) in 2014, to 6.8% (IQR 6.1-7.6%), 10.0% (IQR 8.9-11.5%) and 11.1% (IQR 9.7-13.0%) in 2024 if treatment is initiated at a CD4 <350, <500, or immediately, respectively. The absolute number of TDR cases is predicted to decrease 4.4-8.1% when treating earlier compared to treating at CD4 <350 due to the preventative effects of earlier treatment. Most cases of TDR can be averted by increasing second-line treatment (additional 7.1-10.2% reduction), followed by increased viral load monitoring (<2.7%) and pre-therapy genotyping (<1.0%). Only increasing second-line treatment is cost-effective, ranging from $1612 to $2234 (IQR $450-dominated) per QALY gained. CONCLUSIONS: While earlier treatment initiation will result in a predicted increase in the proportion of patients infected with drug-resistant HIV, the absolute numbers of patients infected with drug-resistant HIV is predicted to decrease. Increasing use of second-line treatment to all patients with confirm

Published
2014

7. Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models

Author

Eaton, J.W., Menzies, N.A., Stover, J., Cambiano, V., Chindelevitch, L., Cori, A., Hontelez, J.A., Humair, S., Kerr, C.C., Klein, D.J., Mishra, S., Mitchell, K.M., Nichols, B.E., Vickerman, P., Bakker, R, Barnighausen, T., Bershteyn, A., Bloom, D.E., Boily, M.C., Chang, S.T., Cohen, T., Dodd, P.J., Fraser, C., Gopalappa, C., Lundgren, J., Martin, N.K., Mikkelsen, E., Mountain, E., Pham, Q.D., Pickles, M., Phillips, A., Platt, L., Pretorius, C., Prudden, H.J., Salomon, J.A., Vijver, D.A. van de, Vlas, S.J. de, Wagner, B.G., White, R.G., Wilson, D.P., Zhang, L., Blandford, J., Meyer-Rath, G., Remme, M., Revill, P., Sangrujee, N., Terris-Prestholt, F., Doherty, M., Shaffer, N., Easterbrook, P.J., Hirnschall, G., Hallett, T.B., Eaton, J.W., Menzies, N.A., Stover, J., Cambiano, V., Chindelevitch, L., Cori, A., Hontelez, J.A., Humair, S., Kerr, C.C., Klein, D.J., Mishra, S., Mitchell, K.M., Nichols, B.E., Vickerman, P., Bakker, R, Barnighausen, T., Bershteyn, A., Bloom, D.E., Boily, M.C., Chang, S.T., Cohen, T., Dodd, P.J., Fraser, C., Gopalappa, C., Lundgren, J., Martin, N.K., Mikkelsen, E., Mountain, E., Pham, Q.D., Pickles, M., Phillips, A., Platt, L., Pretorius, C., Prudden, H.J., Salomon, J.A., Vijver, D.A. van de, Vlas, S.J. de, Wagner, B.G., White, R.G., Wilson, D.P., Zhang, L., Blandford, J., Meyer-Rath, G., Remme, M., Revill, P., Sangrujee, N., Terris-Prestholt, F., Doherty, M., Shaffer, N., Easterbrook, P.J., Hirnschall, G., and Hallett, T.B.

Abstract

Contains fulltext : 138145.pdf (publisher's version ) (Open Access), BACKGROUND: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per muL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. METHODS: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per muL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per muL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. FINDINGS: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per muL or less

Published
2014

8. Cost-effectiveness of PrEP in HIV/AIDS control in Zambia: a stochastic league approach

Author

Nichols, B.E., Baltussen, R.M., Dijk, J.H. van, Thuma, P.E., Nouwen, J.L., Boucher, C.A.B., Vijver, D.A. van de, Nichols, B.E., Baltussen, R.M., Dijk, J.H. van, Thuma, P.E., Nouwen, J.L., Boucher, C.A.B., and Vijver, D.A. van de

Abstract

Item does not contain fulltext, BACKGROUND: Earlier antiretroviral therapy initiation and pre-exposure prophylaxis (PrEP) prevent HIV, although at a substantial cost. We use mathematical modeling to compare the cost-effectiveness and economic affordability of antiretroviral-based prevention strategies in rural Macha, Zambia. METHODS: We compare the epidemiological impact and cost-effectiveness over 40 years of a baseline scenario (treatment initiation at CD4 <350 cells/muL) with treatment initiation at CD4 <500 cells per microliter, and PrEP (prioritized to the most sexually active, or nonprioritized). A strategy is cost effective when the incremental cost-effectiveness ratio (ICER) is <$3480 (<3 times Zambian per capita GDP). Stochastic league tables then predict the optimal intervention per budget level. RESULTS: All scenarios will reduce the prevalence from 6.2% (interquartile range, 5.8%-6.6%) in 2014 to about 1% after 40 years. Compared with the baseline, 16% of infections will be averted with prioritized PrEP plus treatment at CD4 <350, 34% with treatment at CD4 <500, and 59% with nonprioritized PrEP plus treatment at CD4 <500. Only treating at CD4 <500 is cost effective: ICER of $62 ($46-$75). Nonprioritized PrEP plus treating at CD4 <500 is borderline cost effective: ICER of $5861 ($3959-$8483). Initiating treatment at CD4 <500 requires a budget increase from $20 million to $25 million over 40 years, with a 96.7% probability of being the optimal intervention. PrEP should only be considered when the budget exceeds $180 million. CONCLUSIONS: Treatment initiation at CD4 <500 is a cost-effective HIV prevention approach that will require a modest increase in budget. Although adding PrEP will avert more infections, it is not economically feasible, as it requires a 10-fold increase in budget.

Published
2014

9. Cost-Effectiveness of Pre-Exposure Prophylaxis (PrEP) in Preventing HIV-1 Infections in Rural Zambia: A Modeling Study

Author

Nichols, B.E., Boucher, C.A.B., Dijk, J.H. van, Thuma, P.E., Nouwen, J.L., Baltussen, R.M., Wijgert, J. van de, Sloot, P.M., Vijver, D.A. van de, Nichols, B.E., Boucher, C.A.B., Dijk, J.H. van, Thuma, P.E., Nouwen, J.L., Baltussen, R.M., Wijgert, J. van de, Sloot, P.M., and Vijver, D.A. van de

Abstract

Contains fulltext : 118224.pdf (publisher's version ) (Open Access), BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine effectively prevents new HIV infections. The optimal scenario for implementing PrEP where most infections are averted at the lowest cost is unknown. We determined the impact of different PrEP strategies on averting new infections, prevalence, drug resistance and cost-effectiveness in Macha, a rural setting in Zambia. METHODS: A deterministic mathematical model of HIV transmission was constructed using data from the Macha epidemic (antenatal prevalence 7.7%). Antiretroviral therapy is started at CD4<350 cells/mm(3). We compared the number of infections averted, cost-effectiveness, and potential emergence of drug resistance of two ends of the prioritization spectrum: prioritizing PrEP to half of the most sexually active individuals (5-15% of the total population), versus randomly putting 40-60% of the total population on PrEP. RESULTS: Prioritizing PrEP to individuals with the highest sexual activity resulted in more infections averted than a non-prioritized strategy over ten years (31% and 23% reduction in new infections respectively), and also a lower HIV prevalence after ten years (5.7%, 6.4% respectively). The strategy was very cost-effective at $323 per quality adjusted life year gained and appeared to be both less costly and more effective than the non-prioritized strategy. The prevalence of drug resistance due to PrEP was as high as 11.6% when all assumed breakthrough infections resulted in resistance, and as low as 1.3% when 10% of breakthrough infections resulted in resistance in both our prioritized and non-prioritized scenarios. CONCLUSIONS: Even in settings with low test rates and treatment retention, the use of PrEP can still be a useful strategy in averting infections. Our model has shown that PrEP is a cost-effective strategy for reducing HIV incidence, even when adherence is suboptimal and prioritization is imperfect.

Published
2013

10. Intrathecal production and secretion of vascular endothelial growth factor during Cryptococcal Meningitis.

Author

Coenjaerts, F.E., Flier, M. van der, Mwinzi, P.N., Brouwer, A.E., Scharringa, J., Chaka, W.S., Aarts, M., Rajanuwong, A., Vijver, D.A. van de, Harrison, T.S., Hoepelman, A.I., Coenjaerts, F.E., Flier, M. van der, Mwinzi, P.N., Brouwer, A.E., Scharringa, J., Chaka, W.S., Aarts, M., Rajanuwong, A., Vijver, D.A. van de, Harrison, T.S., and Hoepelman, A.I.

Abstract

Contains fulltext : 57852.pdf (publisher's version ) (Closed access), BACKGROUND: Patients with cryptococcal meningitis (CM) show elevated intracranial pressure (ICP) and blood-brain barrier (BBB) disruption in most cases. Elevated ICP is an important contributor to mortality. Vascular endothelial growth factor (VEGF) might be the mediator of BBB disruption during CM. METHODS: We measured VEGF levels in serum, plasma, and cerebrospinal fluid (CSF) of 95 patients and 63 control subjects, and we analyzed the required trigger and cellular source of VEGF secretion in vitro. RESULTS: Cryptococcus neoformans and its capsular antigens dose-dependently induced VEGF secretion by polymorphonuclear neutrophils, monocytes, and peripheral blood mononuclear cells (PBMCs). VEGF production by PBMCs induced by antigens strongly exceeded production by monocytes (P<.001). The addition of major histocompatibility complex class II antibody inhibited this production of VEGF (P=.005). Confirming the in vitro data, patients with CM showed significantly elevated VEGF levels in CSF (P<.001), plasma (P=.028), and serum (P<.001), compared with healthy control subjects. Calculated VEGF indices demonstrated that VEGF was produced intrathecally. CONCLUSIONS: Our findings suggest that VEGF plays a role in the pathophysiology of CM. We propose that CD4(+) T lymphocytes--stimulated by monocytes acting as antigen-presenting cells--are the cells that produce VEGF in response to cryptococcal antigens.

Published
2004

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