Initiation of HIV therapy

In this paper, we numerically show that the dynamics of the HIV system is sensitive to both the initial condition and the system parameters. These phenomena imply that the system is chaotic and exhibits a bifurcation behavior. To control the system, we propose to initiate an HIV therapy based on both the concentration of the HIV-1 viral load and the ratio of the CD4 lymphocyte population to the CD8 lymphocyte population. If the concentration of the HIV-1 viral load is higher than a threshold, then the first type of therapy will be applied. If the concentration of the HIV-1 viral load is lower than or equal to the threshold and the ratio of the CD4 lymphocyte population to the CD8 lymphocyte population is greater than another threshold, then the second type of therapy will be applied. Otherwise, no therapy will be applied. The advantages of the proposed control strategy are that the therapy can be stopped under certain conditions, while the state variables of the overall system is asymptotically stable with fast convergent rate, the concentration of the controlled HIV-1 viral load is monotonic decreasing, as well as the positivity constraint of the system states and that of the dose concentration is guaranteed to be satisfied. Computer numerical simulation results are presented for an illustration

Personalizing HIV therapy, mission impossible?

Sustained HIV suppression depends on a number of factors including therapy adherence, management of side effects, viral resistance and individual characteristics of patients and therapeutic settings. Treatment response rates range up to 90% in therapy naïve patients but decline to approximately 50% in patients who received several antiretrovirals during treatment history. Furthermore, HIV protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) plasma concentrations display high inter- and intra individual variability and the therapeutic window is comparably narrow. In this therapeutic setting the personalization of dosing regimens has been suggested in many cases to tailor the ARV plasma concentrations with the intention to maximize therapy success and minimize side effects in the individual. However, personalizing therapy by modifying the dosing regimen bears the danger of losing therapeutic efficacy, increasing side effects or causing viral resistance. This topical review identifies pharmacokinetic and pharmacodynamic models of antiretroviral therapy appraising the potential application to HIV therapy and discusses its future in the light of new drug classes and fix-dose combinations

Anti-HIV therapy: pipeline approaches and future directions

Human immunodeficiency virus (HIV), with about 30 million deaths and double infections (in developing countries), is an open challenge today for global scientists. Developing safe and effective measurements against it has become the prime need of hour. Though, putting it at health priority, various efforts like chemotherapy, vaccines and others are attempted globally over last decade. Consequently, highly active antiretroviral therapy was introduced but fails to completely block the viral replication due to drug resistance and various other severe side effects. The antigenic variability and lack of appropriate experimental models is the major obstacle in the development of an ever effective treatment against HIV. However, to overcome the present hurdles and to emerge a preventive HIV vaccine efforts at various platforms are done. A renewed, coordinated research, preclinical studies, clinical trials together with sufficient long term scientific and commercial commitments are made. Few of the therapeutic efforts viz. RNA interference (RNAi) based replication arrest of HIV, viral enzymes’ inhibitors, nanotechnology based HIV control and various preclinically trialed vaccines are reviewed in this paper. Also, the observed toxicity of existing therapeutic regimen, key challenges and future prospects for the development of better tolerated prophylactic HIV-1 vaccine are discussed

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Frequency and reasons for delayed treatment initiation after HIV diagnosis: cross-sectional study in Lahore, Pakistan

Background: Well-timed initiation of HIV therapy enhances life expectancy, decreases mortality and morbidity, and inhibits the transmission of HIV and complications related to it. The purpose of the present survey is to investigate the frequency and reasons for delayed initiation of anti-retroviral therapy (ART) and to determine its relationship with various socio-demographic variables and HIV-related characteristics. Methods: The analysis is based on a cross-sectional study involving 355 people living with HIV (diagnosed by PCR) who were more than 18 years of age and not receiving HIV therapy before enrolment at the HIV clinics of two selected tertiary-care teaching hospitals in Lahore, Pakistan. In this study, delayed initiation of ART was defined as not attending the HIV management centre or a clinic for ART within 3 months of a confirmed diagnosis. The participants were selected using a systematic probability sampling technique. Bivariate logistic regression was performed using a backward stepwise technique to establish the variables related to delayed onset of HIV therapy. Factors significant at p <= 0.20 were considered for multivariate analysis, which was used to describe the association between independent factors and delayed initiation of treatment. Results: Delayed onset of ART was observed in 28.5% of individuals. Factors such as no schooling (AOR = 5.92; 95% CI: 1.38-25.41; p = 0.017) and occasional household income (AOR = 3.88; 95% CI: 1.01-14.89; p = 0.048) were significantly associated with late onset of ART. Our research findings also indicated that the main reasons for late beginning of HIV therapy were: feeling healthy (45.5%), did not have time to go to the HIV treatment centre (42.6%), did not want to discuss HIV test result (37.6%), and fear of stigma and discrimination within their community (35.6%). Conclusions: Late commencement of HIV therapy in Pakistan is common, and an improved connection is needed between identification of HIV and beginning of therapy. HIV management centres should counsel and monitor patients from the time of a positive HIV test result until they initiate therapy

Estimating HIV Medication Adherence and Persistence: Two Instruments for Clinical and Research Use

Antiretroviral therapy (ART) requires lifelong daily oral therapy. While patient characteristics associated with suboptimal ART adherence and persistence have been described in cohorts of HIV-infected persons, these factors are poor predictors of individual medication taking behaviors. We aimed to create and test instruments for the estimation of future ART adherence and persistence for clinical and research applications. Following formative work, a battery of 148 items broadly related to HIV infection and treatment was developed and administered to 181 HIV-infected patients. ART adherence and persistence were assessed using electronic monitoring for 3 months. Perceived confidence in medication taking and self-reported barriers to adherence were strongest in predicting non-adherence over time. Barriers to adherence (e.g., affordability, scheduling) were the strongest predictors of non-adherence, as well as 3- and 7-day non-persistence. A ten-item battery for prediction of these outcomes (www.med.unc.edu/ncaidstraining/adherence/for-providers) and a 30-item battery reflective of underlying psychological constructs can help identify and study individuals at risk for suboptimal ART adherence and persistence

Similar mortality and reduced loss to follow-up in integrated compared with vertical programs providing antiretroviral treatment in sub-saharan Africa.

Vertical HIV programs have achieved good results but may not be feasible or appropriate in many resource-limited settings. Médecins sans Frontières has treated HIV in vertical programs since 2000 and over time integrated HIV treatment into general health care services using simplified protocols. We analyzed the survival probability among patients receiving antiretroviral therapy (ART) from 2003 to 2010 in integrated versus vertical programs in 9 countries in sub-Saharan Africa

Clinical impact of double protease inhibitor boosting with Lopinavir/Ritonavir and Amprenavir as part of salvage antiretroviral therapy

Purpose: Double protease inhibitor (PI) boosting is being explored as a new strategy in salvage antiretroviral (ARV) therapy. However, if a negative drug interaction leads to decreased drug levels of either or both PIs, double PI boosting could lead to decreased virologic response. A negative drug interaction has been described between amprenavir (APV) and lopinavir/ritonavir (LPV/r). This observational cohort study assessed the virologic impact of the addition of APV to a salvage ARV regimen, which also contains LPV/r, compared to a regimen containing LPV/r alone. Method: Patients initiated on a salvage ARV regimen that included LPV/r obtained from the expanded access program in Toronto, Canada, were evaluated. APV (600-1,200 mg bid) was added at the discretion of the treating physician. Results: Using multivariate Cox proportional hazards models, we found that the addition of APV to a LPV/r-containing salvage regimen was not significantly associated with time to virologic suppression (< 50 copies/mL; adjusted hazard ratio [HR] = 0.75, p = .12) or with time to virologic rebound (adjusted HR = 1.46, p = .34). Those patients who received higher doses of APV had an increased chance of virologic suppression (p = .03). In a subset of 27 patients, the median LPV Ctrough was significantly lower in patients receiving APV (p = .04), and the median APV Ctrough was reduced compared to reported controls. Conclusion: Our data do not support an additional benefit in virologic reduction of double boosting with APV and LPV/r relative to LPV/r alone in salvage ARV therapy. Our study's limitations include its retrospective nature and the imbalance between the two groups potentially confounding the results. Although these factors were adjusted for in the multivariate analysis, a prospective randomized controlled trial is warranted to confirm our findings