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Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu-Natal, South Africa: implications for future treatment options.

ABSTRACT: BACKGROUND:Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy. METHODS:We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches. RESULTS:Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients. CONCLUSIONS:The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.

SUBMITTER: Singh A

PROVIDER: S-EPMC3196677 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu-Natal, South Africa: implications for future treatment options.

Singh Ashika A Sunpath Henry H Green Taryn N TN Padayachi Nagavelli N Hiramen Keshni K Lie Yolanda Y Anton Elizabeth D ED Murphy Richard R Reeves Jacqueline D JD Kuritzkes Daniel R DR Ndung'u Thumbi T

Journal of acquired immune deficiency syndromes (1999) 20111101 3

<h4>Background</h4>Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.<h4>Methods</h4>We sequenced the pol gene of viruses from 45 individuals failing at least 6 month ...[more]

PMID: 21709569

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Project description:ObjectivesResearch on migration and HIV has largely focused on male migration, often failing to measure HIV risks associated with migration for women. We aimed to establish whether associations between migration and HIV infection differ for women and men, and identify possible mechanisms by which women's migration contributes to their high infection risk.DesignData on socio-demographic characteristics, patterns of migration, sexual behavior and HIV infection status were obtained for a population of 11,677 women aged 15-49 and men aged 15-54, resident members of households within a demographic surveillance area participating in HIV surveillance in 2003-04.MethodsLogistic regression was conducted to examine whether sex and migration were independently associated with HIV infection in three additive effects models, using measures of recent migration, household presence and migration frequency. Multiplicative effects models were fitted to explore whether the risk of HIV associated with migration differed for males and females. Further modeling and simulations explored whether composition or behavioral differences accounted for observed associations.ResultsRelative to non-migrant males, non-migrant females had higher odds of being HIV-positive (adjusted odds ratio [aOR] = 1.72; 95% confidence interval [1.49-1.99]), but odds were higher for female migrants (aOR = 2.55 [2.07-3.13]). Female migrants also had higher odds of infection relative to female non-migrants (aOR = 1.48 [1.23-1.77]). The association between number of sexual partners over the lifetime and HIV infection was modified by both sex and migrant status: For male non-migrants, each additional partner was associated with 3% higher odds of HIV infection (aOR = 1.03 [1.02-1.05]); for male migrants the association between number of partners and HIV infection was non-significant. Each additional partner increased odds of HIV infection by 22% for female non-migrants (aOR = 1.22 [1.12-1.32]) and 46% for female migrants (aOR = 1.46 [1.25-1.69]).ConclusionsHigher risk sexual behavior in the context of migration increased women's likelihood of HIV infection.

Project description:Antimicrobial resistance (AMR) is a serious global public-health threat. Evidence suggests that antimicrobial stewardship (AMS) is a valuable tool to facilitate rational antibiotic use within healthcare facilities. A cross-sectional situational analysis using a questionnaire was conducted to determine the current status of antimicrobial stewardship (AMS) activities in all public-sector hospitals in KwaZulu-Natal (KZN). The survey had a 79% (57, N = 72) response rate. A total of 75% of hospitals had an antimicrobial stewardship committee (AMSC), 47% (20, N = 43) had a formal written statement of support from leadership, and 7% (3, N = 43) had budgeted financial support. Only 37% (16, N = 43) had on-site or off-site support from a clinical microbiologist, and 5% (2, N = 43) had an on-site infectious disease (ID) physician. Microbiologist input on pathogen surveillance data (aOR: 5.12; 95% CI: 4.08-22.02; p-value = 0.001) and microbiological investigations prior to the commencement of antibiotics (aOR: 5.12; 95% CI: 1.08-42.01; p-value = 0.041) were significantly associated with having either on- or off-site microbiology support. Respondents that had a representative from microbiology on the AMSC were significantly associated with having and interrogating facility-specific antibiograms (P = 0.051 and P = 0.036, respectively). Those facilities that had access to a microbiologist were significantly associated with producing an antibiogram (aOR: 4.80; 95% CI: 1.25-18.42; p-value = 0.022). Facilities with an ID physician were significantly associated with having a current antibiogram distributed to prescribers within the facility (P = 0.010) and significantly associated with sending prescribers personalized communication regarding improving prescribing (P = 0.044). Common challenges reported by the facilities included suboptimal hospital management support; a lack of clinicians, pharmacists, nurses, microbiologists, and dedicated time; the lack of a multidisciplinary approach; low clinician buy-in; inadequate training; a lack of printed antibiotic guidelines; and financial restrictions for microbiological investigations. The survey identified the need for financial, IT, and management support. Microbiology and infectious disease physicians were recognized as scarce human resources.

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Project description:BackgroundThe CD4 cell count signifies the health of an individual's immune system. The use of data-driven models enables clinicians to accurately interpret potential information, examine the progression of CD4 count, and deal with patient heterogeneity due to patient-specific effects. Quantile-based regression models can be used to illustrate the entire conditional distribution of an outcome and identify various covariates effects at the respective location.MethodsThis study uses the quantile mixed-effects model that assumes an asymmetric Laplace distribution for the error term. The model also incorporated multiple random effects to consider the correlation among observations. The exact maximum likelihood estimation was implemented using the Stochastic Approximation of the Expectation-Maximization algorithm to estimate the parameters. This study used the Centre of the AIDS Programme of Research in South Africa (CAPRISA) 002 Acute Infection Study data. In this study, the response variable is the longitudinal CD4 count from HIV-infected patients who were initiated on Highly Active Antiretroviral Therapy (HAART), and the explanatory variables are relevant baseline characteristics of the patients.ResultsThe analysis obtained robust parameters estimates at various locations of the conditional distribution. For instance, our result showed that baseline BMI (at [Formula: see text] 0.05: [Formula: see text]), baseline viral load (at [Formula: see text] 0.05: [Formula: see text] [Formula: see text]), and post-HAART initiation (at [Formula: see text] 0.05: [Formula: see text]) were major significant factors of CD4 count across fitted quantiles.ConclusionsCD4 cell recovery in response to post-HAART initiation across all fitted quantile levels was observed. Compared to HIV-infected patients with low viral load levels at baseline, HIV-infected patients enrolled in the treatment with a high viral load level at baseline showed a significant negative effect on CD4 cell counts at upper quantiles. HIV-infected patients registered with high BMI at baseline had improved CD4 cell count after treatment, but physicians should not ignore this group of patients clinically. It is also crucial for physicians to closely monitor patients with a low BMI before and after starting HAART.

Dataset Information

Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu-Natal, South Africa: implications for future treatment options.

Publications

Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu-Natal, South Africa: implications for future treatment options.

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