Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.

BACKGROUND: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. METHODS AND FINDINGS: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions­a proxy for recent infection­yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs­K101E, K103N, Y181C, and G190A­accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. CONCLUSIONS: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.

BACKGROUND: The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. METHODS: We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. RESULTS: Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. CONCLUSIONS: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Sjogren's syndrome presenting with hypokalemic periodic paralysis.

We report a rare case of a 38-year-old female who presented with sudden onset flaccid quadriplegia and respiratory arrest with no significant past clinical history. She was later found to have hypokalemia due to distal renal tubular acidosis and further diagnosed as case of Sjogrens Syndrome.

Possible transmission of HIV Infection due to human bite.

The potential risk of HIV-1 infection following human bite although epidemiologically insignificant, but it is biologically possible. There are anecdotal reports of HIV transmission by human bites particularly if saliva is mixed with blood. The oral tissues support HIV replication and may serve as a previously unrecognized HIV reservoir. The HIV infected individuals have more viruses in blood than saliva, possibly due to the potent HIV-inhibitory properties of saliva. The case presented here is of a primary HIV infections following a human bite where in the saliva was not blood stained but it got smeared on a raw nail bed of a recipient. The blood and saliva of the source and blood of the recipient showed a detectable viral load with 91% sequence homology of C2-V3 region of HIV gp120 between the two individuals. The recipient did not receive PEP [post exposure prophylaxis] as his family physician was unaware of salivary transmission. The family physician should have taken PEP decision after proper evaluation of the severe and bleeding bite. Hence it is necessary to treat the HIV infected human bites with post exposure prophylaxis.

Harmonic analysis of peripheral pulse for screening subjects at high risk of diabetes.

Power spectral density (PSD) of peripheral pulses in human has been investigated in the past for its clinical applications. Continuing the efforts, data acquired using Peripheral Pulse Analyser in research projects sponsored by Board of Research in Nuclear Sciences in 207 control subjects, 18 descendants of diabetic patients and 22 patients with systemic hypertension have been subjected to PSD analysis for its study of harmonics. Application software, named Pulse Harmonic Analyser specifically developed for this work, selected 131,072 samples from each data file, obtained PSD, derived 52 PHA parameters and saved them in an Excel sheet. Coefficient of variation in control data was reduced significantly by application of Central Limit Theorem, which enabled use of parametric methods for statistical analysis of the observations. Data in hypertensive patients have shown significant difference in comparison to that of controls in eight parameters at low values of α and ß. Data in offspring of diabetic patients also have shown significant difference in one parameter indicating its usefulness in screening subjects with genetic disposition of acquiring Type-II Diabetes. PHA analysis has also yielded sub-harmonic components, which are related to combined variability in the heart rate, pulse volume and pulse morphology and has a potential to become method of choice for real time variability monitoring.

Nonopportunistic neurologic manifestations of the human immunodeficiency virus: an Indian study.

CONTEXT: HIV-1 is a neurotropic virus. In a resource-limited country such as India, large populations of affected patients now have access to adequate chemoprophylaxis for opportunistic infections (OIs), allowing them to live longer. Unfortunately the poor availability of highly active antiretroviral therapy (HAART) has allowed viral replication to proceed unchecked. This has resulted in an increase in the debilitating neurologic manifestations directly mediated by the virus. OBJECTIVE: The main objective of this study was to identify and describe in detail the direct neurologic manifestations of HIV-1 in antiretroviral treatment (ART)-naive, HIV-infected patients (excluding the neurologic manifestations produced by opportunistic pathogens). DESIGN: Three hundred successive cases of HIV-1 infected, ART-naive patients with neurologic manifestations were studied over a 3-year period. Each case was studied in detail to identify and then exclude manifestations due to opportunistic pathogens. The remaining cases were then analyzed specially in regard to their occurrence and the degree of immune suppression (CD4+ cell counts). SETTINGS AND PATIENTS: The study was carried out in an apex, tertiary, referral care center for HIV/AIDS in India. All patients were admitted for a detailed analysis. No interventions were carried out, as this was an observational study. RESULTS: Of the 300 cases, 67 (22.3%) had neurologic manifestations due to the direct effects of HIV-1. The HIV infection involved the neuroaxis at all levels. The distribution of cases showed that the region most commonly involved was the brain (50.7%). The manifestations included stroke syndromes (29.8%), demyelinating illnesses (5.9%), AIDS dementia complex (5.9%), and venous sinus thrombosis (4.4%). The other manifestations seen were peripheral neuropathies (35.8% of cases), spinal cord pathologies (5.9% of cases), radiculopathies (4.4% of cases), and a single case of myopathy. The onset of occurrence of these diseases and their progression were then correlated with the CD4+ cell counts. CONCLUSIONS: HIV infection is responsible for a large number of nonopportunistic neurologic manifestations that occur across a large immune spectrum. During the early course of the disease, the polyclonal hypergammaglobulinemia induced by the virus results in demyelinating diseases of the central- and peripheral nervous systems (CNS and PNS). As the HIV infection progresses, the direct toxic effects of the virus unfold, directly damaging the CNS and PNS, resulting in protean clinical manifestations.

Comparative evaluation of immunogenicity, reactogenecity and safety of purified chick embryo cell rabies vaccine and neural tissue rabies vaccine.

OBJECTIVES: 1. To compare the protective antibody titres on day 14, 30 and 90 after giving intramuscular (IM) injections of PCECV and subcutaneous injections of Nervous Tissue Vaccine. 2. To compare the immunogenicity and safety of PCECV and NTV. METHODS AND MATERIALS: The study enrolled cases in three groups. Group 'C' or control group: (n = 38) : This group comprised of 38 normal healthy volunteers without dog-bite. Group 'A' (n = 102): This group included cases of dog-bite fulfilling inclusion/exclusion criteria. Each one of Group A and C were given PCECV as post exposure treatment (PET) on day 0-3-7-14-30 and 90. Group 'B' (n = 50): This group included 50 cases of dog-bite who received NTV. The rabies virus neutralizing antibody titres were estimated by RFFIT (Rapid Fluorescent Focus Inhibition Test) on day 0, 14, 30 and 90 days. 45 recipients of PCECV were re-tested for persistence of Protective Antibodies at the end of 1 year. RESULTS: Of these 37, 91 and 45 cases were evaluable in Groups C, A and B respectively. The antibody titres in Groups A, B, C were 13.4, 3.2, 22.8 IU/ml respectively; the protective titre being 0.5 IU/ml.5% PCECV recepients had delayed response on day 30.14% of NTV recepients did not seroconvert. CONCLUSIONS: The Immunogenicity, Reactogenicity and safety of PCECV is well established. 5% of PCECV receipients showed a delayed sero conversion. 14% of NTV receipients did not sero convert at all. Therefore it is desirable to estimate antibody titres on day 14 after vaccination. If difficult, then all the cases of animal bite must receive passive immunization with rabies immunoglobulins.

Thrombotic microangiopathies presenting as an obstetric emergency.

Thrombotic microangiopathies are disorders that arise due to a diffuse endothelial damage. They predominantly manifest either as thrombotic trombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). When they arise as a complication of pregnancy and associated disorders they are associated with a high mortality and morbidity.

Clinical validation of software for a versatile variability analyzer: Assessment of autonomic function.

Study of physiological variability is an upcoming area of research having manifold clinical applications. Considerable work has been done on heart rate variability and blood pressure variability during the past four decades. Electronics division, Bhabha Atomic Research Centre, has developed an instrument called medical analyzer, which can be used to study several variabilities simultaneously. This instrument has been used to collect data from control subjects and patients with established diagnosis. The data has been analyzed with the help of a software package developed for this purpose and has been found to be consistent with expected manifestations of the disease on the autonomic nervous system. The description of the software package and results of the study are briefly described in this paper.

Nonopportunistic neurologic manifestations of the human immunodeficiency virus: an Indian study.

CONTEXT: HIV-1 is a neurotropic virus. In a resource-limited country such as India, large populations of affected patients now have access to adequate chemoprophylaxis for opportunistic infections (OIs), allowing them to live longer. Unfortunately the poor availability of highly active antiretroviral therapy (HAART) has allowed viral replication to proceed unchecked. This has resulted in an increase in the debilitating neurologic manifestations directly mediated by the virus. OBJECTIVE: The main objective of this study was to identify and describe in detail the direct neurologic manifestations of HIV-1 in antiretroviral treatment (ART)-naive, HIV-infected patients (excluding the neurologic manifestations produced by opportunistic pathogens). DESIGN: Three hundred successive cases of HIV-1 infected, ART-naive patients with neurologic manifestations were studied over a 3-year period. Each case was studied in detail to identify and then exclude manifestations due to opportunistic pathogens. The remaining cases were then analyzed specially in regard to their occurrence and the degree of immune suppression (CD4+ cell counts). SETTING AND PATIENTS: The study was carried out in an apex, tertiary, referral care center for HIV/AIDS in India. All patients were admitted for a detailed analysis.No interventions were carried out, as this was an observational study. RESULTS: Of the 300 cases, 67 (22.3%) had neurologic manifestations due to the direct effects of HIV-1. The HIV infection involved the neuroaxis at all levels. The distribution of cases showed that the region most commonly involved was the brain (50.7%). The manifestations included stroke syndromes (29.8%), demyelinating illnesses (5.9%), AIDS dementia complex (5.9%), and venous sinus thrombosis (4.4%). The other manifestations seen were peripheral neuropathies (35.8% of cases), spinal cord pathologies (5.9% of cases), radiculopathies (4.4% of cases), and a single case of myopathy. The onset of occurrence of these diseases and their progression were then correlated with the CD4+ cell counts. CONCLUSION: HIV infection is responsible for a large number of nonopportunistic neurologic manifestations that occur across a large immune spectrum. During the early course of the disease, the polyclonal hypergammaglobulinemia induced by the virus results in demyelinating diseases of the central- and peripheral nervous systems (CNS and PNS). As the HIV infection progresses, the direct toxic effects of the virus unfold, directly damaging the CNS and PNS, resulting in protean clinical manifestations.