Can Mycobacterium tuberculosis infection lead to cancer? Call for a paradigm shift in understanding TB and cancer.

Infections are known to cause tumours though more attributed to viruses. Strong epidemiological links suggest association between bacterial infections and cancers as exemplified by Helicobacter pylori and Salmonella spp. Infection with Mycobacterium tuberculosis (M. tb), the etiological agent of tuberculosis (TB), has been reported to predispose patients to lung cancers and possibly in other organs as well. While this etiopathogenesis warrant inclusion of M. tb in IARC's (International Agency for Research on Cancer) classified carcinogenic agents, the lack of well-defined literature and direct experimental studies have barred the research community from accepting the role of M. tb as a carcinogen. The background research, case studies, and experimental data extensively reviewed in Roy et al., 2021; provoke the debate for elucidating carcinogenic properties of M. tb. Moreover, proper, timely and correct diagnosis of both diseases (which often mimic each other) will save millions of lives that are misdiagnosed. In addition, use of Anti Tubercular therapy (ATT) in misdiagnosed non-TB patients contributes to drug resistance in population thereby severely impacting TB disease control measures. Research in this arena can further aid in saving billions of dollars by preventing the superfluous use of cancer drugs. In order to achieve these goals, it is imperative to identify the underlying mechanism of M. tb infection acting as major risk factor for cancer.

Evolution of SARS-CoV-2: BA.4/BA.5 Variants Continues to Pose New Challenges.

The acquisition of a high number of mutations, notably, the gain of two mutations L452R and F486V in RBD, and the ability to evade vaccine/natural infection-induced immunity suggests that Omicron is continuing to use "immune-escape potential" as an evolutionary space to maintain a selection advantage within the population. Despite the low hospitalizations and lower death rate, the surges by these variants may offset public health measures and disrupt health care facilities as seen recently in Portugal and the USA. Interestingly these BA.4/BA.5 variants have been found to be more severe than the earlier-emerged Omicron variants. We believe that aggressive COVID-19 surveillance using affordable testing strategies might actually help understand the evolution and transmission pattern of new variants. The sudden dip in reporting of new cases in some of the low- and middle-income countries is an alarming situation and needs to be addressed as this could lead to undetected transmission of future variants of interest/concern of SARS-CoV-2 in large population settings, including advent of a 'super' virus. It would be interesting to examine the possible role/influence, if any, of the two different kinds of vaccines, the spike protein-based versus the inactivated whole virus, in the evolution of BA.4/BA.5.

Role of multiple factors likely contributing to severity-mortality of COVID-19.

COVID-19 stalled the world in 2020 and continues to be the greatest health crisis of this generation. While the apparent case fatality rates across fluctuates around ~2% globally, associated mortality/death rate (deaths per million population) varies distinctly across regions from the global average of ~600 per million population. Heterogeneous factors have been linked with COVID-19 associated mortalities and these include age, share of geriatric population, comorbidities, trained immunity and climatic conditions. Apart from direct or indirect role of endemic diseases, dietary factors and host immunity in regulating COVID-19 severity, human behaviour will inevitably control outcome of this pandemic. Comprehensive understanding of these factors will have a bearing on management of future health crises.

Structure-Function Analyses of New SARS-CoV-2 Variants B.1.1.7, B.1.351 and B.1.1.28.1: Clinical, Diagnostic, Therapeutic and Public Health Implications.

SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus 2) has accumulated multiple mutations during its global circulation. Recently, three SARS-CoV-2 lineages, B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) and B.1.1.28.1 (P.1), have emerged in the United Kingdom, South Africa and Brazil, respectively. Here, we have presented global viewpoint on implications of emerging SARS-CoV-2 variants based on structural-function impact of crucial mutations occurring in its spike (S), ORF8 and nucleocapsid (N) proteins. While the N501Y mutation was observed in all three lineages, the 501Y.V1 and P.1 accumulated a different set of mutations in the S protein. The missense mutational effects were predicted through a COVID-19 dedicated resource followed by atomistic molecular dynamics simulations. Current findings indicate that some mutations in the S protein might lead to higher affinity with host receptors and resistance against antibodies, but not all are due to different antibody binding (epitope) regions. Mutations may, however, result in diagnostic tests failures and possible interference with binding of newly identified anti-viral candidates against SARS-CoV-2, likely necessitating roll out of recurring "flu-like shots" annually for tackling COVID-19. The functional relevance of these mutations has been described in terms of modulation of host tropism, antibody resistance, diagnostic sensitivity and therapeutic candidates. Besides global economic losses, post-vaccine reinfections with emerging variants can have significant clinical, therapeutic and public health impacts.

High resistance to antiretroviral drugs: the Indian experience.

Effective antiretroviral treatment (ART) has significantly reduced the morbidity and mortality among people living with HIV/AIDS. The emergence of drug resistance is the major obstacle to the successful implementation of long-term treatment strategy of HIV disease. Hence, monitoring the resistance to ART is an essential task. The MGM Medical College in Navi Mumbai is the only national facility with the capacity to monitor ART resistance using tissue culture technique. The main objective of the study was to determine the prevalence of primary and secondary resistance between May 1997 and April 2003. Four hundred and sixty viral isolates of 74 individuals were tested for ART resistance using tissue culture-based protocol (McGill University, Canada). These included 287 primary and 173 follow-up viral isolates. Following activation of tissue culture, a panel of 12 antiretroviral drugs in concentrations from 0.038 mg/mL to 0.090 mg/mL was tested. The resistance was determined on the basis of the production of p24 antigen at the end of 72 and 144 hours of incubation. The overall resistance against reverse transcriptase inhibitors (RTIs) was 33.7% and that to protease inhibitors (PIs) was 21.5%. However, prevalence of primary resistance among ART näive to RTIs was 14/208 (6.7%) of isolates and that to (PIs) was 2/79(2.5%) of isolates. The incidence of resistance to RTI was 22/500 years (4.4/100 years) and that to PIs was 8/253.6 years (3.2/100 years). It is possible that non-B subtypes of HIV-1 that are prevalent in most developing countries are likely to develop resistance rapidly after ART. However, common factors that influence development of resistance such as poor adherence, inadequate 'wild' doses and regimens, and poor monitoring were not validated in the study. Unless active surveillance is instituted, these factors can pose major challenge for the management of people on ART in developing countries.

The natural history of human immunodeficiency virus infection among adults in Mumbai.

BACKGROUND: Natural history studies of untreated HIV infection are useful for clinicians, public health experts and policymakers to improve and monitor care, plan services and control, and to model the epidemic. Several natural history studies on homosexual men and intravenous drug users have been published from developed countries. A few studies have emerged on heterosexual populations from Africa. With an emerging epidemic, a similar study was required in India. This study was designed to determine the progression of HIV disease in a prevalent cohort of adult HIV-seropositive patients. METHODS: A prevalent cohort of 1009 patients comprising 488 asymptomatic HIV-seropositive persons, 259 with AIDS-related complex (ARC), and 262 with acquired immunodeficiency syndrome (AIDS) were recruited for the study at Sir J.J. Hospital, Mumbai. A case-control study was conducted to determine the correlation of clinical features and other factors with disease progression. Disease progression was determined from the asymptomatic stage to that of ARC and AIDS using time series analysis. The incubation period from HIV to AIDS was also determined, using Weibull curves. RESULTS: The median incubation periods for progression were: HIV to AIDS-7.9 years and ARC to AIDS--1.9 years. The median survival after developing AIDS was 19.2 months. A comparison of progressors and non-progressors revealed that disease progression correlated with clinical features such as chronic fever (OR 5.6), persistent generalized lymphadenopathy (OR 4.7), persistent cough for >1 month (OR 3.5), chronic diarrhoea (OR 3.3), oral candidiasis (OR 3.2), >10% loss of body weight within 1 month (OR 2.9), incident tuberculosis (OR 2.8) and herpes zoster (OR 2.5). The annual incidence of active clinical tuberculosis was 86/1503 person-years (5.7/ 100 person-years), the median time to occurrence of active tuberculosis was 21.6 months and the annual incidence of mortality was 96/2009 person-years (4.8/100 person-years, 95% CI 3.4, 6.2). CONCLUSION: Progression to AIDS and death was faster among the heterosexual cohort in Mumbai than that reported for homosexual men and haemophiliacs in the USA and Europe. Strategies need to be developed to prevent the occurrence of tuberculosis among HIV-infected patients because that would help to reduce the morbidity and mortality. This is the first large study from the Indian subcontinent of a longitudinal follow up of HIV-infected persons. The findings will be useful for advocacy and assessing the impact of antiretroviral therapy (ART) in India.

Community prevalence of sexually transmitted diseases and human immunodeficiency virus infection in Tamil Nadu, India: a probability proportional to size cluster survey.

BACKGROUND: Human immunodeficiency virus (HIV) infection and AIDS is threatening the survival of many nations. To evaluate ongoing interventional strategies and burden of illness estimates, valid data on the prevalence of HIV are required. Often, in the absence of community prevalence data, estimates are based on surrogate markers such as prevalence of HIV in antenatal clinics. Even though the antenatal prevalence of HIV is easier to measure and can be repeated for evaluation, it is important to establish the association between antenatal and community prevalence of sexually transmitted diseases (STDs) and HIV, so that the validity of the estimates can be verified. METHODS: A 'probability proportional to size' cluster survey was conducted in three randomly selected districts of Tamil Nadu in India. The basic unit of the survey was households from rural and urban clusters. Adults 15-45 years of age from the selected households were eligible for recruitment. Demographic, behavioural and laboratory data were collected. Clinical examination was done to identify STD syndromes and blood, urine, vaginal/urethral and endocervical swabs were taken for laboratory diagnosis of STDs from the subjects. Direct smear examination for Trichomonas vaginalis; serological tests for syphilis, hepatitis B, HIV, herpes simplex virus 2, Chlamydia trachomatis; and culture of Neisseria gonorrhoeae and Haemophilus ducreyi were performed on the collected specimens. The data were analysed adjusting for cluster effect. RESULT: We selected and screened 1981 individuals (1157 women and 824 men) for STDs and HIV from 1114 households representing the 25 million projected adult population of Tamil Nadu. The overall community prevalence of STDs including HIV and hepatitis B in Tamil Nadu was 14.6% (CI: 14.1-15.1), and 8.3% (CI: 7.9-8.6) when HIV and hepatitis B were excluded. Community prevalence of HIV and hepatitis B infection was 1.8% (CI:1.7-1.9) and 5.3% (CI: 5.1-5.5), respectively. The distribution of HIV involved both rural and urban regions of Tamil Nadu. On clinical examination, at least one STD syndrome was noted in 486 (24.5%) of the women subjects; vaginal discharge was the most common and found in 421 women (38.4%). CONCLUSION: The prevalence of STD and HIV in Tamil Nadu is higher than expected and has extended into the non-high risk population (generalized epidemic).

Antiretroviral therapy and HIV prevention in India: modeling costs and consequences of policy options.

OBJECTIVES: The objective of this study is to assess the costs, cost-effectiveness, and HIV epidemic impact of 3 antiretroviral therapy (ART) policy options. STUDY DESIGN: We constructed an epidemiologic model to predict the course of the HIV epidemic in the absence of expanded ART availability. Based on background studies of the willingness to pay for ART among patients with AIDS, of the costs to the government of the alternative treatment interventions, and of ART's likely effects on HIV transmission, we simulated the consequences of 3 possible alternative government ART policies. RESULTS: A program to reduce the negative consequences of the currently unstructured private-sector provision of ART is the most cost-effective of the 3 options at a 10% discount rate and least cost-effective at a 3% rate. The costs and cost-effectiveness of all options are highly sensitive to the effect of ART on condom use. CONCLUSION: The design of ART policy should capitalize on the potential of ART to decrease HIV transmission through institutional arrangements that reward effective prevention programs, thereby raising the likelihood that treatment has beneficial rather than negative external effects.