ANATOMIC PATHOLOGY

 Frozen Section of Thyroid and Parathyroid Specimens

[Letter to the Editor] 

William C. Faquin, Sanford I. Roth

We read with great interest the recent article by Drs Anton and Wheeler describing the role of frozen section in the evaluation of thyroid and parathyroid specimens, and we were pleased to see their emphasis on the use of preoperative fine needle aspiration and intraoperative cytologic preparations to guide the surgical management of these lesions. There are, however, a few points that we feel deserve further comment.

The authors suggest that the distinction between a thyroid adenoma and an adenomatous nodule represents a pathologic diagnostic dilemma; however, in our opinion, this is misleading because both lesions are benign and will be managed similarly. Furthermore, the pathologic distinction between hyperplastic thyroid nodules, so-called adenomatous nodules, and thyroid adenomas has been shown in many cases to be unreliable as supported by the finding that, even in multinodular goiters, more than 60% of nodules are monoclonal proliferations.

With regard to the hyalinizing trabecular adenoma, the authors do not mention that a small subset of these tumors has been shown to have metastatic potential and hence the preferred term used by the World Health Organization, hyalinizing trabecular tumor. Molecular studies indicate that hyalinizing trabecular tumors share some of the molecular changes seen in papillary thyroid carcinomas such as the RET/PTC gene rearrangement, and thus these tumors may in fact represent an indolent variant of papillary carcinoma rather than a separate entity.

With respect to the parathyroid glands, we would stress that an experienced parathyroid (endocrine) surgeon very seldom needs to call for a frozen section to identify the tissue as parathyroid. At the Massachusetts General Hospital, the extent to which our 4 endocrine surgeons performing these operations use the frozen section for the purpose of identifying tissue as parathyroid is estimated to be less than 1% of cases, and usually only when there has been a previous thyroid or parathyroid operation. Frozen sections are predominantly used for distinguishing normal from abnormal glands (ie, to distinguish an adenoma or a double adenoma from primary chief cell hyperplasia).

Although not mentioned by the authors, in our experience, the use of an intraoperative fat stain for evaluating intracellular and extracellular fat is helpful for distinguishing normal from abnormal parathyroid tissue. This is particularly true in children in whom stromal fat is sparse or absent or in very small biopsies in which the stromal fat is irregularly distributed. In fact, at our institution, frozen section examination of extremely small samples of normal parathyroid glands of less than 1 to 2 mm is easily done and very informative, especially in conjunction with use of a fat stain. In addition, our surgeons often apply the intraoperative parathyroid assay in conjunction with a single frozen section, and, in our hands, this has proven very successful.

Finally, we would like to point out that the normal parathyroid glands do not technically contain water clear cells. Water clear cells have a specific ultrastructure, with a cytoplasm filled with enlarged vacuoles thought to represent abnormal secretory vesicles not found in the vacuolated chief cells of the normal gland. Water clear cells are only present in water clear hyperplasia and water clear adenomas, whereas the glycogen-rich chief cell is a normal variant of the chief cell secretory cycle.

Archives of Pathology and Laboratory Medicine: Vol. 130, No. 9, pp. 1260–1260.

 

 

Initial Biopsy Influences Number of Trips to the Operating Room

Allison Gandey

August 25, 2006 — A new study has found that breast cancer patients undergoing excisional biopsy need more surgeries, resulting in higher cost of care compared with patients having percutaneous biopsies. The researchers, presenting at the recent 42nd annual meeting of the American Society of Clinical Oncology, advise that percutaneous biopsy be considered the preferred approach in the diagnosis of breast cancer. This recommendation mirrors that of the American Society of Breast Surgeons.

"A major goal of modern breast medicine is to minimize the number of patients with benign lesions who undergo open surgical breast biopsies for diagnosis," the society's board of directors points out in a public statement. "Image-guided percutaneous needle biopsy is the diagnostic procedure of choice for image-detected breast abnormalities. It should be readily available to all patients with image-detected lesions." The specialists add that there are relatively few patients who should undergo excisional biopsy as the initial procedure for diagnosis.

In the present analysis, the investigators looked at more than 2400 women with invasive breast cancer. They compared clinical and treatment factors for patients who had excisional vs percutaneous biopsy. The researchers estimated total costs; facility fees, including operating rooms, radiology suites, and pathology processing; and professional fees. They performed a multivariate logistic regression to determine factors associated with biopsy type.

"Patients undergoing excisional biopsy required a greater number of surgical procedures for margin control and lymph-node assessment compared with percutaneous-biopsy patients," reported lead author Waddah Al-Refaie, MD, from the MD Anderson Cancer Center in Houston, Texas.

 

Diagnose With a Needle and Go to the Operating Room Once for Definitive Treatment

The research team found that percutaneous biopsy was used in the vast majority of patients (74%). Only 26% underwent an excisional biopsy. "Excisional biopsy exacted a cost increase 1.7 times that of percutaneous biopsy, with a difference of more than $3400 at our institution," Dr. Al-Refaie noted.

Of excisional biopsies, 86% were performed prior to referral. After adjusting for age, tumor size, and year of diagnosis, the researchers found that excisional biopsy was significantly associated with an increased number of surgical procedures required for definitive treatment compared with percutaneous biopsy (odds ratio, 1.667; P < .001).

"For patients with a diagnosis of breast cancer," the board of the American Society of Breast Surgeons says in the statement, "the goal is to make the diagnosis with a needle and to go to the operating room one time for definitive treatment." 

ASCO 42nd Annual Meeting: Abstract 598. Presented June 3, 2006.

 

 

“Benign,” Metastasizing Adenomyoepithelioma of the Breast: A Report of 2 Cases

Celina M. Nadelman, Kevin O. Leslie, Michael C. Fishbein

Adenomyoepitheliomas of the breast are rare tumors composed of a proliferation of 2 cell populations. For the most part, they are considered to be benign, but they locally recur. Those neoplasms that metastasize are deemed to have come from a histologically malignant primary tumor. Herein, Authors describe 2 cases of metastases of histologically “benign” adenomyoepitheliomas of the breast to the lung. In both cases, the primary neoplasms and the metastases did not show histologic features of malignancy. These unique cases represent another example of neoplasms that can metastasize in the absence of histologic features that would suggest malignant behavior. Establishing the diagnosis, determining optimal therapy, and predicting outcome are problematic because of the rarity of this entity. Perhaps, classification of adenomyoepitheliomas should be changed to recognize those neoplasms with malignant behavior.

Adenomyoepithelioma of the breast is a rare neoplasm first described by Hamperl in 1970 and further classified by Tavassoli in 1991; it is characterized by a biphasic proliferation of inner (ductal) epithelial and outer myoepithelial cells, arranged in spindled sheets, cords, tubules, and/or lobules. The majority of adenomyoepitheliomas are well circumscribed and can even be encapsulated. Satellite nodules that are well circumscribed are often present as well. Most breast adenomyoepitheliomas are considered to be benign or to have low-grade malignant potential, characterized by the propensity for local recurrence. Although most of the lesions are reported to be benign, a minority can progress to a more malignant form, giving rise to metastases. In these cases, malignancy arises from either the epithelial or myoepithelial component or both and has thus been subclassified as undifferentiated, myoepithelial, epithelial, or myoepithelial– epithelial carcinoma. Features that would predict recurrence potential and/or metastasis are not well established; however, cases that behave in an aggressive manner usually have some histologic features suggesting malignancy.

Archives of Pathology and Laboratory Medicine: Vol. 130, No. 9, pp. 1349–1353.

Nucleolar Grade But Not Fuhrman Grade is Applicable to Papillary Renal Cell Carcinoma

Sika-Paotonu D, Bethwaite PB, McCredie MR et al

This study was undertaken to determine the validity of Fuhrman grading in a series of papillary renal cell carcinomas (PRCCs), to examine the interrelationship and prognostic significance of the individual components of the grading system, and further to determine whether any observed predictive value was independent of other prognostic indicators. Ninety cases of PRCC were studied. Fifty-nine tumors were of type 1 and 31 were of type 2. There were 33 TNM stage 1, 26 stage 2, 18 stage 3, and 12 stage 4 tumors, whereas division of cases according to pT category showed 14 pT1a, 20 pT1b, 25 pT2, 15 pT3a, 4 pT3b, and 11 pT4 tumors. Ten tumors were grade 1, 58 grade 2, and 22 grade 3 when predominant Fuhrman grade was assigned, whereas grading according to the high-power field containing the highest grade (focal grade) showed 40 grade 2, 49 grade 3, and 1 grade 4 tumors. Measurements of nuclear size (area, major axis, perimeter) and shape (shape factor, compactness) were undertaken using image analysis. Nuclear area ranged from 27.63 to 116.39 muM, major axis length 6.70 to 14.06 muM, and nuclear perimeter 20.05 to 41.77 muM. Shape factor ranged from 0.805 to 0.878 and compactness from 14.33 to 15.66. Predominant nucleolar grade using the criteria of the Fuhrman classification was nucleolar grade 1 for 13 tumors, nucleolar grade 2 for 56 tumors, and nucleolar grade 3 for 21 tumors. Focal nucleolar grade based on the high-power field showing the greatest degree of nuclear pleomorphism, was grade 2 for 38 tumors and grade 3 for 52 tumors. pT category, TNM stage, focal Fuhrman grade, and PRCC type were significantly associated with survival. Of the various measures of the components of the Fuhrman classification, only focal nucleolar grade was associated with survival, on univariate analysis. On multivariate analysis, focal nucleolar grade and tumor diameter were independently associated with survival, whereas TNM stage retained significance independent of other parameters. It is concluded that assessment of nucleolar prominence rather than Fuhrman grade is applicable for stratification of tumors within TNM stage or pT category for PRCC and that this should be based upon the high-power field showing the greatest degree of nuclear pleomorphism.

Am J Surg Pathol. 2006 Sep;30(9):1091-1096.

 

 

Cadaver Autopsy Led to Varicella Outbreak in Healthcare Workers

NEW YORK (Reuters Health) Sept 04 - Researchers in India describe a hospital outbreak of chickenpox in which the source of infection was a cadaver.

The index patient was a 36-year-old male renal transplant recipient with a history of extensive mucocutaneous vesicular eruptions for 1 week and a fever for 3 days. The work-up suggested the patient had disseminated varicella-zoster virus infection with organ involvement, Dr. Navin Paul and Dr. Mini E. Jacob, from Christian Medical College in Vellore, India, report.

Despite prompt treatment with intravenous antimicrobial agents, the patient's condition worsened and 12 hours after being hospitalized he went into cardiopulmonary arrest and died.

Twelve hours later, an autopsy was performed, which was attended by a pathologist, two assistants, and 19 medical students. The pathologist and assistants reported a prior history of chickenpox, whereas the medical students were not questioned regarding chickenpox history or vaccination status.

Masks and aprons were worn by all the attendees, but during the autopsy, sectioning of the liver released blood that splashed on to the skin of some of the attendees.

Twelve days later, the first of four cases of chickenpox was reported among the attendees. In all cases, the subjects reported being exposed to the splashed blood. Conversely, none of the unaffected participants reported such exposure.

Two of the affected attendees reported a prior history of chickenpox, while two did not. To prevent further spread of the disease, three of the patients were isolated in the hospital, while the fourth agreed to home confinement.

Eight persons were identified who had come in close contact with the three hospitalized patients prior to diagnosis. Five of these patients reported no prior history of chickenpox. Although they didn't acquire chicken pox during the outbreak, four of the five patients would develop the disease in the next 5 years, "implying that they lacked immunity to the varicella-zoster virus at the time of their exposure to the primary contacts," Drs. Paul and Jacob state.

"Our unique case series demonstrates the importance of assessing healthcare workers' susceptibilities to the varicella-zoster virus before exposing them to situations with increased risk of infection acquisition," the researchers conclude.

Clin Infect Dis 2006;43:599-601.

 

CLINICAL PATHOLOGY

 

Role of Anticyclic Citrullinated Peptide in the Diagnosis of Early Rheumatoid Factor-Negative Suspected Rheumatoid Arthritis: Is It Worthwhile to Order the Test?

Panchagnula, Renuka, Rajiv, S R. , Prakash, J , Chandrashekara, S , Suresh, K P.

 

Background: Anticyclic citrullinated peptide (anti-CCP) is a relatively new serologic marker, which has been proposed for use in the diagnosis of rheumatoid arthritis (RA) and is said to be a highly specific.

Objective: The aim of the study was to evaluate the role of anti-CCP in a South Indian population of patients with suspected RA in the early stages when rheumatoid factor is negative and clinical presentation is atypical.

Methods: Patients with early inflammatory arthritis who were rheumatoid factor-negative were investigated for anti-CCP. The patients were reviewed by a rheumatologist and, based on American College of Rheumatology criteria, were diagnosed with RA or another disease after a follow-up period of 3 to 6 months. The rheumatologist was blinded to the results of the anti-CCP. The sensitivity and specificity of anti-CCP was estimated in comparison to follow up and final clinical diagnosis. The anti-CCP was estimated by the enzyme-linked immunosorbent assay method using a commercially available kit (Euroimmune).

Results: One hundred forty-three patients with a mean age of 47.1 years and a male to female ratio of 0.22:1 were recruited for the study. Thirty cases were positive for anti-CCP and 41 cases were finally diagnosed RA. Twenty-six of the 30 anti-CCP-positive patients were diagnosed with RA. Thus, the sensitivity of anti-CCP in our institution for the diagnosis of RA in the early stage in a group of rheumatoid factor-negative patients with atypical presentation was 63.4% with 36.6% false-negatives and the specificity was 96.1% with 3.9% false-positive cases. The positive predictive value of anti-CCP was 86.7% and the negative predictive value was 86.7%. Kappa statistic of agreement, [chi]2 McNemar test, indicated anti-CCP to be an efficient test in this study population.

Conclusion: Anti-CCP is a useful and highly specific but not absolutely specific or sensitive test to detect RA and supplements rheumatoid factor in the presence of a strong clinical suspicion.

JCR: Journal of Clinical Rheumatology. 12(4):172-175, August 2006.

 

 

PSA Predicts Prostate Cancer Survival

Metastatic Prostate Cancer Survival Related to PSA Drop After Treatment 

Daniel DeNoon

Aug. 29, 2006 -- How long will a man with advanced prostate cancer survive? That may be related to how low his PSA level drops after androgen-deprivation therapy.

The finding comes from University of Michigan researcher Maha Hussain, MD, and colleagues. They're conducting a study of men newly diagnosed with prostate cancer that has spread to other parts of their bodies. For men with this deadly metastatic cancer, it is big news.

It depends on a simple blood test. Prostate cells -- especially prostate cancer cells -- give off a marker called PSA (prostate-specific antigen).

After seven months of androgen-deprivation therapy, which is standard treatment for metastatic prostate cancer, men with low PSA levels have only one-fourth the chance of dying as men with higher PSA levels. Those with undetectable PSA levels have only one-fifth the risk of death as men with higher PSA levels.

"Low or undetectable PSA after seven months of androgen-deprivation therapy is a powerful predictor of risk of death in patients with new metastatic prostate cancer," Hussain said, in a news release. "These findings could help patients avoid ineffective treatment."

PSA Test Predicts Prostate Cancer Death

Metastatic prostate cancer is usually fatal. Some patients die quickly. Others survive for years. Until now, there's been no reliable way to tell a patient which group he's in.

Standard treatment for spreading prostate cancer is to give a man a drug that blocks male hormones. It's called androgen-deprivation therapy. It's not a cure. Eventually, the body becomes resistant to the drug. But treatment fails earlier in some men than in others.

Now there may be a way to predict this treatment failure. Hussain and colleagues studied 1,345 men who were on androgen-deprivation therapy for seven months.

The men whose PSA levels stayed above 4.0 ng/mL survived only 13 months on average after the seven months of treatment. The men whose PSA levels were 4.0 ng/mL or less but more than 0.2 ng/mL survived an average 3.5 years. And the men whose PSA levels were undetectable (less than or equal to 0.2 ng/mL) lived for six years.

The findings could also provide what the researchers call a "window of opportunity" to test new treatments for advanced prostate cancer.

Hussain and colleagues are now testing whether successful androgen-deprivation therapy can be prolonged by stopping and starting treatment after the seven-month "induction" period.

The study appears in the Aug. 20 issue of the Journal of Clinical Oncology. 

WebMD Medical News

 

MICROBIOLOGY

 

Rotavirus Vaccines: An Update

[Concise Reviews of Pediatric Infectious Diseases]

Dennehy, Penelope H.

Rotavirus is a major killer of children, causing approximately 450,000 deaths per year worldwide. Rotavirus is also a major cause of acute gastroenteritis in the United States, infecting nearly all children by age 4. In the United States, rotavirus causes approximately 3.2 million episodes of diarrhea each year, resulting in 500,000 office visits, 60,000 hospitalizations, and at least 20 deaths annually. Rotavirus is responsible for as many as 50% of pediatric admissions to hospitals because of diarrhea and 20% to 25% of cases of pediatric diarrhea in outpatient clinics. Vaccination is the only control measure likely to have a significant impact on the incidence of severe dehydrating rotavirus disease.

Rotaviruses are segmented, double-stranded RNA viruses with at least 7 distinct groups (A through G). Group A rotaviruses are the most important cause of severe acute gastroenteritis in infants and young children worldwide. Group A rotaviruses contain 2 structural proteins that define the serotype of the virus and are considered critical to vaccine development because they are targets for neutralizing antibodies that may provide protection. These are the VP7 glycoprotein (G protein) and the VP4 protease-cleaved protein (P protein). Many G and P serotypes have been identified in human rotaviruses, but 4 rotavirus strains (G1, G3 and G4, each combined with P[8] and G2 combined with P[4]) make up 96% of the globally identified strains. Predominant serotypes vary from year to year and region to region, implying that successful rotavirus vaccines may require inclusion of all the major P or G types causing disease in a specific region.

Naturally acquired rotavirus infections provide the greatest protection against reinfection causing severe disease. After a first natural infection, infants and young children are protected against subsequent symptomatic disease regardless of whether the first infection was symptomatic. After a first infection, 40% of children are protected against any subsequent infection with rotavirus, 75% are protected against any rotavirus diarrhea, and 88% are protected against severe rotavirus diarrhea. Second, third, and fourth infections confer progressively greater protection. No child with 2 previous infections has subsequently developed severe rotavirus diarrhea.

The components of the immune response that protect children from rotavirus infection and disease are not completely understood. Both serum and mucosal antibodies are probably important. Antibodies to both the VP4 and VP7 proteins neutralize virus infectivity. However, in vaccine studies, correlation between these antibodies and protection has been poor. The first infection with rotavirus elicits a serum neutralizing antibody response to the serotype of the infecting virus. Subsequent infections elicit a broader, cross-reactive response. Studies have suggested that antibody is important in the resolution of infection and in protection against subsequent infection, whereas cell-mediated immunity is most important in the resolution of rotavirus infections. Because a reliable immune correlate of protection has not been found, each new vaccine candidate must be tested in large field trials for efficacy.

All currently available rotavirus vaccines are live, orally administered vaccines that aim to mimic the protection given by naturally occurring rotavirus infection. They are designed to prevent moderate to severe rotavirus diarrhea and dehydration but not necessarily mild rotavirus disease. Attenuation of rotaviruses for use as oral vaccines may be achieved in several ways. The most extensively evaluated approach is based on the “Jennerian” concept, involving immunization of infants with animal rotaviruses that are naturally attenuated for humans. More recently, human rotaviruses attenuated by passage in tissue culture have been developed.

Research to develop a safe, effective rotavirus vaccine began in the mid-1970s, when investigators demonstrated that previous infection with animal rotavirus strains protected laboratory animals from experimental infection with human rotaviruses. Researchers postulated that live animal strains that were naturally attenuated for humans, when given orally, might mimic the immune response to natural infection and protect children against disease. Three such live, nonhuman rotavirus vaccines, 2 bovine-based and 1 a rhesus monkey vaccine, demonstrated variable efficacy in field trials and gave particularly disappointing results in developing countries. Development of these Jennerian vaccines has been abandoned.

The next generation of vaccines was designed to include more than 1 rotavirus G-serotype to provide broader immunity. The ability of rotaviruses to reassort during mixed infections in laboratory cell culture allowed the production of reassortant vaccines. Reassortant viruses contain some genes from the animal rotavirus parent and some genes from the human rotavirus parent. Because both VP4 and VP7 are thought to be important in protection, human-animal reassortant rotaviruses for use as vaccines include either human VP7 or VP4 genes to provide protective immune responses.

Using this method, the gene of a single human VP7 serotype was substituted onto the backbone of a parent (serotype G3) rhesus rotavirus (RRV) strain. Ultimately, this led to the production of a tetravalent rhesus rotavirus vaccine (RRV-TV, Rotashield), which comprised a mixture of 4 virus strains representing G types G1 to G4: 3 rhesus-human reassortant strains contained the VP7 genes of human serotypes G1, G2, and G4 substituted for the VP7 gene of the parent RRV, and the fourth strain was serotype G3 of RRV. The vaccine was administered to infants in 3 oral doses at 2, 4 and 6 months of age.

In August 1998, Rotashield was licensed in the United States. After inclusion of this vaccine in the immunization schedule for infants and immunization of almost 1 million children, several cases of vaccine-associated intussusception were reported. The period of greatest risk of intussusception was shown to be 3-10 days after the first of 3 oral doses. Although the true overall incidence of intussusception was difficult to assess, a group of international experts suggested a consensus rate of 1 per 10,000 vaccinated infants. The pathogenic mechanisms involved in intussusception after vaccination with Rotashield are currently unknown. As a consequence of this rare but potentially dangerous adverse effect, the manufacturer withdrew the vaccine from the US market 9 months after its introduction.

Two new rotavirus vaccines have been developed. One of these, RotaTeq, was licensed for use in the US in February 2006; recommendations for its routine use are to be published in the summer of 2006. This vaccine is composed of 5 bovine/human reassortant rotavirus strains based on a bovine rotavirus strain backbone and incorporating genes coding for the VP7 of human serotypes G1, G2, G3, and G4, as well as a human VP4 gene with P[8] specificity. The rationale for inclusion of both human VP7 and VP4 genes was that the vaccine would induce broadly reactive antibodies to both neutralization proteins of the common human serotypes. RotaTeq is given orally and has been well tolerated in clinical trials and provides good protection against rotavirus disease. RotaTeq has undergone a large-scale safety trial in 11 countries, which excluded any potential association with serious adverse events such as intussusception.

The second vaccine, Rotarix, is an attenuated live monovalent oral human rotavirus vaccine containing a G1, P[8] strain representing the most common of the human rotavirus VP7 and VP4 antigens. More than 70,000 infants have been enrolled in clinical trials conducted in Europe, the United States, Latin America, and Asia to evaluate the safety and efficacy of this vaccine. These studies demonstrate that Rotarix is an effective, safe and well-tolerated vaccine. A large-scale safety trial in Central and South America excluded any potential association of Rotarix with intussusception. Rotarix is now licensed in Mexico and some countries in Central and South America and is expected to be available in the European Union in 2006. However, Rotarix is not yet approved for rotavirus vaccination in the United States.

The Pediatric Infectious Diseases Journal, Volume 25(9), September 2006, pp 839-840

 

 

AIDS in India

[EDITORIAL] 

Solomon, S; Solomon, S S; Ganesh, A K

HIV infection in India was first detected in 1986 among female sex workers in Chennai. Today, with an estimated 5.134 million infections, India is home to the second largest population of people living with HIV and AIDS (PLHA). This article describes the state of the epidemic in India, the main contributing factors, and suggestions for changes that should be made in the management of the epidemic.

NUMBERS

The executive director of the Global Fund for AIDS, TB and Malaria, suggested that in 2004, India overtook South Africa in having the largest number of people living with HIV/AIDS in the world. The true prevalence of HIV in India is still debatable. Some of the available estimates of incidence have been carried out among sex workers in Maharashtra (22.1 per 100 person years) and drug users in Chennai (4.53%).  There is an urgent need for more studies estimating incidence of HIV in India. The case reporting system for HIV in the country requires improvement as sentinel surveillance has detected HIV in states that had not reported any infections.

AT RISK POPULATIONS

Although the epidemic was initially described among sex workers, the prevalence of HIV among sex workers has more or less stabilised because of targeted interventions, increased condom use, and empowerment strategies that encourage sex workers to demand safe sex from clients. Meanwhile, housewives with single partners are gradually accounting for a larger proportion of infections. These monogamous women are primarily put at risk by the extramarital sexual behaviour of their husband, from whom their infection is most probably acquired. The housewife is becoming the new face of the epidemic in India; a trend that necessitates research on microbicides and other female controlled HIV/STD prevention technologies.

VOLUNTARY COUNSELLING AND TESTING

Data clearly show that HIV has spread to all groups of Indian society. Over 90% of those infected with the virus are not aware of their status. Most diagnoses occur at late stages of the disease. While the number of voluntary counselling and testing centres is on the rise in both government and non-governmental settings in India, facilities have been underused because of (a) inaccurate perceptions of personal risk (b) a widespread belief that HIV is restricted to high risk populations such as sex workers, drug users, and truck drivers and (c) the persistence of stigma surrounding HIV.

Antenatal women and surgical patients routinely undergo a HIV antibody test in most medical institutions. On the basis of a positive result, health care is often denied to patients. In such situations, the test is often not adequately discussed with patients and a risk assessment not carried out. The possibility of a patient having a false negative test result is thus overlooked; consequently, necessary post-exposure prophylaxis for an occupational risk may be withheld.

TREATMENT, CARE, AND SUPPORT

Treatment guidelines

HAART is started in India based on the WHO criteria: absolute CD4 count <200 cell/µl, patient has an AIDS defining illness or CD4 200-350 with opportunistic infections. Before the introduction of CD4 counts, WHO staging of disease was used to start HAART. However, today, WHO staging for initiation of HAART is restricted to rural areas where CD4 estimation is not available. The most common first line regimen is a fixed dose generic combination of stavudine (d4T) + lamivudine (3TC) + nevirapine (NVP). All NNNRTIs and NRTIs that are currently used in developed settings are being manufactured on a large scale by generic producers in India. Most of the PIs are also manufactured by Indian pharmaceutical companies. The commonly used agents have been evaluated for their safety, efficacy, and tolerability among Indian patients with encouraging results.

Accessibility

It is essential to strengthen all testing protocols to include referral of HIV positive clients to well-established treatment, care, and support facilities. Anecdotal evidence suggests that the disclosure of a positive test result in the absence of proper guidance and counselling may lead some patients to access inappropriate medical treatment, suffer depression, contemplate or commit suicide, and even engage in high risk activities with intent to further transmit their infection.

The 3x5 initiative marked a shift in thinking in the response to the HIV/AIDS epidemic: it brought urgency to treatment and a commitment of public resources that were until that point only spent on prevention of HIV. Under this initiative, globally, WHO/UNAIDS aimed to rapidly scale up HIV/AIDS treatment and care to three million people in developing countries by the year 2005. In India, NACO has committed to providing free antiretrovirals to 100 000 persons under this initiative by the year 2007. As of 2005, about 35 000 patients in public and private sectors were receiving HAART.

There is a lack of trained HIV physicians in India. Few hospitals and physicians provide health care for people living with HIV/AIDS, partly because of reluctance among healthcare personnel to deliver treatment to this population. Reasons for this reluctance include personal values and prejudices, an inaccurate perception of occupational risks entailed in health care, and the belief that HIV negative patients will refuse to share health care facilities with people living with HIV.

Antiretroviral agents

Antiretroviral (ARV) agents are widely available in India. ARV drugs may be prescribed by any physician and many pharmacists dispense such drugs without prescription; some patients have been prescribed suboptimal doses of drugs. Given that medical insurance does not cover AIDS treatment and there are comparatively few, and geographically widespread, free government ARV supplying centres, most patients fund their own treatment. Faced with financial constraints and being unaware of the implications of suboptimal doses, patients often buy one or two of the three drugs prescribed. Many persons taking ARV treatment are transient users and poorly adherent.

Such mono/dual therapy or suboptimal adherence has been linked with an increased risk of development of drug resistance thereby limiting future options for care. The emergence of drug resistant viral strains could severely affect and even wipe out the competitive advantage provided by the generic drugs offered by Indian pharmaceutical companies.

To prevent the realisation of this situation, the number of free ARV supplying centres needs to be increased and access improved. The distribution of ARV agents must also be better regulated; physicians should be accredited to prescribe HAART and pharmacists made to comply with the Indian Drug Act (1940) that prohibits the sale of specified drugs without prescriptions.

Patients are often maintained with HAART without adequate CD4 monitoring arising from a lack of affordability, poor laboratory infrastructure in the public sector, and disregard of treatment guidelines. This can be life threatening in certain instances such as the use of NVP in men with CD4 over 400 or women with CD4 higher than 250.

Affordability

Highly active ARV therapy has improved the survival of persons living with HIV and AIDS the world over. A precipitous decrease in the cost of HAART was made possible by the successive introduction of generic versions. Of note is the impact on first line drugs. For example, stavudine + lamivudine + NVP that cost about US$740 per month in 1998 became available for less than US$20 in 2005. However, given that the per capita income of India is US$620 per year, even this regimen is unaffordable for most patients infected with HIV. While the reduced cost of such generic drugs permitted the initiation of HAART in the country, this regimen is now almost never used in more economically developed countries because of the availability of newer and less toxic agents.

Coinfections

High rates of coinfections among people living with HIV/AIDS complicate the management of HIV. HBV/HCV coinfection is widely prevalent among HIV infected injecting drug users. Tuberculosis (TB) is also highly prevalent among HIV infected persons in India, especially those with lower CD4 counts. There have also been reports of high rates of coinfection with Kala-Azar in India. The most commonly used regimens for HIV and TB include the drugs NVP and rifampin respectively, both of which are hepatotoxic and interact with each other resulting in suboptimal dosing.

Continuing medical education (CME) for physicians

CME for medical professionals is not mandatory in India. HIV disease management is dynamic and knowledge among physicians treating HIV is often dated or limited to the product promotion education that pharmaceutical representatives engage in. Rash and Steven-Johnsons syndrome are still common in India as most physicians are unaware of how to dose escalate when starting a patient with a NVP containing regimen. Physicians are still unfamiliar with the principles of switching ARV agents in patients failing therapy. Physicians prescribing ARV agents should have a thorough understanding of the principles of HAART and should become familiar with laboratory tests that are relevant to HIV disease monitoring.

Adherence issues

The availability of fixed dose ARV combinations reduces pill burden and thus facilitates improved adherence. However, most people infected with HIV in India are poorly educated and do not understand the need to continue HAART when they feel better or when their CD4 counts have risen significantly. Interruption of therapy places them at a high risk for developing drug resistance; this occurs even more easily with NNRTIs, which have long serum half-lives. Some temporarily stop treatment, restarting when adequate funding becomes available. In sero-concordant couples, where only one partner may clinically require HAART, they often share their drugs with their HIV negative partner or spouse. To achieve optimal adherence, clinics should evaluate and use a number of measures such as directly observed treatment, family counselling, and intensive patient education.

Second line ARV regimens

Less than 10% of the patients can afford a PI based regimen. Plasma viral load (PVL) measurement is almost never carried out because of financial constraints. A clinician usually identifies that a patient is failing therapy when successive CD4 counts show declines or when the patient starts developing new opportunistic infections. This can be a few months to years after virological failure and by this stage the patients could have accumulated enough mutations to render the remaining NRTIs, namely didanosine, abacavir, and tenofovir, useless. If second line agents are to be more effectively and appropriately used in India, then PVL quantification must become a routine part of HIV monitoring. Low cost techniques to estimate PVL are an urgent requirement in resource constrained settings such as India. There are few studies in India evaluating the rates of treatment failure and drug resistance among patients. Drug resistance to 3TC among treatment naive patients has recently been reported by Sachdeva and colleagues.

PREVENTION OF MOTHER TO CHILD TRANSMISSION OF HIV

There are about 27 million live births per year in India. The government of India has introduced VCT for all ANC attendees in the public sector. In the private sector, HIV testing is carried out routinely for all pregnant women. The prevalence of HIV among antenatal women is 0.1 to 2.25% across the country. Women found HIV positive in government centres are treated with a single dose of NVP at the onset of labour with one dose given to the child 72 hours after birth. Mothers are counselled about the risk of HIV transmission through breast-feeding but the decision to use formula milk is left to the mother.

SUCCESS STORIES

Management of sexually transmitted infections (STIs)

India has a high rate of STIs, an estimated 6% to 9% among the general population, roughly 40 million new infections a year. STI, especially ulcerative STIs, increase the risk of HIV transmission. Appropriate management of STIs can reduce a person’s susceptibility to HIV; STI treatment has been prioritised and has improved considerably in India. In rural areas where laboratory facilities are unavailable, syndromic management of STIs is being advocated. To strengthen this effort, diagnostic tests should be made more widely available.

HUMAN RIGHTS ISSUES

Physicians in India have always held a disproportionate power over their patients. Demands from activist networks of people living with AIDS to be treated with dignity, protected from discrimination by employers, and given access to education, care, and ARV drugs has led to an increase in general awareness about patients’ rights.

QUACKS AND MAGIC CURES

Ineffective regulation of medical practitioners, patient ignorance, and an unwelcoming modern health sector, lure people living with HIV/AIDS towards quack doctors and magic cures. In 1997 the Delhi State government introduced the Delhi Quackery Prohibition Bill in the Assembly after reports that nearly 30 000 quacks were operating in the capital alone. Little is known on the interactions between ARV drugs and the drugs dispensed by quacks. Patients often interrupt HAART to use such alternative medication or even engage in their concomitant use.

CONCLUSION

In the past 20 years, the country has made substantial investment in HIV prevention. In the past five years there has been significant scale up of VCT services and capacity building for care and support. While retaining this focus to prevent backsliding of prevention, the next decade should be devoted to developing excellence in HIV care, reducing stigma thereby permitting increased uptake of services and making additional efforts to tackle the disparity in distribution and affordability of ARV agents.

Postgraduate Medical Journal, Volume 82(971), September 2006, pp 545-547

 

 

BOTTOM LINE 

Ten points for poster preparations

T Moshkovska

Posters should be

• Informative
• Interesting
• Impressive
• Memorable

They should

• Draw attention to the issue being considered
• Provide essential information only
• Be designed for their audience
• Have a balance of pictures, text, and colour

As a result the audience should

• Think about the issue
• Want to become involved with the issue

 

Postgraduate Medical Journal 2006;82:300