Indian J Med Res 121, April 2005, pp 377-394 377 The prolonged course of human immunodeficiency virus (HIV) infection is marked by a decrease in the number of circulating CD4+ T helper cells and persistent viral replication, resulting in immunologic decline and death from opportunistic infections and neoplasms1,2. Acute HIV infection is characterized by a rapid rise in plasma viraemia with a concomitant drop in CD4 count within 3-6 wk of exposure (Fig.1). Associated symptoms with this initial stage of infection occur to varying degrees of severity and may include fever, sore throat, skin rash, lymphadenopathy, splenomegaly, myalgia, arthritis, and, less often, meningitis3. The acute phase is followed by a clinically latent period with low level viral replication and a gradual fall in CD4 count where the patient can remain asymptomatic for several months to years. Mean duration of survival after diagnosis with HIV in India is 92 months4. Median time for progression from HIV infection to acquired immunodeficiency syndrome (AIDS) was 7.9 yr in one study of patients from Mumbai5. This number is subject to a reporting bias given that fewer than 10 per cent of AIDS cases in India have been reported. With CD4 counts less than 200 cells/ µl, patients are at high risk for developing opportunistic infections (OIs) like tuberculosis (TB), Pneumocystis carinii pneumonia (PCP), toxoplasmosis, and cryptococcal meningitis (Fig.2). Before the availability of antiretroviral therapy, median survival after diagnosis of AIDS was 12 to 18 months6. This has changed dramatically since the advent of highly active Key words AIDS - antiretroviral therapy - developing countries - generic - HAART - HIV - India - natural history - OIs - opportunistic infections - tuberculosis Clinical profile of HIV in India N. Kumarasamy*, Snigdha Vallabhaneni**, Timothy P. Flanigan+, Kenneth H. Mayer+ & Suniti Solomon* *Y.R.G. Center for AIDS Research & Education (CARE), Chennai, India, **Brown Medical School, Providence, RI, & +Division of Infectious Disease, Department of Medicine, The Miriam Hospital, Brown University, Providence, RI, USA Accepted February 17, 2005 The clinical course of human immunodeficiency virus (HIV) disease and pattern of opportunistic infections varies from patient to patient and from country to country. The clinical profile of HIV disease in India includes a wide range of conditions like tuberculosis, cryptococcal meningitis, popular pruritic eruptions, and cytomegalovirus retinitis, among others. Tuberculosis is the most common opportunistic infection in Indian patients with HIV. Occurrence of various AIDS- associated illnesses determines disease progression. Mean survival time of Indian patients after diagnosis of HIV is 92 months. In this review, we discuss the clinical profile of HIV disease through an organ system-based approach. With the availability of antiretroviral therapy at lower cost, the clinical profile of HIV disease in India is now changing to include drug-related toxicities and immune reconstitution syndrome. 378 INDIAN J MED RES, APRIL 2005 antiretroviral therapy (HAART) in the developed world and generic HAART in the developing world (Kumarasamy N, unpublished observation). Specific AIDS-defining illnesses, CD4 counts, and HIV RNA levels predict survival of patients with HIV infection7,8. Disease progression correlates with clinical features such as chronic fever, persistent cough for >1 month, chronic diarrhoea, oral candidiasis, severe chronic herpes simplex virus (HSV) infection, >10 per cent loss of body weight within 1 month, and incident tuberculosis 5. Generalized lymphadenopathy and herpes zoster (shingles) can occur early in the course of illness and do not correlate with more rapid progression. Patients with CD4 counts less that 200 cells/µl are 19 times more likely to die than those with CD4 counts greater than 350 cells/µl4. Clinical course and pattern of opportunistic infections varies from patient to patient and from country to country,9,10. For example, TB is the most common OI in HIV patients in India4 (Fig.3), whereas OIs like Mycobacterium avium complex (MAC) and Kaposi’s sarcoma, frequently reported in the developed world, are not as commonly reported in India11-14. The progression and outcome of HIV/ AIDS is influenced by factors such as baseline health and nutritional status, environment, endemic diseases, and access to therapy. It is important to understand the presentation of HIV disease in the local context. In this review the clinical profile of HIV disease in India is discussed through an organ-system based approach. Pulmonary manifestations of HIV Pulmonary diseases associated with HIV are among the most common and some of the most serious presenting illnesses in HIV-infected individuals. This section addresses some common pulmonary disease such as TB, PCP, and bacterial pneumonia. Tuberculosis: HIV-TB co-infection is a serious problem worldwide, but especially of concern in India where background rates of TB are the highest in the world19. Prevalence of HIV among patients with radiologic or bacteriologic confirmation of TB in India ranges from 2.8 to 9.4 per cent20-24. These numbers reflect a rise in co-infection rates over the last decade. In India, the most common opportunistic infection among people with HIV infection is pulmonary tuberculosis4,15-18. Understanding HIV-TB co-infection is of great importance because of increasing prevalence of co-infection, severity of clinical presentation of TB in HIV-positive patients, rapid progression of HIV disease in TB patients, and challenges in treatment of co-infected patients given possibility of drug interactions and immune reconstitution syndrome. The risk of developing TB after an infectious contact is 5-10 per cent per year among HIV infected individuals compared to 5-10 per cent during the lifetime of HIV-negative individuals 25. Unlike cryptococcal meningitis or toxoplasmosis, which occur at very low CD4 counts, TB is unique in that it can occur over a wide range of CD4 counts, although it is more frequent at CD4 counts <300 cells/µl. The clinical and radiological presentation of TB in HIV patients differs according to the degree of immunosuppression. The typical presentation of cough, sputum, dyspnoea, fever, and weight loss with apical lobe infiltrates or cavitary lesions on chest radiograph might only be seen in patients with very high CD4 counts whose immune systems are more comparable to HIV-uninfected individuals. TB in HIV patients with CD4 counts less than 300 cells/µl can present in an atypical pattern. Radiographic studies may show middle and lower lobe infiltrates, miliary TB, tubercular pneumonia, and hilar or mediastinal lymphadenopathy20,26. Chest radiographs can also be normal in immunocompromised patients despite presence of Mycobacterium tuberculosis in sputum. Extra-pulmonary tubercular manifestations occur in 46 to 79 per cent of patients with pulmonary TB and HIV27,28, and is more frequent in severely immunocompromised patients29. Extra-pulmonary TB has been reported in many organs: lymph nodes (most common), spleen, liver, bone, bone marrow, heart, central nervous system, gastrointestinal tract, kidneys, adrenals, thyroid, and prostate28. The resulting clinical conditions include persistent fever, pleural and 379 pericardial effusions, ascites, pancreatitis, back pain, anaemia, mental status abnormalities, and renal failure, among others. In one study in India, extra- pulmonary TB was the cause of 69 per cent of previously unexplained prolonged fever in 100 HIV- positive patients30. In another study, severe weight loss in HIV patients, defined as loss of greater than 10 per cent of body weight in one month, significantly correlated with diagnoses of pulmonary and extra- pulmonary tuberculosis (relative risk: 17.7)31. Mantoux skin testing for TB in HIV patients is challenging because results depend on the patient’s immune status. Tuberculin positivity is less prevalent among HIV seropositive patients as compared to HIV seronegative patients (22.6% vs 76.4%; P < 0.001)20 due to anergy resulting from immunosuppression. Therefore, results of skin testing in HIV patients should be interpreted with caution. Sputum smear positivity among HIV/TB co-infected patients has been reported in 21 to 83 per cent of patients 21,27; there was no statistically significant difference in these rates between HIV-positive and -negative patients17,18. Just as HIV infection can contribute to the severity of TB, there is increasing evidence that TB can affect HIV disease progression. Patients with active TB were found to have higher HIV plasma viral loads (PVLs) than asymptomatic patients with HIV and those with OIs other than TB32. Pro-inflammatory cytokine production, particularly TNF- alpha, by tuberculous granulomas is thought to contribute to HIV viral replication. The risk of death in a cohort of Indian HIV-infected patients with TB was 3.5 times greater than the risk in HIV infected patients without TB with matched CD4 counts4. Most of these deaths were caused by disease progression rather that TB itself. Given the mortality and morbidity caused by TB, it is extremely crucial to treat TB appropriately in HIV-infected patients. HIV-infected patients respond as well as HIV-negative patients and can be similarly treated. If the patient does not respond to standard regimens, it is important to consider multi- drug resistant TB. Liver function and inflammation should be carefully monitored. Physicians should also be aware of immune reconstitution syndrome (IRS), which is described as a paradoxical worsening of clinical status after initiation of HAART in a patient with an active opportunistic infection such as TB33. The incidence KUMARASAMY et al: CLINICAL PROFILE OF HIV (Duration of infection) Fig. 1. Natural history of HIV Infection. Adapted from: Favci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 1996; 124 : 654. CD4 cells/µl) 380 INDIAN J MED RES, APRIL 2005 of IRS among HIV/TB co-infected southern Indian patients was 7.3 per cent 34. It is important to continue TB treatment and give supportive therapy to patients with IRS. Current World Health Organization (WHO) guidelines recommend starting HAART between two weeks and two months after initiating TB treatment in patients with a CD4 count less than 200cells/µl35. For patients with CD4 counts between 200 cells/µl and 350 cells/µl, HAART can be started after the initiation phase of TB treatment because of the utilization of rifampicin. HIV treatment can be deferred if CD4 count is greater than 350 cells/µl. Preventive therapy for TB using isoniazid with and without other drugs among HIV-positive patients in Africa, where TB burden is also high, has been shown to be cost effective, safe, and successful at decreasing mortality36,37. No guidelines for TB prophylaxis exist in India due to lack of data in this setting. The safety, tolerability, and efficacy of TB prophylaxis among Indian HIV-positive patients needs to be studied. Atypical mycobacteria like M. avium, which is the organism responsible for causing MAC, has only been reported by a few studies from India 11,38,39. The reason for the low incidence of MAC in India might have to do with low background prevalence or lack of diagnostic capabilities. Pneumocystis jerovecii pneumonia (PCP): Pneumocystis jerovecii causes severe pneumonia in patients with AIDS. Occurrance of PCP establishes the diagnosis of AIDS40 and it is the most common AIDS-defining illness in the developed world41. In India, however, very low rates (0.7 to 7%)4,22,28,30 of PCP have been reported. Some reasons for this could be the predominance of other pulmonary diseases like TB, and due to underdiagnosis of incident cases. PCP occurs in patients with CD4 counts under 200 cells/ µl; studies from Delhi and Chennai reported median CD4 counts of patients with PCP of 142 and 87 cells/ µl respectively4,29. According to a large natural history study, Indian patients with PCP were 4.5 times more likely to die than patients without PCP 4. Median survival after diagnosis of PCP in this study was 24 months4. In the Indian context, PCP can simultaneously occur with other pulmonary infections, including TB, cryptococcosis, and cytomegalovirus42. A case report from Pondicherry describes a patient who presented with clinical and radiologic evidence that suggested TB, was treated without response, and was found to have PCP on autopsy43. Therefore, a diagnosis of PCP must be considered in patients with a diverse array of pulmonary, clinical and radiological presentations. Induced sputum, with 28-55 per cent sensitivity for PCP can be used as an alternative to invasive and expensive bronchoalveolar lavage (BAL) to diagnose PCP44-45. PCP responds to high dose co- trimaxazole. Adjuvant use of steroids in patients with hypoxaemia is important and results in decreased mortality and morbidity. Efficacy of co-trimaxazole against PCP, toxoplasmosis, salmonellosis, Haemophilus infection, and staphylococcal infection in patients with HIV has been well documented46. The National Institutes of Health (NIH) treatment guidelines recommend the use of co-trimaxazole prophylaxis when CD4 counts are less that 200 cells/µl47. Indian patients whose CD4 counts are less than 200 cells/ µl have a 3-fold increased risk of death if they are not on cotrimaxazole prophylaxis4. WHO/UNAIDS recommends use of cotrimaxazole prophylaxis in HIV-positive adults with CD4 counts less than 500 cells/µl in Africa48 but prospective trials in Indian patients are needed to help develop guidelines for clinical practice in our setting. Given its efficacy and affordability, co-trimaxazole prophylaxis is an important consideration in the management of HIV. Physicians should be aware of the possibility of hypersensitivity reaction (usually rash and fever) to cotrimaxazole. Bacterial pneumonia: Bacterial pneumonia was reported as an opportunistic infection in 1.8 per cent of a large southern Indian cohort of HIV-positive patients. Similar to HIV4 negative individuals, the most common causes of acute community acquired pneumonia, are encapsulated bacteria, Streptococcus pneumonia and Haemophilus influenzae49. Rates of bacterial pneumonia can be up to 25-fold higher among HIV infected adults than in the general community50, with the most significant predictor of 381 risk being level of immunosuppression. Although bacterial pneumonias can occur relatively early in the course of HIV, frequency of occurrence is inversely proportional to CD4 count. Incidence of serious disseminated pneumococcal infections is 100-fold more frequent in individuals with very low CD4 counts50. Among others, smoking and a history of pneumonia are additional risk factors for bacterial pneumonia. Interestingly, resulting mortality in HIV- infected individuals is not significantly higher than in the general population. Several strategies that include long-term prophylaxis with cotrimaxazole, vaccinations, and smoking cessation have been suggested to lower the risk from bacterial pneumonias. Pneumococcal vaccination prevents morbidity due to pneumococcus47. Studies are needed to evaluate the potential benefit of this vaccine in Indian HIV-positive patients. If the clinical picture and radiological evidence do not fit TB, PCP, or bacterial pneumonia, or the patient does not improve on therapy targeted at these infections, it is important to consider the possibility of cytomegalovirus (CMV) infection, cryptococcosis, aspergillosis, toxoplasmosis, Penicillium marnefeii, Kaposi’s sarcoma, and squamous cell carcinoma, as all of them have been reported in Indian patients with HIV and severe immunosuppression28,51. Oral lesions in HIV Ear, nose, and throat specialists, as well as dentists, can play an important role in identifying individuals infected with HIV because oral manifestations of HIV disease are common and are among the first signs of HIV infection and immunosuppression. Oral lesions are important not only in early diagnosis but also in monitoring the progress of disease. Studies show that oral lesions often co-occur with other diseases, especially pulmonary infections. For example, one study showed that 39 per cent of those with oral lesions had concurrent pulmonary TB 52. This underlines the importance of examination of the oral cavity for clues about the level of immunity and the overall health status of the patient. Oral candidiasis: Oral candidiasis occurs frequently in individuals with HIV infection; it has been reported as the most common HIV-associated condition, occurring in up to 70 per cent of cases 4,15,16,18,52,53. KUMARASAMY et al: CLINICAL PROFILE OF HIV Fig. 2. Mean CD4 count for patients presenting with opportunistic infections at YRG Care, Chennai, India. TB, Tuberculosis; PCP, Pneumocystis Carinii pneumonia; OHL, Oral hairy leukoplakia; CMV, cytomegalo virus; Rec Bact Respirato, recurrent bacterial respiratory infection. Opportunistic Infections Cryptococcal meningi Gasteroenteropathy PCP CMV Retinitis Rec. Bact. RespiratO Papular pruritic eru Extrapulmonary TB Pulmonary Tuberculos Oral Candidiasis Molluscum Contagiosu Toxoplasmosis OHL 325 300 275 250 225 200 175 150 125 100 Herpes simplexHerpes zosterDermatophyte infection Cryptosporidial diarrhoea Mean CD4 and cells /µl tis ptions is o 382 INDIAN J MED RES, APRIL 2005 The psuedomembaranous “white patches” variant of candidiasis is associated with more severe immunosuppression than the erythmetous, hyperplastic or angular chelitis types54. Median CD4 counts of patients with candida ranged between 107 and 189 cells/µl in different studies4,29. The positive predictive value of oral candidiasis for low CD4 count is greater than 75 per cent18. The presence of oral candidiasis indicates the need to start PCP prophylaxis. Periodontal disease: HIV infection is associated with three characteristic presentation of periodontal disease: necrotizing periodontal disease, linear gingival erythema (LGE), and exacerbated attachment loss55. LGE is described by rapid loss of bone and soft tissue in clean mouths where there is very little plaque or calculus to account for the gingivitis. However, it is difficult to distinguish LGE from non HIV-related periodontal disease when background prevalence of periodontal disease is high. Gingivitis of unspecified kind has been reported in 24 to 47 per cent of HIV positive cohorts52. LGE has a 70 per cent positive predictive value for low CD4 count (CD4 <200 cells/µl)56. Oral hairy leukoplakia (OHL): Worldwide, prevalence of OHL among HIV infected individual ranges from 0 to 26 per cent54. One study in south India reported OHL in 4 per cent of 594 HIV positive individuals4. In this study, median CD4 count was 129 cells/µl, and median survival after diagnosis was 41 months. The positive predictive value of OHL for low CD4 count has been reported at 66 per cent56. Oral ulcers: Oral ulcers in HIV can be caused by a number of infections, primarily, HSV. Background prevalence of latent HSV-1 infection in India is 78 per cent57. Herpes simplex lesions are the third most common mucocutaneous lesion in HIV-infected individuals after candida and dermatophytosis58. In one study, 5.7 per cent of HIV-positive individuals had active HSV ulcers (median CD4 count=219 cells/µl)4. Recurrent oral and genital herpes is also fairly common. CMV can cause oral ulcers, as can tuberculosis, histoplasmosis and Crypotococcus neoformans52. Apthous ulcers caused by unknown immunologic and virologic factors59, are also common in HIV-positive individuals. It is important to distinguish infectious causes of ulcers from apthous ulcers in order to target treatment with antimicrobials as opposed to anti- inflammatory agents. Oral pigmentation: Oral pigmentation, patchy brown to brownish-black asymmetrical lesions usually greater than 1cm, which are distinctive from racial oral pigmentation, have been reported in up to 23 per cent of HIV positive individuals52. The etiology of these lesions is unclear and needs investigation. Dermatologic conditions associated with HIV HIV infection is associated with several dermatologic conditions, which can be the initial presenting signs of HIV. Cutaneous manifestations can occur in up to 90 per cent of HIV-infected individuals61 and can be classified into five groups: infectious, auto-immune, drug-induced, HIV-related, and cutaneous malignancies. Often, these conditions present atypically, are much more severe, and need prolonged treatment in HIV infected patients than in the general population. Most dermatologic conditions are less frequent and less severe with the use of HAART. Infectious: Herpes zoster can occur early in the course of HIV disease and generally precedes other skin manifestations of HIV disease. In patients with HIV, it can present with necrotizing ulcers in a multi- dermatomal pattern, can last longer than the usual 2-3 wk, and heal leaving prominent scars. A study which showed increased prevalence of herpes zoster among injection drug user in Manipur, attributed it to the newly blossoming HIV epidemic in that population61. Eight per cent of patients with HIV had herpes zoster, at a median CD4 count of 250 cells/ µl. There was no associated increase in mortality4. HSV-1 was described in the oral lesions. HSV 1/ 2 can also be found in genital and anal areas. Prevalence of HSV-2 in a high risk HIV-negative cohort attending a STD clinic in Pune was reported to be 43 per cent62. This study showed that HSV infection, especially recent incident infection can 383 increase chances of HIV acquisition. Control of herpes in both the HIV-infected and uninfected partner might reduce the risk of transmission and acquisition of HIV. Human papilloma virus (HPV), which causes oral, genital, and anal warts has been reported in 29 per cent of buccal mucosal cells and 63 per cent of cervical cells in female sex workers in Kolkata63. As CD4 counts drop below 200 cells/µl, warts can grow rapidly and be difficult to control. Molluscum contagiosum, characterized by pearly pink papules with central umbilications, can be a disfiguring skin infection when it occurs in a disseminated fashion in severely immunocompromised individuals. Molluscum contagiosum accounted for 14 per cent of cutaneous lesions in one histopathalogic study of cutaneous lesions in Indian patients with HIV14. Giant molluscum, and xerosis/acquired ichthyosis were associated with advanced HIV diseases58. Disseminated Penicillium marneffei infection, which can be confused with molluscum contagiosum has been reported in Manipur51. This report, along with earlier ones64 from the same area, established the endemicity of this organism in eastern India. Staphylococal skin infection is the most common cutaneous bacterial infection in HIV patients. It was reported in 1.3 per cent of 833 HIV-positive Indian patients, and occurred at a mean CD4 count of 410 cells/µl65. Histoplasmosis, cryptococcosus, scabies and dermatophyte infections are also among infectious dermatopathalogic conditions affecting Indian patients with HIV13. Systemic infections like syphilis and TB have dermatologic manifestations that are seen in HIV- positive individuals. In a histopathalogic study of cutaneous lesions, 13 of 195 patients had cutaneous TB and 14 had syphilis13. Syphilis afflicts up to 25 per cent of HIV-positive individuals66, and can present in the primary stage as a chancre, in the secondary stage with mucocutaneous features and in the tertiary stage with neurologic and cardiac involvement. Standard of care is to conduct a veneral disease research laboratory (VDRL) or rapid plasma reagin (RPR) test for all patients who are HIV positive and treat if found to be reactive on a confirmatory test. Autoimmune: Papular pruritic eruption (PPE) is a unique dermatosis associated with advanced HIV infection, characterized by sterile papules, nodules, or pustules with a hyperpigmented, urticarial appearance, and pruritis67. When patients present with intractable, unexplained itching, physicians must consider a diagnosis of PPE and investigate for HIV infection. KUMARASAMY et al: CLINICAL PROFILE OF HIV Fig. 3. Spectrum of Opportunistic Infections among Patients at YRG CARE, Chennai, India (N= 6815). 384 INDIAN J MED RES, APRIL 2005 Alopecia, vitiligo, psoriasis, eosinophillic folliculitis, and seborrhoeic dermatitis are all examples of autoimmune conditions associated with HIV. These conditions occur with greater frequency and severity in HIV-positive patients. Drug-induced: With increasing affordability and accessibility of generic HAART, dermatologic conditions associated with HIV also include the spectrum of toxicities resulting from HIV therapy. While the safety, tolerability and efficacy of generic HAART regimens has been established, there are associated toxicities that can manifest cutaneously: from generalized morbilliform exanthema to severe Steven Johnson’s Syndrome (SJS). Of the 1286 patients who were on HAART at YRG CARE, 21 per cent complained of pruritis, and 11 per cent had rash, 87 per cent of these rashes were attributed to nevirapine. SJS occurred in 11 individuals, all on nevirapine 68. In addition to HAART, reaction to co-trimaxazole prophylaxis, which is recommended for all patients with CD4 counts below 200 cells/µl, can also present as an allergic rash. Cutaneous malignancies: Cutaneous malignancies reported in Indian literature include squamous cell carcinoma, basal cell carcinoma, and Kaposi’s sarcoma13. Kaposi’s sarcoma has been widely reported in the developed world and parts of Africa. However, there have been few reports of this malignancy in India12-14. This stark difference in prevalence might be related to differences in transmission of HIV that contribute to risk of developing Kaposi’s sarcoma and low prevalence of human herpes virus-8 in India69. Neurologic manifestations of HIV Neurological complications of HIV disease can be seen in 20% of outpatients in HIV clinics and almost half of HIV patients being treated as inpatients70. Since many of them are caused by treatable pathogens, it is important to understand the spectrum of neurologic diseases in India. They can be categorized into opportunistic infections, malignancy, AIDS related dementia, and vasculitis/ stroke. Opportunistic infections in central nervous system (CNS): Cryptococcal meningitis (CM) has been reported as the most common opportunistic infection of the CNS of Indian patients with HIV 70-73. It accounted for 2-4.7 per cent of all opportunistic infections in two large HIV-positive patient cohorts in Mumbai and Chennai4,29. In another study of 100 HIV-positive patients evaluated for neurological disorders, 37 patients had CM, 6 of them with concurrent tuberculous meningitis71. In southern Indian patients, diagnosis of CM was associated with a 7-fold increase in risk of death4. The median CD4 count at presentation was 91 cells/µl, with a median survival after diagnosis at 22 months. In a study that included HIV-positive and negative patients with cryptococcal infection, those with HIV infection were found to have poorer cerebrospinal fluid (CSF) cell response and higher mortality74. Poor prognostic factors for CM include positive blood cultures, altered mental status, CSF antigen titre above 1:1024, positive CSF India ink smear, CSF white cell count below 20cells/µl3, and elevated CSF pressures75. Gold standard diagnosis of CM requires demonstration of organism in CSF. However, serum cryptococcal antigen can be used as a reasonable adjunct for diagnostic purposes. Treatment involves intravenous (IV) administration of amphoterecin B for 2 wk of induction therapy. Risk of renal toxicity with amphoterecin treatment is high. Prospective trials comparing efficacy of flucanazole and amphoterecin therapy in Indian patients are needed. Toxoplasmosis is also a common OI of the CNS76. In a large south Indian cohort of HIV-positive patients, median CD4 count at time of diagnosis was 135 cells/µl4. Diagnosis of toxoplasmosis was associated with a 2.6 fold increased risk of mortality4. CNS toxoplasmosis was significantly associated with a complaint of headache, and accounted for 30 per cent of HIV-positive patient presenting with seizures77. Neurocystocercosis, reported in 8 patients in a recent review78, along with CNS lymphoma should be considered as differential diagnoses for mass occupying lesions like toxoplasmosis. Diagnosis of toxoplasmosis is challenging because the gold standard for diagnosis involves brain biopsy. 385 However, diagnosis is usually based on CNS imaging studies demonstrating typical mass lesions. Serum anti-toxoplasmosis antibodies have been used as adjuncts but cannot rule in or rule out infection with certainty because of an almost 20 per cent false negative rate79, and high baseline seroprevalence of antibodies without active encephalitis (30% in health volunteers and 68% in HIV positive individuals in Mumbai)80. Despite the prevalence of pulmonary and extra- pulmonary TB in Indian patients, TB meningitis is less common than cryptococcal meningitis and toxoplasmosis. It accounted for 18 per cent of patients with meningitis in a large cohort of patients evaluated for neurological complications70. The course of TB meningitis in HIV patients is different from HIV- negative patients: cognitive dysfunction is more common, and pathological features demonstrate reduced and atypical inflammatory responses, and extensive vasculopathy. There is absence of or minimal meningeal enhancement and absence of communicating hydrocephalus on computed tomography (CT) scan in HIV-positive patients. As expected, mortality is higher in the HIV positive group81. Other CNS opportunistic infections reported in India include herpes encephalitis, fulminant pyogenic meningitis, meningococcal meningitis, acanthamoeba infection, aspergillus infection, rhizopus infection, and neurosyphillis71,72. There have also been a few scattered cases of primary multifocal leukoencephelopathy71,77,82. Acute Guillain-Barre-like syndrome affecting the peripheral nervous system has also been reported in India71. Prevalence and incidence of all CNS infections decreased after initiation of HAART in developed countries83 and we might observe similar trends as generic antiretroviral therapy becomes more widely available in India. Malignancy: In Western literature, non-Hodgkins lymphoma (NHL) is the second most common HIV- related malignancy after Kaposi’s sarcoma, occurring in 2-5 per cent of AIDS patients75. However, reports of CNS NHL in Indian patients with AIDS are few and far between. One study reported that CNS lymphoma was found in 2 per cent of Indian patients with HIV presenting with seizures84. An autopsy study of 85 AIDS patients in Mumbai revealed no cases of CNS lymphoma76. CNS lymphoma should still be considered as an alternative diagnosis to space occupying lesions like toxoplasmosis and TB meningitis. AIDS dementia complex: Reports about AIDS dementia complex (ADC) in India are minimal. Review of literature revealed one study in Jaipur of 30 AIDS patients, 4 of whom were diagnosed with ADC85. It is possible that ADC is under-recognized and under-reported given that it is a chronic problem without a simple diagnostic test. However, ADC is important to recognize and manage because it impacts the quality of life of patients and impinges on their ability to function and perform their daily activities of living. HAART remains the only option for management of ADC. Vasculitis/stroke: Stroke in patients with AIDS can be secondary to a number of causes - haematogenous fungal infection, herpes simplex encephalitis, cerebral varicella zoster or neurosyphilis, among others. HIV infection itself can cause vascular endothelial damage, predisposing patients with advanced disease to stroke. In an autopsy study of AIDS patients, infarcts/ haemorrhages were present in 15 per cent of cases76. Psychiatric illnesses: HIV/AIDS is confounded by psychiatric illnesses, both pre-existing, and ones that develop after learning of diagnosis. Pre-existing illnesses such as drug and alcohol dependence predispose patients to behaviour that puts them at risk for acquiring HIV infection. Patients with this history must be carefully counseled regarding risks of alcohol and drug use, especially in the context of HIV disease. A study that assessed HIV patients 4-6 wk after they learned of their positive status, found that 40 per cent were depressed and 36 per cent had anxiety86. Serious suicidal intent was seen in 14 per cent. Presence of pain, concurrent alcohol abuse, poor family relations, and presence of AIDS in the spouse were significant factors associated with depression, anxiety, and suicidal ideation86. Supportive counselling accompanying clinical care is crucial for these patients. 386 INDIAN J MED RES, APRIL 2005 Gastrointestinal manifestations of HIV Esophagitis: Esophagitis, causing dysphagia or odynophagia, is very common among patients with advanced HIV disease. The majority of patients with dysphagia or odynophagia have candidal esophagitis alone or occasionally in association with other infectious pathogens, such as CMV or HSV. It is important to treat this condition effectively because it could lead to malnutrition and further deterioration of health in an already compromised patient. When evaluating dysphagia and odynophagia, physicians should also consider HIV-unrelated conditions like gastroesophageal reflux disease and peptic ulcer disease, which are common in the Indian population. Diarrhoeal diseases: Chronic diarrhoea is a major problem in HIV infected persons, affecting up to 76 per cent of those with AIDS16. It is associated with a 3.3 fold increased risk of disease progression 5. In reports from north, south and east India, Isospora belli and Cryptosporidium parvum were the two most common causes of chronic diarrhoeal disease in HIV infected persons87-90. Blastocystis hominis, Strongyloides stercoralis, Entamoeba histolytica, Giardia lamblia, enteropathogenic Escherichia coli, Enterocytozoon bieneusi and Campylobacter jejuni are other causative agents of diarrhoea in Indian patients with HIV. There was no geographic pattern to the frequency of organisms. At YRG CARE, Chennai, stools of HIV-positive patients with and without diarrhoea were tested. Interestingly, Cryptosporidium parvum was present in 70 per cent of stools of those with diarrhoea and 66 per cent of those without diarrhoea. Those without diarrhoea had a mean CD4 count of 406 cells/ µl compared to 213 cells/µl of those with diarrhoea91. Cryptosporidium is endemic in the water supply in many parts of India92, and the prevalence of infections and the associated morbidity point to the importance of counseling patients regarding the importance of boiling water before consumption. Abdominal mass lesions: Abdominal mass lesions in HIV patients can be caused by abdominal tuberculosis and abdominal lymphoma. These diagnoses should both be considered in patients presenting with diarrhoea, pain, obstruction, bleeding, or perforation (which occur with luminal involvement) or dull pain in association with fevers and a rising alkaline phosphatase (in case of hepatic involvement). In one study, patients with abdominal tuberculosis had a significantly higher risk of being HIV-positive compared with those with pulmonary tuberculosis and voluntary blood donors (16.6 vs 6.9 and 1.4%, respectively)95. Hepatitis B and C: Hepatitis B and C have the same risk factors for transmission as HIV. Concurrent infection with HIV and hepatitis B and/or C is of great concern in the developed world where co-infection rates are as high as 89 per cent in some cohorts 94. In India, rates of co-infection with HIV and hepatitis B are reported between six and 33 per cent 4,95. In a study in the eastern state of Manipur, where intravenous drug use is high, 92 per cent of HIV- positive intravenous drug users (IVDUs) were co- infected with hepatitis C96. In addition, in a study of slum residents in Chennai, IVDUs were almost 28 times more likely to be HCV infected than those denying injection drug use (IDU) 97. In a predominantly non-IVDU population, HIV-HCV co- infection rates have been reported between 4.8 and 21.4 per cent4,98. End-stage liver disease caused by HCV is an important cause of death among HIV patients in the United States99. In India, co-infection with hepatitis C has been found to be associated with almost an 8 fold increased risk of disease progression 4. Compounded by the prevalence of chronic alcoholism in HIV infected persons, and hepatotoxic drugs used in the treatment of HIV disease, co-infection with hepatitis B and C are important considerations in the management of patients with HIV. A study in south India of high risk individuals attending a HIV voluntary counselling and testing centers found the prevalence of hepatitis B and C to be 5 and 3 per cent, respectively 100. Because the prevalence of hepatitis B and C in HIV infected patients is generally low, routine baseline, testing for these viruses is not recommended unless the patient has a history of injection drug use, or has elevated transaminase levels. 387 Ocular manifestations of HIV A variety of ocular conditions associated with AIDS in India have been reported: extensive blepharitis and spontaneous lid ulcer101, extensive molluscum contagiosum102, frosted branch angiitis due to CMV retinitis103, subretinal cysticercosis, herpes simplex keratitis104, bilateral papilloedema with cryptococcal meningitis, acute retinal necrosis syndrome105, squamous cell carcinoma, and immune recovery vitritis following treatment with protease inhibitors106. The most common ophthalmic opportunistic infection in India is CMV retinitis, which almost always occurs in patients with CD4 counts <50 cells/µl107,108. Variable degrees of visual loss are frequently associated with CMV retinitis and occur due to retinal necrosis, macular oedema secondary to retinitis, optic nerve involvement and retinal detachment. Less common ocular infections are Toxoplasma gondii, varicella-zoster virus, and Pneumocystis carinii109. The second most common ophthalmic manifestation of HIV infection is non-infectious retinopathy (HIV retinopathy), reported in 13-15 per cent of HIV patients presenting to an ophthalmologist107,108. This condition, characterized by cotton wool spots, can be an early sign of HIV infection, and must be differentiated from diabetic and hypertensive retinopathy. Given the range of ocular manifestations of HIV, routine ocular examinations and screening for visual loss is recommended in patients with CD4 counts < 50 cells/µl. HIV-associated malignancies Patients with AIDS are at increased risk for developing NHL. In the first report of lymphoid malignancies in India, 24 of 30 AIDS-related malignancies were NHL110. The other patients were reported to have Hodgkin’s disease, and plasmacytoma110. There is also a report of Promyelocytic leukemia (M3) in an AIDS patient from Manipur, eastern India111. In addition to lymphomas, Kaposi’s sarcoma, squamous cell carcinoma, and cervical cancer are malignancies of concern in HIV- infected individuals. Women Among special concerns for women with HIV are recurrent vaginal candidiasis, menstrual disorders, anaemia, increased risk of cervical cancer, effects of HIV on pregnancy, and mother-to-child transmission of HIV. Cervical cancer is the most important cause of cancer-related deaths among KUMARASAMY et al: CLINICAL PROFILE OF HIV Fig. 4. Cost of HAART per year and number of patients who are initiating HAART at YRG Care, Chennai, India. Adopted from: Ganesh AK, Kumarasamy N, Cecelia AJ, Mayer KH, Flanigan TP, Solomon S. Impact of falling costs of antiretrovial therapy on VCT services: Experience from south India. XVth International AIDS Conference. 11-16th July 2004. Abstract:TuPeD 5122. Cost of HAART in US$* New Patients on HAART *US$ 1=INR 45 388 INDIAN J MED RES, APRIL 2005 women in India. In Indian women, HIV infection is associated with a greater than a 2-fold risk of having an abnormal pap smear112, which subsequently puts them at increased risk for cervical cancer. There are very few studies on HIV disease in Indian women; more studies on the clinical spectrum of HIV disease in women are needed in India. Children Vertical transmission is responsible for between 67 and 87 per cent of paediatric HIV infection, with the majority of the remaining infections occurring due to blood transfusions113,114. The clinical features of HIV infection in children are different from those in adults. Perinatally infected children become symptomatic by five years of age. Failure to thrive is the most common clinical condition associated with HIV infection in children113,114. Pulmonary and extra- pulmonary tuberculosis was consistently the most frequent opportunistic infection reported in two major studies in Indian children with HIV113,114. Although frequencies differed, oral candidiasis, hepatosplenomegaly, recurrent respiratory tract infection, Pneumocystis carinii pneumonia, chronic lung disease, persistent generalized lymphadenopathy, chronic diarrhoea, pyrexia of unknown origin, chronic hypertrophic parotitis, chronic ottorrhoea, bacterial skin infection, and PPE have also been reported in Indian children113,114. A prospective study evaluating the efficacy of clinically-directed selective screening for HIV among the paediatric population found that the presence of oral candidiasis was a significant independent risk factor for predicting HIV infection; the presence of multiple clinical conditions including severe malnutrition, serious pyogenic infections, disseminated tuberculosis, chronic diarrhoea were also associated with increased risk of being HIV positive115. Like children in the U.S. and Europe, systemic and pulmonary findings are common in Indian children. Lymphoid interstitial pneumonitis (LIP) is a distinctive marker of paediatric HIV infection. This disease is marked by chronic progressive cough, digital clubbing, and fine reticular densities on chest X-ray without fever. LIP affects children far more often than adults and is associated with a good prognosis compared to other opportunistic infection116. PCP however, was seen much less commonly in Indian cohorts (3.4- 3.9%)113,114 than Western cohorts where it is the most common AIDS diagnosis in infancy116. Recurrent bacterial infection should raise suspicion for HIV infection. In addition, like children with HIV in Africa, Indian children are also afflicted by wasting, malnutriton, and chronic diarrrhoeal disease, with cryptosporidium being the major causative organism. Appropriate immunizations, prophylaxis with co- trimaxazole, and preventative measures such as boiling water must be taken in order to avoid morbidity and Fig. 5. Reduction in death rate following HAART at the YRG Care, Chennai, India 389 mortality in children. Little is known about the natural history of HIV disease in Indian children, and further research is needed. Changing clinical presentation of HIV in the context of HAART Highly active anti-retroviral therapy (HAART) has changed the face of HIV/AIDS by leading to a dramatic decrease in HIV-related morbidity and mortality among those with access to therapy117. Until recently, HAART was not accessible to a vast majority of the 5.1 million Indians living with HIV in India118 primarily due to its high cost. However, production of anti-retroviral medications by Indian generic manufacturers in the developing world has drastically reduced the price of HAART to less than one US$/day (Rs.800/month)119, and significantly increased access to treatment in resource-limited settings120 (Fig. 4). In India, generic HAART has been shown to be safe, well tolerated and effective at increasing CD4 counts, and suppressing plasma viral load in patients with advanced HIV, comparable to the experience with proprietary HAART121,122. Similar to developed countries, Indian patients on HAART are experiencing a decrease in the number of opportunistic infections, and HIV-related morbidity and mortality. At YRG CARE, Chennai, after the introduction of generic HAART, death rates fell from 25 per 100 person years in 1997 to 5 per 100 person years in 2003 (unpublished observation) (Fig.5). There was a significant decrease in the number of incident opportunistic infections, especially tuberculosis, in patients on HAART. As data on HIV disease after the introduction of HAART become more available, descriptions of treated disease will include side effects and toxicities of therapy. An analysis of patients on HAART at YRG Care, Chennai, found that pruritis, nausea, and rash were the most common adverse events associated with HAART68. Others included vomiting, anaemia, hepatitis, pancreatitis, peripheral neuropathy, lipoatrophy, lipodystrophy, and SJS. These toxicities were comparable to those reported with proprietary HAART in the developed world. Lipodystrophy was noted primarily in patients on stavudine-based HAART whereas hepatitis and SJS were associated with use of nevirapine. Stavudine and nevirapine- based HAART is currently the cheapest and most widely available triple drug regimen in resource limited settings. The prevalence of adverse events related to these drugs may rise as the use of antiretroviral therapy increases. Immune reconstitution is of increasing concern in the developing world as HAART becomes more available in settings where opportunistic infections, especially TB, are abundant. The clinical presentation of IRS is an apparent clinical deterioration of the patient despite treatment. This could indicate a successful, though undesirable, effect of HAART, or instead, treatment failure and subsequent progression of the opportunistic infection. The emergence of drug resistance is becoming a major concern as the use of generic HAART increases. Recently, a genotypic analysis of the sequences of HIV-1 from drug naïve patients in south India showed that 6 and 14 per cent of patients had mutations at nucleoside reverse transcriptase and/or non- nucleoside reverse transcriptase (NNRTI) resistance positions, respectively123. This is especially significant because reverse transcriptase-based regimens with an NNRTI are very commonly used, and alternate protease inhibitor-based therapy remains very expensive and unaffordable to most patients. NNRTI resistance is important to consider because resistance to one NNRTI signifies resistance to every drug in that class, disqualifying the use of both efavirenz and nevirapine, the two most commonly used antiretrovirals in India. Conclusion HIV disease in India has a diverse range of manifestations in multiple organ systems. As the HIV epidemic grows, it is important for primary care physicians as well as specialists to learn to suspect and test for HIV infection. Early detection of HIV optimizes chemoprophylaxis for opportunistic infections and provides an opportunity for secondary HIV prevention. In addition, with the availability of HAART, treatment can vastly reduce morbidity and KUMARASAMY et al: CLINICAL PROFILE OF HIV 390 INDIAN J MED RES, APRIL 2005 mortality in Indian patients. In the new era of generic HAART, physicians must be trained to identify and manage the toxicities associated with HAART as well. References 1. Haynes BF, Pantaleo G, Fauci AS. Towards an understanding of the correlates of protective immunity to HIV infection. Science 1996; 271 : 324-8. 2. Pantaleo G, Fauci AS. Immunopathogenesis of HIV infection. Annu Rev Microbiol 1996; 50 : 825-54. 3. Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Annal Int Med 1996; 93 : 4386-91. 4. Kumarasamy N, Solomon S, Flanigan TP, Hemalatha R, Thyagarajan SP, Mayer KH. Natural history of human immunodeficiency virus disease in southern India. Clin Inf Dis 2003; 36: 79-85. 5. Hira SK, Shroff HJ, Lanjewar DN, Dholkia YN, Bhatia VP, Dupont HL. The natural history of human immunodeficiency virus infection among adults in Mumbai. Natl Med J India 2003; 16:126-31. 6. Mocroft A, Johnson MA, Philips AN. Factors affecting survival in patients with acquired immune deficiency syndrome. AIDS 1996; 10 : 1057-65. 7. Petruckevitch A, Del Amo J, Phillips AN, Johnson AM, Stephenson J, Desmond N, et al. Disease progression and survival following specific AIDS-defining conditions: a retrospective cohort study of 2048 HIV-infected persons in London. AIDS 1998; 12 : 1007-13. 8. Friedland GH, Saltzman B, Vileno J, Freeman K, Schrager LK, Klein RS. Survival differences in patients with AIDS. J Acquir Immune Defic Syndr 1991; 4:144-53. 9. d’ Arminio Monfote A, Vago L, Lazarin A, Boldorini R, Bini T, Guzzetti S, et al. AIDS defining illnesses in 250 HIV-infected patients : a comparitive study of clinical autopsy diagnosis. AIDS 1992; 6 : 467-74. 10. Mohar A, Romo J, Salido F, Jessurun J, Ponce de Leon S, Reyes E, et al. The spectrum of clinical and pathological manifestations of AIDS in consecutive series of autopsied patients in Mexico. AIDS 1992; 6 : 467-73. 11. Mirdha BR. Mycobacterium avium-intracellulare in stool in HIV-seropositive man. Indian J Gastroenterol 2003; 22 : 25. 12. Kumarasamy N, Solomon S, Yesudian P, Sugumar P. First report of Kaposi’s sarcoma in an AIDS patient from Madras, India. Indian J Dermatol 1996; 41 : 23-5. 13. Lanjewar DN, Bhosale A, Iyer A. Spectrum of dermatopathologic lesions associated with HIV/AIDS in India. Indian J Pathol Microbiol 2002; 45 : 293-8. 14. Shroff HJ, Dashatwar DR, Deshpande RP, Waigmann HR. AIDS-associated Kaposi’s sarcoma in an Indian female. J Assoc Physicians India. 1993; 41:241-2. 15. Singh A, Bairy I, Shivananda PG. Spectrum of opportunistic infections in AIDS cases. Indian J Med Sci 2003; 57 : 16-21. 16. Misra SN, Sengupta D, Satpathy SK. AIDS in India: recent trends in opportunistic infections. Southeast Asian J Trop Med Public Health 1998; 29 : 373-6. 17. Solomon S, Kumarasamy N, Anuradha S, Vennila R, Pal JA. TB and HIV infection - an association. Indian J Med Microbiol 1994; 12 : 313-4. 18. Ghate MV, Mehendale SM, Mahajan BA, Yadav R, Brahme RG, Divekar AD, et al. Relationship between clinical condition and CD4 cell counts in HIV-infected persons, Pune, Maharashtra, India. Natl Med J India 2000; 13 : 183-7. 19. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999; 282 : 677-86. 20. Prasad R, Saini JK, Gupta R, Kannaujia RK, Sarin S, Suryakant, et al. A comparative study of clinico- radiological spectrum of tuberculosis among HIV seropositive and HIV seronegative patients. Indian J Chest Dis Allied Sci 2004; 46 : 99-103. 21. Ramachandran R, Datta M, Subramani R, Baskaran G, Paramasivan CN, Swaminathan S. Seroprevalence of human immunodeficiency virus (HIV) infection among tuberculosis patients in Tamil Nadu. Indian J Med Res 2003; 118 : 147-51. 22. Gothi D, Joshi JM. Clinical and laboratory observations of TB in a Mumbai (India) Clinic. Post Grad Med J 2004; 80 : 97-100. 23. Sharma SK, Aggarwal G, Seth P, Saha PK. Increasing HIV seropositivity among adult tuberculosis patients in Delhi. Indian J Med Res 2003; 117 : 239-42. 24. Deivanayagam CN, Rajasekaran S, Venkatesan R, Mahilmaran A, Ahmed PR, Annadurai S, et al. Prevalence of acquired MDR-TB and HIV co-infection. Indian J Chest Dis Allied Sci 2002; 44 : 237-42. 25. Ravilglione M, Harries A, Msika R, Wilkinson D, Nunn P. Tuberculosis and HIV current status in Africa. AIDS 1997; 11 (Suppl B) : S115-23. 391 26. Vajpayee M, Kanswal S, Seth P, Wig N, Pandey RM. Tuberculosis infection in HIV-infected Indian patients. AIDS Patient Care STDS 2004; 18 : 209-13. 27. Kumar P, Sharma N, Sharma NC, Patnaik S. Clinical profile of tuberculosis in patients with HIV Infection/AIDS . Indian J Chest Dis Allied Sci 2002; 44 : 159-63. 28. Lanjewar DN, Duggal R. Pulmonary pathology in patients with AIDS: an autopsy study from Mumbai. HIV Med 2001; 2 : 266-71. 29. Vajpayee M, Kanswal S, Seth P, Wig N. Spectrum of opportunistic infections and profiles of CD4 cell counts among AIDS patients in Northern India. Infection 2003; 31 : 336-40. 30. Rupali P, Abraham OC, Zachariah A, Subramanian S, Mathai D. Aetiology of prolonged fever in antiretroviral- naive human immunodeficiency virus-infected adults. Natl Med J India 2003; 16 : 193-9. 31. Hira SK, Dupont HL, Lanjewar DN, Dholakia YN. Severe weight loss: the predominant clinical presentation of tuberculosis in patients with HIV infection in India. Natl Med J India 1998; 11 : 256-8. 32. Kumarasamy N, Solomon S, Purnima M, Tokhuga Yepthomi, C. Venkatesan, R. Edwin Amalraj, et al. High plasma viral load in persons co-infected with HIV and tuberculosis in south India. 9th International Congress on Infectious Diseases; 2000 April, 10-13; Buenos Aires, Argentina (abstr). 33. Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002; 81 : 213-27. 34. Kumarasamy N, Chaguturu S, Mayer KH, Solomon S, Yepthomi T, Balakrihnan P, et al. Incidence of immune reconstitution syndrome in HIV-TB co-infected patients after initiation of generic HAART in India. J Acquir Immun Defic Syndr 2004; 37 : 1574-6. 35. World Health Organization. Scaling up anti-retroviral therapy in resource limited settings: treatment guidelines for a public health approach. 2003 Geneva. 36. Whalen CC, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J. Accelerated course of HIV infection after tuberculosis. Am J Respir Crit Care Med 1995; 151 : 129-35. 37. Bell JC, Rose DN, Sacks HS. Tuberculosis preventive therapy for HIV-infected people in sub-Saharan Africa is cost-effective. AIDS. 1999; 13 :1549-56. 38. Sengupta D, Lal S, Shrinivas. Opportunistic infection in AIDS. J Indian Med Assoc 1994; 92 : 24-6. 39. Shenoy R, Kapadi SN, Pai KP, Kini H, Mallya S, Khadilkar UN, et al. Fine needle aspiration diagnosis in HIV-related lymphadenopathy in Mangalore, India. Acta Cytol 2002; 46 : 35-9. 40. Morbidity and Mortality Weekly Report. 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults. MMWR 1993; 41 RR-17: http://www.cdc.gov/ mmwr/preview/mmwrhtml/00018871.htm. accessed on October 4, 2004. 41. Jones JL, Hanson DL, Dworkin MS, Alderton DL, Fleming PL, Kaplan JE, Ward J. Surveillance for AIDS- defining opportunistic illnesses, 1992-1997. MMWR CDC Surveill Summ 1999; 48 : 1-22. 42. Deshmukh SD, Ghaisas MV, Rane SR, Bapat VM. Pneumocystis carinii pneumonia and its association with other opportunistic infections in AIDS - an autopsy report of five cases. Indian J Pathol Microbiol 2003; 46 : 207-11. 43. Arora VK, Tumbanatham A, Kumar SV, Ratnakar C. Pneumocystis carinii pneumonia simulating as pulmonary tuberculosis in AIDS. Indian J Chest Dis Allied Sci 1996; 38 : 253-7. 44. Usha MM, Rajendran P, Thyagarajan SP, Solomon S, Kumarasamy N, Yepthomi T, et al. Identification of Pneumocystis carinii in induced sputum in AIDS patients in Chennai (Madras). Indian J Pathol Microbiol 2000; 43 : 291-6. 45. Pitchenik AE, Ganjei P, Torres A, Evans DA, Rubin E, Baiser H. Sputum examination for the diagnosis of Pneumocystis carinii pneumonia in the acquired immune deficiency syndrome. Am Rev Respire Dis 1986; 133 : 226-9. 46. Dworkin MS, Williamson F, Jones JL, Kaplan JE; Adult and Adolescent Spectrum of HIV Disease Project. Prophylaxis with trimethoprim-sulfamethoxazole for HIV- infected patients: impact on risk for infectious diseases. Clin Infect Dis 2001; 33 : 393-8. 47. National Institutes of Health. 2001 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus U.S. Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA): http:// www.aidsinfo.nih.gov/guidelines/op_infections/ OI_112801.html#pneumonia. accessed on October 25, 2004. 48. UNAIDS. WHO/UNAIDS Secretariat Recommendations on the Use of Cotrimaxazole in Adults and Children living with HIV/AIDS in Africa: http://www.unaids.org/html/ pub/publications/irc-pub04/recommendation_en_pdf.pdf. accessed on October 25, 2004. KUMARASAMY et al: CLINICAL PROFILE OF HIV 392 INDIAN J MED RES, APRIL 2005 49. Bansal S, Kashyap S, Pal LS, Goel A. Clinical and bacteriological profile of community acquired pneumonia in Shimla, Himachal Pradesh. Indian J Chest Dis Allied Sci 2004; 46 : 17-22. 50. Feikin DR, Feldman C, Schuchat A, Janoff EN. Global strategies to prevent bacterial pneumonia in adults with HIV disease. Lancet Infect Dis 2004; 4 : 445-55. 51. Ranjana KH, Priyokumar K, Singh TJ, Gupta ChC, Sharmila L, Singh PN, et al. Disseminated Penicillium marneffei infection among HIV-infected patients in Manipur state, India. J Infect 2002; 45 : 268-71. 52. Ranganathan K, Reddy BVR, Kumarasamy N, Solomon S, Viswanathan R, Johnson NW. Oral lesions and conditions associated with human immunodeficiency virus infection in 300 south Indian patients. Oral Dis 2000; 6 : 152-7. 53. Anil S, Chalacombe SJ. Oral Lesion in HIV and AIDS in Asia. Oral Dis 1997; 3 (Suppl 1): 36-40. 54. Holmes K, Stephen LXG. Oral lesions of HIV infections in developing countries. Oral Dis 2002; 8 (Suppl 2) : 40-3. 55. Robinson PG. Treatment of HIV associated periodontal disease. Oral Dis 1997; 3 (Suppl 1) : S238-40. 56. Patton LL. Sensitivity, specificity, and positive predictive value of oral opportunistic infections in adults with HIV/AIDS as markers of immune suppression and viral burden. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 90 : 182-8. 57. Cowan FM, French RS, Mayaud P, Gopal R, Robinson NJ, de Oliveira SA, et al. Seroepidemiological study of herpes simplex virus types 1 and 2 in Brazil, Estonia, India, Morocco, and Sri Lanka. Sex Transm Infect 2003; 79 : 286-90. 58. Singh A, Thappa DM, Hamide A. The spectrum of mucocutaneous manifestations during the evolutionary phases of HIV disease: an emerging Indian scenario. J Dermatol 1999; 26 : 294-304. 59. Woo S-B, Sonis ST. Recurrent aphthous ulcers: a review of diagnosis and treatment. J Am Dent Assoc 1996; 127 : 1202-13. 60. Coldiron BM, Bergstresser PR. Prevalence and clinical spectrum of skin disease in patients infected with human immunodeficiency virus. Arch Dermatol 1989; 125 : 357- 61. 61. Panda S, Sarkar S, Mandal BK, Singh TB, Singh KL, Mitra DK, et al. Epidemic of herpes zoster following HIV epidemic in Manipur, India. J Infect 1994; 28 : 167-73. 62. Reynolds SJ, Risbud AR, Shepherd ME. Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India. J Infect Dis 2003; 187 : 1513-21. 63. Chatterjee R, Mukhopadhyay D, Murmu N, Jana S. Prevalence of human papillomavirus infection among prostitutes in Calcutta. J Environ Pathol Toxicol Oncol 2001; 20 : 113-7. 64. Singh PN, Ranjana K, Singh YI, Singh KP, Sharma SS, Kulachandra M, et al. Indigenous disseminated Penicillium marneffei infection in the state of Manipur, India: report of four autochthonous cases. J Clin Microbiol 1999; 37 : 2699-702. 65. N. Kumarasamy, Solomon S, Madhivanan P, Ravikumar B, Thyagarajan SP, Yesudian P. Dermatologic manifestations among human immunodeficiency virus patients in south India. Int Journal of Dermatol 2000; 39 : 192-5. 66. Trent J, Kirsner, R. Cutaneous manifestations of HIV: a primer. Adv Skin Wound Care 2004; 17 : 116-29. 67. Bason MM, Berger TG, Nesbitt Jr LT. Pruritic papular eruption of HIV-disease. Int J Dermatol 1993; 32 : 784-9. 68. Kumarasamy N, Lai A, Cecelia AJ, Saghayam S, Solomon S, Flanigan TP, et al. Toxicities and adverse events following Generic HAART in South Indian HIV- infected individuals. 7th International Congress on Drug Therapy and HIV Infection, Glasgow, UK, Nov 14-18, 2004. Abstract no. P189. 69. Ablashi D, Chatlynne L, Cooper H, Thomas D, Yadav M, Norhanom AW, et al. Seroprevalence of human herpesvirus-8 (HHV-8) in countries of Southeast Asia compared to the USA, the Caribbean and Africa. Br J Cancer 1999; 81 : 893-7. 70. Wadia RS, Pujari SN, Kothari S, Udhar M, Kulkarni S, Bhagat S, Nanivadekar A. Neurological manifestations of HIV disease. J Assoc Physicians India 2001; 49 : 343-8. 71. Satishchandra P, Nalini A, Gourie-Devi M, Khanna N, Santosh V, Ravi V, et al. Profile of neurologic disorders associated with HIV/AIDS from Bangalore, south India (1989-96). Indian J Med Res 2000; 111 : 14-23. 72. Santosh V, Shankar SK, Das S, Pal L, Ravi V, Desai A, et al. Pathological lesions in HIV positive patients. Indian J Med Res 1995; 101 : 134-41. 73. Aquinas SR, Tarey SD, Ravindran GD, Nagamani D, Ross C. Cryptococcal meningitis in AIDS - need for early diagnosis. J Assoc Physicians India 1996; 44 : 178-80. 74. Khanna N, Chandramuki A, Desai A, Ravi V. Cryptococcal infections of the central nervous system: an analysis of predisposing factors, laboratory findings and outcome in patients from South India with special reference to HIV infection. J Med Microbiol 1996; 45 : 376-9. 75. Mamidi A, DeSimone JQ, Pomerantz RJ. Central nervous system infections in individuals with HIV-1 infection. J Neurovirol 2002; 8 : 158-67. 393 76. Lanjewar DN, Jain PP, Shetty CR. Profile of central nervous system pathology in patients with AIDS: an autopsy study from India. AIDS 1998; 12 : 309-13. 77. Chadha DS, Handa A, Sharma SK, Varadarajulu P, Singh AP. Seizures in patients with human immunodeficiency virus infection. J Assoc Physicians India 2000; 48 : 573-6. 78. Garg RK, Kar AM. Neurocysticercosis: Diagnosis and treatment in special situations. In: Singh G, Prabhakar S, editor. Taenia solium cysticercosis. Wallingford, CABI Publishing; 2002 p. 281-7. 79. Mathew MJ, Chandy MJ. Central nervous system toxoplasmosis in acquired immunodeficiency syndrome : An emerging disease in India. Neurol India 1999; 47 : 182-7. 80. Meisheri YV, Mehta S, Patel U. A prospective study of seroprevalence of Toxoplasmosis in general population, and in HIV/AIDS patients in Mumbai, India. J Postgrad Med 1997; 43 : 93-7. 81. Katrak SM, Shembalkar PK, Bijwe SR, Bhandarkar LD. The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 2000; 181 : 118-26. 82. Shankar SK, Satishchandra P, Mahadevan A, Yasha TC, Nagaraja D, Taly AB, et al. Low prevalence of progressive multifocal leukoencephalopathy in India and Africa: is there a biological explanation? J Neurovirol 2003; 9 (Suppl 1) : 59-67. 83. Maschke M, Kastrup O, Esser S, Ross B, Hengge U, Hufnagel A. Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry 2000; 69 : 376-80. 84. Garg RK. HIV infection and seizures. Postgrad Med J 1999; 75 : 387-90. 85. Kothari K, Goyal S. Clinical profile of AIDS. J Assoc Physicians India 2001; 49 : 435-8. 86. Chandra PS, Ravi V, Desai A, Subbakrishna DK. Anxiety and depression among HIV-infected heterosexuals - a report from India. J Psychosom Res 1998; 45 : 401-9. 87. Prasad KN, Nag VL, Dhole TN, Ayyagari A. Identification of enteric pathogens in HIV-positive patients with diarrhoea in northern India . J Health Popul Nutr 2000; 18 : 23-6. 88. Joshi M, Chowdhary AS, Dalal PJ, Maniar JK. Parasitic diarrhoea in patients with AIDS. Natl Med J India 2002; 15 : 72-4. 89. Mohandas, Sehgal R, Sud A, Malla N. Prevalence of intestinal parasitic pathogens in HIV-seropositive individuals in Northern India. Jpn J Infect Dis 2002; 55 : 83-4. 90. Anand L, Dhanachand C, Brajachand N. Prevalence and epidemiologic characteristics of opportunistic and non- opportunistic intestinal parasitic infections in HIV positive patients in Manipur. J Commun Dis 1998; 30 :19-22. 91. Kumarasamy N, Flanigan T, Mahajan A, Amalraj E, Mayer K, Solomon S. Comparative study of chronic diarrhea in persons with HIV in South India. 13th World AIDS Conference, July 9-14, 2000; Durban, South Africa. Abstr: MoPeB 2267. 92. Current WL, Garcia LS. Cryptosporidiosis. Clin Microbiol Rev 1991; 4 : 325-58. 93. Rathi PM, Amarapurkar DN, Borges NE, Koppikar GV, Kalro RH. Spectrum of liver diseases in HIV infection. Indian J Gastroenterol 1997; 16 : 94-5. 94. Quan CM, Krajden M, Grigoriew GA, Salit IE. Hepatitis C virus infection in patients infected with the human immunodeficiency virus. Clin Infect Dis 1993; 17 : 117-9. 95. Sud A, Singh J, Dhiman RK, Wanchu A, Singh S, Chawla Y. Hepatitis B virus co-infection in HIV infected patients. Trop Gastroenterol 2001; 22 : 90-2. 96. Saha MK, Chakrabarti S, Panda S, Naik TN, Manna B, Chatterjee A, et al. Prevalence of HCV & HBV infection amongst HIV seropositive intravenous drug users & their non-injecting wives in Manipur, India. Indian J Med Res 2000; 111 : 37-9. 97. Marx MA, Murugavel KG, Sivaram S, Balakrishnan P, Steinhoff M, Anand S, et al. The association of health- care use and hepatitis C virus infection in a random sample of urban slum community residents in southern India. Am J Trop Med Hyg 2003; 68 : 258-62. 98. Bhattacharya S, Badrinath S, Hamide A, Sujatha S. Co- infection with hepatitis C virus and human immunodeficiency virus among patients with sexually transmitted diseases in Pondicherry, South India. Indian J Pathol Microbiol 2003; 46 : 495-7. 99. Rockstroh JK, Spenglerb U. HIV and hepatitis C virus co- infection. Lancet 2004; 4 : 437-44. 100. Hepatitis B, Hepatitis C and human immunodeficiency virus co-infection in Chennai, India. Maya Chatterjee Rogers, N. Kumarasamy, Sreekanth K. Chaguturu, Timothy P. Flanigan, Kenneth H. Mayer, P. Balakrishnan, and Suniti Solomon. 11th Conference on Retroviruses and Opportunistic Infections. Feb 8-11th, 2004, San Francisco USA. Abstract no:V -60. 101. Biswas J, Madhavan HN, Kumarasamy N, Solomon S. Blepharitis and lid ulcer as initial ocular manifestations in acquired immunodeficiency syndrome (AIDS) patients. Ind J Ophthalmol 1997; 45 : 233-4. 394 INDIAN J MED RES, APRIL 2005 Reprint requests: Dr N. Kumarasamy, YRG Center for AIDS Research and Education Voluntary Health Services Tharamani, Chennai 600113, India e-mail:kumarasamy@yrgcare.org 102. Biswas J, Therese L, Kumarasamy N, Solomon S. Lid abscess with extensive molluscum contagiosum in a patient with acquired immunodeficiency syndrome (AIDS). Ind J Ophthalmol 1997; 45 : 234-6. 103. Biswas J, Raizada S, Gopal L, Kumarasamy N, Solomon S. Bilateral frosted branch angiitis and cytomegalovirus retinitis in a case of acquired immunodeficiency syndrome. (Brief Reports) Ind J Ophthalmol 1999; 47 : 195-7. 104. Pramod NP, Hari R, Sudhamathi K, Ananadakannan K, Thyagarajan SP. Influence of human immunodeficiency virus status on the clinical history of herpes simplex keratitis. Ophthalmologica 2000; 214 : 337-40. 105. Jalali S, Rao UR, Lakshmi V. Acute retinal necrosis syndrome in an HIV positive case: the first case reported from India. Ind J Ophthalmol 1996; 44 : 95-7. 106. Choudhury S, Biswas J, Kumarasamy N, Solomon S. Immune recovery vitritis presenting as panuveitis following therapy with protease inhibitors - a case report. Insight 1999; 17 :61-4. 107. Biswas J, Joseph AE, Raizada S, Kumarasamy N, Solomon S. Ophthalmic manifestations of acquired immunodeficiency syndrome in India. Ind J Ophthalmol 1999; 47 : 87-93. 108. Biswas J, Madhavan HN, George AE, Kumarasamy N, Solomon S. Ocular lesions in the first 100 HIV positive cases in a referral eye centre in India. Am J Ophthalmol 2000; 129 : 1-8. 109. Biswas J. Acquired immune deficiency syndrome (AIDS) and the eye. J Assoc Phys India 2001; 49 : 551-7. 110. Agarwal B, Ramanathan U, Lokeshwas N, Nair R, Gopal R, Bhatia K, et al. Lymphoid neoplasms in HIV- positive individuals in India. J Acquir Immune Defic Syndr 2002; 29 : 181-3. 111. Gatphoh ED, Zamzachin G, Devi SB, Punyabati P. AIDS related malignant disease at regional institute of medical sciences. Indian J Pathol Microbiol 2001; 44 : 1-4. 112. Joshi S, Chandorkar A, Krishnan G, Walimbe A, Gangakhedkar R, Risbud A, et al. Cervical intraepithelial changes & HIV infection in women attending sexually transmitted disease clinics in Pune, India. Indian J Med Res 2001; 113 : 161-9. 113. Madhivanan P, Mothi SN, Kumarasamy N, Yepthomi T, Venkatesan C, Lambert JS, et al. Clinical Manifestations of HIV infected Children. Indian J of Pediatr 2001; 70 : 615-20. 114. Merchant RH, Oswal JS, Bhagwat RV, Karkare J. Clinical profile of HIV infection. Indian Pediatr 2001; 38 : 239-46. 115. Karande S, Bhalke S, Kelkar A, Ahuja S, Kulkarni M, Mathur M. Utility of clinically-directed selective screening to diagnose HIV infection in hospitalized children in Mumbai, India. J Trop Pediatr 2002; 48 : 149-55. 116. Khare M, Sharland M. Pulmonary manifestations of pediatric HIV infection. Indian J Pediatr 1999; 66 : 895-904. 117. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced HIV infection. NEJM 1998; 338 : 853-60. 118. National AIDS Control Organization. A note on HIV estimates 2003: http://www.naco.nic.in/indianscene/ esthiv.htm accessed on August 17, 2004. 119. Angerer T, Wilson d, Ford N, Kasper T. Access and activism: the ethics of providing anti-retroviral therapy in developing countries. AIDS 2001; 15 (Suppl 5) : S81-90. 120. Kumarasamy, N. Generic antiretroviral drugs - will they be the answer to HIV in the developing world? Lancet 2004; 364 : 3-4. 121. Kumarasamy N, Solomon S, Chaguturu SK, Mahajan AP, Flanigan TP, Balakrishnan P, et al. The safety, tolerability and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India. AIDS 2003; 17 : 2267-9. 122. Kumarasamy N, Vallabhaneni S, Flanigan TP, Balakrishnan P, Cecelia AJ, Carpenter CCJ, et al. Rapid Viral Load Suppression Following Generic HAART in Southern Indian HIV-Infected Patients. AIDS 2005; 19 : (in press). 123. Balakrishnan P, Kumarasamy N, Solomon S, Vidya S, Kantor R, Shafer RW, et al. Protease and reverse transcriptase mutations at drug resistance positions in untreated HIV-1 Clade C infected Southern Indian patients. XVth International World AIDS Conference, 2004 July 11-16; Bangkok, Thailand. abstr B5715.