Effect of HAART on natural history of AIDS-related opportunistic disorders

COMMENTARY

In healthy men the degree of protection that aspirin provides against non-fatal myocardial infarction is similar to that of the cholesterol-lowering statins (table). This similarity is true for men at high risk of myocardial infarction, such as the participants in the Thrombosis Prevention Trial, as well as for low-risk men, such as those in the Physicians’ Health Study. Despite their similarity in ability to prevent myocardial infarction, aspirin and the statins probably differ in their mode of action. However, what is known is that aspirin is far cheaper than the statins and hence much more cost effective. Most countries can afford aspirin for the primary prevention of myocardial infarction. Should aspirin thus be advised for everybody in the prevention of myocardial infarction? No, since only men have been investigated so far; the US Women’s Health Study, to which over 40 000 healthy middle-aged women have been recruited, should provide information on the potential of aspirin to prevent myocardial infarction in women. Furthermore, in low-risk individuals the absolute risk of myocardial infarction is less than 0·5% per year,6 so any protective measure, even aspirin, will have only a marginal effect. This point explains why, in the primary-prevention trials cited above, total mortality was not significantly influenced. A third reason for limiting aspirin use is that, although the drug is well tolerated by most individuals, even low doses can cause gastric discomfort and, in rare cases, severe gastrointestinal bleeding or cerebral bleeding. Although the risk of stroke is very low, among healthy men there is one excess disabling stroke for every three non-fatal myocardial infarctions prevented with aspirin (ref 10 and the Thrombosis Prevention Trial), a safety problem not oberved with the statins. In low-risk individuals this adverse effect may outweigh the benefit, although in the very large Physicians’ Health Study this was not firmly established. Hence only high-risk men should be advised to take aspirin on top of making changes in lifestyle, such as giving up smoking, making dietary changes, increasing physical activity and, in patients with hypertension, lowering blood pressure. Although there are questions ahout the primary prevention of myocardial infarction that remain to be answered, the Thrombosis Prevention Trial clearly indicates that there are other and less expensive drugs for reducing the incidence of myocardial infarction than the statins, the cost of which may run up to £350 a year per person.

Freek W A Verheugt Department of Cardiology, University Hospital Nijmegen, 6500 HB Nijmegen, Netherlands 1

Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106. 2 Chesebro JH, Fuster V, Elveback LR, et al. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med 1984; 310: 209–14. 3 Schwartz L, Bourassa MG, Lespérance J, et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 1988; 318: 1714–19. 4 Juul-Möller S, Edvardsson N, Jahnmatz B, Rosén A, Sorensen S, Omblus R. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet 1992; 340: 1421–25. 5. Verheugt FWA. In search of a superaspirin for the heart. Lancet 1997; 349: 1409–10. 6 Steering Committee of the Physicians’ Health Study Research Group.

228

Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989; 321: 129–35. 7 Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 296: 313–16. 8 Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–07. 9 Gotto AM. AFCAPS/TexCAPS. Presented at the 70th Scientific Sessions of the American Heart Association, Orlando, Florida, March 1997. 10. Hennekens CH, Peto R, Hutchison GB, Doll R. An overview of the British and American aspirin studies. N Engl J Med 1988; 318: 923–24.

Effect of HAART on natural history of AIDS-related opportunistic disorders See pages 252, 256 The remarkable activity against HIV of regimens that contain protease inhibitors, termed highly active antiretroviral therapy (HAART), has received much attention. Use of protease inhibitors, in combination with other active agents, has led to a striking reduction in AIDS-associated morbidity and mortality, the first such improvement since the recognition of the HIV epidemic in 1981.1 In this issue of The Lancet, two groups report the effect of HAART on the natural history of specific opportunistic infections, which still cause the majority of AIDS-related complications. The reports add to published work on HAART-related topics, which can be divided into two distinct types—some, like the report of Andrew Carr and colleagues, describe improvement or resolution of opportunistic conditions, including Kaposi’s sarcoma,2 progressive multifocal leucoencephalopathy,3 and molluscum contagiosum,4 whereas others, like that of Elizabeth Race and colleagues, report a fundamental change in the natural history of a previously wellcharacterised disorder (table). Carr and colleagues describe improvement of microsporidiosis and cryptosporidiosis after the start of HAART. In their study, nine patients with symptoms for almost a year had clinical and at least transient microbiological responses to HAART. The investigators’ excitement at finding a therapeutic regimen for these previously refractory conditions—and at the implications for control of other opportunistic infections—was, however, tempered by the subsequent failure of response in four patients during the 13-month follow-up. As Carr and colleagues note, neither infection was eradicated; instead the infections remained stable only for as long as the HAART-induced immunological improvements were sustained. The Carr paper and similar reports have opened a debate on opportunistic infections—whether prophylactic therapy, primary or secondary (maintenance), can be stopped. This issue has arisen barely after the ink dried on the updated recommendations for prophylaxis drawn up by the US Public Health Service and the Infectious Disease Society of America.5 At first glance, the evidence for discontinuing prophylaxis is compelling: four patients with cytomegalovirus (CMV) retinitis who received HAART but no anti-CMV drugs, had no recurrence of the retinitis for 4–7 months after the start of HAART, well beyond the median time for relapse.6 Another report has suggested that Pneumocystis carinii pneumonia prophylaxis can be safely discontinued.7 However, as Carr and colleagues show, the effect of HAART may be only transient. The question of whether prophylaxis for

THE LANCET • Vol 351 • January 24, 1998

COMMENTARY

Clinical effect of opportunistic disorder Opportunistic disorder

Effect

Cryptosporidiosis (Carr) Clinical/microbiological Microsporidiosis (Carr) resolution coincident with 2+ log reduction in viral load Kaposi’s sarcoma2 Regression of lesions coincident with 1·3 log reduction in viral load Progressive multifocal Remission of hemiparesis and leucoencephalopathy3 improved radiographic findings Molluscum Resolution of severe disease contagiosum4 coincident with 10-fold rise in CD4 cells Mycobacterium avium Development of MAC complex(Race) lymphadenitis at institution of HAART Cytomegalovirus6,8,9 Stabilisation of retinitis, allowing discontinuation of maintenance therapy6 Development of acute CMV retinitis despite marked rise in CD4 cell counts8 Atypical (non-retinitis) manifestations of CMV9 Hepatitis B*10 Resolution of e-antigen in patient with 5-year history of e-antigen positive hepatitis B, coincident with 2 log decrease in HIV viral load *Hepatitis B is not a CDC-defined AIDS-indicator condition. MAC=Mycobacterium avium complex; CMV=cytomegalovirus.

Mycobacterium avium-intracellulare (MAC) can be discontinued is now being addressed in a large clinical trial directed by the US National Institutes of Health. The outcome of this and similar studies will guide future management of patients at potential risk of opportunistic infections. Race and colleagues describe a new clinical syndrome among patients with advanced AIDS. Within weeks of starting HAART, they became systemically ill, with lymphadenopathy, fever, leucocytosis, and malaise sufficient to require hospital admission. Examination revealed only local MAC adenitis, better known as scrofula in immune-competent children. What happened to these patients such that something as seemingly routine as scrofula made them ill enough to be admitted to hospital? In a word, inflammation. Once the John Wayne of the human immune response—the beneficent tough guy who came in and cleaned up the mess, whatever it was, with no consequences to the neighbours—inflammation is now better known for the problems it can create. These are neurological sequelae after bacterial meningitis, collagen vascular diseases, and adult respiratory distress syndrome. And now there is HAART-induced immune enhancement to be added to the list. An unanticipated (and unwanted) consequence of HAART may be exuberant inflammation around established infection, resulting in worrying symptoms that occur, ironically, because of improved immune function. The observation that improved inflammation makes a person ill has been reported with other AIDS-related opportunistic infections newly receiving HAART.8 Five patients with initial CD4 cell counts of under 100 cells/µL were treated with HAART;8 when CD4 counts

THE LANCET • Vol 351 • January 24, 1998

improved greatly, they developed CMV retinitis. The authors of the report speculated that a “HAART-induced inflammatory immune response” might have converted a subclinical ocular infection into active retinitis. In another report 210 patients newly begun on HAART9 developed early and unusual clinical manifestations of CMV disease: pneumonitis, pseudotumoral colitis, adenitis, and symptoms of viraemia. Improved HAART-associated inflammation may bedevil the management of patients coinfected with hepatitis B.10 A patient with AIDS and who had been positive for HBeAg and HBs Ag for 5 years was started on HAART. The hepatitis flared up and caused hepatomegaly, vomiting, and worsening of biochemical indices of liver function, accompanied by a rise in hepatitis B virus DNA. Eventually, the DNA titre decreased to below baseline, the HBeAg disappeared, and the antibody responses to HBcAg and HBeAg increased. This syndrome may be of especial importance for AIDS patients coinfected with hepatitis B, C, or both. Because protease inhibitors are mildly hepatotoxic, worsening of liver function at the start of HAART may be interpreted as drug-related toxicity, so that HAART is discontinued. The case cited above10 suggests an opposite explanation —that transient worsening might be due to the effectiveness of HAART. The concept of the “clinical flare” at the start of a therapeutic regimen has a long and distinguished lineage, predating AIDS. Patients with tuberculosis have been known to show a “paradoxical reaction” to effective chemotherapy.11 Their lymph nodes or other areas of infection initially expand, rather than shrink, despite other evidence of a beneficial clinical response. A paradoxical reaction in critical anatomical areas, such as the central nervous system, may cause alarming symptoms; in all patients, it may be mistaken for a failure of therapy. Although the cause of the paradoxical reaction is not well understood, corticosteroid therapy is effective. A related feature may complicate therapy of another mycobacterial disease, lepromatous leprosy. In such patients, effective chemotherapy may initially produce lepra type-1 reactions (reversal reactions) or lepra type-2 reactions (erythema nodosum leprosum),12 with development of fever, new skin lesions, and other symptoms. These reactions may be due to a local increase in cell-mediated immunity; the result could include an increase in CD4 cell numbers and production of proinflammatory cytokines in response to the M leprae already present, not unlike the phenomenon described by Carr and Race. Corticosteroid therapy or, if severe, thalidomide for erythema nodosum leprosum might be effective. The protease inhibitors have been widely used in HIV infection for less than 3 years, yet they have already profoundly influenced morbidity and mortality rates. The two reports in today’s Lancet show that HAART also may exert an important effect on the natural history of opportunistic conditions. The Carr paper has set the stage for a debate on the implications, for prophylactic treatment of opportunistic infection, of HAARTassociated improvement in immune function. At issue is the need to balance patients’ safety against the advantage, both medical and psychological, of taking fewer pills. The Race paper shows that the single thing we know best in AIDS, the clinical presentation of opportunistic infections, may change fundamentally when immune 229

COMMENTARY

function improves. Taken together, these reports show yet again that, even as therapeutic options improve, HIV infection continues to challenge and to surprise.

Kent A Sepkowitz Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA 1

Centers for Disease Control and Prevention. Update: trends in AIDS incidence. Morbid Mortal Weekly Rep 1997; 46: 165–173. 2 Murphy M, Armstrong D, Sepkowitz KA, Ahkami RN, Myskowski PL. Regression of AIDS-related Kaposi’s sarcoma following treatment with an HIV-1 protease inhibitor. AIDS 1997; 11: 261–62. 3 Elliott B, Aromin I, Gold R, Flanigan T, Mileno M. 2–5 year remission of AIDS-associated progressive multifocal leucoencephalopathy with combined antiretroviral therapy. Lancet 1997; 349: 850. 4 Hicks CB, Myers SA, Giner J. Resolution of intractable molluscum contagiosum in a human immunodeficiency virus infected patient after institution of antiretroviral therapy with ritonavir. Clin Infect Dis 1997; 24: 1023-25. 5 Centers for Disease Control and Prevention. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with the human immunodeficiency virus. Morbid Mortal Weekly Rep 1997; 46(RR-12): 1–46. 6 Whitcup SM, Fortin E, Nussenblatt RB, Polis MA, Muccioli C, Belfort R. Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis. JAMA 1997; 277: 1519–20. 7 Schneider MME, Borleffs JCC, Jaspers AJJ, Hoepelman M. Discontinuation of Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients with an increase of their CD4 cell counts (> 200/mm3) due to aggressive antiretroviral therapy. Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997 (abstract LB–11). 8 Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–45. 9 Gilquin J, Piketty C, Thomas V, Conzalez-Canali G, Kazatchkine MD. Acute CMV infection in AIDS patients receiving combination therapy including protease inhibitors. Program and Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Washington, DC, USA, 1997 (abstract 354) . 10 Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor. Lancet 1997; 349: 996–97. 11 Chloremis CB, Padiatellis C, Zoumboulakis D,Yannakos D. Transitory exacerbation of fever and roentgenographic findings during treatment of tuberculosis in children. Am Rev Tuberc 1955; 72: 527–36. 12 Gelber RH. Leprosy (Hansen’s disease). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases, 4th edn. New York: Churchill Livingstone, 1995: 2243-50.

Genetics of diabetic complications

speculations that the microvascular complications of both type 1 and type 2 diabetes themselves might have important genetic determinants. Most investigators, having grappled with the genetics of diabetes per se, have taken only tentative steps towards examining specific candidate genes for variants that might predispose to diabetic complications.9,10 So what is the evidence that diabetic complications have a genetic basis? Many diabetologists will have come across families in which members seem to succumb to the same severe complications, whereas other patients with apparently similar glycaemic control remain spared. Few formal studies confirming this clinical impression have been published, but it is known that only 30–50% of patients with diabetes become nephropathic, however poor their glycaemic control. There have been a few reports on the familial clustering of diabetic nephropathy.11-13 On the other hand, retinopathy seems to affect all patients to some extent, provided they are followed up for long enough. The possibility that genetic factors contribute to the severity of retinopathy is not excluded by this observation. One major concern is that familial clustering of complications may be due to factors other than genes, such as environmental factors. The Diabetes Control and Complications Trial (DCCT) has shown that, at least in type 1 diabetes, glycaemic control plays an important part in the development of complications,14 and it is plausible that diet, lifestyle, and glycaemic control might be more similar among members of a family than among unrelated individuals. The situation is made even more complex by the fact that other putatively familial conditions, such as hypertension, are known to influence the development of diabetic complications. Recently the DCCT Research Group reported on the familial concordance of complications in their study groups.15 Family members with diabetes (either type 1 or type 2) were identified by questioning 217 probands (all type 1) who had been recruited into either the conventional or the intensive treatment arms of the study. The presence and severity of microvascular complications was assessed in 241 relatives and the results compared with those from the last annual review of the respective 217 DCCT participants. If genetic factors are important in the development of complications, clustering will occur between sibling/sibling and in parent/offspring pairs with diabetes. Since these pairs share 50% of autosomal genes, the maximum intraclass (familial) correlation is theoretically 0·5 (provided the putative gene does not contribute susceptibility to diabetes as well (figure).

In 1965 Neel described diabetes mellitus as the “geneticist’s nightmare”.1 Twin, family, and transracial studies suggested that inherited factors were important in the aetiology of the disease. It is now recognised that multiple genes, interacting with the environment, contribute to disease susceptibility. Despite the complexity of the picture, it has been possible to reduce the nightmare into just a “bad dream” by concentrating on Intraclass correlations for diabetes with or without retinopathy specific subgroups of type 1 and type 2 A B Diabetes and Diabetes and diabetes. Thus in recent years the genes retinopathy retinopathy responsible for some cases of maturity-onset Siblings concordant for diabetes of the young (MODY),2-4 Diabetes diabetes Diabetes and and maternally inherited diabetes,5 and severe only retinopathy retinopathy insulin resistance6 have been identified and If susceptibility to retinopathy is due to an If retinopathy is an invariable consequence several genome-wide searches have autosomal gene, inherited separately from of diabetes, intraclass correlation suggested possible loci for the more diabetogenes but presumably resulting in coefficient between parent/offspring and 7 common forms of type 2 diabetes. The the phenotype only in the presence of sibling pairs will be 1, whether the diabetes, affected siblings with diabetes retinopathy is entirely due to environmental genetic basis of type 1 diabetes has also will, on average be concordant for factors (eg hyperglycaemia), or whether come under close scrutiny, with several gene retinopathy 50% of the time (ie, the gene(s) predisposing to diabetes and loci, including the HLA and insulin gene sibling/sibling, and retinopathy are the same or are closely regions, being implicated in many offspring/sibling/intraclass correlation linked on the human genome. Thus a high coefficient=0·5 if single gene is responsible intraclass correlation coefficient does not populations.8 for all the susceptibility). Lower values always imply genetic mechanisms. If the situation with diabetes were not provide less evidence of a genetic cause. difficult enough, there have been persistent

230

THE LANCET • Vol 351 • January 24, 1998