AIDS PREDICTION AND INTERVENTION

852 ACUTE NEUROPATHY COINCIDENT WITH SEROCONVERSION FOR ANTI-LAV/HTLV-III

SIR,-Attention has lately been focused on symptoms associated with seroconversion for LAV/HTLV-III. 1,2 Among neurological symptoms, only encephalopathy3 and lymphocytic meningitis3,4 have been reported. We report here two cases where seroconversion for LAV coincided with acute neuropathy. On Nov 22, 1985, a 53-year-old homosexual man presented with transient fever and diarrhoea followed by a truncal rash and intense pain in the calves. He was admitted on Dec 6. 6 days later, he had facial diplegia, sensory and motor impairment of the legs with areflexia, and a short period of confusion with hallucinations. On Dec 16 sensory and motor impairment extended to the arms. His

leucocyte count was 15 000/1 (46% lymphocytes, 5% being large basophilic cells). Transaminase and alkaline phosphatase activities were increased threefold. EEG showed bilateral temporal slow waves. A computerised tomographic scan was normal. A CSF sample showed 100 lymphocytes/1; protein 4 g/l. Blood culture for cytomegalovirus (CMV) was negative. There was no serological evidence for recent infection by CMV, Epstein-Barr virus, toxoplasmosis, hepatitis B virus, or measles. However, tests for antiLAV became positive in both serum and CSF (table). T4 lymphocytes (465/1) and T4/T8 ratio (0-25) were both decreased, while the number of T8 cells (1891/1) was increased. Neurological symptoms disappeared over 3 months, except for causalgia and areflexia of the legs. CSF indices tend toward normal. Cervical and axillary lymph-nodes became enlarged and subsequently disappeared. The patient had had a single sexual partner (symptomless but positive for LAV) for 20 years. Their last sexual intercourse had been in August, 1985. A 32-year-old woman, not addicted to drugs, married, and the mother of two healthy children 8 and 10 years old, presented in November, 1985, with fever, cervical lymphadenopathy, and a truncal maculopapular rash. Serum was taken for toxoplasmosis antibody examination and a sample was stored. Within 10 days and without treatment, the patient was symptomless. On Jan 11, 1986, fever recurred, followed by purpura of the legs. On admission, on Jan 21, she had multiple enlarged lymph nodes and splenomegaly. On Jan 31 abrupt onset of left facial palsy was noted. Her leucocyte count was 7500/jnl (56% lymphocytes, of which 1307o were large hyperbasophilic cells). The T4/T8 ratio (0’39) was low, essentially because of an increase in T8 lymphocytes (2510/1). The platelet count was 25 000/1. Lumbar puncture was not attempted for fear of bleeding. There was no serological evidence for recent EpsteinBarr or hepatitis B virus infection or toxoplasmosis. CMV was not found in blood

or

in urine culture.

Serological tests for LAV were positive. The same tests applied to stored in November, 1985, were negative, thus seroconversion. In late February, 1986, the confirming purpura had disappeared and the lymph-nodes and spleen had decreased in size. Facial palsy is less severe but the thrombocytopenia (50 000/1-11) persists. Further questioning of the patient reveals that she had had intercourse over the past 2 years

the

serum

recent

TESTS FOR LAV ANTIBODY IN TWO CASES SEROCONVERTING WITH ACUTE NEUROPATHY

assay; WB=western blotting; RIPA=radioimmunoprecipitation assay; IFA=immunof!uorescence assay; NT=not tested.

ELISA=enzyme-linked immunosorbent

with a bisexual partner who remains seronegative.

was

positive for LAV;

her husband

lymphotropic and neurotropic. In most reported neurological complications have been in patients with positive serological tests and symptoms of AIDS or AIDS-related complex. They usually follow a chronic course.5 The two cases reported here show that neurotropism may be symptomatic early in the infection and that primary LAV infection should be included among the causes of acute polyneuropathy. LAV is both

cases,

Centre Médico-Chirurgical Foch, 92151 Suresnes, France

Hôpital Raymond Poincaré,

ANNE MARIE PIETTE FRANK TUSSEAU DOMINIQUE VIGNON ANTOINE CHAPMAN GENEVIEVE PARROT

Garches

JACQUES LEIBOWITCH

Institut Pasteur, Paris

LUC MONTAGNIER

1. 2. 3. 4.

5

et al. Acute AIDS retrovirus infection. Definition of clinical illness associated with seroconversion. Lancet 1985; i: 537-40. Lindskov R, Orskov Lindhardt B, Weismann K, et al. Acute HTLV-III infection with roseola-like rash. Lancet 1986; i: 447. Carne CA, Smith A, Elkington SG, et al Acute encephalopathy coincident with seroconversion for anti-HTLV-III. Lancet 1985; ii: 1206-08. Ho DD, Sarngadharan MG, Resnick L, Di Marzo-Veronese F, Rota TR, Hirsch MS Primary human T-lymphotropic virus type III infection Ann Intern Med 1985, 103: 880-83. Ho DD, Rota TR, Scholley RT, et al Isolation of HTLV III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immuno-deficiency syndrome. N Engl J Med 1985; 313: 1493-97.

Cooper DA, Gold J, Maclean P,

AIDS PREDICTION AND INTERVENTION

SIR,-McEvoy and Tillettl have described a statistical method for predicting the course of AIDS in the UK. This method is a valuable tool for forecasting over quite short periods but it does not allow for changes in the epidemiological pattern-ie, a change in the exponential growth rate of the incidence of AIDS. We urgently need an epidemiological model which takes into account the underlying characteristics of the disease (eg, the long latency between infection and onset of symptoms) and changes in the habits of high-risk groups (eg, in numbers of sexual contacts). In building a model for a new disease, the best way is to start with a simple one, gradually increasing the complexity. Using data from the San Francisco Centers for Disease Control study cohort,2 which provides longitudinal data on homosexual and bisexual men from the longest time window (from 1978) currently available, we have attempted to reconstruct and predict the future course of the epidemic in this high-risk group. From data for the year 1978 and from a priori assumptions about the underlying disease process, it was possible to reconstruct, at least qualitatively, the course of future numbers of seropositive men and the cumulative number of cases of AIDS for 1978-84. Some results are presented in the figure. The actual course of the epidemic is represented by the 14 data points reported by Curran et al.The three curves represent the results of three simulation studies. These were based on the following tentative assumptions: (a) there is, on average, one potential effective sexual contact per person per year (ie, a contact that will produce a new infected person if one is infectious and the other susceptible); (b) after exposure to infection, the average length of time of the infectious period is 3, 5, or 10 years (three exponential distributions which correspond with the three curves in the figure); and (c) 10% of those infected will go on to acquire AIDS after an average incubation period which is of the same length as the infectious period (3, 5, or 10 years). The San Francisco CDC data come from a hepatitis B study cohort of homosexual and bisexual men numbering 6875 in 1978. By the time the first 2 cases of AIDS were diagnosed, in 1980, 24% already had antibodies to HTLV-III. Some 4% of samples were already seropositive in 1978. On the basis of the limited data for 1978 (a retrospectively estimated 275 seropositive men and no reported cases of AIDS) and on the tentative model assumptions, the simulation for 1979-84 fits quite well. In the event (and a posteriori)

853 Mathematical models and simulations may also prove evaluating the impact of intervention measures. Mathematisch-Statistische Catholic University, Nijmegen, Netherlands

Adviesafdeling,

helpful

J. A. M. VAN DRUTEN TH

DE

BOO

Rijksinstituut voor Volksgezondheid en Milieuhygiene (RIVM), Bilthoven

J. C. JAGER

GG en GD, Amsterdam

R. A. COUTINHO

RIVM, Bilthoven

E. J.

1. 2.

in

S. H. HEISTERKAMP

RUITENBERG

McEvoy M, Tillett HE. Some problems in the prediction of future numbers of cases of the acquired immunodeficiency syndrome in the UK. Lancet 1985; ii: 541-42. Curran JW, Meade Morgan W, Hardy AM, Jaffe HW, Darrow WW, Dowdle WR. The

epidemiology

of AIDS Current

status

and future prospects. Science

1985; 229:

1352-57. 3.

4.

Jaffe HW, Darrow WW, Echenberg DF, et al. The acquired immunodeficiency syndrome in a cohort of homosexual men. a six-year follow-up study. Ann Intern Med 1985; 103: 210-14. Riesenberg DE. AIDS-prompted behavior changes reported. JAMA 1986; 255: 171-76.

Analysis

of San Francisco CDC cohort data.

,

Simultaneous prediction of the number of individuals with HTLV-III/LAV and cases diagnosed with AIDS (cumulative); results of three simulations using the initial retrospective data for 1978. Infectious/incubation periods are on average 3, 5, or 10 years. tActual San Francisco experience 1979-84.

SERUM TRIMETHOPRIM AND SULPHAMETHOXAZOLE LEVELS IN AIDS

antibody

SiR,—The pharmacokinetics of high-dose co-trimoxazole in the of Pneumocystis carinii pneumonia (PCP) is not well

treatment

documented. We measured

6-4%

(95% confidence interval 0-8-21-4%) of men who

were

for more than five years have acquired AIDS. However, cohort members diagnosed in other cities may not be reported to the San Francisco Health Department.3 Furthermore there may be a delay between onset of symptoms, diagnosis, and time of reporting. This may partly explain why the reported data points of the San Francisco cohort study lie below the simulated curves corresponding to a 10% frequency of clinical AIDS. Furthermore the average incubation period may be longer than is generally assumed (1-5 years). Awareness of AIDS, education, and counselling may lead to changes in sexual life style, and such changes do seem to have occurred in San Francisco and other areas. A San Francisco questionnaire study in November, 1983, suggested that homosexual men had reduced high-risk sexual practices, such as unprotected anal intercourse and oral-genital contact, during the preceding year. According to studies by the Denver Metro Health Clinic the mean number of sexual partners for homosexual and bisexual men decreased from 5-33 to 3-22 after the respondents learned about AIDS.4Those who are planning and evaluating intervention programmes need to be able to predict the likely effects of reductions in contact rates. Starting from the figures reported in 19832 (3919 seropositive cases and 84 cases of AIDS) we used the model to predict cases for 1984-88. If the infectious/incubation period is 3 years and the contact rate did not change, the "prediction" for 1984 is 5003 seropositive men and 189 cases of AIDS. The true numbers were, respectively, 4675 and 166. If AIDS awareness and counselling halved the contact rate between homosexual men in the San Francisco study cohort, the numbers predicted by the model would be 4478 seropositive cases and 181 cases with AIDS diagnosed in the year 1984 (cumulative). For the year 1988 the model predicts, on this lower contact rate, 5487 seropositives and 430 cases of AIDS. Without this 50% reduction in contact rate these numbers would be 6386 and 496, respectively, in 1988. The results of these simulation studies indicate that, after the onset of an AIDS epidemic in a high-risk group of homosexual men, an immediate and large reduction in contact rate is required; a 50% reduction in contacts after a delay of several years, leads to a limited reduction in cases of AIDS (other ways of protection not being taken into account). These predictions are still tentative, and we are extending the model. However, even this simple model can provide insight into the time-dependent relation between the number of people with HTLV-111 antibody and the cumulative number of cases of AIDS.

seropositive

serum trimethoprim (TMP) and levels in seven patients with sulphamethoxazole (SMZ) bronchoscopically confirmed PCP associated with AIDS. The daily doses were TMP 20 mg/kg and SMZ 100 mg/kg, by mouth in five patients and intravenously in two. All patients had normal liver and renal function. Serum was collected 1 -5h after an oral dose or 1’5h after completion of the intravenous infusion, for measurement of drug levels.’ The results, as mean (and range) in g/ml, were:

Drug TMP SMZ

Ratio TMP:SMZ

Day 2-4 8-7(7-0-11-0) 274.2 2 (241-317) 1:31-55

Day 8-10 9-4(4-7-11-9) 342 . 5 (277-536) 4 1:36-4

Absolute SMZ levels were higher and TMP:SMZ ratios were lower than those cited in other similar studies. Winston et a12 reported lower levels of SMZ and a ratio of TMP:SMZ of about 1:20 when high-dose intravenous co-trimoxazole. Similarly Gordin et al reported that during the treatment of PCP in AIDS the level of SMZ did not exceed 150 µ/ml. In both studies adult patients were receiving TMP 10-20 mg/kg and SMZ 50-100 mg/kg daily. The frequency of adverse reactions to co-trimoxazole in the treatment of PCP associated with AIDS was as high as 8307o in some studies, and these were serious enough to necessitate a change of therapy in about half of the cases.3 In our series all seven patients required a change in therapy because of side-effects. This is in contrast to a frequency of 14% when high-dose co-trimoxazole is used for the treatment of PCP in other immunocompromised

using

groups.22

The reason for the high frequency of side-effects of cotrimoxazole in AIDS remains obscure, although an increased atopic tendency, as seen in other viral infections such as cytomegalovirus or Epstein-Barr virus, has been suggested. Gordin et al3 have discounted high serum levels of SMZ as a contributing factor. Our results, however, suggest that high serum SMZ levels may be partly responsible. This has therapeutic implications in that it may be necessary to administer the TMP and SMZ separately, in a lower dosage and in a different ratio to that found in the proprietary preparations of co-trimoxazole. Fairfield Infectious Diseases Hospital, Fairfield, 3078 Victoria, Australia 1 2.

3

FRANCIS J. BOWDEN P. J. HARMAN C. R. LUCAS

Bury RW, Mashford ML. Analysis of trimethoprim and sulphamethoxazole in human plasma by high pressure liquid chromatography. J Chromatogr 1979; 163: 114-17. Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprim-sulphamethoxazole for the treatment of Pneumocystis carinii pneumonia. Ann Intern Med 1980; 92: 762-69 Gordin FM, Simon GL, Wofsy CB, Mills J. Adverse reactions to trimethoprimsulphamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern

Med 1984; 100:

495-99