Empirical evidence for the severe but localized impact of AIDS on population structure.

Despite considerable speculation on the demographic impact of AIDS, there has been, until now, little scientific evidence to establish its existence or scale. Because of the widespread implications of these predictions, methods to combine demography and epidemiology to study empirical situations have been an urgent priority. This study derives the extent and mechanisms of demographic impacts of AIDS from routine data (the 1991 census) in a severely affected country, Uganda. Three characteristics are of particular note: first, the emergence of demographic impacts much earlier than previously estimated; second, their localization with negative population growth at parish but not at district or national scales; third, a greater impact on the number of children than previously predicted, due as much to changes in population fertility as mortality. The emergence of demographic impacts at this stage highlights original aspects of the interdependence of HIV infection and demographic growth not previously recorded and the need to target preventive interventions to youth in developing countries.

PIP: This paper derives the extent and mechanisms of demographic impacts of AIDS from 1991 census data for Uganda. Reports from Uganda indicate a wide range of different HIV prevalences according to geographical area. For example, HIV prevalence varies from 20% in some areas to 13% in the Rakai and less than 2% in the Pallisa districts. Within Rakai, prevalence varies by parish from 1% to 40%. Analysis of the data points to the potential severity of AIDS; large sections of the population structure pyramid may be missing and there is evidence of negative population growth at the parish level. The study also shows, however, how localized the impact of AIDS is at this stage and that such impact does not apply generally to population growth in Africa or even at the national or district levels. Estimated deficits in adults by age were consistent with the distribution of reported AIDS cases, but the deficits were far greater among children. The magnitude of deficits among 0-4 year olds is not fully explained by direct AIDS mortality, with the model showing the important role of reduced fertility due to HIV mortality in women. There is a need to target youth in developing countries with HIV/AIDS prevention interventions.

HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women.

A crucial requirement in the rational design of a prophylactic vaccine against the human immunodeficiency virus (HIV) is to establish whether or not protective immunity can occur following natural infection. The immune response to HIV infection is characterized by very vigorous HIV-specific cytotoxic T-lymphocyte (CTL) activity. We have identified four HIV-1 and HIV-2 cross-reactive peptide epitopes, presented to CTL from HIV-infected Gambians by HLA-B35 (the most common Gambian class I HLA molecule). These peptides were used to elicit HIV-specific CTLs from three out of six repeatedly exposed but HIV-seronegative female prostitutes with HLA-B35. These women remain seronegative with no evidence of HIV infection by polymerase chain reaction or viral culture. Their CTL activity may represent protective immunity against HIV infection.

PIP: A crucial requirement in the rational design of a prophylactic vaccine against HIV is to establish whether or not protective immunity can occur following natural infection. The immune response to HIV infection is characterized by very vigorous HIV-specific cytotoxic T-lymphocyte (CTL) activity. Four HIV-1 and HIV-2 cross-reactive peptide epitopes were identified, presented to CTL from HIV-infected Gambian women by HLA-B35 (the most common Gambian class 1 HLA molecule). The study population consisted of 20 women: 14 had been prostitutes for more than 5 years and reported little condom usage and 6 were long-term sexual partners of HIV-infected men. Peptide-stimulated cultures were also set up from 8 known seropositive donors with HLA-B35 or B53, and from a control group of volunteers at low-risk of HIV infection with HLA-B35 (12 Gambian and 7 European) and 2 Gambians with HLA-B53. Specific CTL activity against one or more peptides was repeatedly detected after 10-14 days in the peptide-stimulated cultures from 3 of the 6 high-risk seronegative women with HLA-B35, but not in their three counterparts with HLA-B53 nor in any of the low-risk volunteers. The strongest responses were generated toward the HIV-1 pol peptide, which lies close to the active site of reverse transcriptase, and to the nef peptide, which is conserved between HIV-1 and -2. HIV-specific CTL in seronegative subjects could potentially be a response to acute HIV infection, before the development of antibodies, but the women were still seronegative and virus-culture negative 3 months after the CTL were first detected, making recent infection extremely unlikely. These women remain seronegative with no evidence of HIV infection by polymerase chain reaction or viral culture. Their CTL activity may represent protective immunity against HIV infection.

A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma.

Kaposi's sarcoma (KS) is a previously rare, tumour-like lesion of controversial biological nature. KS has since the early 1980s become frequent in patients with AIDS, particularly in homosexuals. KS is also endemic in Central Africa predominantly in otherwise healthy men but also in women and children. Recently, evidence for the presence of novel, herpes virus DNA sequences in more than 90% of AIDS Kaposi lesions (AKS) was presented. This DNA was identified using representational difference analysis (RDA) generating short, unique sequences with variable homology to several herpes virus, but no intact virus was recovered. If these DNA-sequences are also present in other, non-HIV-associated forms of Kaposi's sarcoma this would strongly suggest a specific, aetiopathological involvement of this putative new herpes virus in the pathogenesis of Kaposi's sarcoma, rather than a contamination of yet another opportunistic virus in immunosuppressed AIDS patients.

PIP: Samples were examined by polymerase chain reaction (PCR) for the presence of the putative Kaposi's sarcoma herpes virus (KSHV). KS DNA from HIV-negative, African, endemic (EKS) samples, and epidemic HIV-positive KS (AKS), and sporadic KS (SKS) samples were tested from Tanzania and Sweden. All of the HIV KS (18 African EKS and 4 Swedish SKS) as well as the HIV-positive AIDS-related KS (16 African and 7 Swedish AKS) biopsies were shown to contain the previously described DNA sequences. KS lesions from children, females, and males in various tissues were analyzed including skin, lymph nodes, gut and oral mucosa. All forms of KS showed a single PCR product of the expected size (233 base pairs). To exclude amplification of other types of herpes virus, virus preparations of Epstein-Barr virus (EBV), herpes simplex virus, cytomegalovirus, vesicular stomatitis, and human herpes virus type 6 (HHV6) were assayed, again by PCR, using the KSHV primers. No PCR products were obtained with any of these virus strains. However, most HIV-positive and HIV-negative KS DNA samples also contained either EBV and/or HHV6 sequences. All biopsies from non-KS tissues (cells) of HIV-positive and HIV-negative individuals were consistently negative for KSHV by PCR. The observation that the same herpes virus-like DNA sequence is present in endemic and sporadic, as well as AIDS-related, Kaposi's sarcoma cases suggests a possible pathogenic association between this putative novel, herpes-like virus and KS. The herpes virus-like DNA sequences described by Y. Chang in 1994 may indeed represent a novel herpes (KSHV), etiopathologically associated with various clinical forms of Kaposi's sarcoma. Its pathogenic importance is indicated by its presence in different KS tissues with various clinical types of KS and its absence from non-KS-involved tissues. Furthermore, the presence of KSHV in KS of children suggests a nonsexual mode of transmission.

Antibody to Rmp (outer membrane protein 3) increases susceptibility to gonococcal infection.

The severe adverse effects of gonococcal infection on human fertility suggests that Neisseria gonorrhoeae would exert powerful selection for the development of a protective immune response in humans. N. gonorrhoeae is an obligate human pathogen and must persist in humans to survive. Since it is an ecologically successful organism, it must have evolved strategies to evade any human immune response it elicits. In a longitudinal study among 243 women working as prostitutes and experiencing frequent gonococcal infection, younger women, women with HIV infection, and women with antibody to the gonococcal outer membrane protein 3 (Rmp) were at increased risk of infection (adjusted odds ratio 3.4, CI95% 1.1-10.4, P < 0.05). Rmp is highly conserved in N. gonorrhoeae and the blocking of mucosal defences may be one of its functions. As similar proteins occur in many gram negative mucosal pathogens, the enhancing effect of such proteins may be a general strategy whereby bacteria evade human immune responses.

PIP: Between March 1985 and July 1986 researchers enrolled 243 female prostitutes in Pumwani community of Nairobi, Kenya, in a longitudinal study to examine the relationship between the antibody to the gonococcal outer membrane protein 3 (Rmp Ab) and gonococcal mucosal infection. Few women used condoms. 69% were HIV-1 seropositive. Just 9.5% (23) of the women had not had any gonococcal infections, despite probable exposure to them, indicating the possibility of some acquired protective immunity to Neisseria gonorrhoea. 90.5% had had at least 1 gonococcal infection. Women with Rmp Ab faced a greater risk of gonococcal infection than those who were Rmp Ab negative (OR = 3.4;l p .05), denoting that Rmp Ab increases susceptibility to gonococcal mucosal infections. Women older than 29 years were at lower risk of gonococcal infection than those younger than 29 years (odds ratio [OR] = 0.3; p .03). Women who used oral contraceptives (OCs) were also likely to be infected with N. gonorrhoea (OR = 3; p = .062). Further, 31% of OC users had cervical ectopy compared to just 14% of nonusers (OR = 2.8; p .005), suggesting that the effect of OCs on the cervix make it more susceptible to gonococcal infection. Rmp Ab also exists in many other gram-negative mucosal pathogens, often playing the same role as it does in N. gonorrhoea infection. Thus, Rmp Ab may be a common scheme bacteria used to elude human immune responses. These findings provide more understanding as to why N. gonorrhoea is an ecologically successful human pathogen.

Unique pattern of HTLV-III (AIDS-related) antigen recognition by sera from African children in Uganda (1972).

Of 75 sera collected in the West Nile district of Uganda over a 1-year period between 1972 and 1973, 50 (66%) had antibody reactivity to human T-cell lymphotropic virus subgroup III (HTLV-III) at low titer levels. Sera were initially screened by HTLV-III enzyme linked immunosorbent assay and sera with values less than normal mean + 2 SD were removed from testing. The remaining sera were tested for positivity by an amplified Western blotting procedure which incorporated a three-layer immunoperoxidase procedure. Immunoglobulin reactive with HTLV-III Mr 24,000, 41,000, and 76,000 proteins were present in nearly all positive sera. The antibody status of this group was unlike any normal or acquired immunodeficiency syndrome-risk group previously tested. The high prevalence and relatively low titers suggest the detection as early as 1972 of a relative or predecessor of HTLV-III or of HTLV-III itself but existing in a population acclimated to its presence. It further suggests a likely African origin of HTLV-III.

PIP: Sera from 75 children from an isolated subsistence farming region of the Ugandan Nile valley in 1972-1973 showed a unique pattern of antibody titer to HTLV-III: a high prevalence but low titer for a limited number of viral proteins. The sera were originally collected at random as controls for a study of Burkitt's lymphoma. Mean age was 6.4 years. Sera were tested quantitatively by ELISA and 50 of 55 positives were confirmed by Western blot. The most prominent bands had molecular weights of 76,000, 41,000 and 24,000, coinciding with HTLV-III antigens previously described. The geometric mean titer was 295 with a range of 100-1000. The results suggest high prevalence of a closely related virus in this population.

The influence of HIV status on single and multiple drug reactions to antituberculous therapy in Africa.

OBJECTIVE: To document the influence of HIV status on drug reactions occurring in patients on antituberculous therapy in Harare, Zimbabwe. DESIGN: Retrospective cohort study. SETTING: City of Harare Tuberculosis Unit. PATIENTS: Records of 906 patients with tuberculosis, of whom 162 reacted to antituberculous therapy, were analysed. RESULTS: Reactions to antituberculous drugs were more frequent in HIV-positive (98 out of 363) than in HIV-negative (64 out of 543; P less than 0.0001) patients. The most common drug reaction was cutaneous hypersensitivity, occurring in 139 patients, 89 (64%) of whom were HIV-positive. Thiacetazone was implicated in 115 (82.7%) of the 139 cutaneous reactions and streptomycin in 10 (7.2%). Almost all cutaneous reactions occurred within 8 weeks of beginning treatment. Severe cutaneous reactions occurred more often in HIV-positive patients (P less than 0.001) and the only two deaths occurred in this group. Reactions to multiple drugs occurred in 18 HIV-positive and three HIV-negative patients (P = 0.017). CONCLUSIONS: The use of thiacetazone and streptomycin in antituberculous drug regimens should be reassessed in those countries where coinfection with HIV and tuberculosis is common.

Trends in HIV-1 prevalence may not reflect trends in incidence in mature epidemics: data from the Rakai population-based cohort, Uganda.

OBJECTIVES: To assess whether trends in serial HIV-1 prevalence reflect trend in HIV incidence, and to decompose the effects of HIV-1 incidence, mortality, mobility and compliance on HIV-1 prevalence in a population-based cohort. DESIGN: Two-year follow up (1990-1992) of an open cohort of all adults aged 15-59 years, resident in a sample of 31 representative community clusters in rural Rakai District, Uganda. METHODS: A detailed household enumeration was concluded at baseline and in each subsequent year. All household residents were listed, and all deaths and in- and out-migrations that occurred in the intersurvey year wee recorded. In each year, all consenting adults were interviewed and provided a serological sample; 2591 adults aged 15-59 years were enrolled at baseline. RESULTS: HIV prevalence among adults declined significantly 1990 and 1992 (23.4% at baseline, 21.8% in 1991, 20.9% in 1992; P < 0.05). Declining prevalence was also observed in subgroups, including young adults aged 15-24 years (from 20.6 to 16.2% over 3 years; P < 0.02), women of reproductive age (from 27.1 to 23.5%; P < 0.05), and pregnant women (from 25.4 to 20.0%; not significant), However, HIV incidence did not change significantly among all adults aged 15-59 years (2.1 +/- 0.4 per 100 person-years of observation (PYO) in 1990-1991 and 2.0 +/- 0.3 per 100 PYO in 1991-1992], nor in population subgroups. HIV-related mortality was high (13.5 per 100 PYO among the HIV-positive), removing more infected persons that were added by seroconversion. Net out-migration also removed substantial numbers of HIV-positive individuals. CONCLUSIONS: In this mature HIV epidemic, HIV prevalence declined in the presence of stable and incidence. HIV-related mortality contributed most to the prevalence decline. Prevalence was not an adequate surrogate measure of incidence, limiting the utility or serial prevalence measures in assessing the dynamics of the HIV epidemic and in evaluating the impact of current preventive strategies.

PIP: Findings are reported from a 2-year follow-up study of an open cohort of people aged 15-59 years living in a sample of 31 representative community clusters in rural Rakai district, Uganda, to measure whether trends in serial HIV-1 prevalence reflect trends in HIV incidence, and to gain insight into the effects of HIV-1 incidence, mortality, mobility, and compliance upon HIV-1 prevalence. In each year of study, all consenting adults provided a serological sample and were interviewed; 2591 adults were enrolled at baseline. HIV prevalence among adults declined significantly between 1990 and 1992; from 23.4% in 1990, to 21.8% in 1991, and 20.9% in 1992. Declining prevalence was also observed in subgroups, including young adults aged 15-24 years from 20.6% to 16.2%, reproductive-age women from 27.1% to 23.5%, and pregnant women from 25.4% to 20.0%. The decline in HIV prevalence among pregnant women, however, is not significant. HIV incidence did not change significantly among all adults aged 15-59 years, nor in population subgroups. HIV-related mortality was 13.5/person-year of observation among those who were HIV-positive. Substantial numbers of HIV-infected individuals were also loss to emigration.

An epidemiological study of tuberculosis and HIV infection in Tanzania, 1991-1993.

OBJECTIVE: In Tanzania during the past 6 years reported tuberculosis (TB) cases have nearly doubled, with proportionately much greater increases in smear-negative and extrapulmonary cases compared with smear-positive cases. At the same time, HIV infection has become widespread throughout the country. This survey was undertaken in order to study the association of TB and HIV and to determine the impact of HIV on present and future TB cases in Tanzania. METHODS: The survey design provided for HIV testing of a representative country-wide sample of approximately one-sixth of all new and relapse cases registered between January 1991 and December 1993, with linkage to demographic, clinical and bacteriological data for these cases. HIV surveillance data were used for comparison purposes. RESULTS: A total of 6928 TB cases from all of the country's 20 mainland regions were tested. The overall HIV seroprevalence was 32%. Both crude and adjusted odds ratios (OR) for HIV infection were higher in women, those aged 25-44 years, urban residents, cases of smear-negative and extrapulmonary disease, and persons with a bacille Calmette-Guérin (BCG) vaccination scar. The age-and sex-adjusted relative risk for HIV infection in TB patients compared to blood donors in the same regions was 7.1 (95% confidence interval, 6.6-7.5), and was significantly higher among those aged 25-34 years. Of 3360 patients with bacteriological culture results 46% were culture-positive for Mycobacterium tuberculosis. Drug susceptibility tests were performed on 1164 isolates with the overall rate of drug resistance of 6.2%. Rates of initial resistance were low in both HIV-positive (4%) and HIV-negative (5.8%) patients. Rates of acquired resistance were higher (19% overall) and did not vary significantly by HIV serostatus. Initial combined resistance to both isoniazid and rifampicin was uncommon (0.4%) as was monoresistance to rifampicin (0.3%). CONCLUSIONS: The higher OR for women and young adults reflect the higher rates of HIV infection in those populations. The finding that smear-positive relapse cases were no more likely to have HIV infection than new smear-positive cases suggests that the treatment regimen for new cases is effective in HIV-associated TB. The low rates of both initial and acquired drug resistance in HIV-positive patients is further evidence of adequacy of treatment. The higher relative risk for HIV infection among patients aged 25-34 years suggests increased HIV-related TB transmission. Finally, it is estimated that approximately two-thirds of the increase in the rate of smear-positive tuberculosis in the country can be directly attributed to HIV infection.

PIP: The number of tuberculosis (TB) cases reported in Tanzania during the past six years has nearly doubled. Concurrently, HIV infection has become widespread throughout the country. This survey was conducted to study the association between TB and HIV, and to determine the impact of HIV upon present and future TB cases in the country. The survey design provided for HIV testing of a representative country-wide sample of approximately 17% of all new and relapse TB cases registered between January 1991 and December 1993. 6928 TB cases were tested from all of the country's mainland regions to find an overall HIV seroprevalence of 32%. Both crude and adjusted odds ratios for HIV infection were higher in women, those aged 25-44 years, urban residents, cases of smear-negative and extrapulmonary disease, and persons with a BCG vaccination scar. The age- and sex-adjusted relative risk for HIV infection in TB patients compared to blood donors in the same regions was 7.1, and was significantly higher among those aged 25-34 years. 46% of the 3360 patients with bacteriological culture results were culture-positive for Mycobacterium tuberculosis. Drug susceptibility tests were performed on 1164 isolates with the overall drug resistance rate of 6.2%. Rates of initial resistance were 4% among HIV-positive patients and 5.8% among HIV-negative patients. There was a 19% overall rate of acquired resistance which did not vary significantly by HIV serostatus. Initial combined resistance to both isoniazid and rifampicin was 0.4%; there was a 0.3% monoresistance to rifampicin. The authors estimate that approximately two-thirds of the increase in the rate of smear-positive TB in Tanzania can be directly attributed to HIV infection.

Chemotherapy of African AIDS diarrhoea: a preliminary study.

OBJECTIVE: To determine whether combined chemotherapy with tinidazole, thiabendazole and cotrimoxazole is more effective than placebo in treatment of AIDS diarrhoea in Zambia. DESIGN: Single-blind prospective comparison in consecutive patients, randomized alternately to placebo or chemotherapy. SETTING: A district hospital in Zambia. PATIENTS: Sixty-four HIV-seropositive patients with chronic diarrhoea were considered for inclusion in the study. Of these, 25 patients were not eligible for randomization (in 13 cases because of spontaneous remission); 11 were randomized, but excluded from the analysis (seven failed to attend for a scheduled visit and four died), leaving 28 patients who completed the study. MAIN OUTCOME MEASURES: Proportion of diarrhoea-free days in the 7 days following treatment, as determined by daily stool counts. RESULTS: There were 38 diarrhoea-free days out of 89 (43%) in the placebo group, and 39 out of 72 (54%) in the chemotherapy group; this difference was not statistically significant. CONCLUSIONS: The high level of spontaneous remission probably indicates a natural fluctuation in stool frequency and demonstrates the need for placebo-controlled studies in any assessment of therapy for AIDS diarrhoea. Our findings do not allow us to conclude that the chemotherapy used is ineffective, since the number of patients was low, but will help in our understanding of the natural history of the disorder and the design of future studies.

PIP: One of the principal features of AIDS in Africa is the diarrhea wasting syndrome known as "slim disease." Although several researchers have tried to identify the pathogens implicated in diarrhea, none can be found in a large proportion of cases. Treatment regimens must be particularly effective in Africa, a region with many competing demands upon the drug budget. In this context, the authors compared the effects of a placebo against the effects of a drug regimen against diarrhea in 28 HIV-seropositive patients with chronic diarrhea. The regimen of combined chemotherapy with tinidazole, thiabendazole, and cotrimoxazole would be expected to eradicate or substantially many of the pathogens most frequently implicated in such cases. There were 38 diarrhea-free days out of 89 in the placebo group and 39 out of 72 in the chemotherapy group; a difference which was not statistically significant. The high level of spontaneous remission observed in this study most likely indicates a natural fluctuation in stool frequency and demonstrates the need for placebo-controlled studies in any assessment of therapy for AIDS diarrhea. The authors stress that the small number of patients involved in the study precludes them from ruling that the combined chemotherapy is ineffective.

Genital ulceration as a risk factor for human immunodeficiency virus infection.

Among 115 heterosexual men who presented with genital ulcers to a sexually transmitted disease clinic in Nairobi, Kenya, the prevalence of serum antibody to HIV was 16.5%. A past history of genital ulcers was reported by 12 (63%) of 19 men with antibody to HIV versus 30 (31%) of 96 without antibody (P = 0.008). HIV infection was also positively associated with lack of circumcision, but was not associated with the etiology of the current genital ulcer. Logistic regression analysis (adjusted for age, number of recent sex partners, recent prostitute contact, circumcision, tribal ethnic identity, past history of urethritis, and current diagnoses) confirmed only the association between prior history of genital ulcer disease and HIV infection; (P = 0.04, odds ratio 2.35, 95% confidence limits, 1.01-5.47). The incidence of genital ulcers, particularly chancroid, is much higher in parts of Africa than in Europe or North America. This may contribute to the increased risk of heterosexual transmission of HIV in Africa. Aggressive control of chancroid and syphilis may offer one very feasible approach to reducing transmission of HIV in this region.

Surveillance for AIDS in Uganda.

In the developed world, surveillance for AIDS has provided up-to-date information for researchers, clinicians, public health workers and policy makers. In Africa, however, there is no standardized format or methodology for AIDS surveillance. In August 1987, Uganda developed a clinical case definition for AIDS reporting, based upon the World Health Organization (WHO) clinical case definition for AIDS in Africa and began formal surveillance. Surveillance is passive and primarily hospital-based. At the end of July 1988, 5142 cases of AIDS had been reported to the Ministry of Health; 4583 (89%) had confirmatory HIV-antibody testing. Of the 4938 (96%) cases that had their sex recorded, 2358 (48%) were male and 2580 (52%) were female. The mean age of 28.4 years for male patients is higher than that of 24.4 years for female patients (P less than 0.0001). Only 18 (less than 1%) cases have been reported in children between 5 and 12 years of age. Case reports are returned via the District Medical Officers to the Ministry of Health where they are entered into a microcomputer from which a monthly report is generated for feedback to the reporting stations. Here we describe a simple national reporting system to follow the progression of the AIDS epidemic which could be established in Africa using limited resources.

Immunological reactivities of Ghanaian sera with HIV-1, HIV-2, and simian immunodeficiency virus SIVagm.

PIP: To learn more about the relative prevalence of viruses from the human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) groups in Ghana, serum samples were collected in 1986 from 47 men and women with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), 57 apparently healthy individuals, and 11 AIDS-free hospital inpatients. Western blot analysis revealed a total of 46 reactive sera. 43 of the 47 serum samples from those with AIDS or ARC were positive; 6 were seropositive for HIV-1, 18 for HIV-2, 17 for both HIV-1 and HIV-2, and the remaining 2 were not reactive with glycoproteins. Of the 2/10 individuals with mild symptoms of HIV infection who proved to be seropositive, 1 was positive for HIV-2 and 1 for HIV-1 and HIV-2. There were no seropositive reactions among the AIDS-free hospital patients, and only 1 such reaction (seropositive for HIV-2) among the healthy individuals. These findings indicate that both HIV-1 (6 cases in this series) and HIV-2 (20 cases) are responsible for the development of AIDS in Ghana, and that there is a high prevalence (18 cases) of cross-reactivity between the 2 viruses. There was no evidence of SIV infection. Further research is needed to determine whether these findings are a result of cross-reactivity between envelope proteins of HIV-1 and HIV-2, double infection of AIDS patients, or infection with a new variant strain. Since prostitutes comprised 25 of the 47 AIDS/ARC patients and 6 of the 10 with mild symptoms of HIV infection, they are an important target for preventive efforts.^ieng

Prevalence of HIV-1 in east African lorry drivers.

Sixty-eight lorry drivers and their assistants were examined for evidence of infection with HIV-1 because of their association and regular contact with prostitutes. Out of a total of 68 drivers, 24 (35.2%) were serologically found to be HIV-1 positive. Epidemiological evidence demonstrated a wide travel history involving seven different countries served by the port of Mombasa. History of other sexually transmitted disorders were significantly higher in HIV-seropositive individuals. The data presented here further support the hypothesis that a major route of heterosexual transmission of HIV in Africa is dissemination through a group such as lorry drivers and their assistants, whose behaviour puts them at risk of acquiring sexually transmitted diseases.

PIP: Participants in the study were drivers and turnboys who passed through a transport depot in Kampala, Uganda, in November 1986. Each participant answered a questionnaire aimed at determining basic demographic data, countries visited within the previous 3 years, level of prostitute contact within those countries, and whether they had had a history of urethral discharge or genital ulceration. A total of 45 drivers and 23 turnboys with a mean age of 38 and 26 years, respectively, were interviewed and blood samples were taken. Serological controls were selected from people of the same age as the study group from individuals donating blood. Serum immunoglobulin (Ig) antibodies to HIV were determined by a competitive enzyme-linked immunosorbent assay and a competitive ELISA using recombinant HIV core and envelope proteins. All serological results were verified by immunoblot assays or were prepared by electrophoretic separation of U937 cell lysates infected with a Ugandan HIV-1 isolate. Antibodies to Treponema pallidum were detected by a hemagglutination test. They were of Ugandan (66.2%) or Kenyan (33.8% ) origin. All were sexually active, and all denied homosexuality and intravenous drug use. The overall HIV-1 seropositivity rate was 35.2%, compared with the control group of 9.2% (24 out of 68 versus 12 out of 130; p 0.01). Using the antigen detection systems, 7 of the seronegative sera proved to be antigen positive. In addition, 4 out of the 24 seropositive sera (16.6%) also proved to be antigen positive. 36.7% of the population admitted more than 50 lifetime sexual partners. Of the remainder, 83.7% had had more than 10 lifetime sexual partners. The level of urethral discharge and genital ulceration revealed a significant difference (p 0.01) between seropositive and seronegative individuals. The overall level (55.8%) of T. pallidum antibodies among drivers and turnboys was significantly higher than in the control group (p 0.01). The drivers had the highest level of T. pallidum antibodies (62.2%) compared with turnboys (43.8%), reflecting the older average age and, thus, the greater sexual experience.

Faecal mycobacteria and their relationship to HIV-related enteritis in Lusaka, Zambia.

The prevalence of infection with mycobacteria, both typical and atypical, is increasing along with prevalence of infection with HIV. Patients with pulmonary tuberculosis (PTB) and patients with chronic diarrhoea are forming a growing proportion of the patient population in hospitals in central Africa. To investigate the possibility that mycobacteria may be responsible for some of the HIV-related enteropathy seen in Lusaka, we studied 89 patients in four different diagnostic groups, clinically, by Mantoux test and by microscopy and culture of stool specimens for mycobacteria. In the HIV-positive group with chronic diarrhoea (n = 31), two patients were found to have mycobacteria on faecal smear and three were culture positive while of the 15 HIV-negative controls, three were smear positive and three were culture positive. Of the 15 patients with proven PTB, three had positive faecal smears but none were culture positive. In the fourth group of 24 patients with suspected PTB, seven were smear positive and five, culture positive. Only in this last group was there some correlation between smear results and culture results. Although this last finding is difficult to explain, it appears that there is no correlation between the symptom of chronic diarrhoea and the presence of mycobacteria in the stool. We conclude that mycobacteria do not play a significant role in the pathogenesis of HIV-related enteropathy in Lusaka.

Recent transmission of tuberculosis in a cohort of HIV-1-infected female sex workers in Nairobi, Kenya.

OBJECTIVES: To describe the epidemiological and clinical characteristics of HIV-related tuberculosis in a female cohort, and to investigate the relative importance of recently transmitted infection and reactivation in the pathogenesis of adult HIV-related tuberculosis. DESIGN: Members of an established cohort of female sex workers in Nairobi were enrolled in a prospective study. Women were followed up regularly and seen on demand when sick. METHODS: Between October 1989 and September 1992 we followed 587 HIV-infected and 132 HIV-seronegative women. Standard protocols were used to investigate common presentations. Cases of tuberculosis were identified clinically or by culture. All available Mycobacterium tuberculosis strains underwent DNA fingerprint analysis. RESULTS: Forty-nine incident and four recurrent episodes of tuberculosis were seen in HIV-infected women; no disease was seen in seronegative sex workers (P = 0.0003). The overall incidence rate of tuberculosis was 34.5 per 1000 person-years amongst HIV-infected participants. In purified protein derivative (PPD) skin test-positive women the rate was 66.7 per 1000 person-years versus 18.1 per 1000 person-years in PPD-negative women. Twenty incident cases (41%) were clinically compatible with primary disease. DNA fingerprint analysis of strains from 32 incident cases identified two clusters comprising two and nine patients; allowing for index cases, 10 patients (28%) may have had recently transmitted disease. Three out of 10 (30%) patients who were initially PPD skin test-negative became PPD-positive. Taken together, 26 incident cases (53%) may have been recently infected. DNA fingerprint analysis also identified two (50%) of the four recurrent tuberculosis episodes as reinfection. CONCLUSIONS: Substantial recent transmission of tuberculosis appears to be occurring in Nairobi amongst HIV-infected sex workers. It may be incorrect to assume in other regions of high tuberculosis transmission that active HIV-related tuberculosis usually represents reactivation of latent infection.

PIP: A 3-year (1989-92) prospective study of 587 HIV-positive and 132 HIV-negative commercial sex workers in Nairobi, Kenya, revealed substantial recent transmission of tuberculosis in the HIV-infected group. The cohort was enrolled at a community clinic that provides counseling, sexually transmitted disease services, and free condoms. In HIV-positive women, 49 incident and 4 recurrent episodes of tuberculosis were diagnosed during the study period; there were no tuberculosis cases among HIV-negative women. The overall incidence rate of tuberculosis was 34.5/1000 person-years among HIV-positive women. 20 incident cases (41%) met the clinical case definition of primary disease. DNA fingerprint analysis of strains from 32 incident cases suggested 10 women (28%) may have had recently transmitted disease. 3 of 10 women who were initially purified protein derivative (PPD) skin test-negative became PPD-positive. Clinical presentation, tuberculin skin testing, and strain clustering data all independently suggested that substantial Mycobacterium tuberculosis transmission was occurring in HIV-infected prostitutes during the study period. As many as 26 (53%) of the 49 patients with incident disease may have recently acquired tuberculosis and DNA fingerprint analysis identified 2 (50%) of the 4 recurrent tuberculosis episodes as reinfection. These findings challenge the assumption that tuberculosis in HIV-infected individuals represents reactivation of latent endogenous infection.

Modelling the economic benefits of tuberculosis preventive therapy for people with HIV: the example of Zambia.

OBJECTIVE: To assess the economic benefits and costs of providing isoniazid preventive therapy for tuberculosis (TB) in HIV-infected persons in Zambia. DESIGN: A spreadsheet model incorporating variables drawn from published studies and unpublished data. SUBJECTS: Data drawn from a number of different studies and published literature involving a range of subjects. SETTING: Zambia. RESULTS: Using data primarily from Zambia we have modelled the costs and benefits of a TB preventive therapy programme using daily isoniazid for 6 months. The basecase scenario assumes recruitment at a voluntary testing and counselling site where HIV seroprevalence is 30%; persons with HIV have a 25% probability of developing active TB during their lifetime; two additional cases of TB would be prevented per person completing a course of preventive therapy; compliance would be 63%, and the efficacy of the isoniazid in preventing active TB of 60%. The costs under this scenario would exceed the benefits by a factor of 1.16 [benefit: cost ratio (BCR) of 0.86]. However, if preventing one case of TB prevented an additional five cases, the benefits would exceed the costs by a significant margin (BCR of 1.71). Other scenarios indicate that the targeted preventive therapy of persons with HIV whose occupation or living situation places them in contact with a large number of others (teachers and students, health personnel, military and police, miners, prisoners, etc.) would yield significant net benefit. The operational challenge for TB preventive therapy is thus to identify and target large numbers of such persons.

PIP: The authors used available data from selected published literature to assess the economic costs and benefits of providing daily isoniazid preventive therapy for tuberculosis (TB) for 6 months in HIV-infected persons in Zambia. The base case scenario assumes recruitment at a voluntary testing and counseling site where HIV seroprevalence is 30%, HIV-infected individuals have a 25% probability of developing active TB during their lifetime, two additional cases of TB would be prevented per person completing a course of preventive therapy, compliance would be 63%, and an efficacy of isoniazid in preventing active TB of 60%. The costs under that scenario would exceed benefits by a factor of 1.16, or a benefit/cost ratio (BCR) of 0.86. However, if preventing one case of TB prevented an additional five cases, the benefits would exceed the costs by a BCR of 1.71. Other scenarios indicate likely significant net benefits from the targeted preventive therapy of HIV-infected persons whose occupation or living situation brings them into contact with a large number of other people.

Serologic and phylogenetic characterization of HIV-1 subtypes in Uganda.

OBJECTIVES: To determine the HIV genetic subtypes present in HIV-1-infected asymptomatic blood donors in Uganda and to evaluate serologic detection of infection by commercial immunoassays; to evaluate samples for HIV-1 group O infections. METHODS: Sixty-four HIV-seropositive plasma samples were collected from the Nakasero Blood Bank, Kampala, Uganda. The plasma were evaluated using commercial HIV enzyme immunoassays (EIA) and a research immunoblot. HIV-1 group M and O infections were identified on the basis of discordant seroreactivity in EIA and reactivity to group M and O antigens on the immunoblot. Regions of gag p24 and env gp41 were amplified using reverse transcriptase polymerase chain reaction, and genetic subtypes were determined by phylogenetic analysis. RESULTS: Serologic testing confirmed that 63 out of 64 plasma units were positive for HIV-1 group M infection and showed no evidence of HIV-1 group O infections. Genetic subtyping determined that 25 samples were subtype A, three subtype C, 22 subtype D, and nine were heterogeneous for subtypes A and D. CONCLUSIONS: Despite the sequence variation observed in Uganda, commercial EIA based on HIV-1 subtype B proteins detected all the infections. In contrast, a peptide-based assay failed to detect three infections by subtype D viruses. This emphasizes the negative impact of HIV genetic variation on assays that rely on peptides to detect HIV infections. The number of infections with heterogeneous subtype (due to mixed infections or recombinant viruses) is high and reflects the growing complexity of the HIV epidemic in endemic regions where multiple subtypes are present in the population.

PIP: Extensive sequence heterogeneity between HIV-1 isolates has led to the classification of HIV-1 into group M (major) subtypes A-J, and group O (outlier). Some isolates have also been found to be the result of recombination between different group M subtypes. Findings are reported from a study conducted to determine the various HIV genetic subtypes in HIV-1-infected asymptomatic blood donors in Uganda and to evaluate the serologic detection of infection by commercial immunoassays. 64 HIV-seropositive plasma samples were collected from the Nakasero Blood Bank in Kampala and evaluated using commercial HIV enzyme immunoassays (EIA) and a research immunoblot. 63 of 64 plasma units were positive for HIV-1 group M infection and showed no evidence of group O infections. According to phylogenetic analysis, 25 samples were subtype A, 3 subtype C, 22 subtype D, and 9 heterogenous for subtypes A and D. Despite the sequence variation observed in this study population, commercial EIA based upon HIV-1 subtype B proteins detected all of the infections. A peptide-based assay failed to detect 3 infections by subtype D viruses.

Improved treatment services significantly reduce the prevalence of sexually transmitted diseases in rural Tanzania: results of a randomized controlled trial.

OBJECTIVE: To evaluate the impact of improved case management for sexually transmitted diseases (STD) at the primary health care level on the incidence and prevalence of STD. DESIGN: Community-randomized controlled trial. SETTING: Mwanza region, Tanzania. SUBJECTS: A random cohort of about 1000 adults aged 15-54 years from each of 12 communities, in six matched pairs. One member of each pair was assigned at random to receive the intervention, and the others served as a comparison community. This cohort was surveyed at baseline and at follow-up 2 years later. About 100 antenatal clinic attenders were also studied in each community on two occasions: the first shortly after the implementation of the intervention, and the second approximately 1 year later. INTERVENTION: Improved services were established for the management of STD, using the syndromic approach, in rural health units. RESULTS: A total of 12,534 individuals were enrolled in the cohort study, of whom 8844 (71%) were seen again 2 years later. The prevalence of serological syphilis (rapid plasma reagin titre > or = 1:8, Treponema pallidum haemagglutinin assay positive) was 6.2% in both intervention and comparison communities at baseline. At follow-up it was 5.0% in the intervention community and 7.0% in the comparison community [adjusted relative risk (RR), 0.71; 95% confidence interval (CI), 0.54-0.93; P < 0.02]. The prevalence of urethritis in males did not differ significantly between intervention and comparison groups at follow-up, but the prevalence of symptomatic urethritis was reduced by about 50% (adjusted RR, 0.51; 95% CI, 0.24-1.10; P = 0.08). There was no significant difference between the groups in the incidence of self-reported STD symptoms over the last year of the follow-up period, or in the prevalence of any STD in antenatal clinic attenders. CONCLUSION: The reduction in HIV incidence previously reported in this intervention study can be attributed to a reduction in the duration, and hence the prevalence of symptomatic STD.

PIP: A community-randomized controlled trial was conducted in Mwanza region, Tanzania, to assess the impact of improved case management for sexually transmitted diseases (STDs) at the primary health care level on the incidence and prevalence of STD. A random cohort of about 1000 adults aged 15-54 years from each of 12 communities, in 6 matched pairs, participated, with 1 member of each pair receiving the intervention and the others serving as controls. The intervention consisted of improved services to manage STDs, using the syndromic approach, in rural health units. 12,534 people were enrolled in the study, of whom 8844 were seen again 2 years later at follow-up. The prevalence of serological syphilis was 6.2% in the intervention and comparison communities at baseline. However, at follow-up, the prevalence was 5.0% in the intervention community and 7.0% in the comparison community. The prevalence of urethritis in males did not differ significantly between intervention and comparison groups at follow-up, but the prevalence of symptomatic urethritis was nonetheless reduced by about 50%. No significant difference was observed between the incidence and control groups in the incidence of self-reported STD symptoms during the last year of the follow-up period or in the prevalence of any STD in antenatal clinic attenders.

Risk factors for Kaposi's sarcoma in HIV-positive subjects in Uganda.

BACKGROUND: Kaposi's sarcoma (KS) is associated epidemiologically with HIV infection and with human herpesvirus 8 (HHV-8 or KSHV). Both KS and HIV infection are common in Uganda. We conducted a case-control study of 458 HIV-seropositive. Ugandan adults with KS and 568 HIV-seropositive subjects without KS to examine risk factors for HIV-associated KS. METHODS: We recruited newly diagnosed adult KS cases from five hospitals in Kampala, Uganda and controls from a large referral clinic for HIV infection at Mulago Hospital. All cases and controls were counselled and tested for HIV and answered an interviewer-administered questionnaire about their home, socio-economic conditions, lifestyle and sexual behaviour before they became ill. Only HIV-seropositive subjects were included in the analysis. RESULTS: There were 295 males and 163 females with KS and 227 male and 341 female controls. Age distribution was similar but there was a higher proportion of cases (45%) than controls (29%) residing in rural regions of Uganda. KS cases were more likely than controls to have a higher level of education (X2 for trend, 4.8; P = 0.03), to have occupations associated with affluence [chi 2 for heterogeneity, 17.3 on 5 degrees of freedom (df); P = 0.004] and to come from larger settlements [adjusted odds ratio (OR) for settlements of > 1000 versus 10-99 houses, 1.8; 95% confidence interval (CI), 1.1-3.0]. Cases were more likely than controls to have high household income (chi 2 for trend, 32.6; P < 0.001) and other markers of urban or rural wealth such as owning several cows (chi 2 for trend, 9.5; P = 0.002). Cases were more likely to travel away from home (adjusted OR, 1.6; 95% CI, 1.1-2.3) and more likely to have spent increasing time in contact with water (chi 2 for trend, 12.3; P < 0.001). Few indices of sexual behaviour were related to risk of KS, including reported number of sexual partners. Cases were more likely than controls to be married to one rather than several spouses (adjusted OR, 1.6; 95% CI, 1.2-2.2) and to have reported a history of sexually transmitted diseases (STD) (adjusted OR, 1.6; 95% CI, 1.2-2.3). CONCLUSIONS: Among HIV-infected subjects, KS cases are characterized by better education and greater affluence, compared with controls. Urban address, travel away from home, exposure to water, monogamous marriage and self-reported STD were also more frequent among KS cases than controls. The higher socio-economic status of persons with HIV and KS may be a marker for enhanced exposure to a possibly sexually transmitted agent, or for a delayed exposure to a childhood infection. The risk posed by exposure to water among KS cases requires further study.

PIP: The risk factors for Kaposi's sarcoma in HIV-infected persons were investigated in a case-control study conducted in Kampala, Uganda, in 1994-96. Cases included 458 HIV-positive Ugandans with newly diagnosed Kaposi's sarcoma, while the control group was comprised of 568 seropositive subjects without Kaposi's sarcoma. Men and women with Kaposi sarcoma were significantly more likely than controls to have a higher educational level, have prestigious professional or military jobs, to come from large settlements (over 1000 houses), to have a high household income, to travel away from home more than seven nights per year, and to have spent increasing time in contact with water. In addition, cases were more likely than controls to be married to one rather than several spouses and to have a history of a sexually transmitted disease. Indices of sexual behavior, including reported number of sexual partners and condom use, were unrelated to Kaposi's sarcoma risk. The higher socioeconomic status of HIV-infected persons with Kaposi's sarcoma may be a marker for enhanced exposure to a sexually transmitted agent such as human herpes virus-8 or for delayed exposure to a childhood infection. The puzzling association between exposure to water and Kaposi's sarcoma warrants further investigation.

An association between HIV-1 subtypes and mode of transmission in Cape Town, South Africa.

OBJECTIVES: To determine HIV-1 env and gag subtypes in male homosexual and heterosexual populations in Cape Town, South Africa. DESIGN: DNA was isolated from blood originating from 61 patients attending local clinics. Samples were divided according to presumed mode of transmission: male homosexual (n = 26), heterosexual/vertical (n = 32), blood transfusion (n = 1) and unknown (n = 2). METHODS: Proviral HIV-1 DNA was subtyped by heteroduplex mobility assay (HMA) based on the 799 base-pair V3-V5 region of the env gene (n = 47) or by sequence analysis of the p17 region of the gag gene (n = 33), or both. For HMA, reference plasmids were constructed containing the V1-V5 env region sequences (1.2-kb) representative of local subtypes. Subtype designation of reference subtypes was confirmed by sequence analysis of the V3-loop region. RESULTS: Analysis of the partial gag sequences and HMA of the V3-V5 env region identified three subtypes: B, C and D. A fourth env subtype, subtype E, was also identified by HMA. Subtypes were found to segregate according to mode of transmission, with subtype B viruses found in 96% (25 out of 26) of the male homosexual group and subtype C viruses found in 81% (26 out of 32) of the heterosexual/vertical transmission group. Subtype B viruses were also found in four heterosexual patients, one patient infected by blood transfusion and in two patients with unknown mode of transmission. Subtype D viruses were found in one male homosexual patient and one heterosexual patient. A subtype E virus was identified in a heterosexual patient. No discrepancy was found in subtype designation in samples analysed in both between the gag and env regions (n = 19). CONCLUSIONS: Subtype B viruses were associated with male homosexual transmission and subtype C viruses with heterosexual transmission, suggesting two independent epidemics. This data may have implications in the selection of appropriate vaccines for different risk groups in the country.

PIP: Investigations of the genetic heterogeneity of human immunodeficiency virus (HIV) -1 are important both to monitor the spread of the virus to new population groups and to the development of vaccines the efficacy of which could be influenced by virus variations. This study analyzed serum samples from 61 HIV-1 infected individuals recruited from clinics in Cape Town, South Africa. The mode of transmission was male homosexual in 26 cases, heterosexual/vertical in 32 cases, blood transfusion in 1 case, and unknown in 2 cases. Proviral HIV-1 DNA was subtyped by heteroduplex mobility assay (HMA) based on the 700 base-pair V3-V5 region of the env gene or by sequence analysis of the p17 region of the gag gene. This process identified 3 subtypes: B, C, and D. A fourth env subtype (E) was also identified by HMA. Subtypes were significantly (p 0.001) associated with the mode of HIV transmission. Subtype B viruses were found in 96% of male homosexual sera and subtype C viruses were identified in 81% of the heterosexual/vertical transmission group. Subtype B viruses were also identified in 4 heterosexuals, 1 person infected through blood transfusion, and the 2 cases where the mode of transmission was unknown. Subtype D viruses were found in 1 male homosexual and 1 heterosexual, while a subtype E virus was identified in a heterosexual patient. These findings imply that heterosexual and homosexual HIV-1 epidemics in South Africa were independent. Both epidemiological and molecular data suggest that the initial epidemic in South Africa was, in part, a result of the introduction of HIV-1 by homosexuals who had sexual contacts with men in the US or Europe. The second, heterosexual epidemic was most likely a result of regional spread.