Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda.

OBJECTIVES: We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. METHODS: NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm(3)) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC(50) (FC) relative to wild-type virus. RESULTS: HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm. CONCLUSIONS: Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility.

Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort.

BACKGROUND: Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We estimated the effect of prophylaxis after ART initiation in adults. METHODS: Participants in our observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug ART with CD4 counts lower than 200 cells per muL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. We estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. DART was registered, number ISRCTN13968779. FINDINGS: 3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, BMI, and previous WHO stage 3 or 4 events on ART. Present prophylaxis significantly reduced mortality (odds ratio 0.65, 95% CI 0.50-0.85; p=0.001). Mortality risk reduction on ART was substantial to 12 weeks (0.41, 0.27-0.65), sustained from 12-72 weeks (0.56, 0.37-0.86), but not evident subsequently (0.96, 0.63-1.45; heterogeneity p=0.02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0.74, 0.63-0.88; p=0.0005), an effect that was maintained with time, but we observed no effect on new WHO stage 4 events (0.86, 0.69-1.07; p=0.17), CD4 cell count (difference vs non-users, -3 cells per muL [-12 to 6]; p=0.50), or BMI (difference vs non-users, -0.04 kg/m(2) [-0.20 to 0.13); p=0.68]. INTERPRETATION: Our results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination ART in Africa. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

BACKGROUND: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. METHODS: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. FINDINGS: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). INTERPRETATION: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors in Ugandan HIV-infected adults.

We evaluated the pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs) in Ugandan adults. The study design was a three-period crossover study (3 tablets [600 mg of lopinavir/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD]; n = 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD; n = 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (n = 20), nevirapine (n = 18), and no NNRTI (n = 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC(0-12)) was 110.1 (34%) microg x h/liter. For efavirenz, the geometric mean lopinavir AUC(0-12) (%CV) values were 91.8 microg x h/liter (58%), 65.7 microg x h/liter (39%), and 54.0 microg x h/liter (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65; P = 0.002) and 0.82 (90% CI, 0.68 to 0.99; P = 0.09), respectively, and the apparent oral clearance (CL/F) values were reduced by 58% and 1%, respectively. For nevirapine, the geometric mean lopinavir AUC(0-12) (%CV) values were 112.9 microg x h/liter (30%), 68.1 microg x h/liter (53%), and 61.5 microg x h/liter (52%), respectively, with corresponding GMR values of 1.66 (90% CI, 1.46 to 1.88; P < 0.001) and 0.90 (90% CI, 0.77 to 1.06; P = 0.27), respectively, and the CL/F was reduced by 57% and 7%, respectively. Higher values for the lopinavir concentration at 12 h (C(12)) were observed with 3 tablets and efavirenz-nevirapine (P = 0.04 and P = 0.0005, respectively), and marginally lower C(12) values were observed with 2 tablets and efavirenz-nevirapine (P = 0.08 and P = 0.26, respectively). These data suggest that 2 tablets of lopinavir-ritonavir BD may be inadequate when dosed with NNRTIs in Ugandan adults, and the dosage should be increased by the addition of an additional adult tablet or a half-dose tablet (100/25 mg), where available.

Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48-week randomized comparison with abacavir/zidovudine/lamivudine in HIV-infected Ugandan adults with low CD4 cell counts.

BACKGROUND: Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa. METHODS: A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/microL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat. RESULTS: The median pre-ART CD4 count was 99 cells/microL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/microL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24-1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34-1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46-0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001). CONCLUSIONS: The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.

Management of HIV-infected patients with MDR- and XDR-TB in resource-limited settings.

The emergence of extensively drug-resistant tuberculosis (XDR-TB) poses a significant public health threat for human immunodeficiency virus (HIV) programmes and tuberculosis (TB) control efforts. Recent reports demonstrate high mortality rates among HIV-infected multidrug-resistant (MDR) and XDR-TB patients compared to those without HIV infection. Transmission of these highly resistant TB strains is occurring both within health facilities and in the community. We review the principles of a sound public health approach to this problem, including early diagnosis, treatment for suspected disease, patient support and adherence and sound infection control measures. In the context of drug-resistant TB, we elaborate on current World Health Organization antiretroviral guidelines addressing management issues related to timing of antiretroviral treatment (ART), drug interactions and drug toxicities among patients receiving both ART and second-line TB regimens. We highlight the important research agenda that exists at the intersection of MDR- and XDR-TB and HIV disease.

Working with risk: occupational safety issues among healthcare workers in Kenya.

The objective of this study was to explore knowledge of, attitudes towards and practice of post-exposure prophylaxis (PEP) among healthcare workers (HCWs) in the Thika district, Kenya. We used site and population-based surveys, qualitative interviews and operational research with 650 staff at risk of needlestick injuries (NSIs). Research was conducted over a 5-year period in five phases: (1) a bio-safety assessment; (2) a staff survey: serum drawn for anonymous HIV testing; (3) interventions: biosafety measures, antiretrovirals for PEP and hepatitis B vaccine; (4) a repeat survey to assess uptake and acceptability of interventions; in-depth group and individual interviews were conducted; and (5) health system monitoring outside a research setting. The main outcome measures were bio-safety standards in clinical areas, knowledge, attitudes and practice as regards to PEP, HIV-sero-prevalence in healthcare workers, uptake of interventions, reasons for poor uptake elucidated and sustainability indicators. Results showed that HCWs had the same HIV sero-prevalence as the general population but were at risk from poor bio-safety. The incidence of NSIs was 0.97 per healthcare worker per year. Twenty-one percent had had an HIV test in the last year. After one year there was a significant drop in the number of NSIs (OR: 0.4; CI: 0.3-0.6; p<0.001) and a significant increase in the number of HCWs accessing HIV testing (OR: 1.55; CI: 1.2-2.1; p=0.003). In comparison to uptake of hepatitis B vaccination (88% of those requiring vaccine) the uptake of PEP was low (4% of those who had NSIs). In-depth interviews revealed this was due to HCWs fear of HIV testing and their perception of NSIs as low risk. We concluded that Bio-safety remains the most significant intervention through reducing the number of NSIs. Post-exposure prophylaxis can be made readily available in a Kenyan district. However, where HIV testing remains stigmatised uptake will be limited - particularly in the initial phases of a programme.

Susceptibility of healthcare workers in Kenya to hepatitis B: new strategies for facilitating vaccination uptake.

Hepatitis B virus (HBV) infection is preventable, yet many healthcare workers (HCWs) in resource-poor countries remain at risk. The aims of this study were to evaluate the susceptibility of HCWs in a Kenyan district to HBV infection, and the feasibility of expanding the Extended Programme of Immunization (EPI) for infants to incorporate hepatitis B vaccination of HCWs. HCWs in Thika district, Kenya were invited to complete an interviewer-administered questionnaire about their immunization status and exposure to blood or body fluids. Participants were asked to provide a blood sample to assess natural or vaccine-induced protection against HBV. All non-immune HCWs were offered hepatitis B vaccination. Thirty percent (168/554) of HCWs reported one or more needlestick injuries (NSIs) in the previous year, with an annual incidence of 0.97 NSIs/HCW/year. Only 12.8% (71/554) of HCWs had received vaccination previously and none had been screened for immunity or for hepatitis B surface antigen. In total, 407 staff provided blood samples; 41% were HBV core antibody, 4% expressed hepatitis B surface antibody from previous vaccination, and 55% were unprotected. Two hundred and twenty-two staff were eligible for vaccine delivered through the EPI infrastructure. Self-motivated uptake of a full course of vaccine was 92% in the smaller health centres and 44% in the district hospital. This study demonstrates the importance of hepatitis B vaccination of HCWs in parts of Africa where high exposure rates are combined with low levels of vaccine coverage. High rates of vaccination can be achieved using childhood immunization systems for the distribution of vaccine to HCWs.

Antiretroviral drugs as a public health intervention for pregnant HIV-infected women in rural South Africa: an issue of cost-effectiveness and capacity.

OBJECTIVE: To estimate cost-effectiveness and capacity requirements for providing antiretroviral drugs to pregnant HIV-infected women in rural South Africa. SETTING: Hlabisa health district, where HIV prevalence among pregnant women was 26.0% in 1997. METHODS: Calculation of the number of paediatric HIV infections averted under three scenarios, and their cost. No intervention was compared with scenario A (zidovudine delivered within current infrastructure), scenario B (zidovudine delivered through enhanced infrastructure), and scenario C (short-course zidovudine plus lamivudine delivered through enhanced infrastructure). Cost-effectiveness was defined as cost per infection averted and cost per potential life-year gained. Capacity was determined in terms of staff and infrastructure required to effectively implement the scenarios. RESULTS: With no intervention, 657 paediatric HIV infections were projected for 1997. In scenario A this could be reduced by 15% at a cost of US$ 574 825, in scenario B by 42% at US$ 1520770, and in scenario C by 47% at US$ 764901. In scenario C, drugs accounted for 76% of costs, whereas additional staff accounted for 18%. Cost per infection averted was US$ 2492 and cost per potential life-year gained (discounted at 3%) was US$ 88. Cost of scenario C was equivalent to 14% of the 1997 district health budget. At least 12 extra counsellors and nurses and one laboratory technician, together with substantial logistical and managerial support, would be needed to deliver an effective intervention. CONCLUSION: Although antiretrovirals may be relatively cost-effective in this setting, the budget required is currently unaffordable. Developing the capacity required to deliver the intervention would pose both a major challenge, and an opportunity, to improve health services.

Increasing rates of malarial fever with deteriorating immune status in HIV-1-infected Ugandan adults.

BACKGROUND: Falciparum malaria and HIV-1 infection are two of the most important health problems facing sub-Saharan Africa. No convincing evidence of an association between symptomatic malaria and HIV-1 infection has been found. OBJECTIVE: To investigate the effect of HIV-associated immunosuppression on malarial fever rates. DESIGN: An observational cohort study in HIV-specific, primary healthcare clinics in Entebbe, Uganda, on 1371 HIV-1-infected adults participating in a randomized trial of 23-valent pneumococcal vaccine. METHODS: Cohort members underwent routine 6 monthly surveillance and had open clinic access when sick. Episodes of fever were assessed according to standardized protocols. Rates of malaria are described according to HIV immune status determined by CD4 T cell counts. RESULTS: Incidence rates of Plasmodium falciparum malarial fever showed a marked inverse relationship with CD4 T cell count; 140, 93 and 57 cases per 1000 pyo for CD4 T cell groups < 200, 200--499 and > 500 respectively, P < 0.001. Malarial fever definitions incorporating parasite density criteria (derived from asymptomatic surveillance) to correct for chance findings of fever and P. falciparum parasitaemia, did not affect the association of incidence rates with immunosuppression. CONCLUSION: These data support an interaction between symptomatic P. falciparum and HIV. Emphasis on mosquito avoidance measures should be an important component of education and counselling of HIV/AIDS patients in malaria-endemic areas, and suggests an additional HIV-related public health problem in Africa.

The changing impact of HIV/AIDS on Kenyatta National Hospital, Nairobi from 1988/89 through 1992 to 1997.

OBJECTIVE: Consequences of the growing HIV/AIDS epidemic for health services in sub-Saharan Africa remain poorly defined. Longitudinal data from the same centre are scarce. We aimed to describe the impact of a rapidly rising HIV/AIDS disease burden on an urban hospital over the last decade. DESIGN AND SETTING: Cross-sectional observational study in 1997, compared to similar data from 1988/89 and 1992. The study was carried out in the Kenyatta National Hospital, Nairobi, Kenya. METHOD: Consecutive adult medical patients were enrolled on admission and then followed up until death or discharge. The main outcome measures were clinical stage, HIV status, bacteraemia, length of stay, bed occupancy, final diagnosis and outcome of hospital admission. RESULTS: In 1997, 518 patients, 493 with HIV serology, were enrolled: HIV prevalence was 40.0%, bed occupancy 190%, the mean length of stay 9.5 days (SD 12) and overall mortality 18.5%. The mean number of HIV-positive admissions per day steadily rose from 4.3 [95% confidence interval (CI), 0.6] patients in 1988/89, through 9.6 (95% CI, 1.4) in 1992, to 13.1 (95% CI, 2.8) or 13.9 adjusted for those enrolled without HIV serology in 1997. In contrast the mean number admitted with clinical AIDS, 1.7 in 1988/89 and 3.3 in 1992, fell to 2.6 cases per day in 1997. With HIV-negative admissions increasing by 37% and bed occupancy nearly doubling in 1997, HIV prevalence appeared to be stabilizing (19 then 39 and 40% respectively). Over time fewer HIV-infected patients were bacteraemic (26, 24 and 14%; P < 0.01); had clinical AIDS (39, 34 and 24% respectively; P < 0.01); or died (36, 35 and 22.6%; P < 0.02). HIV-negative mortality, 14% in 1988/89, rose to 23% in 1992 but fell to 15% in 1997. The mean length of hospital stay (9.5-10 days) did not differ according to HIV status nor did it change across the decade. CONCLUSION: The HIV/AIDS disease burden in Kenyatta National Hospital medical wards has risen inexorably over the last decade. Most recently, the number of HIV-uninfected patients has also risen, leading to bed occupancy figures of 190%. Despite overcrowding and irrespective of HIV status, in-patient mortality has fallen. Time trends suggest fewer clinical AIDS patients are presenting for hospital care, implying a rising community burden of chronic HIV/AIDS disease. Although widely predicted, it is not inevitable that medical services in urban African hospitals dealing with large volumes of HIV/AIDS disease, will collapse or become overwhelmed with chronic, end-stage disease and death.

Pneumococcal vaccination in HIV-1-infected adults in Uganda: humoral response and two vaccine failures.

OBJECTIVES: To assess the feasibility of establishing a pneumococcal vaccine trial among HIV-1-infected adults in Uganda and to characterize their responses to 23-valent pneumococcal polysaccharide vaccine. DESIGN: An open-label pilot trial to assess recruitment and compliance of HIV-1-infected adults in Uganda to vaccination and to determine the immunogenicity of the vaccine. SETTING: A community clinic for HIV-1-infected adults in Entebbe, Uganda. METHODS: Levels of capsule-specific IgG to four common vaccine capsular serotypes were measured before vaccination and 1 month after vaccination. Subsequent rates of disease episodes and deaths, and immunologic responses in two vaccine failures, were followed. RESULTS: One month after-vaccination, both HIV-1-infected (n = 77) and seronegative control subjects (n = 10) demonstrated a significant rise in capsule-specific immunoglobulin G (IgG) for three of four serotypes tested, but levels were significantly lower among HIV-1-infected patients. In 149 patient-years of follow-up, two (2.6%) developed pneumococcal pneumonia, one bacteremic with serotype 1 and one non-bacteremic with serotype 13, a non-vaccine serotype; both patients showed inadequate killing of the organism in vitro. In this same follow-up period, 29 (38%) patients died. CONCLUSION: HIV-1-infected adults in Uganda are at high risk of pneumococcal disease and show a significant but suboptimal response to pneumococcal vaccine. Although reliable recruitment and follow-up of vaccinees is feasible, evaluation of vaccine efficacy may be compromised by limited responses to common vaccine serotypes, an unknown incidence of disease with non-vaccine serotypes, and a high rate of mortality unrelated to Streptococcus pneumoniae infection.

Immune response following oral administration of cholera toxin B subunit to HIV-1-infected UK and Kenyan subjects.

OBJECTIVE: To determine the effect of HIV-1 infection on immunoglobulin (Ig) G and IgA antibody response and circulating antibody forming cell response to oral immunization with the B subunit of cholera toxin. DESIGN: Healthy UK volunteers, and HIV-1-positive UK and Kenyan volunteers at different clinical stages of HIV-1 infection received two oral immunizations. CD4+ T cells, serum beta 2-microglobulin and neopterin were measured as surrogate markers of disease stage, and correlated with immunization response. METHODS: Serum antitoxin IgG and IgA measured by enzyme-linked immunosorbent assay and antitoxin IgG, IgA and IgM antibody-forming cells detected by enzyme-linked immunospot assay at different times after two oral immunizations. RESULTS: UK HIV-positive volunteers (mean CD4+ T cell count, 52 x 10(6)/l) responded poorly to primary and booster immunization. HIV-infected Kenyans (752 x 10(6)/l CD4+ T cells) had a significant primary and booster antibody response, whereas those with a mean CD4+ T cell count 186 x 10(6)/l had an insignificant primary, but significant booster response. Two oral immunizations induced antibody responses in HIV-positive Kenyan groups (who may have prior immunity from exposure to environmental bacterial toxins) of similar or greater magnitude to healthy UK volunteers. CONCLUSIONS: Mucosal immunization may recall immune memory and be of benefit in early and moderately advanced clinical HIV disease. The findings have important clinical implications in that mucosally targeted vaccines are potentially useful in this group of patients.

Extrapulmonary and disseminated tuberculosis in HIV-1-seropositive patients presenting to the acute medical services in Nairobi.

We studied 506 consecutive adult acute medical admissions to hospital in Nairobi; 95 (18.8%) were seropositive for HIV-1, and 43 new cases of active tuberculosis (TB) were identified. TB was clearly associated with HIV infection, occurring in 17.9% of seropositive patients compared with 6.3% of seronegatives [odds ratio (OR) 3.2; 95% confidence limits (CL) 1.6-6.5]. Extrapulmonary disease was more common in seropositive than seronegative TB patients (nine out of 17 versus five out of 26; OR 4.7; 95% CL 1.01-23.6); this accounted for most of the excess cases of TB seen in seropositive patients. Mycobacteraemia was demonstrated in two of eight seropositive TB patients but in none of 11 seronegative TB patients. No atypical mycobacteria were isolated. The World Health Organization (WHO) clinical case definition for African AIDS did not discriminate well between seropositive and seronegative TB cases. Five out of seven seropositive women with active tuberculosis had delivered children in the preceding 6 months and were lactating, compared with only one out of eight seronegative tuberculous women. An association between recent childbirth, HIV immunosuppression and the development of TB is suggested.

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.

The international epidemiology of disseminated Mycobacterium avium complex infection in AIDS. International MAC Study Group.

OBJECTIVE: To determine rates of disseminated Mycobacterium avium complex (MAC) infection among AIDS patients in developed and developing countries, and to determine whether different rates reflect differences in exposure or immunity, or both. DESIGN: Prospective cohort study. SETTING: University hospitals and outpatient AIDS programs. METHODS: HIV-infected subjects with CD4 counts < 200 x 10(6)/l were interviewed and had CD4 lymphocyte counts, blood cultures for mycobacteria (baseline and at 6 months), and skin tests with purified protein derivative (PPD) and M. avium sensitin. RESULTS: Among 566 study patients rates of disseminated MAC were 10.5-21.6% in New Hampshire, Boston and Finland compared to 2.4-2.6% in Trinidad and Kenya (P < 0.001). PPD skin test reactions > or = 5 mm were present in 20% of patients from Kenya compared to 1% at other sites (P < 0.001). Among patients from the United States and Finland, multiple logistic regression indicated that occupational exposure to soil and water was associated with a decreased risk of disseminated MAC, whereas the following were associated with an increased risk of disseminated MAC: low CD4 count, swimming in an indoor pool, history of bronchoscopy, regular consumption of raw or partially cooked fish/shellfish and treatment with granulocyte colony-stimulating factor. CONCLUSIONS: Rates of disseminated MAC in AIDS are higher in developed than developing countries and are due to both differences in exposure and differences in immunity. These data provide a rationale for prevention of MAC through both active immunization and reduction in exposure to the organism.

The risks and benefits of childhood bacille Calmette-Guérin immunization among adults with AIDS. International MAC study groups.

OBJECTIVE: To define the risks of disseminated bacille Calmette-Guérin (BCG) or disseminated Mycobacterium tuberculosis in adults with AIDS who were immunized with BCG in childhood. DESIGN: HIV-infected patients with CD4 < 200 x 10(6)/l were enrolled from five study sites (New Hampshire, Boston, Finland, Trinidad and Kenya). Prior BCG immunization was determined and blood cultures for mycobacteria were obtained at study entry and at 6 months. Acid-fast bacilli were identified as Mycobacterium tuberculosis complex (MTBC) using DNA probes. MTBC isolates were then typed by both IS6110 restriction fragment length polymorphism and polymerase chain reaction/restriction enzyme analysis. SETTING: Most patients in New Hampshire and Finland were outpatients; most patients in Trinidad were inpatients with terminal illness; and most patients in Kenya were outpatients, although 44 were inpatients with terminal illness. PARTICIPANTS: A total of 566 patients were enrolled, including 155 with childhood BCG immunization; 318 patients had a single study visit and culture, and 248 patients had two study visits and cultures. MAIN OUTCOME MEASURES: Isolation and identification of mycobacteria from blood cultures. RESULTS: Blood cultures were positive for MTBC in 21 patients; none were positive for M. bovis BCG, and 21 were M. tuberculosis-positive. In Trinidad, seven (87%) out of eight isolates of M. tuberculosis were indistinguishable by IS6110 typing; BCG immunization was associated with a decreased risk of bacteremic infection with M. tuberculosis (P = 0.05). CONCLUSIONS: The risk of disseminated BCG among adult AIDS patients with childhood BCG immunization is very low. Childhood BCG immunization is associated with protection against bacteremia with M. tuberculosis among adults with advanced AIDS in Trinidad.

Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial.

OBJECTIVES: To determine the efficacy of isoniazid 300 mg daily for 6 months in the prevention of tuberculosis in HIV-1-infected adults and to determine whether tuberculosis preventive therapy prolongs survival in HIV-1-infected adults. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial in Nairobi, Kenya. SUBJECTS: Six hundred and eighty-four HIV-1-infected adults. MAIN OUTCOME MEASURES: Development of tuberculosis and death. RESULTS: Three hundred and forty-two subjects received isoniazid and 342 received placebo. The median CD4 lymphocyte counts at enrolment were 322 and 346 x 10(6)/l in the isoniazid and placebo groups, respectively. The overall median follow-up from enrolment was 1.83 years (range, 0-3.4 years). The incidence of tuberculosis in the isoniazid group was 4.29 per 100 person-years (PY) of observation [95% confidence interval (CI) 2.78-6.33] and 3.86 per 100 PY of observation (95% CI, 2.45-5.79) in the placebo group, giving an adjusted rate ratio for isoniazid versus placebo of 0.92 (95% CI, 0.49-1.71). The adjusted rate ratio for tuberculosis for isoniazid versus placebo for tuberculin skin test (TST)-positive subjects was 0.60 (95% CI, 0.23-1.60) and for the TST-negative subjects, 1.23 (95% CI, 0.55-2.76). The overall adjusted mortality rate ratio for isoniazid versus placebo was 1.18 (95% CI, 0.79-1.75). Stratifying by TST reactivity gave an adjusted mortality rate ratio in those who were TST-positive of 0.33 (95% CI, 0.09-1.23) and for TST-negative subjects, 1.39 (95% CI, 0.90-2.12). CONCLUSIONS: Overall there was no statistically significant protective effect of daily isoniazid for 6 months in the prevention of tuberculosis. In the TST-positive subjects, where reactivation is likely to be the more important pathogenetic mechanism, there was some protection and some reduction in mortality, although this was not statistically significant. The small number of individuals in this subgroup made the power to detect a statistically significant difference in this subgroup low. Other influences that may have diluted the efficacy of isoniazid include a high rate of transmission of new infection and rapid progression to disease or insufficient duration of isoniazid in subjects with relatively advanced immunosuppression. The rate of drug resistance observed in subjects who received isoniazid and subsequently developed tuberculosis was low.

Pulmonary disease in HIV-infected African children.

Childhood human immunodeficiency virus (HIV) infection is common in most regions of sub-Saharan Africa. Acute and chronic respiratory diseases are major causes of morbidity and mortality in HIV-infected children. They represent a significant added burden in a region where diagnostic capabilities are limited and management decisions are often made on the basis of clinical guidelines alone. Pneumocystis carinii pneumonia is now recognised as an important cause of acute severe pneumonia and death in HIV-infected infants. However, there are few data on incidence and aetiology for more treatable conditions such as bacterial pneumonia. The association of pulmonary tuberculosis and HIV infection is uncertain, and the diagnosis is further confused by the presence of lymphoid interstitial pneumonitis and other chronic HIV-related pulmonary disease. This article reviews the literature and highlights the urgent need for further research in order to improve clinical management and appropriate interventions.

Trial-of-antibiotic algorithm for the diagnosis of tuberculosis in a district hospital in a developing country with high HIV prevalence.

OBJECTIVE: To evaluate a diagnostic algorithm for pulmonary tuberculosis based on smear microscopy and objective response to trial of antibiotics. SETTING: Adult medical wards, Hlabisa Hospital, South Africa, 1996-1997. METHODS: Adults with chronic chest symptoms and abnormal chest X-ray had sputum examined for Ziehl-Neelsen stained acid-fast bacilli by light microscopy. Those with negative smears were treated with amoxycillin for 5 days and assessed. Those who had not improved were treated with erythromycin for 5 days and reassessed. Response was compared with mycobacterial culture. RESULTS: Of 280 suspects who completed the diagnostic pathway, 160 (57%) had a positive smear, 46 (17%) responded to amoxycillin, 34 (12%) responded to erythromycin and 40 (14%) were treated as smear-negative tuberculosis. The sensitivity (89%) and specificity (84%) of the full algorithm for culture-positive tuberculosis were high. However, 11 patients (positive predictive value [PPV] 95%) were incorrectly diagnosed with tuberculosis, and 24 cases of tuberculosis (negative predictive value [NPV] 70%) were not identified. NPV improved to 75% when anaemia was included as a predictor. Algorithm performance was independent of human immunodeficiency virus status. CONCLUSION: Sputum smear microscopy plus trial of antibiotic algorithm among a selected group of tuberculosis suspects may increase diagnostic accuracy in district hospitals in developing countries.