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.

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.

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.

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.

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.

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.

The operation, quality and costs of a district hospital laboratory service in Malawi.

Laboratory services are run down in many low-income countries, severely constraining their input to patient care and disease surveillance. There are few data about the quality and cost of individual components of the laboratory service in poorer countries, yet this information is essential if optimal use is to be made of scarce resources. Staff time, range of tests, workload, and safety procedures were monitored over 12 months (1997-98) in a typical district hospital laboratory in Malawi. Data were collected to calculate the total economic cost of these services. Of the 31203 tests performed, 84% were to support blood transfusion and diagnosis of malaria and tuberculosis (TB). Test quality was reasonable for malaria and TB microscopy and blood transfusion, but poor for haemoglobin estimation. The cost per test ranged from US dollars 0.35 for haemoglobin to US dollars 11.7 per unit of blood issued and the total annual cost of the laboratory service was US dollars 32618. Blood transfusion and microscopy for malaria and TB comprised the majority of tests. Ensuring that these tests are of the highest quality will therefore have the most impact in reducing wastage of laboratory resources. Inadequate quality of haemoglobin estimations is a particular problem. The findings of this study are likely to be relevant to other low-income countries with similar disease burdens.

Are intestinal helminths a risk factor for non-typhoidal Salmonella bacteraemia in adults in Africa who are seropositive for HIV? A case-control study.

In Africa, invasive, non-typhoidal Salmonella (NTS) infections are a common but life-threatening complication in adults who are seropositive for HIV. The high prevalence of human infection with intestinal helminths which penetrate the gut could explain the greater importance of NTS bacteraemia in Africa compared with that in industrialized countries. If helminth infection is a major risk factor for NTS it would provide a locally relevant, public-health target. Intestinal helminth carriage in 57 HIV-positive patients with NTS bacteraemia (the cases) was compared with that in 162 HIV-positive controls who were similar to the cases in terms of age, sex, urban dwelling and socio-economic factors. The prevalence of helminth infection, 29% overall, was lower among the cases (18%) than among the controls (33%), giving a crude odds ratio of 0.40 [with a 95% confidence interval (CI) of 0.21-0.9] and an adjusted odds ratio (aOR) of 0.79 (CI = 0.4-1.8). Five (9%) of the cases and 12 (7%) of the controls were infected with nematodes which penetrate the gut (Ascaris lumbricoides and/or Strongyloides stercoralis). The aOR for infection with these penetrating worms, corrected for age, sex, urban dwelling and phase of study, was 1.40 (CI = 0.4-4.5). The present results do not exclude the possibility that helminths play a role in invasive NTS infections, but are not consistent with helminths being a sufficient risk factor in this population to be a public-health target. Anthelmintics are unlikely to have a major impact on preventing NTS bacteraemia in patients diagnosed HIV-positive in Africa.

Quality assessment of sputum transportation, smear preparation and AFB microscopy in a rural district in Malawi.

SETTING: Ntcheu District, Central Region of Malawi. OBJECTIVES: To assess 1) the feasibility of introducing simple internal quality control procedures for acid-fast bacilli (AFB) microscopy, and 2) the quality of the district sputum smear microscopy service. DESIGN: A simple internal quality control system was piloted in which district laboratory staff assessed: 1) specimen suitability, 2) time between sputum submission and smear examination, 3) smear preparation and staining, and 4) microscopy. Actual times for processing specimens were compared with recommended times. External quality validation was carried out. RESULTS: Of 4805 sputum specimens: 1) documentation was complete in 95%, 2) 93% reached the laboratory within 7 days of collection, 3) 96% of smears were well prepared and stained, and 4) 97% concordance (96.4% smear-positive and 97.6% smear-negative) was demonstrated when 208 smears were re-examined by a second technician. The aggregate index of reliability was 86%. The mean time spent on microscopic examination was 3.8 minutes, compared with the recommended time of 10 minutes. When all smears from 164 patients were assessed externally, 98.2% concordance (98.1% smear-positive and 98.2% smear-negative) was demonstrated. False smear-negative and smear-positive rates were less than 2% each. CONCLUSION: District laboratory staff were able to incorporate simple quality control procedures for AFB microscopy into their routine practice, resulting in a reliable service. The lessons learnt are widely relevant and potentially useful for implementation of a national quality assurance scheme.

HIV care in non-industrialised countries.

The HIV/AIDS epidemic is now most rapidly expanding in the non-industrialised world. As more and more poor people fall sick and die prematurely, the issue of care for the HIV-infected person living in a resource-poor country is of paramount importance. Rational and comprehensive care packages need to be based on proper understanding of the natural history of infection and accurate measurement of the HIV/AIDS disease burden. In the early stages of infection, disease progression is the same in non-industrialised nations as it is in industrialised countries. Once virulent diseases start, survival is short largely because of limited access to inadequate health care. Therefore, early HIV-related disease, as well as AIDS, are targets for care. Needs are diverse but can be considered as more of the same (e.g. to cope with additional cases of TB generated by HIV) and those new services such as voluntary counselling and testing and palliative care. Budgets are limited everywhere, but prioritisation can be promoted through drawing up a hierarchy of care needs. Specific HIV/AIDS services and the provision of anti-retroviral therapy come after basic services are implemented. Affordable ways to use disease-modifying drugs need to be pursued that are relevant to non-industrialised countries and which do not promote AIDS exceptionalism.

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.

Trends in bloodstream infections among human immunodeficiency virus-infected adults admitted to a hospital in Nairobi, Kenya, during the last decade.

Bloodstream infections are a frequent complication in human immunodeficiency virus (HIV)-infected adults in Africa and usually associated with a poor prognosis. We evaluated bloodstream infections across a decade in 3 prospective cross-sectional surveys of consecutive medical admissions to the Kenyatta National Hospital, Nairobi, Kenya. Participants received standard clinical care throughout. In 1988-1989, 29.5% (28 of 95) of HIV-positive patients had bloodstream infections, compared with 31.9% (46 of 144) in 1992 and 21.3% (43 of 197) in 1997. Bacteremia and mycobacteremia were significantly associated with HIV infection. Infections with Mycobacterium tuberculosis, non-typhi species of Salmonella (NTS), and Streptococcus pneumoniae predominated. Fungemia exclusively due to Cryptococcus neoformans was uncommon. Clinical features at presentation remained similar. Significant improvements in the survival rate were recorded among patients with NTS bacteremia (20%-83%; P<.01) and mycobacteremia (0%-73%; P<.01). Standard clinical management can improve outcomes in resource-poor settings.

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.

Rhodococcus equi and HIV-1 infection in Uganda.

OBJECTIVES: To describe three cases of Rhodococcus equi infection in a cohort of HIV-1 infected adults in Entebbe, Uganda and to compare this to the rates and presentation of tuberculosis in this cohort. METHODS: Consecutive HIV-1 infected adults registering with a community HIV/AIDS clinic in Entebbe were enrolled in a cohort between October 1995 and June 1998 as part of an intervention trial of pneumococcal polysaccharide vaccine. Participants were routinely reviewed every 6 months and had open access to the clinic when unwell. Standard protocols were followed for investigation and management of illness. Microbiological investigations followed standard procedures. RESULTS: 1372 (71% female) study participants were followed for 2141 person years of observation (pyo). Rhodococcus equi was isolated from three study participants from blood, a lymph node aspirate and stool. The individuals were undergoing investigation of acute pneumonia, acute cough with cervical lymphadenopathy and chronic fever with wasting, respectively. The clinical features of these cases are described. All had a CD4 T-cell count of <300/ml. The rate of R. equi infection in the cohort was 1.4/1000 pyo. There were 132 cases of pulmonary and extrapulmonary tuberculosis in the cohort which were diagnosed either microbiologically or clinically. The rate of laboratory confirmed mycobacterial disease was 50.1/1000 pyo. The ratio of mycobacterial disease to R. equi disease was 36:1 (95% CI 11-113:1). CONCLUSIONS: Rhodococcus equi infection occurs in HIV-1 infected adults in Africa. The infection is clinically indistinguishable from pulmonary and extra-pulmonary tuberculosis in the cohort described here. Although the rate of R. equi disease is much less than that of tuberculosis, it is important to consider it in the differential diagnosis of tuberculous infection in cases which are smear negative. Rhodococcus equi infection is probably underdiagnosed in Africa due to a lack of microbiological facilities and its resemblance to common commensal organisms.

National and provincial estimated costs and cost effectiveness of a programme to reduce mother-to-child HIV transmission in South Africa.

OBJECTIVE: To estimate the cost and cost effectiveness nationally and for each province of a programme to reduce mother-to-child transmission (MTCT) of HIV in South Africa. METHODS: A model developed to estimate cost and cost effectiveness of interventions in Hlabisa, KwaZulu-Natal, was modified and applied to each province. This model predicts a 37% reduction in paediatric HIV infections if short-course oral zidovudine (ZDV) plus infant formula feed for 4 months is provided within a strengthened health system. Estimates of the number of pregnancies and HIV prevalence among pregnant women per province in 1997 were combined with an estimated 30% MTCT rate. Costs were calculated from a health system perspective, and effectiveness was estimated as cost per infection averted and cost per disability-adjusted life year (DALY) gained. RESULTS: In 1997, 63,397 paediatric HIV infections were estimated to have occurred in South Africa, mainly in KwaZulu-Natal (18,513, 29%) and Gauteng (10,417, 16%). The cost of a national programme is estimated at R155.9 million (1997 rand costs, 0.94% of the national health budget). Major cost items are drugs (R46.4 m, 30%), staff salaries (R45.8 m, 29%), and formula feed (R37.1 m, 24%). Most money would need to be spent in KwaZulu-Natal (R37.6 m, 24% of national cost), Gauteng (R25.2 m, 16%) and the Eastern Cape (R24 m, 15%). National cost per infection averted is R6,724, and R213 per DALY gained. Provincial DALY costs range from R176 to R369. CONCLUSIONS: A national programme preventing 37% of expected paediatric HIV infections would cost a small fraction of the national health budget, at a cost equivalent to R3.89 per capita total population. The cost per DALY gained compares well with established public health and clinical interventions in middle-income countries, even without factoring in the care costs that would be saved through a successful programme. Cost effectiveness is greatest where HIV prevalence is highest.

Royal Society of Tropical Medicine and Hygiene meeting at Manson House, London, 18 March 1999. Fresh from the field: some controversies in tropical medicine and hygiene. HIV and malaria, do they interact?

Malaria and human immunodeficiency virus (HIV) infections are common, widespread and overlapping problems in the tropics. Despite this there has been minimal evidence to support an important interaction, other than during pregnancy in multigravid HIV-infected women. The lack of an interaction in other groups is surprising, and would be unexpected based on present knowledge of anti-malarial immunity. However, most of the reported studies have been cross-sectional and performed in selected groups, making their findings difficult to interpret. Two cohort studies in children were similarly inconclusive, although both hinted at a decreased ability to control parasitaemia with more advanced HIV-disease. Recent work from Entebbe carried out in a well-characterized cohort of HIV-infected adults revealed an increase in malarial fever with deteriorating immune status. Rates by CD4+ T-cell count groups > 500, 200-499 and < 200 cells/microL were 45, 73 and 115 cases per 1000 person-years respectively, P < 0.01 for trend. These findings support an important interaction between HIV and malaria. The public health consequences and the relevance of these findings out with Entebbe are uncertain. The importance of understanding this interaction further must be a priority for sub-Saharan Africa: consequently further studies designed primarily to answer these questions will be necessary. Meanwhile, the optimism that the global malaria situation was largely unaffected by the HIV pandemic may need to be reconsidered.

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.

23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial.

BACKGROUND: Infection with Streptococcus pneumoniae is a frequent and serious problem for HIV-immunosuppressed adults. Vaccination is recommended in the USA and Europe, but there are no prospective data that show vaccine efficacy. METHODS: 1392 (937 female) HIV-1-infected adults in Entebbe, Uganda, were enrolled. 697 received 23-valent pneumococcal polysaccharide vaccine and 695 received placebo. The primary endpoint was first event invasive pneumococcal disease. Secondary endpoints included vaccine serogroup-specific invasive disease, all (probable and definite) pneumococcal events, all-cause pneumonia, and death. FINDINGS: First invasive events occurred in 25 individuals (24 bacteraemias, one pyomyositis), 15 in the vaccine arm and ten in the placebo arm (hazard ratio [HR] 1.47; 95% CI 0.7-3.3). 22 isolates (88%) were of vaccine-specific serogroups with 15 events in the vaccine arm compared with seven in the placebo arm (HR 2.10; 0.9-5.2). All pneumococcal events had a similar distribution (20 vs 14; HR 1.41; 0.7-2.8) though all-cause pneumonia was significantly more frequent in the vaccine arm (40 vs 21; HR 1.89; 1.1-3.2). Mortality was unaffected by vaccination. INTERPRETATION: 23-valent pneumococcal polysaccharide vaccination is ineffective in HIV-1-infected Ugandan adults and probably has little, or no, public health value elsewhere in sub-Saharan Africa. Increased rates of pneumococcal disease in vaccine recipients may necessitate a reappraisal of this intervention in other settings.