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In Africa, antiretroviral therapy (ART) is delivered with limited laboratory monitoring, often none. In 2003-2004, investigators in the Development of Antiretroviral Therapy in Africa (DART) Trial randomized persons initiating ART in Uganda and Zimbabwe to either laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). CD4 cell counts were measured every 12 weeks in both groups but were only returned to treating clinicians for management in the LCM group. Follow-up continued through 2008. In observational analyses, dynamic marginal structural models on pooled randomized groups were used to estimate survival under different monitoring-frequency and clinical/immunological switching strategies. Assumptions included no direct effect of randomized group on mortality or confounders and no unmeasured confounders which influenced treatment switch and mortality or treatment switch and time-dependent covariates. After 48 weeks of first-line ART, 2,946 individuals contributed 11,351 person-years of follow-up, 625 switches, and 179 deaths. The estimated survival probability after a further 240 weeks for post-48-week switch at the first CD4 cell count less than 100 cells/mm³ or non-Candida World Health Organization stage 4 event (with CD4 count <250) was 0.96 (95% confidence interval (CI): 0.94, 0.97) with 12-weekly CD4 testing, 0.96 (95% CI: 0.95, 0.97) with 24-weekly CD4 testing, 0.95 (95% CI: 0.93, 0.96) with a single CD4 test at 48 weeks (baseline), and 0.92 (95% CI: 0.91, 0.94) with no CD4 testing. Comparing randomized groups by 48-week CD4 count, the mortality risk associated with CDM versus LCM was greater in persons with CD4 counts of <100 (hazard ratio = 2.4, 95% CI: 1.3, 4.3) than in those with CD4 counts of ≥100 (hazard ratio =1.1, 95% CI: 0.8, 1.7; interaction P= 0.04). These findings support a benefit from identifying patients immunologically failing first-line ART at 48 weeks. [ABSTRACT FROM AUTHOR]

In a randomized comparison of nevirapine or abacavir with zidovudine plus lamivudine, routine viral load monitoring was not performed, yet 27% of individuals with viral failure at week 48 experienced resuppression by week 96 without switching. This supports World Health Organization recommendations that suspected viral failure should trigger adherence counseling and repeat measurement before a treatment switch is considered. [ABSTRACT FROM AUTHOR]

In low-income countries, children ≥4 years and adults with low CD4 count have equally high mortality risk in the 3 months after initiation of antiretroviral therapy, similar to that of untreated individuals. Bacterial infections play a major role; targeted interventions could have important benefits.Background. Adult mortality in the first 3 months on antiretroviral therapy (ART) is higher in low-income than in high-income countries, with more similar mortality after 6 months. However, the specific patterns of changing risk and causes of death have rarely been investigated in adults, nor compared with children in low-income countries.Methods. We used flexible parametric hazard models to investigate how mortality risks varied over the first year on ART in human immunodeficiency virus–infected adults (aged 18–73 years) and children (aged 4 months to 15 years) in 2 trials in Zimbabwe and Uganda.Results. One hundred seventy-nine of 3316 (5.4%) adults and 39 of 1199 (3.3%) children died; half of adult/pediatric deaths occurred in the first 3 months. Mortality variation over year 1 was similar; at all CD4 counts/CD4%, mortality risk was greatest between days 30 and 50, declined rapidly to day 180, then declined more slowly. One-year mortality after initiating ART with 0–49, 50–99 or ≥100 CD4 cells/μL was 9.4%, 4.5%, and 2.9%, respectively, in adults, and 10.1%, 4.4%, and 1.3%, respectively, in children aged 4–15 years. Mortality in children aged 4 months to 3 years initiating ART in equivalent CD4% strata was also similar (0%–4%: 9.1%; 5%–9%: 4.5%; ≥10%: 2.8%). Only 10 of 179 (6%) adult deaths and 1 of 39 (3%) child deaths were probably medication-related. The most common cause of death was septicemia/meningitis in adults (20%, median 76 days) and children (36%, median 79 days); pneumonia also commonly caused child deaths (28%, median 41 days).Conclusions. Children ≥4 years and adults with low CD4 values have remarkably similar, and high, mortality risks in the first 3 months after ART initiation in low-income countries, similar to cohorts of untreated individuals. Bacterial infections are a major cause of death in both adults and children; targeted interventions could have important benefits. [ABSTRACT FROM AUTHOR]

Background. We investigated virological response and the emergence of resistance in the Nevirapine or Abacavir (NORA) substudy of the Development of Antiretroviral Treatment in Africa (DART) trial. Methods. Six hundred symptomatic antiretroviral-naive human immunodeficiency virus (HIV)-infected adults (CD4 cell count, <200 cells/mm3) from 2 Ugandan centers were randomized to receive zidovudine-lamivudine plus abacavir or nevirapine. Virology was performed retrospectively on stored plasma samples at selected time points. In patients with HIV RNA levels >1000 copies/mL, the residual activity of therapy was calculated as the reduction in HIV RNA level, compared with baseline. Results. Overall, HIV RNA levels were lower in the nevirapine group than in the abacavir group at 24 and 48 weeks (P<.001), although no differences were observed at weeks 4 and 12. Virological responses were similar in the 2 treatment groups for baseline HIV RNA level <100,000 copies/mL. The mean residual activity at week 48 was higher for abacavir in the presence of the typically observed resistance pattern of thymidine analogue mutations (TAMs) and M184V (1.47 log10 copies/mL) than for nevirapine with M184V and nonnucleoside reverse-transcriptase inhibitor mutations, whether accompanied by TAMs (0.96 log10 copies/mL) or not (1.18 log10 copies/mL). Conclusions. There was more extensive genotypic resistance in both treatment groups than is generally seen in resource-rich settings. However, significant residual activity was observed among patients with virological failure, particularly those receiving zidovudine-lamivudine plus abacavir. [ABSTRACT FROM AUTHOR]

Background. We sought to investigate renal function in previously untreated symptomatic human immunodeficiency virus (HIV)-infected adults with CD4+ cell counts of !200 cells/mm3 who were undergoing antiretroviral therapy (ART) in Africa. Methods. The study was an observational analysis within a randomized trial of ART management strategies that included 3316 participants with baseline serum creatinine levels of ⩽360 mmol/L. Creatinine levels were measured before ART initiation, at weeks 4 and 12 of therapy, and every 12 weeks thereafter. We calculated estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault formula. We analyzed the incidence of severely decreased eGFR (<30 mL/min/1.73 m2) and changes in eGFR to 96 weeks, considering demographic data, type of ART, and baseline biochemical and hematological characteristics as predictors, using random-effects models. Results. Sixty-five percent of the participants were women. Median values at baseline were as follows: age, 37 years; weight, 57 kg; CD4+ cell count, 86 cells/mm3; and eGFR, 89 mL/min/1.73 m2. Of the participants, 1492 (45%) had mild (⩾60 but <90 mL/min/1.73 m2) and 237 (7%) had moderate (⩾30 but ⩾60 mL/min/1.73 m2) impairments in eGFR. First-line ART regimens included zidovudine-lamivudine plus tenofovir disoproxil fumarate (for 74% of patients), nevirapine (16%), and abacavir (9%) (mostly nonrandomized allocation). After ART initiation, the median eGFR was 89-91 mL/min/1.73 m2 for the period from week 4 through week 96. Fifty-two participants (1.6%) developed severe reductions in eGFR by week 96; there was no statistically significant difference between these patients and others with respect to first-line ART regimen received (Pp.94). Lower baseline eGFR or hemoglobin level, lower body mass index, younger age, higher baseline CD4+ cell count, and female sex were associated with greater increases in eGFR over baseline, with small but statistically significant differences between regimens (P < .001 for all). Conclusions. Despite screening, mild-to-moderate baseline renal impairment was relatively common, but these participants had greatest increases in eGFR after starting ART. Severe eGFR impairment was infrequent regardless of ART regimen and was generally related to intercurrent disease. Differences between ART regimens with respect to changes in GFR through 96 weeks were of marginal clinical relevance, but investigating longer-term nephrotoxicity remains important. [ABSTRACT FROM AUTHOR]

We investigated the effect of RANTES polymorphisms on human immunodeficiency virus type 1 (HIV-1) disease progression in an urban population of Uganda. HIV-positive individuals homozygous for the INT1.1C polymorphism, which had been associated previously with low RANTES expression, were less likely to die than were those with other genotypes (hazard ratio, 0.53 [95% confidence interval, 0.33– 0.83]; P = .007). This report of a non-human leukocyte antigen genetic association with HIV-1 and/or acquired immunodeficiency syndrome disease progression in an African population reveals a genetic effect different from that reported elsewhere for African Americans and may impact therapeutic strategies targeting the RANTES pathway in HIV infection. [ABSTRACT FROM AUTHOR]

We investigated the immunogenicity of a 7-valent conjugate pneumococcal vaccine (CPV) in human immuno deficiency virus-infected Ugandan adults and measured the effect of past pneumococcal polysaccharide vaccine (PPV) receipt given as part of a controlled trial. Two doses of CPV, 4 weeks apart, were given to 54 past PPV recipients and 55 past placebo recipients (84% female; median CD4 cell count, 251 cells/μL [range, 1-936 cells/μL]). Postvaccination anticapsular immuno globulin G (IgG) concentrations were directly correlated with CD4 cell count (P< .01 for all serotypes). There were significant increases in anticapsular IgG concentrations for all serotypes after the first dose (P< .01) and for all serotypes except 14 and 9V after the second dose. Past receipt of PPV did not affect vaccine response. [ABSTRACT FROM AUTHOR]

Identifying correlates of immunity or susceptibility to disease promotes understanding of pathogenesis and development of diagnostic tools, treatments, and vaccines. There is evidence that type 1 cytokine responses are associated with protection against tuberculosis, and suppression of type 1, or switching to type 2 responses, with susceptibility, but this has not been studied prospectively. We studied a cohort of 631 HIV-1-infected Ugandan adults. At enrolment we performed whole blood cultures for type 1 (interferon [IFN]-γ, interleukin [IL]-2) and type 2/immunosuppressive (IL-5, IL-10) responses to mycobacterial antigens (purified protein derivative [PPD] and culture filtrate proteins [CFP]). The incidence of tuberculosis was not associated with IFN-γ responses, but was higher among participants with IL-2 responses (adjusted rate ratios [RR]: PPD 3.48; CFP 3.99; P < 0.001). For tuberculin skin test-positive participants, high incidence was also associated with an IL-10 response to PPD (adjusted RR 6.24, P = 0.03); for those with a BCG scar, high incidence was associated with positive IL-5 responses (adjusted RRs: PPD 3.64, P = 0.006; CFP 3.44, P = 0.04). The association with IL-2 production may reflect a response to tuberculous infection or to activating disease; the associations with IL-10 and IL-5 are in keeping with the expected role of immunosuppressive or type 2 cytokines. [Copyright &y& Elsevier]

To investigate transmission of human herpesvirus (HHV)-8, 2546 mother-child pairs were recruited from rural clinics in South Africa and were tested for antibodies against lyric and latent HHV-8 antigens. The prevalence of antibodies in children increased with increasing maternal antibody titer (lyric, χ12 = 26, and P<.001; latent, χ12 = 55, and P<.001). HHV-8 DNA was detectable in 145 of 978 maternal saliva samples (mean virus load, 488,450 copies/mL; range, 1550–660,000 copies/mL) and in 12 of 43 breast-milk samples (mean virus load, 5800 copies/mL; range, 1550–12,540 copies/mL). The prevalence of HHV-8 DNA in maternal saliva was unrelated to latent anti-HHV-8 antibody status but was higher in mothers with the highest titers of lyric antibodies than in other mothers (34% vs. 8%; P < .001). The prevalence of lyric anti-HHV-8 antibodies in children was 13% (70/528) if the mother did not have HHV-8 in saliva and was 29% (8/28) if the mother had a high HHV-8 load (>50,000 copies/mL) in saliva (odds ratio, 2.6; 95% confidence interval, 1.1–6.2). The presence of HHV-8 DNA in maternal saliva was unrelated to latent antibodies in children. Saliva could be a route of transmission of HHV-8 from person to person, although other routes cannot be ruled out. [ABSTRACT FROM AUTHOR]

We have investigated the association between the concentration of anti-polysaccharide pneumococcal capsule-specific (anti-PS) immunoglobulin G and the killing activity, in serum, in invasive pneumococcal disease (IPD) events and response to 23-valent polysaccharide vaccine in human immunodeficiency virus (HIV)-infected Ugandans. Case patients with IPD had lower concentrations of anti-PS IgG before and after vaccination and before the IPD event (P <.01 for 5 [i.e., 4, 9V, 14, 18C, and 19F] of 6 serotypes assessed). After vaccination, case patients were less likely than were control subjects to develop detectable serum killing activity against the 2 serotypes tested-for 19F, this activity was detected in 16% of case patients versus 37% of control subjects (P = .08); for 23F, it was detected in 11% of case patients versus 40% of control subjects (P = .02). Thus, absolute concentration of anti-PS IgG and an attenuated response to polysaccharide are associated with risk of IPD in HIV-infected adults. [ABSTRACT FROM AUTHOR]

It has been suggested that type 1 immune responses protect against tuberculosis (TB), while type 2 responses, such as those induced by helminths, may suppress protective responses and increase susceptibility to TB. Factors associated with progression to active TB were investigated in a cohort of HIV-1-infected Ugandan adults, a group at high risk of TB. High rates of subsequent progression to active TB were associated with eosinophil counts  0.4 × 109/L at enrolment. Eosinophilia at enrolment was associated with male gender, low socio-economic status, high CD4+ T cell counts, and schistosomiasis, but adjusting for these factors did not explain the association of eosinophilia with progression to active TB (adjusted rate ratio = 2.76, P = 0.004). Eosinophilia is most likely to be indicative of a type 2 immune response induced by helminth infection in this Ugandan cohort, but the mechanism of the observed association between eosinophilia and risk of TB remains to be determined. [Copyright &y& Elsevier]

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. [ABSTRACT FROM PUBLISHER]

Presents a study that discusses the trends in bloodstream infections among HIV-infected adults admitted to a hospital in Nairobi, Kenya in the 1990s. Importance of good prognosis of the disease; Complications of HIV virus; Treatment of patients; Significance of standard clinical management.

Prophylaxis for specific HIV-associatcd infections has made a major difference in the industrialized world to patient survival and the quality of life. However, the HIV epidemic is spreading most rapidly in the poor developing world, where prophylaxis is neither currently used nor recommended. Streptococcus pneumoniae. Mycobacterium tuberculosis and non-typhi sahnonellae are the pathogens responsible for much of the morbidity and mortality associated with HIV infection in the tropics. Because these problems often present relatively early in the course of the HIV disease, prophylaxis may be cost-effective and increase the years of productive life.Prevention of pneumococcal disease has not been considered a priority in the developing world. Penicillin chemoprophylaxis may be efficacious; immunization which is recommended for all HIV seropositive adults in the USA, has not been used. The importance of studies to test both efficacy and cost compared to benefit is discussed. The problem of HIV-associated tuberculosis is of major importance and several intervention studies are now in progress. The efficacy of chemoprophylaxis may be limited if the problem is largely acute infection rather than reactivated disease and if shown to be effective compliance will present a major operational difficulty. Systemic salmonellosis is greatly underdiagnosed but may be the leading cause of death. Recurrent infection can be prevented by chemoprophylaxis but this will be costly. The use of novel or currently unlicensed vaccines may eventually prove to be the most effective means of controlling the burden of disease and death caused by salmonellosis. [ABSTRACT FROM PUBLISHER]

In East Africa, Streptococcus pneumoniae is a common and serious, but potentially preventable, human immunodeficiency virus type 1 (HIV-1)-associated pathogen. For 54 HIV-1-infected women, baseline levels of capsule-specific antibody to 2 of 4 pneumococcal serotypes were lower than levels in 15 seronegative women (P < .05). After immunization, specific antibody to all 4 serotypes increased in HIV-1-infected and -uninfected women (P < .05). Convalescent levels for 2 of 4 serotypes were greater in seronegative women, but the levels were not different between HIV- 1-infected women with (n = 21) or without (n = 33) prior invasive pneumococcal disease. The baseline functional activity to kill S. pneumoniae type 14 was lower in HIV-1-infected than -uninfected women but also rose significantly in all groups after immunization. It is concluded that HIV-1 infection in Kenyan women is associated with decreased levels of natural antibody to selected pneumococcal capsular serotypes, but the vaccine is immunogenic in these patients who are at high risk of invasive pneumococcal disease. [ABSTRACT FROM PUBLISHER]

Skin tests with 0.1 mL of intermediate-strength Mycobacterium tuberculosis purified protein derivative (PPD) and 0.1 mL of Mycobacterium avium sensitin were conducted on 484 healthy subjects from diverse geographic sites. Reactions of ⩾5 mm to one antigen that exceeded the reaction to the other by ⩾3 mm were considered M. avium- or PPD-dominant. PPD-dominant reactions were more frequent at sites where routine Bacille Calmette-Guérin immunization is done or where there are high rates of tuberculosis: New Hampshire, 2%; Boston, 7%; Finland, 14%; Trinidad, 26%; and Kenya, 28%. However, rates of M. avium-dominant reactions ranged from 7% to 12% at all sites. Analysis of dominant reactions based on a more stringent 10-mm minimum reaction size showed similar trends. These data suggest that exposure to MAC is similar in developed and developing countries but that broad mycobacterial immunity is greater in developing countries and may contribute to the lower rates of disseminated MAC infections in AIDS in these areas. [ABSTRACT FROM PUBLISHER]