Christine Watera

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.

Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults

Objective Despite the recognition of Cryptococcus neoformans as a major cause of meningitis in HIV-infected adults in sub-Saharan Africa, little is known about the relative importance of this potentially preventable infection as a cause of mortality and suffering in HIV-infected adults in this region. Design A cohort study of 1372 HIV-1-infected adults, enrolled and followed up between October 1995 and January 1999 at two community clinics in Entebbe, Uganda. Methods Systematic and standardized assessment of illness episodes to describe cryptococcal disease and death rates. Results Cryptococcal disease was diagnosed in 77 individuals (rate 40.4/1000 person-years) and was associated with 17% of all deaths (77 out of 444) in the cohort. Risk of infection was strongly associated with CD4 T cell counts < 200 × 106 cells/l(75 patients) and World Health Organization (WHO) clinical stage 3 and 4 (68 patients). Meningism was present infrequently on presentation (18%). Clinical findings had limited discriminatory diagnostic value. Serum cryptococcal antigen testing was the most sensitive and robust diagnostic test. Cryptococcal antigenaemia preceded symptoms by a median of 22 days (> 100 days in 11% of patients). Survival following diagnosis was poor (median survival 26 days; range 0–138). Conclusions Cryptococcal infection is an important contributor to mortality and suffering in HIV-infected Ugandans. Improvements in access to effective therapy of established disease are necessary. In addition, prevention strategies, in particular chemoprophylaxis, should be evaluated while awaiting the outcome of initiatives to make antiretroviral therapy more widely available.

Effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression in a large cohort of HIV-1-positive persons in Uganda.

The effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression was investigated in 1045 adults in Uganda. At enrollment and every 6 months, a clinical history, examination, and laboratory investigations that included CD4 cell counts were done. HIV-1 envelope subtype was assessed mainly by peptide serology supplemented by heteroduplex mobility assay and DNA sequencing. A multivariate analysis of survival was performed to assess the prognostic value of HIV-1 subtype on death. A marginal general linear model also determined the effect of subtype on CD4 cell count during follow-up. Subtype D was associated with faster progression to death (relative risk, 1.29; 95% confidence interval, 1.07-1.56; P=.009) and with a lower CD4 cell count during follow-up (P=.001), compared with subtype A, after adjusting for CD4 cell count at enrollment. In Africa, envelope subtype D is associated with faster disease progression, compared with subtype A.

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

BackgroundFalciparum 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. ObjectiveTo investigate the effect of HIV-associated immunosuppression on malarial fever rates. DesignAn 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. MethodsCohort 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. ResultsIncidence 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. ConclusionThese 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.

Helminth Infection Is Not Associated with Faster Progression of HIV Disease in Coinfected Adults in Uganda

BACKGROUND We studied a cohort of human immunodeficiency virus (HIV)-infected adults in Uganda who were not receiving antiretroviral therapy, to explore the impact of helminths on HIV progression in areas where antiretrovirals are not available. METHODS A total of 663 patients were screened for helminths, treated presumptively with albendazole and selectively with praziquantel, and monitored for 6 months. Blood samples were analyzed for CD4+ cell count and HIV-1 RNA. RESULTS Schistosoma mansoni, hookworm, Strongyloides stercoralis, and Mansonella perstans were the most prevalent helminths. Helminth infection was not associated with higher viral load, lower CD4+ cell count, or faster decrease in CD4+ cell count preceding antihelminthic therapy. The effect of coinfection on HIV disease progression varied with species. CD4+ cell counts were highest in subjects with hookworm and Mansonella perstans infection. For most helminths, effective treatment was associated with greater decrease in CD4+ cell count than in those in whom infection was still present at follow-up. A highly significant decrease in viral load at 6 months was seen in patients with persistent Mansonella perstans infection at follow-up. Mortality was lower in subjects with hookworm infection at enrollment. CONCLUSION Helminth infection was not associated with more-advanced HIV disease or faster disease progression. Antihelminthic therapy may not be beneficial in slowing HIV progression in coinfected adults.

Treatment of Schistosoma mansoni Infection Increases Helminth-Specific Type 2 Cytokine Responses and HIV-1 Loads in Coinfected Ugandan Adults

BACKGROUND Studies showing that helminths stimulate type 2 cytokine responses and influence responses to unrelated antigens suggest that helminths may accelerate human immunodeficiency virus type 1 (HIV-1) disease progression in coinfected individuals and that antihelminthic therapy may be beneficial. By the same logic, however, the increase in type 2 cytokines occurring immediately after antischistosomal treatment might increase viral replication and be detrimental. METHODS To assess the effect of antischistosomal therapy on immune responses and HIV-1 replication, a cohort of 163 Ugandans coinfected with Schistosoma mansoni and HIV-1 was treated with praziquantel. CD4(+) T lymphocyte counts, eosinophil counts, and plasma HIV-1 RNA concentrations were measured before treatment and 1 month and 5 months after treatment. Schistosoma mansoni- and Mycobacterium tuberculosis-specific cytokine responses and serum interleukin (IL)-10 concentrations were analyzed. RESULTS Transient increases in viral load and sustained decreases in CD4(+) T lymphocyte count were observed, especially in subjects with higher-intensity infections. Despite enhanced posttreatment S. mansoni-specific type 2 responses, no increase in eosinophils or in M. tuberculosis-specific type 2 responses nor any decline in M. tuberculosis-specific interferon (IFN)-gamma responses were seen. A significant decline in circulating IL-10 concentrations was observed. CONCLUSION Although the mechanisms underlying the increase in viral load after treatment with praziquantel are unclear, these results do not support the hypothesis that treating schistosomiasis is beneficial in the management of HIV-1 disease in Africa.

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: A multicentre retrospective cohort study

Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20–1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0·626]). Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase ( RT ) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.

23-Valent pneumococcal polysaccharide vaccine in HIV-infected Ugandan adults: 6-year follow-up of a clinical trial cohort

23-Valent pneumococcal polysaccharide vaccine was previously reported to be ineffective in HIV-infected Ugandan adults. Prolonged follow-up of trial participants confirmed persistent excess of all-cause pneumonia in vaccine recipients [hazard ratio (HR) 1.6; 95% confidence interval (CI) 1.0-2.4], but surprisingly a survival advantage favouring vaccination (HR 0.84; CI 0.7-1.0). An explanation for the improvement in survival in the face of excess morbid events is lacking; a role for vaccine in HIV care in Africa remains unlikely.

Transmitted antiretroviral drug resistance among newly HIV-1 diagnosed young individuals in Kampala.

Objective:To assess the emergence of transmitted HIV-1 drug resistance (TDR) in Kampala, Uganda, 10 years after the scale-up of antiretroviral treatment (ART) and to compare with a previous survey among antenatal clinic attendees in 2007 (reporting 0% TDR). Design:A cross-sectional survey was conducted among newly HIV-1 diagnosed, antiretroviral-naive young adults attending two large voluntary counseling and testing centers within the geographic area of Kampala. Methods:Proxy criteria for recent HIV-1 infection were used as defined by the WHO. Population sequencing of the pol gene was performed on plasma samples with HIV-1 RNA at least 1000 copies/ml. Surveillance drug resistance mutations (SDRMs) were identified according to the 2009 WHO list for surveillance of TDR. HIV-1 subtypes were designated using maximum likelihood phylogenetic reconstruction. Results:Genotypic test results were obtained for 70 of 77 (90.9%) participants. SDRMs were identified in six samples yielding a prevalence of TDR of 8.6% (95% confidence interval 3.2–17.7%). Two had SDRMs to nucleoside reverse-transcriptase inhibitors (D67G and L210W), three had SDRMs to nonnucleoside reverse transcriptase inhibitors (G190A, G190S, and K101E), and one had SDRMs to protease inhibitors (N88D). Frequencies of HIV-1 subtypes were A (36/70, 51.4%), C ( two of 70; 2.9%), D (23/70, 32.9%), and unique recombinant forms (nine of 70, 12.9%). Conclusion:This repeated survey suggests an increase in TDR in Kampala, compared with a previous survey. This finding justifies increased vigilance with respect to surveillance of TDR in areas in Africa where ART programs are rolled-out.

Feasibility and Effectiveness of Cotrimoxazole Prophylaxis for HIV-1-Infected Adults Attending an HIV/AIDS Clinic in Uganda.

Background: Cotrimoxazole is recommended for prevention of opportunistic infections in symptomatic HIV patients in sub-Saharan Africa. Methods: We examined the feasibility and effectiveness of daily cotrimoxazole prophylaxis in a well-established cohort of HIV-infected adults attending clinics in Entebbe, Uganda. We compared mortality and morbidity rates for 12 months before and after the introduction of cotrimoxazole. Results: Between August 2000 and February 2002, 94% of cohort members were enrolled onto cotrimoxazole prophylaxis. Revisits were scheduled every 4 weeks to replenish pills; patients attended 61% of revisits. The main reasons for nonenrollment and defaulting were lack of transport, being away from home, and sickness. Drug-related adverse events, mainly itching and rash, were seen in 4% of participants. Although bacterial resistance rate to cotrimoxazole was high, the adjusted mortality incidence rate ratio was significantly reduced after the introduction of cotrimoxazole (0.76; 95% confidence interval, 0.60-0.96; P = 0.020). Overall febrile events and morbidity rates were unchanged after the introduction of cotrimoxazole, but the incidence of malaria was reduced (incidence rate ratio, 0.31; 95% confidence interval, 0.13-0.72). Conclusions: Cotrimoxazole prophylaxis can be introduced into routine HIV clinic activities and is associated with a reduction in overall mortality and malaria morbidity, even in an area with high bacterial resistance. These results reinforce the need for large-scale provision of cotrimoxazole prophylaxis for all HIV-positive patients in developing countries.