Expression of type I interferon-associated genes at antiretroviral therapy interruption predicts HIV virological rebound.

Although certain individuals with HIV infection can stop antiretroviral therapy (ART) without viral load rebound, the mechanisms under-pinning 'post-treatment control' remain unclear. Using RNA-Seq we explored CD4 T cell gene expression to identify evidence of a mechanism that might underpin virological rebound and lead to discovery of associated biomarkers. Fourteen female participants who received 12 months of ART starting from primary HIV infection were sampled at the time of stopping therapy. Two analysis methods (Differential Gene Expression with Gene Set Enrichment Analysis, and Weighted Gene Co-expression Network Analysis) were employed to interrogate CD4+ T cell gene expression data and study pathways enriched in post-treatment controllers versus early rebounders. Using independent analysis tools, expression of genes associated with type I interferon responses were associated with a delayed time to viral rebound following treatment interruption (TI). Expression of four genes identified by Cox-Lasso (ISG15, XAF1, TRIM25 and USP18) was converted to a Risk Score, which associated with rebound (p < 0.01). These data link transcriptomic signatures associated with innate immunity with control following stopping ART. The results from this small sample need to be confirmed in larger trials, but could help define strategies for new therapies and identify new biomarkers for remission.

Gender disparities operate in opposite directions for hospitalizations and mortality among individuals receiving long-term ART in rural Uganda.

OBJECTIVES: We conducted an analysis to determine if differences in health-seeking behaviour can explain gender disparities in mortality among long-term survivors receiving antiretroviral therapy (ART) in rural Uganda. METHODS: From June 2012 to January 2014, we enrolled patients receiving a first-line ART regimen for at least 4 years without previous viral load (VL) testing in Jinja, Uganda. We measured HIV VL at study entry. We switched participants to second-line therapy, if VL was ≥ 1000 copies/mL on two measurements, and followed participants for 3 years. We collected clinical and behavioural data at enrolment and every 6 months after that. We used Poisson regression to examine factors associated with hospitalizations and Cox proportional hazards modelling to assess mortality to September 2016. RESULTS: We enrolled 616 participants (75.3% female), with a median age of 44 years and a median duration of ART use of 6 years. Of these, 113 (18.3%) had VLs ≥ 1000 copies/mL. Hospitalizations occurred in 101 participants (7% of men vs. 20% of women; P < 0.001). A total of 22 (3.6%) deaths occurred, 9% of men vs. 2% of women (P < 0.001). Multivariate modelling revealed that mortality was associated with age [adjusted hazard ratio (AHR) = 1.07 per year increase; 95% confidence interval (CI): 1.01-1.13], male gender (AHR = 2.57; 95% CI 1.06-6.23) and time-updated CD4 counts (AHR = 0.67 per 100 cell increment; 95% CI: 0.52-0.88). Virological failure was not associated with mortality (P = 0.762). CONCLUSION: Female patients receiving ART in rural Uganda were three times more likely to be hospitalized than men, but male mortality was nearly four times higher. Facilitating care for acute medical problems may help to improve survival among male ART patients.

Combined HIV Adolescent Prevention Study (CHAPS): comparison of HIV pre-exposure prophylaxis regimens for adolescents in sub-Saharan Africa-study protocol for a mixed-methods study including a randomised controlled trial.

BACKGROUND: HIV remains a major public health issue, especially in Eastern and Southern Africa. Pre-exposure prophylaxis is highly effective when adhered to, but its effectiveness is limited by cost, user acceptability and uptake. The cost of a non-inferiority phase III trial is likely to be prohibitive, and thus, it is essential to select the best possible drug, dose and schedule in advance. The aim of this study, the Combined HIV Adolescent PrEP and Prevention Study (CHAPS), is to investigate the drug, dose and schedule of pre-exposure prophylaxis (PrEP) required for the protection against HIV and the acceptability of PrEP amongst young people in sub-Saharan Africa, and hence to inform the choice of intervention for future phase III PrEP studies and to improve strategies for PrEP implementation. METHODS: We propose a mixed-methods study amongst young people aged 13-24 years. The first component consists of qualitative research to identify the barriers and motivators towards the uptake of PrEP amongst young people in South Africa, Uganda and Zimbabwe. The second component is a randomised clinical trial (ClinicalTrials.gov NCT03986970, June 2019) using a novel ex vivo HIV challenge method to investigate the optimal PrEP treatment (FTC-TDF vs FTC-TAF), dose and schedule. We will recruit 144 amongst HIV-negative uncircumcised men aged 13-24 years from voluntary male medical circumcision clinics in two sites (South Africa and Uganda) and randomise them into one of nine arms. One group will receive no PrEP prior to surgery; the other arms will receive either FTC-TDF or FTC-TAF, over 1 or 2 days, and with the final dose given either 6 or 20 h prior to surgery. We will conduct an ex vivo HIV challenge on their resected foreskin tissue. DISCUSSION: This study will provide both qualitative and quantitative results to help decide the optimum drug, dose and schedule for a future phase III trial of PrEP. The study will also provide crucial information on successful strategies for providing PrEP to young people in sub-Saharan Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT03986970 . Registered on 14 June 2019.

Lack of effectiveness of adherence counselling in reversing virological failure among patients on long-term antiretroviral therapy in rural Uganda.

OBJECTIVES: The current World Health Organization and Uganda Ministry of Health HIV treatment guidelines recommend that asymptomatic patients who have a viral load (VL) ≥ 1000 HIV-1 RNA copies/mL should receive adherence counselling and repeat VL testing before switching to second-line therapy. We evaluated the effectiveness of this strategy in a large HIV treatment programme of The AIDS Support Organisation Jinja in Jinja, Uganda. METHODS: We measured the HIV VL at enrolment, and for participants with VL ≥ 1000 copies/mL we informed them of their result, offered enhanced adherence counselling and repeated the VL measurement after 3 months. All blood samples with VL ≥ 1000 copies/mL were sequenced in the polymerase (pol) region, a 1257-bp fragment spanning the protease and reverse transcriptase genes. RESULTS: One thousand and ninety-one participants were enrolled in the study; 74.7% were female and the median age was 44 years [interquartile range (IQR) 39-50 years]. The median time on antiretroviral therapy (ART) at enrolment was 6.75 years (IQR 5.3-7.6 years) and the median CD4 cell count was 494 cells/µL (IQR 351-691 cells/µL). A total of 113 participants (10.4%) had VLs ≥ 1000 copies/mL and were informed of the VL result and its implications and given adherence counselling. Of these 113 participants, 102 completed 3 months of follow-up and 93 (91%) still had VLs ≥ 1000 copies/mL. We successfully genotyped HIV for 105 patients (93%) and found that 103 (98%) had at least one mutation: eight (7.6%) had only one mutation, 94 (89.5%) had two mutations and one sample (1%) had three mutations. CONCLUSIONS: In this study, enhanced adherence counselling was not effective in reversing virologically defined treatment failure for patients on long-term ART who had not previously had a VL test.

HIV-1 drug resistance testing at second-line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third-line.

OBJECTIVES: The number of patients on second-line antiretroviral therapy is growing, but data on HIV drug resistance patterns at failure in resource-constrained settings are scarce. We aimed to describe drug resistance and investigate the factors associated with extensive resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), in patients failing second-line therapy in the HIV outpatient clinic at Arua Regional Referral Hospital, Uganda. METHODS: We included patients who failed on second-line therapy (two consecutive viral loads ≥1000 copies/mm3 by SAMBA-1 point-of-care test) and who had a drug resistance test performed between September 2014 and March 2017. Logistic regression was used to investigate factors associated with NRTI genotypic sensitivity score (GSS) ≤1. RESULTS: Seventy-eight patients were included: 42% female, median age 31 years and median time of 29 months on second-line therapy. Among 70 cases with drug resistance test results, predominant subtypes were A (47%) and D (40%); 18.5% had ≥1 major protease inhibitor mutation; 82.8% had ≥1 NRTI mutation and 38.5% had extensive NRTI resistance (NRTI GSS ≤1). A nadir CD4 count ≤100/ml was associated with NRTI GSS ≤1 (OR 4.2, 95% CI [1.3-15.1]). Thirty (42.8%) patients were switched to third-line therapy, composed of integrase inhibitor and protease inhibitor (60% darunavir/r) +/- NRTI. A follow-up viral load was available for 19 third-line patients at 12 months: 84.2% were undetectable. CONCLUSIONS: Our study highlights the need for access to drug resistance tests to avoid unnecessary switches to third-line therapy, but also for access to third-line drugs, in particular integrase inhibitors. Low nadir CD4 count might be an indicator of third-line drug requirement for patients failing second-line therapy.

Deriving an optimal threshold of waist circumference for detecting cardiometabolic risk in sub-Saharan Africa.

BACKGROUND: Waist circumference (WC) thresholds derived from western populations continue to be used in sub-Saharan Africa (SSA) despite increasing evidence of ethnic variation in the association between adiposity and cardiometabolic disease and availability of data from African populations. We aimed to derive a SSA-specific optimal WC cut-point for identifying individuals at increased cardiometabolic risk. METHODS: We used individual level cross-sectional data on 24 181 participants aged ⩾15 years from 17 studies conducted between 1990 and 2014 in eight countries in SSA. Receiver operating characteristic curves were used to derive optimal WC cut-points for detecting the presence of at least two components of metabolic syndrome (MS), excluding WC. RESULTS: The optimal WC cut-point was 81.2 cm (95% CI 78.5-83.8 cm) and 81.0 cm (95% CI 79.2-82.8 cm) for men and women, respectively, with comparable accuracy in men and women. Sensitivity was higher in women (64%, 95% CI 63-65) than in men (53%, 95% CI 51-55), and increased with the prevalence of obesity. Having WC above the derived cut-point was associated with a twofold probability of having at least two components of MS (age-adjusted odds ratio 2.6, 95% CI 2.4-2.9, for men and 2.2, 95% CI 2.0-2.3, for women). CONCLUSION: The optimal WC cut-point for identifying men at increased cardiometabolic risk is lower (⩾81.2 cm) than current guidelines (⩾94.0 cm) recommend, and similar to that in women in SSA. Prospective studies are needed to confirm these cut-points based on cardiometabolic outcomes.International Journal of Obesity advance online publication, 31 October 2017; doi:10.1038/ijo.2017.240.

Heterogeneity of HIV incidence: a comparative analysis between fishing communities and in a neighbouring rural general population, Uganda, and implications for HIV control.

OBJECTIVES: To describe HIV heterogeneity in rural Uganda using incidence data collected between January 2012 and December 2014 among fishing cohort (FC) and in an adjacent rural general population cohort (GPC). METHODS: In the FC, eligible HIV high-risk adults aged 18+ years were enrolled, followed and HIV tested every 3 months. Demographic and sexual behaviour data were also collected. The GPC, approximately 47 km away from the FC, was followed through annual surveys, and sociodemographic and behavioural data collected. A subset of GPC with comparable risk profiles to the FC was selected. We presented sociodemographic and risk profiles and also computed stratified HIV incidence. Cox regression was used to assess factors associated with HIV incidence. RESULTS: Overall HIV incidence was higher in the FC than in the 'high-risk' GPC, 6.04 and 0.56 per 100 person years at risk, respectively, with a rate ratio (RR) of 10.83 (95% CI 6.11 to 19.76). This was higher among those aged 18-24 years, unmarried and those with more than two sex partners in the past year, RR of 15.44, 22.99 and 19.29, respectively. In the FC, factors associated with high incidence in multivariate analysis were duration in the community and unprotected sex. The factors in the GPC were ethnicity, marital status and duration in the community. CONCLUSIONS: We have observed a substantial heterogeneity in HIV incidence. The high incidence in fishing communities is contributing greatly to the overall HIV burden in Uganda, and thus urgent combination prevention efforts are needed towards national goal to reduce HIV epidemic.

The need for an integrated approach for chronic disease research and care in Africa.

With the changing distribution of infectious diseases, and an increase in the burden of non-communicable diseases, low- and middle-income countries, including those in Africa, will need to expand their health care capacities to effectively respond to these epidemiological transitions. The interrelated risk factors for chronic infectious and non-communicable diseases and the need for long-term disease management, argue for combined strategies to understand their underlying causes and to design strategies for effective prevention and long-term care. Through multidisciplinary research and implementation partnerships, we advocate an integrated approach for research and healthcare for chronic diseases in Africa.

H3Africa multi-centre study of the prevalence and environmental and genetic determinants of type 2 diabetes in sub-Saharan Africa: study protocol.

The burden and aetiology of type 2 diabetes (T2D) and its microvascular complications may be influenced by varying behavioural and lifestyle environments as well as by genetic susceptibility. These aspects of the epidemiology of T2D have not been reliably clarified in sub-Saharan Africa (SSA), highlighting the need for context-specific epidemiological studies with the statistical resolution to inform potential preventative and therapeutic strategies. Therefore, as part of the Human Heredity and Health in Africa (H3Africa) initiative, we designed a multi-site study comprising case collections and population-based surveys at 11 sites in eight countries across SSA. The goal is to recruit up to 6000 T2D participants and 6000 control participants. We will collect questionnaire data, biophysical measurements and biological samples for chronic disease traits, risk factors and genetic data on all study participants. Through integrating epidemiological and genomic techniques, the study provides a framework for assessing the burden, spectrum and environmental and genetic risk factors for T2D and its complications across SSA. With established mechanisms for fieldwork, data and sample collection and management, data-sharing and consent for re-approaching participants, the study will be a resource for future research studies, including longitudinal studies, prospective case ascertainment of incident disease and interventional studies.

The Medical Research Council (UK)/Uganda Virus Research Institute Uganda Research Unit on AIDS--'25 years of research through partnerships'.

For the past 25 years, the Medical Research Council/Uganda Virus Research Institute Uganda Research Unit on AIDS has conducted research on HIV-1, coinfections and, more recently, on non-communicable diseases. Working with various partners, the research findings of the Unit have contributed to the understanding and control of the HIV epidemic both in Uganda and globally, and informed the future development of biomedical HIV interventions, health policy and practice. In this report, as we celebrate our silver jubilee, we describe some of these achievements and the Unit's multidisciplinary approach to research. We also discuss the future direction of the Unit; an exemplar of a partnership that has been largely funded from the north but led in the south.

Group M consensus Gag and Nef peptides are as efficient at detecting clade A1 and D cross-subtype T-cell functions as subtype-specific consensus peptides.

OBJECTIVE: Evaluating HIV-1 specific T-cell response in African populations is sometimes compromised by extensive virus diversity and paucity of non-clade B reagents. We evaluated whether consensus group M (ConM) peptides could serve as comparable substitutes for detecting immune responses in clade A and clade D HIV-1 infection. METHODS: Frequencies, breadths and polyfunctionality (≥ 3 functions: IFN-γ, IL-2, TNF-α and Perforin) of HIV-specific responses utilizing ConM, ConA and ConD Gag and Nef peptides was compared. RESULTS: Median genetic distances of infecting gag sequences from consensus group M were (8.9%, IQR 8.2-9.7 and 9%, IQR 3.3-10) for consensus A and D, respectively. Of 24 subjects infected with A and D clade virus, Gag responses were detected in comparable proportions of subjects when using ConM peptides 22/24, ConA peptides 17/24, and ConD peptides 21/24; p=0.12. Nef responses were also detected at similar proportions of subjects when using ConM peptides 15/23, ConA peptides 19/23, and ConD peptides 16/23, p=0.39. Virus-specific CD4+ and CD8+ T-cell polyfunctionality were also detected in similar proportions of infected individuals when using different peptide sets. CONCLUSIONS: These data support the use of consensus group M overlapping peptide sets as reagents for detecting HIV-specific responses in a clade A and D infected population, but underscore the limitations of utilizing these reagents when evaluating the breadth of virus-specific responses.

Field study of dried blood spot specimens for HIV-1 drug resistance genotyping.

Dried blood spots (DBS) are an alternative specimen type for HIV drug resistance genotyping in resource-limited settings. Data relating to the impact of DBS storage and shipment conditions on genotyping efficiency under field conditions are limited. We compared the genotyping efficiencies and resistance profiles of DBS stored and shipped at different temperatures to those of plasma specimens collected in parallel from patients receiving antiretroviral therapy in Uganda. Plasma and four DBS cards from anti-coagulated venous blood and a fifth card from finger-prick blood were prepared from 103 HIV patients with a median viral load (VL) of 57,062 copies/ml (range, 1,081 to 2,964,191). DBS were stored at ambient temperature for 2 or 4 weeks or frozen at -80 °C and shipped from Uganda to the United States at ambient temperature or frozen on dry ice for genotyping using a broadly sensitive in-house method. Plasma (97.1%) and DBS (98.1%) stored and shipped frozen had similar genotyping efficiencies. DBS stored frozen (97.1%) or at ambient temperature for 2 weeks (93.2%) and shipped at ambient temperature also had similar genotyping efficiencies. Genotyping efficiency was reduced for DBS stored at ambient temperature for 4 weeks (89.3%, P = 0.03) or prepared from finger-prick blood and stored at ambient temperature for 2 weeks (77.7%, P < 0.001) compared to DBS prepared from venous blood and handled similarly. Resistance profiles were similar between plasma and DBS specimens. This report delineates the optimal DBS collection, storage, and shipping conditions and opens a new avenue for cost-saving ambient-temperature DBS specimen shipments for HIV drug resistance (HIVDR) surveillances in resource-limited settings.

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.

Personal barriers to antiretroviral therapy adherence: case studies from a rural Uganda prospective clinical cohort.

BACKGROUND: Although good adherence to antiretroviral therapy (ART) is essential for successful treatment outcomes, some patients may have specific personal barriers to ART adherence. OBJECTIVES: To study specific personal barriers to ART adherence. METHODS: Quantitative data on patients' health status, ART adherence, CD4 cell counts and viral loads were collected, and qualitative data on life experiences of five patients with poor ART outcomes and adherence were also collected. RESULTS: Out of 35 patients with poor immunological and virological ART outcomes, 17 (49%) also had poor ART adherence. Patient 1 had no living child and did not disclose her HIV serostatus to her spouse because she wanted to have a child. Patient 2 was an orphan with neither social nor family support. Patient 3 stopped ART when she conceived, returned to the study clinic when pregnant again and was sickly. She was switched to second-line ART with satisfactory outcomes. Patient 4, a 14 year old orphan had missed ART for 2 months when his treatment supporter was away. Patient 5 aged 66 years stopped ART which he blamed for his erectile dysfunction. CONCLUSION: ART adherence counselling should target specific personal barriers to ART adherence like: lack of family support, health and sexual life concerns, desire to have children and family instability.

Residual activity of two HIV antiretroviral regimens prescribed without virological monitoring.

Virological residual activity (VRA) denotes the degree of HIV RNA suppression achieved by antiretroviral therapy in the presence of resistant virus. This concept is particularly important in resource-limited settings, where rapid switching after detection of virological failure may not be feasible. Using data from the NORA trial, we estimated VRA for two regimens-zidovudine-lamivudine-abacavir (ZDV-3TC-ABC) and zidovudine-lamivudine-nevirapine (ZDV-3TC-NVP)-and related this to the phenotypic drug sensitivity of the component drugs in the two regimens. Plasma samples at weeks 0, 48, and 96 were retrospectively assayed for HIV-1 RNA, and genotypic/phenotypic resistance testing was performed if HIV-1 RNA exceeded 1,000 copies/ml. Virological residual activity (VRA) was defined as the difference between log(10)(HIV RNA) at week 48 or 96 and week 0 and related to 50% inhibitory concentration (IC(50)) relative to wild-type virus for ZDV and ABC (fold change [FC]). Twenty-seven samples in the ZDV-3TC-NVP group and 56 in the ZDV-3TC-ABC group contributed to the analysis. Mean VRA was significantly higher in the ZDV-3TC-ABC group than in the ZDV-3TC-NVP at week 48 (1.62 versus 0.90) and week 96 (1.29 versus 0.78). There was a weak and nonsignificant relationship between VRA and ZDV FC, with VRA decreasing by 0.1 log(10) copies/ml per 2-fold increase in ZDV. The association with ABC FC was much stronger, with a marked reduction in VRA occurring at ABC FC values greater than approximately 2. This information should be considered in future treatment guidelines relevant to resource-poor settings.

Adenovirus-based vaccines: comparison of vectors from three species of adenoviridae.

In order to better understand the broad applicability of adenovirus (Ad) as a vector for human vaccine studies, we compared four adenovirus (Ad) vectors from families C (Ad human serotype 5 [HAdV-5; here referred to as AdHu5]), D (HAdV-26; here referred to as AdHu26), and E (simian serotypes SAdV-23 and SAdV-24; here referred to as chimpanzee serotypes 6 and 7 [AdC6 and AdC7, respectively]) of the Adenoviridae. Seroprevalence rates and titers of neutralizing antibodies to the two human-origin Ads were found to be higher than those reported previously, especially in countries of sub-Saharan Africa. Conversely, prevalence rates and titers to AdC6 and AdC7 were markedly lower. Healthy human adults from the United States had readily detectable circulating T cells recognizing Ad viruses, the levels of which in some individuals were unexpectedly high in response to AdHu26. The magnitude of T-cell responses to AdHu5 correlated with those to AdHu26, suggesting T-cell recognition of conserved epitopes. In mice, all of the different Ad vectors induced CD8(+) T-cell responses that were comparable in their magnitudes and cytokine production profiles. Prime-boost regimens comparing different combinations of Ad vectors failed to indicate that the sequential use of Ad vectors from distinct families resulted in higher immune responses than the use of serologically distinct Ad vectors from the same family. Moreover, the transgene product-specific antibody responses induced by the AdHu26 and AdC vectors were markedly lower than those induced by the AdHu5 vector. AdHu26 vectors and, to a lesser extent, AdC vectors induced more potent Ad-neutralizing antibody responses. These results suggest that the potential of AdHu26 as a vaccine vector may suffer from limitations similar to those found for vectors based on other prevalent human Ads.

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.

An African perspective on mucosal immunity and HIV-1.

HIV prevention mandates an understanding of the mechanisms of mucosal immunity with attention to some unique features of the epidemic and mucosal environment in the developing world. An effective vaccine will have to induce mucosal protection against a highly diverse virus, which is equipped with a number of immune evasion strategies. Its development will require assessment of mucosal immune responses, and it will have to protect a mucosal environment where inflammation and altered immune responses are common because of the presence of other mucosal infections, such as sexually transmitted infections and parasites, and where nutritional status may also be compromised. Ideally, not only prevention methods would protect adults but also provide cover against gastrointestinal transmission through maternal milk. Prevention might also be complemented by microbicides and circumcision, two alternative approaches to mucosal protection. It seems unlikely that a single solution will work in all instances and intervention might have to act at multiple levels and be tailored to local circumstances. We review here some of the mucosal events associated with HIV infection that are most relevant in an African setting.

Transmitted antiretroviral drug resistance surveillance among newly HIV type 1-diagnosed women attending an antenatal clinic in Entebbe, Uganda.

To evaluate transmitted HIV-1 drug resistance and study the natural polymorphism in pol of HIV-1 strains of newly diagnosed women attending an antenatal clinic in Uganda we sequenced the protease and reverse transcriptase genes for 46 HIV-1 strains from the threshold surveillance. Of the 46 sequences analyzed, 48.0% were subtype A1 (n 22), 39.0% subtype D (n 18), 2.0% subtype A2 (n 1), 2.0% subtype C (n 1), and 9.0% intersubtype recombinant A1/D (n 4). Overall, many minor mutations were identified in the protease sequences. None of the strains had major associated mutations to any RTI drug or drug class interest after genotyping 37 samples of our cohort. The HIV drug resistance prevalence estimate in Entebbe following the HIVDR-TS methodology is less than 5% as set out by WHO guidelines.