Design of an observational multi-country cohort study to assess immunogenicity of multiple vaccine platforms (InVITE).

In response to the COVID-19 pandemic, COVID-19 vaccines have been developed, and the World Health Oraganization (WHO) has granted emergency use listing to multiple vaccines. Studies of vaccine immunogenicity data from implementing COVID-19 vaccines by national immunization programs in single studies spanning multiple countries and continents are limited but critically needed to answer public health questions on vaccines, such as comparing immune responses to different vaccines and among different populations.

Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children.

Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis in HIV-uninfected, exposed (HUE) children variably reduces clinical malaria burden despite antifolate resistance, but data regarding achieved serum levels and adherence are lacking. Serum samples from 70 HUE children aged 3-12 months from Rakai, Uganda, enrolled in an observational study were assayed for random SMX levels using a colorimetric assay. Adherence with TMP-SMX prophylaxis data (yes/no) was also collected. Of 148 visits with concurrent SMX levels available, 56% had self-reported adherence with TMP-SMX therapy. Among these 82 visits, mean (standard deviation) level was 19.78 (19.22) µg/mL, but 33% had SMX levels below half maximal inhibitory concentrations (IC50) for Plasmodium falciparum with some, but not all, of the reported antifolate resistance mutations reported in Uganda. With TMP-SMX prophylaxis, suboptimal adherence is concerning. Sulfamethoxazole levels below IC50s required to overcome malaria parasites with multiple antifolate resistance mutations may be significant. Further study of TMP-SMX in this context is needed.

Elevated cytomegalovirus IgG antibody levels are associated with HIV-1 disease progression and immune activation.

OBJECTIVE: To assess the association between cytomegalovirus (CMV) IgG antibody levels, HIV disease progression, and immune activation markers. DESIGN: A prospective cohort study was conducted among women enrolled in a trial that was designed to determine the effect of acyclovir on HIV disease progression in Rakai, Uganda. METHODS: The primary endpoints were progression to a CD4 T-cell count less than 250 cells/µl, nontraumatic death, or initiation of antiretroviral therapy (ART). CD4 T-cell counts, HIV viral load, C-reactive protein (CRP), and soluble CD14 levels were assessed biannually for 24 months. CMV IgG antibodies were measured at baseline among all women and annually among a subset of women who initiated ART. RESULTS: There were 300 HIV/CMV-coinfected participants who contributed a total of 426.4 person-years with a median follow-up time of 1.81 years. Compared with the lowest CMV IgG tertile group at baseline, the highest CMV IgG tertile group was associated with an increased risk to reach a primary endpoint independent of acyclovir use, age, CD4 T-cell count, and HIV viral load at baseline [adjusted hazard ratio = 1.59; (95% CI = 1.05-2.39); P = 0.027]. Among pre-ART visits (n = 1200), women in the highest baseline CMV IgG tertile had increasing annual rates of soluble CD14 and CRP levels, which was not observed for the low CMV IgG tertile group. Compared with pre-ART visits, CMV IgG antibody levels were higher post-ART initiation, and concurrent levels remained associated with soluble CD14 and CRP during suppressive ART (n = 88 person-visits). CONCLUSION: The magnitude of the immune response to CMV was associated with HIV disease progression and immune activation in sub-Saharan Africa.

Longitudinal household surveillance for malaria in Rakai, Uganda.

BACKGROUND: HIV and malaria exert co-pathogenic effects. Malaria surveillance data are necessary for public health strategies to reduce the burden of disease in high HIV prevalence settings. METHODS: This was a longitudinal cohort study to assess the burden of malaria in rural Rakai, Uganda. Households were visited monthly for 1 year to identify confirmed clinical malaria (CCM), or parasitaemia with temperature >37.5 °C, and asymptomatic parasitaemia (AP). Interviews of the adult or child's caregiver and clinical and laboratory assessments were conducted. Rapid diagnostic testing for malaria and anaemia was performed if participants were febrile and anti-malarial treatment given per Uganda Ministry of Health 2010 guidelines. Blood was drawn at every household visit to assess for parasitaemia, and blood smears were assessed at the Rakai Health Science Programme laboratory. RESULTS: A total of 1640 participants were enrolled, including 975 children aged 6 months up to 10 years, 393 adult caregivers, and 272 adolescent/adult household members from 393 randomly selected households in two representative communities. 1459 (89 %) participants completed all study visits. CCM was identified in 304 (19 %) participants, with the highest incidence rate for CCM of 0.38 per person-year (ppy) identified in children <5 years, and rates decreased with age; the rates were 0.27, 0.16, and 0.09 ppy for ages 5-<10 years, 10-<18 years, and adults 18+ years, respectively. AP was identified in 943 (57 %) participants; the incidence rate was 1.99 ppy for <5 years, 2.72 ppy for 5-<10 years, 2.55 ppy for 10-<18 years, and 0.86 ppy among adults, with 92 % of cases being attributed to Plasmodium falciparum by smear. 994 (61 %) individuals had at least one positive smear; 342 (21 %) had one positive result, 203 (12 %) had two, 115 (7 %) had three, and 334 (21 %) had >3 positive smears during follow-up. Seasonal rates generally followed the rains and peaked during July, then decreased through November before increasing again. CONCLUSIONS: Plasmodium falciparum infection remains high in rural Uganda. Increased malaria control interventions should be prioritized. Trial registration Clinicaltrials.gov identifier NCT01265407.

Durable Suppression of HIV-1 after Virologic Monitoring-Based Antiretroviral Adherence Counseling in Rakai, Uganda.

OBJECTIVES: HIV viral load is recommended for monitoring antiretroviral treatment and identifying treatment failure. We assessed the durability of viral suppression after viral load-triggered adherence counseling among patients with HIV viremia 6 months after ART initiation. DESIGN: Observational cohort enrolled in an antiretroviral treatment program in rural Uganda. METHODS: Participants who underwent routine viral load determination every 24 weeks and had at least 48 weeks of follow-up were included in this analysis. Patients with viral loads >400 copies/ml at 24 weeks of treatment were given additional adherence counseling, and all patients were followed to assess the duration of viral suppression and development of virologic failure. RESULTS: 1,841 participants initiating antiretroviral therapy were enrolled in the Rakai Health Sciences Program between June 2005 and June 2011 and were followed with viral load monitoring every 24 weeks. 148 (8%) of patients did not achieve viral suppression at 24 weeks and were given additional adherence counseling. 85 (60%) of these patients had undetectable viral loads at 48 weeks, with a median duration of viral suppression of 240 weeks (IQR 193-288 weeks). Failure to achieve an undetectable viral load at 48 weeks was associated with age <30 years and 24 week viral load >2,000 copies/ml in multivariate logistic regression analysis. CONCLUSIONS: The majority of patients with persistent viremia who were provided adherence counseling achieved robust viral suppression for a median 4.6 years. Access to virologic monitoring and adherence counseling is a priority in resource-limited settings.

Decreased monocyte activation with daily acyclovir use in HIV-1/HSV-2 coinfected women.

OBJECTIVES: Several clinical trials have demonstrated that daily treatment of HIV-infected individuals with the antiherpes drug acyclovir slightly decreases HIV-1 viral load and slows disease progression. This study examines if this slowing in clinical progression is a direct cause of the decrease in viral load or an indirect effect of lower immune activation due to lower levels of herpetic reactivation. METHODS: Women who participated in a randomised clinical trial of daily acyclovir use (n=301) were monitored every 6 months for changes in immune activation. Soluble CD14 (sCD14), a marker for monocyte activation, and C-reactive protein (CRP), a marker for general immune activation, were measured by ELISA. RESULTS: Initial levels of sCD14 and CRP were not predictive of HIV disease progression when controlling for initial CD4+ cell count and HIV viral load. sCD14 levels, but not CRP, decreased in the acyclovir treatment arm at a significantly faster rate than the placebo group, which was independent of changes in HIV viral load and CD4+ cell count in a multivariant mixed-effects model (p=0.039). However, the magnitude of this decrease was relatively small with a total estimated decrease of sCD14 of 15% of initial levels. CONCLUSIONS: These data suggest that decreased monocyte activation may play a minor role in the ability of daily acyclovir use to slow HIV disease progression. CLINICAL TRIAL REGISTRATION NUMBER: NCT00405821.

Vaginal Cytomegalovirus Shedding Before and After Initiation of Antiretroviral Therapy in Rakai, Uganda.

Vaginal shedding of cytomegalovirus (CMV) DNA was determined longitudinally among 96 women coinfected with human immunodeficiency virus (HIV), herpes simplex virus 2, and CMV starting antiretroviral therapy (ART) during a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Vaginal CMV was detected in 75 of 96 women (78.0%) and 379 of 1080 individual visits (35.1%). ART status, higher HIV RNA viral load before ART initiation, and younger age were significantly associated with increased frequency of CMV shedding (P < .01). Compared to pre-ART, CMV shedding peaked from month 2 to month 4 after ART initiation, suggesting possible immune reconstitution inflammatory syndrome. Further studies need to determine the clinical significance of asymptomatic CMV shedding.

Hypertension, cardiovascular risk factors and antihypertensive medication utilisation among HIV-infected individuals in Rakai, Uganda.

OBJECTIVES: To assess the prevalence of hypertension, elevated blood pressure and cardiovascular risk factors among HIV-positive individuals in rural Rakai District, Uganda. METHODS: We assessed 426 HIV-positive individuals in Rakai, Uganda from 2007 to 2010. Prevalence of hypertension and elevated blood pressure assessed by clinical measurement was compared to clinician-recorded hypertension in case report forms. Multiple logistic regression and z-tests were used to examine the association of hypertension and elevated blood pressure with age, sex, body mass index (BMI), CD4 cell count and antiretroviral treatment (ART) use. For individuals on antihypertensives, medication utilisation was reviewed. RESULTS: The prevalence of hypertension (two elevated blood pressure readings at different time points) was 8.0% (95% CI: 5.4-10.6%), and that of elevated blood pressure (one elevated blood pressure reading) was 26.3% (95% CI: 22.1-30.5%). Age ≥50 years and higher BMI were positively associated with elevated blood pressure. ART use, time on ART and CD4 cell count were not associated with hypertension. Eighty-three percent of subjects diagnosed with hypertension were on antihypertensive medications, most commonly beta-blockers and calcium channel blockers. CONCLUSIONS: Hypertension is common among HIV-positive individuals in rural Uganda.

Is CD4 monitoring needed among ugandan clients achieving a virologic and immunologic response to treatment?

It is unclear whether ongoing CD4 monitoring is needed following immunologic and virologic response to antiretroviral therapy (ART). We investigated the proportion of clients who achieved a virologic and immunologic response and then had a subsequent CD4 count <200 cells/µL despite continued virologic suppression. Included in this analysis were clients receiving ART through the Rakai Health Sciences Program between June 2004-May 2013 who achieved a CD4 ≥200 cells/µL and VL ≤400 copies/mL and who had three sets of CD4 and VL measurements (defined as a sequence) within a 390 day period. A CD4 decline was defined as any drop in CD4 count to <200 cells/µL during a period of viral suppression. A total of 1553 clients were included, 68% females, mean age of 35.5 years (SD 8.3), median baseline CD4 count 183 cells/µL (IQR 106-224). 43 (2.8%) clients developed CD4 declines, the majority, 32/43 (74%), among individuals whose initial CD4 was <300 cells/µL. Of the 43 clients with CD4 declines, 24 had an additional CD4 measurement and 20/24 (83%) achieved a CD4 ≥200 cell/µL on their next measurement (median 285 cells/µL; IQR 220-365). CD4 declines were significantly greater among those with lower CD4 at sequence initiation [adjusted hazard ratio (AHR) 4.3 (95% CI 2.1, 9.0) CD4 200-249 versus ≥350 cells/µL]. Clients who achieved an immunologic and virologic response to ART were unlikely to experience a subsequent CD4 count decline to <200 cells/µL, and among those experiencing a decline, the majority were transient in nature. Thus, ongoing CD4 monitoring could be omitted.

Multi-Media Educational Tool Increases Knowledge of Clinical Trials in Uganda.

BACKGROUND: Informed consent is premised on the participants' understanding the scope of the research and the associated risks and benefits. The objective was to evaluate the improvement in knowledge in a population unfamiliar with clinical trial concepts about "what it means to be part of a clinical trial" using an innovative educational tool called the 'Speaking Book'. METHODS: This was a randomized controlled trial conducted at a research site in Uganda. 201 participants were randomized to: 1) clinical trials information session control arm, or 2) clinical trials information session followed by instruction in the use of the Speaking Book with a take-home copy (intervention arm). After the session, participants of both groups completed a 22-item multiple-choice test on the rights and responsibilities of participants. Participants returned after one week to complete the same test to assess knowledge retention. The mean pre- and post-test score difference was assessed according to trial arm using an unpaired t-test of proportions. RESULTS: Ninety-one (90%) participants completed both the initial and follow-up tests in the control arm and 100 (100%) in the intervention arm. The average age of participants was 38 years, 53% were female and 67% were employed; 20% had previously been invited to participate in a clinical trial; of these, 19% had participated. The mean difference in proportion of correct responses from test 1 to test 2 was 2.7% (95%CI 0.3%-5.0%) for the control arm and 11.6% (95%CI 9.3%-13.7%) for the intervention arm (t-score= -5.3, p-value<0.0001). CONCLUSION: Participants who had instruction in the use of the Speaking Book had a larger increase in knowledge than those who had no access to this tool. To better engage patients unfamiliar with clinical trial concepts, innovative educational techniques can assist to increase knowledge to make an informed decision about participation in a clinical trial.

Reactivation of herpes simplex virus type 2 after initiation of antiretroviral therapy.

BACKGROUND: The association between initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection and possible herpes simplex virus type 2 (HSV-2) shedding and genital ulcer disease (GUD) has not been evaluated. METHODS: GUD and vaginal HSV-2 shedding were evaluated among women coinfected with HIV and HSV-2 (n = 440 for GUD and n = 96 for HSV-2 shedding) who began ART while enrolled in a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Monthly vaginal swabs were tested for HSV-2 shedding, using a real-time quantitative polymerase chain reaction assay. Prevalence risk ratios (PRRs) of GUD were estimated using log binomial regression. Random effects logistic regression was used to estimate odds ratios (ORs) of HSV-2 shedding. RESULTS: Compared with pre-ART values, GUD prevalence increased significantly within the first 3 months after ART initiation (adjusted PRR, 1.94; 95% confidence interval [CI], 1.04-3.62) and returned to baseline after 6 months of ART (adjusted PRR, 0.80; 95% CI, .35-1.80). Detection of HSV-2 shedding was highest in the first 3 months after ART initiation (adjusted OR, 2.58; 95% CI, 1.48-4.49). HSV-2 shedding was significantly less common among women receiving acyclovir (adjusted OR, 0.13; 95% CI, .04-.41). CONCLUSIONS: The prevalence of HSV-2 shedding and GUD increased significantly after ART initiation, possibly because of immune reconstitution inflammatory syndrome. Acyclovir significantly reduced both GUD and HSV-2 shedding and should be considered to mitigate these effects following ART initiation.

Frequent detection of HPV before and after initiation of antiretroviral therapy among HIV/HSV-2 co-infected women in Uganda.

OBJECTIVES: Most data on HPV and antiretroviral therapy (ART) come from high-resource countries with infrequent sampling for HPV pre- and post-ART initiation. Therefore, we examined the frequency of cervical HPV DNA detection among HIV/HSV-2 co-infected women followed monthly for 6 months both before and after initiation of ART in Rakai, Uganda. METHODS: Linear Array was used to detect 37 HPV genotypes in self-collected cervicovaginal swabs from 96 women who initiated ART. Random-effects log-binomial regression was used to compare the prevalence of HPV detection in the pre- and post-ART periods and determine other potential risk factors, including CD4 counts and HIV viral load. RESULTS: Nearly all women had detectable HPV in the 6 months preceding ART initiation (92%) and the cumulative prevalence remained high following initiation of therapy (90%). We found no effect of ART on monthly HPV DNA detection (prevalence ratio: 1.0; 95% confidence interval: 0.96, 1.08), regardless of immune reconstitution or HIV viral suppression. Older age and higher pre-ART CD4 counts were associated with a significantly lower risk of HPV DNA detection. CONCLUSIONS: ART did not impact HPV detection within 6 months of therapy initiation, highlighting the importance of continued and consistent screening, even after ART-initiation and immune reconstitution.

Virologic versus immunologic monitoring and the rate of accumulated genotypic resistance to first-line antiretroviral drugs in Uganda.

BACKGROUND: Viral load monitoring (VLM) to identify individuals failing antiretroviral therapy (ART) is not widely available in resource-limited settings. We compared the genotypic resistance patterns between clients with VLM versus immunological monitoring (IM). METHODS: Between 2004-2008, 559 ART naïve clients were enrolled in a prospective cohort, initiated on ART, and monitored with viral load (VL) and CD4+ cell counts every 6 months (VLM group). From February 2008 through June 2009, 998 clients on ART for 36-40 months (corresponding to the follow-up time of the VLM group) at the same clinic and monitored with CD4+ cell counts every 6 months were recruited into a cross sectional study (IM group). Samples from VLM clients at 12, 24 and 36 months and IM clients at 36-40 months with VL > 2000 copies/ml underwent genotypic drug resistance testing. RESULTS: Baseline characteristics were similar. Virologic failure (VL > 400 copies/ml) at 12, 24 and 36 months in the VLM group were 12%, 6% and 8% respectively, and in the IM group 10% at 36-40 months. Samples from 39 VLM and 70 IM clients were genotyped. 23/39 (59%) clients in the VLM group (at 12, 24 or 36 months) compared to 63/70 (90%) in the IM group, (P < 0.0001) had at least 1 non-nucleoside reverse transcriptase mutation. 19/39 (49%) of VLM clients had an M184V mutation compared to 61/70 (87%) in the IM group (P < 0.0001). Only 2/39 (5%) of VLM clients developed thymidine analogue mutations compared to 34/70 (49%) of IM clients (P < 0.0001). CONCLUSIONS: Routine VL monitoring reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda.

Antiretroviral drug susceptibility among HIV-infected adults failing antiretroviral therapy in Rakai, Uganda.

We analyzed antiretroviral drug susceptibility in HIV-infected adults failing first- and second-line antiretroviral treatment (ART) in Rakai, Uganda. Samples obtained from participants at baseline (pretreatment) and at the time of failure on first-line ART and second-line ART were analyzed using genotypic and phenotypic assays for antiretroviral drug resistance. Test results were obtained from 73 samples from 38 individuals (31 baseline samples, 36 first-line failure samples, and six second-line failure samples). Four (13%) of the 31 baseline samples had mutations associated with resistance to nucleoside or nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). Among the 36 first-line failure samples, 31 (86%) had NNRTI resistance mutations and 29 (81%) had lamivudine resistance mutations; only eight (22%) had other NRTI resistance mutations. None of the six individuals failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Genotypic resistance to drugs included in first-line ART regimens was detected prior to treatment and among participants failing first-line ART. PI resistance was not detected in individuals failing second-line ART. Surveillance for transmitted and acquired drug resistance remains a priority for scale-up of ART.

Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial.

BACKGROUND: Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV-1 disease progression in Rakai, Uganda. METHODS: We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per µL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer-generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per µL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to-treat analysis used Cox proportional hazards models, adjusting for baseline log(10) viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821. FINDINGS: 440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0·75, 95% CI 0·58-0·99; p=0·040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50,000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0·62, 0·43-0·96; p=0·03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50,000 copies per mL (0·90, 0·54-1·5; p=0·688). No safety issues related to aciclovir treatment were identified. INTERPRETATION: Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50,000 copies per mL or more before initiation of antiretroviral treatment. FUNDING: National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA).

A randomized controlled trial to evaluate the effectiveness of a board game on patients' knowledge uptake of HIV and sexually transmitted diseases at the Infectious Diseases Institute, Kampala, Uganda.

BACKGROUND: As the number of HIV infections continues to rise, the search for effective health education strategies must intensify. A new educational board game was developed to increase HIV peoples' attention and knowledge to HIV and sexually transmitted infections (STIs) information. The object of this study was to assess the effect of this educational board game on the uptake of knowledge. METHODS: A randomized controlled trial where patients attending the Infectious Diseases Clinic, Kampala, Uganda were randomized to either play the board game (intervention arm) or to attend a health talk (standard of care arm). Participants' knowledge was assessed before and after the education sessions through a questionnaire. RESULTS: One hundred eighty HIV-positive participants were enrolled, 90 for each study arm. The pretest scores were similar for each arm. There was a statistically significant increase in uptake of knowledge of HIV and STIs in both study arms. Compared with patients in the standard of care arm, participants randomized to the intervention arm had higher uptake of knowledge (4.7 points, 95% confidence interval: 3.9 to 5.4) than the controls (1.5 points, 95% confidence interval: 0.9 to 2.1) with a difference in knowledge uptake between arms of 3.2 points (P < 0.001). Additionally, both participants and facilitators preferred the board game to the health talk as education method. CONCLUSIONS: The educational game significantly resulted in higher uptake of knowledge of HIV and STIs. Further evaluation of the impact of this educational game on behavioral change in the short and long term is warranted.

Performance of a prototype malaria rapid diagnostic test versus thick film microscopy among HIV-positive subjects in rural Rakai, Uganda.

In this study, we report the performance of a prototype malaria rapid diagnostic test, Malaria F-test (MFT), compared with thick blood films from HIV-positive Ugandans undergoing malaria testing. In total, 21/154 samples (13.6%) were concordantly positive by both thick film and MFT and 129/154 samples (83.8%) were concordantly negative; 1 sample (0.6%) was thick film-positive but MFT-negative and 3 samples (1.9%) were thick film-negative but MFT-positive. The sensitivity of MFT was 95.5% (95% CI 77.2-99.9%) compared with thick film microscopy and the specificity was 97.7% (95% CI 93.5-99.5%). MFT was simple, rapid and effective for detection of Plasmodium falciparum among HIV-positive subjects in a rural, malaria-endemic African setting.

Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda.

OBJECTIVE: Most antiretroviral treatment program in resource-limited settings use immunologic or clinical monitoring to measure response to therapy and to decide when to change to a second-line regimen. Our objective was to evaluate immunologic failure criteria against gold standard virologic monitoring. DESIGN: Observational cohort. METHODS: Participants enrolled in an antiretroviral treatment program in rural Uganda who had at least 6 months of follow-up were included in this analysis. Immunologic monitoring was performed by CD4 cell counts every 3 months during the first year, and every 6 months thereafter. HIV-1 viral loads were performed every 6 months. RESULTS: A total of 1133 participants enrolled in the Rakai Health Sciences Program antiretroviral treatment program between June 2004 and September 2007 were followed for up to 44.4 months (median follow-up 20.2 months; IQR 12.4-29.5 months). WHO immunologic failure criteria were reached by 125 (11.0%) participants. A virologic failure endpoint defined as HIV-1 viral load more than 400 copies/ml on two measurements was reached by 112 participants (9.9%). Only 26 participants (2.3%) experienced both an immunologic and virologic failure endpoint (2 viral load > 400 copies/ml) during follow-up. CONCLUSION: Immunologic failure criteria performed poorly in our setting and would have resulted in a substantial proportion of participants with suppressed HIV-1 viral load being switched unnecessarily. These criteria also lacked sensitivity to identify participants failing virologically. Periodic viral load measurements may be a better marker for treatment failure in our setting.