Status of HIV-infected patients classified as lost to follow up from a large antiretroviral program in southwest Nigeria.

BACKGROUND: Loss to follow-up (LTFU) is a term used to classify patients no longer being seen in a clinical care program, including HIV treatment programs. It is unclear if these patients have transferred their care services elsewhere, died, or if there are other reasons for their LTFU. To better understand the status of patients meeting the criteria of LTFU, we traced a sample of HIV-infected patients that were LTFU from the Lagos University Teaching Hospital (LUTH) antiretroviral program. METHODS: We conducted a cross-sectional study of HIV-infected adult patients who enrolled for care between 2010 and 2014 at LUTH and were considered LTFU. Patients with locator information were traced using phone calls. Face-to-face interviews were used to collect data from successfully traced and consenting participants. Predictors of LTFU from LUTH, disengagement from care and willingness to re-engage in care in LUTH were assessed. RESULTS: Of 6108 registered patients, 3397 (56%) were LTFU and being unmarried was a predictor of being LTFU from LUTH. Of 425 patients that were traced, 355 (84%) were alive and 70 (16%) were dead. Two hundred and sixty-eight patients consented to interviews; 96 (35.8%) of these had transferred to another clinic for care while 172 (64.2%) were disengaged from care. More than half (149/268; 55.6%) were not on antiretroviral therapy (ART). Some of the primary reasons for LTFU were; long distance to clinic (56%) and feeling healthy (6.7%). Predictor of disengagement from care within the interviewed cohort was not having started ART. The predictors of willingness to re-engage in care included, not having started ART, male sex and longer duration in HIV care prior to LTFU. CONCLUSION: Most of the interviewed cohort that was LTFU were truly disengaged from care and not on ART. Interventions are required to address processes of re-engagement of patients that are LTFU.

Predictors of tuberculosis knowledge, attitudes and practices in urban slums in Nigeria: a cross-sectional study.

INTRODUCTION: Nigeria is among six countries responsible for the majority of tuberculosis (TB) cases in the world. The Nigerian government has emphasized community-based case finding to increase detection of TB. This process requires efforts to improve knowledge, attitudes and practices (KAP) of TB, particularly in the poorest of communities. This study presents data from a KAP survey administered in two underserved Nigerian communities. METHODS: a structured survey was administered by trained interviewers among adult residents in two slum communities in Lagos, Nigeria. Participants were selected through multistage random sampling. KAP scores were computed and the predictors of higher scores were assessed. RESULTS: a total of 504 respondents were surveyed. The mean KAP scores were relatively low: 9.8 ± 7.1 for knowledge (out of a maximum 34), 5.3 ± 3.4 for attitude (maximum = 10), and 5.2 ± 1.5 for practice (maximum = 7). The predictors of good knowledge were increasing age, post secondary education and professional occupation. The predictors of positive attitude were post secondary education and good TB knowledge. Good knowledge was a predictor of good practice. CONCLUSION: our findings underscore the need to improve the education about TB in underserved communities. Improving KAP scores will ultimately lead to higher rates of TB detection and treatment.

Tuberculosis Incidence and Risk Factors Among Human Immunodeficiency Virus (HIV)-Infected Adults Receiving Antiretroviral Therapy in a Large HIV Program in Nigeria.

Background. Despite the benefits of antiretroviral therapy (ART), tuberculosis (TB) is the leading cause of mortality among human immunodeficiency virus (HIV)-infected persons in Africa. Nigeria bears the highest TB burden in Africa and second highest HIV burden globally. This long-term multicenter study aimed to determine the incidence rate and predictors of TB in adults in the Harvard/AIDS Prevention Initiative in Nigeria (APIN) and President's Emergency Plan for AIDS Relief (PEPFAR) Nigeria ART program. Methods. This retrospective evaluation used data collected from 2004 to 2012 through the Harvard/APIN PEPFAR program. Risk factors for incident TB were determined using multivariate Cox proportional hazards regression with time-dependent covariates. Results. Of 50 320 adults enrolled from 2005 to 2010, 11 092 (22%) had laboratory-confirmed active TB disease at ART initiation, and 2021 (4%) developed active TB after commencing ART. During 78 228 total person-years (PY) of follow-up, the TB incidence rate was 25.8 cases per 1000 PY (95% confidence interval [CI], 24.7-27.0) overall, and it decreased significantly both with duration on ART and calendar year. Risk factors at ART initiation for incident TB included the following: earlier ART enrollment year, tenofovir-containing initial ART regimen, and World Health Organization clinical stage above 1. Time-updated risk factors included the following: low body mass index, low CD4(+) cell count, unsuppressed viral load, anemia, and ART adherence below 80%. Conclusions. The rate of incident TB decreased with longer duration on ART and over the program years. The strongest TB risk factors were time-updated clinical markers, reinforcing the importance of consistent clinical and laboratory monitoring of ART patients in prompt diagnosis and treatment of TB and other coinfections.

Trained community volunteers improve tuberculosis knowledge and attitudes among adults in a periurban community in southwest Nigeria.

Nigeria has the world's 10th largest tuberculosis (TB) burden. Targeted community-based interventions can potentially help reduce TB incidence. We designed an intervention in a periurban community where 10 community volunteers were trained to provide community TB education and also detect and refer TB suspects to a nearby clinic. To determine the effect of the intervention on knowledge, attitude, and preventive practices of TB, we compared results from a pre-intervention survey with those of a post-intervention survey. Pre-intervention, respondents had a mean knowledge score of 10.6 ± 7.0 of a possible 34, a mean attitude score of 5.8 ± 3.3 of a possible 10, and a mean practice score of 5.3 ± 1.4 of a possible 7. The intervention significantly increased the mean knowledge score to 16 ± 5.4 (P < 0.001) and mean attitude score to 7.0 ± 1.8 (P < 0.001); however, there was no statistically significant difference in the mean practice score. Eight TB suspects were referred to the clinic, and one suspect was subsequently diagnosed with TB. The use of trained community volunteers to share information on TB improved the overall knowledge and attitudes of respondents. Continued empowerment of the community should be encouraged to promote TB prevention and care.

Time-Dependent Predictors of Loss to Follow-Up in a Large HIV Treatment Cohort in Nigeria.

BACKGROUND: Most evaluations of loss to follow-up (LTFU) in human immunodeficiency virus (HIV) treatment programs focus on baseline predictors, prior to antiretroviral therapy (ART) initiation. As risk of LTFU is a continuous issue, the aim of this evaluation was to augment existing information with further examination of time-dependent predictors of loss. METHODS: This was a retrospective evaluation of data collected between 2004 and 2012 by the Harvard School of Public Health and the AIDS Prevention Initiative in Nigeria as part of PEPFAR-funded program in Nigeria. We used multivariate modeling methods to examine associations between CD4(+) cell counts, viral load, and early adherence patterns with LTFU, defined as no refills collected for at least 2 months since the last scheduled appointment. RESULTS: Of 51 953 patients initiated on ART between 2004 and 2011, 14 626 (28%) were LTFU by 2012. Factors associated with increased risk for LTFU were young age, having nonincome-generating occupations or no education, being unmarried, World Health Organization (WHO) stage, having a detectable viral load, and lower CD4(+) cell counts. In a subset analysis, adherence patterns during the first 3 months of ART were associated with risk of LTFU by month 12. CONCLUSIONS: In settings with limited resources, early adherence patterns, as well as CD4(+) cell counts and unsuppressed viral load, at any time point in treatment are predictive of loss and serve as effective markers for developing targeted interventions to reduce rates of attrition.

Twenty years of prospective molecular epidemiology in Senegal: changes in HIV diversity.

Over a 20-year period we have observed the dynamics of HIV-1 subtypes and HIV-2 infection in a prospective cohort of registered female sex workers (FSW) in Dakar, Senegal. Prevalence and incidence rates for HIV-1 and HIV-2 are described from 290 seroprevalent and 193 seroincident subjects who were among the 3,910 women enrolled between 1985 and 2004. We report a significant decrease of HIV-2 prevalence in the cohort, parallel to the introduction and rise of HIV-1 infection. In 328 HIV-1-infected women, a 385-bp C2-V3 fragment of the envelope gene was sequenced and classified into the following subtypes or recombinant forms: 239 (72%) were subtype A [of which 180 (55%) were CRF02_AG and 53 (16%) were A3], 10 (3%) were B, 12 (4%) were C, 11 (4%) were D, 18 (6%) were G, 24 (7%) were CRF06_cpx, and 7 (2%) were CRF09_cpx. We found an increasing proportion of CRF02_AG over many years, but recently subsubtype A3 has over-taken CRF02_AG, with the largest proportion of new infections. The predominance of existing HIV-1 subtypes did not preclude the emergence and increase of other closely related subtypes or recombinant forms. This 20-year prospective serological and sequence analysis of HIV viruses reveals a complex and changing HIV epidemic in Senegal.

The complexity of circulating HIV type 1 strains in Oyo state, Nigeria.

Multiple HIV-1 subtypes and circulating recombinant forms (CRFs) are known to circulate in West Africa. We undertook a survey of HIVs in Oyo state, in southwestern Nigeria. We analyzed 71 samples from Ibadan, the capital city, and 33 samples from Saki, 100 miles west of Ibadan. We sequenced part of the gag gene and the envelope C2V3 region from 102 and 89 samples, respectively. In the 87 samples for which both genes were sequenced, subtype G and CRF02_AG were found in equal proportions (32.2% each). Other samples included CRF06_cpx (8.0%), subtype A (2.3%), C (1.1%), unclassified (1.1%), or discordant sequences suggesting the presence of a large number of recombinants involving CRF02_AG and/or subtype G (20.7%) or other subtypes (2.3%). The subtype/CRF designation was concordant in two gene fragments in the majority of samples evaluated. However, we observed differences in subtype distribution between the two locations with a predominance of subtype G in Ibadan and CRF02 in Saki. This is the first in-depth analysis of HIV variability at a state level in Nigeria. Our analysis revealed a significant level of viral heterogeneity and a geographical difference in subtype distribution, and demonstrated that CRF02_AG does not account for the majority of circulating strains.

Direct evidence of lower viral replication rates in vivo in human immunodeficiency virus type 2 (HIV-2) infection than in HIV-1 infection.

Studies have shown that human immunodeficiency virus type 2 (HIV-2) is less pathogenic than HIV-1, with a lower rate of disease progression. Similarly, plasma viral loads are lower in HIV-2 infection, suggesting that HIV-2 replication is restricted in vivo in comparison to that of HIV-1. However, to date, in vivo studies characterizing replication intermediates in the viral life cycle of HIV-2 have been limited. In order to test the hypothesis that HIV-2 has a lower replication rate in vivo than HIV-1 does, we quantified total viral DNA, integrated proviral DNA, cell-associated viral mRNA, and plasma viral loads in peripheral blood samples from groups of therapy-naïve HIV-1-infected (n = 21) and HIV-2-infected (n = 18) individuals from Dakar, Senegal, with CD4(+) T-cell counts of >200/microl. Consistent with our previous findings, total viral DNA loads were similar between HIV-1 and HIV-2 and plasma viral loads were higher among HIV-1-infected individuals. Proportions of DNA in the integrated form were also similar between these viruses. In contrast, levels of viral mRNA were lower in HIV-2 infection. Our study indicates that HIV-2 is able to establish a stable, integrated proviral infection in vivo, but that accumulation of viral mRNA is attenuated in HIV-2 infection relative to that in HIV-1 infection. The differences in viral mRNA are consistent with the differences in plasma viral loads between HIV-1 and HIV-2 and suggest that lower plasma viral loads, and possibly the attenuated pathogenesis of HIV-2, can be explained by lower rates of viral replication in vivo.

Long-term intrapatient viral evolution during HIV-2 infection.

Background. Disease progression and transmission of human immunodeficiency virus (HIV) type 2 are attenuated, compared with HIV-1, which is consistent with the lower plasma viral loads observed in HIV-2 infection. Although numerous studies have characterized the intrapatient evolution of viral sequences during HIV-1 infection, prospective studies examining intrapatient evolution during HIV-2 infection have been limited.Methods. We examined viral sequence evolution in the C2V3C3 region of the viral env gene in 8 HIV-2-infected individuals from Dakar, Senegal, over the course of approximately 10 years. To compare results with HIV-1 infection, we reanalyzed data from our previous study that prospectively examined intrapatient viral evolution in HIV-1-infected individuals from the same population.Results. HIV-2 sequences from early and late time points were phylogenetically intermixed for all subjects. No distinct trends were observed in terms of increases or decreases in fragment size or the number of N-linked glycosylation sites, and ratios of synonymous substitutions per synonymous site to nonsynonymous substitutions per nonsynonymous site suggested selection to be neutral or negative. In homologous env C2V3 sequences, rates of viral divergence and diversification were slower in individuals infected with HIV-2 than in those infected with HIV-1.Conclusions. Viral evolution occurs slowly in HIV-2 infection, which is consistent with the slow disease progression of HIV-2 and supports the notion that viral evolution may be a relevant correlate for disease progression.

Genomic sites of human immunodeficiency virus type 2 (HIV-2) integration: similarities to HIV-1 in vitro and possible differences in vivo.

Retroviruses have distinct preferences in integration site selection in the host cell genome during in vitro infection, with human immunodeficiency virus type 1 (HIV-1) integration strongly favoring transcriptional units. Additionally, studies with HIV-1 have shown that the genomic site of proviral integration may impact viral replication, with integration in heterochromatin associated with a block in viral transcription. HIV-2 is less pathogenic than HIV-1 and is believed to have a lower replication rate in vivo. Although differences in integration site selection between HIV-2 and HIV-1 could potentially explain the attenuated pathogenicity of HIV-2, no studies have characterized integration site selection by HIV-2. In this study, we mapped 202 HIV-2 integration sites during in vitro infection of peripheral blood mononuclear cells with a primary HIV-2 isolate. In addition, we assayed for in vivo proviral integration within heterochromatin in 21 HIV-1-infected subjects and 23 HIV-2-infected subjects, using an alphoid repeat PCR assay. During in vitro infection, HIV-2 displayed integration site preferences similar to those previously reported for HIV-1. Notably, 82% of HIV-2 integrations mapped to Refseq genes, and integration strongly favored regions of the genome with high gene density and high GC content. Though rare, the proportion of HIV-2 subjects with evidence of proviral integration within heterochromatin in vivo was higher than that of HIV-1-infected subjects. It is therefore possible that integration site selection may play a role in the differences in HIV-1 and HIV-2 in vivo pathogenesis.

Distinct human immunodeficiency virus type 1 subtype A virus circulating in West Africa: sub-subtype A3.

Phylogenetic analyses demonstrate significant diversity in worldwide circulating strains of human immunodeficiency virus type 1 (HIV-1). Detailed studies have revealed a complex pattern of intersubtype recombinations, as well as evidence of sub-subtypes circulating in various populations. In this study, we characterized an HIV-1 strain that had previously been identified as a distinct subcluster within the subtype A radiation based on partial sequence data. These viruses were of particular interest given that we recently found that their prevalence was significantly higher in dually infected individuals compared to women who were singly infected with HIV-1. Five viruses isolated from commercial sex workers in Dakar, Senegal, were full-length PCR amplified and sequenced. Phylogenetic analyses indicated that, whereas three of these viruses were closely related and clustered overall within the HIV-1 subtype A radiation, they were distinct from previously characterized sub-subtype A1 and A2 viruses. The clustering pattern was maintained in the individual gag, pol, and env regions of the genome. Distance calculations between these viruses, which we termed A3, and other reference sub-subtype A1 and A2 viruses fell in the range of distances between previously characterized sub-subtype groups. In addition, we found evidence of two A3-containing recombinants in our cohort. These recombinants are mosaics composed of sequence from both sub-subtype A3 and CRF02_AG, the major circulating recombinant form in this West African population. Based on phylogenetic analyses, we propose that the group of viruses found in the Dakar sex worker cohort, previously referred to as HIV-1 A subcluster 2, be referred to as HIV-1 sub-subtype A3.

Molecular epidemiology of human immunodeficiency virus type 1 sub-subtype A3 in Senegal from 1988 to 2001.

The global human immunodeficiency virus (HIV)epidemic is characterized by significant genetic diversity in circulating viruses. We have recently characterized a group of viruses that form a distinct sub-subtype within the subtype A radiation, which we have designated HIV type 1 (HIV-1) sub-subtype A, circulating in West Africa. A prospective study of a cohort of female sex workers (FSW) in Dakar, Senegal over an 18-year period indicated that an A3-specific sequence in the C2-V3 region of the env gene was found in 46 HIV-1-infected women. HIV-1 sub-subtype A3 appeared in the FSW population as early as 1988 and continued to be transmitted as of 2001. We also found that HIV-1 A3 is not confined to the FSW cohort in Senegal but is also circulating in the general population in Dakar. Furthermore, analyses of viral sequences from a few other West and Central African countries also demonstrated evidence of HIV-1 A3 sequence in isolates from HIV-1-infected people in Ivory Coast, Nigeria, Niger, Guinea Bissau, Benin, and Equatorial Guinea. Overall, because of the evidence of sub-subtype A3 in the general population in Senegal, as well as in a few neighboring West and Central African countries, along with the increasing incidence of infection with A3-containing viruses in the Dakar high-risk FSW population, we feel that HIV-1 sub-subtype A3 viruses are important to distinguish and monitor.