Current HIV Research (v.13, #3)

Meet Our Editorial Board Member by Marc Bulterys (173-173).

Immunological and Virological Outcomes of Patients Switched from LPV/r to ATV/r-Containing Second- Line Regimens by A.S. Akanmu, T. Adeyemo, F. Lesi, F.O. Bello, K. Okwuegbuna, K. Oloko, A. Awolola, F.T. Ogunsola, P. Okonkwo, P.J. Kanki (176-183).
Background: Atazanavir/ritonavir (ATV/r) recently became the preferred protease inhibitor (PI) for use in Nigeria since it is dosed once daily, which may improve treatment adherence and has fewer side effects than lopinavir/ritonavir (LPV/r) - the most widely available PI in resource-limited settings. We, therefore, aimed to evaluate the immunologic and virologic effects of switching patients to an ATV/r-containing regimen.
Methods: In a large antiretroviral treatment programme at the Lagos University Teaching Hospital in Nigeria, 400 patients were switched to ATV/r-based second-line ART. We conducted a retrospective evaluation of immunologic and virologic outcomes following 24 months on the ATV/r regimens.
Results: Of the 400 patients switched to an ATV/r containing regimen, 255 were virologically suppressed on LPV/r prior to switch, 107 were switched due to failure on a first-line regimen, 28 were on saquinavir/ritonavir (SQV/r)-based regimen, while 10 were unintentionally switched while non-suppressed on a LPV/r-based regimen. Demonstrable and sustained immunological responses were documented as the median (IQR) CD4+ cell count increased steadily from 466 (323) cells/mm3 at the time of switch to 490 (346) cells/mm3 at 6 months, and 504 (360) cells/mm3 at 24 months. Of 99 patients evaluated 12 months after ATV/r switch, 2 (2%) had detectable viral load (VL). None of the 26 (0%) in this group evaluated at 24 months had detectable viral load.
In a comparison group of 576 patients who were maintained on LPV/r-based second line regimens, 359 (62.3%) had undetectable viral loads. Of 318 patients with VL data 24 months later, 25 (7.9%) had detectable VL. There was no significant difference between the proportion of patients maintained on LPV/r (7.9%) and those switched to ATV/r (0%) in the development of virologic failure after 24 months of follow-up.
Conclusion: Among patients that were switched to ATV/r-containing regimens, we found improvements in immunological responses and no increase in risk of virologic failure.

Treatment Discontinuation in Adult HIV-Infected Patients on First-Line Antiretroviral Therapy in Nigeria by O.O. Agbaji, I.O. Abah, K.D. Falang, A.O. Ebonyi, J. Musa, P. Ugoagwu, P.A. Agaba, A.S. Sagay, T. Jolayemi, P. Okonkwo, J.A. Idoko, Phyllis J. Kanki (184-192).
Background: Retention in care and treatment services is critical to health outcomes of individuals diagnosed and living with HIV. We evaluated the incidence of and risk factors for treatment discontinuation (TD) in a large adult HIV population on ART in Nigeria.
Method: A retrospective cohort study of adult HIV patients initiated on first-line ART between 2004 and 2011 at the Jos University Teaching Hospital (JUTH) in Nigeria. Follow up information of participants was retrieved from various sources (patient visit database, pharmacy data and patients charts) up to the end of 2012. The primary study endpoint was TD, defined as discontinuation of ART for any reason, including death or loss to follow-up (lack of pharmacy pick-up for periods ≥12 months). The Incidence and hazard for TD were estimated by Kaplan-Meier and Cox proportional regression analysis, respectively.
Result: Overall, 3,362 (28%) patients discontinued treatment during 49,436 person-years (py) of follow-up (incidence rate (IR) 6.8 TD per 100 py). The hazard of treatment discontinuation decreased with increasing age (adjusted hazard ratio (aHR 0.99; 95% CI 0.98 - 0.99). Other independent risk factors for treatment discontinuation were: being unmarried (aHR 1.24; 95% CI: 1.12-1.38), having primary or secondary level of education as compared to tertiary level education (aHR 1.24; 95% CI: 1.12-1.40) and average percent adherence to drug refill visits <95% (adjusted hazard ratio (aHR) 2.13; 95% CI: 1.9-2.40). Compared to tenofovir, greater hazard of TD was noted in patients initiated on ART containing didanosine (aHR) 1.73; 95% CI: 1.03-2.91), but lower in those initiated on zidovudine containing regimen (aHR 0.77; 95% CI: 0.69-0.86).
Conclusion: Long-term treatment discontinuation rate in this study was comparable to estimates in resource-rich countries. Younger patients, as well as patients with lower educational levels and those with poor adherence had significant hazards for treatment discontinuation and should be the target of interventions to reduce treatment discontinuation and improve retention, especially within the first year of ART.

Mother-to-Child Transmission Outcomes of HIV-Exposed Infants Followed Up in Jos North-Central Nigeria by Atiene S. Sagay, Augustine O. Ebonyi, Seema T. Meloni, Jonah Musa, Stephen Oguche, Chinedu C. Ekwempu, Tinuade Oyebode, Emeka Ejeliogu, Godwin E. Imade, Oche O. Agbaji, Prosper Okonkwo, Phyllis J. Kanki (193-200).
Objective: Since 2010, Nigeria has adopted World Health Organization (WHO) 'Option B' which requires administration of triple antiretroviral prophylaxis or treatment (ART) to all HIVinfected pregnant women. We studied the transmission outcomes of HIV-exposed children up to 18 months of age.
Design: This was a retrospective, observational study of HIV-infected pregnant women and their exposed infants who accessed prevention of mother to child transmission (PMTCT) services at Jos University Teaching Hospital, Jos, North-central Nigeria.
Methods: HIV-infected women were enrolled during antenatal care or at labor/delivery between January 1, 2010 and December 31, 2012. Antiretroviral (ARV) prophylaxis/therapy was provided according to the 2010 Nigerian PMTCT guidelines (adapted WHO 2010 guidelines); Infant HIV diagnosis was performed at 6 weeks and at 6 months. HIV antibody diagnosis was used for exposed children at 18 months.
Results: A total of 996 HIV-exposed children were followed up. Of those children, 140 (14.1%) were lost to follow up by 18 months of age. Twelve children (1.4%) died (all HIV negative) before 18 months of age and six infants (0.7%) were confirmed to be HIV-infected (4 by the age of 6 months and 2 thereafter) and were referred for treatment. A total of 838 (84.1%) children tested HIV negative at 18 months and were discharged.
Mother-to-child transmission (MTCT) of HIV by 18 months was lower among women on ART before pregnancy compared to those women who started ART/Triple ARV prophylaxis during pregnancy/delivery. (0.4%; 3/700 vs 2.0%; 3/150 P=0.05).
Home delivery was associated with higher transmission than facility delivery (p=0.03). Mode of delivery or method of infant feeding had no significant impact on vertical transmission by 18 months.
Conclusion: In North-central Nigeria where HIV is prevalent, ART started before pregnancy is enormously effective in preventing mother-to-child transmission. Adoption of WHO 'Option B+' deserves serious consideration in such settings.

Loss to Follow-Up within the Prevention of Mother-to-Child Transmission Care Cascade in a Large ART Program in Nigeria by Holly E. Rawizza, Charlotte A. Chang, Beth Chaplin, Isah A. Ahmed, Seema T. Meloni, Tinuade Oyebode, Bolanle Banigbe, Atiene S. Sagay, Isaac F. Adewole, Prosper Okonkwo, Phyllis J. Kanki, the APIN PEPFAR Team (201-209).
Background: The 2013 WHO guidelines incorporated simplified and more effective antiretroviral regimens for the purposes of preventing mother-to-child transmission of HIV. With ideal implementation of these recommendations, perinatal HIV transmission could be reduced to less than 2%. However, loss to follow-up (LTFU) has the potential to erode the success of programs and a number of studies report high rates of LTFU within the prevention of mother-to-child transmission (PMTCT) care cascade. We evaluated the timing and magnitude of LTFU in a large programmatic PMTCT cohort in Nigeria in order to focus future efforts to reduce loss in this high burden setting.
Methods: From 2004-2014, the APIN/Harvard PEPFAR program supported antenatal HIV screening for nearly one million pregnant women and provided PMTCT care to over 30,000 women. The care cascade for women enrolling in the PMTCT program includes antenatal, delivery, and infant follow-up services through 12-18 months of life. In this retrospective cohort analysis, we examined data collected between 2004-2014 from 31 clinical sites in Nigeria and assessed the numbers of mothers and infants enrolled and LTFU at various points along the care cascade.
Results: Among 31,504 women (median age 30, IQR: 27-34) entering PMTCT care during the antenatal period, 20,679 (66%) completed the entire cascade of services including antenatal, delivery, and at least one infant follow-up visit. The median gestational age at presentation for antenatal care services was 23 weeks (IQR: 17-29). The median infant age at last follow-up visit was 12 months (IQR: 5-18). The greatest loss in the PMTCT care cascade occurred prior to delivery care (21%), with a further 16% lost prior to first infant visit. Of the 38,223 women who entered at any point along the PMTCT cascade, an HIV DNA PCR was available for 20,202 (53%) of their infants. Among infants for whom DNA PCR results were available, the rate of HIV transmission for infants whose mothers received any antenatal and/or delivery care was 2.8% versus 20.0% if their mother received none.
Conclusion: In this large cohort analysis, the proportion of women LTFU in the PMTCT care cascade was lower than that reported in previous cohort analyses. Nevertheless, this proportion remains unacceptably high and inhibits the program from maximally achieving the goals of PMTCT care. We also provide the largest analysis to date on rates of perinatal HIV transmission, with low rates among women receiving NNRTI- or PI-based regimens, approaching that reported in clinical trials. However, among mothers who received any antenatal care, infant outcomes were unknown for 48%, and women presented later in pregnancy than that recommended by current guidelines. Implementation research to evaluate ways to improve integration of services, particularly transitions from antenatal to delivery and pediatric care, are critically needed to reduce LTFU within PMTCT programs and achieve the ultimate goal of eliminating pediatric HIV infection.

Patterns of Adherence and Loss to Follow-Up in Pediatric Patients on ART in Nigeria by Seema T. Meloni, Beth Chaplin, Charlotte Chang, Holly Rawizza, Prosper Okonkwo, Phyllis J. Kanki (210-218).
Introduction: High levels of adherence to antiretroviral therapy (ART) and retention in treatment programs are required for successful virologic suppression and treatment outcomes. While there have been numerous studies focusing on adherence and loss to follow-up (LTFU) in adults, studies in children and young adolescents are limited. For this study, we examined patterns of adherence and LTFU in HIV-infected pediatric patients receiving ART in PEPFAR-funded sites in Nigeria.
Methods: We conducted a retrospective observational study utilizing data that had been collected during the course of care in a large pediatric ART program in Nigeria.
Results: A total of 3,513 children ages 0-14.9 years enrolled at 31 different sites between June 2005 and March 2011 were included in the study. Of the enrolled patients, 1,987 (56%) were LTFU by the end of the study period. LTFU was highest in those ages<2 years and those ≥13 years (versus aged 2-12.9 years). Year of ART initiation was a strong predictor of LTFU across all age groups. For those patients retained to 12 months, less than half showed optimal adherence (≥95%). While there were no differences in adherence rates at month 12 by age group, those aged 10 years and older did have declining adherence starting at 18 months.
Discussion: Adherence is critical for optimal ART patient outcomes. We found both low adherence and high LTFU rates in our study cohort. Additional studies focused on barriers to adherence and development of age-specific intervention programs are critical to improving overall pediatric outcomes.

HIV Type 1 Subtype A1 Dominates in Armenia by Vita Laga, Alexander Vasilyev, Ilya Lapovok, Samvel Grigoryan, Arshak Papoyan, Nataliya Glushchenko, Elena Kazennova, Marina Bobkova (219-225).
Objective: There is scarce information about the molecular epidemiology of HIV-infection in Armenia (former USSR). The objective of this work was to estimate the distribution of HIV-1 subtypes in this country and get any information about HIV drug resistance in naÏve patients.
Design: A joint study involving 78 patients was carried out in Yerevan, Armenia and Moscow, Russia in 2009-2013. The cohort studies included mostly IDUs (28.2%) and heterosexuals (69.2%).
Results: The phylogenetic analyses based on population sequencing of partial pol gene found subtype A1 being the most prevalent (92.3%), followed by subtype B (3.9%). The HIV-1 tropism inferred from env V3-loop sequences was determined in 27 samples, among them R5-tropic viruses were found in 13 (48.1%) patients and X4- variants – in 14 (51.9%) patients. The prevalence of drug resistance in naïve patients was low (1.5%) with the only one mutation K219Q found.
Conclusion: The composition and distribution of HIV-1 genetic variants in Armenia are evidently influenced by the Russian and other FSU countries epidemic, due to the significant volume of Armenian migrant/re-emigrant flows. Continued surveillance of HIV-1 circulating subtypes and drug resistance in Armenia is important for the proper management of HIV infection in this country.

We have previously shown that soluble HIV-1 Tat protein down regulates surface expression of the interleukin (IL)-7 receptor alpha-chain (CD127) on human CD8 T cells resulting in impaired T cell proliferation and cytolytic capacity. Once taken up by CD8 T cells, Tat translocates to the inner leaflet of the plasma membrane where it interacts with the cytoplasmic tail of CD127 inducing receptor internalization and degradation by the proteasome. Here we characterized the regions of Tat required to interact with CD127 and induce receptor down regulation from the cell surface. To do this, a series of histidine-tagged Tat deletion mutants were generated and expressed as purified soluble protein, or cloned into a DNA expression vector and transfected into primary human CD8 T cells and a CD127 expressing Jurkat cell line. Protein-protein interactions were assessed by co-immunoprecipitation. Substitution of the first 10 Nterminal residues or deletion of residues 17-21 prevented Tat from interacting with and down regulating CD127 from the cell surface. Deletion of the basic region also prevented Tat from down regulating CD127 but did not prevent Tat from binding to the receptor. Notably, an endogenously expressed Tat variant lacking the basic region caused an accumulation of CD127 at the cell surface. We propose a model where Tat interacts with CD127 via its N-terminal region and recruits cellular factors via its basic region to down regulate CD127 from the cell surface.

Implementing Implementation Science: An Approach for HIV Prevention, Care and Treatment Programs by Barrot H. Lambdin, Ben Cheng, Trevor Peter, Jessie Mbwambo, Tsitsi Apollo, Megan Dunbar, Ifeoma C. Udoh, Adithya Cattamanchi, Elvin H. Geng, Paul Volberding (244-246).
Though great progress has been realized over the last decade in extending HIV prevention, care and treatment in some of the least resourced settings of the world, a substantial gap remains between what we know works and what we are actually achieving in HIV programs. To address this, leaders have called for the adoption of an implementation science framework to improve the efficiency and effectiveness of HIV programs. Implementation science (IS) is a multidisciplinary scientific field that seeks generalizable knowledge about the magnitude of, determinants of and strategies to close the gap between evidence and routine practice for health in real-world settings. We propose an IS approach that is iterative in nature and composed of four major components: 1) Identifying Bottlenecks and Gaps, 2) Developing and Implementing Strategies, 3) Measuring Effectiveness and Efficiency, and 4) Utilizing Results. With this framework, IS initiatives draw from a variety of disciplines including qualitative and quantitative methodologies in order to develop new approaches responsive to the complexities of real world program delivery. In order to remain useful for the changing programmatic landscape, IS research should factor in relevant timeframes and engage the multi-sectoral community of stakeholders, including community members, health care teams, program managers, researchers and policy makers, to facilitate the development of programs, practices and polices that lead to a more effective and efficient global AIDS response. The approach presented here is a synthesis of approaches and is a useful model to address IS-related questions for HIV prevention, care and treatment programs. This approach, however, is not a panacea, and we will continue to learn new ways of thinking as we move forward to close the implementation gap.

HIV Replication at Low Copy Number and its Correlation with the HIV Reservoir: A Clinical Perspective by Loredana Sarmati, Gabriella D&#39;;Ettorre, Saverio Giuseppe Parisi, Massimo Andreoni (250-257).
The efficacy of combination therapy (antiretroviral therapy - ARV) is demonstrated by the high rates of viral suppression achieved in most treated HIV patients. Whereas contemporary treatments may continuously suppress HIV replication, they do not eliminate the latent reservoir, which can reactivate HIV infection if ARV is discontinued. The persistence of HIV proviral DNA and infectious viruses in CD4+ T cells and others cells has long been considered a major obstacle in eradicating the HIV virus in treated patients. Moreover, recent studies have demonstrated the persistence of HIV replication at low copies in most patients on suppressive ARV. The source of this 'residual viraemia' and whether it declines over years of therapy remain unknown. Similarly, little is known regarding the biological relationships between the HIV reservoir and viral replication at low copies. The question of whether this 'residual viraemia' represents active replication or the release of non-productive virus from the reservoir has not been adequately resolved.
From a clinical perspective, both the quantification of the HIV reservoir and the detection of low levels of replication in full-responder patients on prolonged ARV may provide important information regarding the effectiveness of treatment and the eradication of HIV. To date, the monitoring of these two parameters has been conducted only for research purposes; the routine use of standardised tests procedure is lacking.
This review aims to assess the current data regarding the correlation between HIV replication at low copies and the HIV reservoir and to provide useful information for clinicians.