INTRODUCTION Unlike most high-income countries where subtype B viruses predominate, the Cuban HIV-1 epidemic is characterized by a great diversity of subtypes and circulating recombinant forms. Some studies have shown that HIV variants exhibiting a preference for the CXCR4 co-receptor (X4-tropic) could have impacts on disease pathogenesis, with clinical implications for antiviral treatment plans. Determination of HIV co-receptor tropism is crucial for clinicians in deciding whether maraviroc is an appropriate antiviral.

OBJECTIVE Characterize V3 sequence variability and its relation to viral tropism across different subtypes circulating in Cuba and explore how this may affect treatment success with maraviroc.

METHODS We designed a cross-sectional study that included 72 plasma samples obtained at the Pedro Kourí Tropical Medicine Institute in Havana, Cuba. We sequenced the C2V3 env region and assessed subtype based both on env and pol sequences; tropism was predicted by Geno2pheno analysis. Additionally, 35 V3-loop Cuban sequences, obtained from a previous study, were incorporated into the analysis. Statistical associations among virological, clinical and epidemiological variables were assessed by a chi-square test.

RESULTS Tropism prediction for 72 variants revealed that CRF19_cpx was associated with dual-tropic R5X4 viruses (p = 0.034). Moreover, when 35 sequences from a former study were added, the association was significant not only for R5X4 (p = 0.019) but also for X4-tropic variants (p = 0.044). Alignment of 107 V3-loop sequences showed wide diversity among the different HIV-1 subtypes circulating in Cuba.

CONCLUSIONS In accordance with G2P, CRF19_cpx is a genetic variant with a high proportion of X4 and R5X4-tropic viruses. The results from the present study suggest that the Cuban recombinant could be a more pathogenic variant and that maraviroc may not be suitable for patients infected with CRF19_cpx.

KEYWORDS HIV, CCR5 receptor antagonists, maraviroc, HIV envelope glycoprotein gp120, Cuba

The HIV/AIDS epidemic is an ongoing threat to public health. Its elimination requires greater efforts to broaden antiretroviral treatment coverage, availability and personalization. HIV drug resistance is currently a global problem due to its continuing increase in recent years, undermining efficacy of antiretroviral therapy. Pretreatment HIV drug-resistance surveillance is part of WHO’s strategy for addressing antiretroviral drug resistance. This paper describes and analyzes pretreatment HIV drug-resistance surveillance in Cuba. It presents a chronology of HIV resistance studies in untreated patients, along with their results and programmatic actions related to first- and second-line treatment regimens. Cuba’s incorporation into the Global HIV Drug Resistance Surveillance Laboratories Network and the advantages of having a WHO-designated laboratory in which to conduct periodic studies of HIV drug-resistance surveillance are described. HIV drug-resistance surveillance in Cuba is a necessary tool in HIV/AIDS monitoring and control, as it obtains population-scale data used to inform programmatic decisions related to optimizing first- and second-line treatments for children and adults, as well as helping meet goals of eliminating HIV transmission.

KEYWORDS HIV, anti-HIV agents, drug resistance, viral, antiretroviral agents, Cuba

INTRODUCTION Approximately 73% of persons with HIV who receive antiretroviral therapy in Cuba are in viral suppression. The non-response of the remaining 27% could be due to several factors including adverse drug reactions and HIV resistance to antiretroviral drugs, as well as social factors and idiosyncratic characteristics of each patient. Genetic information explains from 20% to 95% of a drug’s effects and variations in response. Considering optimization of therapeutic efficacy in our country, genetic factors of the host should be identified.

OBJECTIVE Identify polymorphisms affecting genetic variability of responses to antiretroviral drugs.

EVIDENCE ACQUISITION A literature review was conducted (of original articles, published theses, clinical reports and bibliographic review studies, from 2000 to 2018, in Spanish and English listed in MEDLINE/PubMed, SciELO, LILACS, PharmGKB and Google Scholar) with the following key words: pharmacogenetics, human immunodeficiency virus, anti-retroviral agents, genetic polymorphism, genetic techniques, pharmacogenomic variants.

DEVELOPMENT The review identified 77 relevant publications meeting specific quality criteria. A summary table was built with data collected on antiretroviral drugs, genes and proteins involved in polymorphic variations, their associated effects and relevant scientific references. Information was included on polymorphisms related to 12 antiretroviral drugs used in HIV therapy. Polymorphisms determine variations in proteins involved in drug transport and metabolism and in elements of immunity. Relevant pharmacogenetic biomarkers recognized by drug regulatory agencies were identified.

CONCLUSIONS The study identified genetic variations (single-nucleotide polymorphisms) associated with 12 antiretroviral drugs. In most cases, no statistically significant causal association was found. Identifying polymorphic variations is a medium- and long-term objective that requires statistical support and adoption of strategies to optimize antiretroviral therapy. An approach combining plasma-level monitoring and pharmacogenetic analysis is recommended to optimize therapy for HIV patients.

KEYWORDS Pharmacogenetics, HIV, anti-retroviral agents, antiretroviral therapy, genetic polymorphism, genetic techniques, pharmacogenomic variants.

INTRODUCTION By the end of 2017, there were more than 28,000 individuals living with HIV in Cuba, over 80% receiving antiretroviral therapy, which dramatically reduces viral replication, improves immune status and decreases risk of transmission. These results could be jeopardized by emergence of HIV-1 drug resistance. In 2009, a test for HIV-1 genotypic resistance was introduced in routine clinical practice in Cuba.

OBJECTIVE Investigate antiretroviral resistance and its relation to subtype distribution in HIV-1 treatment-naïve and previously treated patients in Cuba.

METHODS Resistance and HIV-1 subtype distribution were determined in 342 antiretroviral treatment-naïve patients and 584 previously treated for HIV-1 whose blood specimens were sent to the Pedro Kourí Tropical Medicine Institute during 2009–2014. Transmitted drug resistance was determined using the Calibrated Population Resistance Tool v.6. Drug resistance analysis was conducted using the algorithm Rega v9.1.0.

RESULTS Prevalence of transmitted drug resistance was 11.4%, and 41% of mutated viruses exhibited dual-class resistance to nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor. Overall, 84.9% of patients had ≥1 resistance mutation, 80% had ≥1 nucleoside reverse transcriptase inhibitor mutation, 71.4% had ≥1 non-nucleoside reverse transcriptase inhibitor mutation and 31.7% had ≥1 protease inhibitor mutation. K65R and K101E mutations were significantly more frequent in subtype C, L210W in CRF19_cpx, and M47V/I in CRF BGs (20, 23, 24). Full class resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and multidrug resistance were detected in 21.2%, 32.4%, 8% and 4.1% of patients, respectively. Average percentage resistance to nucleoside reverse transcriptase inhibitor, protease inhibitor, full class resistance to nucleoside reverse transcriptase inhibitor, protease inhibitor and multidrug resistance increased in patients failing two or more regimens. Nevertheless, after 2011, a declining trend was observed in the frequency of multidrug resistance and full class resistance to nucleoside reverse transcriptase inhibitors and protease inhibitors.

CONCLUSIONS Detected levels of transmitted drug resistance highlight the need for a national surveillance study in treatment-naïve patients. Resistance prevalence is high in previously treated patients but appears to be decreasing over time. The frequency of resistance mutations in recombinant forms of HIV in Cuba needs further study.

KEYWORDS Antiretroviral therapy, highly active antiretroviral therapy, HIV, anti-HIV agents, drug resistance, multiple drug resistance, Cuba

INTRODUCTION In recent years, global initiatives to address the AIDS epidemic have produced promising advances through access to effective treatment programs. However, lack of adherence to antiretroviral therapy is a problem for pediatric patients.

OBJECTIVE Explore antiretroviral therapy adherence in children and adolescents living with HIV/AIDS in Cuba and examine its relationship with psychosocial, individual and treatment factors.

METHODS A qualitative study was carried out of 21 caregivers of children and adolescents with HIV/AIDS. Demographics and information on treatment regimen were collected by chart review. In-depth interviews were conducted to assess adherence and examine its relationship with psychosocial, individual and treatment factors. Interviews were transcribed and the information was grouped by factor category. Adherence was analyzed in relation to these three sets of factors.

RESULTS Caregivers interviewed reported adequate adherence in 17 of the 21 children. Lack of adherence was linked primarily to psychosocial factors such as additional responsibility taken on by the caregiver while grappling with his or her own illness, the presence of untreated psychological symptoms in the caregiver, perceived difficulties with family support, the child’s age, and assigning treatment responsibilities to the child without taking into account his/her psychological maturity.

CONCLUSIONS The study revealed a high level of antiretroviral therapy adherence. It reconfirmed the fundamental importance of the caregiver and family support for therapeutic success in children and adolescents living with HIV/AIDS. These results, as well as the factors identified in cases of nonadherence, can contribute to a framework for assessment and specialized interventions to optimize pediatric antiretroviral adherence.

KEYWORDS HIV, AIDS, antiretroviral therapy, patient adherence, patient compliance, patient nonadherence, treatment adherence, treatment compliance, treatment nonadherence, Cuba

AIDS is a major cause of death in the Caribbean, a region with a high prevalence of HIV. However, prevalence in Cuba’s population aged 15 to 49 years, despite a slight increase in recent years, is considered extremely low (0.1%). At the close of 2010, 5692 Cuban patients were receiving antiretroviral therapy. SIDATRAT, an informatics system, was developed at the Pedro Kourí Tropical Medicine Institute in Havana to ensure proper monitoring and followup of drug administration. Functioning on a web platform utilizing an Apache server, PHP and MySQL, it records patients’ general information, CD4 counts, viral load and data from other laboratory tests, as well as endoscopic and imaging studies. It also compiles information on their AIDS classification, opportunistic infections, HIV subtype and resistance studies, followup consultations, drug regimen, adverse reactions to medications, changes in drug combinations, and survival; and tracks total number of individuals under treatment. SIDATRAT follows the client-server philosophy and enables access by authorized users throughout Cuba via the health informatics network. SIDATRAT has been found effective in supporting quality care for persons living with HIV/AIDS and universal access to antiretroviral therapy, compiling most of the information needed for decisionmaking on patient health and therapies. SIDATRAT has been offered to the UNDP office in Havana for sharing with other developing countries that may wish to adapt or implement it.

This article addresses an emerging issue in health care systems: the impact of judicial rulings on public policy regarding financing and delivery of health care services, and the attendant tensions, contradictions and questions. In Colombia, HIV/AIDS patients’ use of a legal instrument called tutela, or writ of protection, has produced abundant jurisprudence and prompted health authorities to respond with decisions about HIV/AIDS service coverage that do not consider epidemiologic criteria and sustainability, introducing distortions in the health care system with respect to financing, priority-setting and universality.

KEYWORDS Health care systems, HIV, AIDS, legislation and jurisprudence, rights, universal coverage, Colombia

INTRODUCTION The use of highly active antiretroviral therapy has reduced progression to AIDS and increased survival among seropositive persons; yet, appearance of resistant viruses may jeopardize these benefits. In Cuba, HIV mainly affects adults; at the end of 2009 of the 41 children infected, 25 were still alive; of these, 22 were under antiretroviral treatment. Until now, nothing was known about HIV-1 antiviral resistance and viral subtypes in the pediatric population in Cuba.

OBJECTIVE This study aims to identify presence of antiretroviral-resistant HIV-1 strains in Cuban children and their mothers, and to provide a phylogenetic characterization and comparison of pol gene sequences in the same.

METHODS Plasma samples were collected from 22 children and their mothers, all HIV-1–infected, from 2004 through 2009. Reverse transcription polymerase chain reaction was used to amplify the pol gene fragment coding for HIV protease and reverse transcriptase enzymes; this was then sequenced and subjected to phylogenetic analysis of HIV subtypes and recombinant forms to compare sequences between mothers and children. HIV mutations conferring antiretroviral resistance were determined.

RESULTS Viral amplification was achieved in samples from 11 children and 8 mothers. Subtypes detected were: CRF19_cpx in five children, subtype B in three, CRF18_cpx in two, and subtype C in one child. In all mother–child pairs, samples were grouped within the same viral subtype in the phylogenetic tree. One mother was under treatment and five children had been treated before the sample was collected. In viruses amplified from samples of children under treatment, resistance was most frequently found to lamivudine (3 cases) and nevirapine (4 cases). Two untreated children carried resistant viruses possibly acquired from their mothers.

CONCLUSIONS This is the first study to describe HIV-1 antiviral resistance in the pediatric population in Cuba; it also identified viral subtypes infecting the mother−child pairs studied. We recommend antiretroviral resistance assays before initiating treatment in pregnant seropositive women and their newborns.

KEYWORDS HIV, AIDS, antiretroviral therapy, antiviral drug resistance, phylogeny, infectious disease transmission, vertical, Cuba

The following errata have been corrected in all versions of this article

Page 24: Byline, ”Joan Alemán” should read “Yoan Alemán.”

Page 31, The Authors: ”Joan Alemán” should read “Yoan Alemán Campos.”