Articles tagged as "15 million accessing treatment"

Addressing barriers to universal access: focus on the pre-ART phase

Quantifying and addressing losses along the continuum of care for people living with HIV infection in sub-Saharan Africa: a systematic review.

Kranzer K, Govindasamy D, Ford N, Johnston V, Lawn SD. J Int AIDS Soc. 2012 Nov 19;15(2):17383.

Introduction: Recent years have seen an increasing recognition of the need to improve access and retention in care for people living with HIV/AIDS. This review aims to quantify patients along the continuum of care in sub-Saharan Africa and review possible interventions.

Methods: We defined the different steps making up the care pathway and quantified losses at each step between acquisition of HIV infection and retention in care on antiretroviral therapy (ART). We conducted a systematic review of data from studies conducted in sub-Saharan Africa and published between 2000 and June 2011 for four of these steps and performed a meta-analysis when indicated; existing data syntheses were used for the remaining two steps.

Results: The World Health Organization estimates that only 39% of HIV-positive individuals are aware of their status. Among patients who know their HIV-positive status, just 57% (95% CI, 48 to 66%) completed assessment of ART eligibility. Of eight studies using an ART eligibility threshold of≤200 cells/µL, 41% of patients (95% CI, 27% to 55%) were eligible for treatment, while of six studies using an ART eligibility threshold of≤350 cells/µL, 57% of patients (95% CI, 50 to 63%) were eligible. Of those not yet eligible for ART, the median proportion remaining in pre-ART care was 45%. Of eligible individuals, just 66% (95% CI, 58 to 73%) started ART and the proportion remaining on therapy after three years has previously been estimated as 65%. However, recent studies highlight that this is not a simple linear pathway, as patients cycle in and out of care. Published studies of interventions have mainly focused on reducing losses at HIV testing and during ART care, whereas few have addressed linkage and retention during the pre-ART period.

Conclusions: Losses occur throughout the care pathway, especially prior to ART initiation, and for some patients this is a transient event, as they may re-engage in care at a later time. However, data regarding interventions to address this issue are scarce. Research is urgently needed to identify effective solutions so that a far greater proportion of infected individuals can benefit from long-term ART.

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Who Starts? Factors Associated with Starting Antiretroviral Therapy among Eligible Patients in Two, Public HIV Clinics in Lilongwe, Malawi. 

Feldacker C, Johnson D, Hosseinipour M, Phiri S, Tweya H. PLoS One. 2012;7(11):e50871. Epub 2012 Nov 30.

Background: Lighthouse Trust operates two, public, integrated HIV clinics, Lighthouse (LH) and Martin Preuss Center (MPC), in Lilongwe, Malawi. Approximately 20% of patients eligible for antiretroviral therapy (ART) do not start ART. We explore individual and geographic factors that influence whether ART-eligible patients initiate ART.

Methods: Adult patients eligible for ART between 2008-2011 were included. Analysis was stratified by clinic. Using logistic regression, we evaluated factors associated with initiating ART including gender, age, body mass index (BMI), employment, tuberculosis (TB), eligible at initial registration, WHO stage, CD4, months in pre-ART care (from initial registration to eligibility date), and patient neighborhood distance to clinic.

Results: Of 14,216 study patients, 4841 were from LH; 9285 were from MPC. At LH and MPC, respectively, median age was 34.2 and 33.8 years; median BMI was 22.0 and 20.6; and median distance was 5.6 and 4.9 Km. In multivariate models, odds of starting ART was highest among those older than 35 years and those eligible for ART based on WHO stages 3-4 vs. those in WHO stages 1-2 with CD4<250. Patients with 1-12 months in pre-ART were at least 11 times more likely to start ART than peers with less pre-ART time. At LH, living 2.5-5 Km from the clinic increased the likelihood of starting ART over patients living closer.

Conclusions: Length of the pre-ART period is the most significant predictor of starting ART among eligible patients. Better understanding of motivation for retention in pre-ART care may reduce attrition along the treatment cascade.

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Attrition from HIV Testing to Antiretroviral Therapy Initiation among Patients Newly Diagnosed with HIV in Haiti.

Noel E, Esperance M, McLaughlin M, Bertrand R, Devieux J, Severe P, Marcelin A, Nicotera J, Delcher C, Griswold M, Meredith G, Pape JW, Koenig SP. J Acquir Immune Defic Syndr. 2012 Dec 18. [Epub ahead of print]

Objective: We report rates and risk factors for attrition in the first cohort of patients followed through all stages from HIV testing to ART initiation.

Design: Cohort study of all patients diagnosed with HIV between January and June, 2009.

Methods: We calculated the proportion of patients who completed CD4 cell counts and initiated ART or remained in pre-ART care during two years of follow-up, and assessed predictors of attrition.

Results: Of 1,427 patients newly diagnosed with HIV, 680 (48%) either initiated ART or were retained in pre-ART care for the subsequent two years. One thousand eighty-three patients (76%) received a CD4 cell count and 973 (90%) returned for result; 297 (31%) had CD4 cell count <200 cells/µl and of these, 256 (86%) initiated ART. Among 429 patients with CD4 >350 cells/µl, 215 (50%) started ART or were retained in pre-ART care. Active TB was associated with lower odds of attrition prior to CD4 cell count (OR: 0.08; 95% CI: 0.03-0.25) but also higher odds of attrition prior to ART initiation (OR: 2.46; 95% CI: 1.29-4.71). Lower annual income (≤$US125) was associated with higher odds of attrition prior to CD4 cell count (OR 1.65; 95% CI: 1.25-2.19), and prior to ART initiation among those with CD4 cell count >350 cells/µl (OR: 1.74; 95% CI: 1.20-2.52).After tracking patients through a national database, the retention rate increased to only 57%.

Conclusion: Fewer than half of patients newly diagnosed with HIV initiate ART or remain in pre-ART care for two years in a clinic providing comprehensive services. Additional efforts to improve retention in pre-ART are critically needed.

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Editor’s notes: The first of three papers presents a systematic review of the published data addressing the entire HIV care pathway, including HIV testing, pre-ART care comprising assessment of ART eligibility, retention in pre-ART care prior to ART eligibility, initiation of ART and retention in ART care. The second paper describes factors associated with ART initiation in a large cohort of patients in Malawi.The third paper presents the results of a prospective cohort study conducted at the GHESKIO clinic, the oldest and largest HIV testing facility in Haiti. GHESKIO tests nearly 30 000 patients per year for HIV, and follows patients from HIV testing through pre-ART care, ART initiation and follow-up. Their results show high rates of attrition at every step from HIV testing to ART initiation, losses occurring mainly prior to ART initiation with fewer than half of patients newly diagnosed with HIV initiating ART or remaining in pre-ART care. This is a vital study because it confirms the results of other relevant studies conducted in Africa, and highlights how the care pathway, especially prior to ART initiation is a global challenge. All research conducted in different parts of the world concur with the urgent need to address operational questions to improve the retention in pre-ART care (prior to ART eligibility and initiation).

All three papers raise a very sensitive issue, which has been poorly explored, the pre-ART care phase. Indeed, the current inclination towards earlier initiation of ART requires earlier diagnosis and regular monitoring until treatment eligibility. Poor pre-ART retention in care, or the failure to link patients from HIV testing to HIV care and retain them until they are eligible for ART, is a problem that has recently surfaced in the research literature. Without effective retention in pre-ART care – beginning with HIV testing and continuing until the first antiretrovirals are dispensed – even patients who have long been aware of their HIV status will access care only when seriously ill, which is often well after treatment eligibility. Unfortunately, only a handful of quantitative studies reporting on rates of pre-ART linkage and loss in sub-Saharan Africa have been published, and many of these are limited in the time periods and outcomes they consider. More operational research addressing the retention in care of individuals not yet eligible for ART is therefore essential. There appear to be several reasons for the poor showing of pre-ART care. Most patients during this stage are asymptomatic and may not perceive themselves to require medical care. Since little therapeutic care is offered during the pre-ART period, patients must take on faith that making the effort to come to the clinic for monitoring is worth the costs of doing so. Current approaches to providing care often require multiple clinic visits, e.g., to first provide a blood sample for a CD4 count and then return a week later to receive the results. Choosing to "wait and see what happens" may well be a preferred strategy for patients who lack resources for transport, risk losing employment by taking time off work, or fear being recognized as a client of an HIV clinic.  A number of interventions are being tried to improve retention in pre-ART care, though very few have been rigorously evaluated. Most interventions aim either to reduce the costs that patients perceive in seeking pre-ART care or increasing the perceived benefits of care. Interventions to reduce costs are more common and focus on structural changes in the delivery of care (fewer visits, more convenient locations, shorter waiting times, etc.). Interventions to increase benefits may offer more services at each visit (e.g., provision of cotrimoxazole or food parcels). There is little evidence so far as to whether these interventions will be effective. A possible way forward might also be the involvement of the local personnel such as community-based workers. Community may provide tangible support in increasing knowledge of HIV, obtain information about any changes or movements in patients’ lives, continue to follow patients in the social environment where they live, and support them to make periodic clinic visits.

HIV testing, HIV Treatment
Africa, Latin America
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Epidemiology

BED estimates of HIV incidence: Resolving the differences, making things simpler

Hargrove J, van Schalkwyk C, Eastwood H. PLoS One. 2012;7(1):e29736. Epub 2012 Jan 3

Hargrove, Schalkwyk, and Eastwood set out to develop a simple method for optimal estimation of HIV incidence using the BED capture enzyme immunoassay. They used existing BED data to estimate mean recency duration, false recency rates and HIV incidence with reference to a fixed time period, T. They compared BED and cohort estimates of incidence referring to identical time frames before generalising this approach to suggest a method for estimating HIV incidence from any cross-sectional survey. They found that follow-up and BED analyses of the same, initially HIV-negative, cases followed over the same set time period T, produce estimates of the same HIV incidence, permitting the estimation of the BED mean recency period for cases who have been HIV-positive for less than T. Follow-up of HIV-positive cases over T, similarly, provides estimates of the false-recent rate appropriate for T. Knowledge of these two parameters for a given population allows the estimation of HIV incidence during T by applying the BED method to samples from cross-sectional surveys. An algorithm is derived for providing these estimates, adjusted for the false-recent rate. The resulting estimator is identical to one derived independently using a more formal mathematical analysis. Adjustments improve the accuracy of HIV incidence estimates. Negative incidence estimates result from the use of inappropriate estimates of the false-recent rate and/or from sampling error, not from any error in the adjustment procedure. Referring all estimates of mean recency periods, false-recent rates, and incidence estimates to a fixed period T simplifies estimation procedures and allows the development of a consistent method for producing adjusted estimates of HIV incidence of improved accuracy. Unadjusted BED estimates of incidence, based on life-time recency periods, would be both extremely difficult to produce and of doubtful value.

For abstract access click here. 

Editor’s note: Being able to measure HIV incidence is key to tracking the impact of HIV prevention strategies in real ‘new HIV infections’ terms. Unlike HIV prevalence, which can be measured relatively easily as a snapshot at a particular point in time, HIV incidence rates, which give an indication of how quickly the epidemic is progressing or receding over a specified time period, are difficult to obtain. Following cohorts of initially HIV-negative people is time-consuming, challenging, and costly and, as well, the resultant data may be biased. These authors set out to make estimating HIV incidence simpler, while acknowledging the inherent weaknesses of the BED assay. This assay assesses the increasing proportion of HIV IgG in total IgG following seroconversion. People who may falsely appear as recent infections include those in late-stage HIV, elite controllers, non-progressors, and people on antiretroviral therapy. What remains clear is that we need tests that can identify long-term infection with greater certainty if we are to correctly estimate HIV incidence without complicated mathematical adjustments.

Epidemiology
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Treatment

Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): A systematic review and meta-analysis

Gupta A, Nadkarni G, Yang WT, Chandrasekhar A, Gupte N, Bisson GP, Hosseinipour M, Gummadi N. PLoS One. 2011;6(12):e28691. Epub 2011 Dec 29

Gupta and colleagues systematically reviewed observational studies of early mortality post-antiretroviral therapy initiation in low- and middle-income countries (LMIC) in Asia, Africa, and Central and South America, as defined by the World Bank, to summarize what is known. Studies published in English between January 1996 and December 2010 were searched in Medline and EMBASE. Three independent reviewers examined studies of mortality within one year post-ART. An article was included if the study was conducted in a low- or middle-income country, participants were initiating ART in a non-clinical trial setting and were ≥15 years. Fifty studies were included; 38 (76%) from sub-Saharan Africa, 5 (10%) from Asia, 2 (4%) from the Americas, and 5 (10%) were multi-regional. Median follow-up time and pre-ART CD4 cell count ranged from 3-55 months and 11-192 cells/mm(3), respectively. Loss-to-follow-up, reported in 40 (80%) studies, ranged from 0.3%-27%. Overall, sub-Saharan Africa had the highest pooled 12-month mortality probability of 0.17 (95% CI 0.11-0.24) versus 0.11 (95% CI 0.10-0.13) for Asia, and 0.07 (95% CI 0.007-0.20) for the Americas. Of 14 (28%) studies reporting cause-specific mortality, tuberculosis (5%-44%), wasting (5%-53%), advanced HIV (20%-37%), and chronic diarrhea (10%-25%) were most common. Independent factors associated with early mortality in 30 (60%) studies included: low baseline CD4 cell count, male sex, advanced World Health Organization clinical stage, low body mass index, anaemia, age greater than 40 years, and pre-ART quantitative HIV RNA. Significant heterogeneity in outcomes and in methods of reporting outcomes exist among published studies evaluating mortality in the first year after antiretroviral therapy initiation in low- and middle-income countries. Early mortality rates are highest in Sub-Saharan Africa, and opportunistic illnesses such as TB and wasting syndrome are the most common reported causes of death. Strategies addressing modifiable risk factors associated with early death are urgently needed.

For abstract access click here. 

Editor’s note: Mortality in the first 12 months after starting antiretroviral therapy is more than three times higher in low- and middle-income countries than it is in high-income countries, with the highest mortality rates seen in sub-Saharan Africa. Differences in nutrition levels, incidence of opportunistic illnesses, socioeconomic levels, and disease stage at presentation may explain regional differences in mortality (17% sub-Saharan Africa, 11% Asia, and 7% Latin America). Most deaths occur in the first three months, reflecting people’s advanced stage of disease at treatment initiation. Preventing late presentation (defined as having a CD4 count below 200 cells/μL) is the big challenge, with men and older people at higher risk for this and subsequent mortality. In addition to starting antiretroviral treatment earlier, identifying and treating tuberculosis infection could reduce deaths in the first year of HIV treatment significantly because TB is such a large contributor to early mortality.

HIV Treatment
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Non-subtype B infection

The epidemiology and clinical correlates of HIV-1 co-receptor tropism in non-subtype B infections from India, Uganda, and South Africa

Ataher Q, Portsmouth S, Napolitano LA, Eng S, Greenacre A, Kambugu A, Wood R, Badal-Faesen S, Tressler R. J Int AIDS Soc. 2012 Jan 26;15:2

The introduction of C-C chemokine receptor type-5 (CCR5) antagonists as antiretroviral therapy has led to the need to study HIV co-receptor tropism in different HIV-1 subtypes and geographical locations. This study was undertaken to evaluate HIV-1 co-receptor tropism in the developing world where non-B subtypes predominate, in order to assess the therapeutic and prophylactic potential of CCR5 antagonists in these regions. HIV-1-infected patients were recruited into this prospective, cross-sectional, epidemiologic study from HIV clinics in South Africa, Uganda, and India. Patients were infected with subtypes C (South Africa, India) or A or D (Uganda). HIV-1 subtype and co-receptor tropism were determined and analysed with disease characteristics, including viral load and CD4+ and CD8+ T cell counts. CCR5-tropic (R5) HIV-1 was detected in 96% of treatment-naive and treatment-experienced patients in India, 71% of treatment-experienced South African patients, and 86% (subtype A/A1) and 71% (subtype D) of treatment-naive and treatment-experienced Ugandan patients. Dual/mixed-tropic HIV-1 was found in 4% of Indian, 25% of South African and 13% (subtype A/A1) and 29% (subtype D) of Ugandan patients. Prior antiretroviral treatment was associated with decreased R5 tropism; however, this decrease was less in subtype C from India (treatment-experienced: 94%, treatment-naive: 97%) than in subtypes A (treatment-experienced: 59%; treatment-naive: 91%) and D (treatment-experienced: 30%; treatment-naive: 79%). R5 virus infection in all three subtypes correlated with higher CD4+ count. R5 HIV-1 was predominant in treatment-naive individuals with HIV-1 subtypes C, A, and D and treatment-experienced individuals with subtypes C and A. Higher CD4+ count correlated with R5 prevalence, while treatment experience was associated with increased non-R5 infection in all subtypes.

For abstract access click here. 

Editor’s note: HIV interacts with the CD4 molecule on target cells using its envelope gp120 glycoprotein and then docks with the cell’s chemokine cell co-receptors to gain entry into the cell. In the early stages of HIV infection, CCR5 (C-C chemokine type 5)-using viruses predominate and are associated with a slower progression to AIDS. Over time, CXCR4-using viruses appear and are associated with more rapid CD4 cell depletion, disease progression, and a higher risk of death. The antiretroviral drug maraviroc is a first-in-class CCR5 antagonist. Because it works against CCR5-tropic viruses but not CXCR4 viruses, it is important to know whether different non-B sub-types are more likely to use CCR5 or CXCR4. The findings here are very encouraging: CCR5 was the predominant co-receptor for treatment-naive patients in India (subtype C) and Uganda (subtypes A and D) and for treatment-experienced people in South Africa (subtype C). Since transmitted HIV-1 is mainly R5, maraviroc could play a role in both oral and topical pre-exposure prophylaxis, particularly in subtype C settings, either alone or in combination with an agent that blocks X4 or both R5 and X4 viruses.

HIV Treatment
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Microbicides

First phase 1 double-blind, placebo-controlled, randomized rectal microbicide trial using UC781 gel with a novel index of ex vivo efficacy

Anton PA, Saunders T, Elliott J, Khanukhova E, Dennis R, Adler A, Cortina G, Tanner K, Boscardin J, Cumberland WG, Zhou Y, Ventuneac A, Carballo-Diéguez A, Rabe L, McCormick T, Gabelnick H, Mauck C, McGowan I, PLoS One. 2011;6(9):e23243. Epub 2011 Sep 28

Successful control of the HIV pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. Anton and colleagues report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability, and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo. HIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1:1:1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint. All 36 subjects enrolled completed the 7-14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1(BaL) showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration. Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant adverse events (AEs), high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538).

For abstract access click here

Editor’s note: One has to respect the altruism of these 36 study subjects and their perseverance – they all completed the study. They were HIV-negative men (n=26) and women (n=10), with a history of consensual receptive anal intercourse at least once in their lives. They were willing to be sexually abstinent from rectal sex for 1 week prior to treatment and for 1 week before and 1 week after each of 3 sigmoidoscopies. The latter involved a preparatory enema and biopsies of colonic tissue (28 to be precise). The results of this study have advanced the topical PrEP [microbicide] field by a leap. This is not because the product UC781 has promise. In fact, further development is not being pursued because of its stability, solubility, and other reasons. Rather, for the first time, an ex vivo (outside the body) biomarker of efficacy was used to test how well a rectal microbicide could block HIV infection. The biopsy specimens of participants in the UC781 groups (particularly those in the 0.25% concentration group) had enough of a UC781 tissue concentration from pre-biopsy topical application to suppress HIV infection of the tissue. Rectal HIV transmission is 20-200 times more likely than vaginal transmission, possibly as a result of the rectum’s single-cell epithelial lining and resident activated immune cells, combined with the risk of trauma with inadequate lubrication. The development of an acceptable, safe, and efficacious rectal microbicide is on the pathway to the long-term goal of a combination microbicide that can be used in both sexual compartments (vagina and rectum).

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Epidemiology

Molecular and epidemiological characterization of HIV-1 infection networks involving transmitted drug resistance mutations in Northern Greece

Skoura L, Metallidis S, Buckton AJ, Mbisa JL, Pilalas D, Papadimitriou E, Papoutsi A, Haidich AB, Chrysanthidis T, Tsachouridou O, Antoniadou ZA, Kollaras P, Nikolaidis P, Malisiovas N. J Antimicrob Chemother. 2011 Dec;66(12):2831-7. Epub 2011 Sep 19

The objective of this study was to determine the contribution of transmission clusters to transmitted drug resistance in newly diagnosed antiretroviral-naive HIV-1-infected patients in Northern Greece during 2000-07. The prevalence of transmitted drug resistance was estimated in 369 individuals who were diagnosed with HIV-1 infection in the period 2000-07 at the National AIDS Reference Laboratory of Northern Greece. Phylogenetic analysis was performed using a maximum likelihood method on partial pol sequences. Transmitted drug resistance was defined in accordance with the surveillance drug resistance mutation list (2009 update). The overall prevalence of transmitted drug resistance in the population studied was 12.5% [46/369, 95% confidence interval (CI) 9.1%-15.8%], comprising 7.6% (28/369) resistant to nucleoside reverse transcriptase inhibitors, 5.4% (20/369) resistant to non-nucleoside reverse transcriptase inhibitors and 3.3% (12/369) resistant to protease inhibitors. Dual class resistance was identified in 3.8% (14/369). Infection with subtype A was the sole predictor associated with transmitted drug resistance in multivariate analysis (odds ratio 2.15, 95% CI 1.10-4.19, P = 0.025). Phylogenetic analyses revealed three statistically robust transmission clusters involving drug-resistant strains, including one cluster of 12 patients, 10 of whom were infected with a strain carrying both T215 revertants and Y181C mutations. Skoura and colleagues’ findings underline the substantial impact of transmission networks on transmitted drug resistance in Northern Greece.

For abstract access click here

Editor’s note: HIV drug resistance can be transmitted and it can be acquired while on treatment. In both cases, it is a concern because it limits therapeutic options. Drug resistance testing at HIV diagnosis is routine in Greece and time trends in Northern Greece demonstrate a significant increase since 2000, particularly in resistance to NNRTIs (non-nucleoside reverse transcriptase inhibitors). Among the study overall population of people who were newly diagnosed and had never been on antiretroviral treatment, 53% of people were infected with subtype B, 33% with subtype A, and 14% with other subtypes. There was a strong correlation between sub-type A and transmitted drug resistance. In Northern Greece, patients with sub-type A belong predominantly to the native Greek population and are treated through the public health programme. Among the 17 people linked in clusters of cases with the same resistance patterns, 10 had dual drug resistant HIV-1 strains, highlighting not only the importance of surveillance at the population level but also of resistance testing to determine optimum treatment regimens for individuals who are starting their treatment pathway with a strike or even two against them.

Epidemiology
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