2018

14th February Rhee et al., Mutational correlates of virological failure in individuals receiving WHO-recommended tenofovir-containing regimen


Mutational correlates of virological failure in individuals receiving a WHO-recommended tenofovir-containing first-line regimen: an international collaboration.    EBioMedicine

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure on a WHO-recommended TDF-containing first-line regimen. Rhee et al. aimed to identify TDF regimen-associated mutations (TRAMs) by comparing the proportion of each reverse transcriptase mutation in 2’873 individuals with virological failure on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50’803 antiretroviral-naïve individuals.

The authors identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen: A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F.

In conclusion, the study shows that the spectrum of TDF-selected mutations extends beyond K65R/N and K70E/G/Q. Several of the additional TDF-selected mutations are non-polymorphic mutations that are currently not considered surveillance drug resistance mutations yet may be important for monitoring TDF associated transmitted drug-resistance. Additionally, the clinical significance of several mutations that occurred commonly in combination with K65R including A62V, S68G/N/D, L74I, V75L and Y115F requires further phenotypic and clinical studies to better understand their effects on both TDF and the newly developed prodrug tenofovir alafenamide (TAF).

pdf publication

1st February Caniglia et al., Comparison of monitoring strategies based on CD4 cell counts in virally suppressed HIV-positive individuals


Comparison of dynamic monitoring strategies based on CD4 cell counts in virally suppressed, HIV-positive individuals on combination antiretroviral therapy in high-income countries: a prospective, observational study.     Lancet HIV

Caniglia et al. on behalf of the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems aimed to establish whether information about an individual’s time-varying CD4 cell count can provide any additional benefit in determining when monitoring frequency can be decreased.

The authors compared three strategies using different CD4 cell count thresholds to determine whether CD4 cell count and HIV RNA viral load was measured every 3–6 months (when below the threshold) or every 9–12 months (when above the threshold). The threshold was 200 cells per μL in the first strategy, 350 cells per μL in the second strategy, and 500 cells per μL in the third strategy.

They found that the different strategies had no effect on survival, AIDS-free survival, and mean CD4 cell count at 2 years, suggesting that decreasing monitoring to annually when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL does not worsen the short-term clinical and immunological outcomes of HIV-positive individuals with viral suppression. However, the authors found that decreasing monitoring frequency when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL results in an increased risk of virological failure at 2 years. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2.01 (1.17–3.43) for threshold 200 and 1.24 (0.89–1.73) for threshold 350.

In conclusion, the study-results suggest that in virologically suppressed individuals on ART in resource-rich settings, the CD4 threshold at which monitoring frequency can be decreased to annually might be as low as 200 cells per μL with no effect on clinical and immunological outcomes after 2 years. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further research is warranted to obtain more precise effect estimates over longer periods of follow-up, and to determine the generalisability of these results to resource-limited settings.

PubMed

29th January Lodi et al., Immediate ART in older HIV positive patients


Effect of immediate initiation of antiretroviral treatment in HIV-positive individuals aged 50 years or older.    Journal of Acquired Immune Deficiency Syndromes

Clinical guidelines recommend immediate initiation of combined antiretroviral therapy for all HIV-positive individuals. However, those guidelines are based on trials of relatively young participants.

Lodi et al. on behalf of the HIV-CAUSAL Collaboration of HIV cohorts from Europe and the Americas aimed to estimate the 5-year risk of all-cause mortality and non-AIDS mortality among ART-naive, AIDS-free individuals aged between 50 and 70 years.

The study included 9’596 individuals (28% US Veterans) with median age of 55 (52–60) years and CD4 count of 336 (182–513) at baseline. The 5-year risk of all-cause mortality was 0.40% (95% confidence interval (CI): 0.10 to 0.71) lower for the general HIV population and 1.61% (95% CI: 0.79 to 2.67) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm3. The 5-year risk of non-AIDS mortality was 0.17% (95% CI: 20.07 to 0.43) lower for the general HIV population and 1% (95% CI: 0.31 to 2.00) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm3.

In conclusion, immediate initiation of ART seems to be beneficial in reducing all-cause mortality in AIDS-free patients aged 50 years or older, despite their low baseline CD4 count. More effort should be made into diagnosing HIV earlier, particularly in older patients to ensure timely initiation of treatment and follow-up for concomitant comorbidities, thereby maximizing the benefit of early treatment for HIV.

PubMed

25th January Leitman et al., HLA-B*14:02-env-restricted CD8+ T-cells in HIV control


HLA-B*14:02-restricted env-specific CD8+ T-cell activity has highly potent antiviral efficacy associated with immune control of HIV infection.    Journal of Virology

Immune control of HIV infection is typically associated with effective Gag-specific CD8+ T-cell responses. To investigate further the potential role of non-Gag-specific CD8+ T-cell responses in control of HIV infection, Leitman et al. focused here on HLA-B*14, where the dominant HIV-specific CD8+ T-cell response is in Env but not Gag specific.

The authors demonstrated that Env-specific HLA-B*14-restricted activity was substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV were observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This was reflected by an increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, they showed that HLA-B*14:02 was significantly more strongly associated with viremic control than HLA-B*14:01.

In conclusion, the studies indicate that, although Gag-specific CD8+ T-cell responses may usually have greater antiviral efficacy against HIV for the several reasons described above, influences such as functional avidity of individual responses are also critically important factors that may override protein specificity in contributing to immune control of HIV infection. This finding is relevant to the development of vaccines designed to generate effective antiviral CD8+ T-cell responses.

pdf publication

18th January Del Amo et al., Educational level and response to antiretroviral treatment


Inequalities by educational level in response to combination antiretroviral treatment and survival in HIV-positive men and women in Europe (1996-2013): a collaborative cohort study.    AIDS

Del Amo et al. on behalf of COHERE in Euro-Coord aimed to investigate differences by educational level in virological and immunological response to combined antiretroviral treatment (cART), as well as incidence of all-cause mortality and new AIDS-defining events in HIV-positive men and women in COHERE data from 1996 to 2013.

Of 24’069 HIV-positive patients, 9% had not completed primary education, 32% had completed primary, 44% secondary, and 15% tertiary education. Overall, 21% were women, who were overrepresented in lower educational strata. During 132’507 person-years of follow-up, 1’081 individuals died; cumulative mortality decreased with higher educational level (P<0.001). Over 122 765 person-years, new AIDS events or death occurred in 2598 individuals; differences by education were more marked than for death alone (P<0.001). Virological response was achieved by 67% of patients without completed basic education, 85% with completed primary education, 82% with secondary, and 87% with tertiary (P<0.001). Patients with higher education had higher CD4+ cell count at cART initiation and at each time after cART but rate of CD4+ cell count recovery did not differ.

In conclusion, the study-results support the argument for sustained educational efforts at the European level to improve active citizenship, social cohesion, and health impacting on the macro-level determinants. They also reinforce the need for proximal down-stream interventions on clinical and preventive care among less educated HIV-positive patients once they are linked to care to address inequities.

pdf publication

17th January Bouteloup et al., Reference curves for CD4 response


Reference curves for CD4 T-cell count response to combination antiretroviral therapy in HIV-1-infected treatment-naïve patients.      HIV Medicine

Bouteloup et al. on behalf of COHERE in EuroCoord aimed to provide ‘reference curves’ for CD4 T-cell responses during the first 12 months of combination antiretroviral therapy (cART) for patients with virological suppression, according to the characteristics of the patients at cART initiation. Data on 27 cohorts across 35 European countries were provided for the present analysis. All persons aged ≥ 18 years who started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL 6 months after cART initiation were included in the study.

A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249. The median observed CD4 counts at 6, 9 and 12 months were 382, 402 and 420 cells/lL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL was generally required in order that patients stayed ‘on track’ (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those who started with CD4 counts in the higher percentiles.

In conclusion, the study proposes reference curves for the CD4 count that may be used as an additional tool for the clinician when evaluating responses to cART. A web tool is available at http://shiny.isped.u-bordeaux.fr/CD4refcurves

PubMed

11th January Monge et al., Combined antiretroviral treatment in migrants in Europe


Timing of cART initiation in male and female migrants living with HIV in Western Europe: an observational cohort study (1997-2013).    AIDS

The Migrant Health Working Group on behalf of COHERE in EuroCoord aimed to evaluate differences in timing of combined antiretroviral treatment (cART) initiation by geographical origin in male and female HIV-positive patients in COHERE. They included 151 674 individuals (72.9% men) from Western Europe between January 1997 and March 2013, with known geographical origin and at least 1 CD4+ cell count measurement while cART-naïve.

Median CD4+ cell count falls far below 250 cells/ml in all groups and was lowest in sub-Saharan African (SSA: 161), Caribbean men (161) and in Asian women (185). Among men, the adjusted probability of cART initiation was lower in migrants compared with natives, but differences depended on initial CD4+ cell count. In women, no meaningful differences were observed between natives and most migrant groups. However, SSA women had a 31% higher probability of cART initiation when recruited at a CD4+ more than 500 cells/ml and 9% (4–14%) lower when recruited at CD4+ less than 100 cells/ml.

In conclusion, the study-results highlight late initiation of cART in the migrant population in Western Europe and differences in timing of cART initiation for some groups within migrant communities, especially for men. Addressing existing barriers to access HIV testing and care and ensuring universal and free access to cART is important to advance in the elimination of inequities and in the control of the HIV epidemic in Western Europe.

PubMed

10th January Judd et al., Triple-class failure by age and perinatal HIV


Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.    HIV Medicine

Judd et al. on behalf of COHERE in EuroCoord aimed to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection.

A total of 5’972 participants starting antiretroviral therapy (ART) from 1998, aged 500 HIV-1 RNA copies/mL despite ≥4 months of use.

The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall (17 vs. 8 weeks) and highest in perinatally infected participants aged 10–14 years (49 weeks). The cumulative proportion with TCVF 5 years after starting ART was 9.6% in participants with perinatally acquired infection and 4.7% in participants with heterosexually acquired infection. Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10–14 years, African origin, pre-ART AIDS, NNRTI based initial regimens, higher pre-ART viral load and lower pre-ART CD4.

In conclusion, for participants with perinatal HIV infection, these findings indicate the need to diagnose and start ART earlier in childhood, and adopt a strategic approach in ART selection to prevent the emergence of resistance. These measures may help children and adolescents achieve and sustain virological suppression as they approach adulthood.

pdf publication

4th January Stirrup et al., Predictors of CD4 recovery following initiation of ART


Predictors of CD4 cell recovery following initiation of antiretroviral therapy among HIV-1 positive patients with well-estimated dates of seroconversion.     HIV Medicine

Stirrup et al. on behalf of CASCADE Collaboration in EuroCoord aimed to investigate factors that predict speed of recovery and long-term CD4 cell count in HIV-1 seroconverters initiating combination antiretroviral therapy (cART), and to quantify the influence of very early treatment initiation. They used data from the CASCADE multinational cohort collaboration of HIV-1 seroconverters and analysed pre- and post-treatment data of patients with seroconversion dates estimated January 2003 - March 2014 (n=7600).

The authors found that “true’ CD4 count at cART initiation was the strongest predictor of CD4 count beyond 3 years on cART. CD4 recovery was more rapid for patients in whom treatment was initiated within 4 months. For a given CD4 count, higher viral load (VL) at initiation was strongly associated with higher post-treatment CD4 recovery. Use of an integrase-inhibitor regimen at treatment initiation was found to be associated with a moderate improvement in post-treatment recovery in CD4 relative to the NNRTI regimen.

In conclusion, CD4 count at cART initiation is the most important factor in predicting post-treatment recovery, but VL provides substantial additional information. If cART is initiated in the first 4 months following seroconversion, recovery of CD4 counts appears to be more rapid. The finding that higher plasma VL at treatment initiation predicts more rapid CD4 cell recovers is maybe explained by some evidenced that higher VL levels are associated with sequestration of CD4 cells in lymphoid tissue and that this is associated with a more rapid initial increase in circulating CD4 cells following the initiation of cART.

PubMed

3rd January Trickey et al., CD4:CD8 and CD8 as Markers for Mortality


CD4:CD8 ratio and CD8 count as prognostic markers for mortality in Human Immunodeficiency Virus–infected patients on antiretroviral therapy: The Antiretroviral Therapy Cohort Collaboration (ART-CC).    Clinical Infectious Diseases

Trickey et al. on behalf of the Antiretroviral Therapy Cohort Collaboration aimed to investigate whether the CD4:CD8 ratio or CD8 counts were independently associated with all-cause, AIDS, and non-AIDS mortality in patients treated with antiretroviral therapy (ART) with suppressed viral load and CD4 count >350 cells/μL For the analysis, the authors combined data from 13 European and North American cohorts participating in the Antiretroviral Therapy Cohort Collaboration.

During 276’526 person-years, 1’834 of 49’865 patients (3.7%) died (249 AIDS-related; 1’076 non-AIDS-defining; 509 unknown/unclassifiable deaths). There was little evidence that CD4:CD8 ratio was prognostic for all-cause mortality after adjustment for other factors: the adjusted hazard ratio (aHR) for lower vs middle tertile was 1.11. The association of CD8 count with all-cause mortality was U-shaped with a higher mortality for those with higher and lower values compared with those with values near the median (aHR 1.13 and 1.11, respectively). AIDS related mortality declined with increasing CD4:CD8 ratio and decreasing CD8 count.

In conclusion, the study does not lend strong support to use CD4:CD8 ratio and CD8 count as a prognostic marker for non-AIDS related mortality in virally suppressed patients on ART. However, the failure of many patients in this long-term treated HIV-infected population to reach the levels of CD4:CD8 ratio or CD8 count considered to be normal in the general population may indicate ongoing immune dysregulation. This may have longer-term consequences than the authors have been able to study here, or associations may be only with specific causes of death.

PubMed