A national audit of the management of HIV-2 in adults in the UK

Abstract

Background

HIV-2 is rare in the UK. Many UK centres therefore only treat small numbers of people and there are few clinical trials to guide treatment. The British HIV Association (BHIVA) 2010 guidelines for management of HIV-2 formed the basis for this national audit, which aims to describe current practice and adherence to guidelines.

Methods

All UK centres providing HIV care were contacted via the BHIVA “Members Matters” newsletter, and asked to submit anonymised, retrospective data for individuals living with HIV-2 accessing care at their service.

Results

Thirty-five sites responded and data were analysed for 167 individuals. Nearly half of individuals accessed care at one of four large London centres (77/167, 46%).

Most people living with HIV-2 have taken antiretroviral therapy (ART) (132/167, 79%). The most common reasons for initiating treatment were clinical disease (34/89, 38%) and pregnancy (11/89, 12%). Most treatment-naïve individuals were initiated on a protease inhibitor based regimen (70/89, 79%). The use of integrase strand transfer inhibitor based regimens has increased over time.

A significant minority of patients did not have baseline drug resistance testing performed, despite having a detectable viral load (15/52, 29%). Virological failure occurred in a minority of individuals (21/132, 16%); the most common drug regimen change in this context was the addition of an integrase strand transfer inhibitor (12/26 regimen changes, 46%).

Conclusions

Most individuals living with HIV-2 were managed according to national guidance, with key areas for improvement including the choice of ART, drug resistance testing and the management of virological failure. It is hoped that this national audit, performed in conjunction with the updated 2021 BHIVA guidelines will improve the care of individuals living with HIV-2 in the UK.

Keywords

HIV-2 audit CD4 antiretroviral

Background

HIV-2 is rare in the UK, affecting a fraction of the total number of people living with HIV.¹ Approximately 140 people were recorded by Public Health England in 2021 as under follow up for HIV-2, with an additional 40 living with both HIV-1 and HIV-2 (Sara Croxford, personal communication). Many centres treat small numbers of people with HIV-2 and there are few clinical trials to guide treatment.^1,2

HIV-2 is associated with slower disease progression and lower transmission risk than HIV-1.³ It is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs) which remain among first-line treatments for HIV-1.^4,5,6

The British HIV Association (BHIVA) 2010 guidelines for management of HIV-2 formed the basis for this national audit,⁴ aiming to describe current practice and adherence to guidelines, particularly with respect to antiretroviral therapy (ART).

Methods

All BHIVA members were asked, via the “Members Matters” newsletter, to submit anonymised, retrospective data using an online data collection proforma or a form sent by secure email for individuals with HIV-2. The audit was not part of the formal BHIVA audit work plan and was registered with the Northern Care Alliance NHS Group Clinical Audit Department. Audit standards (Table 1) were identified from the BHIVA 2010 HIV-2 guideline.⁴ Data were collected between March 2019 and February 2020, apart from one London centre which experienced delays due to the COVID-19 pandemic and submitted in October 2021.

Table 1.

Audit standards.

When to start ART		Results
1	What proportion of individuals living with HIV-2 have ever started ART?	132/167, 79%
2	Where individuals have initiated ART, what were the CD4 count and viral load at the time of treatment initiation?	Median CD4 count 336 copies/ml (IQR 97–535) HIV-2 viral load 190 (IQR 0–5508) n = 89
Which ART to start
3	For individuals living with HIV-2 who were treatment-naïve at the time of the 2010 guideline publication, which ART regimen was initiated, and was a recommended regimen chosen?	PI based regimen 70/89, 79% • DRV/r 48/89, 54% INSTI based regimen 20/89, 22% • RAL 10/20, 50% • DTG 10/20, 50% 4/89 (4%) received a regimen not recommended by national guidance
4	For treatment-experienced individuals living with HIV-2 who changed their ART regimen subsequent to the publication of the 2010 guideline, which ART regimens have been used, and were these regimens consistent with the guideline?	PI based regimen 31/36, 86% • DRV/r 21/31, 68% INSTI based regimen 8/36, 22% • RAL 7/8, 88% • DTG 1/8, 12% 3/36 (8%) received a regimen not recommended by national guidance
Managing virological failure
6	For individuals living with HIV-2 who experienced virological failure, which ART regimen were they taking at the time that this occurred, and was a recommended regimen chosen?	See Table 2
7	For individuals living with HIV-2 who experienced virological failure, which ART regimen were they changed to, and was a recommended regimen chosen?	See Table 3
8	Was baseline drug resistance testing performed for all individuals living with HIV-2 who had a detectable viral load	Performed in 37/52 (71%) individuals
9	Was drug resistance testing performed for all individuals living with HIV-2 who experienced virological failure	3/21, 14% of individuals who experienced virological failure did not have drug resistance testing performed
Managing HIV1/2 dual infection
10	For individuals living with both HIV-1 and HIV-2, was baseline drug resistance testing performed for both viruses?	Performed in 15/21 (71%) individuals
11	For individuals living with both HIV-1 and HIV-2, were ART regimens including drugs known to be active against both viruses chosen?	1/10 (10%) treatment naïve individual started a non-recommended regimen
11		3/21 (14%) treatment experience individuals switched to a non-recommended regimen
Pregnancy
12	For pregnant women living with HIV-2 who had a detectable viral load, how many were initiated on an appropriate ART regimen?	7/7 (100%) of pregnant women with a detectable viral load during pregnancy initiated ART

¹DRV/r: ritonavir boosted darunavir; DTG: dolutegravir; INSTI: integrase inhibitor; PI: protease inhibitor; RAL: raltegravir.

Data collected were: demographics, latest viral load and CD4 count, current and previous antiretroviral regimens, CD4 count at ART start for ART-naïve individuals, management of virological failure, emergent resistance and ART in pregnancy. Anonymised data were analysed using Microsoft Excel.

Results

Demographics

Forty sites responded, with five stating that they did not care for any individuals living with HIV-2. Anonymised data were provided for 174 individuals. Seven individuals were excluded from the analysis because they died or were lost to follow up prior to the publication of the 2010 BHIVA guideline.⁴ All those accessing care after 2010, including those who have since died or been lost to follow up, were included.

Forty-six percent (77/167) of individuals accessed care at one of four large London centres. Most other centres provided care for a small number of individuals, with 26 of the 35 centres caring for five or fewer.

Most people living with HIV-2 in the UK are female (114/167, 68%), and Black African (147/167, 88%). Most are aged over 45 years (134/167, 82%).

Timing of ART

Most people living with HIV-2 (132/167, 79%) have taken ART.

Eighty-nine of those who received ART were ART-naïve at the time of guideline publication (89/132, 67%). Median CD4 count at ART initiation was 336 cells/mm³ (n = 89, CD4% 21%; (IQR 97–535) and median HIV-2 viral load was 190 copies/ml (n = 89, IQR 0–5508). Thirty-seven individuals had undetectable HIV-2 RNA when initiating ART (37/89, 41%). The most common reasons for initiating treatment were clinical disease (34/89, 38%) and pregnancy (11/89, 12%); low CD4 count (9/89, 10%) and high viral load (5/89, 6%) were uncommon indications.

Thirty-four individuals living with HIV-2 had never taken ART. Of these, 26 have never had a detectable viral load (26/34, 77%).

Choice of ART

Of 89 individuals who were treatment naïve at the time of guideline publication and initiated ART, 70 received a protease inhibitor (PI)-based regimen (70/89, 79%), most commonly ritonavir-boosted darunavir (48/89, 54%; once daily dosing in 16, twice daily dosing in 20 and no dosing information in 12).

Integrase strand transfer inhibitor (INSTI)-based regimens were started by 20 individuals (20/89, 22%). Ten took raltegravir and 10 dolutegravir (once daily dolutegravir dosing in 6/10 individuals; twice daily in 4/10). All INSTI-based regimens were initiated in 2015 or later, indicating that their use has increased with time.

Four individuals received an initial ART regimen which was not recommended by national guidelines (4/89, 4%). Two took efavirenz/emtricitabine/tenofovir and two an atazanavir-based regimen.

Thirty six individuals were treatment experienced in 2010 but changed ART regimen after guideline publication. Most switched to a PI-based regimen (31/36, 86%), with fewer switching to INSTIs (8/36, 22%). Despite switching after the publication of the guidelines, four individuals received ART not recommended for treatment of HIV-2 (4/36, 11%). Two individuals switched to an NNRTI-based regimen; 2 received a PI with reduced anti-HIV-2 activity (atazanavir and nelfinavir).

The most common reason for ART switch was patient preference.

Managing virological failure

Baseline resistance testing

Ninety-one included individuals were diagnosed with HIV-2 in 2010 or later. Thirty-nine of these 91 individuals had undetectable HIV-2 RNA at baseline, and therefore baseline resistance testing was not requested or was unsuccessful (39/91, 43%).

Of the remaining 52 individuals, 15 did not have baseline drug resistance testing despite detectable baseline viral load (15/52, 29%). Of these 15 individuals, two had not initiated ART, and four have had drug resistance testing performed later in their care.

Managing virological failure

Twenty one of the 132 individuals who have taken ART experienced virological failure (21/132, 16%) (defined as documented drug resistance at the time of viraemia or increasing viral load on treatment requiring a change in medication). In three cases drug resistance testing was not performed (3/21, 14%).

Virological failure occurred on a total of 26 drug regimens in 21 individuals. In four cases, individuals were receiving a regimen not recommended by national guidelines at the time that virological failure occurred (4/21, 19%). ((1): tenofovir disoproxil/emtricitabine and nevirapine, (2): tenofovir diroproxil/emtricitabine, atazanavir, ritonavir, (3): tenofovir disoproxil/emtricitabine/efavirenz). The remaining regimens are described in Table 2. The most common ART change at time of virological failure was the addition of an INSTI (Table 3).

Table 2.

Drug regimens at time of virological failure.

Drug regimen at time of virological failure	Number of cases of virological failure
PI based regimen
Lopinavir/ritonavir	4
Darunavir/ritonavir^b	7
Darunavir/cobicistat^c	2
INSTI based regimen
Raltegravir^d	3
Elvitegravir/cobicistat	2
PI and INSTI based regimen
Darunavir/r and raltegravir^e	4

^aDosing information was not provided for all regimens.

^b600/100 mg BD in 5 regimens.

^c800/150 mg OD in 2 regimens.

^d1200 mg OD in 1 regimen, 400 mg BD in 4 regimens.

^eDarunavir dosing 600/100 mg BD in one regimen.

Table 3.

Changes made to drug regimens in the context of virological failure and their outcomes.

Change	Number of times this change was made	Any additional changes also made	Did further virological failure occur?
Added dolutegravir to existing regimen	7	1 person also switched LPV/r to DRV/c	Yes, in 1/6 on TDF/FTC/DRV/r/DTG¹
Added dolutegravir to existing regimen	7	1 also switched EVG/c to DTG	Yes, in 1/6 on TDF/FTC/DRV/r/DTG¹
Added raltegravir to existing regimen	5	1 person also switched LPV/r to DRV/r	Yes, in 1/5 cases on TDF/FTC/DRV/r/RAL²
Changed raltegravir to dolutegravir	4	—	No
Changed raltegravir to boosted darunavir	1	—	No
Stopped boosted darunavir, started dolutegravir	1	—	No
Change boosted lopinavir to boosted darunavir	1	—	No
Added boosted darunavir to existing regimen	1	Also added etravirine	Yes on TDF/ETV/DRV/r³
Changed elvitegravir to dolutegravir	1	—	No
Changed NRTI backbone	1	—	Yes on ABC/3TC/RAL⁴

Dosing information:

1. DRV/r 600/100 mg BD, DTG 50 mg BD.

2. DRV/r 800/100 mg OD.

3. DRV/r 800/100 mg OD.

4. Dosing information not provided.

HIV1/2 dual infection

Twenty-one individuals (21/167, 13%) were reported as living with both HIV-1 and HIV-2. Ten were treatment naïve in 2010 and subsequently started ART (10/21, 48%): eight with boosted darunavir; one with boosted lopinavir and one with tenofovir/FTC/efavirenz, which is not active against both viruses. The most common reason for treatment initiation was clinical disease in 8/10 individuals.

Nine individuals were treatment experienced in 2010 and later changed ART regimen (9/21, 43%). In three cases the new regimen was not one recommended in guidelines due to lack of activity against both viruses (tenofovir/FTC/rilpivirine, tenofovir/etravirine/boosted darunavir and tenofovir/FTC/boosted atazanavir). Of the remaining six individuals, three changed to a PI-based regimen, and three switched to a regimen containing raltegravir.

Two people did not initiate ART. Six individuals did not have baseline drug resistance testing (6/21, 29%).

Pregnancy

Thirty-six women living with HIV-2 have been pregnant whilst receiving care. No vertical transmission has been documented in these pregnancies.

Eight women have never initiated ART, including during pregnancy (8/35, 22%). One of these has had a detectable viral load, on one occasion not during pregnancy.

Twelve pregnancies occurred after 2010. Of these, seven had a detectable viral load during pregnancy and before starting ART (7/12, 58%). All women initiated ART, which consisted of a ritonavir-boosted PI in six cases and abacavir/3TC/dolutegravir in the other.

Discussion

This audit assessed practice among participating UK centres providing care for adults living with HIV-2 against the BHIVA 2010 guideline.⁴ Thirty-five centres provided information for 167 individuals. The majority were managed according to national guidance, with key areas of divergence including choice of ART, drug resistance testing and the management of virological failure.

The optimal management of individuals living with HIV-2 has not been established in randomised controlled trials, and therefore guidelines are based on non-randomised studies, in vitro data and extrapolation from evidence in HIV-1. Since 2010, there have been significant changes to the management of individuals living with HIV-1, and some new evidence pertaining to HIV-2. The 2010 guideline has now been replaced by the BHIVA guidelines for the management of HIV-2, 2021.⁷

ART is now recommended for all individuals living with HIV-2, regardless of CD4 count and viral load. Most individuals living with HIV-2 in the UK have already initiated ART, with the commonest indications being clinical disease and pregnancy.

The 2021 guidelines recommend either boosted darunavir or dolutegravir. This is already the case for 65% of individuals living with HIV-2 in the UK who started therapy after 2010. Lopinavir was the recommended initial PI in the 2010 guidelines, indicating that practice may have already changed prior to the 2021 guideline publication. The updated guideline includes new recommendations on dosing, which may lead to a change for some.

There remains a minority of individuals taking antiretroviral agents to which HIV-2 has intrinsic resistance. Non-recommended regimens were used more frequently in individuals with HIV-1/2 co-infection, and these individuals were likely to experience virological failure.

Resistance testing was not always done at baseline and at virological failure. Many factors limit availability of resistance testing, including a significant minority having an undetectable viral load, limited availability⁷ and a relatively high limit of quantification (≥500 copies/ml).⁷ However, there remained several individuals for whom resistance testing was not performed despite these factors, some of whom subsequently experienced virological failure.

In terms of limitations, we asked centres to provide information over a relatively long period, including people who have transferred care in or out. We were not able to de-duplicate and it is possible that some individuals had data submitted from more than one centre. Forty centres responded, out of over 150 providing care for individuals living with HIV in the UK. However, as PHE data suggest that there are 180 people with confirmed HIV-2 in the UK and we received information on 167 individuals, reasonable coverage was achieved, albeit with possible bias towards larger centres.

Management of HIV-2 is complex due to the limited evidence base to guide treatment decisions. Additionally, most treating centres manage five or fewer individuals, limiting the scope for clinicians to develop expertise. Establishment of a national advisory service on HIV-2 management is warranted. This would provide input on supporting best practice in HIV-2 management, support procurement of investigational and unlicensed therapies, and give input into the management of complex cases given the limited available options in the context of treatment failure and virological resistance. It is hoped that the 2021 BHIVA guidelines will improve the care of individuals living with HIV-2 in the UK.

Supplemental Material

Supplemental Material - A national audit of the management of HIV-2 in adults in the UK

Supplemetary Material for A national audit of the management of HIV-2 in adults in the UK by Maya Tickell-Painter, Jane R Deayton, David R Chadwick, Iain Reeves and Clare L van Halsema in International Journal of STD & AIDS

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Maya Tickell-Painter

David R Chadwick

Supplemental Material

Supplemental material for this article is available online.

References

Public Health England . Prevalence of HIV infection in the UK in 2018. Health Prot Rep 2019; 13: 39.

Gottlieb

Raugi

Smith

. 90-90-90 for HIV-2? Ending the HIV-2 epidemic by enhancing care and clinical management of patients infected with HIV-2. Lancet HIV 2018; 5: e390–e399.

Andersson

Norrgren

da Silva

, et al. Plasma viral load in HIV-1 and HIV-2 singly and dually infected individuals in Guinea-Bissau, West Africa: significantly lower plasma virus set point in HIV-2 infection than in HIV-1 infection. Arch Intern Med 2000; 160: 3286–3293.

Gilleece

Chadwick

Breuer

, et al. British HIV Association guidelines for antiretroviral treatment of HIV-2 positive individuals 2010. HIV Med 2010; 11: 611–619.

Waters

Ahmed

Angus

, et al. BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. Available at: https://www.bhiva.org/file/RVYKzFwyxpgiI/treatment-guidelines-2016-interim-update.pdf (2016, accessed November 2021).

European AIDS Clinical Society . Guidelines version 10.0. Available at: https://www.eacsociety.org/files/guidelines-10.0_final_2_2.pdf (2019, accessed November 2021).

Reeves

Cromarty

Deayton

, et al. British HIV association guidelines for the management of HIV-2 2021. Available at: https://www.bhiva.org/HIV-2-guidelines (accessed November 2021).

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.22 MB