South Africa introduces tuberculin skin test for IPT eligibility in new guidelines
The South African Department of Health launched new guidelines on isoniazid preventative therapy (IPT) for HIV-infected individuals at the 6th South African AIDS conference held in Durban in June this year. The greatest change in the IPT guidelines is the introduction of the tuberculin skin test (TST) for people living with HIV to determine the duration for which isoniazid should be taken to prevent TB disease.
Previous South African IPT guidelines issued in 2010 dropped the requirement for TST, based on World Health Organization (WHO) recommendations. Current WHO guidelines state that “TST is not a requirement for initiating IPT in people living with HIV,” in order to simplify the operational delivery of IPT. Tuberculin skin testing requires refrigerated supplies of tuberculin which may not be feasible in many settings, for example. However, in some settings where it is feasible, TST can help to identify those who would benefit most from IPT, according to the WHO.
The new South African guidelines state that all people living with HIV should be initiated on IPT after active TB has been ruled out. In those eligible for antiretroviral treatment (with a CD4 cell count of less than 350 cells/mm3), IPT should begin after ART initiation, and once active TB has been ruled out.
The main reason for the inclusion of TST in the TB screening algorithm for IPT in South Africa is because many health care workers do not feel confident using symptom screening alone to exclude active TB in people living with HIV. This prevented more people from being initiated on IPT. The Department of Health believed that the introduction of TST would provide an alternative, more accurate method of ruling out TB.
Tuberculin skin testing is used to determine whether a person has been exposed to TB. A positive result shows that the person is mounting an immune reaction to the presence of TB and may be latently infected. Isoniazid preventive therapy significantly reduces a person’s subsequent risk of developing active TB.
A negative result can mean one of two things. Either the person has very poor immune function, in which case they may be unable to mount a reaction to the skin test despite being exposed to TB, or they may not have been exposed to TB.
The Botswana IPT trial showed that people with HIV who received IPT had no significant reduction in their risk of developing active TB if they were TST negative prior to starting IPT. (Samandari).
According to the new South African guidelines, the introduction of TST will be phased in as soon as health care workers are trained to read TST results and after demonstration projects have identified any operational problems that need to be addressed. People should still be initiated on IPT using previous guidelines until the health system is able to implement TST for all people living with HIV.
According to the guidelines, people with HIV should take IPT for six months if TST is not available and if active TB has been excluded. The same applies if a person tests TST negative and is not on antiretroviral therapy. However, if a person tests TST negative and is on ARVs, they should continue IPT for 12 months.
The latter recommendation is based on the results of a South African study conducted in Khayelitsha which found that a 12-month course of IPT in people taking antiretroviral therapy reduced the risk of developing active TB by 37% during a follow-up period of at least 12 months. In that study TST was not required and so there is no information about the relative performance of IPT according to TST status in South Africans taking antiretroviral therapy. (Rangaka).
Those who test TST positive should take IPT for 36 months, regardless of whether or not they are also taking ARVs. Pregnant women should not be excluded from receiving IPT, and the same guidance should be followed for pregnant women.
The Department of Health has already started training health care workers on the new guidance.
One of the main barriers to implementing the scale up of TST is that patients need to return to the health facility 48 hours after the test is done to have the result read. This burden often results in a loss to follow-up with patients not returning to have the results read.
According to the South African guidelines, if there are no signs of TB, all people living with HIV should be started on IPT unless the person is using alcohol or if there are adherence or side-effect concerns. In 2011/12, the South African Department of Health initiated 373,073 people on IPT and 91% of all people living with HIV were screened for TB.
However, as highlighted in a study conducted within the provincial Eastern Cape Department of Health in South Africa, also presented at the launch of the guidelines, there were already problems in the implementation of the previous IPT guidelines in South Africa. The study showed that the IPT guidelines are not known about and that many doctors and consultants are not committed to the implementation of the guidelines.
One of the main barriers is that TST is only conducted by TB nurses as most nurses are not confident to read the TST results. Also, there is not enough focus on training nurses already responsible for antiretroviral treatment initiation and monitoring to read TST results.
Furthermore many health care workers have fears regarding isoniazid toxicity and resistance and are hence reluctant to initiate patients on isoniazid.
One of the recommendations made in the study was to develop TST standard operating procedures where all patients could receive TST on a Monday and all nurses would be able to read the results on a Wednesday or Thursday morning at allocated times. This could reduce the waiting time for patients who spend hours waiting to have their TST results read at the health facilities.
South African Department of Health. Launch of 2013 Isoniazid Preventative Therapy Guidelines. 6th South African AIDS Conference, Durban, June 2013.
MX Rangaka et al. Randomized controlled trial of isoniazid preventive therapy in HIV-infected persons on antiretroviral therapy. Nineteenth International AIDS Conference, Washington DC, abstract THLBB03, 2012. (Read a news report on this study here).
Samandari T et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 377(9777):1588-98, 2011. (Read a news report on this study here).
ARV and TB drug supply issues threaten South Africa’s ARV programme
HIV activist groups in South Africa are calling on the Minister of Health to address drug supply chain problems which are causing HIV and tuberculosis (TB) drug stock-outs in the country’s Eastern Cape province.
According to a report launched at the 6th South African AIDS Conference by a coalition consisting of the Rural Health Advocacy Project (RHAP), Doctors Without Borders (MSF), the Treatment Action Campaign (TAC) and SECTION 27, 40% of the 70 facilities surveyed by MSF and TAC during May 2013 in the Mthatha catchment area in the Eastern Cape province had experienced HIV and/or TB drug stock-outs. More than 100,000 people, on antiretrovirals (ARVs) or TB treatment, depend on 300 facilities served by the Mthatha depot.
Medical staff at 24% of the affected facilities were forced to send patients home without treatment because they experienced stock-outs of essential HIV and TB drugs. These stock-outs were reported to last, on average, 45 days at a time and have been ongoing since October 2012. The organisations estimated that at least 5494 adults were not able to take some of their ARVs and 561 children were sent home without treatment since September 2012 when the drug supply issues began.
Lamivudine (3TC), tenofovir, nevirapine, efavirenz, paediatric ARV formulations and Rifafour (a fixed-dose combination of four TB drugs) are the main medications affected.
“This situation is catastrophic. It means many thousands of people living with HIV have risked treatment interruption for months now. The stock-outs consequently undermine clinical benefits of life-saving ARV treatment. Over time, more deaths will occur as a result and the likelihood of increased drug resistance is significant,” says Dr Amir Shroufi, Deputy Medical Co-ordinator for MSF in South Africa. There have been a number of reports of patients receiving dual or even monotherapy in the Eastern Cape and Gauteng.
“I have been taking ARVs since 2008. Each year this [a stock-out] happens at least six times. I go to the clinic and they tell me there is no medication for me,” said a 36 year-old unemployed man who lives in a rural village in the Eastern Cape.
"The national Department of Health should create an emergency team to respond to stock-outs – given the extent, importance, and frequency of essential drugs stock-outs nationwide.” John Stephens, SECTION 27
“It is very difficult for patients. We are telling them to adhere, but when they arrive at the clinic, which can take up to two hours to access by car in the rural Eastern Cape areas, they are told there is nothing for them and that they must come back another time,” said Vuyokazi Gonyela, the TAC Eastern Cape District Organiser.
On 10 October 2012, staff at Mthatha depot in the Eastern Cape staged a strike, following which 29 individuals were suspended, leaving the depot with only 10 working employees. Coupled with chronic supply chain issues, this precipitated widespread drug stock-outs in the region.
The survey followed an intervention by MSF and TAC volunteers during December 2012, which continued for three months, to respond to the burgeoning Mthatha depot crisis by supporting staffing, managing and ensuring drug delivery at the depot. This intervention helped to clear the backlog of drug orders and to bring the depot closer to normal levels of functioning.
“The MSF/TAC emergency intervention in the Mthatha depot from December 2012 to March 2013 has shown that it is possible to correct a disastrous situation with limited resources, even if the impact remains short-lived without large systemic changes and action from the provincial Department of Health”, said Gonyela, who led the intervention.
The main causes for the drug supply problems are the lack of an early warning system for facilities to be able to report potential shortages, drug suppliers failing to meet tender quotas, government failing to pay suppliers, and poor ordering practices at health facilities and medicine depots.
South Africa has one of the largest ARV programmes in the world with over 2 million people initiated on ARVs in the public sector. However, drug stock-outs are occurring across the country and are not limited to HIV and TB medication, but extend to other basic chronic medication such as hypertension (blood pressure) and diabetes medication, according to Dr Francois Venter, Deputy Director of the Wits Reproductive Health and HIV Institute (WHRI). This was reiterated by a number of healthcare workers attending the conference.
“The national Department of Health should create an emergency team to respond to stock-outs – given the extent, importance, and frequency of essential drugs stock-outs nationwide,” said John Stephens of SECTION 27.
The organisations are recommending that when stock-outs are identified, the underlying reasons must be established for each and appropriate action undertaken, and the individuals responsible for the stock-outs must be clearly identified.
In response to the drug supply problems, the organisations have set up a civil society monitoring group which will focus on solving the drug supply problems and continue monitoring drug supply across the country.
“We are aware of the drug stock-outs across the country and share your concerns,” said Helecine Snyman, Head of Affordable Medicines at the South African Department of Health.
Van Cutsem G et al. Preventing and monitoring drug stock-outs: The role of civil society. 6th South African AIDS Conference, Durban, June 2013.
The Chronic Crisis: Essential drug stock-outs risk unnecessary death and drug resistance in South Africa. MSF South Africa, 18 June 2013. Available at http://www.msf.org.za/publication/eastern-cape-hiv-drug-stockouts-patients-risk
Emergency Intervention at Mthatha depot: The hidden cost of inaction. MSF South Africa, January 2013. Available at http://www.msf.org.za/sites/default/files/publication/documents/emergency-intervention-Mthatha-depot.pdf
Higher CD4 threshold for ARV initiation did not overwhelm HIV clinics in Khayelitsha, South Africa
Successive expansions in eligibility for antiretroviral therapy in South Africa have not resulted in sharp increases in ART initiation in Khayelitsha, South Africa, a large township outside Cape Town, according to a study presented by Médecins Sans Frontières (MSF/Doctors without Borders) at the 6th South African AIDS conference.
In 2010 the WHO revised the adult ART guidelines and raised the ART initiation threshold to “secure the greatest likelihood of survival and quality of life for the greatest number” of people living with HIV. The new guidelines were implemented incrementally in South Africa with all pregnant women and TB/HIV co-infected people being initiated on ART at a CD4 of 350 cells/mm3 from April 2010, and all people with a CD4 below 350 cells/mm3 being initiated on ART from August 2011. In April 2012 eligibility for treatment was extended to all HIV-positive people diagnosed with tuberculosis.
In June 2013 WHO issued new guidelines recommending that all adults with CD4 cell counts below 500 should receive antiretroviral treatment. Concerns have been expressed regarding the new guidance, such as the substantial increase in demand for ART, displacement of patients in urgent need of treatment due to exhaustion of limited treatment budgets, saturation of the capacity of health services and exposure of patients to ART for longer.
In order to evaluate the impact of guideline changes on the demand for treatment and service utilisation in an area with a very high prevalence of HIV, researchers from MSF Khayelitsha and the University of Cape Town carried out a cross-sectional study comparing the uptake of ART across four time periods related to the changes in South African treatment guidelines outlined above. Khayelitsha has a population of approximately 500,000 people with 16 health facilities providing HIV and drug-resistant TB care. There are 25,875 patients on ART at the moment.
The researchers found that the increase in the number of ART initiations has remained steady, with the median increase per year being 20% between 2007 and 2012.
However this average conceals considerable variation. The biggest year-on-year increases in treatment initiation occurred in 2008 and 2009, before South African treatment guidelines expanded treatment eligibility beyond a CD4 cell threshold of 200 cells/mm3.
The number of people initiated on treatment actually fell by 2% in 2011. The small decrease in initiations in 2011 may be due to stabilisation of coverage under these guidelines. Another possible explanation is capacity constraints; the nurse mentoring programme was being scaled up during 2011 to enable more nurses to initiate patients on ART.
The study also found that the average CD4 cell count at which people initiated treatment rose from 135 cells/mm3 to 221 cells/mm3 between 2008 and 2012. Yet, although the proportion of people initiating treatment with symptomatic WHO stage 4 HIV disease fell from 21% to 11%, the total number remained stable. In other words, although the proportion of seriously ill people starting treatment declined – meaning that the vast majority of people starting treatment now have less complex requirements – the number of seriously ill people starting treatment remains the same, implying that the burden on clinical services has grown substantially.
“Our concern should not only be about initiating patients at a higher CD4 count, but to find ways to get patients to access care earlier when their CD4 counts are higher,” said Gabriela Patten of MSF.
Decreased time to ART initiation after nurse midwife HIV and Antenatal care integration
MSF also found a decreased time to ART initiation in pregnancy when HIV and antenatal care became integrated in Khayelitsha. The median time to initiation was 7 days after integrating services, compared to 36 days to initiation under previous arrangements.
The proportion of women initiating ART before delivery also increased from 55% in women at the same service, using doctors on specific days of the week, to 85.6% when women were initiated on ART by nurses.
2670 women were booked for antenatal care from May to November 2012. Excluding women with known HIV-infected status and who were already on ART, 95% of women tested for HIV (2286 of 2670). Of those who tested at booking, 36% were diagnosed HIV-positive (562 of 2286). HIV prevalence (among all women) was 31% (834 of 2670). 48.2% of women who tested in pregnancy were eligible for ART at a CD4 count of less than 350 cells/mm3 (271 of 562). Of these women who were eligible for ART, 85% initiated prior to delivery and 95% of all initiations were done by two midwives authorised to initiate ARV treatment.
The median time to initiation was seven days (IQR 5-12 days). 60% of women initiated within one week of eligibility and 78% within two weeks. Some of the reasons for delay in ART initiation were lack of readiness for ART or not having disclosed their status to their partners (18%), obstetric complications or transfer to a referral hospital (16%), work or travel schedule (11%) or being at less than 14 weeks of gestation (6.8%).
Patten G et al. Gradual increase in ART initiation following the implementation of the new WHO guidelines in Khayelitsha, South Africa, 6th South African AIDS Conference, Durban, June 2013, abstract 2288233.
Cox V et al. Reasons for delay in antiretroviral treatment initiation after nurse midwife HIV/antenatal care integration in Khayelitsha, South Africa, 6th South African AIDS Conference, Durban, June 2013, abstract 2288221.
South African AIDS conference discusses new aspects of male medical circumcision
Three studies examining new aspects of Voluntary Medical Male Circumcision (VMMC) were presented at the 6th South African AIDS conference.
The first looked at the sexual practices of men accessing VMMC services, the second compared the outcomes of VMMC for HIV-positive and HIV-negative men and the third evaluated the acceptance of VMMC amongst secondary-school learners.
Randomised clinical trials conducted in Kenya, South Africa and Uganda have demonstrated that male circumcision reduces the risk of HIV acquisition by between 50% and 75% and that this effect is sustained for at least five years.
Circumcision programmes are being implemented widely as part of HIV prevention activities in southern Africa. Operational research is evaluating the perfomance of these programmes and their impact on sexual behaviour.
Sexual behaviours among MMC participants
Abstinence from sexual intercourse during the wound-healing period after medical circumcision is presumed to be important for reducing the risk of HIV acquisition during this period through unhealed wounds.
A study in Kwazulu-Natal evaluated the resumption of sexual activity among men who underwent medical circumcision. 76.1 % of 775 men who received VMMC observed the six-week abstinence recommendation, with the remainder having post-operative coital activity by five weeks post-operation. Men with more than one partner were less likely to observe the six-week abstinence recommendation (p<0.001).
68.6% of the participants indicated that their sexual partners were unwilling to test for HIV - 46.9% of these already knew their status, while 22% were male partners who had already been tested prior to undergoing circumcision.
50.1% of the participants had a mean of more than one partner before circumcision. 65.6% of participants had used a condom at last sexual intercourse. Condom use began to decline eight months after the circumcision. At eight months, condom use had declined to 54.8% and to 52.1% at 12 months (p<0.001).
Among the study participants, the HIV incidence was 0.3% or 2.9 per 1000 person years, after 12 months. The prevalence of STI symptoms before circumcision was 18.4%. The incidence of STI symptoms was 0.7% or 1 per 1000 person years after 12 months.
Outcomes in HIV-positive men
MMC has health benefits such as prevention of STI transmission and urinary tract infections that might facilitate HIV transmission. For this reason, MMC programmes should not discourage HIV-infected men from undergoing MMC.
The Perinatal HIV Research Unit (PHRU) compared circumcision outcomes (such as adverse events, specifically wound infection) in HIV-positive and HIV-negative men through a retrospective medical record review of all men circumcised in February 2011.
Prior to circumcision, 26 (3.9%) of the males were found to be HIV-infected. The median CD4 count was 323 cells/mm3 (IQR: 270-449). Of all the HIV-infected males, none developed wound infection post-circumcision, but five of the 648 HIV-negative males did (0.8%).
VMMC uptake in secondary schools
Medical circumcision is most likely to reduce a man’s risk of HIV acquisition if it takes place before he becomes sexually active, or as soon as possible after sexual debut. For this reason, targeting of young men through secondary schools is a key means of maximising the population impact of medical circumcision on HIV transmission.
Researchers reported on a male medical circumcision programme among secondary school learners in the Vulindlela rural district in KwaZulu Natal province, 170 km from Durban
Boys were recruited from 42 secondary schools in the sub-district through a three-phase recruitment strategy which involved community consultation, MMC awareness-raising in schools during break-time and peer recruitment.
Peer recruitment was implemented though a local NGO, Zimnandi Zonke.
4873 MMCs were performed between March 2011 and December 2012. Only one male experienced an adverse effect and this was minor and self-resolving. 3575 (73%) of the males circumcised by the programme were between the ages of 15 and 19. The acceptability of VMMC was high among this population of school learners.
HIV testing and counselling (HCT) was provided at the school or at the study clinic. Learners who tested positive were referred to the study clinic or a primary health care clinic. The MMC procedure took place on Saturdays and post-operative procedures were undertaken in schools to avoid disruption of schooling.
Phili R et al. Risk compensation and sexual behaviour change among males following male circumcision in KwaZulu-Natal. 6th South African AIDS Conference, Durban. June 2013, abstract 2289164.
Laher F et al. Circumcision of HIV-infected males at a programme in Soweto. 6th South African AIDS Conference, Durban. June 2013, abstract 2276895.
Ngcobo N et al. Implementation of voluntary medical male circumcision (VMMC) using a school-based programme to target adolescent males In KwaZulu-Natal, South Africa. Poster: Ps 2-72 2287868. 6th South African AIDS Conference, Durban. June 2013, abstract 2287868.
Linezolid effective in treating XDR-TB in Khayelitsha, including for those HIV co-infected
New evidence from South Africa demonstrating how the high-strength antibiotic linezolid is effective in treating extensively drug-resistant TB (XDR-TB), even in patients with HIV, was presented at the 6th South African AIDS conference.
Preliminary results of a study conducted in South Korea have shown that the addition of linezolid to a failing regimen for the treatment of XDR-TB resulted in culture conversion and no relapse after completion of treatment in 13 patients. Final results of this study in HIV-negative patients are awaited in late 2013.
Data are lacking on the use of linezolid in HIV-positive people, particularly in respect of efficacy and safety while taking antiretroviral therapy.
Médecins Sans Frontières (MSF/Doctors without Borders’) carried out a pilot programme in which it evaluated the use of linezolid as part of community-based drug-resistant TB treatment in Khayelitsha. The data reported at the South African AIDS Conference concerned the outcomes of 16 patients treated with linezolid as part of a combination of drugs – including six HIV-positive patients – over a two-year period. To date, 71% of these patients have ‘culture-converted’ which is an early indicator that the two-year treatment regimen will be successful.
Nine of the patients had pre-XDR or XDR TB, seven patients had standard M/XDR treatment failure and the median treatment duration was eight months. Ten (71%) culture converted (three of which are HIV-positive), and are still culture negative and are receiving ongoing treatment. Three patients (21%), experienced treatment failure within the first nine months and are all now deceased. The time to death after treatment withdrawal was one to four months. One (8%) HIV-negative patient remains culture positive after three months and is receiving ongoing treatment.
MSF’s linezolid pilot programme – one of the first in Africa to include patients co-infected with HIV – suggests that linezolid’s efficacy is not compromised when patients are also taking HIV treatment.
MSF reported that the first patient to be cured of XDR-TB with a linezolid-containing regimen completed her course of treatment on 16 August 2013. Phumeza Tusile received treatment in a community setting at the Lizo Nobanda TB Care Centre in the Western Cape province.
“What makes Phumeza’s story inspiring is that when she started, her chances of cure were even less than the 20% treatment success rate that we often associate with XDR-TB diagnosed patients who are offered the standard XDR-TB treatment regimen,” said Dr Jennifer Hughes, MSF TB doctor and Phumeza’s treating physician. “Phumeza’s cure is nothing short of miraculous, and is due to access to a more effective drug and her sheer determination to beat the disease.”
Yet access to the drug in South Africa is limited due to high prices.
Linezolid offers XDR-TB patients facing few treatment options new hope, but pharmaceutical company Pfizer is the only supplier in South Africa and holds several patents on linezolid in the country, resulting in high prices that prevent the wider use of the drug for DR-TB. A six-month supply can cost R123,000 (USD 12) in the private sector. The South African Department of Health pays USD 29 per 600mg tablet, which means that to treat one patient with linezolid daily for six months will cost USD 5; MSF must pay the private sector price of USD 58 per tablet.
“As linezolid is only one part of an already expensive treatment regimen, we’ve seen that the high cost in both the public and private sectors limits doctors’ willingness and ability to prescribe the drug for their patients,” says Julia Hill, MSF Access Campaign Advocacy Officer in South Africa.
A generic version of linezolid manufactured by the Indian pharmaceutical company Hetero costs US$2.50 per tablet — over 90% cheaper. The product has been approved as a good-quality generic product by the Global Fund’s Expert Review panel.
Local evidence of linezolid’s use as a DR-TB drug is good news for South Africa, where over 10,000 people a year are diagnosed with the disease and whose chance of survival is typically less than 50% using the standard treatment regimen. Generally, between 5 to 8% of DR-TB patients are resistant to the few second-line drugs available and are considered to have pre-XDR or XDR-TB.
The MSF data from Khayelitsha contribute to a growing body of evidence on linezolid’s effectiveness against DR-TB, with results similar to studies in the US, Europe and Asia, which have shown a combined treatment success rate of 68%. While linezolid, like most drugs used to treat TB, has several negative side effects with long-term use, it offers patients hope of treatment when other options have run out.
Dr Vivian Cox, Medical Co-ordinator of MSF’s Khayelitsha project, urged the South African Department of Health to re-open its TB drug tender for linezolid to a broader range of bidders. She also urged that generic versions of linezolid should receive fast-track registration in South Africa, and encouraged the South African government to consider whether it can use flexibilities available under international trade agreements, such as compulsory licensing, in order to reduce the price through local generic manufacture.