Targeted viral load testing combined with clinical and immunological evaluation in cases of first-line antiretroviral treatment failure prevented unnecessary treatment switches in 25% of patients in a public sector hospital in India, Bharat Rewari and colleagues reported in the online advance edition of the Journal of Acquired Immune Deficiency Syndromes.
With the increased scale-up of antiretroviral therapy in low- and middle-income countries defining, detecting and managing treatment failure has become a critical challenge.
Within the context of limited resources national treatment programmes have developed algorithms to address this challenge. So evaluation of these programmes is essential to developing effective treatment monitoring strategies that assure appropriate and timely switching to second-line antiretroviral therapy.
In 2004 India (the National AIDS Control Organisation or NACO) adopted a public health approach and began to provide free antiretroviral treatment.
At present over 320,000 HIV-infected people receive treatment at more than 260 public sector facilities throughout the country.
The standardised first-line consists of either zidovudine (AZT) or stavudine (d4T) with lamivudine (3TC) in combination with either nevirapine (NVP) or efavirenz (EFV). Routine laboratory testing of those on first-line antiretrovirals includes CD4 cell count at baseline and then every six months.
Viral load testing, as in most resource-poor settings, is not routinely used in the public health sector. Treatment failure is based upon immunologic or clinical criteria.
In 2008 NACO piloted a national strategy to provide free second-line antiretroviral treatment in the public health sector at two large urban ART centres: Government Hospital of Thoracic Medicine, Tambaran in Chennai and Sir J.J. Hospital in Mumbai.
Patients, aged 18 years of age or over, on standard first-line antiretroviral therapy for six months or longer with good treatment adherence (routine self-report of 95% adherence or more) were referred for second-line evaluation if
1) their CD4 cell counts had declined to pre-ART levels, or
2) if their CD4 cell counts had dropped to less than fifty percent of their highest on-treatment level, or
3) if they failed to reach a CD4 cell count of 100/mm³, or
4) if they developed a World Health Organization stage 3 or 4 AIDS-defining illness.
NACO guidelines recommend that patients with poor treatment adherence get further counselling to be re-assessed (CD4 cell count) within a one to three month period.
Patients with a non-opportunistic infectious illness are treated and then re-assessed after completion of treatment.
Pulmonary tuberculosis (TB) is not automatically considered as evidence of treatment failure; those with suspected TB are referred for TB evaluation and treatment to be re-evaluated (HIV clinical and immunological status) after eight weeks of TB therapy.
At each site those referred for second-line treatment were seen by a clinical expert review panel to determine who should get viral load confirmatory testing.
Patients with a viral load of 10,000 copies/ mL or above were then referred to start second-line treatment after additional counselling. The standard second-line treatment is: tenofovir+lamivudine+zidovudine and lopinavir/ritonavir (TDF/3TC/AZT+LPV/r). .
During the six month pilot phase (January 1-July 1, 2008) of the 224 patients referred to the clinical expert panels at the two hospitals 154 met the criteria for evaluation. 82% (127) were male. 57 (37%) had antiretroviral experience before enrolment in the government programme. All the women were treatment-naïve.
The median length of time on first-line antiretroviral treatment at the time of referral was 27 months (range 5-50 months); the median CD4 cell count was 78 cells/mm³ (range 3-357cells/mm³).
Of the 122 (79%) patients with WHO immunologic or clinical treatment failure and recommended for viral load testing 87 (71%) had a viral load of 10,000 copies/mL or more and recommended for second-line treatment.
This means viral load testing provided a 71% positive predictive value (PPV) for “definitive virologic failure” among this cohort.
29 (24%) had a viral load under 400 copies/mL, and six (5%) had a viral load between 400 and 10,000 copies/mL.
The authors note that close to 25% of patients with clinical or immunological failure who were referred for evaluation were, in fact, virally suppressed. Viral load testing to routinely confirm virologic failure, they note, not only prevented unnecessary switches but meant patients could get the most out of the cheaper first-line option.
Within a resource-poor setting unnecessary switching means added programme costs and exhausting the only second-line treatment available, they add.
The authors note that studies in Asia and Africa have shown how immunological criteria have failed to identify virologic treatment failure. They cite studies in Uganda and South Africa that showed the positive predictive value of clinical and immunological criteria to be very low, 14% and 21%, respectively.
Their findings, they stress, support others in advocating for the “urgent need for low-cost point-of-care viral load testing technologies to guide the detection and clinical management of treatment failure in resource-limited settings.”
Given the limitations of cost and the feasibility of routine viral load testing in India the authors suggest a viral load test at the programme level six months after the start of first-line ART to determine virologic efficacy and adherence.
They note the high level (37%) of treatment experienced patients in their evaluation probably reflects the extensive access to HIV treatment in the private sector in large urban settings, such as Mumbai and Chennai; so increasing the risk of treatment failure among this cohort.
Those with previous exposure to antiretrovirals would benefit from early viral load testing, they add.
The authors note that in India as in other low- and middle-income countries patients with undetected virologic failure for long periods of time are at risk of accumulating multiple drug resistant mutations. The consequence of which will be to limit the effectiveness of available second-line antiretroviral regimens.
They add this also highlights the urgent need to identify second-line regimens for those who have failed first-line without worrying about the limited effectiveness because of cross-resistance.
Targeted confirmatory viral load testing, they note, for patients with immunologic and clinical failure has been adopted in other resource-limited settings as well as being strongly recommended in the 2010 revision of the WHO antiretroviral guidelines http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf
The authors add that “NACO has expanded second-line ART to 10 Centers of Excellence which are linked to all public sector ART facilities across India.”
They conclude “the inclusion of targeted HIV RNA (viral load) testing in the evaluation of treatment failure can prevent unnecessary switches to second-line treatment” [in the context of a resource-limited programmatic setting in India].
Rewari BB et al. Evaluating patients for second-line antiretroviral therapy in India: the role of targeted viral load testing. Journal of Acquired Immune Deficiency Syndromes, advance online publication, October 6, 2010. (Link to abstract).