Predicting Virological Decay in Patients Starting cART

In This Article

Abstract and Introduction

Abstract

Objective: Model trajectories of viral load measurements from time of starting combination antiretroviral therapy (cART), and use the model to predict whether patients will achieve suppressed viral load (≤200 copies/ml) within 6-months of starting cART.

Design: Prospective cohort study including HIV-positive adults (UK Collaborative HIV Cohort Study).

Methods: Eligible patients were antiretroviral naive and started cART after 1997. Random effects models were used to estimate viral load trends. Patients were randomly selected to form a validation dataset with those remaining used to fit the model. We evaluated predictions of suppression using indices of diagnostic test performance.

Results: Of 9562 eligible patients 6435 were used to fit the model and 3127 for validation. Mean log₁₀ viral load trajectories declined rapidly during the first 2 weeks post-cART, moderately between 2 weeks and 3 months, and more slowly thereafter. Higher pretreatment viral load predicted steeper declines, whereas older age, white ethnicity, and boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitors based cART-regimen predicted a steeper decline from 3 months onwards. Specificity of predictions and the diagnostic odds ratio substantially improved when predictions were based on viral load measurements up to the 4-month visit compared with the 2 or 3-month visits. Diagnostic performance improved when suppression was defined by two consecutive suppressed viral loads compared with one.

Conclusions: Viral load measurements can be used to predict if a patient will be suppressed by 6-month post-cART. Graphical presentations of this information could help clinicians decide the optimum time to switch treatment regimen during the first months of cART.

Introduction

Combination antiretroviral therapy (cART) based on at least three antiretroviral drugs from at least two drug classes slows HIV replication and prevents transmission of HIV. Factors taken into consideration when selecting a patient's first cART-regimen include: the presence/absence of genotypic resistance against specific antiretroviral drugs; potential side-effects; comorbidities; drug interactions and patient preference.^[1] Current guidelines recommend monitoring the effectiveness of first-line cART using routine viral load measurements (copies of HIV-1 RNA/millilitre of plasma),^[1–3] at about 4-weeks after initiation of treatment and then every 3-months to confirm undetectable viral load levels.^[1]

HIV-dynamic studies have improved our understanding of the process of virus elimination after initiation of cART.^[4–5] During the first few weeks of treatment there is a rapid decline in viral load, primarily because of the decay of productively infected cells.^[4,6–8] The rate of decay becomes slower thereafter because of the release of HIV viruses by macrophages and other long-lived cells of the lymph nodes.^[4,5,8] Finally, the decline levels off, probably because of reservoirs of long-lived cells still producing HIV virus.^[4] In some cases the viral load level may rise again, for example, because of nonadherence to the cART regimen or emergence of resistant virus.^[4]

Clinicians may be tempted to increase monitoring or switch drug therapy during the phase of slow viral load decline, even though this is predictable and the patient is likely to achieve viral suppression. Early treatment switching may be unnecessary and has disadvantages, including that the new regimen may be less effective than the current one, a reduction in the number of available future treatment options, and the possibility of side-effects associated with the new regimen. Conversely, delays in switching regimen after virologic failure has occurred could result in the accumulation of resistance mutations, immunologic decline, and an increased risk of clinical events. Guidelines recommend that a switch of cART-regimen should be considered if a patient's viral load fails to fall to undetectable levels (<50 copies/ml) after 24–36 weeks of treatment.^[1,2]

In this article we model repeated measurements of viral load from start of cART to the first suppressed viral load. Among patients with at least two observed measurements, we use this model to predict a patient's future post-cART viral load measurements given their observed measurements up to 2,3, or 4 months post-cART. Based on these future measurements we predict whether patients will achieve a suppressed viral load measurement within 26-weeks of start of cART, test the reliability of these predictions, and show how this information can be used to enhance decisions on when to switch first-line cART.

Lippincott Williams & Wilkins

Table 1. Characteristics of the 9562 eligible patients.
	Pretreatment HIV-1 RNA (copies/ml)
	<10 k^b	10 k to <100 k	100 k to <500 k	≥500 k
Number of patients	756	3372	3825	1609
Median (IQR)^a age (years)	36 (31–42)	37 (31–43)	37 (32–44)	38 (33–45)
Male (%)	56	74	79	79
Risk group (%)
Homo/bisexual	35	55	61	59
IDU	4	2	2	2
Heterosexual	55	37	32	35
Other/not known	6	5	4	4
Ethnicity (%)
White	40	57	61	62
Black African	43	27	23	25
Other	14	14	14	12
Not known	3	2	2	1
First-line cART-regimen (%)
NNRTI-based	52	63	67	63
PI-based	8	5	5	5
Boosted-PI	33	27	23	27
Other	7	5	5	5
Median (IQR) pretreatment HIV-1 RNA (log₁₀ copies/ml)	3.43 (2.86–3.78)	4.67 (4.43–4.86)	5.32 (5.15–5.50)	5.88 (5.71–6.00)
Median (IQR) pretreatment CD4⁺ cell count (cells/μl)	272 (180–400)	236 (159–320)	180 (84–270)	114 (42–218)

^aIQR, Inter quartile range.
^bk, A thousand.
cART, combination antiretroviral therapy.

Table 2. Validation of the model for predicting future suppression by 6 months since start of treatment given observations up to a specified visit.
	2-month visit	3-month visit	4-month visit
Number patients^a	1927	1127	698
Observed suppressed	81%	69%	51%
Predicted suppressed	80%	67%	51%
Sensitivity [95% CI]	86% [84%, 88%]	81% [79%, 84%]	80% [76%, 85%]
Specificity [95% CI]	46% [41%, 51%]	63% [58%, 68%]	79% [75%, 83%]
PPV [95% CI]	87% [85%, 89%]	83% [80%, 86%]	80% [76%, 84%]
NPV [95% CI]	44% [39%, 49%]	60% [55%, 65%]	79% [75%, 84%]
LR+ [95% CI]	1.60 [1.45, 1.76]	2.21 [1.92, 2.55]	3.86 [3.12, 4.78]
LR− [95% CI]	0.30 [0.26, 0.36]	0.30 [0.25, 0.35]	0.25 [0.20, 0.31]
DOR [95% CI]	5.25 [4.09, 6.74]	7.49 [5.65, 9.93]	15.60 [10.77, 22.56]

^aNumber of patients not suppressed at the specified visit and with at least one future measurement.
CI, confidence interval; DOR, diagnostic odds-ratio; LR−, likelihood ratio of a negative result; LR+, likelihood ratio of a positive result; NPV, negative predictive value; PPV, positive predictive value.