Potential impact of new World Health Organization criteria for antiretroviral treatment for prevention of mother-to-child HIV transmission

Abstract

We reviewed the potential impact of new World Health Organization criteria for antiretroviral therapy using data from 1025 HIV-infected women and infants followed through 24 months in Lusaka, Zambia. The new criteria require initiating therapy among 68% of pregnant women and, if fully effective, would prevent 92% of maternal deaths and 88% of perinatal and postnatal infections. Using CD4 <350 cells/uL, irrespective of clinical stage, is more efficient and stricter CD4 cut-offs would be counter-productive.

The World Health Organization (WHO) recently revised criteria for initiating antiretroviral therapy (ART) among adults in low resource settings[1]. The new guidelines recommend ART for adults with clinical stage III or IV (regardless of CD4 count) or with CD4 <350 cells/uL (regardless of clinical stage) [1]. These guidelines simplify and liberalize prior guidelines that required stage III if CD4 count was 200-350 cells/uL. Programs to prevent mother-to-child HIV transmission are now one of the major sites where HIV-infected adults are identified and treated. This population is of high priority for ART since treatment is life-saving for women, a major factor protecting the health of their children, and ART has a direct role in reducing HIV transmission to the child[2].

Here we describe the potential impact of these guideline revisions using data collected from a trial in Lusaka, Zambia, conducted prior to the widespread availability of ART[3]. As part of this trial, 1025 HIV-infected women were recruited during pregnancy and followed after delivery for 24 months. At enrollment CD4 counts and plasma viral load were measured and clinical stage determined using a standardized history. No woman with stage IV disease was identified. PCR tests were performed on child blood samples collected at birth, 1 week, 1 month, monthly to 6 months and 3-monthly to 24 months. Children were breastfed to 4 months, thereafter practices were heterogeneous: some women weaned as per random assignment and others continued to breastfeed [3]. The median duration of breastfeeding in the whole cohort was 12 months.

We examined associations between maternal characteristics measured during pregnancy used to define eligibility for ART, including CD4 count, viral load, clinical stage and old and new WHO criteria. We examined the capacity of these characteristics to predict: (1) mortality among women between delivery and 24 months; (2) perinatal transmission, defined as HIV infection in the child detected before 6 weeks of age; and (3) postnatal transmission, defined as infection detected only after 6 weeks. Kaplan-Meier methods were used to calculate the risk of these outcomes, Cox Proportional Hazards models to determine relative risks, and, among those with the endpoint, the proportion who would have met criteria for ART was calculated to estimate the preventive fraction. The latter parameter can be used to infer the highest possible percentage of endpoint that could be averted if ART were fully effective. ART only became available towards the end of the study and all person-time was censored once ART was initiated.

In our cohort, 54% of women had CD4 count <350 cells/uL but most deaths (88%) occurred in this group (Table 1). 68% of women met the new WHO treatment criteria, that include clinical stage III in addition to CD4 count <350, and 92% of deaths occurred in this group. Applying the new criteria or using only CD4 count <350 cell/uL would result in treating 10.1 and 8.4 women respectively per death averted. A viral load of 48,428 copies/ml classified the same proportion of women in need of treatment as a CD4 count <350 but identified a smaller proportion of deaths (76%) consistent with prior data[4]. Adding viral load to CD4 count resulted in performance similar to the new WHO criteria. Adding viral load to the new WHO criteria would identify 96% of deaths but would require treating 76% of women. To account for hemodilution during pregnancy, some have suggested that lower CD4 thresholds be used in pregnant women to avoid over-treatment. Our data suggests making this adjustment is unwise as CD4 count thresholds of 200, 250 and 300 cells/uL would identify only 59%, 72% and 79% of deaths among women, respectively.

Table 1.

Percent of the pregnant population who would need antiretroviral therapy, rates and relative risks of maternal mortality and perinatal and postnatal HIV transmission and the preventable fraction, assuming a fully effective intervention, by various criteria for initiating antiretroviral therapy

	Mortality among women 24 months after delivery				Perinatal HIV transmission (detected by 6 weeks)			Postnatal HIV transmission (detected after 6 weeks)
	N (%) in population	Maternal mortality	Relative Risk (95% CI)	N (%) in deaths	Transmission rate	Relative Risk (95% CI)	N (%) in infections	Transmission rate	Relative Risk (95% CI)	N (%) in infections
CD4 counts
<350	554 (54.2)	0.162	7.2 (3.6-14.5)	66 (88.0)	0.184	2.9 (1.9-4.3)	98 (76.6)	0.206	5.6 (3.1-10.0)	66 (82.5)
≥350 cells/uL	469	0.026		9	0.066		30	0.044		14
Viral load
≤50,000	560	0.041		18	0.061		33	0.051		20
>50,000	462 (45.2)	0.172	4.4 (2.6-7.6)	57 (76.0)	0.216	3.8 (2.6-5.7)	95 (74.2)	0.237	5.4 (3.3-9.0)	60 (75.0)
WHO clinical stage
I/II	616	0.071		33	0.101		62	0.108		46
III/IV	409 (39.9)	0.138	2.0 (1.3-3.2)	42 (56.0)	0.176	1.8 (1.3-2.5)	66 (51.6)	0.147	1.4 (0.9-2.2)	34 (42.5)
Old criteria *
Eligible	377 (36.8)	0.197	5.2 (3.2-8.7)	54 (72.0)	0.205	2.4 (1.7-3.4)	72 (56.3)	0.219	3.4 (2.2-5.3)	46 (57.5)
Not	648	0.043		21	0.087		56	0.078		34
New criteria §
Eligible	698 (68.1)	0.134	6.2 (2.7-14.2)	69 (92.0)	0.167	3.4 (2.0-5.7)	112 (87.5)	0.170	4.5 (2.3-8.6)	70 (87.5)
Not	327	0.024		6	0.050		16	0.042		10
Either CD4 or viral load ‡
One or both	677 (66.1)	0.141	8.4 (3.4-20.9)	70 (93.3)	0.174	4.0 (2.4-6.9)	113 (88.3)	0.184	7.6 (3.5-16.6)	73 (91.3)
Neither	347	0.019		5	0.044		15	0.028		7

^*Old criteria: Stage IV or CD4 count <200 or CD4 200-350 and clinical stage III

^§New criteria: Stage III or IV or CD4 < 350

^*Either CD4 count <350 or viral load >50,000 copies/ml

Note on denominators: 1025 women are included in the analysis of mortality which includes all unique, untreated women enrolled (but not necessarily randomized) with live-births and some follow-up. Women missing baseline data are excluded when the specific parameter is examined but are considered not to meet criteria for aggregate definitions. Denominators for perinatal transmission (n=1055) include all infants born in the study to untreated women (including subsequent pregnancies among enrolled women) with at least one PCR result regardless of whether randomized. Denominators for postnatal transmission (n=78) are further restricted to children free of HIV infection and followed after 6 weeks of age.

The old WHO criteria and clinical stage perform poorly to detect perinatal and postnatal HIV transmission. The new criteria, however, would detect 88% of perinatal and postnatal HIV infections. CD4 count <350 alone would detect almost the same number of postnatal infections (83%) but a lower percentage (76%) of perinatal infections (Table 1). Both viral load and CD4 count are independent predictors of transmission. For perinatal transmission, viral load (relative risk [RR]=3.1 95% CI: 2.0-4.6) is the stronger predictor in multivariate analysis controlling for CD4 count (RR=2.0 95% CI: 1.3-3.0). For postnatal transmission, their contributions are similar: viral load (RR=3.8 95% CI: 2.2-6.3) and CD4 (RR=3.8 95% CI: 2.1-6.8). Combining viral load and CD4 count as either/or criteria for initiating therapy would lead to better results than the new WHO criteria while treating slightly fewer women.

If we adjust for the expected efficacy of ART to reduce perinatal and postnatal transmission[2], applying the new criteria among pregnant women could prevent 82% of all infections even if no extended postnatal interventions are applied among the other women. It is desirable to implement these extended interventions to reduce transmission among women not needing ART[5] but these interventions will be more costly per infection averted as the transmission rate in this sub-set is lower.

Clinical staging is useful in settings where laboratory testing cannot be done, is unreliable or delayed but its value when laboratory results are available is limited. Our data indicate that its inclusion increases the number of women treated with only marginal increase in coverage of women and infants at risk.

Our estimates of the proportion of deaths and infections averted are directly proportional to the proportion of the population meeting each criterion. The distribution of the severity of disease is likely to vary across settings and over time depending on stage of the epidemic, referral patterns and service coverage etc. Other studies have reported less advanced disease than our cohort[2] but the distribution of CD4 counts and clinical stage that we observed is similar to a large multi-site aggregation of data on pregnant women participating in the MTCT-Plus program in 8 African countries[6].

Our data provide evidence-base support for the treatment thresholds in the revised WHO treatment guidelines. Our analysis also provides estimates of the large positive impact these guidelines could have if widely implemented on reducing mortality among women and HIV transmission to children.