Community Based Antiretroviral Treatment in Rural Zimbabwe

Abstract

Treatment of HIV has reduced HIV/AIDS-related mortality. Sustaining >90% virologic suppression in sub-Saharan Africa requires decentralized care and prevention services to rural communities. In Zimbabwe, the number of people receiving antiretroviral treatment (ART) has increased rapidly. However, access to treatment monitoring tools such as viral load and drug resistance testing is limited. We assessed virologic treatment outcomes among ART recipients in Nyamutora, a rural community receiving bimonthly ART and prevention services. We enrolled all ART recipients (143) at 6-monthly visits in the Nyamutora community in 2014 and 2015. Whole blood samples were collected in K-EDTA tubes, transported to Harare for CD4 counts and viral load testing, and genotype was obtained in participants with viral loads >1,000 copies/ml. Ages ranged from 2 to 75 years (median 43 years) with a median 42 months on ART at follow-up. Eight of 143 (6%) had viral loads >1,000 copies/ml at one of the 3 visits, 7 on first-line nevirapine (NVP)-based ART and 1 on second-line LPV/r-based ART. Seven participants had sequence data available, and five had drug resistance mutations, K65R, T69N, K101E, K103N, Y181C/I, M184V, and G190A. Virologic failure (p = .001) and drug resistance mutations (p = .01) on first-line NVP-based ART were associated with younger age by univariate exact logistic regression. The participants had high viral suppression (94%) despite less than optimal (NVP based) ART regimens without laboratory monitoring. Virologic failure and drug resistance were higher among children and adolescents. Effective ART delivery to the community achieved high rates of virologic suppression and minimal drug resistance.

Introduction

Antiretroviral treatment (ART) has been available in Zimbabwe in the public sector since 2004.¹ The country's first National Antiretroviral Therapy Program was implemented following World Health Organization (WHO) guidelines for ART, using two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment initiation and boosted protease inhibitors for second-line treatment.² In 2015, there were an estimated 1.4 million of Zimbabwe's 13 million citizens living with the HIV.³

According to 2013 Zimbabwean HIV guidelines, patients with CD4 counts less than 500 cells/mm³ or with an AIDS defining illness or WHO clinical stages 3 and 4 were initiated on HIV treatment.² An estimated 732,919 adults and 55,061 children were receiving ART in 2014. However, despite treatment of 63% and 55% of eligible adults and children, HIV treatment-monitoring is limited.⁴ Patients are largely followed with CD4 counts and clinical observation. Viral load monitoring and HIV drug resistance tests are limited by high costs, inaccessibility, lack of resources, laboratory equipment, cold transport, analysis, and storage. There is a need to access remote communities and to acquire sample analytes that are easier to collect, transport, store, and analyze.

In rural Africa, most people on HIV treatment rely on the public health ART programs (Ministry of Health and Child Care) from clinics often more than 20 km away. Significant transport cost to access HIV and TB treatment is a major barrier to medication adherence and effective care in sub-Saharan Africa.^5

–8 Health service delivery and point of care monitoring are important components of HIV test and treat programs and advances in prevention and care.^9

–13 Saving African Families Enterprise (SAFE) (https://www.facebook.com/SAFEinformation.org) initiated the delivery of drugs directly to a rural community in Karoi district, Zimbabwe. This is a tobacco-farming region 200 km North-West of Harare. Since 2007, ART has been delivered to the community by the Chidamoyo Christian Hospital with the help of community health workers. To assess the effectiveness of community based ART, we measured CD4 counts, viral load (VL), and HIV drug resistance among consenting rural villagers receiving community based ART.

Materials and Methods

Study population and sample collection

One hundred forty-three (143) individuals receiving ART (142 first line and 1 second line) were enrolled after consenting to participate in the study between 2014 and 2015 in Nyamutora village, Karoi. This was a cross-sectional study that had limited longitudinal data in a subset of patients, that is, 106 participants with at least one follow-up visit. The majority of participants were enrolled at the first visit (101), but additional participants were recruited at first (20) and second follow-up (22) time points. All the recruited participants (143) were receiving ART through an outreach team from the Chidamoyo Christian Hospital (https://www.youtube.com/watch?v=f7se3-zhndo), which distributes antiretroviral drugs provided by the Ministry of Health and Child Welfare (MoHCW) decentralized ART program.¹⁴ This is accomplished through single-day drug delivery by Chidamoyo Christian Hospital Clinic staff (one counselor, one pharmacy assistant, and one nurse).¹⁵

Whole blood samples were collected in EDTA tubes for CD4 counts, VL, and HIV drug resistance testing every 6 months for a period of 18 months (maximum of three samples per participant). Samples were transported to Harare at 4°C and analyzed at a central laboratory. Demographic and clinical data were collected at study enrollment and follow-up visits. CD4 count, VL, and genotypic testing results were returned to the Chidamoyo Christian Hospital for clinical management.

Laboratory procedures

Absolute CD4+ T lymphocyte counts were performed using a Partec CyFlow counter (CyFlow, Partec, Munster, Germany) on whole blood samples at the time of arrival in the laboratory. Samples were centrifuged at 1,000 × g for 10 min at 4°C to separate plasma.¹⁶ Aliquots of plasma (1 ml) were stored at −80°C for viral load (VL) and drug resistance testing. Plasma VL testing was performed on a COBAS AmpliPrep/COBAS TaqMan system v2 (Roche, Penzberg, Germany), with a lower limit of detection of 20 copies/ml.

HIV drug resistance testing

Plasma samples with viral loads >1,000 copies/ml were centrifuged at 23,000 rpm for 1 h, at 4°C to pellet the virus. Viral RNA was extracted using a PureLink Viral RNA/DNA Kit (Thermo Fisher Scientific) as per manufacturer's instructions. Complimentary DNA synthesis and nested polymerase chain reaction (PCR) were done to amplify an 849-bp reverse transcriptase gene fragment spanning codons 21–304, using primers and amplification conditions described previously.¹⁷ Amplicons were sequenced on a 3130xl Genetic Analyzer (Applied Biosystems) following a previously published Southern African Treatment Research Network (SATuRN) protocol.¹⁶ Sequences were analyzed using Sequencher v5.4 (Gene Codes Co.), and drug resistance mutations were detected using the Stanford HIV drug resistance database (HIVdb).¹⁸

Statistical analysis

Tables and graphs of the observed resistance mutations and frequencies were generated. Statistical calculations were performed in Stata/MP 13.0 statistical software (StataCorp, College Station, TX). Exact methods were used to analyze each descriptive variable individually for relationship to any virologic failure or drug resistance by the final sampling time point, which could be the last sampling before loss to follow-up or death or the second 6-monthly follow-up visit. Exact logistic regression was used to analyze continuous variables, that is, age and time on ART and Fisher's exact test were used to analyze categorical variables, that is, sex, age category, NNRTI-backbone, cotrimoxazole treatment, reported adverse drug reactions, and use of traditional herbs. Median statistical comparisons were done using nonparametric Wilcoxon rank-sum (Mann–Whitney) test. Where age or time on treatment was analyzed as continuous predictors for presence of drug resistance, analyses were stratified by adult or child classification (≤17, >17 years old).

Ethics statement

Ethical approval was obtained from the Medical Research Council of Zimbabwe (MRCZ). A written informed consent (or assent, in the case of children ≤17 years of age) was obtained from each study participant.

Results

One hundred forty-three (143) participants were enrolled. One hundred one participants were enrolled at the initial visit, 20 participants were enrolled at the first follow-up visit, and 22 participants were enrolled at the second follow-up visit. Of the 101, 85 were seen at both follow-up visits, and 5 were present at one follow-up visit. Eleven participants were not followed up because they were deceased (3), absent (5), or had transferred their care to another facility (3) at the follow-up visit(s). Of the 20 enrolled at first follow-up, 16 were present at the second follow-up visit and 4 were absent. Twenty-two (22) participants were enrolled at the last visit (second follow-up). Of the 143 enrollees, 137 were on known ART regimens and 6 were on unknown regimens due to incomplete documentation. Table 1 summarizes the characteristics of study participants.

Table 1.

Demographics and Clinical Characteristics of Study Participants

		Based on virological monitoring
Characteristics	Participants (n = 143)	Suppressed (VL <1,000 c/ml)	Failure (VL >1,000 c/ml)	p
Sex, n (%)
Male	43 (30)	41 (95)	2 (5)	.52^a
Female	95 (66)	89 (94)	6 (6)
Unknown	5 (4)	5 (100)	—
Current drug regimens, n (%)
TDF/3TC/NVP	72 (50.4)	68 (47.6)	4 (2.8)
TDF/3TC/EFV	24 (16.8)	24 (16.8)	0
AZT/3TC/NVP	12 (8.4)	9 (6.3)	3 (2.1)
D4T/3TC/NVP	26 (18.2)	26 (18.2)	0
D4T/3TC/EFV	2 (1.4)	2 (1.4)	0
ABC/ddI/LPV/r	1 (0.7)	0	1 (0.7)
Unknown	6 (4.2)	6 (4.2)	0
Clinical history/demographics at second follow-up, median (95% CI)
Age in years	43 (39–44)	43 (40–44)	16 (6–40)	.002^b
CD4 count, cells/mm³	476 (444–556)	479 (449–559)	423 (90–1,501)	.74^b
Time on ART, months	42 (38–49)	42 (37–49)	50 (25–62)	.64^b
Participants at each visit^c
Baseline/first visit	101	95	6
First follow-up visit	107	—	—
Second follow-up visit	124	122	2

p-Value based on Fisher's exact test.

p-Value based on nonparametric Wilcoxon rank-sum test.

Total participants across all visits was 143; however, due to staggered enrollment and loss to follow-up/death, there were fewer than 143 participants at each visit.

3TC, lamivudine; ABC, abacavir; ART, antiretroviral treatment; AZT, zidovudine; c/ml, copies per milliliter; CI, confidence interval; D4T, stavudine; DDI, didanosine; EFV, efavirenz; LPV/r, lopinavir-boosted ritonavir; mm³, cubic millimeter; NVP, nevirapine; TDF, tenofovir; VL, viral load.

Antiretroviral treatment regimens

All except one participant receiving second-line ART (abacavir, didanosine, and lopinavir boosted ritonavir) (ABC/ddI/LPV/r) were on first-line regimens as recommended by Zimbabwean ART guidelines.¹⁹ As WHO recommendations promote substitution of stavudine (d4T) with tenofovir (TDF) rather than zidovudine (AZT),²⁰ the majority of participants (67%) were receiving TDF and lamivudine (3TC), with nevirapine (NVP) or efavirenz (EFV). Despite efforts to phase out d4T,²¹ 28 (20%) of the participants were receiving d4T-containing regimens. Fifteen of 20 (75%) children were receiving NVP-based ART, with 8 of the 15 (53%) receiving AZT/3TC/NVP. Six of the participants were on unknown drug regimens and none of the six had virologic failure (Table 1). All of the virologic failures on first line were on NVP-based regimens as shown in Figure 1.

FIG. 1.

Percentage of participants on different ART regimens. Numbers in bars represent participants with virologic failure among children and adults. The plain regions of the bars represent the proportion of children (≤17 years of age), while the checked regions represent the proportion of adults (>17 years of age).

Virologic failure and drug resistance

Of the 143 participants, 8 had at least one viral load >1,000 copies/ml. Of the eight participants with virological failure (VF), two had confirmed VF at both baseline and follow-up, two died, one had insufficient sample at follow-up, two were suppressed at baseline and developed resistance at follow-up, and only one participant with VF at baseline achieved viral suppression at follow-up (Table 2). One participant (NVK067) had 1,484 copies/ml that failed to amplify after two PCR attempts and sequencing could not be performed. There was insufficient plasma to re-extract from the original sample.

Table 2.

Participants with Virological Failure and Drug Resistance Mutations

Sample ID	Sex	Age	ART regimens	Baseline VL (log₁₀ c/ml)	Baseline mutations	Follow-up VL (log₁₀ c/ml)	Follow-up mutations
NVK001	F	34	TDF/3TC/NVP	3.08	Y181C	Deceased	Not assessed
NVK015^a	M	30	TDF/3TC/NVP	<20	Not assessed	4.87	K65R, K101E, G190A
NVK058	M	4	AZT/3TC/NVP	5.00	No mutations	Insufficient sample	Not assessed
NVK067^a	F	46	TDF/3TC/NVP	<20	Not assessed	3.17	Failed amplification
NVK073	F	5	AZT/3TC/NVP	3.61	K103N, M184V	4.25	K103N, M184V
NVK082	F	3	AZT/3TC/NVP	3.76	No mutations	<20	Not assessed
NVK088^b	F	17	ABC/ddI/LPV/r	5.30	T69N, Y181I	Deceased	Not assessed
NVK097	F	10	TDF/3TC/NVP	5.08	K65R, K103N	4.25	K65R, K103N, Y181C, G190A

Sequence results at follow-up are not presented for participants deceased, absent, or suppressed.

Two subjects suppressed at baseline and with virologic failure at follow-up.

One participant was on second-line treatment.

F, female; M, male.

In this study, we used the detection of >1,000 copies/ml of HIV RNA to identify virologic failure, a level of viremia recommended by WHO in LMICs to prompt adherence counseling, genotyping, and consideration of second-line ART.²² The detection of low level viremia (LLV) afforded by the Roche assay^23
–25 identified LLV from >20 to 200 copies/ml in 12/143 (8%), and one participant had a viral load of 322 copies/ml at the last visit. However, none of the 12 participants with LLV developed VF (>1,000 copies/ml) at a subsequent follow-up visit (Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/aid).

Seven of the eight samples with VF (VL >1,000 copies/ml) were successfully sequenced and five had drug resistance mutations. One had a single mutation, and four had two or more mutations detected. All virologic failures on first-line ART were on NVP-based regimens. Two children had persistent VF and continued treatment with NVP. A 5-year-old girl (NVK073) with K103N and M184V at baseline maintained these mutations after 12 months of AZT/3TC/NVP. However, a 10-year-old girl (NVK097) on TDF/3TC/NVP with K65R and K103N gained two NNRTI mutations, G190A and Y181C at 12 months follow-up (Table 2).

None of the predictor variables except age were significantly associated with VF and drug resistance mutations at the end of the study period (second follow-up visit), as shown in Tables 3 and 4.

Table 3.

Categorical Variables and Virological Failure

	VF	No VF	Fisher's exact test (p-value)
Sex (6 with unknown gender)
Male	2	41	.52
Female	6	89
Adult (>17 years) (three with unknown age)
Yes	3	117	.002
No	5	15
Cotrimoxazole cotreatment
Yes	3	51	.65
No	5	84
Reported adverse drug reactions
Yes	5	48	.13
No	3	87
Use of traditional herbs
Yes	0	4	.79
No	8	131
NNRTI-backbone (six with unknown regimen)
NVP	7	103	.22
EFV	0	26

NNRTI, non-nucleoside reverse transcriptase inhibitor; VF, virologic failure.

Table 4.

Continuous Variables and Drug Resistance

Resistance mutations	Odds ratio	p	95% CI
Age	0.93	.01	0.87–0.98
Time on ART	0.99	.99	0.94–1.05

Children (≤17 years) were more likely to experience VF compared to adults (p = .002, Fisher's exact test) if age was treated categorically (Table 3). Younger age was significantly associated with drug resistance mutations in a continuous framework, and the odds of observing a mutation decreased by .93 for each year of age at enrollment (Table 4). However, when the analysis was restricted to adults (>17 years), there was no significant association between age and VF (p = .35) or drug resistance mutations (p = .17). When the analysis was restricted to children (≤17 years) only, there was no significant association between age and VF (p = .63) or drug resistance mutations (p = .59), using Exact logistic regression.

In summary, of 143 total subjects, 85 were present at all three visits, 21 had 2 visits, and 37 had only 1 visit (22 of the 37 were enrolled at the last visit). Fourteen participants were lost to follow-up; 3 participants transferred out of the study and 11 were absent at the first or second follow-up visits. Three participants died during the course of the study.

Discussion

The 90-90-90 HIV goals of the WHO aim at 90% of people with HIV knowing their status, 90% of all HIV diagnosed people linked to care and receiving ART, and viral suppression of 90% of people receiving ART by 2020.²⁶ The last 90 depends on access to ART which has increased through continued reductions in the cost of generic drugs. First-line treatment with WHO prequalified fixed dose combination d4T, 3TC plus NVP, the most widely used combination in 2007–2008, was provided for less than $100 per person per year.²⁷ Assessing virologic suppression on ART depends on a cost effective VL measurement, a challenge to health service delivery to rural patients in resource limited settings.^28
–30 Models of community-based ART with task shifting to primary care have been evolving in Africa.^31
–33 In Nyamutora, access to care was achieved by regular (2 monthly) delivery of ART^11,12,34 to a village site within 3–4 km of the recipients' rural homes. Monitoring viral load with blood samples obtained in the community provided evidence for effective treatment.³⁵

Of 143 participants living with HIV/AIDS, 94% (135/143) had suppressed viral loads (VL <1,000 copies/ml) over the available follow-up period. The lower threshold recommended for plasma HIV genotyping with either ViroSeq or TruGene^36,37 is >1,000 copies/ml and one sample with low copy numbers (1,484 copies/ml) could not be amplified (NVK067). Among 142 on first-line ART, only 5% (7/142) of participants had a VL >1,000 copies/ml with a limited number of mutations observed. Of the 143 participants only 1 was on second-line ART with reverse transcriptase-related drug resistance mutations persisting from first-line ART.

Antiretroviral treatment and drug resistance

The first-line ART combination regimens recommended by national guidelines in Zimbabwe in 2010 included both stavudine and nevirapine. However, by 2013¹⁹ the WHO and Zimbabwe recommended the phase out of stavudine and substitution of TDF in ART regimens²⁰ due to persistent peripheral neuropathy. This was the most common problem self-reported by 49 of 143 participants (34%), consistent with the persistence of stavudine-induced peripheral neuropathy, as shown in previous studies.^38,39 Similarly the WHO recommendations for first-line ART in 2013 suggest EFV as the preferred NNRTI with NVP as an alternative.⁴⁰ Nevertheless, because of cost and availability, most participants (71/143) were receiving TDF +3TC + NVP, a controversial regimen⁴¹ reviewed by Tang et al. in 2011, which may have reduced effectiveness^42

–45 compared to a fixed dose combination of TDF +3TC + EFV.⁴⁶ In this study most participants (7/8) with VF were receiving NVP-based ART, as shown in Table 3. Of the 143 participants, 110 (77%) were on NVP-based regimens, with only 26 (18%) on EFV-based regimens. Three children ages 3, 4, and 5 years receiving AZT +3TC + NVP had virologic failure (Table 2) supporting the importance of EFV as the NNRTI backbone of choice in children aged 3–10 years of age.⁴⁶ Fifty-four of the 143 (38%) were concurrently provided cotrimoxazole as recommended by the WHO to reduce opportunistic infections, mortality, morbidity, and rates of hospitalization in HIV infected adults and children.⁴⁷

Drug resistance mutations were identified in five of the seven participants with virologic failure and genotype, two of the five had TDF (K65R) resistance mutations, and three of the five had NNRTI mutations Y181C and K103N. The two participants (NVK015 and NVK097) with TDF-associated K65R mutations at follow-up might benefit from switching to AZT, an NRTI more effective in the setting of K65R mutation.¹⁸ Considering that five of the seven (71%) participants had NRTI and NNRTI resistance mutations, alternative classes of antiretroviral drugs will be needed to regain and maintain viral suppression in these children with the limited available regimens. However, only one individual had the M184V mutation despite the use of 3TC in all first-line regimens.⁴⁸

Younger age (≤17) was significantly associated with detection of drug resistance, p = .002 (Fisher's exact test) suggesting higher levels of ART failure in children and adolescents compared to adults in this population. This is consistent with studies showing high rates of ART failure in children due to complexities such as appropriate adjustments in ART dosing, intermittent adherence, changes in drug metabolism with age, inconsistent caregivers, and physical and psychosocial trauma, all of which could result in subtherapeutic drug concentrations and ART failure.^49

–55 Virologic monitoring, particularly among younger ART recipients, is warranted based on an increased frequency of inadequate adherence and suboptimal viral suppression.

Conclusion

This model of community based treatment delivery demonstrated good virological outcomes, retention in care, and drug adherence. Failure of NVP-based ART and neurotoxicity due to stavudine underscores the current recommendations for EFV and TDF and the transition to integrase strand transfer inhibitor-based regimens. New point of care testing and blood collection and provider task shifting are needed to monitor and treat people living with HIV/AIDS in rural ART programs. Community-drug delivery, with timely laboratory monitoring and adherence support in resource-limited settings, can sustain virologic suppression in >90% of adults, but treatment of children and adolescents remains a challenge.

Footnotes

Acknowledgments

The authors thank the staff of the Chidamoyo Christian Hospital for collecting samples, providing clinical data, and for their continuing care and support to the community of Nyamutora. The authors acknowledge support received from the Salvation Army in Zimbabwe and financial support from SAFE. The authors also acknowledge support from the Department of Infectious Diseases, Stanford University School of Medicine, the Stanford–SPARK program (Stanford University Medical Center), the African Institute of Biomedical Science and Technology, the Biomedical Research and Training Institute in Zimbabwe, Letten Foundation Institute of Clinical Medicine, University of Oslo, and the Medical Research Council (MRC) in South Africa.

Sequence Data

The sequences have been submitted to GenBank under accession numbers KX197115–KX197122.

Author Disclosure Statement

No competing financial interests exist.

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