Option B+ Malawi
Polly Clayden, HIV i-Base
Malawi began Option B+ (universal lifelong ART for pregnant and breastfeeding women) in 2011, which led to a rapid scale up of women accessing ART irrespective of CD4 count.
Since then the Malawi programme has matured and Treat All has been adopted for all populations including pregnant women – both nationally and in WHO guidelines. As with non-pregnant adults, pregnant women receive a first-line ART regimen of efavirenz/tenofovir DF/lamivudine (EFV/TDF/3TC).
The 11th INTEREST Workshop – also conducted in Malawi – included a number of posters from studies designed to monitor and evaluate various aspects of the programme including: ART uptake, retention in care, long-term safety, treatment failure, and maternal and infant adverse events and outcomes.
These are: The National Evaluation of Malawi’s PMTCT programme (NEMAPP), PROBE (PMTCT Retention of Option B+ Evaluation) study and The Option B+: ART Safety and Durability during First and Subsequent Pregnancies research study at Bwaila District Hospital in Lilongwe.
ART in pregnancy and partner’s HIV disclosure protective against early infant transmission
NEMAPP reported good ART coverage and generally low vertical transmission.  Starting ART during pregnancy and partner’s HIV status disclosure to the mother were protective against early infant transmission. 
NEMAPP is a two-year longitudinal cohort study across 54 health facilities, started in November 2014, using two-stage cluster sampling to evaluate infants at 4-12 weeks of age. Mothers attending an under-5 clinic were tested for HIV and HIV-exposed infants received DNA testing at baseline, 12 and 24 months.
Of 2125 HIV positive mothers, 2082 (96.1%) knew their status before or during pregnancy and 1865 (88.5% but varying widely between 54.9% and 100% across sites) were diagnosed and started ART in pregnancy. The vertical transmission rate was 4.2% (95% CI 2.9 to 6.1) overall: women receiving ART 2.5% (95% CI 1.6 to 3.9) and 17.9% (95% CI 13.0 to 21.2) for those not receiving ART. The rate of transmission varied from 1.4% (95% CI 0.5 to 3.9) in women who started ART before pregnancy to 20.2% (95% CI 5.8 to 50.7) in those starting ART postpartum.
Early infant transmission was lower if a woman started ART before compared with during their pregnancy: 2.3 vs 3.5%, p=0.014. It was also lower for those that disclosed their status to their partners: 2.0 vs 5.8%, p=0.008.
In multivariate analysis for the subgroup of women receiving ART during pregnancy, the likelihood of early infant transmission almost doubled if a woman started ART during compared with before pregnancy: aOR 1.9, p=0.032. Partner’s HIV status disclosure to the mother was also significantly protective against early infant transmission, aOR 0.39, p=0.011.
Maternal health status or missed ART, exclusive breastfeeding and infant nevirapine prophylaxis were not associated with early transmission among mothers receiving ART.
Low maternal mortality and morbidity postpartum
Mothers had low mortality and morbidity at 4-26 weeks postpartum associated with increased ART uptake in asymptomatic women in an analysis of maternal health in NEMAPP. 
Of 1307 women evaluated, 67.3% (n=879) were 6-12 weeks postpartum and 1151 (n=88.1%) receiving ART.
At ART initiation 171 (13.1%) women had minor illness and 51 (3.9%) major illness according to self-reported health status. Of these 155/171 (90.6%) and 47 (90.4%) respectively reported improved health status.
In a nested cohort study including 580 women, their health status at enrollment was: 94% normal, 3.6% minor illness not affecting normal activities and 0.7% major illness needing daily assistance. Of the 580 women 56.2% had CD4 >500 cells/mm3 and 71.9% undetectable viral load.
More women receiving ART reported normal health than those who stopped ART (95.6 vs 87.5%) p<0.001, as did more women with CD4 >500 cells/mm3 (97.2 vs 92.8), p=0.02. In multivariate analysis adjusted for ART status and duration of known HIV status poor functional health was associated with CD4 <500 cells/mm3, aOR 2.6, p=0.03.
No difference in ART use or vertical transmission rates in adolescent mothers compared with older ones
Limited evidence suggests that vertical transmission prevention outcomes in young and adolescent women are worse than for adult women. 
A national evaluation comparing the use of services (uptake of antenatal testing and ART) and vertical transmission rates between young or adolescent mothers and adult mothers found adolescents less likely to be newly identified HIV positive. But among the known HIV positive women, there was no difference between age groups in ART use or vertical transmission rates.
The study included 33,744 mother-infant-pairs: 53.8% were defined as young (12-24 years) and 20.5% were adolescent (12-19 years) mothers. Overall 97.8% reported having an HIV test before or during last pregnancy.
Young mothers had more likely missed antenatal HIV testing than adult mothers: OR 1.8 (95% CI 1.2 to 2.7). Of all the mothers 11.3% were diagnosed with HIV before or during pregnancy; this was lower in young (4.6%) and adolescent (2.8%) mothers.
Adolescents were less likely newly identified HIV positive (previously negative) then young and adult mothers: OR 0.5 (95%CI 0.2 to 0.9). But newly identified HIV positive (previous unknown) young mothers might have missed earlier diagnoses more frequently than adult mothers: OR 3.5 (95% CI 0.9 to14.4).
Among the known HIV positive women, 94.7% reported receiving ART, with no difference between young or adolescent and adult mothers. Overall vertical transmission rate at 4-26 weeks was 4.7%, with no difference between young or adolescent and adult mothers.
Asymptomatic women and those with better treatment literacy more likely to access ART
Accessing ART in health centres, being asymptomatic and treatment literacy were associated with high ART uptake.  But after starting treatment, neither of these predictors were associated with default or transferring to another health facility, according to a national assessment of Option B+ outcomes.
This was a secondary data analysis of the PROBE study. PROBE was a retrospective cohort of women attending antenatal clinics. The main variables in the study were: women coming for a second routine visit (uptake) and default and transfer out (outcomes).
The analysis revealed, of 2739 women with 17,769 observations and complete information, 410 defaulted, 39 transferred out, 14 died and 4 stopped.
In Cox proportional hazards model the risk of defaulting was 30% lower in the Ministry of Health compared with Christian Health Association of Malawi facilities: HR 0.7 (95% CI 0.56 to 0.87). Pregnant women had a 64% higher risk of defaulting than breast feeding women: HR 1.64 (95% CI 1.29 to 2.07). Default rate was 21% lower among adults compared with adolescents: HR 0.79 (95% CI 0.62 to 0.99); 40% lower in women with ART education compared with those without: HR 0.6 (95% CI 0.47 to 0.77); and 61% higher in symptomatic women compared with asymptomatic: HR 1.61(95% CI 1.05 to 2.48).
In multistate model (using sub-hazards) women accessing services in health centres had 65% probability of ART uptake: SHR 0.35 (95% CI 0.30 to 0.41); 182% in women with ART education: SHR 2.82 (95% CI 2.43 to 3.26); and 19% lower among symptomatic women: SHR 0.81 (95% CI 0.70 to 0.94).
The investigators noted that after starting ART the risk of either defaulting or transferring to another facility was not significantly associated with any predictor.
Unmarried women and those in new relationships more likely to be lost to follow up
Of 299 newly diagnosed, ART naive pregnant women enrolled in the prospective observational study from May 2015 to November 2016 at Bwaila Hospital, 35 (12%) were lost to follow up, including 9/35 before delivery.  Being unmarried and in a newer relationship were associated with loss to follow up.
The study defined loss to follow up as missing after 90 days from last documented visit, excluding those that died. A trained community liaison was informed of all missed visits and traced the participants physically or by phone until they either found them or had made three attempts to do so.
At enrollment participants were a median age of 26 years (IQR 26-30) and the majority were married (89%) and/or had been in the relationship for one year or more (77%). The median follow up was 11 months (IQR 8-14). Three died during the study. Of the participants lost to follow up 6/35 (17%) were brought back into care after they were traced.
The overall incidence of loss to follow up per month was 1% (95% CI 0.8 to 1.5). Being married and staying longer in a relationship were associated with lower risk of loss to follow up, respectively: HR 0.4 (95% CI 0.18 to 0.88), p=0.023, and HR 0.43 (95% CI 0.22 and 0.84), p=0.01.
Although being unmarried and in a newer relationship were associated with loss to follow up the investigators added that this is not exhaustive. It is important to identify women undergoing socio-economic as well as treatment related risk factors to ensure that women are maintained in care and ART during pregnancy and beyond.
High rates of unintended pregnancy and low rates of contraception
Like many African countries that adopted Option B+ by 2015, Malawi has high fertility rates and infrequent use of contraception. An analysis of pregnancy intentions of women enrolled in the programme revealed extremely high rates of unintended pregnancies and low rates of contraceptive use. 
This prospective study included the 299 newly diagnosed, ART naive pregnant women in the cohort described above and 427 who had been receiving ART for six months or more.
The newly diagnosed women were: younger than those already receiving ART (26 vs 31 years); had been in a relationship for shorter time (5 vs 7.6 years); were less likely to have an HIV positive partner (11 vs 59%); and had fewer living children (1.8 vs 2.3), all p<0.05. Newly diagnosed women also had shorter travel time to the clinic. Similar proportions were married (88 vs 92%) and reported physical or verbal abuse (17 vs 15%).
The majority of participants reported having and unintended pregnancy: 55 vs 76%, newly diagnosed and receiving ART respectively. Only 6 vs 14% in the respective groups reported using contraception. Of those with an unintended pregnancy 7 vs 18% (12/164 vs 59/325) reported using contraception.
Multivariate analysis showed no significant difference between newly diagnosed women and those receiving ART in the rates of: mistimed pregnancy (OR 1.32); unwanted pregnancy (OR 2.27); contraceptive use (OR 1.44); and unintended pregnancy with contraceptive use (OR 1.76).
Overall 76% of women in the programme reported an unintended pregnancy and only 18% used any contraceptive method. “This highlights the missed opportunity to engage these women in family planning and suggests shortfalls in the integration of ART and family planning under Option B+ in Malawi”, the investigators wrote.
Lower viral load suppression at delivery with longer duration of ART
Unsurprisingly women in the cohort with longer duration of ART during pregnancy had lower risk of unsuppressed viral load at delivery. 
Women are frequently diagnosed with HIV and start ART late in pregnancy but it is unclear whether they achieve viral suppression and how this varies with time on ART in Malawi. Investigators from the Bwaila district hospital study also looked prospectively at the association between time on ART and viral load (> 1000 and >40 copies/mL) at delivery in the newly diagnosed women.
For the 299 participants enrolled, the median gestation age at first antenatal visit was 22.1 weeks (IQR 18.1-26.3). The median duration of ART before delivery was 17 weeks (IQR 13-21). Of 253 (84.3%) with viral load measurements at delivery, 40 (15.9%) and 78 (31%) had >1000 and >40 copies/mL respectively.
Compared with women who had received ART for 12 weeks or less at the time of delivery, women who received ART for 13-20 weeks, RR 0.52 (95% CI 0.36 to 0.74), or 21-35 weeks, RR 0.26 (95% CI 0.14-0.48) were less likely to have viral load >40 copies/mL.
Hepatoxicity rate does not support routine laboratory monitoring
An analysis of hepatoxicity risk does not support routine laboratory monitoring pregnant women receiving EFV-based ART. 
Pregnant women start ART with TDF/3TC/EFV without routine liver enzyme monitoring. Previous studies have shown conflicting results risk for hepatotoxicity in pregnant women on EFV-based regimens.
This study was also conducted at Bwaila Hospital, in the cohort of 299 women.
The investigators evaluated laboratory values from the first 6 months on ART (enrollment, months 3 and 6) for DAIDS Grade 1 or higher alanine aminotransferase (ALT, >50 IU/L) (Fisher’s exact tests)
Prevalence of elevated ALT at baseline was 0.3%, 0.4% at month 3, and 7.2% at month 6. The 6-month incidence of elevated ALT was 7.9%. Only 3 women (1.1%) had DAIDS Grade 3 or 4 ALT levels. All 3 women were postpartum and not taking other hepatotoxic medications. Of these women, one remained on TDF/3TC/EFV with resolved ALT levels, one switched to a non-EFV regimen, and one died of fulminant hepatitis despite ART discontinuation.
This analysis found no significant association with low CD4 count (p=0.62) or WHO stages >2 (p=0.28, although twice as many women developed elevated ALT compared with stage 1: 13.3 vs 6.7%) with the development of hepatoxicity. Data on viral hepatitis co-infection status were not available.
The investigators suggested that symptom monitoring is likely reasonable under a public health approach.
High prevalence of syphilis
Another analysis from Bwaila Hospital reported worrying prevalence of syphilis among HIV positive pregnant women. 
This cross-sectional study aimed to estimate the prevalence of syphilis and describe risk factors in this population.
Women were screened for syphilis using point-of-care rapid Alere determine TP tests. All women who tested positive were treated on the same day with a single dose of benzathine penicillin by intramuscular injection. Women testing positive were also encouraged to send their partners for treatment.
Of 350 pregnant women enrolled, the mean age was 28.3 years and mean gestational age was 22 weeks; 89% were married; and 88% lived with the partner.
The prevalence of syphilis in these women was 6% (95% CI 3.9% to 9.0%). Relationship duration was shorter in women testing positive for syphilis but this was not statistically significant. No factors (level of education, parity, marital status, WHO staging, and partner characteristics for current pregnancy) were significantly associated with the prevalence of syphilis.
“Aggressive measures are urgently needed to strengthen universal syphilis screening and testing efforts at antenatal clinics to prevent mother to child transmission of syphilis” the investigators wrote.
High rate of antenatal depression
Nearly half of the women in an antenatal depression study self-reported a history of anxiety or depression. 
Women included in this baseline analysis (n=729) were starting ART for the first time or had been on ART for 6 months or more.
The investigators assessed depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS). In Malawi, a score of >6 has been shown to indicate probable major depression, and was considered a positive result.
The majority of women were currently married (90%), unemployed (62%), and had not intended their pregnancy (68%). Nine percent (n=68) of women screened positive for depression, and 46% (n=328) self-reported a history of depression or anxiety.
Women were more likely to screen positive for depression: who self-reported a history of depression or anxiety aOR 2.83 (95% CI 1.63 to 4.92); had ever experienced verbal intimate partner violence aOR 2.01 (95% CI 1.12 to 3.60); had not intended their current pregnancy aOR 1.97 (95% CI 1.02 to 3.80), or were unmarried aOR 2.14 (95% CI 1.07- 4.27).
Depressive symptoms affect a notable proportion of HIV positive women in antenatal care on ART in Malawi (9.5%), and nearly half of the women self-reported a history of depression or anxiety. Clinicians in clinics without routine depression screening should be watchful for antenatal depression among women with a history of depression or anxiety, intimate partner violence, unintended pregnancy, or are unmarried.
Education and having an HIV positive partner protective against ART failure
An analysis of treatment failure among women already receiving ART at first antenatal visit found an overall prevalence of 7%.  Having more education and having an HIV positive partner were protective against ART failure.
This study, again at Bwaila Hospital, included 434 women. The median age of the women was 30.8 years (IQR 26.9-34.2); 93% were married and 82% attended antenatal clinic in the second trimester.
The overall prevalence of ART failure was 7.1% (95% CI 5.1 to 10.0). Women with secondary or tertiary education had reduced odds of ART failure compared with women with none or primary education: OR 0.67 (95% CI 0.27 to 1.70. For women who knew their partners’ HIV status, those with HIV positive partners also had reduced odds of ART failure compared with those with negative partners: OR 0.45 (95% CI 0.10 to 2.03).
The investigators suggested countries with limited resources for viral load screening at first antenatal clinic visit should develop mechanisms to identify women at risk of having developed ART failure to prompt switch to an alternative and effective regimen during pregnancy.
Saturday clinic feasible to improve retention in study
The addition of a Saturday clinic is a feasible way to reduce visit duration and accommodate retention in care. 
The Bwaila Hospital study enrollment did not meet its targets in the first year due to constraints including a shortage of clinic space and clinic overcrowding. The investigators hypothesised that adding a Saturday clinic would reduce overcrowding and visit duration during the week and would improve retention and enrollment.
This was an observational study of participant visit duration before and after Saturday clinic introduction and an anonymous Likert-type scale acceptability survey.
The investigators observed a total of 77 visits: 28 before and 49 after adding the Saturday clinic. They found the average time spent with a nurse during a follow-up visit went down from 78 minutes before to 57 minutes after the addition of the Saturday clinic, p=0.0337. But the average time spent with a clinician was not significantly affected, p=0.270.
The majority of women surveyed on both weekdays and Saturdays reported that time spent in clinic was acceptable. Six out of the 46 women surveyed said that Saturday was their preferred day. The effect of adding the Saturday clinic on retention is yet to be determined.
The addition of a Saturday clinic is a feasible way to reduce visit duration and accommodate retention. Subject surveys indicate this is an acceptable way to decrease crowding and improve subject satisfaction.
The 11th INTEREST Workshop included an abundance of data from the Malawi Option B+ programme. But some of these summaries are a bit sketchy as unfortunately not all the posters materialised at the meeting.
The observation that women with partners who have not disclosed their HIV status are more likely to transmit to their infants is important. This is the first time that HIV status disclosure between partners has been documented to affect vertical transmission at national level.
The study looking at contraception also noted that in Malawi 33% of pregnancies are mistimed and 11% unwanted. And 39% discontinue their modern contraceptive within 12 months due to method-related concerns/side effects (26%) or desire to become pregnant (26%). It would be interesting to know if any of the women with unintended pregnancies on ART and using contraception were using hormonal implant methods and this could be linked to EFV. This study highlights a missed opportunity to engage women in ART programmes with family planning.
The study linking longer duration of ART with viral suppression at delivery came as no surprise. That under a third of women had viral load <40 copies/mL is likely to be improved with the introduction of dolutegravir and swifter viral decline.
All references are to the programme and abstracts of the 11th International workshop on treatment, pathogenesis and prevention work in resource-limited settings (INTEREST), 16-19 May 2017, Lilongwe, Malawi (published in Reviews in Antiviral Therapy & Infectious Diseases 2017_02).
- Tippett Barr B et al. National evaluation of Option B+ in Malawi: high maternal ART coverage and low early infant transmission in all areas of the country. Poster abstract 182.
- Tippett Barr B et al. Predictors of mother-to-child transmission in women on ART: results from a national evaluation of Malawi’s PMTCT programme. Poster abstract 183.
- Landes M et al. Maternal health and ART use at 4-26 weeks postpartum in Option B+ in Malawi. Poster abstract 88.
- Van Lettow M et al. PMTCT programme utilisation and HIV transmission rates in young and adolescent mothers: a nationally representative sample of women screened at 4-26 weeks postpartum in Malawi. Poster abstract 181.
- Mganga A et al. Uptake and ART outcomes of women initiating antiretroviral therapy under Option B+ in Malawi: Cox proportional hazards and multistate survival models. Poster abstract 143.
- John M et al. Loss to follow up among newly diagnosed HIV positive pregnant women in the Option B+ programme in Malawi. Poster abstract 27.
- Melhado C et al. Contraceptive failure and pregnancy intentions among ART-naive and ART adherent HIV-infected pregnant women enrolled in Option B+. Poster abstract 87.
- Chagomerana et al. Viral suppression at delivery among pregnant women newly initiated on antiretroviral therapy (ART) during pregnancy: PMTCT Option B+ in Malawi. Poster abstract 151.
- Harrington B et al. Incidence and timing of hepatoxicity among HIV positive pregnant women initiating efavirenz-based ART through Option B+ in Malawi. Poster abstract 136.
- Phulusa J et al. Prevalence of syphilis infection among HIV-infected pregnant women attending antenatal clinic at Bwaila Hospital in Lilongwe, Malawi. Poster abstract 162.
- Harrington B et al. Prevalence and factors associated with antenatal depression among women enrolled in Option B+ PMTCT in Malawi. Poster abstract 33.
- Chagomerana et al. Prevalence of antiretroviral therapy (ART) treatment failure among HIV-infected pregnant women at first antenatal care: PMTCT Option B+ in Malawi. Poster abstract 148.
- Stanczyk B et al. Evaluation of strategies for improving subject retention in The Option B+ ART safety and durability during first and subsequent pregnancies study. Poster abstract 66.