Journal Club is designed to inform ICAP staff and colleagues of the latest scientific literature by providing a succinct summary and critical analysis of important studies, and by discussing the implications of the research on clinical work.

This month’s journal club summarizes selected abstracts from CROI 2014. All abstracts can be found here.

Adult Care and Treatment

Cotrimoxazole Prophylaxis Discontinuation Among ART-Treated Adults: A Randomized Non-Inferiority Trial.
Polyak CS, Yuhas K, Benson S, Khaemba M, Walson J, Richardson B, and John-Stewart G.


This study is a non-blinded, non-inferiority, randomized clinical trial comparing discontinuation versus continuation of cotrimoxazole (CTX) prophylaxis among HIV-infected adults in Western Kenya, which is a malaria endemic area, who were enrolled from 2012-2013. Eligibility criteria included: ART for ≥18 months and CD4 count ≥350 cells/mm<sup>3</sup>. Pregnant women and persons on second-line regimens were excluded. Participants were randomized to discontinue (stop CTX arm; n=250) or continue CTX (CTX arm; n=249) and followed for one year with routine study visits every three months as well as sick visits on an as-needed basis. All participants were provided insecticide treated bed nets and water filters. The primary outcome was a composite endpoint of non-traumatic mortality and morbidity, including malaria (fever with a positive rapid diagnostic test or smear), pneumonia (fever, cough, or tachypnea with abnormal exam or radiograph), and diarrhea (≥3 loose stools in 24 hours). The secondary outcome was severe (grade 3 or higher) adverse events. Incidence of the primary outcome was 13.4/100 person-years (py [34 cases]) in the CTX arm, compared with 30.4/100 py (77 cases) in the stop CTX arm, for an incidence rate ratio (IRR) of 2.27 (95% CI 1.52, 3.38). This difference was driven by the malaria component of the endpoint, which had an IRR of 33.02 (95% CI 4.52, 241.02). There was no significant difference in mortality, pneumonia, or diarrhea between the two arms. There was no significant difference in severe adverse events between study arms (IRR 2.00 95% CI 0.90, 4.44).

This study shows that discontinuation of CTX in adults on ART with immune reconstitution in a malaria-endemic area resulted in an increased incidence of mortality and morbidity, primarily due to malaria. These findings are consistent with those from the ARROW trial in children, and will inform ongoing revisions to the WHO CTX guidelines.

One Year Outcomes Following Community-Based HIV Self-Testing: A Prospective Study in Malawi.
Choko AT, MacPherson P, Webb EL, Ball H, Sambakunsi R, Mdolo A, Makombe SD, Desmond N, Hayes R, and Corbett EL.


This study evaluates community-based HIV-self testing with a trained community counselor in 14 neighborhoods in Blantyre, Malawi. HIV prevalence in these neighborhoods is 18.5%. Each neighborhood was randomized to receive HIV self-testing with a trained community counselor, or the standard of care, in order to examine HIV self-testing and subsequent linkage to care. Two residents from each intervention neighborhood were trained as community counselors to provide HIV self-testing using OraQuick rapid tests to a total of 16,660 adults (≥16 years) across the study. 76% of all adults in the intervention arm self-tested; 89% (n=11,266) returned test kits with a completed questionnaire, and among them 98% reported that they would recommend self-testing to friends and family. Despite access to HCT, 44% of participants were first-time testers. Among women 16-19 years of age, uptake of self-testing reached approximately 50% by 2 months and 100% by 12 months. However uptake was progressively lower in each of the older age groups examined, with the lowest uptake in women ≥50 years old. Among men, similar age trends for testing uptake were seen. Testing coverage was lower for men as compared to women in each age group. Within these neighborhoods, 40% (937/2,342) of all people living with HIV (PLWH) were already in care, and an additional 500 PLWH (78% of those who reported newly testing HIV-positive) linked to care as a result of self-testing. This latter figure may be an underestimate as individuals may have linked to care in other areas and this would not have been measured. Quality assurance of self-testing results was performed for 559 participants and showed a sensitivity of 93.8% and specificity of 100%, compared to blood-based HIV tests. Approximately 3% of participants reported feeling forced to test, but among them 94% reported they would recommend self-testing to friends or family. In addition, a few cases of gender-based violence were ascertained through in-depth qualitative interviews.

This study shows that there was a high level of uptake of HIV self-testing, including among men, and especially among young adults. Self-testing resulted in high linkage to care if positive results were reported to the community counselor. Monitoring for potential adverse events will be necessary when establishing programs for HIV self-testing.

Measure of ART Adherence Associated with Virological Failure in Rakai, Uganda.
Ndyanabo A, Makumbi F, Nakigozi G, Serwadda D, Reynolds SJ, Chang L, Grabowski M, Wawer M, Gray R, and Kong X.

This retrospective study examined 2710 patients ≥ 15 years old who initiated ART from 2004 to 2012 in Rakai, Uganda to determine whether common adherence measures including pharmacy refill, appointment attendance, and pill count were associated with first virological failure. Viral load testing was performed at six month intervals and > 95% adherence was measured by pill count, appointment attendance (scheduled at two week intervals during the first 3 months of ART, monthly for the first year, and every two months thereafter), or pharmacy refills during the six months prior to viral load monitoring. Pill count was calculated as: ([dispensed-returned pills]/[pills prescribed])*100; appointment attendance as: (total appointments attended without delay/total expected appointments)*100; and pharmacy refills as: (dispensed medication/pills prescribed)*100. The primary outcome was first virological failure using the WHO 2013 definition (viral load ≥1000 copies/ml). Virological failure was found in 16% of participants (n=426) of whom 6.3% (n=27) subsequently died. Median time to death after virological failure was 12.5 months. After detection of first virological failure, 23% of patients were switched to second-line regimens. Hazard ratios for virological failure by the different measures of adherence (>95% adherent to non-adherent) were as follows: pill count HR 0.50, 95% CI 0.38-0.67; appointment attendance HR 0.46, 95% CI 0.37-0.58; and pharmacy refill HR 0.29, 95% CI 0.22-0.37. The risk of virological failure (adjusted for baseline regimen, WHO stage, CD4 count, year of ART initiation, and ART experience) in those younger than 40 years of age was over two-fold that of those 40 and older. The adjusted risk was significantly lower for those who initiated ART at later years, but there was no difference by gender, regimen, baseline WHO stage or CD4 count. _This study shows that participants who were >95% adherent per each of the adherence measures used were less likely to have first virological failure, with the strongest association seen between pharmacy refills and virological failure. Programs should select an adherence measure that is easy to implement. When poor adherence is detected, intervening with adherence support may help to prevent virological failure._

Age-Disparate Relationships and HIV Incidence Amongst Rural South African Women.
Harling G, Newell ML, Tanser F, Kawachi I, Subramanian SV, and Barninghausen T.


This population-based cohort study of women in rural KwaZulu-Natal, South Africa examined whether age of a woman’s most recent sexual partner at time of HIV testing was associated with subsequent HIV acquisition. Age-disparate relationships have been considered “risky” for young women due to higher HIV prevalence among older men and potentially a social and economic power imbalance allowing for coercion of women into high-risk behavior. A total of 458 seroconversions occurred among younger women aged 15-29 years (n=2,444 with 5,913 py of follow-up), with an incidence rate (IR) of 7.75 per 100 py. Age-disparity was not associated with HIV acquisition in younger women, when measured continuously (HR 1.00, 95% CI 0.97-1.03, for one year increase in partner’s age) or when measured categorically (HR 0.98, 95% CI 0.81-1.20, for male partner > 5 years older and HR 0.98, 95% CI 0.67-1.43, for male partner > 10 years older, compared to same age partner). A total of 116 seroconversions occurred among older women aged 30-50 y (n=1,737 with 5,714 py of follow-up), with an IR of 2.03 per 100 py. Age-disparity was associated with decreased seroconversion in older women; as partner age increased, HIV incidence decreased. A male partner > 5 years and > 10 years older was associated with one-third and one-half decrease in HIV incidence, respectively (HR 0.63, 95% CI 0.81-0.76 and HR 0.48, 95% CI 0.35-0.67).

This study is the first to report that younger women in age-disparate relationships do not have an increased risk of HIV seroconversion, while older women in similar partnerships may have a protective benefit.


Effect of Xpert MTB/RIF on Early Mortality in Adults with Suspected TB: A Pragmatic Randomized Trial.
Churchyard G, MCarthy K, Fielding KL, Stevens W, Chihota V, Nicol M, Ndjeka N, Grant AD, Mametja D.


Xpert MTB/RIF is a cartridge-based automated nucleic acid amplification test that has greater sensitivity than sputum smear microscopy, and can identify _Mycobacterium tuberculosis_ and rifampicin resistance from unprocessed sputum samples in <2 hours. In 2011, South Africa phased in Xpert MTB/RIF, replacing sputum smear microscopy in laboratories, as the first-line diagnostic test for tuberculosis (TB). This study was a pragmatic cluster randomized trial to evaluate the effect of Xpert on early mortality among adults suspected of TB. Twenty laboratories in four South African provinces were randomized to immediate Xpert implementation (intervention arm, n=10) vs. microscopy, with Xpert deferred (control arm, n=10). At two primary health clinics served by each laboratory, adults with suspected TB were investigated by clinic staff (with 1 sputum specimen for Xpert at intervention sites or 2 sputum specimens for fluorescence microscopy at control sites, and CXR and/or culture as per algorithm). Adults not on TB treatment who had a sputum sample requested were enrolled in the study. Clinical and demographic data were collected at baseline; at six months, TB test results and ART and TB treatment data were collected from clinic records and participant interview, and vital status was determined by interview of patients or relatives and using the National Vital Status Register. A total of 4,972 persons with suspected TB were screened for the study, of whom 4,712 (94.8%) were eligible and 4,656 (98.8%) contributed data. Median age was 36 years; 62% were female, and of 76% who knew their HIV status, 62% reported being HIV-positive (median self-reported CD4 count 310 cells/mm3, 33% ever on ART), with no difference by study arm. Participants in the Xpert arm were less likely to have a BMI <18.5 (8.7% vs. 12.4%) and were more likely to be asymptomatic (9.8% vs. 6.0%). Ninety-nine percent (N=4,608) of participants had known vital status at 6 months, with 207 (4.5%) deaths. There was no difference in six month mortality risk between study arms (3.9% Xpert vs. 5.0% microscopy, RR 0.86, 95% CI 0.56, 1.28). After adjusting for age, sex, HIV status, BMI, and number TB symptoms, the RR<sub>adj</sub> was 1.10 (95% CI 0.75, 1.62). Mortality risk at six months was greater for participants who self-reported they were HIV-positive, not on ART (OR<sub>adj</sub> 3.32, 95% CI 2.03, 5.41), and those with unknown HIV status (OR<sub>adj</sub> 2.41, 95% CI 1.47, 3.98) compared to those who reported being HIV negative.

Although Xpert has the potential to improve TB case finding and identification of drug resistant TB, mortality in this cohort of adults suspected of TB was high, and was not influenced by Xpert implementation. These findings highlight the importance of ensuring that all persons suspected of TB are tested for HIV, and that those with HIV infection are linked to care and started on ART if eligible

Xpert as the First-Line TB Test in South Africa: Yield, Initial Loss to Follow-Up, Proportion Treated.
Fielding KL, McCarthy KM, Cox H, Erasmus L, Ginindza S, Vassall A, Mvusi L, Dye C, Grant AD, Churchyard GJ.


As part of the study described above (Abstract 95), investigators evaluated the effect of Xpert implementation on three secondary outcomes: 1) yield (proportion of patients investigated for TB with a positive index test result); 2) initial loss to follow-up (not starting TB treatment within 28 days) among those index test positive; and 3) proportion of patients investigated for TB who initiated TB treatment within 6 months of index test. Laboratory results were obtained from the National Health Laboratory Service database, and TB treatment start dates from clinic registers or participant interview. Among 4,411 patients with a TB diagnostic lab result available, the yield was greater in the Xpert vs. microscopy arm (9.2% [200/2,176] vs. 7.8% [174/2,235], adjusted prevalence ratio [APR] 1.49 [95% CI 1.00, 2.23]). Among 374 patients with a positive index test result, initial loss to follow-up was similar by study arm (17% [34/200] Xpert vs. 14.9% [26/174] microscopy; adjusted risk ratio [aRR] 0.96 [95% CI 0.48-1.93]). Among 4,656 patients, 541 (11.6%) were treated for TB over the 6 month follow-up period. The proportion starting TB treatment was similar by study arm (10.8% [250/2,324] Xpert vs. 12.5% [291/2,332] microscopy, aRR 1.04 [95% CI 0.76, 1.43]). Overall, 71.1% (385/541) of individuals treated for TB had microbiological confirmation (78.4% [196/250] Xpert vs. 64.9% [189/291] microscopy, APR 1.20 [95% CI 0.98, 1.47]).

Xpert increased the proportion of patients suspected of TB who tested positive by 50%, and thus has the potential to facilitate rapid TB treatment initiation by nurses. However Xpert implementation did not reduce initial loss to follow up, or increase the proportion of patients suspected of TB starting TB treatment. These findings highlight the importance of establishing systems to ensure that patients with positive test results start TB treatment promptly.

Pediatric Care and Treatment

Virologic Efficacy of Efavirenz Maintenance Therapy in Neviripine Prophylaxis-Exposed Children.
Coovadia A. Abrams E, Strehlau R, Shiau S, Pinillos F, Martens, L Hunt G, Wei-Yann T, Morris L, Kuhn L NEVEREST 3Study Team.


Lopinavir/ritonavir (LPV/r)-based regimens are recommended as first line ART for children <3 years of age in low-resource countries, mainly due to widespread non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure among young children who become HIV-infected despite PMTCT prophylaxis. While use of LPV/r is well justified from a virologic control point of view, potential disadvantages of its use as first line ART for young children include: cost, drug-drug interactions with anti-TB medications, metabolic complications, and poor palatability. With efforts to eliminate MTCT, evaluation of “re-cycling” NNRTIs, meaning the use of NNRTI regimens in HIV-positive young children after initial NNRTI exposure during PMTCT, is of high interest. The NEVEREST 3 Study is a randomized clinical trial which aimed to evaluate the efficacy of transition to efavirenz (EFV)-based maintenance therapy among NVP-exposed 3-5 year old children who initiated LPV/r early in life (i.e. <2 years of age) and were virologically suppressed (i.e. VL <50 copies/ml). Eligible participants (n=298) were randomly assigned to continue LPV/r (n=148) or switch to EFV-based ART (n=150) and were followed for 48 weeks. The mean age was 4.1 years, average age of initiating LPV/r was 9 months, and average duration of ART was 3.5 years. After 48 weeks, no statistically significant differences in virologic treatment failure (defined either VL >50 copies/ml or >1000 copies/ml) were detected. Confirmed viral load >1000 copies/ml was infrequent in both groups: 2.8% in the EFV group vs. 2.2% in the LPV/r group (delta -0.6%, 95% CI -3.4-4.3%).

These results indicate that in settings where viral load monitoring is available, “NNRTI re-cycling” strategies may be a valuable option for HIV-infected children >3 years of age with prior PMTCT-related NNRTI exposure who have been virologically suppressed on LPV/r. Further research is needed to elucidate the cost of implementing recycling strategies such as this.

Prevention of Mother to Child Transmission

Efficacy and Safety of Lopinavir-ritonavir Versus Efavirenz in HIV+ Pregnant and Breast-Feeding Ugandan Women.
Cohan D, Paul Natureeba P, Plenty A, Luwedde F, Mwesigwa J, Ades V, Charlebois E, Clark T, Nzarubara, B, Kamya M, Okong P, Havlir D.


The 2013 WHO guidelines recommend EFV-based ART for all HIV-infected pregnant women under Option B+ to prevent mother to child transmission and safeguard the health of the mother. The PROMOTE Study (Prevention of Malaria and HIV in Tororo) was an open label, randomized trial which enrolled 389 HIV-infected ART-naïve pregnant Ugandan women to receive AZT/3TC/ LPV/r or AZT/3TC/EFV through postnatal age 12 months. In addition, all women received cotrimoxazole prophylaxis, infants received either zidovudine or nevirapine postnatal prophylaxis per Ugandan guidelines, and women were counseled to breastfeed for up to 12 months. This abstract reports findings from a sub-study of the PROMOTE Study. The primary outcomes were virologic suppression, immunologic reconstitution and safety. At baseline there were no significant differences between the two groups; the mean age was 29 years, median Pre-ART CD4 count was 370 cells/mm<sup>3</sup> and viral load was 61,611 copies/ml. At the time of delivery, 97.6% of women in the EFV arm maintained an undetectable viral load (< 400 copies/ml), compared with 85.7% of women in the LPV/r arm (p<0.001). Women in the EFV arm were also more likely to maintain viral suppression throughout breastfeeding (83.8% vs. 74.3%, p=0.03). However, women on LPV/r experienced greater CD4 count recovery 24 weeks after ART initiation (+178 cells/mm<sup>3</sup> vs. +109 cells/<sup>mm3</sup>, p<0.01), although there was no difference in clinical outcomes (WHO Stage IV and death). Grade I/II gastrointestinal adverse events were more frequent with LPV/r (IRR 1.69, 95% CI 1.41-2.02, p < .0001), but there were no differences in numbers of Grade III/IV adverse events. There were no differences in preterm birth, spontaneous abortion, stillbirth or neonatal death between study arms. Women in both arms reported high rates of adherence. HIV transmission was extremely low: 2/374 (0.5%, 95% CI 0.01-1.9%) at 12 months. One child was infected in utero and another through breastfeeding; both were in the LPV/r arm. There was no difference in HIV-free infant survival between the two arms (92.9% [LPV/r] vs. 97.2% [EFV], p=.10).

These data support current WHO-recommended EFV-based first line treatment regimens for pregnant and breastfeeding women at all CD4 counts and provide reassurance that high levels of viral suppression are achievable with low transmission rates to infants.

Infant Lopinavir/r Versus 3TC To Prevent Postnatal HIV-1 Transmission: The ANRS 12174 Trial.
Kankasa C, Nagot N, Meda N, Tumwine J, Aku A, Jackson D , Vallo R, Tylleskar T, Van de Perre P, and ANRS 12174 Trial Group.


WHO recommends breastfeeding for infants born to HIV-infected women for 12 months, with either maternal ART or prolonged infant prophylaxis during the period of exposure to reduce the risk of HIV transmission. However, the recommendation for prolonged infant prophylaxis for up to 12 months is based on data extrapolated from studies where prophylaxis was used for up to 6 months only. This study (ANRS 12174) was an open label, randomized trial comparing infant LPV/r vs. lamivudine (3TC) prophylaxis regimens to prevent postnatal HIV-1 transmission during breastfeeding for up to 50 weeks postnatal age. The primary outcome was HIV acquisition at 50 weeks postpartum; secondary outcomes included death, HIV-free survival and severe adverse events. 1273 infants with negative birth PCR were enrolled from Burkina Faso, South Africa, Uganda and Zambia and randomized at 1 week of age to either LPV/r or 3TC until cessation of breastfeeding at 12 months of age. Mothers received standard of care as per national guidelines for HIV-infected pregnant women who were not eligible to receive combination antiretroviral therapy (ART). Infants received standard of care per national guidelines (mostly daily nevirapine) before randomization to either LPV/r or 3TC if birth PCR was negative at age 7 days. Infants received HIV testing at 6 weeks and then quarterly until 12 months of age. Baseline characteristics of infants were the same in both study arms. Median duration of breastfeeding was 42 weeks (interquartile range: 41-42). Adherence was slightly higher in the 3TC arm (92.5% vs. 90%, p=0.01). HIV transmission at 50 weeks was similar, with 8 cases in the LPV/r arm and 9 in the 3TC arm, giving HIV infection rates of 1.39% (95% CI 0.70 – 2.76%) and 1.53% (95% CI 0.80 – 2.91%), respectively (p=0.83). The majority of infections (8 of 17) occurred after 6 months. Mortality was also similar in both arms:18 (2.83%) in the LPV/r arm and 15 (2.35%) in the 3TC arm (p=0.57). The majority of deaths were due to malnutrition and pneumonia and were not HIV-related, as PCR prior to death was negative. HIV-free survival was similar between arms: 96.5% (94.6-97.7%) for LPV/r and 96.3% (94.4-97.5%) for 3TC (p=0.85). One third of infants in both arms experienced severe adverse events, including severe anemia and neutropenia, with no difference between groups.

This is the first study to report on postnatal HIV transmission with two infant prophylaxis regimens for a total of 12 months post birth. Both LPV/r and 3TC were effective at decreasing postnatal HIV transmission during breastfeeding. The low rates of transmission at 50 weeks are reassuring, and support infant breastfeeding for up to 12 months as recommended by WHO under option A.

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