Antiretroviral therapy (ART) in resource-limited settings has expanded in the last decade, reaching >8 million individuals and reducing AIDS mortality and morbidity. Continued success of ART programs will require understanding the emergence of HIV drug resistance patterns among individuals in whom treatment has failed and managing ART from both an individual and public health perspective. We review data on the emergence of HIV drug resistance among individuals in whom first-line therapy has failed and clinical and resistance outcomes of those receiving second-line therapy in resource-limited settings.
Resistance surveys among patients initiating first-line nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based therapy suggest that 76%–90% of living patients achieve HIV RNA suppression by 12 months after ART initiation. Among patients with detectable HIV RNA at 12 months, HIV drug resistance, primarily due to M184V and NNRTI mutations, has been identified in 60%–72%, although the antiretroviral activity of proposed second-line regimens has been preserved. Complex mutation patterns, including thymidine-analog mutations, K65R, and multinucleoside mutations, are prevalent among cases of treatment failure identified by clinical or immunologic methods. Approximately 22% of patients receiving second-line therapy do not achieve HIV RNA suppression by 6 months, with poor adherence, rather than HIV drug resistance, driving most failures. Major protease inhibitor resistance at the time of second-line failure ranges from 0% to 50%, but studies are limited.
Resistance of HIV to first-line therapy is predictable at 12 months when evaluated by means of HIV RNA monitoring and, when detected, largely preserves second-line therapy options. Optimizing adherence, performing resistance surveillance, and improving treatment monitoring are critical for long-term prevention of drug resistance.
antiretroviral drug resistance; resource-limited settings; second-line therapy
To determine, for the WHO algorithm for point-of-care diagnosis of HIV infection, the agreement levels between pediatricians and non-physician clinicians, and to compare sensitivity and specificity profiles of the WHO algorithm and different CD4 thresholds against HIV PCR testing in hospitalized Malawian infants.
In 2011, hospitalized HIV-exposed infants <12 months in Lilongwe, Malawi were evaluated independently with the WHO algorithm by both a pediatrician and clinical officer. Blood was collected for CD4 and molecular HIV testing (DNA or RNA PCR). Using molecular testing as the reference, sensitivity, specificity, and positive predictive value (PPV) were determined for the WHO algorithm and CD4 count thresholds of 1500 and 2000 cells/mm3 by pediatricians and clinical officers.
We enrolled 166 infants (50% female, 34% <2 months, 37% HIV-infected). Sensitivity was higher using CD4 thresholds (<1500, 80%; <2000, 95%) than with the algorithm (physicians, 57%; clinical officers, 71%). Specificity was comparable for CD4 thresholds (<1500, 68%, <2000, 50%) and the algorithm (pediatricians, 55%, clinical officers, 50%). The positive predictive values were slightly better using CD4 thresholds (<1500, 59%, <2000, 52%) than the algorithm (pediatricians, 43%, clinical officers 45%) at this prevalence.
Performance by the WHO algorithm and CD4 thresholds resulted in many misclassifications. Point-of-care CD4 thresholds of <1500 cells/mm3 or <2000 cells/mm3 could identify more HIV-infected infants with fewer false positives than the algorithm. However, a point-of-care option with better performance characteristics is needed for accurate, timely HIV diagnosis.
pediatric; point-of-care; Africa; early infant diagnosis; HIV; clinical algorithm
Viral suppression is a key indicator of antiretroviral therapy (ART) response among HIV-infected patients. Dried blood spots (DBS) are an appealing alternative to conventional plasma-based virologic testing, improving access to monitoring in resource-limited settings. However, validity of DBS obtained from fingerstick in field settings remains unknown.
Investigate feasibility and accuracy of DBS vs plasma collected by healthcare workers in real-world settings of remote hospitals in Malawi. Compare venous DBS to fingerstick DBS for identifying treatment failure.
We recruited patients from ART clinics at two district hospitals in Malawi, collecting plasma, venous DBS (vDBS), and fingerstick DBS (fsDBS) cards for the first 149 patients, and vDBS and fsDBS only for the subsequent 398 patients. Specimens were tested using Abbott RealTime HIV-1 Assay (lower detection limit 40 copies/ml (plasma) and 550 copies/ml (DBS)).
21/149 (14.1%) had detectable viremia (>1.6 log copies/ml), 13 of which were detectable for plasma, vDBS, and fsDBS. Linear regression demonstrated high correlation for plasma vs. DBS (vDBS: β=1.19, R2 0.93 (p<0.0001); fsDBS β=1.20, R2 0.90 (p<0.0001)) and vDBS vs. fsDBS (β=0.88, R2 0.73, (p<0.0001)). Mean difference between plasma and vDBS was 0.51 log copies/ml [SD: 0.33] and plasma and fsDBS 0.46 log copies/ml [SD: 0.30]. At 5000 copies/ml, sensitivity was 100%, and specificity was 98.6% and 97.8% for vDBS and fsDBS, respectively, compared to plasma.
DBS from venipuncture and fingerstick perform well at the failure threshold of 5000 copies/ml. Fingerstick specimen source may improve access to virologic treatment monitoring in resource-limited settings given task-shifting in high-volume, low-resource facilities.
Over 150 000 Malawians have started antiretroviral therapy (ART), in which first-line therapy is stavudine/lamivudine/nevirapine. We evaluated drug resistance patterns among patients failing first-line ART on the basis of clinical or immunological criteria in Lilongwe and Blantyre, Malawi.
Patients meeting the definition of ART failure (new or progressive stage 4 condition, CD4 cell count decline more than 30%, CD4 cell count less than that before treatment) from January 2006 to July 2007 were evaluated. Among those with HIV RNA of more than 1000 copies/ml, genotyping was performed. For complex genotype patterns, phenotyping was performed.
Ninety-six confirmed ART failure patients were identified. Median (interquartile range) CD4 cell count, log10 HIV-1 RNA, and duration on ART were 68 cells/μl (23–174), 4.72 copies/ml (4.26–5.16), and 36.5 months (26.6–49.8), respectively. Ninety-three percent of samples had nonnucleoside reverse transcriptase inhibitor mutations, and 81% had the M184V mutation. The most frequent pattern included M184V and nonnucleoside reverse transcriptase inhibitor mutations along with at least one thymidine analog mutation (56%). Twenty-three percent of patients acquired the K70E or K65R mutations associated with tenofovir resistance; 17% of the patients had pan-nucleoside resistance that corresponded to K65R or K70E and additional resistance mutations, most commonly the 151 complex. Emergence of the K65R and K70E mutations was associated with CD4 cell count of less than 100 cells/μl (odds ratio 6.1) and inversely with the use of zidovudine (odds ratio 0.18). Phenotypic susceptibility data indicated that the nucleoside reverse transcriptase inhibitor backbone with the highest activity for subsequent therapy was zidovudine/lamivudine/tenofovir, followed by lamivudine/tenofovir, and then abacavir/didanosine.
When clinical and CD4 cell count criteria are used to monitor first-line ART failure, extensive nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance emerges, with most patients having resistance profiles that markedly compromise the activity of second-line ART.
Africa; antiretroviral failure; public health approach; resistance; resource-limited setting
In sub-Saharan Africa, although male involvement in antenatal care is associated with positive outcomes for HIV-infected women and their infants, men rarely accompany female partners. We implemented a project to increase the number of male partners attending an antenatal clinic at Bwaila Hospital in Lilongwe, Malawi. We evaluated changes in the proportion of women who came with a partner over three periods. During period 1 (January 2007 – June 2008) there was didactic peer education. During period 2 (July 2008 – September 2009) a peer-led male-involvement drama was introduced into patient waiting areas. During period 3 (October 2009 – December 2009) changes to clinical infrastructure were introduced to make the clinic more male-friendly. The proportion of women attending ANC with a male partner increased from 0.7% to 5.7% to 10.7% over the three periods. Peer education through drama and male-friendly hospital infrastructure coincided with substantially greater male participation, although further gains are necessary.
HIV; antenatal; male involvement; HIV counseling and testing; disclosure; prevention of mother to child transmission; couple
HIV-1 and Plasmodium falciparum malaria cause substantial morbidity in Sub-Saharan Africa, especially as co-infecting pathogens. We examined the relationship between presence of P. falciparum DNA in plasma samples and clinical malaria as well as the impact of atazanavir, an HIV-1 protease inhibitor (PI), on P. falciparum PCR positivity.
ACTG study A5175 compared two NNRTI-based regimens and one PI-based anti-retroviral (ARV) regimen in antiretroviral therapy naïve participants. We performed nested PCR on plasma samples for the P. falciparum 18s rRNA gene to detect the presence of malaria DNA in 215 of the 221 participants enrolled in Blantyre and Lilongwe, Malawi. We also studied the closest sample preceding the first malaria diagnosis from 102 persons with clinical malaria and randomly selected follow up samples from 88 persons without clinical malaria.
PCR positivity was observed in 18 (8%) baseline samples and was not significantly associated with age, sex, screening CD4+ T-cell count, baseline HIV-1 RNA level or co-trimoxazole use within the first 8 weeks. Neither baseline PCR positivity (p = 0.45) nor PCR positivity after initiation of antiretroviral therapy (p = 1.0) were significantly associated with subsequent clinical malaria. Randomization to the PI versus NNRTI ARV regimens was not significantly associated with either PCR positivity (p = 0.5) or clinical malaria (p = 0.609). Clinical malaria was associated with a history of tuberculosis (p = 0.006) and a lower BMI (p = 0.004).
P. falciparum DNA was detected in 8% of participants at baseline, but was not significantly associated with subsequent development of clinical malaria. HIV PI therapy did not decrease the prevalence of PCR positivity or incidence of clinical disease.
In 2011, Malawi implemented Option B+ (B+), lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women. We aimed to describe changes in service uptake and outcomes along the antenatal prevention of mother-to-child transmission (PMTCT) cascade post-B+ implementation.
Pre/post study using routinely collected program data from 2 large Lilongwe-based health centers.
We compared the testing of HIV-infected pregnant women at antenatal care, enrollment into PMTCT services, receipt of ART, and 6-month ART outcomes pre-B+ (October 2009–March 2011) and post-B+ (October 2011–March 2013).
A total of 13,926 (pre) and 14,532 (post) women presented to antenatal care. Post-B+, a smaller proportion were HIV-tested (99.3% vs. 87.7% post-B+; P < 0.0001). There were 1654 (pre) and 1535 (post) HIV-infected women identified, with a larger proportion already known to be HIV-infected (18.1% vs. 41.2% post-B+; P < 0.0001) and on ART post-B+ (18.7% vs. 30.2% post-B+; P < 0.0001). A significantly greater proportion enrolled into the PMTCT program (68.3% vs. 92.6% post-B+; P < 0.0001) and was retained through delivery post-B+ (51.1% vs. 65% post-B+; P < 0.0001). Among those not on ART at enrollment, there was no change in the proportion newly initiating ART/antiretrovirals (79% vs. 81.9% post-B+; P = 0.11), although median days to initiation of ART decreased [48 days (19, 130) vs. 0 days (0, 15.5) post-B+; P < 0.0001]. Among those newly initiating ART, a smaller proportion was alive on ART 6 months after initiation (89.3% vs. 78.8% post-B+; P = 0.0004).
Although several improvements in PMTCT program performance were noted with implementation of B+, challenges remain at several critical steps along the cascade requiring innovative solutions to ensure an AIDS-free generation.
HIV; PMTCT; Option B+; retention; Malawi; Africa
Although pneumonia is the leading cause of child mortality worldwide, little is known about the quality of routine pneumonia care in high burden settings like Malawi that utilize World Health Organization’s Integrated Management of Childhood Illnesses (IMCI) guidelines. Due to severe human resource constraints, the majority of clinical care in Malawi is delivered by non-physician clinicians called Clinical Officers (COs).
To assess the quality of child pneumonia care delivered by Malawian COs in routine care conditions.
At an outpatient district-level clinic in Lilongwe, Malawi, 10 COs caring for 695 children who presented with fever, cough, or difficulty breathing were compared to IMCI pneumonia diagnostic and treatment guidelines.
Fewer than 1% of patients received an evaluation by COs that included all 16 elements of the history and physical examination. The respiratory rate was only determined in 16.1% of patients presenting with cough or difficulty breathing. Of the 274 children with IMCI-defined pneumonia, COs correctly diagnosed 30%, and administered correct pneumonia care in less than 25%. COs failed to hospitalize 40.8% of children with severe or very severe pneumonia.
IMCI pneumonia care quality at this Malawian government clinic is alarmingly low. Along with reassessing current pneumonia training and supervision approaches, novel quality improvement interventions are necessary to improve care.
Pneumonia; Guidelines; Developing countries; Paediatrics
Many African infants fail to receive their diagnostic HIV molecular test results and subsequently, antiretroviral therapy (ART). To determine whether a point-of-care molecular HIV test increases ART access for hospitalized Malawian infants, we simulated a point-of-care test using rapid HIV RNA polymerase chain reaction (Rapid PCR) and compared patient outcomes to an optimized standard care that included assessment with the World Health Organization (WHO) clinical algorithm for HIV infection plus a DNA PCR with a turnaround time of several weeks (standard care).
Randomized controlled trial.
Hospitalized HIV-exposed Malawian infants <12 months old were randomized into Rapid PCR or standard care. Rapid PCR infants obtained molecular test results within 48 hours to facilitate immediate ART, similar to a point-of-care test. Standard care infants meeting clinical criteria were also offered inpatient ART. The primary outcome was appropriate in-hospital ART for DNA or RNA PCR-confirmed HIV-infected infants.
300 infants were enrolled. A greater proportion of HIV-infected infants receiving Rapid PCR, versus standard care, started inpatient ART (72.3% vs 47.8%, p=0.016). Among molecular test-negative infants, 26.9% receiving standard care unnecessarily initiated inpatient ART, versus 0.0% receiving Rapid PCR (p<0.001). Rapid PCR modestly reduced the median days to ART (3.0 vs 6.5, p=0.001) but did not influence outpatient follow-up for HIV-infected infants (78.1% vs 82.4%, P = 0.418).
Rapid PCR, versus an optimized standard care, increased the proportion of hospitalized HIV-infected infants initiating ART and reduced ART exposure in molecular test-negative infants, without meaningfully impacting time to ART initiation or follow-up rates.
point-of-care; early infant diagnosis of HIV; presumptive diagnosis; Africa; DNA PCR
To evaluate the feasibility and effectiveness of dried blood spots (DBS) use for viral load (VL) monitoring, describing patient outcomes and programmatic challenges that are relevant for DBS implementation in sub-Saharan Africa.
We recruited adult antiretroviral therapy (ART) patients from five district hospitals in Malawi. Eligibility reflected anticipated Ministry of Health VL monitoring criteria. Testing was conducted at a central laboratory. Virological failure was defined as >5000 copies/ml. Primary outcomes were program feasibility (timely result availability and patient receipt) and effectiveness (second-line therapy initiation).
We enrolled 1,498 participants; 5.9% were failing at baseline. Median time from enrollment to receipt of results was 42 days; 79.6% of participants received results within 3 months. Among participants with confirmed elevated VL, 92.6% initiated second-line therapy; 90.7% were switched within 365 days of VL testing. Nearly one-third (30.8%) of participants with elevated baseline VL had suppressed (<5,000 copies/ml) on confirmatory testing. Median period between enrollment and specimen testing was 23 days. Adjusting for relevant covariates, participants on ART >4 years were more likely to be failing than participants on therapy 1–4 years (RR 1.7, 95% CI 1.0-2.8); older participants were less likely to be failing (RR 0.95, 95% CI 0.92-0.98). There was no difference in likelihood of failure based on clinical symptoms (RR 1.17, 95% CI 0.65-2.11).
DBS for VL monitoring is feasible and effective in real-world clinical settings. Centralized DBS testing may increase access to VL monitoring in remote settings. Programmatic outcomes are encouraging, especially proportion of eligible participants switched to second-line therapy.
Programs for integration of family planning into HIV care must recognize current practices and desires among clients to appropriately target and tailor interventions. We sought to evaluate fertility intentions, unintended pregnancy, contraceptive and condom use among a cohort of HIV-infected women seeking family planning services within an antiretroviral therapy (ART) clinic.
200 women completed an interviewer-administered questionnaire during enrollment into a prospective contraceptive study at the Lighthouse Clinic, an HIV/ART clinic in Lilongwe, Malawi, between August and December 2010.
Most women (95%) did not desire future pregnancy. Prior reported unintended pregnancy rates were high (69% unplanned and 61% unhappy with timing of last pregnancy). Condom use was inconsistent, even among couples with discordant HIV status, with lack of use often attributed to partner’s refusal. Higher education, older age, lower parity and having an HIV negative partner were factors associated with consistent condom usage.
High rates of unintended pregnancy among these women underscore the need for integ rating family planning, sexually transmitted infection (STI) prevention, and HIV services. Contraceptive access and use, including condoms, must be improved with specific efforts to enlist partner support. Messages regarding the importance of condom usage in conjunction with more effective modern contraceptive methods for both infection and pregnancy prevention must continue to be reinforced over the course of ongoing ART treatment.
Determine how routine inpatient provider-initiated HIV testing differs from traditional community-based client-initiated testing with respect to clinical characteristics of children identified and outcomes of outpatient HIV care.
Prospective observational cohort.
Routine clinical data were collected from children identified as HIV-infected by either testing modality in Lilongwe, Malawi in 2008. After one year of outpatient HIV care at the Baylor College of Medicine Clinical Center of Excellence, outcomes were assessed.
Of 742 newly-identified HIV-infected children enrolling into outpatient HIV care, 20.9% were identified by routine inpatient HIV testing. Compared to community-identified children, hospital-identified patients were younger (median 25.0 vs 53.5 months), with more severe disease (22.2% vs 7.8% WHO stage IV). Of 466 children with known outcomes, 15.0% died within the first year of HIV care; median time to death was 15.0 weeks for community-identified children vs 6.0 weeks for hospital-identified children. The strongest predictors of early mortality were severe malnutrition (hazard ratio, 4.3; 95% confidence interval, 2.2 – 8.3), moderate malnutrition (hazard ratio, 3.2; confidence interval, 1.6 – 6.6), age <12 months (hazard ratio, 3.2; 95% confidence interval, 1.4 – 7.2), age 12–24 months (hazard ratio, 2.5; 95% confidence interval, 1.1 – 5.7), and WHO stage IV (hazard ratio, 2.2; 95% confidence interval, 1.1 – 4.6). After controlling for other variables, hospital identification did not independently predict mortality.
Routine inpatient HIV testing identifies a subset of younger HIV-infected children with more severe, rapidly-progressing disease that traditional community-based testing modalities are currently missing.
Africa; Antiretroviral therapy; HIV testing; Malawi; Pediatric HIV; Pediatric hospitals
An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral, and Nutrition study was performed to describe drug exposure and antiviral response.
Women using Combivir®[zidovudine (ZDV)+ lamivudine (3TC)]+Aluvia®[lopinavir/ritonavir(LPV/RTV)] were enrolled. Breast milk (BM) and mother and infant plasma (MP, IP) samples were obtained over 6hrs after observed dosing at 6, 12, or 24wks post-partum for drug concentrations and HIV RNA.
30 mother/infant pairs (10 each at 6, 12,and 24wks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, while LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24wks. The majority (98.3%) of BM concentrations were >HIVwt IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA.
ZDV and 3TC concentrated in BM while LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low ARV concentrations in IP suggests prevention of transmission while breast feeding may be due to ARV effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.
To determine medical eligibility for contraceptive use, contraceptive preference, and acceptance of a copper intrauterine device (IUD) among a cohort of HIV-infected women receiving antiretroviral therapy (ART).
All HIV-infected women who received ART and sought contraceptive services at the Lighthouse clinic, an integrated HIV/ART clinic in Lilongwe, Malawi, between August and December 2010 were invited to participate in a structured interview. Eligibility and preference for the following contraceptive methods were assessed: combined hormonal contraceptives, progestogen-only pills, copper IUD, injectable depot medroxyprogesterone acetate (DMPA), and contraceptive implants.
The final sample included 281 women; five were pregnant. The remaining 276 women were eligible for at least three contraceptive methods, with 242 (87.7%) eligible for all five methods evaluated. After counseling, 163 (58.0%) selected DMPA and 98 (34.9%) selected an IUD as their preferred contraceptive method. Regardless of their method of choice, 222 (79.0%) women agreed to have an IUD placed on the same day.
Most methods of contraception are safe for use by HIV-infected women. Approximately 80% of the women were willing to receive an IUD. Efforts must be made to increase education about, and access to, long-acting reversible methods that may be acceptable and appropriate contraceptive options for HIV-infected women.
Antiretroviral therapy; Contraception; HIV; Intrauterine contraception; Intrauterine device; Malawi; Medical eligibility
The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.
HIV; antiretroviral drug; self-report; HPTN 052; Africa; clinical trial
Kaposi’s sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral therapy (ART). Seventy patients were enrolled. Eighty-one percent had T1 (advanced) KS. Median CD4 and HIV RNA levels were 181 cells/mm3 and 138,641 copies/ml, respectively. We had complete information and suitable plasma and biopsy samples for 66 patients. For 59/66 (89%) patients, a detectable KSHV load was found in plasma (median, 2,291 copies/ml; interquartile range [IQR], 741 to 5,623). We utilized a novel KSHV real-time quantitative PCR (qPCR) array with multiple primers per open reading frame to examine KSHV transcription. Seventeen samples exhibited only minimal levels of KSHV mRNAs, presumably due to the limited number of infected cells. For all other biopsy samples, the viral latency locus (LANA, vCyc, vFLIP, kaposin, and microRNAs [miRNAs]) was transcribed abundantly, as was K15 mRNA. We could identify two subtypes of treatment-naive KS: lesions that transcribed viral RNAs across the length of the viral genome and lesions that displayed only limited transcription restricted to the latency locus. This finding demonstrates for the first time the existence of multiple subtypes of KS lesions in HIV- and KS-treatment naive patients.
KS is the leading cancer in people infected with HIV worldwide and is causally linked to KSHV infection. Using viral transcription profiling, we have demonstrated the existence of multiple subtypes of KS lesions for the first time in HIV- and KS-treatment-naive patients. A substantial number of lesions transcribe mRNAs which encode the viral kinases and hence could be targeted by the antiviral drugs ganciclovir or AZT in addition to chemotherapy.
Routine HIV testing, called provider-initiated opt-out HIV testing and counseling (PITC), is recommended in African countries with high HIV prevalence. However, it is unknown whether PITC increases access to pediatric HIV care. In 2008 the Baylor International Pediatric AIDS Initiative implemented PITC (BIPAI-PITC) at a Malawian hospital. We sought to evaluate the influence of BIPAI-PITC, compared to non-routine HIV testing (NRT), on pediatric HIV care access.
Retrospective data from 7,077 pediatric inpatients were collected during sequential four-month periods of NRT and BIPAI-PITC. In-hospital and one-year outcomes for 337 HIV-infected and HIV-exposed uninfected inpatients not previously enrolled in HIV care were analyzed to assess the clinical influence of each testing strategy.
During BIPAI-PITC, a greater proportion of all hospitalized children received HIV testing (81.0% vs 33.3%, p < 0.001), accessed inpatient HIV-trained care (7.5% vs 2.4%, p < 0.001), enrolled into an outpatient HIV clinic after discharge (3.2% vs 1.3%, p < 0.001), and initiated antiretroviral therapy (ART) following hospitalization (1.1% vs 0.6%, p = 0.010) compared to NRT. Additionally, BIPAI-PITC increased the proportion of hospitalized HIV-infected and HIV-exposed uninfected children receiving DNA PCR testing (73.5% vs 35.2%, p < 0.001), but did not improve outpatient enrollment or ART initiation of identified HIV-infected patients.
BIPAI-PITC increases access to inpatient and outpatient pediatric HIV care for hospitalized children, including DNA PCR testing and ART. Broader implementation of BIPAI-PITC or similar approaches, along with more pediatric HIV-trained clinicians and improved defaulter-tracking methods, would improve pediatric HIV service utilization globally.
Pediatric HIV; Routine HIV Testing; Provider Initiated HIV Testing and Counseling; Early Infant Diagnosis; Africa South of the Sahara
Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes.
The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581.
1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373–522) cells per μL in patients assigned to the early treatment group and 428 (357–522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197–249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52–1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43–0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28–0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5–27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5–32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group.
Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment.
US National Institute of Allergy and Infectious Diseases.
We aimed to improve pediatric inpatient surveillance at a busy referral hospital in Malawi with 2 new programs: (1) the provision of vital sign equipment and implementation of an inpatient triage program (ITAT) that includes a simplified pediatric severity-of-illness score; (2) task-shifting ITAT to a new cadre of health care workers called “Vital Sign Assistants” (VSAs).
This study, conducted on the pediatric inpatient ward of a large referral hospital in Malawi, was divided into 3 phases, each lasting 4 weeks. In Phase A, we collected baseline data. In Phase B, we provided 3 new automated vital sign poles and implemented ITAT with current hospital staff. In Phase C, VSAs were introduced and performed ITAT. Our primary outcome measures were the number of vital sign assessments performed and clinician notifications to reassess patients with high ITAT scores.
We enrolled 3,994 patients who received 5,155 vital sign assessments. Assessment frequency was equal between Phases A (0.67 assessments/patient) and B (0.61 assessments/patient), but increased 3.6-fold in Phase C (2.44 assessments/patient, p<0.001). Clinician notifications increased from Phases A (84) and B (113) to Phase C (161, p=0.002). Inpatient mortality fell from Phase A (9.3%) to Phases B (5.7) and C (6.9%).
ITAT with VSAs improved vital sign assessments and nearly doubled clinician notifications of patients needing further assessment due to high ITAT scores, while equipment alone made no difference. Task-shifting ITAT to VSAs may improve outcomes in pediatric hospitals in the developing world.
pulse oximetry; pediatric early warning score; task-shift; Malawi; ITAT; vital sign
To develop a new pediatric illness severity score, called Inpatient Triage, Assessment, and Treatment (ITAT), for resource-limited settings to identify hospitalized patients at highest risk of death and facilitate urgent clinical re-evaluation.
We performed a nested case-control study at a Malawian referral hospital. The ITAT score was derived from 4 equally-weighted variables, yielding a cumulative score between 0 and 8. Variables included oxygen saturation, temperature, and age-adjusted heart and respiratory rates. We compared the ITAT score between cases (deaths) and controls (discharges) in predicting death within 2 days. Our analysis includes predictive statistics, bivariable and multivariable logistic regression, and calculation of data-driven scores.
A total of 54 cases and 161 controls were included in the analysis. The area under the receiver operating characteristic curve was 0.76. At an ITAT cutoff of 4, the sensitivity, specificity, and likelihood ratio were 0.44, 0.86, and 1.70, respectively. A cumulative ITAT score of 4 or higher was associated with increased odds of death (OR: 4.80; 95% CI: 2.39 – 9.64). A score of 2 for all individual vital signs was a statistically significant independent predictor of death.
We developed an inpatient triage tool (ITAT) appropriate for resource-constrained hospitals that identifies high-risk children after hospital admission. Further research is needed to study how best to operationalize ITAT in developing countries.
vital sign; early warning score; PEWS; pediatric; Malawi; ITAT
The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure.
We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance.
Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M.
Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.
HIV-1; drug resistance; mutations; nucleoside reverse transcriptase inhibitor; NRTI; stavudine; d4T; zidovudine; AZT; tenofovir; TDF; subtypes
Although hypoxemic children have high mortality, little is known about hypoxemia prevalence and oxygen administration in African hospitals. We aimed to determine the hypoxemia prevalence and quality of oxygen treatment by local clinicians for hospitalized Malawian children.
The study was conducted in five Malawian hospitals during January–April 2011. We prospectively measured the peripheral oxygen saturation (SpO2) using pulse oximetry for all children <15 years old and also determined clinical eligibility for oxygen treatment using WHO criteria for children <5 years old. We determined oxygen treatment quality by Malawian clinicians by comparing their use of WHO criteria for patients <5 years old using two standards: hypoxemia (SpO2 <90%) and the use of WHO criteria by study staff.
Forty of 761 (5.3%) hospitalized children <15 years old had SpO2 <90%. No hospital used pulse oximetry routinely, and only 9 of 40 (22.5%) patients <15 years old with SpO2 <90% were treated with oxygen by hospital staff. Study personnel using WHO criteria for children <5 years old achieved a higher sensitivity (40.0%) and lower specificity (82.7%) than Malawian clinicians (sensitivity 25.7%, specificity 94.1%).
Although hypoxemia is common, the absence of routine pulse oximetry results in most hospitalized, hypoxemic Malawian children not receiving available oxygen treatment.
Pneumonia; Pediatrics; Hypoxemia; Pulse oximetry; Integrated Management of Childhood Illness; Africa
Despite Kaposi's sarcoma (KS) being the most prevalent AIDS-associated cancer in resource limited settings, optimal treatment options remain unknown. We assessed whether bleomycin/vincristine compared to vincristine monotherapy was associated with improved treatment outcomes for AIDS-associated KS among patients initiating combination antiretroviral therapy (cART) in Malawi.
All patients initiating cART and chemotherapy for AIDS-related KS were identified from an electronic data system from the HIV Lighthouse Clinic from 2002 to 2011. Treatment responses were compared between patients receiving vincristine monotherapy and vincristine/bleomycin. Binomial regression models were implemented to assess probability of tumor improvement for patients receiving vincristine/bleomycin compared to vincristine monotherapy after a complete cycle of chemotherapy (9–10 months). A chi-squared test was used to compare changes in CD4 count after six months of chemotherapy.
Of 449 patients with AIDS-associated KS on chemotherapy, 94% received vincristine monotherapy and 6% received bleomycin/vincristine. Distribution of treatment outcomes was different: 29% of patients on vincristine experienced tumor improvement compared to 53% of patients on bleomycin/vincristine. Patients receiving bleomycin/vincristine were 2.25 (95% CI: 1.47, 3.44) times as likely to experience tumor improvement as to those on vincristine monotherapy. This value changed little after adjustment for age and baseline CD4 count: 2.46 (95% CI: 1.57, 3.86). Change in CD4 count was similar for patients receiving vincristine monotherapy and bleomycin/vincristine (p = 0.6).
Bleomycin/vincristine for the treatment of AIDS-associated KS was associated with better tumor response compared to vincristine monotherapy without impairing CD4 count recovery. Replication in larger datasets and randomized controlled trials is necessary.
Cerebrospinal fluid fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated cryptococcal meningitis. The identification of factors associated with mortality informs strategies to improve outcomes.
Background. Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes.
Methods. Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality.
Results. Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7–5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0–1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4–11.1), high peripheral white blood cell count (>10 × 109 cells/L; OR, 8.7; 95% CI, 2.5–30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age.
In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART).
Conclusions. CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.
cryptococcal meningitis; Cryptococcus neoformans; HIV; antiretroviral therapy; mortality (determinants)