Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Geographic Opportunistic Infections of Specific Consideration
Last Updated: March 28, 2017; Last Reviewed: March 28, 2017
Malaria continues to contribute disproportionately to the global burden of infectious diseases, especially in sub-Saharan Africa and Southeast Asia. In 2015, the World Health Organization estimated that 97 countries had ongoing malaria transmission, and almost half the world's population, approximately 3.2 billion people, lived in areas with some risk of malaria transmission.1 Of the nearly 214 million cases of malaria worldwide in 2015 (based on reports and models), approximately 88% (188 million) occurred in Africa, the area of the world with the highest HIV prevalence.1 Approximately 438,000 deaths were attributable to malaria in 2015, with ~90% occurring in Africa and 74% of those deaths in children younger than 5 years of age. Fifteen countries, mainly in sub-Saharan Africa, account for 80% of malaria cases and 78% of deaths worldwide.1 Current attributable morbidity and mortality are likely underestimated, given our limited understanding, surveillance, and reporting of non-falciparum infections.
Malaria typically is transmitted by the bite of an infected female Anopheles sp. mosquito. Reports of vertical transmission and infection after blood transfusion do exist, but these routes of transmission are uncommon in non-endemic areas.2-5
Malaria in humans can be caused by any one of five species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi (a zoonotic species that also infects macaques in Southeast Asia).5 Although P. vivax infections are more common and occur in a far wider geographic distribution,6 P. falciparum malaria represents the most serious public health problem because of its tendency toward severe or fatal infections. P. vivax, however, should not be discounted as a risk for travelers in many parts of the world.
Malaria and HIV both cause substantial morbidity and mortality, particularly in sub-Saharan Africa. Given this substantial overlap, even modest interactions between them have public health importance.7,8 Malaria influences the natural history of HIV infection, and HIV infection alters the natural history and severity of malaria.9
Many foreign-born individuals develop malaria in the United States because of distant exposure before their arrival, or as a result of more recent travel for business or family reasons. Similarly, U.S.-born individuals can develop malaria during travel to endemic areas.10-13 Failure to take appropriate chemoprophylaxis is a common problem for both groups of individuals.14,15 People who formerly lived in malarious areas may believe that they are immune, and therefore do not need to take prophylaxis.16 Such patients are at high risk of infection, however, because they likely have lost partial immunity within 6 months after leaving endemic regions.
Consideration of malaria in returning travelers who are febrile is important: Of the nearly 50 million individuals who travel to developing countries each year, between 5% and 11% develop a fever during or after travel.17-20 Malaria is a surprisingly common cause of these fevers.21
The clinical syndromes caused by Plasmodium species depend on prior exposure.22 While many native U.S. travelers have no prior immunity, clinical manifestations in those who have resided in malarious areas depend on whether they lived in an area with stable endemic malaria transmission (year round) or unstable (seasonal, infrequent or very low) transmission.23
In stable endemic areas, children younger than age 5 years may experience chronic infections with recurrent parasitemia, resulting in severe anemia and death. Children who survive these infections usually acquire partial immunity by age 5 years, and if they remain in the area where malaria is endemic, they maintain this immunity into adulthood. In stable endemic areas, adults usually experience asymptomatic or milder infections as a result of this acquired immune response. However, as noted previously, patients who leave endemic areas and subsequently return may be at high risk of disease because they likely have lost partial immunity 6 months after leaving endemic regions.
In unstable transmission areas, protective immunity is not acquired. For populations in these areas, the overwhelming clinical manifestation is acute febrile disease that can be complicated by cerebral malaria, affecting persons of all ages.
When pregnant women in areas of unstable transmission develop acute malaria, the consequences may include spontaneous abortion and stillbirth. In more stable transmission areas, pregnant women, particularly primigravidas, may lose some acquired immunity. Although infections may continue to be asymptomatic, infected pregnant women may acquire placental malaria that contributes to intrauterine growth retardation, low birth weight, and increased infant mortality.
Patients with malaria can exhibit various symptoms and a broad spectrum of severity, depending upon factors such as the infecting species and level of acquired immunity in the host. HIV-immunosuppressed patients in endemic areas may lose acquired malarial immunity, and HIV-immunosuppressed adults with little or no previous malaria exposure (such as travelers) appear to be at increased risk of severe outcomes.24
The incubation period for P. falciparum is from a week to several months, but most often less than 60 days. Patients can present much later (>1 year), but this pattern is more common with other species, especially P. vivax. In non-immune patients, typical symptoms of malaria include fever, chills, myalgias and arthralgias, headache, diarrhea, vomiting, and other non-specific signs. Splenomegaly, anemia, thrombocytopenia, pulmonary or renal dysfunction, and neurologic findings also may be present. Classically, paroxysmal fevers occur every 48 hours for P. falciparum, P. vivax, and P. ovale malaria; those with P. malariae occur every 72 hours. This classic presentation is highly variable, however, and may not be present. P. knowlesi, known to cause human infection in Southeast Asia in travelers to jungle/forested areas, is clinically indistinguishable from other species of malaria, and the overwhelming majority of patients present with uncomplicated disease (~90%).25
Uncomplicated malaria infection can progress to severe disease or death within hours. Malaria with central nervous system symptoms can be particularly ominous. Cerebral malaria refers to unarousable coma not attributable to any other cause in patients infected with P. falciparum; in Africa, case fatality rates with cerebral malaria approach 40%.26-28 The risk of severe and complicated illness is increased in patients with high levels of parasitemia and without partial immunity. Metabolic acidosis is an important manifestation of severe malaria and an indicator of poor prognosis.29 Other acute complications include renal failure, hypoglycemia, disseminated intravascular coagulation, shock, and acute pulmonary edema.30 P. falciparum is the species most commonly responsible for severe disease and death, although the other species can cause severe disease and death as well.25,31
Effect of HIV on Parasitemia and Clinical Severity
HIV infection impairs acquired immunity to malaria that is present in older children and adults in stable endemic areas. Large cohort studies have demonstrated the increased frequency (with rates one- to two-fold higher) of both parasitemia and clinical malaria in HIV-infected adults, with increasing risk and higher-density parasitemia associated with more advanced immunosuppression, particularly among those with CD4 T-lymphocyte (CD4) cell counts <350 cells/mm3.32-34 Increased rates of malaria among individuals with HIV do not appear to be as great as the rates observed with classic opportunistic infections such as tuberculosis and Pneumocystis jirovecii pneumonia.35
In a prospective cohort study in an area with unstable malaria transmission, HIV-infected non-immune adults were found to be at increased risk of severe malaria, and the risk was associated with a low CD4 cell count.36 Non-immune HIV-infected patients were substantially more likely to have severe clinical malaria than were non-immune patients without HIV. In KwaZulu Natal, an area of unstable malaria transmission, HIV-infected adults hospitalized for malaria were substantially more likely to die or require an intensive care unit admission than those who were not HIV-infected.37 In contrast, HIV infection did not confer an increased risk of poor outcomes among partially immune adults in areas with more stable transmission.32 In a cross-sectional study of travelers returning to France from malaria-endemic areas between 2000 and 2003, HIV-infected individuals with CD4 counts <350 cells/mm3 were at significantly higher risk of developing severe malaria, compared with those who were HIV-negative.34
Effects of Malaria on Mother-to-Child HIV Transmission
Placental malaria also has been associated with increased expression of CCR5 receptors in placental macrophages38 and increased viral load,39 raising the possibility of placental malaria leading to increased mother-to-child transmission (MTCT) of HIV. In addition, fetal immune activation by malaria antigens may increase susceptibility to HIV infection.40 Data are conflicting concerning the effect of malaria during pregnancy on risk of MTCT in the pre-ART era and are limited since the widespread use of antiretroviral therapy (ART) for prevention of MTCT.41-43
A malaria diagnosis must be considered in all febrile patients who have traveled to or lived in malaria-endemic areas or who have received blood products, tissues, or organs from individuals who have been to such areas.
Several diagnostic methods are available, including microscopic diagnosis, antigen detection tests, polymerase chain reaction-based assays, and serologic tests, though serologic tests which detect host antibody are inappropriate for the diagnosis of acute malaria.
Direct microscopic examination of intracellular parasites on stained blood films is the standard for definitive diagnosis in nearly all settings because it allows for identification of the species and provides a measure of parasite density. Microscopic diagnosis of P. knowlesi is difficult because it is commonly misidentified as P. malariae, which tends to follow a more benign course. Providers should have a high index of suspicion for P. knowlesi in travelers returning from Southeast Asia.31
In non-immune patients with all types of malaria, symptoms may develop before detectable levels of parasitemia are evident. For this reason, several blood smear examinations taken at 12– to 24-hour intervals may be needed to positively rule out a diagnosis of malaria in symptomatic patients. Guidelines for laboratory diagnosis are summarized elsewhere and are available at the Centers for Disease Control and Prevention (CDC)’s malaria website (https://www.cdc.gov/malaria). Rapid diagnostic tests, particularly for the diagnosis of P. falciparum, can be used depending on the local expertise and practice and can facilitate prompt diagnosis and treatment of infected patients, but must be followed by microscopy.
Pre-travel evaluation by a travel medicine specialist can provide specific education about risk of exposure in various geographic locales, the utility of insecticide-impregnated bed nets in the setting where the individual will be traveling or residing, and the use of DEET (N,N-diethyl-3-methyl-benzamide)-containing repellants.
Infection with P. falciparum can be more severe in HIV-infected patients with low CD4 cell counts and in pregnant women regardless of HIV infection than in other individuals. Because no chemoprophylactic regimen is completely effective, HIV-infected patients with low CD4 cell counts and women who are pregnant or likely to become pregnant should be advised to avoid travel to areas with malaria transmission if possible (AIII). If travel to an endemic area cannot be deferred, use of an effective chemoprophylaxis regimen is essential, along with careful attention to personal protective measures to prevent mosquito bites.
For United States travelers (including HIV-infected patients) to endemic areas, a combination of chemoprophylaxis and personal protective measures can be highly effective in preventing malaria. Recommendations for prophylaxis are the same for HIV-infected patients as for those who are not HIV-infected and are available at CDC’s malaria website (AIII) (https://www.cdc.gov/malaria).
Malaria incidence has been markedly reduced in African adults with HIV who receive cotrimoxazole (trimethoprim-sulfamethoxazole) prophylaxis.44 A recent study of HIV-infected patients in Uganda demonstrated that malaria burden was reduced by 70% with cotrimoxazole, and then reduced another 50% when antiretroviral (ARV) drugs were provided, and finally reduced another 50% with provision of insecticide-treated nets.45 However, cotrimoxazole is not as effective an antimalarial prophylactic regimen as the recommended antimalarials. Therefore, HIV-infected travelers should not rely on prophylaxis with cotrimoxazole for chemoprophylaxis against malaria (AIII).
Because P. falciparum malaria can progress within hours from mild symptoms or low-grade fever to severe disease or death, all HIV-infected patients with confirmed or suspected P. falciparum infections should be admitted to the hospital for evaluation, initiation of treatment, and observation of response to treatment (AIII). Diagnosis prior to treatment should always be pursued; however, treatment should not be delayed when malaria is strongly suspected but laboratory services are unavailable or results will be delayed (AIII).
Choice of treatment is guided by the degree of parasitemia, the species of Plasmodium, a patient’s clinical status, and the likely drug susceptibility of the infecting species (as determined by where the infection was acquired).
For HIV-infected patients who do acquire Plasmodium infection, treatment recommendations are the same as for HIV-uninfected patients (AIII). CDC posts current treatment recommendations on its website (https://www.cdc.gov/malaria) and has clinicians on call 24 hours to provide advice to clinicians on diagnosing and treating malaria (CDC Malaria Hotline: (770) 488-7788; Monday through Friday. 8 a.m. to 4:30 p.m. EST. (770) 488-7100 after hours).
Special Considerations with Regard to Starting ART
There is no reason to defer ART initiation after patients have recovered from acute malaria.
Monitoring of Response to Therapy and Adverse Events (Including IRIS)
Careful monitoring of patients (especially those with P. falciparum malaria) is necessary, including measurement of peripheral parasitemia and hemoglobin and blood glucose levels, as well as assessment of cerebral, pulmonary, and renal function. Frequency of monitoring depends on severity of disease, a patient’s immune status, and the species of Plasmodium.
Chemoprophylaxis or treatment for malaria in patients receiving ARV agents requires attention to potential drug interactions. Several potential drug interactions can occur between antimalarial and HIV drugs as well as other medications used to treat HIV-associated opportunistic infections (see Table 5).46 Providers are also encouraged to check for drug-drug interactions by using an interactive web-based resource from the University of Liverpool at http://www.hiv-druginteractions.org. Mefloquine in repeated doses has been observed to reduce area under the concentration-time curve and maximal plasma concentrations of ritonavir by 31% and 36%, respectively. Insufficient data are available to suggest that dose adjustments are needed.
Quinine levels may be increased by ritonavir-containing regimens or cobicistat; conversely, nevirapine and efavirenz can reduce plasma quinine levels. Potential interactions can occur between ritonavir or cobicistat and chloroquine, but their clinical significance is unclear, and until further data are available, no dose adjustments are recommended.
Artemether-lumefantrine is now approved in the United States for treatment of uncomplicated P. falciparum infection. Data in children suggest that this combination is well tolerated and safe in HIV-infected children,47 however, efficacy data are conflicting in HIV-infected adults. An open-label trial in Tanzania demonstrated excellent efficacy (97.6%) of artemether-lumefantrine for treating uncomplicated P. falciparum malaria in HIV-infected adults on nevirapine-based ART.48 Conversely, 28-day clinical and parasitologic response was sub-optimal in the efavirenz-based ART group, with efficacy of 82.5%, and a 19-fold increased risk of recurrent parasitemia compared to the control group of HIV-infected adults not on ART.48 Artesunate is available for treatment of severe malaria through a compassionate use Investigational New Drug application. A trial in Uganda demonstrated the effectiveness of artesunate plus amodiaquine in HIV-infected children, but treatment was associated with increased risk of neutropenia in those on ART, particularly zidovudine, which was attributed to the amodiaquine component of therapy.49
Ritonavir or cobicistat-boosed ARV regimens and non-nucleoside reverse transcriptase inhibitors have the potential to affect metabolism of artemisinin-containing drugs,50 but the overall effect and clinical significance remain unclear. No dose alterations currently are recommended.
No immune reconstitution inflammatory syndrome (IRIS) has been described in association with malaria.
Managing Treatment Failure
HIV-infected individuals are at increased risk of malaria treatment failure.51 Management of treatment failure is the same in HIV-infected and HIV-uninfected patients, except for considerations about drug interactions between ART and antimalarial drugs. Drug-resistant malaria and possible concomitant infections should be considered in HIV-infected patients whose malaria fails to respond to therapy.
If the species of malaria identified is P. vivax or P. ovale, which can cause recurrence due to hepatic phase of infection, then treatment with primaquine in addition to standard treatment is recommended to prevent recurrence (AI). Guidelines for primaquine treatment do not differ in HIV-infected individuals.
Special Considerations During Pregnancy
Malaria in pregnancy affects both mother and fetus. Infection with P. falciparum during pregnancy can increase maternal risk of severe disease and anemia and risk for stillbirth, preterm birth, and low birth weight.52 The diagnosis of malaria in pregnant women is the same as in women who are not pregnant.
For pregnant women with a diagnosis of uncomplicated malaria caused by P. malariae, P. ovale, chloroquine-sensitive P. vivax, and chloroquine-sensitive P. falciparum, prompt treatment with chloroquine is recommended.53 For pregnant women with a diagnosis of chloroquine-resistant P. vivax, treatment with mefloquine for 7 days is recommended. For pregnant women with a diagnosis of uncomplicated chloroquine-resistant P. falciparum malaria, prompt treatment with mefloquine or quinine and clindamycin is recommended as per CDC guidelines.54
On the basis of extensive experience with its use, chloroquine is considered the drug of choice for prophylaxis and treatment of sensitive strains of malaria in pregnancy. Although quinine at high doses has been associated with an increased risk of birth defects (especially deafness) in some animal species and humans (usually during attempted abortion), use of therapeutic doses in pregnancy is considered safe.53,55 Because of the potential for hypoglycemia, glucose levels should be monitored in pregnant women treated with quinine and their neonates. Clindamycin use has not been associated with birth defects. Animal and human data on use of prophylactic and treatment doses of mefloquine do not suggest teratogenicity and the drug can be used safely during all trimesters.56 One randomized trial of mefloquine used in addition to daily cotrimoxazole for malaria prophylaxis in pregnant women living with HIV demonstrated an increased risk of transmission of HIV to the infant in the mefloquine arm, potentially because of drug interactions.57 Although experience is limited, available data on artemether-lumefantrine during pregnancy suggest that use is not associated with increased adverse events or birth defects.58 A pharmacokinetic study in HIV-uninfected persons found no difference in levels between pregnant and non-pregnant subjects except for small differences in elimination half-life of lumefantrine.59 Data on pharmacokinetics in HIV-infected pregnant women were not included. Because of limited data, atovaquone-proguanil is not recommended for treatment in pregnancy and should be used only if quinine plus clindamycin, quinine monotherapy, or mefloquine are unavailable or not tolerated.55 Tetracyclines are not recommended in pregnancy because of increased risk of maternal hepatotoxicity and staining of fetal teeth and bones. Primaquine use during pregnancy is not recommended because of limited experience with its use and the potential for fetal glucose-6-phosphate dehydrogenase (G6PD) deficiency. After treatment, all pregnant women with P. vivax and P. ovale should receive chloroquine prophylaxis for the duration of pregnancy to avoid relapses. Once-weekly mefloquine can be used for prophylaxis in pregnant women with P. vivax acquired in an area with chloroquine-resistant strains. Women who have normal G6PD screening tests can be treated with primaquine after delivery.
|Preventing Malaria in Patients Traveling to Endemic Areas:
- World Health Organization. World Malaria Report 2015. 2015. Available at http://www.who.int/malaria/publications/world-malaria-report-2015/en/.
- Mungai M, Tegtmeier G, Chamberland M, Parise M. Transfusion-transmitted malaria in the United States from 1963 through 1999. N Engl J Med. Jun 28 2001;344(26):1973-1978. Available at http://www.ncbi.nlm.nih.gov/pubmed/11430326.
- Austin SC, Stolley PD, Lasky T. The history of malariotherapy for neurosyphilis. Modern parallels. JAMA . Jul 22-29 1992;268(4):516-519. Available at http://www.ncbi.nlm.nih.gov/pubmed/1619744.
- Centers for Disease C. Update: self-induced malaria associated with malariotherapy for Lyme disease -Texas. MMWR Morb Mortal Wkly Rep. Oct 4 1991;40(39):665-666. Available at http://www.ncbi.nlm.nih.gov/pubmed/1896006.
- Mali S, Steele S, Slutsker L, Arguin PM, Centers for Disease C, Prevention. Malaria surveillance - United States, 2008. MMWR Surveill Summ. Jun 25 2010;59(7):1-15. Available at http://www.ncbi.nlm.nih.gov/pubmed/20577158.
- Guerra CA, Howes RE, Patil AP, et al. The international limits and population at risk of Plasmodium vivax transmission in 2009. PLoS Negl Trop Dis. 2010;4(8):e774. Available at http://www.ncbi.nlm.nih.gov/pubmed/20689816.
- Korenromp EL, Williams BG, de Vlas SJ, et al. Malaria attributable to the HIV-1 epidemic, sub-Saharan Africa. Emerg Infect Dis. Sep 2005;11(9):1410-1419. Available at http://www.ncbi.nlm.nih.gov/pubmed/16229771.
- Van Geertruyden JP, Menten J, Colebunders R, Korenromp E, D'Alessandro U. The impact of HIV-1 on the malaria parasite biomass in adults in sub-Saharan Africa contributes to the emergence of antimalarial drug resistance. Malar J. 2008;7:134. Available at http://www.ncbi.nlm.nih.gov/pubmed/18647387.
- Slutsker L, Marston BJ. HIV and malaria: interactions and implications. Curr Opin Infect Dis. Feb 2007;20(1):3-10. Available at http://www.ncbi.nlm.nih.gov/pubmed/17197875.
- Kemper CA, Linett A, Kane C, Deresinski SC. Frequency of Travel of Adults Infected with HIV. J Travel Med. Jun 1 1995;2(2):85-88. Available at http://www.ncbi.nlm.nih.gov/pubmed/9815367.
- Simons FM, Cobelens FG, Danner SA. Common health problems in HIV-infected travelers to the (sub)tropics. J Travel Med. Jun 1999;6(2):71-75. Available at http://www.ncbi.nlm.nih.gov/pubmed/10381957.
- Castelli F, Patroni A. The human immunodeficiency virus-infected traveler. Clin Infect Dis. Dec 2000;31(6):1403-1408. Available at http://www.ncbi.nlm.nih.gov/pubmed/11096010.
- Bhadelia N, Klotman M, Caplivski D. The HIV-positive traveler. Am J Med. Jul 2007;120(7):574-580. Available at http://www.ncbi.nlm.nih.gov/pubmed/17602926.
- Smego RA, Jr. Effectiveness of antimalarial drugs. N Engl J Med. Jul 28 2005;353(4):420-422; author reply 420-422. Available at http://www.ncbi.nlm.nih.gov/pubmed/16050053.
- Suh KN, Mileno MD. Challenging scenarios in a travel clinic: advising the complex traveler. Infect Dis Clin North Am. Mar 2005;19(1):15-47. Available at http://www.ncbi.nlm.nih.gov/pubmed/15701545.
- Sherrard AW, McCarthy AE. Travel patterns and health risks for patients infected with HIV. Travel Med Infect Dis. Sep 2009;7(5):291-295. Available at http://www.ncbi.nlm.nih.gov/pubmed/19747664.
- Ryan ET, Wilson ME, Kain KC. Illness after international travel. N Engl J Med. Aug 15 2002;347(7):505-516. Available at http://www.ncbi.nlm.nih.gov/pubmed/12181406.
- Spira AM. Assessment of travellers who return home ill. Lancet. Apr 26 2003;361(9367):1459-1469. Available at http://www.ncbi.nlm.nih.gov/pubmed/12727414.
- Steffen R, Rickenbach M, Wilhelm U, Helminger A, Schar M. Health problems after travel to developing countries. J Infect Dis. Jul 1987;156(1):84-91. Available at http://www.ncbi.nlm.nih.gov/pubmed/3598228.
- Winer L, Alkan M. Incidence and precipitating factors of morbidity among Israeli travelers abroad. J Travel Med. Sep-Oct 2002;9(5):227-232. Available at http://www.ncbi.nlm.nih.gov/pubmed/12962594.
- Wilson ME, Weld LH, Boggild A, et al. Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis. Jun 15 2007;44(12):1560-1568. Available at http://www.ncbi.nlm.nih.gov/pubmed/17516399.
- Mackinnon MJ, Marsh K. The selection landscape of malaria parasites. Science. May 14 2010;328(5980):866-871. Available at http://www.ncbi.nlm.nih.gov/pubmed/20466925.
- Snow RW, Marsh K. The consequences of reducing transmission of Plasmodium falciparum in Africa. Adv Parasitol. 2002;52:235-264. Available at http://www.ncbi.nlm.nih.gov/pubmed/12521262.
- Matteelli A, Casalini C, Bussi G, et al. Imported malaria in an HIV-positive traveler: a case report with a fatal outcome. J Travel Med. Jul-Aug 2005;12(4):222-224. Available at http://www.ncbi.nlm.nih.gov/pubmed/16086898.
- Daneshvar C, Davis TM, Cox-Singh J, et al. Clinical and laboratory features of human Plasmodium knowlesi infection. Clin Infect Dis. Sep 15 2009;49(6):852-860. Available at http://www.ncbi.nlm.nih.gov/pubmed/19635025.
- Severe and complicated malaria. World Health Organization, Division of Control of Tropical Diseases. Trans R Soc Trop Med Hyg. 1990;84 Suppl 2(Suppl 2):1-65. Available at http://www.ncbi.nlm.nih.gov/pubmed/2219249.
- Greenberg AE, Ntumbanzondo M, Ntula N, Mawa L, Howell J, Davachi F. Hospital-based surveillance of malaria-related paediatric morbidity and mortality in Kinshasa, Zaire. Bull World Health Organ. 1989;67(2):189-196. Available at http://www.ncbi.nlm.nih.gov/pubmed/2743538.
- Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med. May 1989;71(265):441-459. Available at http://www.ncbi.nlm.nih.gov/pubmed/2690177.
- English M, Sauerwein R, Waruiru C, et al. Acidosis in severe childhood malaria. QJM. Apr 1997;90(4):263-270. Available at http://www.ncbi.nlm.nih.gov/pubmed/9307760.
- Marsh K, Forster D, Waruiru C, et al. Indicators of life-threatening malaria in African children. N Engl J Med. May 25 1995;332(21):1399-1404. Available at http://www.ncbi.nlm.nih.gov/pubmed/7723795.
- Cox-Singh J, Davis TM, Lee KS, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. Jan 15 2008;46(2):165-171. Available at http://www.ncbi.nlm.nih.gov/pubmed/18171245.
- Whitworth J, Morgan D, Quigley M, et al. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study. Lancet. Sep 23 2000;356(9235):1051-1056. Available at http://www.ncbi.nlm.nih.gov/pubmed/11009139.
- Patnaik P, Jere CS, Miller WC, et al. Effects of HIV-1 serostatus, HIV-1 RNA concentration, and CD4 cell count on the incidence of malaria infection in a cohort of adults in rural Malawi. J Infect Dis. Sep 15 2005;192(6):984-991. Available at http://www.ncbi.nlm.nih.gov/pubmed/16107950.
- Mouala C, Guiguet M, Houze S, et al. Impact of HIV infection on severity of imported malaria is restricted to patients with CD4 cell counts < 350 cells/microl. AIDS. Sep 24 2009;23(15):1997-2004. Available at http://www.ncbi.nlm.nih.gov/pubmed/19654499.
- Laufer MK, van Oosterhout JJ, Thesing PC, et al. Impact of HIV-associated immunosuppression on malaria infection and disease in Malawi. J Infect Dis. Mar 15 2006;193(6):872-878. Available at http://www.ncbi.nlm.nih.gov/pubmed/16479522.
- Cohen C, Karstaedt A, Frean J, et al. Increased prevalence of severe malaria in HIV-infected adults in South Africa. Clin Infect Dis. Dec 1 2005;41(11):1631-1637. Available at http://www.ncbi.nlm.nih.gov/pubmed/16267737.
- Grimwade K, French N, Mbatha DD, Zungu DD, Dedicoat M, Gilks CF. HIV infection as a cofactor for severe falciparum malaria in adults living in a region of unstable malaria transmission in South Africa. AIDS. Feb 20 2004;18(3):547-554. Available at http://www.ncbi.nlm.nih.gov/pubmed/15090809.
- Tkachuk AN, Moormann AM, Poore JA, et al. Malaria enhances expression of CC chemokine receptor 5 on placental macrophages. J Infect Dis. Mar 15 2001;183(6):967-972. Available at http://www.ncbi.nlm.nih.gov/pubmed/11237815.
- Mwapasa V, Rogerson SJ, Molyneux ME, et al. The effect of Plasmodium falciparum malaria on peripheral and placental HIV-1 RNA concentrations in pregnant Malawian women. AIDS. Apr 30 2004;18(7):1051-1059. Available at http://www.ncbi.nlm.nih.gov/pubmed/15096809.
- Steiner K, Myrie L, Malhotra I, et al. Fetal immune activation to malaria antigens enhances susceptibility to in vitro HIV infection in cord blood mononuclear cells. J Infect Dis. Sep 15 2010;202(6):899-907. Available at http://www.ncbi.nlm.nih.gov/pubmed/20687848.
- Msamanga GI, Taha TE, Young AM, et al. Placental malaria and mother-to-child transmission of human immunodeficiency virus-1. Am J Trop Med Hyg. Apr 2009;80(4):508-515. Available at http://www.ncbi.nlm.nih.gov/pubmed/19346367.
- Bulterys PL, Chao A, Dalai SC, et al. Placental malaria and mother-to-child transmission of human immunodeficiency virus-1 in rural Rwanda. Am J Trop Med Hyg. Aug 2011;85(2):202-206. Available at http://www.ncbi.nlm.nih.gov/pubmed/21813835.
- Ezeamama AE, Duggan C, Manji KP, et al. Clinical malaria diagnosis in pregnancy in relation to early perinatal mother-to-child transmission of HIV: a prospective cohort study. HIV Med. May 2014;15(5):276-285. Available at http://www.ncbi.nlm.nih.gov/pubmed/24215465.
- Anglaret X, Chene G, Attia A, et al. Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d'Ivoire: a randomised trial. Cotrimo-CI Study Group. Lancet. May 1 1999;353(9163):1463-1468. Available at http://www.ncbi.nlm.nih.gov/pubmed/10232311.
- Mermin J, Ekwaru JP, Liechty CA, et al. Effect of co-trimoxazole prophylaxis, antiretroviral therapy, and insecticide-treated bednets on the frequency of malaria in HIV-1-infected adults in Uganda: a prospective cohort study. Lancet. Apr 15 2006;367(9518):1256-1261. Available at http://www.ncbi.nlm.nih.gov/pubmed/16631881.
- Khoo S, Back D, Winstanley P. The potential for interactions between antimalarial and antiretroviral drugs. AIDS. Jul 1 2005;19(10):995-1005. Available at http://www.ncbi.nlm.nih.gov/pubmed/15958830.
- Katrak S, Gasasira A, Arinaitwe E, et al. Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfected children. Malar J. 2009;8:272. Available at http://www.ncbi.nlm.nih.gov/pubmed/19948038.
- Maganda BA, Minzi OM, Kamuhabwa AA, Ngasala B, Sasi PG. Outcome of artemether-lumefantrine treatment for uncomplicated malaria in HIV-infected adult patients on anti-retroviral therapy. Malar J. May 30 2014;13:205. Available at http://www.ncbi.nlm.nih.gov/pubmed/24885714.
- Gasasira AF, Kamya MR, Achan J, et al. High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. Clin Infect Dis. Apr 1 2008;46(7):985-991. Available at http://www.ncbi.nlm.nih.gov/pubmed/18444813.
- Parikh S, Gut J, Istvan E, Goldberg DE, Havlir DV, Rosenthal PJ. Antimalarial activity of human immunodeficiency virus type 1 protease inhibitors. Antimicrob Agents Chemother. Jul 2005;49(7):2983-2985. Available at http://www.ncbi.nlm.nih.gov/pubmed/15980379.
- Van Geertruyden JP, Mulenga M, Mwananyanda L, et al. HIV-1 immune suppression and antimalarial treatment outcome in Zambian adults with uncomplicated malaria. J Infect Dis. Oct 1 2006;194(7):917-925. Available at http://www.ncbi.nlm.nih.gov/pubmed/16960779.
- Desai M, ter Kuile FO, Nosten F, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. Feb 2007;7(2):93-104. Available at http://www.ncbi.nlm.nih.gov/pubmed/17251080.
- Griffith KS, Lewis LS, Mali S, Parise ME. Treatment of malaria in the United States: a systematic review. JAMA. May 23 2007;297(20):2264-2277. Available at http://www.ncbi.nlm.nih.gov/pubmed/17519416.
- Centers for Disease Control and Prevention. Part 3: Alternatives for Pregnant Women and Treatment of Severe Malaria. Treatment of Malaria: Guidelines For Clinicians (United States) 2013. Available at https://www.cdc.gov/malaria/diagnosis_treatment/clinicians3.html.
- McGready R, Thwai KL, Cho T, et al. The effects of quinine and chloroquine antimalarial treatments in the first trimester of pregnancy. Trans R Soc Trop Med Hyg. Mar-Apr 2002;96(2):180-184. Available at http://www.ncbi.nlm.nih.gov/pubmed/12055810.
- Centers for Disease Control and Prevention. Update: New Recommendations for Mefloquine Use in Pregnancy. 2011; Available at http://www.cdc.gov/malaria/new_info/2011/mefloquine_pregnancy.html.
- Gonzalez R, Desai M, Macete E, et al. Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-infected women receiving cotrimoxazole prophylaxis: a multicenter randomized placebo-controlled trial. PLoS Med. Sep 2014;11(9):e1001735. Available at http://www.ncbi.nlm.nih.gov/pubmed/25247995.
- Manyando C, Kayentao K, D'Alessandro U, Okafor HU, Juma E, Hamed K. A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy. Malar J. May 01 2012;11:141. Available at http://www.ncbi.nlm.nih.gov/pubmed/22548983.
- Nyunt MM, Nguyen VK, Kajubi R, et al. Artemether-Lumefantrine Pharmacokinetics and Clinical Response Are Minimally Altered in Pregnant Ugandan Women Treated for Uncomplicated Falciparum Malaria. Antimicrob Agents Chemother. Dec 14 2015;60(3):1274-1282. Available at http://www.ncbi.nlm.nih.gov/pubmed/26666942.
- CDC | 2015 STD Treatment Guidelines
- HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C
- AIDSinfo Patient Materials: What is an Opportunistic Infection?
- AIDSource | HIV-Related Conditions
- AETC National HIV Curriculum
- How to Cite These Guidelines
- Adult and Adolescent OI Guidelines Archive